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Post-Notice of Compliance (NOC) Changes: Quality Document

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Contact: Bureau of Policy, Science and International Programs Enquiries

October 15, 2013

Notice

Our file number: 13-107786-650

Health Canada is pleased to announce the release of the revised Post-Notice of Compliance (NOC) Changes - Quality Guidance

The Post-Notice of Compliance (NOC) Changes - Quality Guidance released in September, 2009 provided a more comprehensive guidance outlining the conditions for the categorization of a given post authorization change and recommendations for supporting documentation.

In September 2011, revisions to Post-NOC Changes Quality: Appendix 1 eliminated the Level II (Notifiable Change) category and moved higher risk submissions to the Level I category while placing lower risk ones in the current Level III grouping.

Since the original release of the Post-Notice of Compliance (NOC) Changes - Quality Guidance, Health Canada has received numerous enquiries requesting clarification on the categorization, criteria and application requirements for various changes. Health Canada has revised the complete Quality guidance to add further clarification where appropriate.

Changes in the revised Quality guidance include:

  1. Further revisions or clarifications in Appendix 1 to 4;
  2. Addition of changes to an approved drug administration device for a veterinary drug in Appendix 2;
  3. Additional examples of Level IV changes in Appendix 7;
  4. Addition of a definition in Appendix 8.

As a consequence to the changes in the Quality guidance, the Post-Notice of Compliance Changes: Notices of Change (Level III) form has been revised to include:

  1. For Veterinary Drugs - Appendix 1 - Veterinary Drugs has been deleted and consolidated into Appendix 2;
  2. The addition of the category "Devices" to Section B, "7. Category of Change" for a veterinary drug;
  3. For Biologics (Appendix 3) and Kits/Radiopharmaceuticals/Generators (Appendix 4), sponsors/ manufacturers now have the option to select "Other" from the pick lists in Section B, "8. Change" to report any Level III changes that are not listed in the Post-NOC Changes Quality guidance;
  4. For Biologics (Appendix 3) and Kits/Radiopharmaceuticals/Generators (Appendix 4), a text box has been added to each change in Section B, "8. Change" to allow sponsors/manufacturers to provide additional information on the Level III changes made.

As the Post-Notice of Compliance (NOC) Changes - Quality Guidance will become effective immediately; all post authorized Quality submissions should be reported as per the procedures detailed within.

The effective date (September 30, 2009) has not changed for all other Post-NOC Changes guidance documents. Revisions to the Post-Notice of Compliance (NOC) Changes - Safety and Efficacy Guidance are being assessed and will be posted in the near future.

Questions or concerns related to these guidance documents should be directed to:

Bureau of Policy, Science and International Programs
Therapeutic Products Directorate
Health Canada
1600 Scott Street
Holland Cross, Tower B
2nd Floor, Address Locator 3102C5
Ottawa, Ontario
K1A 0K9

Facsimile: 613-941-1812
E-mail: Policy_Bureau_Enquiries@hc-sc.gc.ca

Guidance Document

  • Date Adopted 2009/09/02
  • Effective Date 2009/09/30
  • Administrative Changes Date 2011/09/15
  • Date Revised (Appendix 1 Human Pharmaceuticals Only) 2011/09/15
  • Date Revised (Appendix 1-8) 2012/10/25
  • Implementation Date (Appendix 1-8) 2013/10/15

Foreword

Guidance documents are meant to provide assistance to industry and health care professionals on how to comply with governing statutes and regulations. Guidance documents also provide assistance to staff on how Health Canada mandates and objectives should be implemented in a manner that is fair, consistent and effective.

Guidance documents are administrative instruments not having force of law and, as such, allow for flexibility in approach. Alternate approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate justification. Alternate approaches should be discussed in advance with the relevant program area to avoid the possible finding that applicable statutory or regulatory requirements have not been met.

As a corollary to the above, it is equally important to note that Health Canada reserves the right to request additional information or material, or define conditions not specifically described in this document, in order to allow the Department to adequately assess the safety, efficacy or quality of a therapeutic product. Health Canada is committed to ensuring that such requests are justifiable and that decisions are clearly documented.

This document should be read in conjunction with the accompanying notice and the relevant sections of other applicable guidance documents.

Table of contents

1. Introduction

1.1 Objectives

  1. To assist with the classification of quality changes made to a new drug that has received a Notice of Compliance (NOC).
  2. To provide sponsors with recommendations on the data to support a change which would be considered sufficient to allow a determination of the impact of the change on the quality of the new drug as it relates to safety, efficacy and/or effective use of the new drug.

1.2 Scope and Application

This guidance document applies to sponsors intending to make changes to new drugs that have received a NOC pursuant to Section C.08.004 of the Food and Drug Regulations. This may include pharmaceuticals, biologics and radiopharmaceuticals for human use and pharmaceutical, radiopharmaceutical and certain biotechnological products for veterinary useFootnote 1. In the absence of a guidance specific to Quality changes to drugs which were approved through a Drug Identification Application - Biologics (DIN-B drugs), the Quality guidance document applies to those products. This guidance also applies to those submissions for which a NOC has been recommended but issuance of the NOC has been placed on hold.

This guidance document should be read in conjunction with the associated Health Canada guidance documents entitled Post-Notice of Compliance (NOC) Changes: Framework and Post-Notice of Compliance (NOC) Changes: Safety and Efficacy as well as other related Health Canada guidance documents. Information regarding general submission requirements and target performance standards may be found in the Health Canada guidance documents: Guidance for Industry: Management of Drug Submissions for drugs intended for human use and Guidance for Industry: Management of Regulatory Submissions for drugs intended for veterinary use.

It is recommended that the principles established in this guidance document be applied to similar Quality changes that occur during the development of the drug and the recommended supporting data be included with the initial New Drug Submission (NDS) or Abbreviated New Drug Submission (ANDS).

1.3 Background

In April 1994, Health Canada released the policy entitled Changes to Marketed New Drug Products. A number of international developments have occurred since this policy was first introduced. This would include an emphasis on applying a science-based and risk-based approach to the pharmaceutical quality assessment of these products. As such, updated guidance documents were needed on the information to support quality changes to new drugs which apply a modernized, science-based, and risk-based approach to this area.

Sponsors are advised to consult the associated guidance document Post-Notice of Compliance (NOC) Changes: Framework for further background information, including a list of policies and guidance documents that will be superceded.

2. Guidance for implementation

2.1 Reporting Categories

The following criteria are meant to provide guidance with respect to the classification of a quality related change. Specific change examples based on the application of these criteria are provided in Appendix 1 (Human Pharmaceuticals), Appendix 2 (Veterinary Drugs), Appendix 3 (Biologics) and Appendix 4 (Schedule C Drugs) that follow. For assistance in classifying a change, sponsors are advised to contact Health Canada. Contact information is provided in Guidance For Industry: Management of Drug Submissions (drugs for human use) or the Guidance For Industry: Management of Regulatory Submissions (drugs for veterinary use).

Sponsors are advised to exercise caution in classifying a series of changes for the same drug product intended to be implemented simultaneously or to be phased in sequentially. Although the individual changes may be classified at a particular reporting category [for example (e.g.), Notifiable Change], collectively the changes may warrant a higher risk reporting category (e.g., Supplement). Sponsors are advised to contact Health Canada for specific guidance regarding filing requirements in such cases.

2.1.1 Level I - Supplements (Major Quality Changes)

Level I - Supplements (Major Quality Changes) are changes that have a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product.

In general, a change that is supported by extensive documentation and/or requiring extensive assessment of the supporting documentation would be considered a Level I - Supplement (Major Quality Change) (e.g., a change supported by in vivo studies). This is to allow Health Canada the opportunity to apply the principles of risk management by having the necessary time for an appropriate assessment of the documentation. This assessment will take into consideration any potential impact upon market availability as well as the adverse effects on the identity, strength, quality, purity, or potency of the drug product.

The changes included in this reporting category shall be filed, along with the recommended supporting data, to Health Canada as a Supplemental New Drug Submission (SNDS) or Supplemental Abbreviated New Drug Submission (SANDS). The change may not be implemented by the sponsor until a NOC has been issued.

2.1.2 Level II - Notifiable Changes (Moderate Quality Changes)

Level II - Notifiable Changes (Moderate Quality Changes) are changes that have a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product.

NOTE: All Level II - Notifiable Changes referred to in this document are not applicable to Human Pharmaceuticals.

The changes included in this reporting category should be filed, along with the recommended supporting data, to Health Canada as a Notifiable Change. All Level II changes should not be implemented by the sponsor until a No Objection Letter (NOL) has been issued.

2.1.3 Level III - Annual Notification (Minor Quality Changes)

Level III - Annual Notification (Minor Quality Changes) are changes that have minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product.

The changes included in this reporting category may be implemented by the sponsor without the prior review by Health Canada of the data supporting such a change. Supporting data for the Level III changes recommended in this guidance documents should not be submitted; however, the data should be available to Health Canada within thirty (30) calendar days, if requested at any time.

2.1.4 Level IV Changes - Record of Changes

Level IV (Quality only) changes are changes to a new drug that are not Level I, Level II or Level III and are not expected to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product. The changes included in this reporting category may be implemented by the sponsor without prior review by Health Canada. The changes should be retained as part of the drug product's record by either the sponsor or the manufacturer and comply with Good Manufacturing Practices (GMP) requirements of Division 2 of the Food and Drug Regulations. A list of examples of Level IV changes is provided in Appendix 7.

3. Documentation

3.1 General Information

The associated guidance document Post-Notice of Compliance (NOC) Changes: Framework should be consulted for details regarding the filing of submissions and annual notifications to Health Canada. Documentation recommended in Section 2.2.3.3 of the aforementioned guidance should be included with a Supplement or Notifiable Change (NC) filing and documentation in Section 2.2.4 should be included with the corresponding Annual Notification.

The change examples presented in Appendix 1 (Human Pharmaceuticals), Appendix 1 (Veterinary Pharmaceuticals), Appendix 2 (Veterinary Drugs), Appendix 3 (Biologics) and Appendix 4 (Schedule C drugs) are intended to assist with the classification of changes made to the Quality information. The information summarized in the tables provides recommendations for:

  1. the conditions to be fulfilled for a given change to be classified as either a Level I, II, or III change. If any of the conditions outlined for a given change are not fulfilled, the change is automatically considered the next higher level of change. For example, if any of the conditions recommended for a Level II - Notifiable Change are not fulfilled, the change is considered a Level I - Supplement. Similarly, if any of the conditions recommended for a Level I - Supplement are not fulfilled, the change would warrant the filing of an NDS or an ANDS;
  2. the supporting data for a given change, either to be submitted to Health Canada and/or maintained by the sponsor. Where applicable, the corresponding modules of the Common Technical Document (CTD) for the supporting data have been identified in brackets. An adequate rationale is required when supporting data cannot be provided; and
  3. the reporting category (e.g., Supplement, Notifiable Change or Annual Notification).

As previously mentioned, it is equally important to note that Health Canada reserves the right to request additional information or material as deemed appropriate, or to define conditions not specifically described in this document.

For convenience, the change examples are organized according to the structure of the Common Technical Document (CTD).

For the recommendations for the conditions, supporting data, and reporting categories for changes that are specific to drugs for veterinary use (e.g., premixes, boluses), sponsors should contact the Veterinary Drugs Directorate (VDD) of Health Canada.

3.2 Supporting Data - Level I and Level II Changes

All data recommended to support the change should be provided with the submission. Where applicable, these data should be provided in the format defined by the International Conference on Harmonisation (ICH) Common Technical Document (CTD). A Quality Overall Summary (QOS) and Comprehensive Summary: Bioequivalence (CS:BE) should also be completed and provided, where applicable. For Veterinary Drug Submissions, data should be provided in the format of the Guidance for Industry: Preparation of Veterinary New Drug Submissions. Refer to existing Health Canada guidance documents for further detail regarding individual product recommendations.

When recommended supporting data cannot be submitted, a detailed rationale should be provided.

Supporting Data Common to Level I and Level II Changes

The following should be included, where applicable, in the submission package for Level I and Level II Quality changes:

  1. a covering letter (including a list of changes describing each in sufficient detail to allow for a quick assessment as to whether the appropriate reporting category has been used);
  2. where relevant, a side-by-side comparison of the previously approved and the proposed information (Module 1.2.8 or under the various modules, if appropriate);
  3. an annotated and non-annotated electronic copy and an annotated hard copy of:
    1. the Certified Product Information Document (CPID);
    2. the Product Monograph or Package Insert (for Veterinary Drugs);
  4. A sample of the inner and outer labels; and
  5. an electronic and hard copy of the revised sections of the QOS or the applicable Health Canada Quality Overall Summary template with the changes clearly noted. If a complete QOS is provided, the revised sections and information should be clearly indicated (Module 2.3).

In addition to the above common information, recommendations are included in Appendices 1, 2, 3 and 4 outlining the specific information to support the various quality changes. It should be noted that the common information is not repeated for the various changes outlined in the appendices.

When cross-references are made to previously submitted information, details on the cross-referenced information should be indicated in the covering letter (e.g., brand name of the drug product, manufacturer's/sponsor's name, submission type, control number, date approved).

Certificate of Suitability (CEP)

At this time, the use of the Certificate of Suitability (CEP) issued by the European Directorate for the Quality of Medicines of the Council of Europe (EDQM) in support of changes to the drug substance is not accepted for Biologics (Schedule D drugs) but is under review in pharmaceuticals for use in humans (Appendix 1 - Human Pharmaceuticals)). On the other hand, for Biologics (Schedule D drugs), the use of Transmissible Spongiform Encephalopathy (TSE)-CEP may be provided to support raw materials, auxiliary materials and reagents at risk of transmitting BSE/TSE agents. Sponsors are encouraged to contact the appropriate Directorate for further guidance.

Production documents (Executed and Master Batch Records)

For Biologics (Schedule D drugs) and Radiopharmaceuticals (Schedule C drugs), in contrast of the requirements for a NDS, production documents are no longer required at time of filing to support any post-NOC changes. However, these may be requested during review and should be available within 15 days upon request.

3.3 Supporting Data - Level III Changes

Any data that may have been generated by the sponsor in support of a Level III change should not be submitted with the Annual Drug Notification but should be available to Health Canada within thirty (30) calendar days, if requested.

Any Level III changes that have been implemented should be annotated in the affected documents (e.g., Product Monograph/Package Insert or CPID) with the filing of the next submission to Health Canada.

3.4 Supporting Data - Level IV Changes

The Quality changes included in this category should be retained as part of the product's record by either the sponsor or the manufacturer and comply with Good Manufacturing Practices (GMP) requirements of Division 2 of the Food and Drug Regulations. These changes should be annotated in the affected documents (e.g., Product Monograph/ Package Insert or CPID) with the filing of the next submission to Health Canada.

3.5 Comparative Studies

3.5.1 Comparative In vivo Studies

A number of changes outlined in Appendices 1, 2, 3 and 4 include recommendations for supporting comparative in vivo studies (e.g., comparative bioavailability studies for Pharmaceuticals, bridging clinical studies for Biologics).

Sponsors should consult the ICH Q5E guideline and applicable Health Canada guidance documents when conducting comparative in vivo studies.

3.5.2 Comparative In vitro Studies

A number of changes outlined in Appendices 1, 2, 3 and 4 include recommendations for supporting comparative in vitro studies (e.g., comparative dissolution studies). Where an in vitro comparison is recommended to support a Post-NOC Change, the comparison should be made to the product manufactured according to the same formulation and manufacturing process used in the pivotal clinical and/or comparative bioavailability studies approved for the original drug submission (e.g., including batch formula, manufacturing process). This is referred to as the "approved product" in the appendices.

Alternative approaches to this recommendation may be acceptable, if scientifically justified. For example, a comparison to a sponsor's marketed product (rather than the product used in the pivotal clinical and/or comparative bioavailability studies) could be justified if a significant body of information has been established for the marketed drug product. For the purposes of this document, a significant body of information for the marketed drug product is likely to exist after a reasonable number of batches of the drug product will be marketed during the specified period of time (e.g., a minimum of 10 batches).

Sponsors should refer to the General Chapters available in the current Schedule B pharmacopoeia for general dissolution and drug release specifications [e.g., United States Pharmacopeia (USP) <711>, USP <724>, European Pharmacopeia (Ph.Eur.) 2.9.3].

In addition, Appendix 5 outlines a number of recommendations for conducting and assessing comparative dissolution profiles (e.g., conditions, similarity).

3.6 Stability Testing

If stability studies are recommended to support a change, these studies should be conducted in accordance with applicable ICH and Health Canada guidance documents, e.g.,:

  1. Stability Testing of New Drug Substances and Products (Q1A(R2));
  2. Stability Testing: Photostability Testing of New Drug Substances and Products (Q1B);
  3. Stability Testing: Requirements for New Dosage Forms (Q1C);
  4. Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products (Q1D);
  5. Evaluation of Stability Data(Q1E);
  6. Stability Testing of Existing Drug Substances and Products;
  7. Stability Testing of Biotechnological/Biological Products (Q5C)

In case where accelerated stability studies are not routinely performed due to the nature of the product, a rationale should be provided.

3.7 Pharmaceutical Development and Quality by Design

The International Conference on Harmonisation (ICH) has developed a guideline, Q8: Pharmaceutical Development and Q8 AnnexFootnote 2 which describe the suggested contents for the 3.2.P.2 Pharmaceutical Development section of a regulatory submission in the Common Technical Document (CTD) format. An equivalent guideline which covers the drug substance is under development by ICH.

The Pharmaceutical Development section is intended to provide a comprehensive understanding of the product and manufacturing process for reviewers and inspectors. The Pharmaceutical Development information for a veterinary drug submission should be provided as outlined in section 6.4.2 of Guidance for Industry: Preparation of Veterinary New Drug Submissions.

The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the establishment of the design space, specifications, and manufacturing controls.

Design space is proposed by the applicant, and is subject to regulatory assessment and approval. Working within the design space is not considered as a change that would require prior approval but should be documented with the requisite Change Controls where necessary. Movement outside of the design space is considered to be a change and would normally initiate a regulatory post approval change process.

For example, some of the Post-NOC Changes that are listed in Appendices 1, 2, 3 and 4 of this guidance document as Level I - Supplements (Major Quality Changes) or Level II - Notifiable Changes (Moderate Quality Changes) may not require approval prior to implementation if they are within the approved design space.

If desired, a sponsor may also establish a new design space for an existing product. This would provide the advantage, once approved, of limiting the necessity to file future submissions for changes within the ranges of the design space.

If proposed and approved, the details of the design space should be recorded in the Certified Product Information Document (CPID). Sponsors are encouraged to discuss with Health Canada when considering the establishment of a design space.

3.8 Consistency lot testing

For Biologics (Schedule D drugs) and for Radiopharmaceuticals (Schedule C drugs) that have a biologic drug substance, Health Canada usually requests consistency samples to support the information provided in Level I or Level II Changes. The consistency samples should be representative of the revised process/proposed change(s) and should come from three to five consecutively manufactured lots. Sponsors are encouraged to discuss consistency lot testing requirements prior to the submission of Level I or Level II changes and this will be confirmed during the review process. Sponsors are also encouraged to consult the Health Canada guidance document "Lot release program for Schedule D (Biologic) drugs" for further guidance.

3.9 On-site evaluation (OSE)

For Biologics (Schedule D drugs) and for Radiopharmaceuticals (Schedule C drugs) that have a biologic drug substance, an on-site evaluation (OSE) may be conducted by Health Canada to support the information provided in Level I or infrequently in Level II Changes. Sponsors are encouraged to discuss OSE requirements prior to the submission of Level I or Level II changes; the requirement for an OSE will be confirmed during the review process.

3.10 Multiple changes

Multiple Level II (Quality) changes to the same drug product may be filed in a single submission provided those changes are related and/or supported by the same information. If the changes are related, the sponsor should indicate the association between the proposed changes. The sponsor should ensure that the documentation for each change complies with the requirements of the corresponding section of the guidance. For submissions that include multiple changes, the sponsor should clearly specify which supporting data supports which change.

If there are too many changes filed within the same submission or major issues are identified with a change which would require extensive time to review, Health Canada may divide the changes into separate submissions.

If the same change is applicable to multiple drugs, a separate submission is required for each drug product but the data may be cross-referenced.

3.11 Interchangeable pharmacopoeial texts

The International Conference on Harmonisation (ICH) has developed a guideline, Q4B: Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions which describes a process for the evaluation and recommendation of selected pharmacopoeial texts to facilitate their recognition by regulatory authorities for use as interchangeable in the ICH regions. Health Canada is in the process of adopting ICH Q4B. Where ICH Q4B annexes have been adopted by Health Canada, such changes should be reported as a change from a House analytical procedure to a Schedule B analytical procedure (see Appendix 1 - Human Pharmaceuticals, numbers 9c and 32c) with supporting analytical method validation data, where appropriate.

4. Appendices

Appendix 1: Quality Post-NOC Changes (Human Pharmaceuticals)

The change examples presented below are intended to assist with the classification of changes made to the Quality information. The information summarized in the tables provides recommendations for:

  1. the conditions to be fulfilled for a given change to be classified as either a Level I, or III change. If any of the conditions outlined for a given change are not fulfilled, the change is automatically considered the next higher level of change. For example, if any of the conditions recommended for a Level III - Annual Notification are not fulfilled, the change is considered a Level I - Supplement. However, in such a case the supporting data for a Supplement will remain the same as for an Annual Notification. Similarly, if any of the conditions recommended for a Level I - Supplement are not fulfilled, the change would warrant the filing of an NDS or an ANDS;
  2. the supporting data for a given change, either to be submitted to Health Canada and/or maintained by the sponsor. Where Master Production Documents are required, these documents should be available in an official language (English or French), or a translation from the original language. Where applicable, the corresponding modules of the Common Technical Document (CTD) for the supporting data have been identified in brackets;
  3. the reporting category [e.g., Supplement, or Annual Notification].

For convenience, the change examples are organized according to the structure of the Common Technical Document (CTD).

Multiple Changes related to the same pharmaceutical drug product falling in the category of Level I -Suppement changes can be filed in a single submission if those changes are related and/or are supported by the same data.

The information provided in the Level III form which is submitted with the annual notification will be audited applying principles of risk management. Sponsors will be required to address any comments arising from such assessments in the time frame notified in the communication from Health Canada. Sponsors will be required to refile the information under cover of a Level I - Supplement if, it is deemed to be the proper classification for the change notified by the sponsor as an Annual Notification. It is expected that the company will perform a full assessment of the proposed change and document the justification as per the change control process of its quality system. It is recommended that the justification for the proposed change to Level III is summarised in a manner to facilitate efficient review [e.g., comparison table of existing versus proposed change].

3.2.S Drug Substance

3.2.S.1 General Information
1. Change in the name of the drug substance
  • Conditions to be Fulfilled: 1
  • Supporting Data: 1-2
  • Reporting Category: Annual Notification
Conditions
  1. Confirmation that the information on the drug substance has not changed as a result of the change [e.g., cross reference(s) should be provided to the previously approved drug submission, including brand name of the drug product, manufacturer's/sponsor's name, submission type, control number, date approved].
Supporting Data
  1. (1.3) Product Monograph [e.g., Where applicable, Title Page, Storage and Stability (Part I), Dosage Forms, Composition and Packaging (Part I), and Pharmaceutical Information (Part II) section] and Inner and Outer Labels.
  2. (S.1.1) Information on the proposed nomenclature of the drug substance [e.g., chemical name(s), compendial name] and evidence that the proposed name for the drug substance is recognized [e.g., Recommended International non-proprietary name (INN), United States Adopted Names (USAN), British Approved Names (BAN)].
3.2.S.2 Manufacture
2. Replacement or addition of a manufacturing site and/or manufacturer involving:
  1. production of the intermediate or drug substance
    • Conditions to be Fulfilled:
      • None
      • 1-5
    • Supporting Data:
      • 1-7, 9-10
      • 1-2, 4-7, 9-10
    • Reporting Category:
      • Supplement
      • Annual Notification
  2. production of the starting material
    • Conditions to be Fulfilled: 1,3-5
    • Supporting Data: 3-7, 9
    • Reporting Category: Annual Notification
  3. testing [e.g., release, stability]
    • Conditions to be Fulfilled: None
    • Supporting Data: 2,6, 8-9
    • Reporting Category: Annual notification
3. Deletion of a manufacturing site or manufacturer for the starting material, intermediate, or drug substance
  • Conditions to be Fulfilled: None
  • Supporting Data: None
  • Reporting Category: Annual Notification
Conditions
  1. No Level I changes in the drug substance specifications [e.g. no change in the polymorphic form for insoluble drug substances as defined by dose-solubility ratio in physiological pH 1.2-6.8 - see Appendix 5] and impurity profile that impacts safety of the drug substance).
  2. The change does not require the filing of a new DMF.
  3. Complete information on the drug substance is available and the sponsor has determined that there is no change in the route of synthesis (i.e. intermediates remain the same), physical characteristics, and impurity profile of the drug substance (no new impurity above 0.10%, no change in the approved total impurity limit and residual solvents within ICH limits) or the change of source is supported by a valid Certificate of Suitability (CEP) issued by the EDQM and there is written assurance that the manufacturing process described in the Canadian DMF is identical to the one evaluated by EDQM.
  4. Where materials of human or animal origin are used in the process, the change of source is supported by a valid TSE Certificate of Suitability (CEP) issued by the EDQM or the manufacturer does not use any new supplier for which assessment of viral safety data or TSE risk assessment is required.
  5. The change concerns drug substances that are discrete chemical entities (i.e. this does not include polymeric complexes).
Supporting Data
  1. (1,5) Viral safety data (ref. Condition 4) or supporting or comparative bioavailability data (ref. Condition 5) (whichever is applicable to be included in CTD modules 1&5).
  2. (1.2.5) For sterile manufacturing, evidence of GMP and/or Establishment License (EL) information [e.g. Confirmation of a satisfactory GMP rating by the Inspectorate], and (S.2.5) process validation and/or evaluation studies for sterilization. For drug substance testing sites evidence of GMP and/or EL information [e.g. Confirmation of a satisfactory GMP rating by the Inspectorate].
  3. (S) Where applicable, updated or new Drug Master File (DMF) (with a Letter of Access provided in Module 1), any relevant information on the starting material, intermediate or drug substance to be provided where available.
  4. Where applicable, a copy of the Certificate of Suitability (CEP) issued by the EDQM.
  5. (S.2) Summary of evaluation confirming that the synthetic route, process controls, control of materials, and specifications of the intermediate or drug substance (as appropriate) in the manufacturing process of the proposed drug substance are the same as those previously approved or revised information if any of the attributes have changed.
  6. (S.2.1) Name, address, and responsibility of the proposed production site or facility involved in manufacturing and/or testing.
  7. (S.2.3) For starting materials, intermediates or drug substances manufactured with reagents obtained from sources that are at risk of transmitting BSE/TSE agents [e.g., ruminant origin], information and evidence that the material does not pose a potential BSE/TSE risk [e.g., name of manufacturer, species and tissues from which the material is a derivative, country of origin of the source animals, its use and previous acceptance] should be provided where available.
  8. (S.4.3) Copies or summaries of validation reports, which demonstrate equivalency of analytical procedures to be used at the proposed testing site or method transfer reports, which demonstrate equivalency of analytical testing results between the approved and proposed sites.
  9. (S.4.4) Description of the batches, certificates of analyses or batch analysis report, and summary of results, in a comparative tabular format, for one batch of the currently approved and proposed starting material, intermediate or drug substance sites.
  10. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of the drug product manufactured using the proposed drug substance into the long term stability programme (bracketing and matrixing with justification would be acceptable for multiple strength products).
4. Change in the manufacturing process
  1. for the drug substance or intermediate.
    • Conditions to be Fulfilled:
      • None
      • 1-8
    • Supporting Data:
      • 1-11
      • 2-6, 8-9, 11
    • Reporting Category:
      • Supplement
      • Annual Notification
  2. for the starting material
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-4, 9
    • Reporting Category: Annual Notification
Conditions
  1. No change in the identicality of the drug substance (as defined in the Health Canada policy Interpretation of "Identical Medicinal Ingredient").
  2. No change in the physical state [e.g. crystalline, amorphous, solid, semi-solid, liquid or gas] of the drug substance.
  3. For low solubility drug substances, no change in the polymorphic form or no change in the particle size distribution of the drug substance.
  4. Where materials of human or animal origin are used in the process, the change of source is supported by a valid TSE Certificate of Suitability (CEP) issued by the EDQM or the manufacturer does not use any new supplier for which assessment of viral safety data or TSE risk assessment is required.
  5. No Level I change in the drug substance specifications.
  6. No change in the route of synthesis (i.e. intermediates remain the same), impurity profile of the drug substance (no new impurity above 0.10%, no change in the approved total impurity limit and residual solvents within ICH limits) or the change of the manufacturing process is supported by a valid Certificate of Suitability (CEP) issued by the EDQM.
  7. The change does not affect the sterilization procedures of a sterile drug substance.
  8. The change concerns drug substances that are discrete chemical entities (i.e. this does not include polymeric complexes).
Supporting Data
  1. (1,5) Viral safety data (ref. Condition 4) or supporting clinical or comparative bioavailability data (ref. Conditions 3,8) (whichever is applicable to be included in CTD modules 1&5).
  2. (S) Updated or new DMF (with a Letter of Access provided in Module 1) or relevant information on the starting material, intermediate or drug substance or Certificate of Suitability (CEP) issued by the EDQM.
  3. (S.2.2) Flow diagram of the proposed synthetic process(es) and a brief narrative description of the proposed manufacturing process(es).
  4. S.2.3) Information on the quality and controls of the materials [e.g., raw materials, starting materials, solvents, reagents, catalysts] used in the manufacture of the proposed starting material, intermediate or drug substance.
  5. (S.2.3) For starting materials, intermediates or drug substances manufactured with reagents obtained from sources that are at risk of transmitting BSE/TSE agents [e.g., ruminant origin], information and evidence that the material does not pose a potential BSE/TSE risk [e.g., name of manufacturer, species and tissues from which the material is a derivative, country of origin of the source animals, its use and previous acceptance] should be provided where available.
  6. (S.2.4) Information on the controls performed at critical steps of the manufacturing process and on intermediates of the proposed drug substance.
  7. (S.2.5) Evidence of process validation and/or evaluation studies for sterilization.
  8. (S.3.1) Evidence for elucidation of structure, where applicable.
  9. (S.4.4) Description of the batches, certificates of analyses or batch analysis report, and summary of results, in a comparative tabular format, for at least one (1) batch of the currently approved and proposed processes.
  10. (S.7.3) Results of two (2) batches with a minimum of three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing of the proposed drug substance.
  11. P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of the drug product, manufactured using the proposed drug substance, into the long term stability programme.
5. Change in the batch size for the drug substance or for a continuous process
  • Conditions to be Fulfilled: 1-3
  • Supporting Data: 1-3
  • Reporting Category: Annual Notification
Conditions
  1. No Level I changes in the drug substance specifications.
  2. The change does not affect the sterilization procedures of a sterile drug substance.
  3. The change concerns drug substances that are discrete chemical entities (i.e. this does not include polymeric complexes).
Supporting Data
  1. (S.2.2) A brief narrative description of the proposed manufacturing process(es).
  2. (S.2.5) Evidence of process validation and/or evaluation studies for sterilization.
  3. (S.4.4) Description of the batches, certificates of analyses or batch analysis report, and summary of results, in a tabular format, for at least one batch.
3.2.S.3 Characterisation

There are no quality change examples for this section at the present time that have not been addressed in other sections.

3.2.S.4 Control of the Drug Substance
6. Change in the standard claimed for the drug substance [e.g., from a Professed to Schedule B pharmacopoeial standard or from one Schedule B standard to a different Schedule B standard]
  • Conditions to be Fulfilled: 1-3
  • Supporting Data: 1-4
  • Reporting Category: Annual Notification
7. Change in the specification for the drug substance to comply with an updated Schedule B pharmacopoeial monograph
  • Conditions to be Fulfilled: 1-2
  • Supporting Data: 1-4
  • Reporting Category: Annual Notification
Conditions
  1. The change is made exclusively to comply with the pharmacopoeia.
  2. No Level I changes to the specifications with respect to functional properties of the drug substance [e.g., particle size distribution, polymorphic form] and to tests that impact safety [e.g. sterility, baterial endotoxins].
  3. No deletion of or relaxation to any of the tests, analytical procedures, or acceptance criteria for tests that do not appear in a pharmacopoeiel monograph.
Supporting Data
  1. (S.4.1) Updated, QC approved, proposed drug substance specification.
  2. (S.4.3) Where a House analytical procedure is used and a Schedule B standard is claimed, results of an equivalency study between the House and compendial methods.
  3. (S.4.4) Description of the batches, certificates of analyses or batch analysis report, and summary of results, in a tabular format, for at least one batch if new tests and/or analytical methods are implemented.
  4. (S.4.5) Justification of the proposed drug substance specification [e.g., demonstration of the suitability of the monograph to control the drug substance, including impurities].
8. Change in the specification for the drug substance involving test and acceptance criteria:
  1. for sterile drug substances, replacing the sterility test with alternate microbiological methods or process parametric release
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-7
    • Reporting Category: Supplement
  2. deletion of a test
    • Conditions to be Fulfilled: 1-5
    • Supporting Data: 2, 7-8
    • Reporting Category: Annual Notification
  3. replacement of a test
    • Conditions to be Fulfilled: 1-6
    • Supporting Data: 2-5, 7-8
    • Reporting Category: Annual Notification
  4. addition of a test
    • Conditions to be Fulfilled: None
    • Supporting Data: 2-5, 7-8
    • Reporting Category: Annual Notification
  5. relaxation of an acceptance criterion
    • Conditions to be Fulfilled: 1-4, 6
    • Supporting Data: 2, 7-8
    • Reporting Category: Annual Notification
  6. tightening of an acceptance criterion
    • Conditions to be Fulfilled: None
    • Supporting Data: 2, 7-8
    • Reporting Category: Annual Notification
Conditions
  1. The change is not necessitated by unexpected events, resulting in failure to meet specifications, arising during manufacture or because of stability concerns.
  2. No change in the polymorphic form and impurity profile that impacts safety or efficacy of the drug product.
  3. The change does not concern sterility testing.
  4. The change concerns drug substances that are discrete chemical entities (i.e. this does not include polymeric complexes).
  5. The deleted test has been demonstrated to be redundant with respect to the remaining tests and does not impact the safety or overall quality of the product [e.g. removal of an organic volatile solvent test after at least 10 commercial scale batches tested and meet acceptance criteria, or provide valid scientific justification].
  6. The relaxed criterion is in accordance with compendial and/or ICH criterion.
Supporting Data
  1. (S.2.5) QC approved process validation and/or evaluation studies or the proposed validation protocol of the proposed drug substance.
  2. (S.4.1) Updated, QC approved, proposed drug substance specification.
  3. (S.4.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  4. (S.4.3) Copies or summaries of validation reports, if new analytical procedures are used.
  5. (S.4.3) Where a House analytical procedure is used and a Schedule B standard is claimed, results of an equivalency study between the House and compendial methods.
  6. (S.4.4) Description of the batches, certificates of analyses for one batch, or batch analysis report and summary of results, of a sufficient number of batches (minimum of ten batches) to support the process parametric release.
  7. (S.4.5) Justification of the proposed drug substance specification [e.g., test parameters, acceptance criteria, or analytical procedures].
  8. (P.2) Where appropriate [e.g., for a change in particle size limit for a poorly soluble drug substance], comparative, multi-point dissolution profiles in the release medium for one batch of the drug product using material from the approved and change drug substance specifications.
9 Change in the specification for the drug substance involving analytical procedures:
  1. deletion of an analytical procedure
    • Conditions to be Fulfilled: 1
    • Supporting Data: 1
    • Reporting Category: Annual Notification
  2. replacement of, alternate, or additional analytical procedure
    • Conditions to be Fulfilled: 1
    • Supporting Data: 1-5
    • Reporting Category: Annual Notification
  3. change from a House analytical procedure to a Schedule B analytical procedure or a change from an approved compendial analytical procedure to an harmonized compendial procedure
    • Conditions to be Fulfilled: None
    • Supporting Data: 1, 3-4
    • Reporting Category: Annual Notification
Conditions
  1. The change does not concern a non-compendial (Schedule B) sterility testing method.
Supporting Data
  1. (S.4.1) Updated, QC approved, proposed drug substance specification.
  2. (S.4.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  3. (S.4.3) Copies or summaries of validation reports, if new analytical procedures are used.
  4. (S.4.3) Comparative analytical results demonstrating that the approved and proposed analytical procedures are equivalent.
  5. (S.4.5) Justification of the proposed drug substance specification.
3.2.S.6 Container Closure System
10. Change in the primary container closure system(s) for the storage and shipment of the drug substance
  • Conditions to be Fulfilled:
    • None
    • 1-2
  • Supporting Data:
    • 1-3
    • 2-3
  • Reporting Category:
    • Supplement
    • Annual Notification
Conditions
  1. Results demonstrate that the proposed container closure system is at least equivalent to the approved container closure with respect to its relevant properties [e.g., including results of transportation or interaction studies, if appropriate].
  2. The change does not impact sterilization parameters of a sterile drug substance.
Supporting Data
  1. (S.2.5) Evidence of process validation and/or evaluation studies for sterilization if different from the current process.
  2. (S.6) Information on the proposed container closure system [e.g., description, specifications].
  3. (S.7.3) Results of a minimum of three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing of the drug substance in the proposed container closure system.
3.2.S.7 Stability
11. Change in the re-test period (or shelf life) for the drug substance
  • Conditions to be Fulfilled: None
  • Supporting Data: 1-2
  • Reporting Category: Annual Notification
Conditions

None

Supporting Data
  1. (S.7.2) Updated post-approval stability protocol and stability commitment.
  2. (S.7.3) Results of stability testing generated on at least two pilot and/or commercial scale batches with stability data to support the proposed re-test period or shelf life.
12. Change in the labelled storage conditions for the drug substance, involving: addition/deletion of a cautionary statement or relaxation/tightening of a temperature criterion (eg. from 15-25 °C to 15-30 °C)
  • Conditions to be Fulfilled: None
  • Supporting Data: 1
  • Reporting Category: Annual Notification
Conditions

None

Supporting Data
  1. (S.7.3) If applicable, stability testing results to support the change to the storage conditions on not less than two (2) lots (pilot or commercial scale).
13. Change to the post-approval stability protocol or stability commitment
  • Conditions to be Fulfilled: None
  • Supporting Data: 1-2
  • Reporting Category: Annual Notification
Conditions

None

Supporting Data
  1. (S.7.1) Justification of the change to the post-approval stability protocol or stability commitment.
  2. (S.7.2) QC approved updated post-approval stability protocol and stability commitment.

3.2.P Drug Product

3.2.P.1 Description and Composition of the Drug Product
14. Addition of a dosage form or strength
  • Conditions to be Fulfilled: None
  • Supporting Data: 1-16
  • Reporting Category: Supplement
Conditions

None

Supporting Data
  1. (1,5) Supporting clinical or comparative bioavailability data, in vitro in vivo correlation (IVIVC) data or a request for a waiver of in vivo studies, e.g.:
    • when the changes in excipients for a new strength of an immediate release solid oral dosage form containing a single drug substance, expressed as percentage (w/w) of total formulation, are greater than the ranges outlined in Appendix 6: supporting clinical or comparative bioavailability data and in vitro data to be included in CTD modules 1,5);
    • when the changes in excipients for new strength of an immediate release solid oral dosage form containing a single drug substance, expressed as percentage (w/w) of total formulation, are less than or equal to the ranges outlined in Appendix 6: supporting in vitro data to be included in CTD modules 1,5).
  2. (1.2.5) GMP and Establishment License (EL) Information [e.g. Confirmation of a satisfactory GMP rating by the Inspectorate].
  3. (1.2.6) Letters of Access if Drug Master Files (DMFs), are submitted for new excipients.
  4. (1.3) Product Monograph [e.g., Where applicable, Title Page, Storage and Stability (Part I), Dosage Forms, Composition and Packaging (Part I), and Pharmaceutical Information (Part II) section] and Inner and Outer Labels.
  5. (S) Confirmation that the information on the drug substance has not changed [e.g., cross reference(s) should be provided to the previously approved drug submission, including brand name of the drug product, manufacturer's/sponsor's name, submission type, control number, date approved].
  6. (P.1) Description and composition of the dosage form.
  7. (P.2) Where applicable, information on Pharmaceutical Development including discussion on the components of the drug product [e.g., choice of excipients, compatibility of drug substance and excipients], comparative in vitro testing [e.g., multi-point dissolution profiles in the release medium for solid dosage units] for the approved and proposed products, discussion of any in vitro and/or in vivo studies.
  8. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates,
  9. (P 3.5) QC approved Process validation protocol of the proposed drug product. In addition, for a sterile drug product, evidence of process validation and/or evaluation studies for sterilization procedures.
  10. (P.4) Control of Excipients, if new excipients are proposed [e.g., specifications, confirmation that none of the excipients are prohibited by the Food and Drug Regulations].
  11. (P.5) Specification(s), Analytical Procedures (if new analytical methods are used), Validation of Analytical Procedures (if new analytical methods are used), Batch Analyses (certificate of analyses for a minimum of one (1) pilot scale batch per strength).
  12. (P.7) Discussion (including description, materials of construction, summary of specifications) on the container closure system, if any of the components have changed.
  13. (P.8.1) Stability Summary and Conclusions (minimum of two pilot scale batches), results of a minimum of six (6) months of accelerated (or intermediate as appropriate) and six (6) months of long term testing of the proposed drug product; (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  14. (P.8.2) Updated post-approval stability protocols and stability commitments to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  15. (R.1) Executed Production Documents for one batch of each new dosage form or strength.
  16. Additional documentation may be required in certain situations, e.g., complexity of the dosage form, ICH guidance, new scientific evidence, clinical requirements.
15. Change in the composition of a solution dosage form
  • Conditions to be Fulfilled:
    • None
    • 1-8
  • Supporting Data:
    • 1-13
    • 2-13
  • Reporting Category:
    • Supplement
    • Annual Notification
Conditions
  1. The changes in excipients of the approved and proposed drug products are considered to be qualitatively the same and quantitatively essentially the same (For the purposes of this document, essentially the same would be interpreted as the amount (or concentration) of each excipient in the test product to be within ±10% of the amount (or concentration) of each excipient in the reference product, as defined in the Health Canada guidance document Pharmaceutical Quality of Aqueous Solutions).
  2. The proposed excipient(s) does/do not function to affect the absorption of the drug substance.
  3. The proposed excipient(s) does/do not function to affect the solubility of the drug substance.
  4. The proposed excipient(s) does/do not function as a preservative.
  5. No change in the specifications of the drug product other than changes to comply with a Schedule B monograph.
  6. No change to the physical characteristics of the drug product [e.g., viscosity, pH, osmolality].
  7. The change does not concern a sterile drug product.
  8. The change concerns a drug product that contains drug substances that are discrete chemical entities (i.e. this does not include polymeric complexes).
Supporting Data
  1. (1,5) Supporting clinical or comparative bioavailability data or a request for a waiver of in vivo studies, e.g.,:
    • when the changes in excipients are not considered to be qualitatively the same and quantitatively essentially the same: supporting clinical or comparative bioavailability data and in vitro data on the physicochemical properties;
    • when the changes in excipients are considered to be qualitatively the same and quantitatively essentially the same: supporting in vitro data on the physicochemical properties.
  2. (1.2.6) Letters of Access if Drug Master Files (DMFs)), are submitted for new excipients.
  3. (1.3.1) Product Monograph (Title page, ''Dosage Forms, Composition, and Packaging'' section).
  4. (S) Confirmation that the information on the drug substance has not changed [e.g., cross reference(s) should be provided to the previously approved drug submission, including brand name of the drug product, manufacturer's/sponsor's name, submission type, control number, date approved]
  5. (P.1) Description and composition of the dosage form.
  6. (P.2) Discussion of the components of the drug product [e.g., choice of excipients, compatibility of drug substance and excipients], comparative in vitro testing on the physicochemical properties for the approved and proposed products, discussion of any in vitro and/or in vivo studies, results of preservative effectiveness testing (if applicable).
  7. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates.
  8. (P 3.5) QC approved Process validation protocol of the proposed drug product. In addition, for a sterile drug product, evidence of process validation and/or evaluation studies for sterilization procedures.
  9. (P.4) Control of Excipients, if new excipients are proposed [e.g., specifications, confirmation that none of the excipients are prohibited by the Food and Drug Regulations].
  10. (P.5) Batch Analyses (certificate of analyses for a minimum of one pilot scale batch per strength).
  11. (P.8.1) Stability Summary and Conclusions (minimum of two pilot scale batches), e.g.,:
    • when the changes in excipients are not considered to be qualitatively the same and quantitatively essentially the same: results of a minimum of three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing of the proposed drug product;
    • when the changes in excipients are considered to be qualitatively the same and quantitatively essentially the same: stability data at the time of filing would not be necessary (see P.8.2 below) (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  12. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  13. (R.1) Executed Production Documents for one batch representative of each strength of the proposed product.
16. Change in the composition of an immediate release dosage form including film-coating, colours, flavours and printing inks. (Film coating could be for enhancing appearance, masking taste and/or ensuring stability)
  • Conditions to be Fulfilled:
    • None
    • 1-8
  • Supporting Data:
    • 1-13
    • 2-7, 9-13
  • Reporting Category:
    • Supplement
    • Annual Notification
Conditions
  1. The changes in excipients of the approved and proposed drug products are considered to be qualitatively the same.
  2. The quantitative changes in excipients, expressed as percentage (w/w) of total formulation, are less than or equal to the ranges outlined in Appendix 6.
  3. The change does not affect performance characteristics of the drug product [e.g. release rate].
  4. The proposed excipient(s) does/do not function to affect the absorption of the drug substance.
  5. The proposed excipient(s) does/do not function to affect the solubility of the drug substance.
  6. The proposed excipient(s) does/do not function as a preservative.
  7. No change in the specifications of the drug product other than appearance and changes to comply with a Schedule B monograph
  8. The change concerns a drug product that contains drug substances that are discrete chemical entities (i.e. this does not include polymeric complexes).
Supporting Data
  1. (1,5) Supporting clinical or comparative bioavailability data or a request for a waiver of in vivo studies (to be included in CTD modules 1,5), e.g.,:
    • when the changes in excipients, expressed as percentage (w/w) of total formulation, are greater than the ranges outlined in Appendix 6: supporting clinical or comparative bioavailability data and in vitro data;
    • when the changes in excipients, expressed as percentage (w/w) of total formulation, are less than or equal to the ranges outlined in Appendix 6: supporting in vitro data.
  2. (1.2.6) Letters of Access if Drug Master Files (DMFs) are submitted for new excipients.
  3. (1.3.1) Product Monograph (Title page, ''Dosage Forms, Composition, and Packaging'' section).
  4. (S) Confirmation that the information on the drug substance has not changed [e.g., cross reference(s) should be provided to the previously approved drug submission, including brand name of the drug product, manufacturer's/sponsor's name, submission type, control number, date approved].
  5. (P.1) Description and composition of the dosage form.
  6. (P.2) Discussion of the components of the drug product [e.g., choice of excipients, compatibility of drug substance and excipients], comparative in vitro testing where applicable [e.g., depending on the solubility and permeability of the drug (refer to Appendix 5), multi-point dissolution profiles in either the release medium or in multiple media covering the physiological pH range] for the approved and proposed products, discussion of any in vitro and/or in vivo studies, results of preservative effectiveness testing (if applicable). Comparitive in vitro dissolution tests are normally not expected for changes in colours, flavours and printing inks.
  7. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates, Process Validation and/or Evaluation.
  8. (P 3.5) QC approved Process validation protocol of the proposed drug product. In addition, for a sterile drug product, evidence of process validation and/or evaluation studies for sterilization procedures.
  9. (P.4) Control of Excipients, if new excipients are proposed [e.g., specifications, confirmation that none of the excipients are prohibited by the Food and Drug Regulations].
  10. (P.5) Specification(s) and Batch Analyses (certificate of analyses for a minimum of one pilot scale batch per strength).
  11. (P.8.1) Stability Summary and Conclusions (minimum of two pilot scale batches) results of a minimum of three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing of the proposed drug product; (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  12. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  13. (R.1) Executed Production Documents for one batch representative of each strength of the proposed product.
17. Change in the composition (qualitative or quantitative) in the release controlling agent of a modified release dosage form (for changes in other excipients in a modified release dosage form, refer to change example #16)
  • Conditions to be Fulfilled:
    • None
    • 1-2 (quantitative changes only)
  • Supporting Data:
    • 1-13
    • 2-8, 10-13
  • Reporting Category:
    • Supplement
    • Annual Notification
Conditions
  1. The change is only quantitative and is within parameters established by an in vitro in vivo correlation previously approved by Health Canada in the original (S)NDS/(S)ANDS.
  2. No change in the specifications of the drug product other than appearance and changes to comply with a Schedule B monograph.
Supporting Data
  1. (1,5) Supporting clinical or comparative bioavailability data (the supporting clinical or comparative bioavailability data may be waived if an acceptable in vitro in vivo correlation has been established).
  2. (1.2.6) Letters of Access if Drug Master Files (DMFs) are submitted for new excipients.
  3. (1.3.1) Product Monograph (Title page, ''Dosage Forms, Composition, and Packaging'' section).
  4. (S) Confirmation that the information on the drug substance has not changed [e.g., cross reference(s) should be provided to the previously approved drug submission, including brand name of the drug product, manufacturer's/sponsor's name, submission type, control number, date approved]
  5. (P.1) Description and composition of the dosage form.
  6. (P.2) Discussion of the components of the drug product [e.g., choice of excipients, compatibility of drug substance and excipients], comparative in vitro testing [e.g., depending on the mechanism for drug release (extended or delayed), drug release profiles in multi media or using different agitation speeds] for the approved and proposed products, discussion of any in vitro and/or in vivo studies, results of preservative effectiveness testing (if applicable).
  7. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates.
  8. (P 3.5) QC approved Process validation protocol of the proposed drug product. In addition, for s sterile drug product, evidence of process validation and/or evaluation studies for sterilization procedures.
  9. (P.4) Control of Excipients, if new excipients are proposed [e.g., specifications, confirmation that none of the excipients are prohibited by the Food and Drug Regulations].
  10. (P.5) Specification(s) and Batch Analyses (certificate of analyses for a minimum of one pilot scale batch per strength).
  11. (P.8.1) Stability Summary and Conclusions (minimum of two pilot scale batches), e.g.,:
    • results of a minimum of three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing of the proposed drug product; (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  12. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  13. (R.1) Executed Production Documents for one batch of each strength.
18. Change to product markings, involving a change in embossing, debossing, or engraving (except scorelines/break lines) [e.g., plain tablet to engraved, engraved to plain, change in engraving] or a change in imprinting [e.g., plain tablet/capsule to imprinted tablet/capsule]
  • Conditions to be Fulfilled: 1
  • Supporting Data: 1-3
  • Reporting Category: Annual Notification
Conditions
  1. The change does not affect the performance characteristics [e.g., release rate] of the drug product.
Supporting Data
  1. (1.3.1) Product Monograph (Title page, ''Dosage Forms, Composition, and Packaging'' sections).
  2. (P.5) Specification(s) and Batch Analyses (certificate of analyses for a minimum of one pilot scale batch per strength).
  3. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
19. Change in scoring configuration, involving:
  1. addition of a scoreline
    • Conditions to be Fulfilled: 1-4
    • Supporting Data: 1-6
    • Reporting Category: Annual Notification
  2. deletion of a scoreline
    • Conditions to be Fulfilled: 1-4
    • Supporting Data: 1, 4-6
    • Reporting Category: Annual Notification
Conditions
  1. The change does not affect the performance characteristics [e.g., release rate] of the drug product.
  2. Changes to the drug product specifications are those necessitated only by the change to the scoring.
  3. The change does not concern a modified release drug product.
  4. Addition or deletion of a score line to a generic product is consistent with a similar score line in the innovator product (Canadian Reference Product).
Supporting Data
  1. (1.3.1) Product Monograph (Title page, ''Dosage Forms, Composition, and Packaging'' sections).
  2. (P.2) Comparative, multi-point dissolution profiles for the approved and proposed products performed using the release conditions.
  3. (P.2) Demonstration of the uniformity of the dosage units of the split tablets.
  4. ((P.5) Specification(s) and Batch Analyses (certificate of analyses for a minimum of one pilot scale batch per strength).
  5. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  6. (R.1) Executed Production Documents for one batch representative of each strength of the proposed product.
20. Change in shape or dimensions of tablets, capsules, suppositories or pessaries
  • Conditions to be Fulfilled: 1-3
  • Supporting Data: 1-6
  • Reporting Category: Annual Notification
Conditions
  1. No change in the qualitative and quantitative composition and mean mass or fill weight.
  2. Changes to the drug product specifications are those necessitated by the change to the drug product shape or dimensions.
  3. The change does not affect the performance characteristics [e.g., release rate] of a drug product.
Supporting Data
  1. (1.3.1) Product Monograph (Title page, ''Dosage Forms, Composition, and Packaging'' sections).
  2. (P.2) Discussion of the differences in manufacturing process(es) between the approved and proposed products and the potential impact on product performance.
  3. (P.2) Comparative, multi-point dissolution profiles for the approved and proposed products performed using the release conditions.
  4. (P.5) Specification(s).
  5. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  6. (R.1) Executed Production Documents for one batch representative of each strength of the proposed product.
21.Change in diluent, involving:
  1. replacement or addition of a diluent for a lyophilized powder or concentrated solution
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-12
    • Reporting Category: Supplement
  2. deletion of a diluent
    • Conditions to be Fulfilled: None
    • Supporting Data: 2
    • Reporting Category: Annual Notification
Conditions

None

Supporting Data
  1. (1.2.6) Letters of Access if Drug Master Files (DMFs) are submitted for new excipients.
  2. (1.3) Product Monograph [e.g., Where applicable, Title Page, Storage and Stability (Part I), Dosage Forms, Composition and Packaging (Part I)] and Inner and Outer Labels.
  3. (S) Confirmation that the information on the drug substance has not changed [e.g., cross reference(s) should be provided to the previously approved drug submission, including brand name of the drug product, manufacturer's/sponsor's name, submission type, control number, date approved].
  4. (P.1) Description and composition of the diluent if it is included with the product.
  5. (P.2) Discussion of the components of the drug product, as appropriate [e.g., choice of excipients, compatibility of the drug product with the diluent with respect to appearance, pH, assay, degradation products, extractables/leachables profile and particulate matter].
  6. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates, Process Validation and/or Evaluation and testing standards for the diluent if it is included with the product.
  7. (P.4) Control of Excipients, if new excipients are proposed [e.g., specifications, confirmation that none of the excipients are prohibited by the Food and Drug Regulations].
  8. (P.5) Batch Analyses (certificate of analyses for a minimum of one pilot scale batch of the diluent if it is included with the product.).
  9. (P.7) Discussion (including description, materials of construction of the container closure system, compatibility studies for the diluent if it is included with the product).
  10. (P.8.1) Stability Summary and Conclusions: results for two pilot scale batches of a minimum of three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing of the diluent if it is included with the product.
  11. (P.8.2) Updated post-approval stability protocol and stability commitment for the diluent if it is included with the product.
  12. (R.1) Executed Production Documents for one batch of the diluent, if it is included with the product.
3.2.P.2 Pharmaceutical Development
22. Change in the approved design space, involving:
  1. establishment of a new design space
    • Conditions to be Fulfilled: None
    • Supporting Data: 1
    • Reporting Category: Supplement
  2. expansion of the approved design space
    • Conditions to be Fulfilled: None
    • Supporting Data: 1
    • Reporting Category: Supplement
  3. reduction in the approved design space (any change that reduces or limits the range of parameters used to define the design space)
    • Conditions to be Fulfilled: None
    • Supporting Data: 1
    • Reporting Category: Annual Notification
  4. process parametric release
    • Conditions to be Fulfilled: None
    • Supporting Data: 1
    • Reporting Category: Supplement
Conditions

None

Supporting Data
  1. (P.2) Pharmaceutical development data to support the establishment or changes to the design space (including changes to process parametric release for sterile products).
3.2.P.3 Manufacture
23. Replacement or addition of a drug product manufacturer / manufacturing site, involving
  1. production of a modified release or a sterile drug product; or production of an immediate release product that does not meet the conditions for Annual Notification
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-6, 8-10
    • Reporting Category: Supplement
  2. production of an immediate release product [e.g., tablet, capsule, liquids, semi-solids]
    • Conditions to be Fulfilled: 1-4
    • Supporting Data: 2-5, 8-11
    • Reporting Category: Annual Notification
  3. primary packaging
    • Conditions to be Fulfilled: 1-3
    • Supporting Data: 2-3, 5-6, 9
    • Reporting Category: Annual Notification
  4. testing [e.g., release, stability]
    • Conditions to be Fulfilled: 3
    • Supporting Data: 2-3, 5, 7-8
    • Reporting Category: Annual Notification
  5. storage and distribution
    • Conditions to be Fulfilled: 3
    • Supporting Data: 2-3
    • Reporting Category: Annual Notification
Conditions
  1. No level 1 change in the Batch Formula, Description of Manufacturing Process , Equipment Class and Process Controls, Controls of Critical Steps and Intermediates, or Drug Product Specifications.
  2. No level 1 change in the container closure system.
  3. The proposed facility has a current satisfactory GMP rating as determined by HPFB Inspectorate or is included in the EL.
  4. Three consecutive production scale batches have been successfully validated at the proposed site as per QC approved validation protocol. (Concurrent validation of three production scale batches would be acceptable for orphan drugs and low volume drug products [e.g. only two batches manufactured per year]).
Supporting Data
  1. (1,5) Supporting clinical or comparative bioavailability data (the supporting clinical or comparative bioavailability data may be waived if an acceptable in vivo/in vitro correlation has been established).
  2. (1.2.5) GMP and Establishment License (EL) Information [e.g. Confirmation of a satisfactory GMP rating by the Inspectorate].
  3. (P) Confirmation that information on the drug product has not changed as a result of the submission [e.g., other that change in site].
  4. (P.2) Comparative in vitro testing [e.g., multi-point dissolution profiles in the release medium for solid dosage units, comparative diffusion test results for semi-solids] for one batch of each strength of the approved and of the product produced at the new site [bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified]. See Appendix 5 for additional detail.
  5. (P.3.1) Name, address, and responsibility of the proposed production site or facility involved in manufacturing and/or testing and/or storage and distribution.
  6. (P.3.5) QC approved Process validation protocol of the proposed drug product. In addition, for a sterile drug product, evidence of process validation and/or evaluation studies for sterilization procedures.
  7. (P.5.3) Copies or summaries of validation/ method transfer reports, which demonstrate equivalency of analytical procedures to be used at the proposed testing site.
  8. (P.5.4) Certificate of analyses for one commercial scale batch (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  9. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the product produced at the new site into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  10. (R.1) Executed Production Documents for one batch representative of each strength of the proposed product.
  11. (P 3.5) Process validation data on three consecutive commercial scale batches and confirmation that the results are in accordance with the QC approved validation protocol. (Concurrent validation of three commercial scale batches would be acceptable for orphan drugs and low volume drug products [e.g. only two batches manufactured per year]).
24. Change in the batch size for the drug product, involving:
  1. increase in batch size beyond a factor of ten (10) times for a Modified Release product
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-7
    • Reporting Category: Supplement
  2. increase in batch size up to and including a factor of ten (10) times for a Modified Release product
    • Conditions to be Fulfilled: 4
    • Supporting Data: 2-3, 5-8
    • Reporting Category: Annual Notification
  3. increase in batch size of an immediate release product [e.g., tablet, capsule, liquid, sterile product, semi-solid]
    • Conditions to be Fulfilled: 1-5
    • Supporting Data: 2-3, 5-8
    • Reporting Category: Annual Notification
  4. a downscaling in the batch size
    • Conditions to be Fulfilled: 1-3, 5
    • Supporting Data: 2-7
    • Reporting Category: Annual Notification
Conditions
  1. Any changes to the manufacturing process and/or to the in-process controls are only those necessitated by the change in batch size, e.g., use of different sized equipment.
  2. The change should not be a result of unexpected events, resulting in failure to meet specifications, arisen during manufacture, or because of stability concerns.
  3. The change in batch size is in comparison to the pivotal clinical/biobatch or to the approved and validated commercial scale batches.
  4. Three consecutive production scale batches have been successfully validated as per QC approved validation protocol (Concurrent validation of three production scale batches would be acceptable for orphan drugs and low volume drug products [e.g. only two batches manufactured per year]).
  5. The change does not affect the sterilization parameters of a sterile drug product.
Supporting Data
  1. (1,5) Supporting clinical or comparative bioavailability data (the supporting clinical or comparative bioavailability data may be waived if an acceptable in vivo/in vitro correlation has been established).
  2. (P.2) Comparative in vitro testing [e.g., multi-point dissolution profiles in the release medium for solid dosage units, comparative diffusion test results for semi-solids] for one batch of each strength of the approved and at the proposed scale.
  3. (P.3.2) Batch formula of the proposed dosage form.
  4. (P.3.5) QC approved process validation protocol of the proposed drug product. Confirmation that the reference batch size has been previously validated as per approved process validation protocol. In addition, for a sterile drug product, evidence of process validation and/or evaluation studies for sterilization procedures.
  5. (P.5.4) Description of the batches and summary of results for at least one commercial scale batch at the proposed scale.
  6. (P.8.2) Updated post-approval stability protocol (QC approved) and stability commitment to place the first commercial scale batch of each strength at the proposed scale into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  7. (R.1.2)Executed Production Documents for one batch representative of each strength of the proposed product.
  8. (P 3.5) Process validation data on three consecutive commercial scale batches and confirmation that the results are in accordance with the QC approved validation protocol (Concurrent validation of three commercial scale batches would be acceptable for orphan drugs and low volume drug products [e.g. only two batches manufactured per year]).
25.Change in the drug product manufacturing process
  • Conditions to be Fulfilled:
    • None
    • 1-8
  • Supporting Data:
    • 1-9
    • 2-10
  • Reporting Category:
    • Supplement
    • Annual Notification
Conditions
  1. The change does not require supporting in vivo data or does not require the filing of a request for a waiver of in vivo studies.
  2. The manufacturing processes for the approved and proposed products use the same principles [e.g.,a change from wet to dry granulation, from direct compression to wet/dry granulation or vice versa would be considered a change in manufacturing principle].
  3. Changes to equipment, operating procedures, and process controls, are minor/non-critical. The equipment used in critical-processes to produce the proposed product may vary in capacity, but are of the same class and operating principles.
  4. The change is not the result of unexpected events, resulting in failure to meet specifications, arising during scale-up/manufacture or because of stability concerns.
  5. The change does not involve the packaging or labelling where the primary packaging provides a metering and/or delivery function.
  6. Three consecutive commercial scale batches have been successfully validated as per QC approved validation protocol; condition could be waived with justification for minor/non-critical changes as outlined in condition #3. (Concurrent validation of three commercial scale batches would be acceptable for orphan drugs and low volume drug products [e.g. only two batches manufactured per year]).
  7. The change is minor/non-critical and does not affect the performance characteristics [e.g., release rate] of a modified release drug product.
  8. The change is minor/non-critical and does not affect the sterilization parameters of a sterile drug product.
Supporting Data
  1. (1,5) Supporting clinical or comparative bioavailability data, where applicable, or a request for a waiver of in vivo studies, e.g.,:
    • for a change using different manufacturing principles [e.g., a change from wet to dry granulation, from direct compression to wet/dry granulation or vice versa would be considered a change in manufacturing principle]
  2. (S) Confirmation that the information on the drug substance has not changed [e.g., cross reference(s) should be provided to the previously approved drug submission, including brand name of the drug product, manufacturer's/sponsor's name, submission type, control number, date approved].
  3. (P.2) Discussion of the development of the manufacturing process, where applicable, comparative in vitro testing [e.g., multi-point dissolution profiles in the release medium for solid dosage units, comparative diffusion test results for semi-solids] for the approved and proposed products, discussion of any in vitro and/or in vivo studies, where applicable.
  4. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates.
  5. (P 3.5) QC approved Process validation protocol of the proposed drug product. In addition, for a sterile drug product, evidence of process validation and/or evaluation studies for sterilization procedures.
  6. (P.5) Specification(s) (if specification(s) have changed), Batch Analyses (certificate of analyses for one commercial scale batch per strength).
  7. (P.8.1) Stability Summary and Conclusions, e.g.,:
    • for a major change to the manufacturing process [e.g., change in equipment class or manufacturing principles]: results for two pilot scale batches of a minimum of three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing of the proposed drug product;
    • for a minor change to the manufacturing process [e.g., change in mixer stirring speed]: stability data at the time of filing would not be necessary (see P.8.2 below). (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  8. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  9. (R.1.2) Executed Production Documents for one batch representative of each strength of the proposed product.
  10. (P 3.5) Process validation data on three consecutive commercial scale batches and confirmation that the results are in accordance with the QC approved validation protocol; supporting data could be waived with justification for minor/non-critical changes as outlined in condition #3. (Concurrent validation of three commercial scale batches would be acceptable for orphan drugs and low volume drug products [e.g. only two batches manufactured per year]).
26. Change in the controls (in-process tests and/or acceptance criteria) applied during the manufacturing process or on intermediates
  1. deletion of a test
    • Conditions to be Fulfilled: 1, 4-5
    • Supporting Data: 1,4
    • Reporting Category: Annual Notification
  2. replacement or addition of a test
    • Conditions to be Fulfilled: 1-4, 6
    • Supporting Data: 1-4
    • Reporting Category: Annual Notification
  3. relaxation or tightening of an acceptance criterion
    • Conditions to be Fulfilled: 1,4
    • Supporting Data: 1-4
    • Reporting Category: Annual Notification
Conditions
  1. The change is not necessitated by unexpected events, resulting in failure to meet specifications, arising during manufacture or because of stability concerns.
  2. The change is within the range of approved acceptance criteria (applies to replacement, not to addition of a test, where applicable).
  3. Any new analytical procedure does not concern a novel, non-standard technique or a standard technique used in a novel way.
  4. The change does not affect the sterilization parameters or procedures of a sterile drug product.
  5. The deleted analytical procedure has been demonstrated to be redundant with respect to the remaining analytical procedures [e.g., colour], and does not pertain to a critical quality attribute of the product [e.g., blend uniformity, weight variation].
  6. The replaced or added analytical procedure maintains or tightens precision, accuracy, specificity and sensitivity.
Supporting Data
  1. (P.3.3) Description of the proposed process controls or acceptance criteria of the critical steps and intermediates.
  2. (P.3.5) QC approved process validation and/or evaluation studies or the proposed validation protocol of the proposed drug product, where appropriate.
  3. (P.5.4) Description of the batches, and summary of results, for at least one commercial scale batch.
  4. (R.1.2) Executed Production Documents for one batch representative of each strength of the proposed product or Master Production Documents.
27. Change in the approved protocol for process validation and/or evaluation studies
  • Conditions to be Fulfilled: 1-2
  • Supporting Data: 1
  • Reporting Category: Annual Notification
Conditions
  1. The change does not concern the critical process parameters and controls of a drug product.
  2. The change does not affect the sterilization procedures of a sterile drug product.
Supporting Data
  1. (P.3.5) QC approved Process validation and/or evaluation studies or the revised validation protocol of the proposed drug product.
3.2.P.4 Control of Excipients
28. Change in the source of an excipient from a vegetable source, synthetic source, or non-TSE [e.g., animal] to a TSE risk [e.g., animal] source, or from a TSE risk [e.g., animal] to a different TSE risk [e.g., animal] source
  • Conditions to be Fulfilled:
    • None
    • 1
  • Supporting Data:
    • 2-4
    • 2-4
  • Reporting Category:
    • Supplement
    • Annual Notification
29. Change in the source of an excipient from a TSE risk [e.g., animal] source to a vegetable or synthetic source
  • Conditions to be Fulfilled: None
  • Supporting Data: 1,3
  • Reporting Category: Annual Notification
Conditions
  1. The change of source is supported by a valid TSE Certificate of Suitability (CEP) issued by the EDQM or excipient is obtained from a previously approved source.
Supporting Data
  1. Declaration from the manufacturer of the excipient that it is entirely of vegetable or synthetic origin.
  2. Details of the source of the excipient (animal species, country of origin) and the steps undertaken in processing to minimize the risk of TSE exposure.
  3. Information demonstrating comparability in terms of physico-chemical characterization of the proposed excipient with the approved excipient.
  4. TSE Certificate of Suitability (CEP) issued by the EDQM, if available, or satisfactory BSE/TSE risk assessment on proposed excipient).
3.2.P.5 Control of Drug Product
30. Change in the standard claimed for the drug product [e.g., from a Professed to Schedule B pharmacopoeial standard] or change in the specification for the drug product to comply with an updated Schedule B pharmacopoeial monograph.
  • Conditions to be Fulfilled: 1-2
  • Supporting Data: 1-5
  • Reporting Category: Annual Notification
Conditions
  1. The change is made exclusively to comply with the pharmacopoeia.
  2. No change to the specification that results in a potential impact on the performance of the drug product.
Supporting Data
  1. (1.3) Product Monograph [e.g., Where applicable, Title Page, Composition and Packaging (Part I), and Pharmaceutical Information (Part II) section] and Inner and Outer Labels.
  2. (P.5.1) Updated, QC approved, proposed drug product specification.
  3. (P.5.3) Where a House analytical procedure is used and a Schedule B standard is claimed, results of an equivalency study between the House and compendial methods.
  4. (P.5.4) Description of the batches, certificates of analyses, and summary of results, for at least one batches (minimum pilot scale) of the drug product tested according to the proposed specification.
  5. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
31. Change in the specification for the drug product tests and acceptance criteria, involving:
  1. for sterile products, replacing the sterility test with process parametric release
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2,5, 7-8
    • Reporting Category: Supplement
  2. deletion of a test
    • Conditions to be Fulfilled: 1, 5-7
    • Supporting Data: 2, 8
    • Reporting Category: Annual Notification
  3. replacement or addition of a test
    • Conditions to be Fulfilled: 1-4, 6-7
    • Supporting Data: 2-6, 8
    • Reporting Category: Annual Notification
  4. relaxation of an acceptance criterion
    • Conditions to be Fulfilled: 1,4, 6-8
    • Supporting Data: 2,5-6,8
    • Reporting Category: Annual Notification
  5. tightening of an acceptance criterion
    • Conditions to be Fulfilled: None
    • Supporting Data: 2,8
    • Reporting Category: Annual Notification
Conditions
  1. The change is not necessitated by unexpected events, resulting in failure to meet specifications, arising during manufacture or because of stability concerns.
  2. The change is within the range of approved acceptance criteria (applies to replacement, not to addition of a test, where applicable).
  3. Any new analytical procedure does not concern a novel, non-standard technique or a standard technique used in a novel way.
  4. No change in the assay limits and no change in the impurity profile that impacts safety of the drug product.
  5. The deleted test has been demonstrated to be either redundant with respect to the remaining tests and/or does not impact the safety or overall quality of the product [e.g. removal of an organic volatile solvent test after at least ten (10) commercial scale batches tested and meet approved acceptance criteria, or provide valid scientific justification].
  6. The change to the specifications does not affect the performance of the drug product including drug release (dissolution) specification for modified release products.
  7. The change does not concern sterility testing.
  8. The relaxed criterion is in accordance with Schedule B compendial monograph.
Supporting Data
  1. (P.3.5) Process validation results.
  2. (P.5.1) Updated, QC approved, proposed drug product specification.
  3. (P.5.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  4. (P.5.3) Copies or summaries of validation reports, if new analytical procedures are used.
  5. (P.5.3) Where a House analytical procedure is used and a Schedule B standard is claimed, results of an equivalency study between the House and compendial methods.
  6. (P.5.4) Description of the batches, and summary of results, for at least one (minimum pilot scale) of the drug product tested according to the proposed specification.
  7. (P.5.4) Description of the batches, and summary of results, of a sufficient number of batches (at least 10 commercial scale batches) to support the process parametric release.
  8. (P.5.6) Justification of the proposed drug product specification [e.g., demonstration of the suitability to control the drug product, including degradation products].
32. Change in the specification for the drug product, for analytical procedures involving:
  1. deletion of an analytical procedure
    • Conditions to be Fulfilled: 5-6
    • Supporting Data: 1,6
    • Reporting Category: Annual Notification
  2. replacement, alternate, or additional analytical procedure
    • Conditions to be Fulfilled: 1-5
    • Supporting Data: 1-6
    • Reporting Category: Annual Notification
  3. change from a House analytical procedure to a Schedule B analytical procedure or a change from an approved compendial analytical procedure to an harmonized compendial procedure
    • Conditions to be Fulfilled: 1,3
    • Supporting Data: 1-6
    • Reporting Category: Annual Notification
Conditions
  1. No change in the approved acceptance criteria other than those permitted by the Schedule B monograph.
  2. The method of analysis is based on the same analytical technique or principle and no new impurities are detected.
  3. Results of method validation demonstrate that the proposed analytical procedure is at least equivalent to the approved analytical procedure.
  4. Any new analytical procedure does not concern a novel, non-standard technique or a standard technique used in a novel way.
  5. The change does not concern sterility testing or does not impact the dissolution test condition [e.g., apparatus, speed, medium] for a modified release product.
  6. The deleted analytical procedure has been demonstrated to be redundant with respect to the remaining analytical procedures for the same test and does not impact the safety or overall quality of the product.
Supporting Data
  1. (P.5.1) Updated, QC approved, proposed drug product specification.
  2. (P.5.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  3. (P.5.3) Copies or summaries of validation reports, if new analytical procedures are used.
  4. (P.5.3) Where a House analytical procedure is used and a Schedule B standard is claimed, results of an equivalency study between the House and compendial methods.
  5. (P.5.4) Description of the batches, and summary of results, for at least one (1) batch (minimum pilot scale) of the drug product tested according to the proposed specification, if applicable.
  6. (P.5.6) Justification of the proposed drug product specification [e.g., demonstration of the suitability to control the drug product, including degradation products], if applicable.
3.2.P.7 Container Closure System
33. Replacement or addition of a primary container closure system for:
  1. sterile drug products
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-6
    • Reporting Category: Supplement
  2. other products
    • Conditions to be Fulfilled: 1-2
    • Supporting Data: 1-2,4-6
    • Reporting Category: Annual Notification
Conditions
  1. No change in the type of container closure [e.g. from HDPE to PET].
  2. The change does not concern a container closure that functions to meter the drug product [e.g., inhalation product].
Supporting Data
  1. (1.3) Product Monograph [e.g., Where applicable, Title Page, Storage and Stability (Part I), Dosage Forms, Composition and Packaging (Part I)] and Inner and Outer Labels.
  2. (P.2) Data demonstrating the suitability of the container closure system [e.g., extractable/leachable testing, permeation testing, light transmission]. For changes to functional packaging, data to demonstrate that the functioning of the new packaging is equivalent to that previously approved.
  3. (P.3.5) For sterile products, process validation and/or evaluation studies. Evidence of process validation for sterilization processes for the container/closure.
  4. (P.7) Information on the proposed container closure system [e.g., description, materials of construction of primary packaging components, specifications, including results of transportation studies, if appropriate].
  5. (P.8.1) Stability Summary and Conclusions, results of a minimum two (2) pilot scale, of three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing and, where applicable, results of photostability studies; (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  6. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
34. Change in the package size, involving:
  1. change in the fill weight / fill volume
    • Conditions to be Fulfilled: 1-3
    • Supporting Data: 1-6
    • Reporting Category: Annual Notification
  2. change in the number of units [e.g., tablets, capsules] per package
    • Conditions to be Fulfilled: 1,3
    • Supporting Data: 1-6
    • Reporting Category: Annual Notification
Conditions
  1. No change in the type of container closure or materials of construction.
  2. The change does not impact the sterilization procedures of a sterile drug product or a container closure that functions to meter an inhalation drug product.
  3. The change is consistent with the posology and treatment duration.
Supporting Data
  1. (1.3) Product Monograph [e.g., Where applicable, Title Page, Storage and Stability (Part I), Dosage Forms, Composition and Packaging (Part I)] and Inner and Outer Labels.
  2. (P.2) Data demonstrating the suitability of the container closure system [e.g., extractable/leachable testing, permeation testing, light transmission]. For changes to functional packaging, data to demonstrate that the functioning of the new packaging is equivalent to that previously approved.
  3. (P.3.5) For sterile products, process validation and/or evaluation studies. Evidence of process validation for sterilization processes for the container/closure.
  4. (P.7) Information on the proposed container closure system [e.g., description, materials of construction of primary packaging components, specifications, including results of transportation studies, if appropriate].
  5. (P.8.1) Stability Summary and Conclusions, results of a minimum two (2) pilot scale, of three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing and, where applicable, results of photostability studies (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  6. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
35. Change in qualitative and/or quantitative composition of any primary or functional secondary container closure component
  • Conditions to be Fulfilled: 1-2
  • Supporting Data: 1-6
  • Reporting Category: Annual Notification
Conditions
  1. The proposed packaging is at least as protective as the approved packaging.
  2. The change does not impact the sterilization procedure of a sterile drug product.
Supporting Data
  1. (1.3) Product Monograph [e.g., Where applicable, Title Page, Storage and Stability (Part I), Dosage Forms, Composition and Packaging (Part I)] and Inner and Outer Labels.
  2. (P.2) Data demonstrating the suitability of the container closure system [e.g., extractable/leachable testing, permeation testing, light transmission]. For changes to functional packaging, data to demonstrate that the functioning of the new packaging is equivalent to that previously approved.
  3. (P.3.5) Where appropriate, process validation and/or evaluation studies.
  4. (P.7) Information on the proposed container closure system [e.g., description, materials of construction of primary packaging components, specifications, including results of transportation studies, if appropriate].
  5. (P.8.1) Stability Summary and Conclusions; results of a minimum of two (2) pilot scale batches, three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing and, where applicable, results of photostability studies. (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  6. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
36. Change in the specification for a primary or functional secondary container closure component where there is no other change in the container closure system
  • Conditions to be Fulfilled: None
  • Supporting Data: 1-2
  • Reporting Category: Annual Notification
Conditions

None

Supporting Data
  1. (P.7) Updated QC approved proposed specifications, including justification.
  2. (P.7) Description of the analytical procedure and, if applicable, validation data.
3.2.P.8 Stability
37. Change in the shelf life for the drug product, involving:
  1. extension
    • Conditions to be Fulfilled: 1-4
    • Supporting Data: 1-5
    • Reporting Category: Annual Notification
  2. reduction
    • Conditions to be Fulfilled: 1, 3, 5
    • Supporting Data: 1-6
    • Reporting Category: Annual Notification
Conditions
  1. No change to the container closure system in direct contact with the drug product or to the recommended storage conditions of the drug product.
  2. Where the approved shelf life is less than 24 months and data for potency, purity and performance for the proposed extension (not exceeding 24 months) does not exhibit significant trends for at least two (2) pilot scale batches. or where the approved shelf life is at least 24 months, full long term stability data is available covering the proposed shelf life and is based on stability data generated on at least three commercial scale batches.
  3. Stability data was generated in accordance with the approved stability protocol.
  4. Significant changes (as defined in ICH's Q1A guideline) were not observed in the stability data.
  5. The reduction in shelf life is due to stability concern and sponsor's assessment has determined that there in no impact on patient safety with the revised shelf life or the reduction in shelf life was not due to stability concern [e.g., business decision to streamline shelf in different regions].
Supporting Data
  1. (P.8.1) Summary of stability testing and results [e.g., studies conducted, protocols used, results obtained].
  2. (P.8.1) Proposed storage conditions and shelf life.
  3. (P.8.2) Updated post-approval stability protocol and stability commitment.
  4. (P.8.2) Justification of the change to the post-approval stability protocol or stability commitment.
  5. (P.8.3) Results of stability testing in fulfilment of the aforementioned condition 2 (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  6. Investigation report in fulfilment of condition #5.
38. Change in the labelled conditions for drug product, or reconstituted/diluted product involving: - storage conditions (relaxation/tightening of storage condition e.g., temperature) - cautionary statement (addition/deletion)
  1. for sterile products
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2
    • Reporting Category: Supplement
  2. for other products
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2
    • Reporting Category: Annual Notification
Conditions

None

Supporting Data
  1. (1.3) Product Monograph [e.g., Where applicable, Title Page, Composition and Packaging (Part I), and Pharmaceutical Information (Part II) section] and Inner and Outer Labels.
  2. (P.8.3) If applicable, stability and/or compatibility testing results to support the change to the storage conditions.
39. Change to the post-approval stability protocol or stability commitment.
  • Conditions to be Fulfilled: None
  • Supporting Data: 1-4
  • Reporting Category: Annual Notification
Conditions

None

Supporting Data
  1. (P.8.1) Proposed storage conditions and shelf life.
  2. (P.8.2) Updated QC approved post-approval stability protocol and stability commitment.
  3. (P.8.2) Justification of the change to the post-approval stability protocol or stability commitment.
  4. (P.8.3) If applicable, stability testing results to support the change to the post-approval stability protocol or stability commitment.

Appendix 2: Quality Post-NOC Changes (Veterinary Drugs)

The Veterinary Drugs Directorate Appendix 2 to the Post-Notice of Compliance (NOC) Changes Quality Guidance Document is intended to clarify the chemistry and manufacturing changes relevant to the approved veterinary drugs. This Appendix 2 was developed by Health Canada in consultation with their stakeholders.

The change examples presented below are intended to assist with the classification of changes made to the Quality information. The information summarized in the tables provides recommendations for:

  1. the conditions to be fulfilled for a given change to be classified as either a Level I, II, or III change. If the conditions outlined for a given change are not fulfilled, the change is automatically considered the next higher level of change. For example, if the conditions recommended for a Level II - Notifiable Change are not fulfilled, the change is considered a Level I - Supplement. Similarly, if the conditions recommended for a Level I - Supplement are not fulfilled, the change would warrant the filing of an NDS or an ANDS;
  2. the supporting data for a given change, either to be submitted to Health Canada and/or maintained by the sponsor. Where Master Production Documents are required, these documents should be available in an official language (English or French), or a translation from the original language.
  3. the reporting category [e.g., Supplement, Notifiable Change or Annual Notification].

Although the Common Technical Document (CTD) format is not applicable to veterinary drugs submissions, but for convenience, the change examples are organized according to the structure of the CTD.

Scope

The VDD Appendix 2 should facilitate sponsors' submissions with respect to the chemistry and manufacturing requirements of Division 8 of the Food and Drug Regulations.

The VDD Appendix 2 should neither be regarded as the only interpretation of the Guidance, nor can it cover every conceivable case for changes to veterinary drugs. Alternative means of complying with Appendix 2: Quality Post-NOC Changes (Veterinary Drugs) could be considered using appropriate scientific justification. When in doubt, sponsors are encouraged to contact the Veterinary Drugs Directorate (VDD) for further guidance.

Appendix 2: Quality Post-NOC Changes (Veterinary Drugs) supersede relevant sections of the Guidance for Industry: Preparation of Veterinary New Drugs Submissions.

Appendix 2: Quality Post-NOC Changes (Veterinary Drugs) is applicable to all veterinary drugs that have a Notice of Compliance (NOC). It is not applicable to veterinary biologics [e.g., biological vaccines] regulated by the Canadian Food Inspection Agency (CFIA). For veterinary biologics, please refer to applicable CFIA guidelines and policies.

When biotechnological tools [e.g., rDNA technology, gene targeting, DNA cloning] are used at any stage during synthesis of drug substance(s), or when biological processes [e.g., fermentation] are used during manufacturing of a veterinary drug product, the sponsor is encouraged to consult the VDD for specifics of conditions, data requirements and submission classifications. In these cases, the VDD will consult Appendix 3: Quality Post-NOC Changes (Biologics), pertaining to products regulated by the Biologics and Genetics Therapeutics Directorate (BGTD).

While ICH Q8, ICH Q9, and ICH Q10 apply to medicinal products for human use only, the related concepts are also expected to be useful in the context of veterinary drug products. It is therefore proposed that the design space concept is made applicable to both human and veterinary drugs and that sponsors of veterinary drugs submissions refer to these relevant ICH guidelines.

Certain post NOC Quality changes could result in the formation of new degredants (s) or detection of previously unknown degradant(s) that require identification and/or qualification. If a sponsor chooses to implement these Quality changes, and an initial assessment indicates that the change(s) may have an impact on the withdrawal period of a veterinary drug used in food producing animals, the VDD recommends that these changes be submitted as Supplements, with appropriate human safety data, regardless of the recommended reporting category for the change outlined in Appendix 2: Quality Post-NOC Changes (Veterinary Drugs). During the review of the Supplement submission, VDD will assess the impact of any change in the withdrawal period and human safety of the drug product.

A veterinary drug may have the identical composition, manufacturing processes, and analytical tests as a corresponding human drug product. If a Post-NOC Quality change has been submitted and approved for the human version of a veterinary drug product, the sponsor should submit, in addition to the requirements in the Guidance, a copy of the approval issued by the TPD or the BGTD and a certification that the animal and human drug products are identical except for the labelling, (i.e., "For Veterinary Use Only").

All Supplements to New Drug Submissions (SNDS) and Notifiable Changes (NC) should be submitted along with the VDD-CPID or an update of the existing VDD-CPID, to account for the proposed change(s) in chemistry and manufacturing information of the approved drug product. Sponsors are encouraged to submit the VDD-QOS document along with their Supplement and Notifiable Change submissions. If a Supplement or a Notifiable Change submission contains more than one change, the sponsor should demonstrate that the proposed changes are consequential and should describe the association between the proposed changes.

3.2.S Drug Substance

3.2.S.1 General Information
1. Change in the name of the drug substance
  • Conditions to be Fulfilled: 1
  • Supporting Data: 1-2
  • Reporting Category: Annual Notification
Conditions
  1. Confirmation that the information on the drug substance has not changed as a result of the change [e.g., cross reference(s) should be provided to the previously approved drug submission, including brand name of the drug product, manufacturer's/sponsor's name, submission type, control number, date approved].
Supporting Data
  1. Package Insert and Inner and Outer Labels.
  2. (S.1.1) Information on the proposed nomenclature of the drug substance [e.g., chemical name(s), compendial name] and evidence that the proposed name for the drug substance is recognized [e.g., Recommended INN, USAN, BAN].
3.2.S.2 Manufacture
2. Replacement or addition of a manufacturing site and/or manufacturer involving:
  1. production of the starting material, intermediate, or drug substance
    • Conditions to be Fulfilled:
      • None
      • 3,5
      • 1-5
    • Supporting Data:
      • 1-6,8-9
      • 2-6,8-9
      • 3-6,8
    • Reporting Category:
      • Supplement
      • Notifiable Change
      • Annual Notification
  2. testing [e.g., release, stability]
    • Conditions to be Fulfilled: 2-3,4-5
    • Supporting Data: 2-5,7
    • Reporting Category: Notifiable Change
3. deletion of a manufacturing site or manufacturer for the starting material, intermediate, or drug substance
  • Conditions to be Fulfilled: None
  • Supporting Data: None
  • Reporting Category: Annual Notification
Condition
  1. No Level I or Level II changes in the drug substance specifications.
  2. No change in the route of synthesis, physical characteristics, and impurity profile of the drug substance (i.e.no new impurity above 0.10%, no change in the approved total impurity limit and residual solvents within ICH or VICH limits).
  3. Where materials of human or animal origin are used in the process, the manufacturer does not use any new supplier for which assessment of viral safety data or TSE risk assessment is required.
  4. The change does not concern a sterile drug substance.
  5. The change concerns drug substances that are discrete chemical entities (i.e. this does not include polymeric complexes).
Supporting Data
  1. (1,5) Viral safety data (ref. Condition 3) or supporting or comparative bioavailability data (ref. Condition 5) (whichever is applicable).
  2. (1.2.5) For sterile manufacturing, evidence of GMP and/or EL information [e.g. Confirmation of a satisfactory GMP rating by the Inspectorate], and process validation and/or evaluation studies for sterilization.
  3. (S) Updated or new DMF (with a Letter of Access), any relevant drug substance information should be provided where available.
  4. (S.2) Confirmation that the synthetic route, process controls, control of materials, and specifications of the intermediate or drug substance (as appropriate) in the manufacturing process of the proposed drug substance are the same as those previously approved or revised information if any of the attributes have changed.
  5. (S.2.1) Name, address, and responsibility of the proposed production site or facility involved in manufacturing and testing.
  6. (S.2.3) For drug substances or drug substances manufactured with reagents obtained from sources that are at risk of transmitting BSE/TSE agents [e.g., ruminant origin], information and evidence that the material does not pose a potential BSE/TSE risk [e.g., name of manufacturer, species and tissues from which the material is a derivative, country of origin of the source animals, its use and previous acceptance] should be provided where available.
  7. (S.4.3) Copies or summaries of validation reports, which demonstrate equivalency of analytical procedures to be used at the proposed testing site.
  8. (S.4.4) Description of the batches, certificates of analyses or batch analysis report, and summary of results, in a comparative tabular format, for one batch of the currently approved and proposed drug substance release testing sites.
  9. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of the drug product manufactured using the proposed drug substance into the long term stability programme (bracketing and matrixing with justification would be acceptable for multiple strength products).
4. Change in the manufacturing process for the drug substance or intermediate
  • Conditions to be Fulfilled:
    • 1
    • 1-4,8
    • 1-8
  • Supporting Data:
    • 1-11
    • 2-9,11
    • 2-6,8-9,11
  • Reporting Category:
    • Supplement
    • Notifiable Change
    • Annual Notification
Conditions
  1. No change in the identicality of the drug substance (as defined in the Health Canada policy Interpretation of "Identical Medicinal Ingredient").
  2. No change in the physical state [e.g. crystalline, amorphous, solid, semi-solid, liquid or gas] of the drug substance.
  3. For low solubility drug substances, no change in the polymorphic form or no change in the particle size distribution of the drug substance
  4. Where materials of human or animal origin are used in the process, the manufacturer does not use any new process for which assessment of viral safety data or TSE risk assessment is required.
  5. No Level I or Level II change in the drug substance specifications.
  6. No change in the route of synthesis (i.e. intermediates remain the same), physical characteristics, and impurity profile of the drug substance (no new impurity above 0.10%, no change in the approved total impurity limit and residual solvents within ICH limits).
  7. The change does not concern a sterile drug substance.
  8. The change concerns drug substances that are discrete chemical entities (i.e. this does not include polymeric complexes).
Supporting Data
  1. (1,5) Viral safety data (ref. Condition 4) or supporting clinical or comparative bioavailability data (ref. Conditions 3,8) (whichever is applicable).
  2. (S) Updated or new DMF (with a Letter of Access) or relevant drug substance information.
  3. (S.2.2) Flow diagram of the proposed synthetic process(es) and a brief narrative description of the proposed manufacturing process(es).
  4. (S.2.3) Information on the quality and controls of the materials [e.g., raw materials, starting materials, solvents, reagents, catalysts] used in the manufacture of the proposed drug substance.
  5. (S.2.3) For drug substances or drug substances manufactured with reagents obtained from sources that are at risk of transmitting BSE/TSE agents [e.g., ruminant origin], information and evidence that the material does not pose a potential BSE/TSE risk [e.g., name of manufacturer, species and tissues from which the material is a derivative, country of origin of the source animals, its use and previous acceptance] should be provided where available.
  6. (S.2.4) Information on the controls performed at critical steps of the manufacturing process and on intermediates of the proposed drug substance.
  7. (S.2.5) Evidence of process validation and/or evaluation studies for sterilization.
  8. (S.3.1) Evidence for elucidation of structure, where applicable.
  9. (S.4.4) Description of the batches, certificates of analyses or batch analysis report, and summary of results, in a comparative tabular format, for at least one (1) batch of the currently approved and proposed processes.
  10. (S.7.3) Results of two (2) batches with a minimum of three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing of the proposed drug substance.
  11. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of the drug product, manufactured using the proposed drug substance, into the long term stability programme.
5. Change in the batch size for the drug substance
  • Conditions to be Fulfilled:
    • None
    • 1-8
  • Supporting Data:
    • 1-3
    • 1-3
  • Reporting Category:
    • Notifiable Change
    • Annual Notification
Conditions
  1. No change in the proportionality of the raw materials.
  2. Changes to the method of manufacture are only those necessitated by change in batch size [e.g., use of different-sized equipment].
  3. The change is not necessitated by unexpected events, resulting in failure to meet specifications, arising during manufacture or because of stability concerns.
  4. No Level I or Level II changes in the drug substance specifications.
  5. Up to 10-fold scale-up or scale-down compared to approved batch size.
  6. The change does not affect the sterilization procedures of a sterile drug substance.
  7. The change concerns drug substances that are discrete chemical entities (i.e. this does not include polymeric complexes).
  8. The change does not concern a sterile drug substance.
Supporting Data
  1. (S.2.2) A brief narrative description of the proposed manufacturing process(es).
  2. (S.2.5) Evidence of process validation and/or evaluation studies for sterilization.
  3. (S.4.4) Description of the batches, certificates of analyses or batch analysis report, and summary of results, in a tabular format, for at least one batch.
6. Change in the controls for the materials used in the manufacture of the drug substance [e.g., raw materials, starting materials, solvents, reagents, catalysts] or the controls performed at critical steps in the process
  • Conditions to be Fulfilled:
    • None
    • 1-5
  • Supporting Data:
    • 1 or 2-4
    • 1 or 2,4
  • Reporting Category:
    • Notifiable Change
    • Annual Notification
Conditions
  1. No Level I or Level II change in the drug substance specifications.
  2. No change in the impurity profile of the drug substance (i.e. no new impurity above 0.1%, no change in the approved total impurity limit and residual solvents within ICH or VICH limits).
  3. The change in control(s) does not constitute a relaxation from the approved controls and is not necessitated by unexpected events, resulting in failure to meet specifications, arising during manufacture or because of stability concerns.
  4. The change does not affect the sterilization procedures of a sterile drug substance.
  5. The change concerns drug substances that are discrete chemical entities (i.e. this does not include polymeric complexes).
Supporting Data
  1. (S.2.3) Information on the quality and controls of the materials [e.g., raw materials, starting materials, solvents, reagents, catalysts] used in the manufacture of the proposed drug substance.
  2. (S.2.4) Information on the controls performed at critical steps of the manufacturing process and on intermediates of the proposed drug substance.
  3. (S.2.5) Evidence of process validation and/or evaluation studies for sterilization.
  4. (S.4.4) Description of the batches, certificates of analyses or batch analysis report, and summary of results, in a comparative tabular format, for at least one batch each of the drug substance manufactured by the current and proposed methods.
3.2.S.3 Characterisation

There are not any quality change examples for this section at the present time that have not been addressed in other sections.

3.2.S.4 Control of the Drug Substance
7. Change in the standard claimed for the drug substance [e.g., from a Professed to Schedule B pharmacopoeial standard or from one Schedule B standard to a different Schedule B standard].
  • Conditions to be Fulfilled: 1-3
  • Supporting Data: 1-4
  • Reporting Category: Annual Notification
8. Change in the specification for the drug substance to comply with an updated Schedule B pharmacopoeial monograph
  • Conditions to be Fulfilled: 1-2
  • Supporting Data: 1-4
  • Reporting Category: Annual Notification
Conditions
  1. The change is made exclusively to comply with the pharmacopoeia.
  2. No Level I or Level II changes to the specifications (i.e., functional properties of the drug substance e.g., particle size distribution, polymorphic form).
  3. No deletion of or relaxation to any of the tests, analytical procedures, or acceptance criteria of the approved specification.
Supporting Data
  1. (S.4.1) Updated, QC approved, proposed drug substance specification.
  2. (S.4.3) Where a House analytical procedure is used and a Schedule B standard is claimed, results of an equivalency study between the House and compendial methods.
  3. (S.4.4) Description of the batches, certificates of analyses or batch analysis report, and summary of results, in a tabular format, for at least one batch if new tests and/or analytical methods are implemented.
  4. (S.4.5) Justification of the proposed drug substance specification [e.g., demonstration of the suitability of the monograph to control the drug substance, including impurities].
9. Change in the specification for the drug substance involving test and acceptance criteria:
  1. for sterile drug substances, replacing the sterility test with process parametric release
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-8
    • Reporting Category: Supplement
  2. deletion of a test
    • Conditions to be Fulfilled:
      • None
      • 1-2,5
    • Supporting Data:
      • 2,7-8
      • 2,7-8
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  3. replacement of a test
    • Conditions to be Fulfilled: 1-7
    • Supporting Data: 2-5,7-8
    • Reporting Category: Annual Notification
  4. addition of a test
    • Conditions to be Fulfilled: 1,3-4,6-7
    • Supporting Data: 2-5,7-8
    • Reporting Category: Annual Notification
  5. relaxation of an acceptance criterion
    • Conditions to be Fulfilled:
      • None
      • 1,4,6-7
    • Supporting Data:
      • 2,7-8
      • 2,7-8
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  6. tightening of an acceptance criterion
    • Conditions to be Fulfilled: 1-2,4,6-7
    • Supporting Data: 2,7-8
    • Reporting Category: Annual Notification
Conditions
  1. The change is not necessitated by unexpected events, resulting in failure to meet specifications, arising during manufacture or because of stability concerns.
  2. The change is within the range of approved acceptance criteria.
  3. Any new analytical procedure does not concern a novel, non-standard technique or a standard technique used in a novel way.
  4. No change in the impurity profile that impacts safety of the drug substance. Acceptance criterion for any Class 3 residual solvent is within the VICH limits (the relaxation of an acceptance criterion for a Class 1 or 2 solvent should be filed as a Notifiable Change).
  5. The deleted test has been demonstrated to be redundant with respect to the remaining tests.
  6. The change does not concern sterility testing.
  7. The change concerns drug substances that are discrete chemical entities (i.e. this does not include polymeric complexes).
Supporting Data
  1. (S.2.5) QC approved Process validation and/or evaluation studies or the proposed validation protocol of the proposed drug substance.
  2. (S.4.1) Updated, QC approved, proposed drug substance specification.
  3. (S.4.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  4. (S.4.3) Copies or summaries of validation reports, if new analytical procedures are used.
  5. (S.4.3) Where a House analytical procedure is used and a Schedule B standard is claimed, results of an equivalency study between the House and compendial methods.
  6. (S.4.4) Description of the batches, certificates of analyses, or batch analysis report and summary of results, of a sufficient number of batches (minimum of ten batches) to support the process parametric release.
  7. (S.4.5) Justification of the proposed drug substance specification [e.g., test parameters, acceptance criteria, or analytical procedures].
  8. (P.2) Where appropriate [e.g., for a change in particle size limit for a poorly soluble drug substance], comparative, multi-point dissolution profiles in the release medium for one batch of the drug product using material from the approved and change drug substance specifications.
10. Change in the specification for the drug substance involving analytical procedures:
  1. deletion of an analytical procedure
    • Conditions to be Fulfilled:
      • None
      • 5
    • Supporting Data:
      • 1
      • 1
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. replacement of, alternate, or additional analytical procedure
    • Conditions to be Fulfilled:
      • None
      • 1-4
    • Supporting Data:
      • 1-4
      • 1-4
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  3. change from a House analytical procedure to a Schedule B analytical procedure or a change from an approved compendial analytical procedure to an harmonized compendial procedure
    • Conditions to be Fulfilled: None
    • Supporting Data: 1,3-4
    • Reporting Category: Annual Notification
Conditions
  1. The method of analysis is based on the same analytical technique or principal and no new impurities are detected.
  2. Results of method validation demonstrate that the proposed analytical procedure is at least equivalent to the approved analytical procedure.
  3. Any new analytical procedure does not concern a novel, non-standard technique or a standard technique used in a novel way.
  4. The change does not concern sterility testing.
  5. The deleted analytical procedure is an alternate and equivalent method.
Supporting Data
  1. (S.4.1) Updated,QC approved, proposed drug substance specification.
  2. (S.4.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  3. (S.4.3) Copies or summaries of validation reports, if new analytical procedures are used.
  4. (S.4.3) Comparative analytical results demonstrating that the approved and proposed analytical procedures are equivalent.
3.2.S.6 Container Closure System
11. Change in the primary container closure system(s) for the storage and shipment of the drug substance
  • Conditions to be Fulfilled:
    • None
    • 1-2
  • Supporting Data:
    • 1-3
    • 2
  • Reporting Category:
    • Notifiable Change
    • Annual Notification
Conditions
  1. Results demonstrate that the proposed container closure system is at least equivalent to the approved container closure with respect to its relevant properties [e.g., including results of transportation or interaction studies, if appropriate].
  2. The change does not concern a sterile drug substance.
Supporting Data
  1. (S.2.5) Evidence of process validation and/or evaluation studies for sterilization if different from the current process.
  2. (S.6) Information on the proposed container closure system [e.g., description, specifications].
  3. (S.7.3) Results of a minimum of three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing of the drug substance in the proposed container closure system.
3.2.S.7 Stability
12. Change in the re-test period (or shelf life) for the drug substance, involving:
  1. Extension
    • Conditions to be Fulfilled:
      • None
      • 1-2,4-7
    • Supporting Data:
      • 1-4
      • 1-4
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. Reduction
    • Conditions to be Fulfilled:
      • None
      • 1,3,5
    • Supporting Data:
      • 1-4
      • 1-4
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
Conditions
  1. No change to the container closure system in direct contact with the drug substance or to the recommended storage conditions of the drug substance.
  2. The approved re-test period (or shelf life) is at least 24 months.
  3. Full long term stability data is available covering the proposed re-test period (or shelf life) and is based on stability data generated on at least three commercial scale batches.
  4. Full long term stability data is available covering the proposed re-test period (or shelf life) or is based on stability data generated on at least three commercial scale batches. If the proposed re-test period (or shelf life) is beyond the available long term data, the extrapolation is in accordance with VICH GL 3 guidelines.
  5. Stability data was generated in accordance with the approved stability protocol.
  6. Significant changes as defined in VICH GL3 guidelines were not observed in the stability data.
  7. The drug substance has not been subject to a previous reduction in re-test period (or shelf life).
Supporting Data
  1. (S.7.1) Summary of stability testing and results [e.g., studies conducted, protocols used, results obtained].
  2. (S.7.1) Proposed storage conditions and re-test period (or shelf life, as appropriate).
  3. (S.7.2) Updated post-approval stability protocol and stability commitment.
  4. (S.7.3) Results of stability testing generated on at least two pilot and/or commercial scale batches with stability data to support the proposed re-test period or shelf life.
13. Change in the labelled storage conditions for the drug substance, involving: addition/deletion of a cautionary statement or relaxation/tightening of a temperature criterion (eg. from 15-25 °C to 15-30 °C)
  • Conditions to be Fulfilled: None
  • Supporting Data: 1
  • Reporting Category: Annual Notification
Conditions

None

Supporting Data
  1. (S.7.3) If applicable, stability testing results to support the change to the storage conditions on not less than two (2) lots (pilot or commercial scale).
14. Change to the post-approval stability protocol or stability commitment
  • Conditions to be Fulfilled: None
  • Supporting Data: 1-2
  • Reporting Category: Annual Notification
Conditions

None

Supporting Data
  1. (S.7.2) QC approved updated post-approval stability protocol and stability commitment.
  2. (S.7.2) Justification of the change to the post-approval stability protocol or stability commitment.

3.2.P Drug Product

3.2.P.1 Description and Composition of the Drug Product
15. Addition of a dosage form or strength
  • Conditions to be Fulfilled: None
  • Supporting Data: 1-14
  • Reporting Category: Supplement
Conditions

None

Supporting Data
  1. (1,5) Supporting clinical or comparative bioavailability data, in vitro in vivo correlation (IVIVC) data or a request for a waiver of in vivo studies, e.g.,:
    • when the changes in excipients for a new strength of an immediate release solid oral dosage form containing a single drug substance, expressed as percentage (w/w) of total formulation, are greater than the ranges outlined in Appendix 6.
    • when the changes in excipients for new strength of an immediate release solid oral dosage form containing a single drug substance, expressed as percentage (w/w) of total formulation, are less than or equal to the ranges outlined in Appendix 6.
  2. (1.2.5) GMP and Establishment License (EL) Information [e.g. Confirmation of a satisfactory GMP rating by the Inspectorate].
  3. (1.2.6) Letters of Access if Drug Master Files (DMFs), are submitted for new excipients.
  4. Package Insert and Inner and Outer Labels.
  5. (S) Confirmation that the information on the drug substance has not changed [e.g., cross reference(s) should be provided to the previously approved drug submission, including brand name of the drug product, manufacturer's/sponsor's name, submission type, control number, date approved].
  6. (P.1) Description and composition of the dosage form.
  7. (P.2) Discussion of the components of the drug product [e.g., choice of excipients, compatibility of drug substance and excipients], comparative in vitro testing [e.g., multi-point dissolution profiles in the release medium for solid dosage units] for the approved and proposed products, discussion of any in vitro and/or in vivo studies.
  8. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates, Process Validation and/or Evaluation or Process Validation Protocol.
  9. (P.4) Control of Excipients, if new excipients are proposed [e.g., specifications, confirmation that none of the excipients are prohibited by the Food and Drug Regulations].
  10. (P.5) Specification(s), Analytical Procedures (if new analytical methods are used), Validation of Analytical Procedures (if new analytical methods are used), Batch Analyses (certificate of analyses for a minimum of one (1) pilot scale batch per strength).
  11. (P.7) Discussion (including description, materials of construction, summary of specifications) on the container closure system, if any of the components have changed.
  12. (P.8.1) Stability Summary and Conclusions (minimum of two pilot scale batches), e.g.,:
    • for a new dosage form: results of a minimum of six (6) months of accelerated (or intermediate as appropriate) and six (6) months of long term testing of the proposed drug product;
    • for a new strength when the changes in excipients for an immediate release solid oral dosage form are greater than the ranges outlined in Appendix 6: results of a minimum of three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing of the proposed drug product;
    • for a new strength when the changes in excipients for an immediate release solid oral dosage form are less than or equal to the ranges outlined in Appendix 6: stability data at the time of filing would not be necessary (see P.8.2 below).
  13. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  14. (R.1) Executed Production Documents for one batch of each new dosage form or strength.
16. Change in the composition of a solution dosage form
  • Conditions to be Fulfilled:
    • None
    • 1-4,8
    • 1-8
  • Supporting Data:
    • 1-12
    • 2-12
    • 2-12
  • Reporting Category:
    • Supplement
    • Notifiable Change
    • Annual Notification
Conditions
  1. The changes in excipients of the approved and proposed drug products are considered to be qualitatively the same and quantitatively essentially the same (as defined in the Health Canada guidance document Pharmaceutical Quality of Aqueous Solutions).
  2. The proposed excipient(s) does/do not function to affect the absorption of the drug substance.
  3. The proposed excipient(s) does/do not function to affect the solubility of the drug substance.
  4. The proposed excipient(s) does/do not function as a preservative or preservative enhancer.
  5. No change in the specifications of the proposed excipient(s) or the drug product.
  6. No change to the physical characteristics of the drug product [e.g., viscosity, pH, osmolality].
  7. The change does not concern a sterile drug product.
  8. The change concerns a drug product that contains drug substances that are discrete chemical entities (i.e. this does not include polymeric complexes).
Supporting Data
  1. (1,5) Supporting clinical or comparative bioavailability data or a request for a waiver of in vivo studies, e.g.,:
    • when the changes in excipients are not considered to be qualitatively the same and quantitatively essentially the same: supporting clinical or comparative bioavailability data and in vitro data on the physicochemical properties;
    • when the changes in excipients are considered to be qualitatively the same and quantitatively essentially the same: supporting in vitro data on the physicochemical properties.
  2. (1.2.6) Letters of Access if Drug Master Files (DMFs)), are submitted for new excipients.
  3. Package Insert and Inner and Outer Labels.
  4. (S) Confirmation that the information on the drug substance has not changed [e.g., cross reference(s) should be provided to the previously approved drug submission, including brand name of the drug product, manufacturer's/sponsor's name, submission type, control number, date approved]
  5. (P.1) Description and composition of the dosage form.
  6. (P.2) Discussion of the components of the drug product [e.g., choice of excipients, compatibility of drug substance and excipients], comparative in vitro testing on the physicochemical properties for the approved and proposed products, discussion of any in vitro and/or in vivo studies, results of preservative effectiveness testing (if applicable).
  7. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates, Process Validation and/or Evaluation.
  8. (P.4) Control of Excipients, if new excipients are proposed [e.g., specifications, confirmation that none of the excipients are prohibited by the Food and Drug Regulations].
  9. (P.5) Batch Analyses (certificate of analyses for a minimum of one pilot scale batch per strength).
  10. (P.8.1) Stability Summary and Conclusions (minimum of two pilot scale batches), e.g.,:
    • when the changes in excipients are not considered to be qualitatively the same and quantitatively essentially the same: results of a minimum of three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing of the proposed drug product;
    • when the changes in excipients are considered to be qualitatively the same and quantitatively essentially the same: stability data at the time of filing would not be necessary (see P.8.2 below).
  11. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  12. (R.1) Executed Production Documents for one batch representative of each strength of the proposed product.
17. Change in the composition of an immediate release solid oral dosage form (other than colours, flavours)
  • Conditions to be Fulfilled:
    • None
    • 1-4,7
    • 1-7
  • Supporting Data:
    • 1-12
    • 2-12
    • 2-12
  • Reporting Category:
    • Supplement
    • Notifiable Change
    • Annual Notification
Conditions
  1. Any qualitative change in the composition does not require supporting in vivo data.
  2. The quantitative changes in excipients, expressed as percentage (w/w) of total formulation, are less than or equal to the ranges outlined in Appendix 6.
  3. The proposed excipient(s) does/do not function to affect the absorption of the drug substance.
  4. The proposed excipient(s) does/do not function to affect the solubility of the drug substance.
  5. The proposed excipient(s) does/do not function as a preservative or preservative enhancer.
  6. No Level I or Level II change in the specifications of the proposed excipient(s) or the drug product.
  7. The change concerns a drug product that contains drug substances that are discrete chemical entities (i.e. this does not include polymeric complexes).
Supporting Data
  1. (1,5) Supporting clinical or comparative bioavailability data or a request for a waiver of in vivo studies, e.g.,:
    • when the changes in excipients, expressed as percentage (w/w) of total formulation, are greater than the ranges outlined in Appendix 6: supporting clinical or comparative bioavailability data and in vitro data;
    • when the changes in excipients, expressed as percentage (w/w) of total formulation, are less than or equal to the ranges outlined in Appendix 6: supporting in vitro data.
  2. (1.2.6) Letters of Access if Drug Master Files (DMFs) are submitted for new excipients.
  3. Package Insert and Inner and Outer Labels.
  4. (S) Confirmation that the information on the drug substance has not changed [e.g., cross reference(s) should be provided to the previously approved drug submission, including brand name of the drug product, manufacturer's/sponsor's name, submission type, control number, date approved]
  5. (P.1) Description and composition of the dosage form.
  6. (P.2) Discussion of the components of the drug product [e.g., choice of excipients, compatibility of drug substance and excipients], comparative in vitro testing [e.g., depending on the solubility and permeability of the drug (refer to Appendix 5), multi-point dissolution profiles in either the release medium or in multiple media covering the physiological pH range] for the approved and proposed products, discussion of any in vitro and/or in vivo studies, results of preservative effectiveness testing (if applicable).
  7. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates, Process Validation and/or Evaluation.
  8. (P.4) Control of Excipients, if new excipients are proposed [e.g., specifications, confirmation that none of the excipients are prohibited by the Food and Drug Regulations].
  9. (P.5) Batch Analyses (certificate of analyses for a minimum of one pilot scale batch per strength).
  10. (P.8.1) Stability Summary and Conclusions (minimum of two pilot scale batches) e.g.,:
    • when the changes in excipients are greater than the ranges outlined in Appendix 6: results of a minimum of three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing of the proposed drug product;
    • when the changes in excipients are less than or equal to the ranges outlined in Appendix 6: stability data at the time of filing would not be necessary (see P.8.2 below).
  11. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  12. (R.1) Executed Production Documents for one batch representative of each strength of the proposed product.
18. Change in the composition (qualitative or quantitative) in the release controlling agent of a modified release solid oral dosage form (for changes in other excipients, refer to change example #17, Change in the composition of an immediate release solid oral dosage form)
  • Conditions to be Fulfilled:
    • None
    • 1
  • Supporting Data:
    • 1-12
    • 1-12
  • Reporting Category:
    • Supplement
    • Notifiable Change
Conditions
  1. The change is within parameters established by an in vitro in vivo correlation previously approved by Health Canada.
Supporting Data
  1. (1,5) Supporting clinical or comparative bioavailability data (the supporting clinical or comparative bioavailability data may be waived if an acceptable in vitro in vivo correlation has been established).
  2. (1.2.6) Letters of Access if Drug Master Files (DMFs) are submitted for new excipients.
  3. Package Insert and Inner and Outer Labels.
  4. (S) Confirmation that the information on the drug substance has not changed [e.g., cross reference(s) should be provided to the previously approved drug submission, including brand name of the drug product, manufacturer's/sponsor's name, submission type, control number, date approved]
  5. (P.1) Description and composition of the dosage form.
  6. (P.2) Discussion of the components of the drug product [e.g., choice of excipients, compatibility of drug substance and excipients], comparative in vitro testing [e.g., depending on the mechanism for drug release (extended or delayed), drug release profiles in multi media or using different agitation speeds] for the approved and proposed products, discussion of any in vitro and/or in vivo studies, results of preservative effectiveness testing (if applicable).
  7. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates, Process Validation and/or Evaluation.
  8. (P.4) Control of Excipients, if new excipients are proposed [e.g., specifications, confirmation that none of the excipients are prohibited by the Food and Drug Regulations].
  9. (P.5) Batch Analyses (certificate of analyses for a minimum of one pilot scale batch per strength).
  10. (P.8.1) Stability Summary and Conclusions (minimum of two pilot scale batches), e.g.,:
    • results of a minimum of three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing of the proposed drug product;
  11. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  12. (R.1) Executed Production Documents for one batch of each strength.
19. Change of a colour or flavour, involving: (for changes to the specifications other than under Condition 3, refer to change examples #38 and #39, Change in the specification for the drug product ...)
  1. qualitative or quantitative addition, deletion or replacement of a colour or flavour
    • Conditions to be Fulfilled: 2-3
    • Supporting Data: 1-10
    • Reporting Category: Notifiable Change
  2. qualitative or quantitative addition, deletion or replacement of a colour or flavour
    • Conditions to be Fulfilled: 1-3
    • Supporting Data: 1-10
    • Reporting Category: Annual Notification
Conditions
  1. The change does not affect the stability of the drug product.
  2. The change does not affect performance characteristics of the drug product [e.g. release rate]
  3. Changes to the drug product specifications are those necessitated only by the change to the colour or flavour.
Supporting Data
  1. (1.2.6) Letters of Access if Drug Master Files (DMFs) are submitted for new excipients.
  2. Package Insert and Inner and Outer Labels.
  3. (P.1) Description and composition of the dosage form [e.g., list of all components of the dosage form, composition of all components that are mixtures]
  4. (P.2) Discussion of the components of the drug product [e.g., choice of excipients, compatibility of drug substance and excipients].
  5. (P.3) Batch Formula.
  6. (P.4) Control of Excipients, if new excipients are proposed [e.g., specifications, confirmation that none of the excipients are prohibited by the Food and Drug Regulations].
  7. (P.5) Batch Analyses (certificate of analyses for a minimum of one pilot scale batch per strength).
  8. (P.8.1) Stability Summary and Conclusions (minimum of two pilot scale batches), e.g.,:
    • results of a minimum of three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing of the proposed drug product;
    • photostability data (where relevant).
  9. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  10. (R.1) Executed Production Documents for one batch representative of each strength of the proposed product.
20. Qualitative change of a non-functional film coating, involving: (for changes to the specifications other than under Condition 2, refer to change examples #38 and #39, Change in the specification for the drug product ...)
  1. Addition or replacement of a non-functional film coating, except colour
    • Conditions to be Fulfilled: 1-2
    • Supporting Data: 1-10
    • Reporting Category: Notifiable Change
  2. deletion of a non-functional film coating, except colour
    • Conditions to be Fulfilled: 1-2
    • Supporting Data: 2-3,5,7-10
    • Reporting Category: Notifiable Change
Conditions
  1. The change does not affect the performance characteristics [e.g., release rate] of the drug product.
  2. Changes to the drug product specifications are those necessitated only by the change to the coating.
Supporting Data
  1. (1.2.6) Letters of Access if Drug Master Files (DMFs) are submitted for new excipients.
  2. Package Insert and Inner and Outer Labels.
  3. (P.1) Description and composition of the dosage form [e.g., list of all components of the dosage form, composition of all components that are mixtures]
  4. (P.2) Discussion of the components of the drug product [e.g., choice of excipients, compatibility of drug substance and excipients], comparative, multi-point dissolution profiles for the approved and proposed products performed using the release conditions.
  5. (P.3) Batch Formula, Process Validation and/or Evaluation [e.g., updated QC approved Process Validation Protocol for a change from an uncoated to a coated tablet].
  6. (P.4) Control of Excipients, if new excipients are proposed [e.g., specifications, confirmation that none of the excipients are prohibited by the Food and Drug Regulations].
  7. (P.5) Batch Analyses (certificate of analyses for a minimum of one pilot scale batch per strength).
  8. (P.8.1) Stability Summary and Conclusions, (minimum of two pilot scale batches), e.g.,:
    • results of a minimum of three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing of the proposed drug product;
    • photostability data (where relevant).
  9. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  10. (R.1) Executed Production Documents for one batch representative of each strength of the proposed product.
21. Qualitative change of a functional film coating, involving: (for changes to the specifications other than under Condition 2, refer to change examples #38 and #39, Change in the specification for the drug product ...)
  1. Addition or replacement of a functional film coating, except colour
    • Conditions to be Fulfilled:
      • None
      • 1-2
    • Supporting Data:
      • 1-12
      • 2-12
    • Reporting Category:
      • Supplement
      • Notifiable Change
  2. deletion of a functional film coating, except colour
    • Conditions to be Fulfilled: None
    • Supporting Data: 1,3-4,6,8-12
    • Reporting Category: Supplement
Conditions
  1. The change does not affect performance characteristics of the drug product [e.g. release rate]
  2. Changes to the drug product specifications are those necessitated only by the change to the coating.
Supporting Data
  1. (1,5) Supporting clinical or comparative bioavailability data (the supporting clinical or comparative bioavailability data may be waived if an acceptable in vitro in vivo correlation has been established)
  2. (1.2.6) Letters of Access if Drug Master Files (DMFs) are submitted for new excipients.
  3. Package Insert and Inner and Outer Labels.
  4. (P.1) Description and composition of the dosage form [e.g., list of all components of the dosage form, composition of all components that are mixtures]
  5. (P.2) Discussion of the components of the drug product [e.g., choice of excipients, compatibility of drug substance and excipients, comparative, multi-point dissolution profiles for the approved and proposed products performed using the release conditions].
  6. (P.3) Batch Formula, Process Validation and/or Evaluation [e.g., updated QC approved Process Validation Protocol for a change from an uncoated to a coated tablet].
  7. (P.4) Control of Excipients, if new excipients are proposed [e.g., specifications, confirmation that none of the excipients are prohibited by the Food and Drug Regulations].
  8. (P.5) Batch Analyses (certificate of analyses for a minimum of one pilot scale batch per strength).
  9. (P.8.1) Stability Summary and Conclusions, (minimum of two (2) pilot scale batches), e.g.,:
    • results of a minimum of three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing of the proposed drug product;
    • photostability data (where relevant).
  10. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  11. (P.8.3) If applicable, stability testing results to support the change to the functional film coating.
  12. (R.1) Executed Production Documents for one batch of each strength.
22. Change to product markings, involving a change in embossing, debossing, or engraving (except scorelines/break lines) [e.g., plain tablet to engraved, engraved to plain, change in engraving] or a change in imprinting [e.g., plain tablet/capsule to imprinted tablet/capsule] (for changes to the specifications other than under Condition 2, refer to change examples #38 and #39, Change in the specification for the drug product ...)
  • Conditions to be Fulfilled: 1-2
  • Supporting Data: 1-3
  • Reporting Category: Annual Notification
Conditions
  1. The change does not affect the stability or performance characteristics [e.g., release rate] of the drug product.
  2. Changes to the drug product specifications are those necessitated only by the change to the markings.
Supporting Data
  1. Package Insert and Inner and Outer Labels.
  2. (P.5) Specification(s).
  3. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
23. Change in scoring configuration, involving: (for changes to the specifications other than under Condition 2, refer to change examples #38 and #39, Change in the specification for the drug product ...)
  1. addition of a scoreline
    • Conditions to be Fulfilled: 1-2,4
    • Supporting Data: 1-6
    • Reporting Category: Notifiable Change
  2. deletion of a scoreline
    • Conditions to be Fulfilled: 1-3
    • Supporting Data: 1,4-6
    • Reporting Category: Annual Notification
Conditions
  1. The change does not affect the stability or performance characteristics [e.g., release rate] of the drug product.
  2. Changes to the drug product specifications are those necessitated only by the change to the scoring.
  3. The change does not concern a modified release drug product.
  4. Addition of a score line to a generic product is consistent with a similar score line in the innovator product (Canadian Reference Product).
Supporting Data
  1. Package Insert and Inner and Outer Labels.
  2. (P.2) Comparative, multi-point dissolution profiles for the approved and proposed products performed using the release conditions.
  3. (P.2) Demonstration of the uniformity of the dosage units of the split tablets.
  4. (P.5) Specification(s).
  5. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  6. (R.1) Executed Production Documents for one batch representative of each strength of the proposed product.
24. Change in shape or dimensions of tablets, capsules, suppositories, or pessaries
  • Conditions to be Fulfilled:
    • 1-2
    • 1-3
  • Supporting Data:
    • 1-6
    • 1-6
  • Reporting Category:
    • Notifiable Change
    • Annual Notification
Conditions
  1. No change in the qualitative and quantitative composition and mean mass or fill weight.
  2. Changes to the drug product specifications are those necessitated by the change to the drug product shape or dimensions.
  3. The change does not concern a modified release drug product.
Supporting Data
  1. Package Insert and Inner and Outer Labels.
  2. (P.2) Discussion of the differences in manufacturing process(es) between the approved and proposed products and the potential impact on product performance
  3. (P.2) Comparative, multi-point dissolution profiles for the approved and proposed products performed using the release conditions.
  4. (P.5) Specification(s).
  5. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  6. (R.1) Executed Production Documents for one batch representative of each strength of the proposed product.
25. Change in diluent, involving:
  1. replacement or addition of a diluent for a lyophilized powder or concentrated solution
    • Conditions to be Fulfilled:
      • None
      • 1
    • Supporting Data:
      • 1-12
      • 2-3,5,9
    • Reporting Category:
      • Notifiable Change
      • Notifiable Change
  2. deletion of a diluent
    • Conditions to be Fulfilled: None
    • Supporting Data: 2
    • Reporting Category: Annual Notification
Conditions
  1. Diluent is commercially available with a valid Drug Identification Number (DIN).
Supporting Data
  1. (1.2.6) Letters of Access if Drug Master Files (DMFs) are submitted for new excipients.
  2. Package Insert and Inner and Outer Labels.
  3. (S) Confirmation that the information on the drug substance has not changed [e.g., cross reference(s) should be provided to the previously approved drug submission, including brand name of the drug product, manufacturer's/sponsor's name, submission type, control number, date approved]
  4. (P.1) Description and composition of the diluent.
  5. (P.2) Discussion of the components of the drug product, as appropriate [e.g., choice of excipients, compatibility of the drug product with the diluent].
  6. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates, Process Validation and/or Evaluation.
  7. (P.4) Control of Excipients, if new excipients are proposed [e.g., specifications, confirmation that none of the excipients are prohibited by the Food and Drug Regulations].
  8. (P.5) Batch Analyses (certificate of analyses for a minimum of one pilot scale batch per strength).
  9. (P.7) Discussion (including description, materials of construction on the container closure system, compatibility studies).
  10. (P.8.1) Stability Summary and Conclusions: results for two pilot scale batches of a minimum of three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing of the proposed product.
  11. (P.8.2) Updated post-approval stability protocol and stability commitment.
  12. (R.1) Executed Production Documents for one batch representative of each strength of the proposed product.
3.2.P.2 Pharmaceutical Development
26. Change in the approved design space, involving:
  1. establishment of a new design space
    • Conditions to be Fulfilled: None
    • Supporting Data: 1
    • Reporting Category: Supplement
  2. expansion of the approved design space
    • Conditions to be Fulfilled: None
    • Supporting Data: 1
    • Reporting Category: Supplement
  3. reduction in the approved design space (any change that reduces or limits the range of parameters used to define the design space)
    • Conditions to be Fulfilled: None
    • Supporting Data: 1
    • Reporting Category: Notifiable Change
  4. process parametric release
    • Conditions to be Fulfilled: None
    • Supporting Data: 1
    • Reporting Category: Supplement
Conditions

None

Supporting Data
  1. (P.2) Pharmaceutical development data to support the establishment or changes to the design space (including changes to process parametric release for sterile products).
3.2.P.3 Manufacture
27. Replacement or addition of a drug product manufacturer / manufacturing site, involving
  1. production of a modified release product
    • Conditions to be Fulfilled:
      • None
      • 1-3
    • Supporting Data:
      • 1-6,8-10
      • 2-6,8-10
    • Reporting Category:
      • Supplement
      • Notifiable Change
  2. production of an immediate release product [e.g., tablet, capsule, liquids, sterile liquids, semi-solids]
    • Conditions to be Fulfilled: 1-2
    • Supporting Data: 2-6,8-10
    • Reporting Category: Notifiable Change
  3. primary packaging
    • Conditions to be Fulfilled: 1-2,4
    • Supporting Data: 2-3,5-6,9
    • Reporting Category: Annual Notification
  4. testing [e.g., release, stability]
    • Conditions to be Fulfilled: 1-2
    • Supporting Data: 2-3,5,7-8
    • Reporting Category: Notifiable Change
  5. storage and distribution
    • Conditions to be Fulfilled: 1-2
    • Supporting Data: 2-3,5
    • Reporting Category: Annual Notification
Conditions
  1. No change in the Batch Formula, Description of Manufacturing Process , Equipment Class and Process Controls, Controls of Critical Steps and Intermediates, or Drug Product Specifications.
  2. No change in the container closure system.
  3. IVIVC data in the original submission application has been approved by Health Canada.
  4. The change does not concern a sterile drug product.
Supporting Data
  1. (1,5) Supporting clinical or comparative bioavailability data (the supporting clinical or comparative bioavailability data may be waived if an acceptable in vivo/in vitro correlation has been established).
  2. (1.2.5) GMP and Establishment License (EL) Information [e.g. Confirmation of a satisfactory GMP rating by the Inspectorate].
  3. (P) Confirmation that information on the drug product has not changed as a result of the submission [e.g., other that change in site].
  4. (P.2) Comparative in vitro testing [e.g., multi-point dissolution profiles in the release medium for solid dosage units, comparative diffusion test results for semi-solids] for one batch of each strength of the approved and of the product produced at the new site (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified). See Appendix 5 for additional detail.
  5. (P.3.1) Name, address, and responsibility of the proposed production site or facility involved in manufacturing and testing.
  6. (P.3.5) QC approved Process validation and/or evaluation studies or the proposed validation protocol of the product produced at the new site (where applicable).
  7. (P.5.3) Copies or summaries of validation reports, which demonstrate equivalency of analytical procedures to be used at the proposed testing site.
  8. (P.5.4) Certificate of analyses for one commercial scale batch (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  9. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the product produced at the new site into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  10. (R.1) Executed Production Documents for one batch representative of each strength of the proposed product.
28. Change in the batch size for the drug product, involving:
  1. Increase in batch size beyond a factor of ten (10) times
    • Conditions to be Fulfilled: 1-3
    • Supporting Data: 1-6
    • Reporting Category: Notifiable Change
  2. Increase in batch size, up to and including a factor of ten (10) times
    • Conditions to be Fulfilled: 1-3
    • Supporting Data: 1-6
    • Reporting Category: Annual Notification
  3. a downscaling in the batch size
    • Conditions to be Fulfilled: 1-3
    • Supporting Data: 1-6
    • Reporting Category: Annual Notification
Conditions
  1. Any changes to the manufacturing process and/or to the in-process controls are only those necessitated by the change in batch size, e.g., use of different sized equipment.
  2. The change should not be a result of unexpected events, resulting in failure to meet specifications, arisen during manufacture, or because of stability concerns.
  3. The change in batch size is in comparison to the pivotal clinical/biobatch, or to the approved and validated commercial scale batches.
Supporting Data
  1. (P.2) Comparative in vitro testing [e.g., multi-point dissolution profiles in the release medium for solid dosage units, comparative diffusion test results for semi-solids] for one batch of each strength of the approved and at the proposed scale.
  2. (P.3.2) Batch formula of the proposed dosage form.
  3. (P.3.5) QC approved Process validation and/or evaluation studies or the proposed validation protocol of the proposed drug product. Confirmation that the reference batch size has been previously validated as per approved process validation protocol.
  4. (P.5.4) Description of the batches and summary of results for at least one commercial scale batch at the proposed scale.
  5. (P.8.2) Updated post-approval stability protocol (QC approved) and stability commitment to place the first commercial scale batch of each strength at the proposed scale into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  6. (R.1.2)Executed Production Documents for one batch representative of each strength of the proposed product.
29. Change in the drug product manufacturing process
  • Conditions to be Fulfilled:
    • None
    • 1
    • 2-7
  • Supporting Data:
    • 1-8
    • 2-8
    • 2-8
  • Reporting Category:
    • Supplement
    • Notifiable Change
    • Annual Notification
Conditions
  1. The change does not require supporting in vivo data.
  2. The manufacturing processes for the approved and proposed products use the same principles and the same classes of equipment [e.g., does not involve a change from a convection mixer to a diffusion mixer].
  3. The same operating procedures, process controls, and formulation are used for the approved and proposed products. The equipment used to produce the proposed product may vary in capacity, but are of the same class and operating principles.
  4. The change is not the result of unexpected events, resulting in failure to meet specifications, arising during manufacture or because of stability concerns.
  5. The change does not involve the packaging or labelling where the primary packaging provides a metering and/or delivery function.
  6. The change does not concern a modified release drug product.
  7. The change does not affect the sterilization parameters of a sterile drug product.
Supporting Data
  1. (1,5) Supporting clinical or comparative bioavailability data, where applicable, or a request for a waiver of in vivo studies, e.g.,:
    • for a change using different manufacturing principles [e.g., from a wet to dry granulation]: supporting clinical or comparative bioavailability data
    • for a change using the same manufacturing principles: supporting in vitro data
  2. (S) Confirmation that the information on the drug substance has not changed [e.g., cross reference(s) should be provided to the previously approved drug submission, including brand name of the drug product, manufacturer's/sponsor's name, submission type, control number, date approved]
  3. (P.2) Discussion of the development of the manufacturing process, where applicable, comparative in vitro testing [e.g., multi-point dissolution profiles in the release medium for solid dosage units, comparative diffusion test results for semi-solids] for the approved and proposed products, discussion of any in vitro and/or in vivo studies, where applicable.
  4. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates, Process Validation and/or Evaluation.
  5. (P.5) Specification(s) (if specification(s) have changed), Batch Analyses (certificate of analyses for one commercial scale batch per strength).
  6. (P.8.1) Stability Summary and Conclusions, e.g.,:
    • for a major change to the manufacturing process [e.g., change in equipment class or manufacturing principles]: results for two pilot scale batches of a minimum of three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing of the proposed drug product;
    • for a minor change to the manufacturing process [e.g., change in mixer stirring speed]: stability data at the time of filing would not be necessary (see P.8.2 below).
  7. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  8. (R.1.2) Executed Production Documents for one batch representative of each strength of the proposed product.
30. Change in the controls (in-process tests and/or acceptance criteria) applied during the manufacturing process or on intermediates
  1. deletion of a test
    • Conditions to be Fulfilled: 1,4-5
    • Supporting Data: 1,4
    • Reporting Category: Annual Notification
  2. replacement or addition of a test
    • Conditions to be Fulfilled: 1-4,6
    • Supporting Data: 1-4
    • Reporting Category: Annual Notification
  3. relaxation or tightening of an acceptance criterion
    • Conditions to be Fulfilled: 1,4
    • Supporting Data: 1-4
    • Reporting Category: Annual Notification
Conditions
  1. The change is not necessitated by unexpected events, resulting in failure to meet specifications, arising during manufacture or because of stability concerns.
  2. The change is within the range of approved acceptance criteria (applies to replacement, not to addition of a test, where applicable).
  3. Any new analytical procedure does not concern a novel, non-standard technique or a standard technique used in a novel way.
  4. The change does not affect the sterilization parameters or procedures of a sterile drug product.
  5. The deleted analytical procedure has been demonstrated to be redundant with respect to the remaining analytical procedures [e.g., colour], and does not pertain to a critical quality attribute of the product [e.g., blend uniformity, weight variation].
  6. The replaced or added analytical procedure maintains or tightens precision, accuracy, specificity and sensitivity.
Supporting Data
  1. (P.3.3) Description of the proposed process controls or acceptance criteria.of the critical steps and intermediates.
  2. (P.3.5) QC approved Process validation and/or evaluation studies or the proposed validation protocol of the proposed drug product, where appropriate.
  3. (P.5.4) Description of the batches, and summary of results, for at least one commercial scale batch.
  4. (R.1.2) Executed Production Documents for one batch representative of each strength of the proposed product or Master Production Documents.
31. Change in the approved protocol for process validation and/or evaluation studies
  • Conditions to be Fulfilled: 1-2
  • Supporting Data: 1
  • Reporting Category: Annual Notification
Conditions
  1. The change does not concern a modified release drug product.
  2. The change does not affect the sterilization procedures of a sterile drug product.
Supporting Data
  1. (P.3.5) QC approved Process validation and/or evaluation studies or the revised validation protocol of the proposed drug product.
32. Change in the manufacturing process of a veterinary medicated premix [e.g. from regular powder to granulated form or and vice versa]
  • Conditions to be Fulfilled:
    • None
    • 1
    • 1-6
  • Supporting Data:
    • 1-9
    • 1,3-9
    • 1,3-9
  • Reporting Category:
    • Supplement
    • Notifiable Change
    • Annual Notification
Conditions
  1. The change does not affect performance characteristics [e.g. bioavailability] of the medicated premix.
  2. The manufacturing processes for the approved and proposed products use the same principles and the same classes of equipment [e.g., does not involve a change from a convection mixer to a diffusion mixer].
  3. The change is not the result of unexpected events, resulting in failure to meet specifications, arising during manufacture or because of stability concerns.
  4. The same operating procedures, process controls, and formulation are used for the approved and proposed products. The equipment used to produce the proposed product may vary in capacity, but are of the same class and operating principles.
  5. Changes to the drug product specifications are those necessitated by the change to the medicated premix form.
  6. No change in the shelf life, the stability protocol, stability tests, and stability commitment of the medicated premix.
Supporting Data
  1. (1.3.1) Package Insert (title page, ''Dosage Forms, Composition, and Packaging'' section).
  2. (1,5) Supporting clinical or comparative bioavailability data
  3. (P.2) Discussion of the differences in manufacturing process(es) between the approved and proposed products and the potential impact on product performance
  4. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates, Process Validation and/or Evaluation.
  5. (P.3.5) Batch formula, process validation and/or evaluation studies or the proposed validation protocol of the proposed medicated premix form.
  6. (P.5) Specification(s), Analytical Procedures and their validation (if new analytical methods are used), Batch Analyses (certificate of analyses for one commercial scale batch).
  7. (P.8.1) Stability Summary and Conclusions (minimum of two pilot scale batches).
  8. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing could be applied, if scientifically justified).
  9. (R.1) Executed Production Documents for one batch representative of each strength of the proposed product.
3.2.P.4 Control of Excipients
33. Change in the source of an excipient from a vegetable, synthetic source, or non-TSE [e.g., animal] to a TSE risk [e.g., animal] source, or from a TSE risk [e.g., animal] source to a different TSE risk [e.g., animal].
  • Conditions to be Fulfilled: None
  • Supporting Data: 2-4
  • Reporting Category: Notifiable Change
34. Change in the source of an excipient from a TSE risk [e.g., animal] source to a vegetable or synthetic source
  • Conditions to be Fulfilled: None
  • Supporting Data: 1,3
  • Reporting Category: Annual Notification
Conditions

None

Supporting Data
  1. Declaration from the manufacturer of the excipient that it is entirely of vegetable or synthetic origin.
  2. Details of the source of the excipient (animal species, country of origin) and the steps undertaken in processing to minimize the risk of TSE exposure.
  3. Information demonstrating comparability in terms of physico-chemical characterization of the proposed excipient with the approved excipient.
  4. TSE Certificate of Suitability (CEP) issued by the EDQM, if available, or satisfactory BSE/TSE risk assessment on proposed excipient (For a veterinary drug used in a food producing animal, as outlined in Section 4 of the Drug Product Information Form (DPIF)).
35. Change in the composition of a medicated premix dosage form
  • Conditions to be Fulfilled:
    • None
    • 1-3,6
    • 1-6
  • Supporting Data:
    • 1-11
    • 2-11
    • 2-11
  • Reporting Category:
    • Supplement
    • Notifiable Change
    • Annual Notification
Conditions
  1. Any qualitative and /or quantitative change in the composition does not require supporting in vivo data.
  2. The proposed excipient(s) does/do not function to affect the absorption of the drug substance.
  3. The proposed excipient(s) does/do not function to affect the solubility of the drug substance.
  4. The proposed excipient(s) does/do not function as a preservative or preservative enhancer.
  5. No Level I or Level II change in the specifications of the proposed excipient(s) or the drug product.
  6. The change concerns a drug product that contains drug substances that are discrete chemical entities (i.e. this does not include polymeric complexes).
Supporting Data
  1. (1,5) Supporting clinical or comparative bioavailability data, where applicable, or a request for a waiver of in vivo studies.
  2. (1.2.6) Letters of Access if Drug Master Files (DMFs) are submitted for new excipients.
  3. (1.3.1) Package insert (title page, ''Dosage Forms, Composition, and Packaging'' section).
  4. (S) Confirmation that the information on the drug substance has not changed [e.g., cross reference(s) should be provided to the previously approved drug submission, including brand name of the drug product, manufacturer's/sponsor's name, submission type, control number, date approved]
  5. (P.1) Description and composition of the dosage form.
  6. (P.2) Discussion of the components of the drug product [e.g., choice of excipients, compatibility of drug substance and excipients].
  7. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates, Process Validation and/or Evaluation.
  8. (P.4) Control of Excipients, if new excipients are proposed [e.g., specifications, confirmation that none of the excipients are prohibited by the Food and Drug Regulations].
  9. (P.5) Batch Analyses (certificate of analyses for a minimum of one pilot scale batch).
  10. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
  11. (R.1) Executed Production Documents for one batch representative of each strength of the proposed product.
36. Change in the analytical test method of an excipient in a medicated premix to comply with an updated version of a Schedule B pharmacopoeial monograph
  • Conditions to be Fulfilled: 1
  • Supporting Data: 1-2
  • Reporting Category: Annual Notification
Conditions
  1. No deletion or relaxation of any of the other tests, analytical procedures, or acceptance criteria of the approved specification of the excipient and the medicatd premix.
Supporting Data
  1. (P.5.1) Updated, QC approved, medicated premix specification.
  2. (P.5.3) Where an updated version of a Schedule B analytical procedure is used, if applicable, results of an equivalency study [e.g. system suitability test] between the current and updated compendial methods.
3.2.P.5 Control of Drug Product
37. Change in the standard claimed for the drug product [e.g., from a Professed to Schedule B pharmacopoeial standard] or change in the specification for the drug product to comply with an updated Schedule B pharmacopoeial monograph.
  • Conditions to be Fulfilled: 1-2
  • Supporting Data: 1-5
  • Reporting Category: Annual Notification
Conditions
  1. The change is made exclusively to comply with the pharmacopoeia.
  2. No change to the specification that results in a potential impact on the performance of the drug product.
Supporting Data
  1. Package Insert and Inner and Outer Labels.
  2. (P.5.1) Updated, QC approved, proposed drug product specification.
  3. (P.5.3) Where a House analytical procedure is used and a Schedule B standard is claimed, results of an equivalency study between the House and compendial methods.
  4. (P.5.4) Description of the batches, certificates of analyses, and summary of results, for at least one batches (minimum pilot scale) of the drug product tested according to the proposed specification.
  5. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
38. Change in the specification for the drug product tests and acceptance criteria, involving:
  1. for sterile products, replacing the sterility test with process parametric release
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2,5,7-9
    • Reporting Category: Supplement
  2. deletion of a test
    • Conditions to be Fulfilled: 1-7
    • Supporting Data: 2,8-9
    • Reporting Category: Annual Notification
  3. replacement or addition of a test
    • Conditions to be Fulfilled: 1-4,6-7
    • Supporting Data: 2-6,8-9
    • Reporting Category: Annual Notification
  4. relaxation of an acceptance criterion
    • Conditions to be Fulfilled:
      • None
      • 1,4,6-7
    • Supporting Data:
      • 2,5-6,8-9
      • 2,5-6,8-9
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  5. tightening of an acceptance criterion
    • Conditions to be Fulfilled: 1,4,6-7
    • Supporting Data: 2,8-9
    • Reporting Category: Annual Notification
Conditions
  1. The change is not necessitated by unexpected events, resulting in failure to meet specifications, arising during manufacture or because of stability concerns.
  2. The change is within the range of approved acceptance criteria (applies to replacement, not to addition of a test, where applicable).
  3. Any new analytical procedure does not concern a novel, non-standard technique or a standard technique used in a novel way.
  4. No change in the impurity profile that impacts safety of the drug substance. Acceptance criterion for any Class 3 residual solvent is within the VICH limits (the relaxation of an acceptance criterion for a Class 1 or 2 solvent should be filed as a Notifiable Change).
  5. The deleted test has been demonstrated to be redundant with respect to the remaining tests and does not impact the safety or overall quality of the product [e.g. removal of an organic volatile solvent test after at least ten (10) commercial scale batches tested and meet approved acceptance criteria, or provide valid scientific justification].
  6. The change to the specifications does not affect the performance of the drug product.
  7. The change does not concern sterility testing.
Supporting Data
  1. (P.3.5) Process validation results.
  2. (P.5.1) Updated, QC approved, proposed drug product specification.
  3. (P.5.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  4. (P.5.3) Copies or summaries of validation reports, if new analytical procedures are used.
  5. (P.5.3) Where a House analytical procedure is used and a Schedule B standard is claimed, results of an equivalency study between the House and compendial methods.
  6. (P.5.4) Description of the batches, and summary of results, for at least one (minimum pilot scale) of the drug product tested according to the proposed specification.
  7. (P.5.4) Description of the batches, and summary of results, of a sufficient number of batches (at least 10 commercial scale batches) to support the process parametric release.
  8. (P.5.6) Justification of the proposed drug product specification [e.g., demonstration of the suitability to control the drug product, including degradation products].
  9. For drug products that contain a drug substance that is not a discrete chemical entity (i.e. this does not include polymeric complexes), demonstration that consistency of quality and of the production process is maintained.
39. Change in the specification for the drug product, for analytical procedures involving:
  1. deletion of an analytical procedure
    • Conditions to be Fulfilled:
      • 5
      • 5-6
    • Supporting Data:
      • 1,6
      • 1,6
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. replacement, alternate, or additional analytical procedure
    • Conditions to be Fulfilled:
      • None
      • 1-5
    • Supporting Data:
      • 1-7
      • 1-7
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  3. change from a House analytical procedure to a Schedule B analytical procedure or a change from an approved compendial analytical procedure to an harmonized compendial procedure
    • Conditions to be Fulfilled: 1,3
    • Supporting Data: 1-7
    • Reporting Category: Annual Notification
Conditions
  1. No change in the approved acceptance criteria.
  2. The method of analysis is based on the same analytical technique or principal and no new impurities are detected.
  3. Results of method validation demonstrate that the proposed analytical procedure is at least equivalent to the approved analytical procedure.
  4. Any new analytical procedure does not concern a novel, non-standard technique or a standard technique used in a novel way.
  5. The change does not concern sterility testing.
  6. The deleted test has been demonstrated to be redundant with respect to the remaining tests and does not impact the safety or overall quality of the product [e.g. removal of an organic volatile solvent test after at least 10 commercial scale batches tested and meet acceptance criteria, or provide valid scientific justification].
Supporting Data
  1. (P.5.1) Updated, QC approved, proposed drug product specification.
  2. (P.5.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  3. (P.5.3) Copies or summaries of validation reports, if new analytical procedures are used.
  4. (P.5.3) Where a House analytical procedure is used and a Schedule B standard is claimed, results of an equivalency study between the House and compendial methods.
  5. (P.5.4) Description of the batches, and summary of results, for at least one (1) batch (minimum pilot scale) of the drug product tested according to the proposed specification, if applicable.
  6. (P.5.6) Justification of the proposed drug product specification [e.g., demonstration of the suitability to control the drug product, including degradation products], if applicable.
  7. For drug products that contain a drug substance that is not a discrete chemical entity (i.e. this does not include polymeric complexes), demonstration that consistency of quality and of the production process is maintained.
40. Addition, deletion or replacement of microtracer used in a medicated premix
  • Conditions to be Fulfilled: 1
  • Supporting Data: 1-4
  • Reporting Category: Annual Notification
Conditions
  1. The proposed microtracer is pre-tested to confirm stability in the drug premix, and there is no change in the stability protocol, stability tests, and stability commitment of the medicated premix.
Supporting Data
  1. Justification of the addition/removal or replacement of the microtracer [e.g., demonstration of the suitability of the new microtracer to control the medicated premix, including batch to batch consistency]. Justification that there is no "statistically significant" deviation from complete mixing.
  2. Information supporting adequacy of batch to batch cleanout of the mixer and other feed manufacturing equipment.
  3. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates, Process Validation and/or Evaluation.
  4. (R.1) Executed Production Documents for one batch representative of each strength of the proposed product.
41. Addition, deletion or replacement of carrier used in a medicated premix
  • Conditions to be Fulfilled: 1-3
  • Supporting Data: 1-4
  • Reporting Category: Annual Notification
Conditions
  1. Confirmation that there is no change in the potency, strength, particle size, and efficacy of the medicated premix.
  2. The proposed carrier is listed as an approved feed ingredient as defined in the Feed Regulations.
  3. There is no change in the stability protocol, stability tests, and stability commitment of the medicated premix.
Supporting Data
  1. Justification of the addition/removal or replacement of the carrier [e.g., demonstration of the suitability of the new carrier to control the drug premix, including batch to batch consistency]. Justification that there is no "statistically significant" deviation from complete mixing.
  2. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates, Process Validation and/or Evaluation.
  3. (R.1) Executed Production Documents for one batch representative of each strength of the proposed product.
  4. Demonstration of homogeneity, non-segregation, and stability properties of the proposed medicated premix.
42. Change of specification for a veterinary drug product used in food producing animals
  • Conditions to be Fulfilled:
    • None
    • 4,6
    • 1-5
  • Supporting Data:
    • 1-8
    • 1,4-5,8-9
    • 1,4-5,8-9
  • Reporting Category:
    • Supplement
    • Notifiable Change
    • Annual Notification
Conditions
  1. The change is not necessitated by unexpected events arising during manufacture or because of stability concerns.
  2. Any new analytical procedure does not concern a novel, non-standard technique or a standard technique used in a novel way.
  3. Acceptance criteria for degradation products and any Class 3 residual solvents are within the VICH GL 10, GL 11, and GL 18 limits, where applicable (the relaxation of an acceptance criterion for a Class 1 or 2 solvent should be filed as a Notifiable Change).
  4. The change to the specifications does not result in a potential impact on the performance of the drug product [e.g.solubility].
  5. The change does not concern sterility testing.
  6. The change does not affect the withdrawal period of the veterinary drug product.
Supporting Data
  1. (P.5.1) Updated, QC approved, proposed drug product specification.
  2. (P.5.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  3. (P.5.3) Copies or summaries of validation reports, if new analytical procedures are used.
  4. (P.5.3) Where a House analytical procedure is used and a Schedule B standard is claimed, results of an equivalency study between the House and compendial methods.
  5. (P.5.4) Description of the batches, certificates of analyses, and summary of results, in a tabular format, for at least two batches (minimum pilot scale) of the drug product tested according to the proposed specification.
  6. (P.5.4) Description of the batches, certificates of analyses, and summary of results, in a tabular format, of a sufficient number of batches (at least 10 commercial scale batches) to support the process parametric release, where aplicable.
  7. (P.5.6) Justification of the proposed drug product specification [e.g., demonstration of the suitability of the monograph to control the drug product, including degradation products].
  8. For drug products that contain a drug substance that is not a discrete chemical entity (i.e. this does not include polymeric complexes), demonstration that consistency of quality and of the production process is maintained.
  9. Confirmation that the withdrawal period has not been affected as a result of the change.
3.2.P.7 Container Closure System
43. Replacement or addition of a primary container closure system
  • Conditions to be Fulfilled:
    • None
    • 1-3
  • Supporting Data:
    • 1-5,7
    • 1-2,4,6
  • Reporting Category:
    • Notifiable Change
    • Annual Notification
44. Change in the package size, involving:
  1. change in the fill weight / fill volume
    • Conditions to be Fulfilled:
      • None
      • 1-3
    • Supporting Data:
      • 1-5,7
      • 1-2,4,6-7
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. a change in the number of units [e.g., tablets, ampoules] per package
    • Conditions to be Fulfilled:
      • None
      • 1-3
    • Supporting Data:
      • 1-5,7
      • 1-2,4,6
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
Conditions
  1. No change in the type of container closure or materials of construction.
  2. The change does not concern a container closure that functions to meter the drug product.
  3. The change is consistent with the posology and treatment duration.
Supporting Data
  1. Package Insert and Inner and Outer Labels.
  2. (P.2) Data demonstrating the suitability of the container closure system [e.g., extractable/leachable testing, permeation testing, light transmission]. For changes to functional packaging, data to demonstrate that the functioning of the new packaging is equivalent to that previously approved.
  3. (P.3.5) For sterile products, process validation and/or evaluation studies.
  4. (P.7) Information on the proposed container closure system [e.g., description, materials of construction of primary packaging components, specifications, including results of transportation studies, if appropriate].
  5. (P.8.1) Stability Summary and Conclusions, results of a minimum two (2) pilot scale, of three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing and, where applicable, results of photostability studies;
  6. (P.8.1) Stability Summary and Conclusions, stability data at the time of filing would not be necessary (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified) (see P.8.2 below).
  7. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
45. Change in qualitative and/or quantitative composition of any primary or functional secondary container closure component
  • Conditions to be Fulfilled:
    • None
    • 1
  • Supporting Data:
    • 1-6
    • 1-4,6
  • Reporting Category:
    • Notifiable Change
    • Annual Notification
Conditions
  1. The proposed packaging is at least as protective as the approved packaging.
Supporting Data
  1. Package Insert and Inner and Outer Labels.
  2. (P.2) Data demonstrating the suitability of the container closure system [e.g., extractable/leachable testing, permeation testing, light transmission]. For changes to functional packaging, data to demonstrate that the functioning of the new packaging is equivalent to that previously approved.
  3. (P.3.5) For sterile products, process validation and/or evaluation studies.
  4. (P.7) Information on the proposed container closure system [e.g., description, materials of construction of primary packaging components, specifications, including results of transportation studies, if appropriate].
  5. (P.8.1) Stability Summary and Conclusions; results of a minimum of two (2) pilot scale batches, three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing and, where applicable, results of photostability studies;
  6. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of each strength of the proposed product into the long term stability programme (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
46. Change in the specification for a primary or functional secondary container closure component, involving deletion, replacement or addition of a test or; relaxation or tightening of an acceptance criterion
  • Conditions to be Fulfilled:
    • None
    • 1-2
  • Supporting Data:
    • 1-2
    • 1-2
  • Reporting Category:
    • Notifiable Change
    • Annual Notification
Conditions
  1. The deleted test has been demonstrated to be redundant with respect to the remaining tests.
  2. Results of method validation demonstrate that the proposed analytical procedure is at least equivalent to the approved analytical procedure.
Supporting Data
  1. (P.7) Updated QC approved proposed specifications, including justification.
  2. (P.7) Description of the analytical procedure and, if applicable, validation data.
3.2.P.8 Stability
47. Change in the shelf life for the drug product, involving:
  1. Extension
    • Conditions to be Fulfilled:
      • None
      • 1-6
    • Supporting Data:
      • 1-4,6
      • 1-2,5
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. Reduction (due to stability concerns)
    • Conditions to be Fulfilled: 1,4
    • Supporting Data: 1-4,6
    • Reporting Category: Notifiable Change
Conditions
  1. No change to the container closure system in direct contact with the drug product or to the recommended storage conditions of the drug product.
  2. The approved shelf life is at least 24 months.
  3. Full long term stability data is available covering the proposed shelf life and is based on stability data generated on at least three commercial scale batches.
  4. Stability data was generated in accordance with the approved stability protocol.
  5. Significant changes (as defined in VICH GL3 guideline were not observed in the stability data.
  6. The drug product has not been subject to a previous reduction in shelf life.
Supporting Data
  1. (P.8.1) Summary of stability testing and results [e.g., studies conducted, protocols used, results obtained].
  2. (P.8.1) Proposed storage conditions and shelf life.
  3. (P.8.2) Updated post-approval stability protocol and stability commitment.
  4. (P.8.2) Justification of the change to the post-approval stability protocol or stability commitment.
  5. (P.8.3) Results of stability testing (i.e., full long term stability data covering the proposed shelf life generated on at least three commercial scale batches of each strength for each approved packaging format/size), if applicable (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified)
  6. (P.8.3) Results of stability testing (i.e., less than full long term stability data covering the proposed shelf life generated on at least two pilot scale batches of each strength for each approved packaging format/size), if applicable (bracketing and matrixing for multiple strengths and packaging components could be applied, if scientifically justified).
48. Change in the labelled storage conditions for the drug product or the diluted or reconstituted product, involving:
  1. addition of a cautionary statement
    • Conditions to be Fulfilled:
      • None
      • 1
    • Supporting Data:
      • 1-2
      • 1-2
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. deletion of a cautionary statement
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2
    • Reporting Category: Notifiable Change
  3. relaxation of a temperature criterion
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2
    • Reporting Category: Notifiable Change
  4. tightening of a temperature criterion
    • Conditions to be Fulfilled: 1
    • Supporting Data: 1-2
    • Reporting Category: Annual Notification
Conditions
  1. The change is not necessitated by unexpected events, resulting in failure to meet specifications, arising during manufacture or because of stability concerns.
Supporting Data
  1. Package Insert and Inner and Outer Labels.
  2. (P.8.3) If applicable, stability testing results to support the change to the storage conditions.
49. Change to the post-approval stability protocol or stability commitment.
  • Conditions to be Fulfilled: None
  • Supporting Data: 1-4
  • Reporting Category: Annual Notification
Conditions

None

Supporting Data
  1. (P.8.1) Proposed storage conditions and shelf life.
  2. (P.8.2) Updated QC approved post-approval stability protocol and stability commitment.
  3. (P.8.2) Justification of the change to the post-approval stability protocol or stability commitment.
  4. (P.8.3) If applicable, stability testing results to support the change to the post-approval stability protocol or stability commitment.
50. Change in the stability protocol or the shelf life for a medicated premix, involving:
  1. extension of the shelf life
    • Conditions to be Fulfilled: 1-6
    • Supporting Data: 1-3,5
    • Reporting Category: Annual Notification
  2. reduction of the shelf life (due to stability concerns)
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-4,6
    • Reporting Category: Notifiable Change
  3. addition of a time point at any time, or deletion of time points beyond the approved expiration period
    • Conditions to be Fulfilled: 1
    • Supporting Data: 1-4
    • Reporting Category: Annual Notification
  4. changes to comply with a relevant VICH guidance [e.g. deletion of a time point from previously approved stability protocol, or change in storage conditions]
    • Conditions to be Fulfilled: 1,5-6
    • Supporting Data: 1-4,6-7
    • Reporting Category: Annual Notification
Conditions
  1. No change to the container closure system in direct contact with the drug product or to the recommended storage conditions of the drug product.
  2. The approved shelf life is at least 24 months.
  3. Full long term stability data is available covering the proposed shelf life and is based on stability data generated on at least three commercial scale batches.
  4. Stability data was generated in accordance with the approved stability protocol.
  5. No significant changes to the stability data (as defined in VICH GL 3:"Stability Testing of New veterinary Drug Substances and Medicinal Products" and VICH GL 8: "Stability Testing for Medicated Premixes".
  6. The medicated premix has not been subject to a previous reduction of an expiration date.
Supporting Data
  1. (P.8.1) Summary of stability testing and results [e.g., studies conducted, protocols used, results obtained].
  2. (P.8.1) Proposed storage conditions and shelf life.
  3. (P.8.2) Updated post-approval stability protocol and stability commitment.
  4. (P.8.2) Justification of the change to the post-approval stability protocol or stability commitment.
  5. (P.8.3) Results of stability testing (i.e., full long term stability data covering the proposed shelf life generated on at least three commercial scale batches, bracketing and matrixing could be applied, if justified)
  6. (P.8.3) Results of stability testing (i.e., less than full long term stability data covering the proposed shelf life generated on at least two pilot scale batches, bracketing and matrixing could be applied, if justified).
  7. Reference to the change in the relevant VICH guidance (VICH GL 3:"Stability Testing of New veterinary Drug Substances and Medicinal Products" and VICH GL 8: "Stability Testing for Medicated Premixes")
51. Change to the post-approval stability protocol or stability commitment of a sterile veterinary drug used as euthanasia drug or an ear implant for bovine and ovine species
  • Conditions to be Fulfilled:
    • None
    • 1-2
  • Supporting Data:
    • 1-5
    • 1-5
  • Reporting Category:
    • Notifiable Change
    • Annual Notification
Conditions
  1. The proposed analytical method is at least equivalent or is superior to detect the drug substance or, impurities, or degradation products as specified in the drug product shelf life specifications
  2. There is no change to the shelf life specifications and the storage conditions.
Supporting Data
  1. (P.8.1) Proposed storage conditions and shelf life.
  2. (P.8.2) Updated post-approval stability protocol and stability commitment.
  3. (P.8.2) Justification of the change to the post-approval stability protocol or stability commitment.
  4. (P.8.3) If applicable, stability testing results to support the change to the post-approval stability protocol or stability commitment.
  5. Copies or summaries of validation reports for the proposed analytical procedures, and comparative results demonstrating that the approved and proposed analytical procedure are equivalent.
3.2.R.2 Devices
52. Change of an approved drug administration device for a veterinary drug:
  1. addition or replacement of a drug administration device that is not an integrated part of the primary packaging of a veterinary drug product
    • Conditions to be Fulfilled:
      • 3,6
      • 1-6
    • Supporting Data:
      • 1-3,6-7
      • 1,3,6-7
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. deletion of a drug administration device that is not an integrated part of the primary packaging of a veterinary drug product
    • Conditions to be Fulfilled: 3
    • Supporting Data: 1,3,6-7
    • Reporting Category: Annual Notification
  3. change in an approved multi-dose administration device for an injectable veterinary drug product
    • Conditions to be Fulfilled: 4
    • Supporting Data: 1-7
    • Reporting Category: Annual Notification
Conditions
  1. No change in the type of drug administration device or materials of construction.
  2. No change in the function, suitability and accuracy of the device.
  3. The required dose of the veterinary drug product must still be accurately delivered in line with the approved posology and the results of such studies should be available.
  4. The change should be consistent with the posology and treatment duration.
  5. The change does not concern a sterile drug product.
  6. No change in the strength, pharmaceutical form, or route of administration of the drug product
Supporting Data
  1. (1.3) Package Insert and Inner and Outer Labels.
  2. Data demonstrating the suitability and compatibility of the materials of construction of the device system [e.g., extractable/leachable testing, permeation testing, light transmission];
  3. Information on the proposed measuring device system [e.g., description, materials of construction of primary packaging components, specifications, including results of transportation studies, if appropriate].
  4. (P.8.1) Stability summary for a moderate change to the drug administration device system [e.g., different materials of construction]; where applicable, in-use stability studies for multidose veterinary drugs.
  5. (P.8.2) Updated post-approval stability protocol.
  6. Amended relevant sections of VDD-CPID, VDD-QOS, or equivalent (including description, detailed drawing and composition of the device material and supplier where appropriate).
  7. Reference to certificate of analysis, or other manufacturer standards for the device, where applicable, demonstrating the delivered dose (accuracy ,precision) of the proposed device.
53. Significant change to a drug administration device used in an extended release veterinary drug [e.g. addition, deletion, replacement of, or change in materials of construction of an extended release device [e.g. for intra ruminal boluses used for continued release] of a veterinary drug product].
  • Conditions to be Fulfilled:
    • None
    • 3-5
    • 1-6
  • Supporting Data:
    • 1-8
    • 1,3-8
    • 1,3-8
  • Reporting Category:
    • Supplement
    • Notifiable Change
    • Annual Notification
Conditions
  1. No change in the type of or materials of construction [e.g. composition of glass bolus].
  2. No change in the shape or dimensions function, suitability and accuracy
  3. The required dose of the veterinary drug product must still be accurately delivered in line with the approved posology and the results of such studies should be available.
  4. The change should be consistent with the posology and treatment duration.
  5. No change in release of the drug product into the digestive system and no impact on bioavailability of the active medicinal ingredient.
  6. The new device is free from BSE / TSE agent [e.g. encapsulated gelatin]
Supporting Data
  1. (1.3) Package Insert and Inner and Outer Labels.
  2. (1,5) Supporting clinical or comparative dose delivery data, where applicable.
  3. Data demonstrating the suitability of the materials of construction of the device system [e.g., extractable/leachable testing, permeation testing, light transmission]. For changes to dose administering device, data to demonstrate that the delivered dose with the new device is equivalent to that previously approved.
  4. (P.7) Information on the proposed dose delivery system [e.g., description, materials of construction of components, specifications, including results of transportation studies, if appropriate].
  5. (P.8.1) Stability Summary and Conclusions, e.g.,:
    • where applicable, results of in-use stability studies for multidose veterinary drugs.
  6. Amended relevant sections of VDD-CPID, VDD-QOS, or equivalent (including description, detailed drawing and composition of the device material and supplier where appropriate).
  7. Reference to certificate of analysis, or other manufacturer standards for the device, where applicable, or data to demonstrate accuracy, precision and compatibility of the device.
  8. TSE Certificate of Suitability (CEP) issued by the EDQM, if available, or satisfactory TSE risk assessment on material of construction of the device as outlined in Section 4 of the Drug Product Information Form (DPIF).
54. Minor changes to a drug administration device used in an extended release veterinary drug:
  1. tightening of specification limits of an administration device for a veterinary drug [e.g. changes in balling gun used for intraruminal boluses to control drug product rate of release].
    • Conditions to be Fulfilled:
      • None
      • 2-3
    • Supporting Data:
      • 1-4
      • 1,4-5
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. minor change to an approved test procedure
    • Conditions to be Fulfilled: 1-3
    • Supporting Data: 3-5
    • Reporting Category: Annual Notification
  3. addition of a new test parameter
    • Conditions to be Fulfilled: 2
    • Supporting Data: 1,4
    • Reporting Category: Annual Notification
Conditions
  1. The change is not a consequence of any commitment placed in the submission review process.
  2. The change should not be the result of unexpected events arising during manufacture.
  3. Any change should be within the range of currently approved limits.
Supporting Data
  1. (1.3) Package Insert and Inner and Outer Labels.
  2. Data demonstrating the suitability of the materials of construction of the measuring device system [e.g., extractable/leachable testing, permeation testing, light transmission]. For changes to measuring device, data to demonstrate that the measuring of the new device is equivalent to that previously approved.
  3. (P.3.5) For sterile products, process validation data and/or evaluation studies, where applicable.
  4. (P.7) Information on the proposed dose delivery system [e.g., description, materials of construction of components, specifications, including results of transportation or interaction studies, if appropriate; detailed description, drawing and composition of the device material and manufacturer specification].
  5. Reference to certificate of analysis, or other manufacturer standards for device, where applicable, or data to demonstrate accuracy, precision and compatibility of the device.

Appendix 3: Quality Post-NOC Changes (Biologics)

The change examples presented below are intended to assist with the classification of changes made to the Quality information of Schedule D (biologic) drugs. The information summarized in the tables provides recommendations for:

  1. the conditions to be fulfilled for a given change to be classified as a either a Level I - Supplement, a Level II - Notifiable Change, or a Level III - Annual Notification. If any of the conditions outlined for a given change are not fulfilled, the change is automatically considered the next higher level of change. For example, if any of the conditions recommended for a Level II - Notifiable Change are not fulfilled, the change is considered a Level I - Supplement. Similarly, if any of the conditions recommended for a Level I - Supplement are not fulfilled, the change would warrant the filing of an NDS;
  2. the supporting data for a given change, is to be submitted to Health Canada and/or maintained by the sponsor. Where applicable, the corresponding modules of the Common Technical Document (CTD) for the supporting data have been identified in brackets. An adequate rationale is required when supporting data cannot be provided.
  3. the reporting category [e.g., Supplement, Notifiable Change or Annual Notification].

For convenience, the change examples are organized according to the format defined by the Common Technical Document (CTD), refer to the Guidance for industry for the preparation of the quality information for drug submissions in CTD format: Biotechnological/Biological (Biotech) products; Blood products; Conventional biotherapeutic products; and Vaccines.

3.2.S Drug Substance

3.2.S.1 General Information
1. Change in the name of the drug substance
  • Conditions to be Fulfilled: 1
  • Supporting Data: 1-2
  • Reporting Category: Annual Notification
Conditions
  1. Confirmation that information on the drug substance has not changed as a result of the submission [e.g., cross reference(s) should be provided to the previously approved drug submission, including brand name of the drug product, manufacturer's /sponsor's name, submission type, control number, date approved].
Supporting Data
  1. (1.3) Product Monograph [e.g., Title Page, Storage and Stability (Part I), Dosage Forms, Composition and Packaging (Part I), and Pharmaceutical Information (Part II) section] and Inner and Outer Labels.
  2. (S.1.1) Information on the proposed nomenclature of the drug substance (chemical name(s), compendial name) and evidence that the proposed name for the drug substance is recognized [e.g., proof of acceptance by WHO, recommended INN, USAN, BAN].
3.2.S.2 Manufacture
2. Change to a drug substance manufacturing facility, involving:
  1. replacement or addition of a manufacturing facility for the bulk drug substance, or any intermediate of the drug substance
    • Conditions to be Fulfilled:
      • None
      • 1-5
    • Supporting Data:
      • 1-7,9-14,16
      • 3,7,9-13
    • Reporting Category:
      • Supplement
      • Notifiable Change
  2. introduction of microbial hosts into a multi-product mammalian cell culture suite or vice versa
    • Conditions to be Fulfilled: None
    • Supporting Data: 14-15
    • Reporting Category: Supplement
  3. conversion of production and related area(s) from campaign to concurrent for a multi-product facility
    • Conditions to be Fulfilled: 5-6
    • Supporting Data: 17-18
    • Reporting Category: Notifiable Change
  4. conversion of a drug substance manufacturing facility from single-product to multi-product
    • Conditions to be Fulfilled: 5
    • Supporting Data: 14,16
    • Reporting Category: Notifiable Change
  5. addition of product(s) to an approved multi-product manufacturing facility
    • Conditions to be Fulfilled: 4-5,7
    • Supporting Data: 14,17
    • Reporting Category: Annual Notification
  6. introduction of a different host/media-type into an approved multi-product facility
    • Conditions to be Fulfilled: 7
    • Supporting Data: 8,16
    • Reporting Category: Annual Notification
  7. deletion of a manufacturing facility or manufacturer for a bulk intermediate, or drug substance
    • Conditions to be Fulfilled: None
    • Supporting Data: None
    • Reporting Category: Annual Notification
Conditions
  1. This is an addition of a manufacturing facility/suite to an approved drug substance manufacturing site.
  2. The process is an exact replicate of the approved process and controls.
  3. The new facility/suite is under the same QA/QC oversight.
  4. No changes have been made to the approved and validated cleaning and change-over procedures.
  5. The proposed change does not involve additional containment requirements.
  6. The manufacturing process is a closed process for shared areas.
  7. No changes to the cleaning protocol are necessary to support the introduction of new products (no changes in acceptance criteria, and no new materials have been introduced that need to be evaluated for clearance in a cleaning step).
Supporting Data
  1. (1.2.5) GMP and EL information.
  2. (S) Updated or new DMF (with a Letter of Access provided in Module 1) or relevant drug substance information.
  3. (S.2.1) Name, address, and responsibility of the proposed production facility or facility involved in manufacturing and testing.
  4. (S.2.3) For drug substances obtained from, or manufactured with reagents obtained from sources that are at risk of transmitting BSE/TSE agents [e.g., ruminant origin], information and evidence that the material does not pose a potential BSE/TSE risk [e.g., name of manufacturer, species and tissues from which the material is a derivative, country of origin of the source animals, its use and previous acceptance]. An EDQM TSE Certificate of Suitability, if available, is acceptable for raw materials, auxiliary materials, and reagents only.
  5. (S.2.4) Information on the controls performed at critical steps of the manufacturing process and on the intermediate of the proposed drug substance.
  6. (S.2.5) Summary of the process validation and/or evaluation studies, including information demonstrating qualification of the equipment [e.g., operational qualification, performance qualification]. The complete report with all raw data could be requested during review.
  7. (S.3.1) Comparability of the approved and proposed drug substance with respect to physico-chemical characterization, biological activity, and impurity profile. (N.B. Occasionally, the sponsor may undertake bridging non-clinical or clinical studies, e.g. bioequivalence, to support the quality data).
  8. (S.4) Information on the in-process control testing to demonstrate lack of carry-over or cross-contamination.
  9. (S.4.4) Description of the batches and summary of results as quantitative data, in a comparative tabular format, for at least three (3) consecutive commercial scale batches of the approved and proposed drug substance (certificates of analysis to be provided in section 3.2.R.3).
  10. (S.7.3) Stability test results from: a) accelerated testing (usually a minimum of three (3) months) or, preferably, forced degradation studies under appropriate time and temperature conditions for the product; and b) three (3) months of real time/real temperature testing on three (3) commercial scale batches of the proposed drug substance, or longer if less than three (3) time points are available (including the zero time point), as well as commitment to notify Health Canada of any failures in the ongoing long term stability studies.
  11. (P.5.4) Description of the batches and summary of results as quantitative data, in a comparative tabular format, for at least three (3) consecutive commercial scale drug product batches manufactured using the proposed drug substance (certificates of analysis to be provided in section 3.2.R.3).
  12. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and commitment to place the first commercial scale batch of the drug product manufactured using the proposed drug substance into the stability programme.
  13. (A.1) Information on the proposed production facility involved in the manufacture of the drug substance, including the complete set of floor plans and flow charts (drawings, room classification, water systems, HVAC systems), as well as the cleaning and shipping validation, as appropriate.
  14. (A.1) Information describing the change-over procedures for shared product-contact equipment and the segregation procedures, as applicable. If no revisions, a signed attestation from the manufacturer that no changes were made to the change-over procedures.
  15. (A.1) Results of the environmental monitoring studies in critical classified areas.
  16. (A.1) Cleaning procedures (including data in a summary validation report and the cleaning protocol for the introduction of new products, as applicable) demonstrating lack of carry-over or cross-contamination.
  17. (A.1) Data demonstrating lack of carry-over or cross-contamination.
  18. Description of the segregation procedures to avoid cross-contamination.
3. Modification to a facility involved in the manufacture of a drug substance, such as:
  1. for an active ingredient manufactured in an open system, any changes which has the potential to increase the environmental risk to the product
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2,5
    • Reporting Category: Notifiable Change
  2. relocation of equipment to another room in the same facility, qualification of a new room or change in classification of an existing room
    • Conditions to be Fulfilled: 1-3
    • Supporting Data: 3-5
    • Reporting Category: Annual Notification
  3. modification to a manufacturing area or modification to an existing service/system [e.g., change to WFI systems or HVAC systems, moving a wall]
    • Conditions to be Fulfilled: 1-2
    • Supporting Data: 3-5
    • Reporting Category: Annual Notification
  4. change in the location of steps in the production process within the same facility
    • Conditions to be Fulfilled: 1
    • Supporting Data: 1,4-5
    • Reporting Category: Annual Notification
Conditions
  1. The change has no impact on the risk of contamination or cross-contamination.
  2. The modification has no product impact.
  3. Re-qualification of the equipment follows the original qualification protocol, if applicable.
Supporting Data
  1. (S.2.4) Information on the in-process control testing.
  2. (S.2.5) Process validation and/or evaluation studies [e.g., equipment qualification]. The proposed validation protocol is acceptable, but data could be requested.
  3. (S.2.5) Information demonstrating re-qualification of the equipment or re-qualification of the change [e.g., operational qualification, performance qualification], as appropriate.
  4. (A.1) Information on the modified production facility/area involved in manufacturing, including the complete set of floor plans and flow charts (drawings, room classification, water systems, HVAC systems).
  5. (A.1) Results of the environmental monitoring studies in critical classified areas.
4. Change to the drug substance fermentation process involving:
  1. a critical change [e.g., incorporation of disposable bioreactor technology]
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-3,6-7,9,11-12
    • Reporting Category: Supplement
  2. a change with moderate potential to adversely impact quality of the product [e.g., extension of the in vitro cell age beyond validated parameters]
    • Conditions to be Fulfilled: 2,4
    • Supporting Data: 2-3,6,8,10
    • Reporting Category: Notifiable Change
  3. a non critical change, such as: change in harvesting and/or pooling procedures which does not affect the method of manufacture, recovery, storage conditions, sensitivity of detection of adventitious agents, or production scale; or duplication of a fermentation train; or addition of identical or similar/comparable bioreactors
    • Conditions to be Fulfilled: 1-6,9-10
    • Supporting Data: 2-3,6,8
    • Reporting Category: Annual Notification
5. Change to the drug substance purification process involving:
  1. a critical change [e.g.,change that impact negatively the viral clearance capacity of the process or the impurity profile of the drug substance]
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2,5-7,9,11-13
    • Reporting Category: Supplement
  2. a change with moderate potential to adversely impact quality of the product [e.g., change in the chemical separation method, for example ion-exchange HPLC to reverse phase HPLC]
    • Conditions to be Fulfilled:
      • 2,4
      • 1-5
    • Supporting Data:
      • 1-2,6-7,10,12
      • 1-2,6,8
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
6. Scale-up of the manufacturing process:
  1. at the fermentation stage
    • Conditions to be Fulfilled: 11-12
    • Supporting Data: 3,6-7,9,11-12,15
    • Reporting Category: Notifiable Change
  2. at the purification stage
    • Conditions to be Fulfilled: 1,3,5,7
    • Supporting Data: 6-7,9,11-12
    • Reporting Category: Notifiable Change
7. Change in supplier of auxiliary materials/reagents of biological origin [e.g., foetal calf serum, insulin, human serum albumin]
  • Conditions to be Fulfilled:
    • None
    • 8
  • Supporting Data:
    • 4,8,13-14
    • 4,8
  • Reporting Category:
    • Notifiable Change
    • Annual Notification
8. Change in source of auxiliary materials/reagents of biological origin
  • Conditions to be Fulfilled:
    • None
    • 8
  • Supporting Data:
    • 4,7,13-14
    • 4,7
  • Reporting Category:
    • Notifiable Change
    • Annual Notification
9. Introduction of reprocessing steps
  • Conditions to be Fulfilled: None
  • Supporting Data: 5,8,10,12
  • Reporting Category: Notifiable Change
Conditions
  1. No change in the principle of the sterilization procedures of the drug substance.
  2. The change does not impact the viral clearance data or the chemical nature of an inactivating agent for a vaccine.
  3. No change in the drug substance specifications outside of the approved ranges.
  4. No change in the impurity profile of the drug substance outside of the approved limits.
  5. The change is not necessitated by recurring events arising during manufacture or because of stability concerns.
  6. The change does not affect the purification process.
  7. The scale-up is linear.
  8. The change is for a compendial auxiliary materials/reagents of biological origin (excluding human plasma-derived materials).
  9. The new fermentation train is identical to the approved fermentation train(s), if applicable.
  10. No change in the approved in vitro cell age.
  11. No change in the proportionality of the raw materials (i.e. the scale-up is linear).
  12. The scale-up involves the use of the same bioreactor (i.e. does not involve the use of a larger bioreactor).
Supporting Data
  1. (S.2.2) Flow diagram (including process and in-process controls) of the proposed manufacturing process(es) and a brief narrative description of the proposed manufacturing process(es).
  2. (S.2.3) Information on the quality and controls of the materials [e.g., raw materials, starting materials, solvents, reagents, catalysts] used in the manufacture of the proposed drug substance.
  3. (S.2.3) If the change results in an increase in the number of population doublings, information on the characterization and testing of the post-production cell bank for recombinant product, or of the drug substance for non-recombinant product.
  4. (S.2.3) For drug substances obtained from, or manufactured with reagents obtained from sources that are at risk of transmitting BSE/TSE agents [e.g., ruminant origin], information and evidence that the material does not pose a potential BSE/TSE risk [e.g., name of manufacturer, species and tissues from which the material is a derivative, country of origin of the source animals, its use and previous acceptance]. An EDQM TSE Certificate of Suitability, if available, is acceptable for raw materials, auxiliary materials, and reagents only.
  5. (S.2.5) Process validation and/or evaluation studies [e.g., for aseptic processing and sterilization].
  6. (S.2.6) Comparability of the approved and proposed product with respect to physico-chemical characterization, biological activity, and impurity profile.
  7. (S.4.4) Description of the batches and summary of results as quantitative data, in a comparative tabular format, for at least three (3) consecutive commercial scale batches of the approved and proposed drug substance (certificates of analysis to be provided in section 3.2.R.3).
  8. (S.4.4) Description of the batches and summary of results as quantitative data, in a comparative tabular format, for one (1) commercial scale batch of the approved and proposed drug substance (certificate of analysis to be provided in section 3.2.R.3).
  9. (S.7.3) Stability test results from: a) accelerated testing (usually a minimum of three (3) months) or, preferably, forced degradation studies under appropriate time and temperature conditions for the product; and b) three (3) months of real time/real temperature testing on three (3) commercial scale batches of the proposed drug substance, or longer if less than three (3) time points are available (including the zero time point), as well as commitment to notify Health Canada of any failures in the ongoing long term stability studies.
  10. (S.7.3) Stability test results from: a) accelerated testing (usually a minimum of three (3) months) or, preferably, forced degradation studies under appropriate time and temperature conditions for the product; and b) three (3) months of real time/real temperature testing on one (1) commercial scale batch of the proposed drug substance, or longer if less than three (3) time points are available (including the zero time point), as well as commitment to notify Health Canada of any failures in the ongoing long term stability studies.
  11. (P.5.4) Description of the batches and summary of results as quantitative data, in a comparative tabular format, for at least three (3) consecutive commercial scale drug product batches manufactured using the proposed drug substance (certificates of analysis to be provided in section 3.2.R.3).
  12. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment to place the first commercial scale batch of the drug product manufactured using the proposed drug substance into the stability programme.
  13. (A.2) Information assessing the risk with respect to potential contamination with adventitious agents [e.g., impact on the viral clearance studies, BSE/TSE risk], or an EDQM TSE Certificate of Suitability, if available.
  14. Information demonstrating comparability of the auxiliary materials/reagents of both sources.
  15. Rationale for regarding the bioreactors as similar/comparable, if applicable.
10. Changes to the cell banks, involving:
  1. generation of new Master Cell Bank (MCB) from the same expression construct with same or closely related cell line; or generation of a new MCB from a different expression construct with the same coding sequence and the same cell line; or adaptation of a MCB into a new fermentation medium
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2,5,7-10
    • Reporting Category: Supplement
  2. generation of a new MCB for a recombinant product or a viral vaccine
    • Conditions to be Fulfilled: 1
    • Supporting Data: 1-2,5,7-9
    • Reporting Category: Notifiable Change
  3. generation of a new Working Cell Bank (WCB) for a bacterial or a viral vaccine
    • Conditions to be Fulfilled:
      • None
      • 2-4
    • Supporting Data:
      • 1-2
      • 1-2
    • Reporting Category:
  4. generation of a new Working Cell Bank (WCB) for a recombinant product (excluding vaccine)
    • Conditions to be Fulfilled: 2-4
    • Supporting Data: 1-2
    • Reporting Category: Annual Notification
  5. Extension of shelf life of the MCB or WCB
    • Conditions to be Fulfilled: 5
    • Supporting Data: 1-2
    • Reporting Category: Annual Notification
11. Changes to the seed banks, involving:
  1. a new Master Seed Bank (MSB); or a Working Seed Bank (WSB) extended beyond an approved passage level
    • Conditions to be Fulfilled: None
    • Supporting Data: 5-9,11
    • Reporting Category: Supplement
  2. generation of a new WSB
    • Conditions to be Fulfilled:
      • 2-3
      • 2-4
    • Supporting Data:
      • 5-9
      • 5-6
    • Reporting Category:
12. Change in cell bank/seed bank testing site
  • Conditions to be Fulfilled: 6
  • Supporting Data: 12
  • Reporting Category: Annual Notification
13. Change in cell bank/seed bank qualification protocol
  • Conditions to be Fulfilled:
    • None
    • 7
  • Supporting Data:
    • 3-4
    • 4
  • Reporting Category:
    • Notifiable Change
    • Annual Notification
Conditions
  1. The new MCB is generated from a pre-approved Master or Working Cell Bank.
  2. The new cell/seed bank is generated from a pre-approved MCB/MSB.
  3. The new cell/seed bank is at the pre-approved passage level.
  4. The new cell/seed bank is released according to a pre-approved protocol.
  5. The testing to support the extension of shelf life is performed according to the pre-approved protocol.
  6. No changes have been made to the tests/acceptance criteria used for the release of the cell/seed bank.
  7. The protocol is considered more stringent (i.e., addition of new tests or tightening of acceptance criteria).
Supporting Data
  1. (S.2.3) Qualification of the cell bank as per ICH Q5D.
  2. (S.2.3) Information on the characterization and testing of the post-production cell bank for recombinant product, or of the product for non-recombinant product.
  3. (S.2.3) Justification of the change to cell bank/seed bank qualification protocol.
  4. (S.2.3) Updated cell bank/seed bank qualification protocol
  5. (S.3.1) Comparability of the approved and proposed product with respect to physico-chemical characterization, biological activity, and impurity profile. (N.B. Occasionally, the sponsor may undertake bridging non-clinical or clinical studies, e.g. bioequivalence, to support the quality data).
  6. (S.4.4) Description of the batches and summary of results as quantitative data, in a comparative tabular format, for the new seed lot (certificate of analysis to be provided in section 3.2.R.3).
  7. (S.4.4) Description of the batches and summary of results as quantitative data, in a comparative tabular format, for at least three (3) consecutive commercial scale batches of the drug substance derived from the new cell/seed bank (certificates of analysis to be provided in section 3.2.R.3).
  8. (S.7.3) Stability test results from: a) accelerated testing (usually a minimum of three (3) months) or, preferably, forced degradation studies under appropriate time and temperature conditions for the product; and b) three (3) months of real time/real temperature testing on three (3) commercial scale batches of the proposed drug substance, or longer if less than three (3) time points are available (including the zero time point), as well as commitment to notify Health Canada of any failures in the ongoing long term stability studies.
  9. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and commitment to place the first commercial scale batch of the drug product manufactured using the proposed drug substance into the long term stability programme.
  10. Supporting non-clinical and clinical data or a request for a waiver of in vivo studies.
  11. Supporting clinical data.
  12. Evidence that the new company/facility is GMP compliant.
14. Change in product-contact equipment/material used in the drug substance manufacturing process, such as:
  1. equipment having different operating principles/properties from those originally approved
    • Conditions to be Fulfilled: 1-3
    • Supporting Data: 1-3
    • Reporting Category: Annual Notification
  2. introduction of new product-contact equipment used in a critical step [e.g., change in equipment model for a continuous centrifuge, water bath for viral inactivation]
    • Conditions to be Fulfilled: 1-3
    • Supporting Data: 1-3
    • Reporting Category: Annual Notification
  3. replacement of equipment with an equivalent equipment
    • Conditions to be Fulfilled: None
    • Supporting Data: 3-4
    • Reporting Category: Annual Notification
  4. replacement of the membrane (filter) used during the UF/DF step
    • Conditions to be Fulfilled: 4
    • Supporting Data: 1,3
    • Reporting Category: Annual Notification
Conditions
  1. The change does not affect equipment used in the fermentation process.
  2. The manufacturing process is not impacted by the change in product-contact equipment.
  3. The change has no product impact.
  4. The change is considered "like for like" [e.g., change in supplier of the same filter].
Supporting Data
  1. (S.2.4) Information on the in-process control testing.
  2. (S.2.5) Process validation and/or evaluation studies, including equipment qualification, as appropriate. The proposed validation protocol is acceptable, but data could be requested.
  3. (S.2.5) Information demonstrating re-qualification of the equipment/material [e.g., operational qualification, performance qualification].
  4. (S.2.5) Demonstration that performance of the proposed equipment is equivalent to the approved equipment (i.e. data from one batch).
15. Change in specifications for the materials, involving:
  1. raw materials, starting materials
    • Conditions to be Fulfilled: 1,3-4
    • Supporting Data: 1,3-6
    • Reporting Category: Annual Notification
  2. solvents, reagents, catalysts
    • Conditions to be Fulfilled: 2-4
    • Supporting Data: 1,3-6
    • Reporting Category: Annual Notification
16. Change in the in-process controls performed at critical steps used in the manufacture of the drug substance
  • Conditions to be Fulfilled: 3-8
  • Supporting Data: 2-6
  • Reporting Category: Annual Notification
17. Change in in-process controls testing site
  • Conditions to be Fulfilled: 3-8
  • Supporting Data: 7
  • Reporting Category: Annual Notification
18. Change in raw materials testing site
  • Conditions to be Fulfilled: 9
  • Supporting Data: 7
  • Reporting Category: Annual Notification
Conditions
  1. The change in specifications for the materials is within the approved ranges.
  2. The Grade of the materials is the same or is of higher quality.
  3. No change in drug substance specifications outside of the approved ranges.
  4. No change in the impurity profile of the drug substance outside of the approved limits.
  5. The change is not necessitated by recurring events arising during manufacture or because of stability concerns.
  6. The replaced analytical procedure maintains or tightens precision, accuracy, specificity and sensitivity, if applicable.
  7. No change in the principle of the sterilization procedures of the drug substance.
  8. No change in the in-process control limits outside of the approved ranges.
  9. No change in specifications of the raw material outside of the approved ranges.
Supporting Data
  1. (S.2.3) Information on the quality and controls of the materials [e.g., raw materials, starting materials, solvents, reagents, catalysts] used in the manufacture of the proposed drug substance.
  2. (S.2.4) Information on the controls performed at critical steps of the manufacturing process and on intermediates of the proposed drug substance.
  3. (S.4.1) Updated, QC approved copy of the proposed drug substance specifications (or where applicable, the final version of the specifications to be signed by QC after HC approval), if changed.
  4. (S.4.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  5. (S.4.3) Copies or summaries of validation reports, if new analytical procedures are used.
  6. (S.4.4) Description of the batches and summary of results as quantitative data, in a comparative tabular format, for one (1) commercial scale batch of the approved and proposed drug substance (certificate of analysis to be provided in section 3.2.R.3).
  7. Evidence that the new company/facility is GMP compliant.
19. Major change to the following process validation protocols used during the manufacture of the drug substance: protocol for the manufacture of cell bank/seed bank, protocol for the introduction of product into an approved mutli-product facility, protocol for the cleaning of equipment [e.g., change in the worst-case scenario during cleaning validation process]
  • Conditions to be Fulfilled: None
  • Supporting Data: 1-2
  • Reporting Category: Notifiable Change
Conditions

None

Supporting Data
  1. (S.2.5) Proposed validation protocol. Process validation and/or evaluation studies could be requested.
  2. Rationale for the change in the validation protocol.
3.2.S.3 Characterisation

There are not any quality change examples for this section at the present time that have not been addressed in other sections.

3.2.S.4 Control of the Drug Substance
20. Changes affecting the quality control (QC) testing of the drug substance (release and stability), involving:
  1. transfer of the QC testing activities for a non-pharmacopoeial assay (in-house) to a new company or to a different facility within the same company
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2
    • Reporting Category: Annual Notification
  2. transfer of the QC testing activities for a pharmacopoeial assay (in-house) to a new company not listed on the Establishment Licence of the manufacturer/sponsor
    • Conditions to be Fulfilled: 1
    • Supporting Data: 1-2
    • Reporting Category: Annual Notification
Conditions
  1. The transferred QC test is not a potency assay or a bioassay.
Supporting Data
  1. (S.2.5) Information demonstrating technology transfer qualification.
  2. Evidence that the new company/facility is GMP compliant.
21. Change in the standard/monograph (i.e. specifications) claimed for the drug substance, involving:
  1. a change from a Schedule B pharmacopoeial standard/monograph to a House standard
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-5
    • Reporting Category: Notifiable Change
  2. a change from a House/Professed standard to a Schedule B pharmacopoeial standard/ monograph or from one Schedule B standard/ monograph to a different Schedule B standard/monograph)
    • Conditions to be Fulfilled: 1-4
    • Supporting Data: 1-3
    • Reporting Category: Annual Notification
22. Change in the specifications for the drug substance to comply with an updated Schedule B pharmacopoeial standard/monograph
  • Conditions to be Fulfilled: 1-2
  • Supporting Data: 1-3
  • Reporting Category: Annual Notification
Conditions
  1. The change is made exclusively to comply with a Schedule B pharmacopoeial monograph.
  2. No change in drug substance specifications outside of the approved ranges.
  3. No deletion of tests or relaxation of acceptance criteria of the approved specifications, except to comply with a Schedule B pharmacopoeial standard/monograph.
  4. No deletion or change to any analytical procedures, except to comply with a Schedule B pharmacopoeial standard/monograph.
Supporting Data
  1. (1.3) Product Monograph [e.g., Where applicable, Title Page, Composition and Packaging (Part I), and Pharmaceutical Information (Part II) section] and Inner and Outer Labels.
  2. (S.4.1) Updated, QC approved copy of the proposed drug substance specifications (or where applicable, the final version of the specifications to be signed by QC after HC approval).
  3. (S.4.3) Where a House/Professed analytical procedure is used and a Schedule B standard/monograph is claimed, results of an equivalency study between the House/Professed and compendial methods.
  4. (S.4.3) Copies or summaries of validation reports, if new analytical procedures are used.
  5. (S.4.5) Justification of specifications with data.
23. Change in the specifications used to release the drug substance, involving:
  1. deletion of a test
    • Conditions to be Fulfilled: None
    • Supporting Data: 1,6
    • Reporting Category: Notifiable Change
  2. addition of a test
    • Conditions to be Fulfilled: 1-2
    • Supporting Data: 1-3,6
    • Reporting Category: Annual Notification
  3. replacement of an analytical procedure
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-3,5-6
    • Reporting Category: Notifiable Change
  4. minor changes to an approved analytical procedure
    • Conditions to be Fulfilled: 3-7
    • Supporting Data: 1,5-6
    • Reporting Category: Annual Notification
  5. a change from a House/Professed analytical procedure to a Schedule B analytical procedure or change from an approved compendial analytical procedure to an harmonized compendial procedure
    • Conditions to be Fulfilled: 3,7
    • Supporting Data: 1-3
    • Reporting Category: Annual Notification
  6. relaxation of an acceptance criterion
    • Conditions to be Fulfilled: None
    • Supporting Data: 1,6
    • Reporting Category: Notifiable Change
  7. tightening of an acceptance criterion
    • Conditions to be Fulfilled: 8-9
    • Supporting Data: 1
    • Reporting Category: Annual Notification
Conditions
  1. No change in the limits/acceptance criteria outside of the approved ranges for the approved assays.
  2. The addition of test is not to monitor new impurity species.
  3. No change in the acceptance criteria outside of the approved ranges.
  4. The method of analysis is the same and is based on the same analytical technique or principle [e.g., a change in column length or temperature, but not a different type of column or method] and no new impurities are detected.
  5. Results of method validation demonstrate that the proposed analytical procedure is at least equivalent to the approved analytical procedure.
  6. The modified analytical procedure maintains or tightens precision, accuracy, specificity and sensitivity.
  7. The change does not concern potency testing.
  8. The change is within the range of approved acceptance criteria.
  9. Acceptance criterion for any Class 3 residual solvent is within the ICH limits.
Supporting Data
  1. (S.4.1) Updated, QC approved copy of the proposed drug substance specifications (or where applicable, the final version of the specifications to be signed by QC after HC approval).
  2. (S.4.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  3. (S.4.3) Copies or summaries of validation reports, if new analytical procedures are used.
  4. (S.4.3) Where a House analytical procedure is used and a Schedule B standard is claimed, results of an equivalency study between the House/Professed and compendial methods.
  5. (S.4.3) Comparative results demonstrating that the approved and proposed analytical procedure are equivalent.
  6. (S.4.5) Justification of the proposed drug substance specifications [e.g., tests, acceptance criteria, or analytical procedures].
3.2.S.5 Reference Standards or Materials used to release the Drug Substance
24. Change the reference standards from pharmacopoeial to House
  • Conditions to be Fulfilled: None
  • Supporting Data: 1-2
  • Reporting Category: Notifiable Change
25. Change the reference standards from House/Professed to pharmacopoeial
  • Conditions to be Fulfilled: 1-2
  • Supporting Data: 1-2
  • Reporting Category: Annual Notification
26. Qualification of a new lot of reference standard against the approved reference standard
  • Conditions to be Fulfilled: 1-2
  • Supporting Data: 2
  • Reporting Category: Annual Notification
27. Change to reference standard qualification protocol
  • Conditions to be Fulfilled:
    • None
    • 2-3
  • Supporting Data:
    • 3-4
    • 4
  • Reporting Category:
    • Notifiable Change
    • Annual Notification
28. Extension of reference standard shelf life
  • Conditions to be Fulfilled: 2
  • Supporting Data: 5
  • Reporting Category: Annual Notification
Conditions
  1. Qualification of the reference standard is performed according to the approved protocol (i.e. no deviation from the approved protocol).
  2. The reference standard is not for a key quality control or in process control assay for a bacterial or a viral vaccine, for bacterial toxins or for a product in lot release group 2.
  3. The protocol is considered more stringent (i.e., addition of new tests or tightening of acceptance criteria). If deletion of tests is proposed, the tests proposed to be deleted were not implemented to monitor the quality of the reference standard [e.g., was implemented for research or validation work].
Supporting Data
  1. (1.3) Revised Product monograph to reflect the change in reference standard.
  2. (S.5) Information demonstrating qualification of the proposed reference standards or materials [e.g., source, characterization, certificate of analysis].
  3. (S.5) Justification of the change to reference standard qualification protocol.
  4. (S.5) Updated reference standard qualification protocol.
  5. (S.7.1) Summary of stability testing and results to support the extension of reference standard shelf life.
3.2.S.6 Container Closure System
29. Change in the primary container closure system(s) for the storage and shipment of the drug substance
  • Conditions to be Fulfilled:
    • None
    • 1-2
  • Supporting Data:
    • 1-2,4
    • 1,3
  • Reporting Category:
    • Notifiable Change
    • Annual Notification
Conditions
  1. The proposed container closure system is at least equivalent to the approved container closure system with respect to its relevant properties.
  2. The change does not concern a sterile drug substance.
Supporting Data
  1. (S.6) Information on the proposed container closure system [e.g., description, specifications].
  2. (S.6) Demonstration of compatibility with the drug substance.
  3. (S.6) Results demonstrating that the proposed container closure system is at least equivalent to the approved container closure system with respect to its relevant properties [e.g., results of transportation or interaction studies, extractable/leachable studies].
  4. (S.7.3) Stability test results from: a) accelerated testing (usually a minimum of three (3) months) or, preferably, forced degradation studies under appropriate time and temperature conditions for the product; and b) three (3) months of real time/real temperature testing on three (3) commercial scale batches of the proposed drug substance, or longer if less than three (3) time points are available (including the zero time point), as well as commitment to notify Health Canada of any failures in the ongoing long term stability studies. Results from one (1) batch may be sufficient based on rationale.
30. Change in the supplier for a primary container closure component, involving:
  1. replacement or addition of a supplier
    • Conditions to be Fulfilled:
      • None
      • 1-2
    • Supporting Data:
      • 1-3
      • None
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. deletion of a supplier
    • Conditions to be Fulfilled: None
    • Supporting Data: None
    • Reporting Category: Annual Notification
Conditions
  1. No change in the type of container closure, materials of construction or in the sterilization process for a sterile container closure component.
  2. No change in the specifications of the container closure component outside of the approved ranges.
Supporting Data
  1. (S.2) Data demonstrating the suitability of the container closure system [e.g., extractable/leachable testing].
  2. (S.6) Information on the proposed container closure system [e.g., description, materials of construction of primary packaging components, specifications].
  3. (S.7.3) Stability test results from:
    1. accelerated testing (usually a minimum of three (3) months) or, preferably, forced degradation studies under appropriate time and temperature conditions for the product; and
    2. three (3) months of real time/real temperature testing on three (3) commercial scale batches of the proposed drug substance, or longer if less than three (3) time points are available (including the zero time point), as well as commitment to notify Health Canada of any failures in the ongoing long term stability studies.
3.2.S.7 Stability
31. Change in the shelf life for the drug substance or for a stored intermediate of the drug substance, involving:
  1. extension
    • Conditions to be Fulfilled:
      • None
      • 1-5
    • Supporting Data:
      • 1-4,6
      • 1-2,5
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. reduction
    • Conditions to be Fulfilled:
      • None
      • 6
    • Supporting Data:
      • 1-5
      • 2-4
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
Conditions
  1. No changes to the container closure system in direct contact with the drug substance with the potential of impact on the drug substance; or to the recommended storage conditions of the drug substance.
  2. The approved shelf life is at least 24 months.
  3. Full long term stability data are available covering the proposed shelf life and are based on stability data generated on at least three (3) commercial scale batches.
  4. Stability data were generated in accordance with the approved stability protocol.
  5. Significant changes (as defined in ICH's Q1A guideline) were not observed in the stability data.
  6. The reduction in the shelf life is not necessitated by recurring events arising during manufacture or because of stability concerns (i.e. problems arising during manufacturing or stability concerns should be reported for evaluation).
Supporting Data
  1. (S.7.1) Summary of stability testing and results [e.g., studies conducted, protocols used, results obtained].
  2. (S.7.1) Proposed storage conditions and shelf life, as appropriate.
  3. (S.7.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment.
  4. (S.7.2) Justification of the change to the post-approval stability protocol or stability commitment.
  5. (S.7.3) Results of stability testing on both upright and inverted samples, except for lyophilized products (i.e., full real time/real temperature stability data covering the proposed shelf life generated on at least three (3) commercial scale batches). For intermediates, data to show that the extension of shelf life has no negative impact on the quality of the drug substance.
  6. (S.7.3) Interim stability testing results and a commitment to notify Health Canada of any failures in the ongoing long term stability studies. Extrapolation of shelf life should be made in accordance with ICH Q1E guideline. For intermediates, data to show that the extension of shelf life has no negative impact on the quality of the drug substance (i.e., batch analysis on three (3) commercial scale batches).
32. Change in the post-approval stability protocol of the drug substance, involving:
  1. major change to the post-approval stability protocol or stability commitment such as deletion of a test, replacement of an analytical procedure, change in storage temperature
    • Conditions to be Fulfilled:
      • None
      • 1-2
    • Supporting Data:
      • 3-6
      • 1-2,4-5
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. addition of time point(s) into the post-approval stability protocol
    • Conditions to be Fulfilled: None
    • Supporting Data: 4-5
    • Reporting Category: Annual Notification
  3. addition of test(s) into the post-approval stability protocol
    • Conditions to be Fulfilled: 3
    • Supporting Data: 4-5
    • Reporting Category: Annual Notification
  4. deletion of time point(s) from the post-approval stability protocol beyond the approved shelf life
    • Conditions to be Fulfilled: None
    • Supporting Data: 4-5
    • Reporting Category: Annual Notification
  5. deletion of time point(s) from the post-approval stability protocol within the approved shelf life
    • Conditions to be Fulfilled: 4
    • Supporting Data: 4-5
    • Reporting Category: Annual Notification
Conditions
  1. For the replacement of an analytical procedure, the results of method validation demonstrate that the new analytical procedure is at least equivalent to the approved analytical procedure.
  2. For the replacement of an analytical procedure, the new analytical procedure maintains or tightens precision, accuracy, specificity and sensitivity.
  3. The addition of test(s) is not due to stability concerns or to the identification of new impurities.
  4. The approved drug substance shelf life is at least 24 months.
Supporting Data
  1. (S.4.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  2. (S.4.3) Copies or summaries of validation reports, if new analytical procedures are used.
  3. (S.7.1) Proposed storage conditions and or shelf life, as appropriate.
  4. (S.7.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment.
  5. (S.7.2) Justification of the change to the post-approval stability protocol or stability commitment.
  6. (S.7.3) If applicable, stability testing results to support the change to the post-approval stability protocol or stability commitment [e.g., data to show greater reliability of the alternate test].
33. Change in the labelled storage conditions for the drug substance, involving:
  1. addition or change of storage condition for the drug substance [e.g., relaxation or tightening of a temperature criterion]
    • Conditions to be Fulfilled:
      • None
      • 1-2
    • Supporting Data:
      • 1-5
      • 1-4
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. addition of a cautionary statement
    • Conditions to be Fulfilled:
      • None
      • 1
    • Supporting Data:
      • 1-2,4-5
      • 1-2,4-5
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  3. deletion of a cautionary statement
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2,4,6
    • Reporting Category: Annual Notification
Conditions
  1. The change is not necessitated by recurring events arising during manufacture or because of stability concerns.
  2. The change consists in the tightening of a temperature criterion within the approved ranges.
Supporting Data
  1. (1.3) Revised Product Monograph [e.g., Where applicable, Title Page, Composition and Packaging (Part I), and Pharmaceutical Information (Part II) section] and Inner and Outer Labels, as applicable.
  2. (S.7.1) Proposed storage conditions and shelf life.
  3. (S.7.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment.
  4. (S.7.2) Justification of the change in the labelled storage conditions/cautionary statement.
  5. (S.7.3) Results of stability testing (i.e., full real time/real temperature stability data covering the proposed shelf life generated on one (1) commercial scale batch).
  6. (S.7.3) Results of stability testing (i.e., full real time/real temperature stability data covering the proposed shelf life generated on at least three (3) commercial scale batches).

3.2.P Drug Product

3.2.P.1 Description and Composition of the Drug Product
34. Change in the description or composition of the drug product, involving:
  1. addition of a dosage form or change in the formulation [e.g., lyophilized powder to liquid, change in the amount of excipient, new diluent for lyophilized product]
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-11
    • Reporting Category: Supplement
  2. change in fill volume (same concentration, different volume)
    • Conditions to be Fulfilled:
      • None
      • 1-2
    • Supporting Data:
      • 2-4,6,8-11
      • 2-4,6,8-10
    • Reporting Category:
      • Supplement
      • Notifiable Change
  3. change in the concentration of the active ingredient [e.g., 20 unit/mL vs 10 unit/mL]
    • Conditions to be Fulfilled:
      • None
      • 2-5
    • Supporting Data:
      • 2-4,6,8,10,12
      • 2-4,6,8
    • Reporting Category:
      • Supplement
      • Notifiable Change
  4. addition of a new presentation [e.g., addition of syringes to vials]
    • Conditions to be Fulfilled: None
    • Supporting Data: 2-3,6,8-10,12
    • Reporting Category: Supplement
Conditions
  1. No Level I changes in the manufacturing process to accommodate the new fill volume.
  2. No change in the dose recommended.
  3. The new concentration is bracketed by existing approved concentrations.
  4. More than two concentrations are already approved (i.e., linear PK/PD profile of the product from at least three (3) different concentrations over the bracketed range has been demonstrated and the two extreme concentrations of the bracketed range have been shown to be bioequivalent or therapeutically equivalent).
  5. The change in concentration does not involve a patent change.
Supporting Data
  1. (1.2.6) Letters of Access [e.g., Drug Master Files (DMFs)], if new excipients are included.
  2. (1.3) Product Monograph [e.g., Title Page, Storage and Stability (Part I), Dosage Forms, Composition and Packaging (Part I), and Pharmaceutical Information (Part II) section] and Inner and Outer Labels.
  3. (S) Confirmation that information on the drug substance has not changed as a result of the submission [e.g., cross reference(s) should be provided to the previously approved drug submission, quoting the date approved and Control Number(s)] or revised information on the drug substance, if any of the attributes have changed.
  4. (P.1) Description and composition of the dosage form.
  5. (P.2) Discussion of the components of the drug product, as appropriate [e.g., choice of excipients, compatibility of drug substance and excipients, the leachates, compatibility with new container closure system (as appropriate)].
  6. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates, Process Validation and/or Evaluation Studies.
  7. (P.4) Control of Excipients, if new excipients are proposed [e.g., specifications, confirmation that none of the excipients are prohibited by the Food and Drug Regulations].
  8. (P.5) Specification(s), Analytical Procedures (if new analytical methods are used), Validation of Analytical Procedures (if new analytical methods are used), Batch Analyses (certificate of analysis for three (3) consecutive commercial scale batches to be provided in section 3.2.R.3). For multiple strength products, container sizes and/or fill volumes, three (3) commercial scale batches at each end are expected. However, other strategies may be acceptable if scientifically justified (refer to ICH Q1D).
  9. (P.7) Information on the container closure system, if any of the components have changed [e.g. description, materials of construction, summary of specifications].
  10. (P.8.3) Stability test results from: a) accelerated testing (usually a minimum of three (3) months) or, preferably, forced degradation studies under appropriate time and temperature conditions for the product; and b) three (3) months of real time/real temperature testing on three (3) commercial scale batches of the proposed drug product, or longer if less than three (3) time points are available (including the zero time point), as well as commitment to notify Health Canada of any failures in the ongoing long term stability studies (consult with Health Canada for changes b and c). Bracketing and matrixing for multiple strength products, container sizes and/or fills may be acceptable if scientifically justified (refer to ICH Q1D).
  11. Supporting clinical data or a request for a waiver of in vivo studies based on scientific evidences.
  12. Supporting clinical data (usually comparative PK/PD) or a request for a waiver of in vivo studies based on scientific evidences.
3.2.P.1 Description and Composition of the Drug Product: Change to an adjuvant

Change in type/structure of a chemical adjuvant or in the type of a biological adjuvant may necessitate the filing of a NDS. Sponsors are encouraged to contact Health Canada for further guidance.

35. Change involving a chemical/synthetic adjuvant
  1. change in supplier of a chemical/synthetic adjuvant
    • Conditions to be Fulfilled:
      • None
      • 1-2
    • Supporting Data:
      • 4-6,10
      • 5
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. change in manufacture of a chemical/synthetic adjuvant
    • Conditions to be Fulfilled:
      • None
      • 1-2
    • Supporting Data:
      • 4-6,10
      • 5
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  3. change in release specifications of a chemical/synthetic adjuvant (including the tests and/or the analytical procedures)
    • Conditions to be Fulfilled:
      • None
      • 1,3
    • Supporting Data:
      • 6-7,10
      • 7-9
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
36. Change involving a biological adjuvant:Footnote 4
  1. change in supplier of a biological adjuvant
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-7,10-11
    • Reporting Category: Supplement
  2. change in manufacture of a biological adjuvant
    • Conditions to be Fulfilled:
      • None
      • 4
    • Supporting Data:
      • 1-7,10
      • 1-5,7
    • Reporting Category:
      • Supplement
      • Notifiable Change
  3. change in release specifications of a biological adjuvant (including the tests and/or the analytical procedures)
    • Conditions to be Fulfilled:
      • None
      • 1,3
    • Supporting Data:
      • 6-10
      • 7-9
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
Conditions
  1. No change in the release specifications of the adjuvant outside of the approved ranges.
  2. The adjuvant is an aluminium salt.
  3. The change in specifications consists in the addition of a new test or in a minor change to an analytical procedure.
  4. No change in the supplier of the adjuvant.
Supporting Data
  1. (S.2.3) Information assessing the risk with respect to potential contamination with adventitious agents [e.g., impact on the viral clearance studies, BSE/TSE risk].
  2. (S.2.3) Information on the quality and controls of the materials [e.g., raw materials, starting materials] used in the manufacture of the proposed adjuvant.
  3. (S.2.4) Information on the controls performed at critical steps of the manufacturing process and on intermediates of the proposed adjuvant.
  4. (S.2.5) Process validation and/or evaluation studies [e.g., for manufacturing of the adjuvant].
  5. (S.3.1) Description of the general properties, characteristic features and characterization data of the adjuvant, as appropriate.
  6. (S.7.3) Stability test results from: a) accelerated testing (usually a minimum of three (3) months) or, preferably, forced degradation studies under appropriate time and temperature conditions for the product; and b) three (3) months of real time/real temperature testing on three (3) commercial scale batches of the proposed adjuvant, or longer if less than three (3) time points are available (including the zero time point), as well as commitment to notify Health Canada of any failures in the ongoing long term stability studies.
  7. (P.5.1) Updated, QC approved copy of the proposed specifications for the adjuvant (or where applicable, the final version of the specifications to be signed by QC after HC approval).
  8. (P.5.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  9. (P.5.3) Copies or summaries of validation reports, if new analytical procedures are used.
  10. (P.5.4) Description of the batches and summary of results as quantitative data, in a comparative tabular format, for at least three (3) consecutive commercial scale batches of the drug product with the approved and proposed adjuvant, as applicable. Certificates of analysis to be provided in section 3.2.R.3.
  11. Supporting non-clinical and clinical data, if applicable.
3.2.P.1 Description and Composition of the Drug Product: Change to a diluentFootnote 5
37. Change to diluent, involving:
  1. replacement of or addition to the source of a diluent
    • Conditions to be Fulfilled:
      • None
      • 1-3
    • Supporting Data:
      • 1-8
      • 1-4
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. change in facility used to manufacture a diluent (same company)
    • Conditions to be Fulfilled: 1-2
    • Supporting Data: 3-4,6-8
    • Reporting Category: Annual Notification
  3. addition of a diluent filling line
    • Conditions to be Fulfilled: 1-2,4
    • Supporting Data: 1-4,6
    • Reporting Category: Annual Notification
  4. addition of a diluent into a Health Canada approved filling line
    • Conditions to be Fulfilled: 1-2
    • Supporting Data: 1-4,6
    • Reporting Category: Annual Notification
  5. deletion of a diluent
    • Conditions to be Fulfilled: None
    • Supporting Data: None
    • Reporting Category: Annual Notification
Conditions
  1. The diluent is water for injection (WFI) or a salt solution (i.e., does not include an ingredient with a functional activity, e.g., a preservative).
  2. After reconstitution, there is no change in the drug product specifications outside of the approved ranges.
  3. The proposed diluent is commercially available in Canada.
  4. The addition of the diluent filling line is in a Health Canada approved filling facility.
Supporting Data
  1. (P.3.3) Flow diagram (including process and in-process controls) of the proposed manufacturing process(es) and a brief narrative description of the proposed manufacturing process(es).
  2. (P.5.1) Updated, QC approved copy of the proposed specifications for the diluent (or where applicable, the final version of the specifications to be signed by QC after HC approval).
  3. (P.5.4) Description of the batches and summary of results as quantitative data, in a comparative tabular format, for at least three (3) consecutive commercial scale batches of the approved and proposed diluent (certificates of analysis to be provided in section 3.2.R.3, as applicable).
  4. (P.8.3) Stability test results from: a) accelerated testing (usually a minimum of three (3) months) or, preferably, forced degradation studies under appropriate time and temperature conditions for the product; and b) three (3) months of real time/real temperature testing on three (3) commercial scale batches of the proposed diluent, or longer if less than three (3) time points are available (including the zero time point).
  5. (P.8.3) Updated stability data on the product reconstituted with the new diluent.
  6. (A.1) Cleaning procedures (including data in a summary validation report) demonstrating lack of carry-over or cross-contamination.
  7. (A.1) Information on the proposed production facility involved in manufacturing the diluent, including the complete set of floor plans and flow charts (drawings, room classification, water systems, HVAC systems).
  8. (1.2.5) GMP and EL information.
3.2.P.2 Pharmaceutical Development

Health Canada is in the process of adopting the ICH Q8 guideline entitled "Pharmaceutical Development". Establishment of a design space or modification of an approved design space requires the filing of a Supplement. Sponsors are encouraged to contact Health Canada for further guidance.

3.2.P.3 Manufacture
38. Change involving a drug product manufacturer/manufacturing facility, such as:
  1. replacement or addition of a manufacturing facility for the drug product (includes primary packaging facility)
    • Conditions to be Fulfilled:
      • None
      • 1-5
    • Supporting Data:
      • 1-6,8-9,11-14
      • 1-4,6,8-9,11-14
    • Reporting Category:
      • Supplement
      • Notifiable Change
  2. replacement of a formulation/filling suite or addition of an equivalent formulation/filling suite
    • Conditions to be Fulfilled: 1
    • Supporting Data: 3-4,6,8,10,12, 14-15
    • Reporting Category: Notifiable Change
  3. replacement or addition of a secondary packaging facility; a labelling/storage facility; or a distribution facility
    • Conditions to be Fulfilled: 2-3
    • Supporting Data: 1-2,4
    • Reporting Category: Annual Notification
  4. modification to a manufacturing area or modification to an existing service/system [e.g., change to WFI systems or HVAC systems, moving a wall]
    • Conditions to be Fulfilled: 6-7
    • Supporting Data: 7,12,14
    • Reporting Category: Annual Notification
  5. deletion of a drug product manufacturing facility
    • Conditions to be Fulfilled: None
    • Supporting Data: None
    • Reporting Category: Annual Notification
Conditions
  1. The proposed facility is a Health Canada approved formulation/filling facility (for the same company/sponsor).
  2. No change in the composition, manufacturing process and drug product specifications.
  3. No change in the container/closure system.
  4. The same validated manufacturing process is used.
  5. The newly introduced product is in the same family of product(s) or therapeutic classification as the one of those already approved at the site and uses the same filling process/equipment.
  6. The change has no impact on the risk of contamination or cross-contamination.
  7. The modification has no product impact.
Supporting Data
  1. (1.2.5) GMP and EL information.
  2. (P) Updated or new DMF (with a Letter of Access provided in Module 1) or relevant drug product information.
  3. (P) Confirmation that information on the drug product has not changed as a result of the submission [e.g., other than change in facility] or revised information on the drug product, if any of the attributes have changed.
  4. (P.3.1) Name, address, and responsibility of the proposed production facility involved in manufacturing and testing.
  5. (P.3.3) Description of the manufacturing process if different from the approved process and information on the controls performed at critical steps of the manufacturing process and on the intermediate of the proposed drug product.
  6. (P.3.5) Process validation and/or evaluation studies [e.g., equipment qualification, media fills, as appropriate]. The proposed validation protocol is acceptable, but data could be requested.
  7. (P.3.5) Information demonstrating re-qualification of the equipment or re-qualification of the change [e.g., operational qualification, performance qualification], as appropriate.
  8. (P.5.4) Description of the batches and summary of results as quantitative data, in a comparative tabular format, for at least three (3) consecutive commercial scale batches of the approved and proposed drug product (certificates of analysis to be provided in section 3.2.R.3). For multiple strength products, container sizes and/or fill volumes, three (3) commercial scale batches at each end are expected. However, other strategies may be acceptable if scientifically justified (refer to ICH Q1D).
  9. (P.8.1) Summary of stability testing and results [e.g., studies conducted, protocols used, results obtained].
  10. (P.8.2) Commitment to place the first commercial scale batch of the drug product manufactured using the proposed formulation/filling suite into the stability programme, and to notify Health Canada of any failures in the ongoing long term stability studies.
  11. (P.8.3) Stability test results from: a) accelerated testing (usually a minimum of three (3) months) or, preferably, forced degradation studies under appropriate time and temperature conditions for the product; and b) three (3) months of real time/real temperature testing on three (3) commercial scale batches of the drug product manufactured using the proposed manufacturing facility, or longer if less than three (3) time points are available (including the zero time point), as well as commitment to notify Health Canada of any failures in the ongoing long term stability studies. Bracketing and matrixing for multiple strength products, container sizes and/or fills may be acceptable if scientifically justified (refer to ICH Q1D).
  12. (A.1) Information on the proposed production facility involved in the manufacture of the drug product, including the complete set of floor plans and flow charts (drawings, room classification, water systems, HVAC systems), as well as the cleaning and shipping validation, as appropriate.
  13. (A.1) Information describing the change-over procedures for shared product-contact equipment or the segregation procedures, as applicable. If no revisions, a signed attestation that no changes were made to the change-over procedures.
  14. (A.1) Results of the environmental monitoring studies in classified areas.
  15. Rationale for considering the proposed formulation/filling suite as equivalent.
39. Effect on the existing drug products in a drug product manufacturing facility involving introduction of a new product or change in concurrence:
  1. conversion of a drug product manufacturing facility from single-product to multi-product
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-3
    • Reporting Category: Notifiable Change
  2. conversion of formulation and filling area(s) from campaign to concurrent for multiple product manufacturing areas
    • Conditions to be Fulfilled: 1
    • Supporting Data: 1-2
    • Reporting Category: Notifiable Change
  3. introduction of new product into an approved multi-product formulation/filling suite
    • Conditions to be Fulfilled: 2-4
    • Supporting Data: 1-3
    • Reporting Category: Annual Notification
Conditions
  1. The manufacturing process is a closed process for shared areas.
  2. The newly introduced product does not introduce significantly different risk issues (i.e., cytotoxic drugs to cytokine manufacturing area).
  3. The newly introduced product is not of significantly different strength (i.e., mg vs g).
  4. The maximum allowable carry-over is not affected by the introduction of the new product.
Supporting Data
  1. (A.1) Cleaning procedures (including data in a summary validation report and the cleaning protocol for the introduction of new products) demonstrating lack of carry-over or cross-contamination.
  2. (A.1) Information describing the change-over procedures for shared product-contact equipment or the segregation procedures, as appropriate. If no revisions, a signed attestation that no changes were made to the change-over procedures.
  3. (A.1) Information on the product(s) which share the same equipment [e.g., therapeutic classification].
40. Change in the drug product manufacturing process, such as:
  1. scale-up of the manufacturing process at the formulation/filling stage
    • Conditions to be Fulfilled: 1-4
    • Supporting Data: 1,3,5-6,8,11
    • Reporting Category: Notifiable Change
  2. addition or replacement of equipment [e.g., formulation tank, filter housing, filling line and head, and lyophilizer] within the existing filling areas
    • Conditions to be Fulfilled:
      • None
      • 5
    • Supporting Data:
      • 1-4,7,10
      • 3-4
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  3. addition or replacement of equipment [e.g., lyophilizer] in a new area [e.g., adjacent room]
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-4,7,9-10
    • Reporting Category: Notifiable Change
  4. product-contact equipment change from dedicated to shared [e.g., formulation tank, filter housing, filling line and head, lyophilizer]
    • Conditions to be Fulfilled: None
    • Supporting Data: 9
    • Reporting Category: Notifiable Change
  5. addition of a new scale bracketed by the approved scales or scale-down of the manufacturing process
    • Conditions to be Fulfilled: 1-4
    • Supporting Data: 1-3,5,7,11
    • Reporting Category: Annual Notification
  6. change in process flow or procedures
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-3,5-6,8
    • Reporting Category: Notifiable Change
Conditions
  1. The proposed scale uses similar/comparable equipment to that approved (N.B. change in equipment size is not considered as using similar/comparable equipment).
  2. Any changes to the manufacturing process and/or to the in-process controls are only those necessitated by the change in batch size [e.g., the same formulation, controls, standard operating procedures (SOPs) are utilized].
  3. The change should not be a result of recurring events having arisen during manufacture or because of stability concerns.
  4. No change in the principle of the sterilization procedures of the drug product.
  5. For product-contact equipment, the change is considered 'like for like' (i.e. in term of product-contact material/equipment size).
Supporting Data
  1. (P.3.3) Description of the manufacturing process if different from the approved process and information on the controls performed at critical steps of the manufacturing process and on the intermediate of the proposed drug product.
  2. (P.3.4) Information on the in-process control testing, as applicable.
  3. (P.3.5) Process validation and/or evaluation studies [e.g., equipment qualification, media fills, as appropriate]. The proposed validation protocol is acceptable, but data could be requested.
  4. (P.3.5) Information demonstrating qualification of the equipment (operational qualification, performance qualification), or qualification of the change, as applicable.
  5. (P.5.4) Description of the batches and summary of results as quantitative data, in a comparative tabular format, for at least three (3) consecutive commercial scale batches of the approved and proposed drug product (certificates of analysis to be provided in section 3.2.R.3). For multiple strength products, container sizes and/or fill volumes, three (3) commercial scale batches at each end are expected. However, other strategies may be acceptable if scientifically justified (refer to ICH Q1D).
  6. (P.8.1) Summary of stability testing and results [e.g., studies conducted, protocols used, results obtained].
  7. (P.8.2) Commitment to place the first commercial scale batch of the drug product manufactured using the proposed formulation/filling suite into the stability programme, and to notify Health Canada of any failures in the ongoing stability studies.
  8. (P.8.3) Stability test results from: a) accelerated testing (usually a minimum of three (3) months) or, preferably, forced degradation studies under appropriate time and temperature conditions for the product; and b) three (3) months of real time/real temperature testing on three (3) commercial scale batches of the proposed drug product, or longer if less than three (3) time points are available (including the zero time point), as well as commitment to notify Health Canada of any failures in the ongoing long term stability studies. Bracketing and matrixing for multiple strength products, container sizes and/or fills may be acceptable if scientifically justified (refer to ICH Q1D).
  9. (A.1) Information on the updated facility, including updated flow diagrams and identification of the products using the new equipment/area.
  10. (A.1) Cleaning procedures (including data in a summary validation report) demonstrating lack of carry-over or cross-contamination.
  11. Rationale for regarding the equipment as similar/comparable, as applicable.
41. Change in the controls (in-process tests and/or acceptance criteria) applied during the manufacturing process or on intermediates, such as:
  1. deletion of an in-process test
    • Conditions to be Fulfilled: 4-5
    • Supporting Data: 4
    • Reporting Category: Annual Notification
  2. replacement or addition of an in-process test
    • Conditions to be Fulfilled: 1-4,6
    • Supporting Data: 1-3,5
    • Reporting Category: Annual Notification
  3. relaxation of an acceptance criterion
    • Conditions to be Fulfilled: None
    • Supporting Data: 1,4-5
    • Reporting Category: Notifiable Change
  4. tightening of an acceptance criterion
    • Conditions to be Fulfilled:
      • None
      • 2
    • Supporting Data:
      • 1,4-5
      • 1
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
Conditions
  1. The change is not necessitated by recurring events arising during manufacture or because of stability concerns.
  2. The change is within the range of approved acceptance criteria.
  3. Any new analytical procedure does not concern a novel, non-standard technique or a standard technique used in a novel way.
  4. No change in the principle of the sterilization procedures of the drug product.
  5. The deleted test has been demonstrated to be redundant with respect to the remaining tests.
  6. The replaced or added analytical procedure maintains or tightens precision, accuracy, specificity and sensitivity.
Supporting Data
  1. (P.3.3) Description of the proposed process controls or acceptance criteria.
  2. (P.3.5) Method validation for any new analytical procedures.
  3. (P.5.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  4. (P.5.4) Data to show that the relaxation has not a negative impact on the quality of the batch. Results for at least one (1) commercial scale batch is required.
  5. Rationale for the change supported by data.
42. Major change to the following process validation protocols used during the manufacture of the drug product: introduction of product into an approved mutli-product facility, protocol for the cleaning of equipment [e.g., change in the worst-case scenario during cleaning validation process]
  • Conditions to be Fulfilled: None
  • Supporting Data: 1-2
  • Reporting Category: Notifiable Change
Conditions

None

Supporting Data
  1. (P.3.5) Proposed validation protocol. Process validation and/or evaluation studies could be requested.
  2. Rationale for the change in the validation protocol.
3.2.P.4 Control of Excipients
43. Change in the standard/monograph (i.e. specifications) claimed for the excipient
  • Conditions to be Fulfilled:
    • None
    • 1-5
  • Supporting Data:
    • 1-4
    • 1-4
  • Reporting Category:
    • Notifiable Change
    • Annual Notification
44. Change in the specification for the excipient to comply with an updated Schedule B pharmacopoeial standard/monograph
  • Conditions to be Fulfilled: 2-3
  • Supporting Data: 1-2,4
  • Reporting Category: Annual Notification
Conditions
  1. The change is from a House/Professed standard to a Schedule B pharmacopoeial standard/monograph.
  2. The change is made exclusively to comply with a Schedule B pharmacopoeial standard/monograph.
  3. No change to the specifications for the functional properties of the excipient outside of the approved ranges nor that results in a potential impact on the performance of the drug product.
  4. No deletion of tests or relaxation of acceptance criteria of the approved specifications, except to comply with a Schedule B pharmacopoeial standard/monograph.
  5. No deletion or change to any analytical procedures, except to comply with a Schedule B pharmacopoeial standard/monograph.
Supporting Data
  1. (P.4.1) Updated excipient specifications.
  2. (P.4.3) Where a House analytical procedure is used and a Schedule B standard/monograph is claimed, results of an equivalency study between the House and compendial methods.
  3. (P.4.4) Justification of the proposed excipient specifications [e.g., demonstration of the suitability of the monograph to control the excipient and potential impact on the performance of the drug product].
  4. Declaration that consistency of quality and of the production process of the excipient is maintained.
45. Change in the specifications used to release the excipient, involving:
  1. deletion of a test
    • Conditions to be Fulfilled: 5
    • Supporting Data: 1,3-4
    • Reporting Category: Annual Notification
  2. addition of a test
    • Conditions to be Fulfilled: 4
    • Supporting Data: 1-4
    • Reporting Category: Annual Notification
  3. replacement of an analytical procedure
    • Conditions to be Fulfilled: 1-3
    • Supporting Data: 1-2
    • Reporting Category: Annual Notification
  4. minor changes to an approved analytical procedure
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2
    • Reporting Category: Annual Notification
  5. a change from a House/Professed analytical procedure to a Schedule B analytical procedure
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2
    • Reporting Category: Annual Notification
  6. to reflect a pharmacopoeial monograph update
    • Conditions to be Fulfilled: None
    • Supporting Data: 1
    • Reporting Category: Annual Notification
  7. relaxation of an acceptance criterion
    • Conditions to be Fulfilled: 4,6
    • Supporting Data: 1,3-4
    • Reporting Category: Annual Notification
  8. tightening of an acceptance criterion
    • Conditions to be Fulfilled: 3-4
    • Supporting Data: 1
    • Reporting Category: Annual Notification
Conditions
  1. Results of method validation demonstrate that the proposed analytical procedure is at least equivalent to the approved analytical procedure.
  2. The replaced analytical procedure maintains or tightens precision, accuracy, specificity and sensitivity.
  3. The change is within the range of approved acceptance criteria or has been made to reflect new pharmacopoeial monograph specifications for the excipient.
  4. Acceptance criterion for any Class 3 residual solvent is within the ICH limits.
  5. The deleted test has been demonstrated to be redundant with respect to the remaining tests or is no longer a pharmacopoeial requirement.
  6. The change to the specifications does not affect the functional properties of the excipient nor result in a potential impact on the performance of the drug product.
Supporting Data
  1. (P.4.1) Updated excipient specifications.
  2. (P.4.3) Where a House analytical procedure is used and a Schedule B standard is claimed, results of an equivalency study between the House and compendial methods.
  3. (P.4.4) Justification of the proposed excipient specifications [e.g., demonstration of the suitability of the monograph to control the excipient and potential impact on the performance of the drug product].
  4. Declaration that consistency of quality and of the production process of the excipient is maintained.
46. Change in the source of an excipient from a vegetable or synthetic source to a TSE risk [e.g., animal] source
  • Conditions to be Fulfilled: None
  • Supporting Data: 2-8
  • Reporting Category: Supplement
47. Change in the source of an excipient from a TSE risk [e.g., animal] source to a vegetable or synthetic source
  • Conditions to be Fulfilled: 2
  • Supporting Data: 1,3,5-7
  • Reporting Category: Notifiable Change
48. Change in manufacture of a biological excipient
  • Conditions to be Fulfilled:
    • None
    • 2
    • 1-2
  • Supporting Data:
    • 3-8
    • 3,5-8
    • 3,5
  • Reporting Category:
    • Supplement
    • Notifiable Change
    • Annual Notification
49. Change in supplier for a human plasma-derived excipient [e.g., human serum albumin]
  • Conditions to be Fulfilled:
    • None
    • 3-4
  • Supporting Data:
    • 4-9
    • 5-7,10
  • Reporting Category:
    • Supplement
    • Notifiable Change
50. Change in supplier of an excipient of non-biological origin or of biological origin (excluding human plasma-derived excipient)
  • Conditions to be Fulfilled:
    • None
    • 1,5
  • Supporting Data:
    • 3,5-8
    • 3
  • Reporting Category:
    • Notifiable Change
    • Annual Notification
51. Change in excipient testing site
  • Conditions to be Fulfilled: 1
  • Supporting Data: 11
  • Reporting Category: Annual Notification
Conditions
  1. No change in the specifications of the excipient or drug product outside of the approved ranges.
  2. The change does not concern a human plasma-derived excipient.
  3. The excipient from the new supplier is a Health Canada approved excipient.
  4. No chemistry and manufacturing changes were made by the supplier of the new excipient since its last approval in Canada.
  5. The excipient does not influence the structure/conformation of the active ingredient [e.g., Protamine involved in the crystallization of the insulin].
Supporting Data
  1. Declaration from the manufacturer of the excipient that it is entirely of vegetable or synthetic origin.
  2. Details of the source or the excipient [e.g., animal species, country of origin] and the steps undertaken in processing to minimize the risk of TSE exposure.
  3. Information demonstrating comparability in term of physico-chemical characterization and impurity profile of the proposed excipient with the approved excipient.
  4. (P.3.3) Information on the manufacturing process and on the controls performed at critical steps of the manufacturing process and on the intermediate of the proposed excipient.
  5. (P.4.5) Description of the batches and summary of results as quantitative data, in a comparative tabular format, for at least three (3) commercial scale batches of the proposed excipient (certificates of analysis to be provided in section 3.2.R.3).
  6. (P.5.4) Description of the batches and summary of results as quantitative data, in a comparative tabular format, for at least three (3) batches of the drug product with the proposed excipient (certificates of analysis to be provided in section 3.2.R.3).
  7. (P.8.3) Stability test results from: a) accelerated testing (usually a minimum of three (3) months) or, preferably, forced degradation studies under appropriate time and temperature conditions for the product; and b) three (3) months of real time/real temperature testing on three (3) batches of the drug product with the proposed excipient, or longer if less than three (3) time points are available (including the zero time point), as well as commitment to notify Health Canada of any failures in the ongoing long term stability studies.
  8. (A.2) Information assessing the risk with respect to potential contamination with adventitious agents [e.g., impact on the viral clearance studies, BSE/TSE risk].
  9. Complete manufacturing and clinical safety data to support the use of the proposed human plasma-derived excipient.
  10. Letter from the supplier certifying that no changes were made to the excipient since its last approval in Canada (DIN provided).
  11. Evidence that the new company/facility is GMP compliant.
3.2.P.5 Control of Drug Product
52. Changes affecting the quality control (QC) testing of the drug product (release and stability), involving:
  1. transfer of the QC testing activities for a non-pharmacopoeial assay (in-house) to a new company or to a different facility within the same company
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2
    • Reporting Category: Notifiable Change
  2. transfer of the QC testing activities for a pharmacopoeial assay (in-house) to a new company not listed on the Establishment Licence of the manufacturer/sponsor
    • Conditions to be Fulfilled: 1
    • Supporting Data: 1-2
    • Reporting Category: Annual Notification
Conditions
  1. The transferred QC test is not a potency assay or a bioassay.
Supporting Data
  1. (P.3.5) Information demonstrating technology transfer qualification.
  2. Evidence that the new company/facility is GMP compliant.
53. Change in the standard/monograph (i.e. specifications) claimed for the drug product, involving:
  1. a change from a Schedule B pharmacopoeial standard/monograph to a House standard
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-5
    • Reporting Category: Notifiable Change
  2. a change from a House/Professed standard to Schedule B pharmacopoeial standard/ monograph or from one Schedule B standard/ monograph to a different Schedule B standard/monograph)
    • Conditions to be Fulfilled: 1-4
    • Supporting Data: 1-3
    • Reporting Category: Annual Notification
54. Change in the specifications for the drug product to comply with an updated Schedule B pharmacopoeial standard/monograph
  • Conditions to be Fulfilled: 1-2
  • Supporting Data: 1-3
  • Reporting Category: Annual Notification
Conditions
  1. The change is made exclusively to comply with a Schedule B pharmacopoeial standard/monograph.
  2. The change to the specifications does not result in a potential impact on the performance of the drug product (i.e., the new standard is not less stringent than the approved standard/specifications).
  3. No deletion of tests or relaxation of acceptance criteria of the approved specifications, except to comply with a Schedule B pharmacopoeial standard/monograph.
  4. No deletion or change to any analytical procedures, except to comply with a Schedule B pharmacopoeial standard/monograph.
Supporting Data
  1. (1.3) Product Monograph [e.g., Where applicable, Title Page, Composition and Packaging (Part I), and Pharmaceutical Information (Part II) section] and Inner and Outer Labels.
  2. (P.4.3) Copies or summaries of validation reports, if new analytical procedures are used.
  3. (P.5.1) Updated, QC approved copy of the proposed drug product specifications (or where applicable, the final version of the specifications to be signed by QC after HC approval).
  4. (P.5.3) Where a House analytical procedure is used and a Schedule B standard is claimed, results of an equivalency study between the House and compendial methods.
  5. Justification of specifications with data.
55. Change in the specifications used to release the drug product, involving:
  1. for sterile products, replacing the sterility test with process parametric release
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2,6,8-9
    • Reporting Category: Supplement
  2. deletion of a test
    • Conditions to be Fulfilled: None
    • Supporting Data: 2,8-9
    • Reporting Category: Notifiable Change
  3. addition of a test
    • Conditions to be Fulfilled: 1-2
    • Supporting Data: 2-4,8
    • Reporting Category: Annual Notification
  4. change in animal species/strains for a test [e.g., new species/ strains, animals of different age, new supplier where genotype of the animal cannot be confirmed]
    • Conditions to be Fulfilled: None
    • Supporting Data: 5,10
    • Reporting Category: Notifiable Change
  5. replacement of an analytical procedure
    • Conditions to be Fulfilled: None
    • Supporting Data: 2-4,7
    • Reporting Category: Notifiable Change
  6. minor changes to an approved analytical procedure
    • Conditions to be Fulfilled: 3-6
    • Supporting Data: 3-4,7
    • Reporting Category: Annual Notification
  7. change from a House/Professed analytical procedure to a Schedule B analytical procedure or change from an approved compendial analytical procedure to an harmonized compendial procedure
    • Conditions to be Fulfilled: 3,6
    • Supporting Data: 2-4
    • Reporting Category: Annual Notification
  8. relaxation of an acceptance criterion
    • Conditions to be Fulfilled: None
    • Supporting Data: 2,8-9
    • Reporting Category: Notifiable Change
  9. tightening of an acceptance criterion
    • Conditions to be Fulfilled: 7-8
    • Supporting Data: 2
    • Reporting Category: Annual Notification
Conditions
  1. No change in the limits/acceptance criteria outside of the approved ranges for the approved assays.
  2. The addition of test is not to monitor new impurity species.
  3. No change in the acceptance criteria outside of the approved ranges.
  4. The method of analysis is the same [e.g., a change in column length or temperature, but not a different type of column or method] and no new impurities are detected.
  5. The modified analytical procedure maintains or tightens precision, accuracy, specificity and sensitivity.
  6. The change does not concern potency testing.
  7. The change is within the range of approved acceptance criteria.
  8. Acceptance criterion for any Class 3 residual solvent is within the ICH limits.
Supporting Data
  1. (P.3.5) Process validation and/or evaluation studies or validation protocol of the proposed drug product.
  2. (P.5.1) Updated, QC approved copy of the proposed drug product specifications (or where applicable, the final version of the specifications to be signed by QC after HC approval).
  3. (P.5.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  4. (P.5.3) Copies or summaries of validation reports, if new analytical procedures are used.
  5. (P.5.3) Data demonstrating that the change in animals gives comparable results with those obtained using the approved animals.
  6. (P.5.4) Description of the batches and summary of results as quantitative data, of a sufficient number of batches to support the process parametric release (certificates of analysis to be provided in section 3.2.R.3).
  7. (P.5.6) Justification for the change to the analytical procedure [e.g., demonstration of the suitability of the analytical procedure to monitor the drug product, including the degradation products].
  8. (P.5.6) Justification of the proposed drug product specifications [e.g., demonstration of the suitability of the monograph to control the drug product, including degradation products].
  9. Declaration/evidences that consistency of quality and of the production process is maintained.
  10. Copies of relevant certificate of fitness for use [e.g., veterinary certificate].
3.2.P.6 Reference Standards or Materials used to release the Drug Product
56. Change the reference standards from pharmacopoeial to House
  • Conditions to be Fulfilled: None
  • Supporting Data: 1-2
  • Reporting Category: Notifiable Change
57. Change the reference standards from House/Professed to pharmacopoeial
  • Conditions to be Fulfilled: 1-2
  • Supporting Data: 1-2
  • Reporting Category: Annual Notification
58. Qualification of a new lot of reference standard against the approved reference standard
  • Conditions to be Fulfilled: 1-2
  • Supporting Data: 2
  • Reporting Category: Annual Notification
59. Change to reference standard qualification protocol
  • Conditions to be Fulfilled:
    • None
    • 2-3
  • Supporting Data:
    • 3-4
    • 4
  • Reporting Category:
    • Notifiable Change
    • Annual Notification
60. Extension of reference standard shelf life
  • Conditions to be Fulfilled: 2
  • Supporting Data: 5
  • Reporting Category: Annual Notification
Conditions
  1. Qualification of the reference standard is performed according to the approved protocol (i.e. no deviation from the approved protocol).
  2. The reference standard is not for a key quality control or in process control assay for a bacterial or a viral vaccine, for bacterial toxins or for a product in lot release group 2.
  3. The protocol is considered more stringent (i.e., addition of new tests or tightening of acceptance criteria). If deletion of tests is proposed, the tests proposed to be deleted were not implemented to monitor the quality of the reference standard [e.g., was implemented for research or validation work].
Supporting Data
  1. (1.3) Revised Product monograph to reflect the change in reference standard.
  2. (P.6) Information demonstrating qualification of the proposed reference standards or materials [e.g., source, characterization, certificate of analysis].
  3. (P.6) Justification of the change to reference standard qualification protocol.
  4. (P.6) Updated reference standard qualification protocol.
  5. (P.8.1) Summary of stability testing and results to support the extension of reference standard shelf life.
3.2.P.7 Container Closure System
61. Modification of a primary container closure system [e.g., new coating, adhesive, stopper, type of glass]
  • Conditions to be Fulfilled:
    • None
    • 1-3
  • Supporting Data:
    • 1-7
    • 1,3
  • Reporting Category:
    • Notifiable Change
    • Annual Notification
62. Addition of a secondary functional container closure system [e.g., pre-filled autoinjector]
  • Conditions to be Fulfilled: None
  • Supporting Data: 1-3,7
  • Reporting Category: Notifiable Change
63. Change from a reusable container to a disposable container with no changes in product-contact material [e.g., change from reusable pen to disposable pen]
  • Conditions to be Fulfilled: None
  • Supporting Data: 1,3,7
  • Reporting Category: Notifiable Change
64. Change from approved single-dose container to multi-dose container
  • Conditions to be Fulfilled: None
  • Supporting Data: 1-7
  • Reporting Category: Notifiable Change
65. Deletion of a container closure system
  • Conditions to be Fulfilled: None
  • Supporting Data: 1
  • Reporting Category: Annual Notification
Conditions
  1. No change in the type of container closure or materials of construction.
  2. No change in the shape or dimensions of the container closure.
  3. The change is made only to improve quality of the container and does not modify the product-contact material [e.g., increase thickness of the glass vial without changing interior dimension].
Supporting Data
  1. (1.3) Product Monograph [e.g., Where applicable, Title Page, Storage and Stability (Part I), Dosage Forms, Composition and Packaging (Part I)] and Inner and Outer Labels, as appropriate.
  2. (P.3.5) For sterile products, process validation and/or evaluation studies, or provide equivalency rationale. For a secondary functional container closure system, validation testing report.
  3. (P.7) Information on the proposed container closure system, as appropriate [e.g., description, materials of construction of primary/secondary packaging components, performance specifications].
  4. (P.7) Results demonstrating protection against leakage, no leaching of undesirable substance, compatibility with the product, and results from the toxicity and the biological reactivity tests.
  5. (P.8.1) Summary of stability testing and results [e.g., studies conducted, protocols used, results obtained].
  6. (P.8.3) Stability test results from: a) accelerated testing (usually a minimum of three (3) months) or, preferably, forced degradation studies under appropriate time and temperature conditions for the product; and b) three (3) months of real time/real temperature testing on three (3) drug product batches stored in the proposed container, or longer if less than three (3) time points are available (including the zero time point), as well as commitment to notify Health Canada of any failures in the ongoing long term stability studies. Bracketing and matrixing for multiple strength products, container sizes and/or fills may be acceptable if scientifically justified (refer to ICH Q1D).
  7. (A.1) Information demonstrating suitability of the proposed container/closure system with respect to its relevant properties [e.g., results from last media fills, results of transportation and/or interaction studies demonstrating preservation of protein integrity and maintenance of the sterility for sterile products, maintenance of the sterility in multi-dose container].
66. Change in the supplier for a primary container closure component, involving:
  1. replacement or addition of a supplier
    • Conditions to be Fulfilled:
      • None
      • 1-2
    • Supporting Data:
      • 1-3
      • None
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. deletion of a supplier
    • Conditions to be Fulfilled: None
    • Supporting Data: None
    • Reporting Category: Annual Notification
Conditions
  1. No change in the type of container closure, materials of construction, shape, dimensions or in the sterilization process for a sterile container closure component.
  2. No change in the specifications of the container closure component outside of the approved ranges.
Supporting Data
  1. (P.2) Data demonstrating the suitability of the container closure system [e.g., extractable/leachable testing].
  2. (P.7) Information on the proposed container closure system [e.g., description, materials of construction of primary packaging components, specifications].
  3. (P.8.3) Stability test results from: a) accelerated testing (usually a minimum of three (3) months) or, preferably, forced degradation studies under appropriate time and temperature conditions for the product; and b) three (3) months of real time/real temperature testing on one (1) drug product batch stored in the proposed container, or longer if less than three (3) time points are available (including the zero time point), as well as commitment to notify Health Canada of any failures in the ongoing long term stability studies. Bracketing and matrixing for multiple strength products, container sizes and/or fills may be acceptable if scientifically justified (refer to ICH Q1D).
67. Change in the specifications used to release a primary or functional secondary container closure component, involving:
  1. deletion of a test
    • Conditions to be Fulfilled: 1-2
    • Supporting Data: 1-2
    • Reporting Category: Annual Notification
  2. addition of a test
    • Conditions to be Fulfilled: 3
    • Supporting Data: 1-2
    • Reporting Category: Annual Notification
  3. replacement of an analytical procedure
    • Conditions to be Fulfilled: 6-7
    • Supporting Data: 1-3
    • Reporting Category: Annual Notification
  4. minor changes to an analytical procedure
    • Conditions to be Fulfilled: 4-7
    • Supporting Data: 1-3
    • Reporting Category: Annual Notification
  5. relaxation of an acceptance criterion
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2
    • Reporting Category: Notifiable Change
  6. tightening of an acceptance criterion
    • Conditions to be Fulfilled: 8
    • Supporting Data: 1
    • Reporting Category: Annual Notification
Conditions
  1. The deleted test has been demonstrated to be redundant with respect to the remaining tests or is no longer a pharmacopoeial requirement.
  2. The change to the specifications does not affect the functional properties of the container closure component nor result in a potential impact on the performance of the drug product.
  3. The change is not necessitated by recurring events arising during manufacture or because of stability concerns.
  4. No change in the acceptance criteria outside of the approved ranges.
  5. The new analytical procedure is of the same type.
  6. Results of method validation demonstrate that the new or modified analytical procedure is at least equivalent to the approved analytical procedure.
  7. The new or modified analytical procedure maintains or tightens precision, accuracy, specificity and sensitivity.
  8. The change is within the range of approved acceptance criteria or has been made to reflect new pharmacopoeial monograph specifications for the container closure component.
Supporting Data
  1. (P.7) Updated, QC approved copy of the proposed specifications for the primary or functional secondary container closure component (or where applicable, the final version of the specifications to be signed by QC after HC approval).
  2. (P.7) Rationale for the change in specifications for a primary container closure component.
  3. (P.7) Description of the analytical procedure and, if applicable, validation data.
3.2.P.8 Stability
68. Change in the shelf life for the drug product, involving:
  1. extension
    • Conditions to be Fulfilled:
      • None
      • 1-5
    • Supporting Data:
      • 1-4,6
      • 1-2,5
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. reduction
    • Conditions to be Fulfilled:
      • None
      • 6
    • Supporting Data:
      • 1-5
      • 2-4
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
Conditions
  1. No changes to the container closure system in direct contact with the drug product with the potential of impact on the drug product; or to the recommended storage conditions of the drug product.
  2. The approved shelf life is at least 24 months.
  3. Full long term stability data are available covering the proposed shelf life and are based on stability data generated on at least three (3) commercial scale batches.
  4. Stability data were generated in accordance with the approved stability protocol.
  5. Significant changes (as defined in ICH's Q1A guideline) were not observed in the stability data.
  6. The reduction in the shelf life is not necessitated by recurring events arising during manufacture or because of stability concerns (i.e. problems arising during manufacturing or stability concerns should be reported for evaluation).
Supporting Data
  1. (P.8.1) Summary of stability testing and results [e.g., studies conducted, protocols used, results obtained].
  2. (P.8.1) Proposed storage conditions and shelf life, as appropriate.
  3. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment.
  4. (P.8.2) Justification of the change to the post-approval stability protocol or stability commitment.
  5. (P.8.3) Results of stability testing on both upright and inverted samples, except for lyophilized products (i.e., full real time/real temperature stability data covering the proposed shelf life generated on at least three (3) commercial scale batches).
  6. (P.8.3) Interim stability testing results and a commitment to notify Health Canada of any failures in the ongoing long term stability studies. Extrapolation of shelf life should be made in accordance with ICH Q1E guideline.
69. Change in the post-approval stability protocol of the drug product, involving:
  1. major change to the post-approval stability protocol or stability commitment such as deletion of a test, replacement of an analytical procedure, change in storage temperature
    • Conditions to be Fulfilled:
      • None
      • 1-2
    • Supporting Data:
      • 3-6
      • 1-2,4-5
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. addition of time point(s) into the post-approval stability protocol
    • Conditions to be Fulfilled: None
    • Supporting Data: 4-5
    • Reporting Category: Annual Notification
  3. addition of test(s) into the post-approval stability protocol
    • Conditions to be Fulfilled: 3
    • Supporting Data: 4-5
    • Reporting Category: Annual Notification
  4. deletion of time point(s) from the post-approval stability protocol beyond the approved shelf life
    • Conditions to be Fulfilled: None
    • Supporting Data: 4-5
    • Reporting Category: Annual Notification
  5. deletion of time point(s) from the post-approval stability protocol within the approved shelf life
    • Conditions to be Fulfilled: 4
    • Supporting Data: 4-5
    • Reporting Category: Annual Notification
  6. replacement of the sterility testing by the container/closure system integrity testing
    • Conditions to be Fulfilled:
      • None
      • 5
    • Supporting Data:
      • 1-2,4-5
      • 4-5
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
Conditions
  1. For the replacement of an analytical procedure, the results of method validation demonstrate that the new analytical procedure is at least equivalent to the approved analytical procedure.
  2. For the replacement of an analytical procedure, the new analytical procedure maintains or tightens precision, accuracy, specificity and sensitivity.
  3. The addition of test(s) is not due to stability concerns or to the identification of new impurities.
  4. The approved drug product shelf life is at least 24 months.
  5. The method used to demonstrate the container/closure system integrity has already been approved as part of a previous application [e.g., NDS, S/NDS, NC].
Supporting Data
  1. (P.5.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  2. (P.5.3) Copies or summaries of validation reports, if new analytical procedures are used.
  3. (P.8.1) Proposed storage conditions and or shelf life, as appropriate.
  4. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment.
  5. (P.8.2) Justification of the change to the post-approval stability protocol or stability commitment.
  6. (P.8.3) If applicable, stability testing results to support the change to the post-approval stability protocol or stability commitment [e.g., data to show greater reliability of the alternate test].
70. Change in the labelled storage conditions for the drug product or the diluted or reconstituted product, involving:
  1. addition or change of storage condition for the drug product [e.g., relaxation or tightening of a temperature criterion]
    • Conditions to be Fulfilled:
      • None
      • 1-2
    • Supporting Data:
      • 1-5
      • 1-4
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. addition of a cautionary statement
    • Conditions to be Fulfilled: 1
    • Supporting Data: 1-2,4-5
    • Reporting Category: Annual Notification
  3. deletion of a cautionary statement
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2,4,6
    • Reporting Category: Annual Notification
Conditions
  1. The change is not necessitated by recurring events arising during manufacture or because of stability concerns.
  2. The change consists in the tightening of a temperature criterion within the approved ranges.
Supporting Data
  1. (1.3) Revised Product Monograph [e.g., Where applicable, Title Page, Composition and Packaging (Part I), and Pharmaceutical Information (Part II) section] and Inner and Outer Labels, as applicable.
  2. (P.8.1) Proposed storage conditions and shelf life.
  3. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment.
  4. (P.8.2) Justification of the change in the labelled storage conditions/cautionary statement.
  5. (P.8.3) Results of stability testing (i.e., full real time/real temperature stability data covering the proposed shelf life generated on one (1) commercial scale batch).
  6. (P.8.3) Results of stability testing (i.e., full real time/real temperature stability data covering the proposed shelf life generated on at least three (3) commercial scale batches).

Appendix 4: Quality Post-NOC Changes (Schedule C Drugs)

Radiopharmaceuticals, kits and generators are listed in Schedule C to the Food and Drugs Act and regulated under the Food and Drug Regulations. Radiopharmaceuticals are pre-radiolabelled drug products ready for patient administration. Kits contain a drug substance of either chemical or biologic origin which is reconstituted with the recommended radioisotope immediately prior to patient administration. Generators contain a parent radionuclide undergoing decay to a daughter radionuclide [e.g., Mo-99 to Tc-99m] which is then eluted from the generator for use either in the reconstitution of kits or for direct administration to the patient. Each of these products contain radionuclides that exhibit spontaneous disintegration of unstable nuclei with the emission of nuclear particles or photons (such as positron, beta negative or gamma ray).

In the guidance below, a radiolabelled product resulting from reconstitution of a kit is referred to as a "reconstituted final drug product" to distinguish it from a pre-radiolabelled drug product (radiopharmaceutical). These two types of radiopharmaceutical products are handled together whereas generators are handled separately. The examples are grouped, in order, as follows:

  • 3.2.S Drug Substance (Kits/radiopharmaceuticals containing drug substance of chemical origin).
  • 3.2.S Drug Substance (Kits/radiopharmaceuticals containing drug substance of biological origin).
  • 3.2.P Drug Product (Kits/radiopharmaceuticals containing drug substance of chemical or biological origin).
  • 3.2.P Drug Product (Generators).

The information summarized in the tables provides recommendations for:

  1. the conditions to be fulfilled for a given change to be classified as a either a Level I, II, or III change. If any of the conditions outlined for a given change are not fulfilled, the change is automatically considered the next higher level of change. For example, if any of the conditions recommended for a Level II - Notifiable Change are not fulfilled, the change is considered a Level I - Supplement. Similarly, if any of the conditions recommended for a Level I - Supplement are not fulfilled, the change would warrant the filing of an NDS;
  2. the supporting data for a given change, either to be submitted to Health Canada and/or maintained by the sponsor. Where applicable, the corresponding modules of the Common Technical Document (CTD) for the supporting data have been identified in brackets. An adequate rationale is required when supporting data cannot be provided. (N.B. Guidance for using CTD document for Schedule C drugs is under development. Therefore, the numbering is not directly relevant to the use of the QIS-R);
  3. the reporting category [e.g., Supplement, Notifiable Change or Annual Notification].

3.2.S Drug Substance (Kits/radiopharmaceuticals containing drug substance of chemical origin)

3.2.S.1 General Information
1. Change in the name of the drug substance
  • Conditions to be Fulfilled: 1
  • Supporting Data: 1-2
  • Reporting Category: Annual Notification
Conditions
  1. Confirmation that the information on the drug substance has not changed as a result of the change [e.g., cross reference(s) should be provided to the previously approved drug submission, including brand name of the drug product, manufacturer's/sponsor's name, submission type, control number, date approved].
Supporting Data
  1. (1.3) Product Monograph [e.g., Where applicable, Title Page, Storage and Stability (Part I), Dosage Forms, Composition and Packaging (Part I), and Pharmaceutical Information (Part II) section] or Package Insert for veterinary drugs, and Inner and Outer Labels.
  2. (S.1.1) Information on the proposed nomenclature of the drug substance [e.g., chemical name(s), compendial name] and evidence that the proposed name for the drug substance is recognized [e.g., Recommended INN, USAN, BAN].
3.2.S.2 Manufacture
2. Replacement or addition of a manufacturing site and/or manufacturer involving:
  1. production of the starting material, intermediate, or drug substance
    • Conditions to be Fulfilled:
      • None
      • 3,5
      • 1-5
    • Supporting Data:
      • 1-6,8-9
      • 2-6,8-9
      • 3-6,8
    • Reporting Category:
      • Supplement
      • Notifiable Change
      • Annual Notification
  2. testing [e.g., release, stability]
    • Conditions to be Fulfilled: None
    • Supporting Data: 2-5,7
    • Reporting Category: Notifiable Change
3. Deletion of a manufacturing site or manufacturer for the starting material, intermediate, or drug substance
  • Conditions to be Fulfilled: None
  • Supporting Data: None
  • Reporting Category: Annual Notification
Conditions
  1. No Level I or Level II changes in the drug substance specifications.
  2. No change in the route of synthesis, physical characteristics, and impurity profile of the drug substance (that is [i.e.] no new impurity above 0.10%, no change in the approved total impurity limit and residual solvents within ICH limits).
  3. Where materials of human or animal origin are used in the process, the manufacturer does not use any new supplier for which assessment of viral safety data or TSE risk assessment is required.
  4. The change does not concern a sterile drug substance.
  5. The change concerns drug substances that are discrete chemical entities (i.e. this does not include polymeric complexes).
Supporting Data
  1. (1,5) Viral safety data (ref. Condition 3) or supporting or comparative bioavailability data (ref. Condition 5) (whichever is applicable to be included in CTD modules 1&5).
  2. (1.2.5) GMP and EL information.
  3. (S) Updated or new DMF (with a Letter of Access provided in Module 1), any relevant drug substance information should be provided where available.
  4. (S.2) Confirmation that the synthetic route, process controls, control of materials, and specifications of the intermediate or drug substance (as appropriate) in the manufacturing process of the proposed drug substance are the same as those previously approved or revised information if any of the attributes have changed.
  5. (S.2.1) Name, address, and responsibility of the proposed production site or facility involved in manufacturing and testing.
  6. (S.2.3) For drug substances or drug substances manufactured with reagents obtained from sources that are at risk of transmitting BSE/TSE agents [e.g., ruminant origin], information and evidence that the material does not pose a potential BSE/TSE risk [e.g., name of manufacturer, species and tissues from which the material is a derivative, country of origin of the source animals, its use and previous acceptance] should be provided where available.
  7. (S.4.3) Copies or summaries of validation reports, which demonstrate equivalency of analytical procedures to be used at the proposed testing site.
  8. (S.4.4) Description of the batches, certificates of analyses or batch analysis report, and summary of results, in a comparative tabular format, for one batch of the currently approved and proposed drug substance release testing sites.
  9. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of the drug product manufactured using the proposed drug substance into the long term stability programme (bracketing and matrixing with justification would be acceptable for multiple strength products).
4. Change in the manufacturing process for the drug substance or intermediate
  • Conditions to be Fulfilled:
    • 1
    • 1-4,8
    • 1-8
  • Supporting Data:
    • 1-11
    • 2-9,11
    • 2-6,8-9,11
  • Reporting Category:
    • Supplement
    • Notifiable Change
    • Annual Notification
Conditions
  1. No change in the identicality of the drug substance (as defined in the Health Canada policy Interpretation of "Identical Medicinal Ingredient").
  2. No change in the physical state [e.g. crystalline, amorphous, solid, semi-solid, liquid or gas] of the drug substance.
  3. For low solubility drug substances, no change in the polymorphic form or no change in the particle size distribution of the drug substance.
  4. Where materials of human or animal origin are used in the process, the manufacturer does not use any new process for which assessment of viral safety data or TSE risk assessment is required.
  5. No Level I or Level II change in the drug substance specifications.
  6. No change in the route of synthesis (i.e. intermediates remain the same), physical characteristics, and impurity profile of the drug substance (no new impurity above 0.10%, no change in the approved total impurity limit and residual solvents within ICH limits).
  7. The change does not concern a sterile drug substance.
  8. The change concerns drug substances that are discrete chemical entities (i.e. this does not include polymeric complexes).
Supporting Data
  1. (1,5) Viral safety data (ref. Condition 4) or supporting clinical or comparative bioavailability data (ref. Conditions 3,8) (whichever is applicable to be included in CTD modules 1&5).
  2. (S) Updated or new DMF (with a Letter of Access provided in Module 1) or relevant drug substance information.
  3. (S.2.2) Flow diagram of the proposed synthetic process(es) and a brief narrative description of the proposed manufacturing process(es).
  4. (S.2.3) Information on the quality and controls of the materials [e.g., raw materials, starting materials, solvents, reagents, catalysts] used in the manufacture of the proposed drug substance.
  5. (S.2.3) For drug substances or drug substances manufactured with reagents obtained from sources that are at risk of transmitting BSE/TSE agents [e.g., ruminant origin], information and evidence that the material does not pose a potential BSE/TSE risk [e.g., name of manufacturer, species and tissues from which the material is a derivative, country of origin of the source animals, its use and previous acceptance] should be provided where available.
  6. (S.2.4) Information on the controls performed at critical steps of the manufacturing process and on intermediates of the proposed drug substance.
  7. (S.2.5) Evidence of process validation and/or evaluation studies for sterilization.
  8. (S.3.1) Evidence for elucidation of structure, where applicable.
  9. (S.4.4) Description of the batches, certificates of analyses or batch analysis report, and summary of results, in a comparative tabular format, for at least one (1) batch of the currently approved and proposed processes.
  10. (S.7.3) Results of two (2) batches with a minimum of three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing of the proposed drug substance.
  11. (P.8.2) Updated post-approval stability protocol and stability commitment to place the first commercial scale batch of the drug product, manufactured using the proposed drug substance, into the long term stability programme.
5. Change in the batch size for the drug substance
  • Conditions to be Fulfilled:
    • None
    • 1-8
  • Supporting Data:
    • 1-3
    • 1-3
  • Reporting Category:
    • Notifiable Change
    • Annual Notification
Conditions
  1. No change in the proportionality of the raw materials.
  2. Changes to the method of manufacture are only those necessitated by change in batch size [e.g., use of different-sized equipment].
  3. The change is not necessitated by unexpected events, resulting in failure to meet specifications, arising during manufacture or because of stability concerns.
  4. No Level I or Level II changes in the drug substance specifications.
  5. Up to 10-fold scale-up or scale-down compared to approved batch size.
  6. The change does not affect the sterilization procedures of a sterile drug substance.
  7. The change concerns drug substances that are discrete chemical entities (i.e. this does not include polymeric complexes).
  8. The change does not concern a sterile drug substance.
Supporting Data
  1. (S.2.2) A brief narrative description of the proposed manufacturing process(es).
  2. (S.2.5) Evidence of process validation and/or evaluation studies for sterilization.
  3. (S.4.4) Description of the batches, certificates of analyses or batch analysis report, and summary of results, in a tabular format, for at least one batch.
6. Change in the controls for the materials used in the manufacture of the drug substance [e.g., raw materials, starting materials, solvents, reagents, catalysts] or the controls performed at critical steps in the process
  • Conditions to be Fulfilled:
    • None
    • 1-5
  • Supporting Data:
    • 1 or 2-4
    • 1 or 2,4
  • Reporting Category:
    • Notifiable Change
    • Annual Notification
Conditions
  1. No Level I or Level II change in the drug substance specifications.
  2. No change in the impurity profile of the drug substance (i.e. no new impurity above 0.1%, no change in the approved total impurity limit and residual solvents within ICH limits).
  3. The change in control(s) does not constitute a relaxation from the approved controls and is not necessitated by unexpected events, resulting in failure to meet specifications, arising during manufacture or because of stability concerns.
  4. The change does not affect the sterilization procedures of a sterile drug substance.
  5. The change concerns drug substances that are discrete chemical entities (i.e. this does not include polymeric complexes).
Supporting Data
  1. (S.2.3) Information on the quality and controls of the materials [e.g., raw materials, starting materials, solvents, reagents, catalysts] used in the manufacture of the proposed drug substance.
  2. (S.2.4) Information on the controls performed at critical steps of the manufacturing process and on intermediates of the proposed drug substance.
  3. (S.2.5) Evidence of process validation and/or evaluation studies for sterilization.
  4. (S.4.4) Description of the batches, certificates of analyses or batch analysis report, and summary of results, in a comparative tabular format, for at least one batch each of the drug substance manufactured by the current and proposed methods.
3.2.S.3 Characterisation

There are not any quality change examples for this section at the present time that have not been addressed in other sections.

3.2.S.4 Control of the Drug Substance
7. Change in the standard claimed for the drug substance [e.g., from a Professed to Schedule B pharmacopoeial standard or from one Schedule B standard to a different Schedule B standard]
  • Conditions to be Fulfilled: 1-3
  • Supporting Data: 1-4
  • Reporting Category: Annual Notification
8. Change in the specification for the drug substance to comply with an updated Schedule B pharmacopoeial monograph
  • Conditions to be Fulfilled: 1-2
  • Supporting Data: 1-4
  • Reporting Category: Annual Notification
Conditions
  1. The change is made exclusively to comply with the pharmacopoeia.
  2. No Level I or Level II changes to the specifications (i.e., functional properties of the drug substance e.g., particle size distribution, polymorphic form).
  3. No deletion of or relaxation to any of the tests, analytical procedures, or acceptance criteria of the approved specification.
Supporting Data
  1. (S.4.1) Updated, QC approved, proposed drug substance specification.
  2. (S.4.3) Where a House analytical procedure is used and a Schedule B standard is claimed, results of an equivalency study between the House and compendial methods.
  3. (S.4.4) Description of the batches, certificates of analyses or batch analysis report, and summary of results, in a tabular format, for at least one batch if new tests and/or analytical methods are implemented.
  4. (S.4.5) Justification of the proposed drug substance specification [e.g., demonstration of the suitability of the monograph to control the drug substance, including impurities].
9. Change in the specification for the drug substance involving test and acceptance criteria:
  1. for sterile drug substances, replacing the sterility test with process parametric release
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-7
    • Reporting Category: Supplement
  2. deletion of a test
    • Conditions to be Fulfilled:
      • None
      • 1-2,5
    • Supporting Data:
      • 2,7
      • 2,7
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  3. replacement of a test
    • Conditions to be Fulfilled: 1-7
    • Supporting Data: 2-5,7
    • Reporting Category: Annual Notification
  4. addition of a test
    • Conditions to be Fulfilled: 1,3-4,6-7
    • Supporting Data: 2-5,7
    • Reporting Category: Annual Notification
  5. relaxation of an acceptance criterion
    • Conditions to be Fulfilled:
      • None
      • 1,4,6-7
    • Supporting Data:
      • 2,7
      • 2,7
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  6. tightening of an acceptance criterion
    • Conditions to be Fulfilled: 1-2,4,6-7
    • Supporting Data: 2,7
    • Reporting Category: Annual Notification
Conditions
  1. The change is not necessitated by unexpected events, resulting in failure to meet specifications, arising during manufacture or because of stability concerns.
  2. The change is within the range of approved acceptance criteria.
  3. Any new analytical procedure does not concern a novel, non-standard technique or a standard technique used in a novel way.
  4. No change in the impurity profile that impacts safety of the drug substance. Acceptance criterion for any Class 3 residual solvent is within the ICH limits (the relaxation of an acceptance criterion for a Class 1 or 2 solvent should be filed as a Notifiable Change).
  5. The deleted test has been demonstrated to be redundant with respect to the remaining tests.
  6. The change does not concern sterility testing.
  7. The change concerns drug substances that are discrete chemical entities (i.e. this does not include polymeric complexes).
Supporting Data
  1. (S.2.5) QC approved Process validation and/or evaluation studies or the proposed validation protocol of the proposed drug substance.
  2. (S.4.1) Updated, QC approved, proposed drug substance specification.
  3. (S.4.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  4. (S.4.3) Copies or summaries of validation reports, if new analytical procedures are used.
  5. (S.4.3) Where a House analytical procedure is used and a Schedule B standard is claimed, results of an equivalency study between the House and compendial methods.
  6. (S.4.4) Description of the batches, certificates of analyses, or batch analysis report and summary of results, of a sufficient number of batches (minimum of ten batches) to support the process parametric release.
  7. (S.4.5) Justification of the proposed drug substance specification [e.g., test parameters, acceptance criteria, or analytical procedures].
10. Change in the specification for the drug substance involving analytical procedures
  1. deletion of an analytical procedure
    • Conditions to be Fulfilled:
      • None
      • 5
    • Supporting Data:
      • 1
      • 1
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. replacement of, alternate, or additional analytical procedure
    • Conditions to be Fulfilled:
      • None
      • 1-4
    • Supporting Data:
      • 1-4
      • 1-4
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  3. change from a House analytical procedure to a Schedule B analytical procedure or a change from an approved compendial analytical procedure to an harmonized compendial procedure
    • Conditions to be Fulfilled: None
    • Supporting Data: 1,3-4
    • Reporting Category: Annual Notification
Conditions
  1. The method of analysis is based on the same analytical technique or principal and no new impurities are detected.
  2. Results of method validation demonstrate that the proposed analytical procedure is at least equivalent to the approved analytical procedure.
  3. Any new analytical procedure does not concern a novel, non-standard technique or a standard technique used in a novel way.
  4. The change does not concern sterility testing.
  5. The deleted analytical procedure is an alternate and equivalent method.
Supporting Data
  1. (S.4.1) Updated, QC approved, proposed drug substance specification.
  2. (S.4.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  3. (S.4.3) Copies or summaries of validation reports, if new analytical procedures are used.
  4. (S.4.3) Comparative analytical results demonstrating that the approved and proposed analytical procedures are equivalent.
3.2.S.6 Container Closure System
11. Change in the primary container closure system(s) for the storage and shipment of the drug substance
  • Conditions to be Fulfilled:
    • None
    • 1-2
  • Supporting Data:
    • 1-3
    • 2
  • Reporting Category:
    • Notifiable Change
    • Annual Notification
Conditions
  1. Results demonstrate that the proposed container closure system is at least equivalent to the approved container closure with respect to its relevant properties [e.g., including results of transportation or interaction studies, if appropriate].
  2. The change does not concern a sterile drug substance.
Supporting Data
  1. (S.2.5) Evidence of process validation and/or evaluation studies for sterilization if different from the current process.
  2. (S.6) Information on the proposed container closure system [e.g., description, specifications].
  3. (S.7.3) Results of a minimum of three (3) months of accelerated (or intermediate as appropriate) and three (3) months of long term testing of the drug substance in the proposed container closure system.
3.2.S.7 Stability
12. Change in the re-test period (or shelf life) for the drug substance, involving:
  1. Extension
    • Conditions to be Fulfilled:
      • None
      • 1-2,4-7
    • Supporting Data:
      • 1-4
      • 1-4
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. Reduction
    • Conditions to be Fulfilled:
      • None
      • 1,3,5
    • Supporting Data:
      • 1-4
      • 1-4
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
Conditions
  1. No change to the container closure system in direct contact with the drug substance or to the recommended storage conditions of the drug substance.
  2. The approved re-test period (or shelf life) is at least 24 months.
  3. Full long term stability data is available covering the proposed re-test period (or shelf life) and is based on stability data generated on at least three commercial scale batches.
  4. Full long term stability data is available covering the proposed re-test period (or shelf life) or is based on stability data generated on at least three commercial scale batches. If the proposed re-test period (or shelf life) is beyond the available long term data, the extrapolation is in accordance with ICH's Q1E guideline.
  5. Stability data was generated in accordance with the approved stability protocol.
  6. Significant changes (as defined in ICH's Q1A guideline) were not observed in the stability data.
  7. The drug substance has not been subject to a previous reduction in re-test period (or shelf life).
Supporting Data
  1. (S.7.1) Summary of stability testing and results [e.g., studies conducted, protocols used, results obtained].
  2. (S.7.1) Proposed storage conditions and re-test period (or shelf life, as appropriate).
  3. (S.7.2) Updated post-approval stability protocol and stability commitment.
  4. (S.7.3) Results of stability testing generated on at least two pilot and/or commercial scale batches with stability data to support the proposed re-test period or shelf life.
13. Change in the labelled storage conditions for the drug substance, involving: addition/deletion of a cautionary statement or relaxation/tightening of a temperature criterion (eg. from 15-25 °C to 15-30 °C)
  • Conditions to be Fulfilled: None
  • Supporting Data: 1
  • Reporting Category: Annual Notification
Conditions

None

Supporting Data
  1. (S.7.3) If applicable, stability testing results to support the change to the storage conditions on not less than two (2) lots (pilot or commercial scale).
14. Change to the post-approval stability protocol or stability commitment
  • Conditions to be Fulfilled: None
  • Supporting Data: 1-2
  • Reporting Category: Annual Notification
Conditions

None

Supporting Data
  1. (S.7.2) QC approved updated post-approval stability protocol and stability commitment.
  2. (S.7.2) Justification of the change to the post-approval stability protocol or stability commitment.

3.2.S Drug Substance (Kits/Radiopharmaceuticals containing drug substance of biological origin)

Refer to Appendix 3: Quality Post-NOC Changes (Biologics) Section 3.2.S

3.2.P Drug Product (Kits/Radiopharmaceuticals containing drug substance of either chemical or biological origin)

3.2.P.1 Description and Composition of the Drug Product
1. Addition or modification of radioactive strength
  • Conditions to be Fulfilled:
    • None
    • 1-5
  • Supporting Data:
    • 1-13
    • 1,3-6,12-13
  • Reporting Category:
    • Supplement
    • Notifiable Change
Conditions
  1. No change in the origin or supplier of radioisotope for radiopharmaceutical.
  2. No change in the formulation with the exception of increased radioactivity.
  3. No change to shelf-life of kit, reconstituted final product or radiopharmaceutical.
  4. No change in reconstitution and/or quality control methodology.
  5. No change in radiochemical purity and/or impurity specifications outside of the approved ranges for reconstituted final product or radiopharmaceutical.
Supporting Data
  1. Supporting batch analyses data to demonstrate the chemical equivalence with approved product for all parameters except total radioactivity, radioactive concentration and specific activity.
  2. (1.2.6) Letters of Access [e.g., Drug Master Files (DMFs)] or detailed information, if new excipients are included such as preservatives, radioprotective agents or reducing agents.
  3. (1.3) Product Monograph (title page, ''Dosage Forms, Composition, and Packaging'' section).
  4. (1.3) Inner and Outer Labels.
  5. (S) Confirmation that the information on the drug substance has not changed as a result of the change.
  6. (P.1) For radiopharmaceuticals, description of the new radioactive strength.
  7. (P.2) Discussion of the components of the drug product [e.g., choice of excipients, compatibility of drug substance and excipients].
  8. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates, Process Validation and/or Evaluation Studies.
  9. (P.4) Control of Excipients, if new excipients are proposed [e.g., specifications, confirmation that none of the excipients are prohibited by the Food and Drug Regulations].
  10. (P.5) Specification(s), Analytical Procedures (if new analytical methods are used), Validation of Analytical Procedures (if new analytical methods are used), Batch Analyses (certificate of analyses for one (1) production scale batch to be provided in section 3.2.R.3).
  11. (P.7) Discussion (including description, materials of construction, summary of specifications) on the container closure system, if any of the components have changed.
  12. (P.8.1) Stability Summary and Conclusions, e.g. for reconstituted final product, or radiopharmaceutical, test results including storage conditions for at least three (3) final product lots in upright and inverted vial orientations, including a minimum of three (3) time points (including the zero time point), as well as commitment to notify Health Canada of any failures in the ongoing long term stability studies. Bracketing and matrixing for multiple strength products, container sizes and/or fills may be acceptable if scientifically justified (refer to ICH Q1D).
  13. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and commitment to place the first commercial scale batch of the drug product manufactured using the proposed drug substance into the long term stability programme.
2. Change in the formulation of a kit or radiopharmaceutical
  • Conditions to be Fulfilled:
    • None
    • 1-8
  • Supporting Data:
    • 1-12
    • 2,9,11
  • Reporting Category:
    • Supplement
    • Notifiable Change
Conditions
  1. No qualitative change in the formulation.
  2. The proposed excipient(s) does/do not function to affect the physicochemical properties of the drug substance.
  3. The proposed excipient(s) does/do not function to affect the solubility of the drug substance.
  4. The proposed excipient(s) does/do not function as a preservative or preservative enhancer or as radioprotective or reducing agent.
  5. No change in the specifications of the proposed excipient(s) or the drug product outside of the approved ranges.
  6. No change to the physical and radiochemical characteristics of the drug product [e.g., pH, chemical and radiochemical purity/impurity, specific activity, osmolality].
  7. The change does not concern sterility or apyrogenicity of the drug product.
  8. The change does not affect the shelf-life of the kit, reconstituted final product or radiopharmaceutical.
Supporting Data
  1. Supporting in vivo clinical and/or bioequivalence/chemical equivalence data or a request for a waiver of in vivo studies.
  2. (1.2.6) Letters of Access [e.g., Drug Master Files (DMFs)] detailed information, if new excipients are included such as preservatives, radioprotective agents or reducing agents.
  3. (1.3) Product Monograph (title page, ''Dosage Forms, Composition, and Packaging'' section).
  4. (S) Confirmation that the information on the drug substance has not changed as a result of the change.
  5. (P.1) Description of each ingredient in the new formulation of the kit or radiopharmaceutical.
  6. (P.2) Discussion of function of each component of the drug product [e.g., choice of excipients, compatibility of drug substance and excipients], comparative in-vitro testing for the approved and changed products, discussion of any in vitro and/or in vivo studies, results of preservative effectiveness testing (if applicable).
  7. (P.4) Control of Excipients, if new excipients are proposed [e.g., specifications, confirmation that none of the excipients are prohibited by the Food and Drug Regulations].
  8. (P.5) Specification(s), Analytical Procedures (if new analytical methods are used), Validation of Analytical Procedures (if new analytical methods are used), Batch Analyses (certificate of analyses for one (1) commercial scale batch).
  9. (P.7) Discussion (including description, materials of construction, summary of specifications) on the container closure system, if any of the components have changed.
  10. (P.8.1) Stability Summary and Conclusions, e.g. for reconstituted final product, or radiopharmaceutical, test results including storage conditions for at least three (3) final product lots in upright and inverted vial orientations, including a minimum of three (3) time points. Bracketing and matrixing for multiple strength products, container sizes and/or fills may be acceptable if scientifically justified (refer to ICH Q1D).
  11. (P.8.2) Updated, QC approved post-approval stability protocol and stability commitment.
  12. (P.8.3) Results of a minimum of three (3) months of accelerated and three (3) months of long term testing of the proposed formulation of kit or longer if less than three (3) time points are available (including the zero time point), as well as commitment to notify Health Canada of any failures in the ongoing long term stability studies.
3. Change of a radioisotope either for reconstitution of a kit or preparation of a radiopharmaceutical, involving:
  1. addition or replacement of a radioisotope
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-12
    • Reporting Category: Supplement
  2. deletion of a radioisotope
    • Conditions to be Fulfilled: 1-5
    • Supporting Data: 2,4,6-7,9-11
    • Reporting Category: Notifiable Change
Conditions
  1. The change does not affect the stability or radiochemical characteristics [e.g., shelf-life, radiochemical purity and/or impurity] of the reconstituted final drug product or radiopharmaceutical product.
  2. Changes to the drug product specifications are those necessitated only by the change to the radioisotope.
  3. No change in the excipient(s) of the drug product.
  4. No change in the mode of decay of the radioisotope.
  5. No change in the shelf-life of the final product (reconstituted final product or radiopharmaceutical).
Supporting Data
  1. (1.2.6) Letters of Access [e.g., Drug Master Files (DMFs)] or detailed information, if new excipients are included such as preservatives, radioprotective agents or reducing agents.
  2. (1.3) Product Monograph (title page, and other relevant sections affecting the change including ''Dosage Forms, Composition, and Packaging'' section).
  3. (P.1) Description of the radioisotope including data for radionuclidic and metallic impurities, name of supplier, country of origin and other relevant data for the radioisotope including decay chart.
  4. (P.2) Scientific rationale for addition or replacement or deletion of a radioisotope for reconstitution of a kit or for production of a radiopharmaceutical.
  5. (P.2) Scientific rationale for change in decay mode of a radioisotope [e.g., positron instead of gamma or vice versa].
  6. (P.3) Batch Formula for radiopharmaceutical.
  7. (P.4) Control of Excipients, if new excipients are proposed [e.g., specifications, confirmation that none of the excipients are prohibited by the Food and Drug Regulations].
  8. (P.5) Specification(s), Analytical Procedures (if new analytical methods are used), Validation of Analytical Procedures (specificity of the analytical method and/or validation of new analytical methods), Batch Analyses (certificate of analyses for one (1) commercial scale batch to be provided in section 3.2.R.3).
  9. (P.5) Reconstitution and quality control procedure, if new procedure is introduced; otherwise, confirmation that these procedures have not been changed.
  10. (P.7) Discussion (including description, materials of construction, summary of specifications) on the container closure system, if any of the components have changed.
  11. (P.8.1) Stability Summary and Conclusions, e.g. for reconstituted final product, or radiopharmaceutical, test results including storage conditions for at least three (3) final product lots in upright and inverted vial orientations, including a minimum of three (3) time points or longer if less than three (3) time points are available (including the zero time point), as well as commitment to notify Health Canada of any failures in the ongoing long term stability studies. Bracketing and matrixing for multiple strength products, container sizes and/or fills may be acceptable if scientifically justified (refer to ICH Q1D).
  12. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment.
3.2.P.2 Pharmaceutical Development

Health Canada is in the process of adopting ICH Q8 "Pharmaceutical Development". Establishment of a design space or modification of an approved design space requires the filing of an Supplement. Sponsors are encouraged to contact Health Canada for further guidance.

3.2.P.3 Manufacture
4. Replacement or addition of a drug product manufacturer / manufacturing site, involving:
  1. production of a kit or radiopharmaceutical
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-8
    • Reporting Category: Supplement
  2. primary packaging (other than vial and stopper such as radiopharmaceutical in syringe)
    • Conditions to be Fulfilled: 1-3
    • Supporting Data: 2-3,5-6,8
    • Reporting Category: Notifiable Change
  3. secondary packaging which impacts temperature control during shipping
    • Conditions to be Fulfilled: 1-3
    • Supporting Data: 2-3,5
    • Reporting Category: Notifiable Change
  4. labelling
    • Conditions to be Fulfilled: 1-3
    • Supporting Data: 2-3,5
    • Reporting Category: Notifiable Change
  5. testing [e.g., release, stability]
    • Conditions to be Fulfilled: 1-3
    • Supporting Data: 2-5
    • Reporting Category: Notifiable Change
  6. storage and distribution
    • Conditions to be Fulfilled: 1-3
    • Supporting Data: 2-3,5
    • Reporting Category: Annual Notification
5. Deletion of any drug product manufacturer / manufacturing site
  • Conditions to be Fulfilled: None
  • Supporting Data: None
  • Reporting Category: Annual Notification
Conditions
  1. No change in the Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates, or Drug Product Specifications outside of the approved ranges.
  2. No significant change in the container closure system [e.g., vial size, type; septum formulation; supplier].
  3. No change in the product shelf-life for the kit, reconstituted final product or radiopharmaceutical.
Supporting Data
  1. Supporting in vivo clinical and/or bioequivalence data.
  2. (1.2.5) GMP and EL information.
  3. (P) Confirmation that information on the drug product has not changed as a result of the submission [e.g., other than change in site] or revised information on the drug product, if any of the attributes have changed.
  4. (P.2.2) Comparative full release test data for one (1) batch of each of the approved and proposed drug products. For kits, test should also include reconstituted final product analyses for various test parameters such as: appearance, pH, chemical and radiochemical purity/impurity, sterility and apyrogenicity.
  5. (P.3) Name, address, and responsibility of the proposed production site or facility involved in manufacturing and testing.
  6. (P.3.5) Process validation and/or evaluation studies. The proposed validation protocol may be sufficient, but data could be requested.
  7. (P.5.4) Batch Analyses (certificate of analyses for one (1) commercial scale batch to be provided in section 3.2.R.3).
  8. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment.
6. Change in the batch size for the drug product, involving:
  1. upscaling or down scaling in the batch size
    • Conditions to be Fulfilled: 1-4
    • Supporting Data: 1-5
    • Reporting Category: Notifiable Change
Conditions
  1. Any changes to the manufacturing process and/or to the in-process controls are only those necessitated by the change in batch-size, e.g., use of different sized equipment (i.e., the same formulation, controls, standard operating procedures (SOPs) are utilized).
  2. The change should not be a result of recurring events arising during manufacture or because of stability concerns.
  3. No change in the principle of the sterilization procedures and no impact on the apyrogenicity of the kit, reconstituted final product or radiopharmaceutical.
  4. The change does not affect the shelf-life of Kit, reconstituted final product or radiopharmaceutical.
Supporting Data
  1. (P.2.2) Comparative full release test data for one (1) batch of each of the approved and proposed drug products. For kits test should also include reconstituted final product analyses for various test parameters such as appearance, pH, chemical and radiochemical purity/impurity and sterility and apyrogenicity.
  2. (P.3) Batch formula of the proposed drug product.
  3. (P.3.5) Process validation and/or evaluation studies. The proposed validation protocol may be sufficient, but data could be requested.
  4. (P.5.4) Description of the batches, certificates of analyses, and summary of results, in a tabular format, for at least one (1) commercial scale batch of the proposed drug product.
  5. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment.
7. Change in the drug product manufacturing process
  • Conditions to be Fulfilled:
    • None
    • 1-5
  • Supporting Data:
    • 1-7
    • 1-7
  • Reporting Category:
    • Supplement
    • Notifiable Change
Conditions
  1. No Level I changes made to the drug product manufacturing process.
  2. The change is not the result of recurring events arising during manufacture or because of stability concerns.
  3. The change does not involve the packaging or labelling where the primary packaging provides a syringe for patient administration purposes.
  4. No change in the principle of the sterilization procedures and no impact on the apyrogenicity of the kit, reconstituted final product or radiopharmaceutical.
  5. The change does not affect the shelf-life of kit, reconstituted final product or radiopharmaceutical.
Supporting Data
  1. (P.2.2) Comparative full release test data for one (1) batch of each of the approved and proposed drug products. For kits test should also include reconstituted final product analyses for various test parameters such as appearance, pH, chemical and radiochemical purity/impurity and sterility and apyrogenicity.
  2. (S) Confirmation that the information on the drug substance has not changed as a result of the change.
  3. (P.2) Discussion of the development of the manufacturing process for the approved and proposed drug products, discussion of any in vitro and/or in vivo studies.
  4. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates, Process Validation and/or Evaluation Studies.
  5. (P.5) Specification(s) (if specification(s) have changed), Batch Analyses (certificate of analyses for one (1) commercial scale batch to be provided in section 3.2.R.3).
  6. (P.8.1) Stability Summary and Conclusions.
  7. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment.
8. Change in the controls (in-process tests and/or acceptance criteria) applied during the manufacturing process or on intermediates, such as:
  1. deletion of an in-process test
    • Conditions to be Fulfilled: 4-5
    • Supporting Data: 4
    • Reporting Category: Annual Notification
  2. replacement or addition of an in-process test
    • Conditions to be Fulfilled: 1-4,6
    • Supporting Data: 1-3,5
    • Reporting Category: Annual Notification
  3. relaxation of an acceptance criterion
    • Conditions to be Fulfilled: None
    • Supporting Data: 1,4-5
    • Reporting Category: Notifiable Change
  4. tightening of an acceptance criterion
    • Conditions to be Fulfilled:
      • None
      • 2
    • Supporting Data:
      • 1,4-5
      • 1
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
Conditions
  1. The change is not necessitated by recurring events arising during manufacture or because of stability concerns.
  2. The change is within the range of approved acceptance criteria.
  3. Any new analytical procedure does not concern a novel, non-standard technique or a standard technique used in a novel way.
  4. No change in the principle of the sterilization procedures and no impact on the apyrogenicity of the kit, reconstituted final product or radiopharmaceutical.
  5. The deleted test has been demonstrated to be redundant with respect to the remaining analytical tests.
  6. The replaced or added analytical procedure maintains or tightens precision, accuracy, specificity and sensitivity.
Supporting Data
  1. (P.3.3) Description of the proposed process controls or acceptance criteria.
  2. (P.3.5) Method validation for any new analytical procedures.
  3. (P.5.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  4. (P.5.4) Data to show that the relaxation has not a negative impact on the quality of the batch. Results for at least one (1) commercial scale batch is required.
  5. Rationale for the change supported by data.
9. Major change to the following process validation protocols used during the manufacture of the kit, reconstituted final product or radiopharmaceutical: introduction of product into an approved mutli-product facility, protocol for the cleaning of equipment [e.g., change in the worst-case scenario during cleaning validation process]
  • Conditions to be Fulfilled: None
  • Supporting Data: 1-2
  • Reporting Category: Notifiable Change
Conditions

None

Supporting Data
  1. (P.3.5) Proposed validation protocol. Process validation and/or evaluation studies could be requested.
  2. Rationale for the change in the validation protocol.
3.2.P.4 Control of Excipients
10. Change in the standard/monograph (i.e. specifications) claimed for the excipient
  • Conditions to be Fulfilled:
    • None
    • 1-5
  • Supporting Data:
    • 1-4
    • 1-4
  • Reporting Category:
    • Notifiable Change
    • Annual Notification
11. Change in the specification for the excipient to comply with an updated Schedule B pharmacopoeial standard/monograph
  • Conditions to be Fulfilled: 2-3
  • Supporting Data: 1-2,4
  • Reporting Category: Annual Notification
Conditions
  1. The change is from a House/Professed standard to a Schedule B pharmacopoeial standard/monograph.
  2. The change is made exclusively to comply with a Schedule B pharmacopoeial standard/monograph.
  3. No change to the specifications for the functional properties of the excipient outside of the approved ranges nor that results in a potential impact on the performance of the drug product.
  4. No deletion of tests or relaxation of acceptance criteria of the approved specifications, except to comply with a Schedule B pharmacopoeial standard/monograph.
  5. No deletion or change to any analytical procedures, except to comply with a Schedule B pharmacopoeial standard/monograph.
Supporting Data
  1. (P.4.1) Updated excipient specifications.
  2. (P.4.3) Where a House analytical procedure is used and a Schedule B standard/monograph is claimed, results of an equivalency study between the House and compendial methods.
  3. (P.4.4) Justification of the proposed excipient specifications [e.g., demonstration of the suitability of the monograph to control the excipient and potential impact on the performance of the drug product].
  4. Declaration that consistency of quality and of the production process of the excipient is maintained.
12. Change in the specifications used to release the excipient, involving:
  1. deletion of a test
    • Conditions to be Fulfilled: 3
    • Supporting Data: 1,3-4
    • Reporting Category: Annual Notification
  2. addition of a test
    • Conditions to be Fulfilled: 2-5
    • Supporting Data: 1-4
    • Reporting Category: Annual Notification
  3. replacement of an analytical procedure
    • Conditions to be Fulfilled: 5,8-9
    • Supporting Data: 1-2
    • Reporting Category: Annual Notification
  4. minor changes to an approved analytical procedure
    • Conditions to be Fulfilled: 5-7,10
    • Supporting Data: 1-2
    • Reporting Category: Annual Notification
  5. a change from a House/Professed analytical procedure to a Schedule B analytical procedure
    • Conditions to be Fulfilled: 5-6,10
    • Supporting Data: 1-2
    • Reporting Category: Annual Notification
  6. to reflect a pharmacopoeial monograph update
    • Conditions to be Fulfilled: 5
    • Supporting Data: 1
    • Reporting Category: Annual Notification
  7. relaxation of an acceptance criterion
    • Conditions to be Fulfilled: 2,4
    • Supporting Data: 1,3-4
    • Reporting Category: Annual Notification
  8. tightening of an acceptance criterion
    • Conditions to be Fulfilled: 1-2
    • Supporting Data: 1
    • Reporting Category: Annual Notification
Conditions
  1. The change is within the range of approved acceptance criteria or has been made to reflect new pharmacopoeial monograph specifications for the excipient.
  2. Acceptance criterion for any Class 3 residual solvent is within the ICH limits.
  3. The deleted test has been demonstrated to be redundant with respect to the remaining tests or is no longer a pharmacopoeial requirement.
  4. The change to the specifications does not affect the functional properties of the excipient nor result in a potential impact on the performance of the drug product.
  5. The change does not concern sterility testing.
  6. No change in the approved acceptance criteria outside of the approved ranges.
  7. The method of analysis is the same [e.g., a change in column length or temperature, but not a different type of column or method] and no new impurities are detected.
  8. Results of method validation demonstrate that the proposed analytical procedure is at least equivalent to the approved analytical procedure.
  9. The replaced analytical procedure maintains or tightens precision, accuracy, specificity and sensitivity.
  10. The change does not concern a kit or radiopharmaceutical that contains a drug substance that is not a discrete chemical entity [e.g., polymeric complexes].
Supporting Data
  1. (P.4.1) Updated excipient specifications.
  2. (P.4.3) Where a House/Professed analytical procedure is used and a Schedule B standard is claimed, results of an equivalency study between the House/Professed and compendial methods.
  3. (P.4.4) Justification of the proposed excipient specifications [e.g., demonstration of the suitability of the monograph to control the excipient and potential impact on the performance of the drug product].
  4. For a kit or radiopharmaceutical containing a drug substance that is not a discrete chemical entity [e.g., polymeric complexes], declaration that consistency of quality and of the production process of the excipient is maintained.
13. Change in the source of an excipient from a vegetable or synthetic source to a TSE risk [e.g., animal] source
  • Conditions to be Fulfilled: None
  • Supporting Data: 2-8
  • Reporting Category: Supplement
14. Change in the source of an excipient from a TSE risk [e.g., animal] source to a vegetable or synthetic source
  • Conditions to be Fulfilled: 3
  • Supporting Data: 1,3,5-7
  • Reporting Category: Notifiable Change
15. Change in manufacture of a biological excipient
  • Conditions to be Fulfilled:
    • None
    • 3
    • 1-4
  • Supporting Data:
    • 3-8
    • 3,5-8
    • 3,5
  • Reporting Category:
    • Supplement
    • Notifiable Change
    • Annual Notification
16. Change in supplier for a human plasma-derived excipient [e.g., human serum albumin]
  • Conditions to be Fulfilled:
    • None
    • 5-6
  • Supporting Data:
    • 4-9
    • 5-7,10
  • Reporting Category:
    • Supplement
    • Notifiable Change
17. Change in supplier of an excipient of non-biological origin or of biological origin (excluding human plasma-derived excipient)
  • Conditions to be Fulfilled: 1,4
  • Supporting Data: 3
  • Reporting Category: Annual Notification
Conditions
  1. No change in the specifications of the excipient or drug product outside of the approved ranges.
  2. No negative impact on the chemical and radiochemical purity/impurity or stability of the drug product.
  3. The change does not concern a human plasma-derived excipient.
  4. Properties of the proposed excipient are not different from those of the approved excipient.
  5. The excipient from the new supplier is a Health Canada approved excipient.
  6. No chemistry and manufacturing changes were made by the supplier of the new excipient since its last approval in Canada.
Supporting Data
  1. Declaration from the manufacturer of the excipient that it is entirely of vegetable or synthetic origin.
  2. Details of the source or the excipient [e.g., animal species, country of origin] and the steps undertaken in processing to minimize the risk of TSE exposure.
  3. Information demonstrating comparability in term of physico-chemical characterization and impurity profile of the proposed excipient with the approved excipient.
  4. (P.3.3) Information on the manufacturing process and on the controls performed at critical steps of the manufacturing process and on the intermediate of the proposed excipient.
  5. (P.4.5) Description of the batches and summary of results as quantitative data, in a comparative tabular format, for at least three (3) commercial scale batches of the proposed excipient (certificates of analysis to be provided in section 3.2.R.3).
  6. (P.5.4) Description of the batches and summary of results as quantitative data, in a comparative tabular format, for at least three (3) batches of the drug product with the proposed excipient (certificates of analysis to be provided in section 3.2.R.3).
  7. (P.8.3) Stability test results from a minimum of three (3) months of accelerated and three (3) months of real time/real temperature testing on three (3) batches of the drug product with the proposed excipient, or longer if less than three (3) time points are available (including the zero time point), as well as commitment to notify Health Canada of any failures in the ongoing long term stability studies.
  8. (A.2) Information assessing the risk with respect to potential contamination with adventitious agents [e.g., impact on the viral clearance studies, BSE/TSE risk].
  9. Complete manufacturing and clinical safety data to support the use of the proposed human plasma-derived excipient.
  10. Letter from the supplier certifying that no changes were made to the excipient since its last approval in Canada (DIN provided).
3.2.P.5 Control of Drug Product
18. Changes affecting the quality control (QC) testing of the drug product, involving:
  1. transfer of the QC testing activities for a non-pharmacopoeial assay (in-house) to a new company or to a different facility within the same company
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2
    • Reporting Category: Notifiable Change
  2. transfer of the QC testing activities for a pharmacopoeial assay (in-house) to a new company not listed on the Establishment Licence of the manufacturer/sponsor
    • Conditions to be Fulfilled: 1
    • Supporting Data: 1-2
    • Reporting Category: Annual Notification
Conditions
  1. The transferred QC test is not a potency assay.
Supporting Data
  1. (P.3.5) Information demonstrating technology transfer qualification.
  2. Evidence that the new company/facility is GMP compliant.
19. Change in the standard/monograph (i.e. specifications) claimed for the drug product, involving:
  1. a change from a Schedule B pharmacopoeial standard/monograph to a House standard
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-5
    • Reporting Category: Notifiable Change
  2. a change from a House/Professed standard to Schedule B pharmacopoeial standard/ monograph or from one Schedule B standard/ monograph to a different Schedule B standard/monograph)
    • Conditions to be Fulfilled: 1-4
    • Supporting Data: 1-3
    • Reporting Category: Annual Notification
20. Change in the specifications for the drug product to comply with an updated Schedule B pharmacopoeial standard/monograph
  • Conditions to be Fulfilled: 1-2
  • Supporting Data: 1-3
  • Reporting Category: Annual Notification
Conditions
  1. The change is made exclusively to comply with a Schedule B pharmacopoeial standard/monograph.
  2. The change to the specifications does not result in a potential impact on the performance of the drug product.
  3. No deletion of tests or relaxation of acceptance criteria of the approved specifications, except to comply with a Schedule B pharmacopoeial standard/monograph.
  4. No deletion or change to any analytical procedures, except to comply with a Schedule B pharmacopoeial standard/monograph.
Supporting Data
  1. (1.3) Product Monograph [e.g., Title Page, Composition and Packaging (Part I), and Pharmaceutical Information (Part II) section] and Inner and Outer Labels.
  2. (P.4.3) Copies or summaries of validation reports, if new analytical procedures are used.
  3. (P.5.1) Updated, QC approved copy of the proposed drug product specifications (or where applicable, the final version of the specifications to be signed by QC after HC approval).
  4. (P.5.3) Where a House analytical procedure is used and a Schedule B standard is claimed, results of an equivalency study between the House and compendial methods.
  5. Justification of specifications with data.
21. Change in the specifications used to release the drug product, involving:
  1. for sterile products, replacing the sterility test with process parametric release
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2,5,7-8
    • Reporting Category: Supplement
  2. deletion of a test
    • Conditions to be Fulfilled: None
    • Supporting Data: 2,7-8
    • Reporting Category: Notifiable Change
  3. addition of a test
    • Conditions to be Fulfilled: 1-2
    • Supporting Data: 2-4,7
    • Reporting Category: Annual Notification
  4. replacement of an analytical procedure
    • Conditions to be Fulfilled: None
    • Supporting Data: 2-4,6
    • Reporting Category: Notifiable Change
  5. minor changes to an approved analytical procedure
    • Conditions to be Fulfilled: 3-6
    • Supporting Data: 3-4,6
    • Reporting Category: Annual Notification
  6. change from a House/Professed analytical procedure to a Schedule B analytical procedure or change from an approved compendial analytical procedure to an harmonized compendial procedure
    • Conditions to be Fulfilled: 3,6-8
    • Supporting Data: 2-4
    • Reporting Category: Annual Notification
  7. relaxation of an acceptance criterion
    • Conditions to be Fulfilled: None
    • Supporting Data: 2,7-8
    • Reporting Category: Notifiable Change
  8. tightening of an acceptance criterion
    • Conditions to be Fulfilled: 9-10
    • Supporting Data: 2
    • Reporting Category: Annual Notification
Conditions
  1. No change in the limits/acceptance criteria outside of the approved ranges for the approved assays.
  2. The addition of test is not to monitor new impurity species.
  3. No change in the acceptance criteria outside of the approved ranges.
  4. The method of analysis is the same [e.g., a change in column length or temperature, but not a different type of column or method] and no new impurities are detected.
  5. The modified analytical procedure maintains or tightens precision, accuracy, specificity and sensitivity.
  6. The change does not concern sterility testing.
  7. The change does not concern test for radionuclidic identity and purity or radiochemical purity.
  8. The change does not concern tests for osmolality, residual solvent or pH for reconstituted final product or radiopharmaceutical.
  9. The change is within the range of approved acceptance criteria.
  10. Acceptance criterion for any Class 3 residual solvent is within the ICH limits.
Supporting Data
  1. (P.3.5) Process validation and/or evaluation studies or validation protocol of the proposed drug product.
  2. (P.5.1) Updated, QC approved copy of the proposed drug product specifications (or where applicable, the final version of the specifications to be signed by QC after HC approval).
  3. (P.5.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  4. (P.5.3) Copies or summaries of validation reports, if new analytical procedures are used.
  5. (P.5.4) Description of the batches and summary of results as quantitative data, of a sufficient number of batches to support the process parametric release (certificates of analysis to be provided in section 3.2.R.3).
  6. (P.5.6) Justification for the change to the analytical procedure [e.g., demonstration of the suitability of the analytical procedure to monitor the drug product, including the degradation products].
  7. (P.5.6) Justification of the proposed drug product specifications [e.g., demonstration of the suitability of the monograph to control the drug product, including degradation products].
  8. Declaration that consistency of quality and of the production process is maintained.
3.2.P.6 Reference Standards or Materials
22. Change the reference standards from pharmacopoeial to House
  • Conditions to be Fulfilled: None
  • Supporting Data: 1-2
  • Reporting Category: Notifiable Change
23. Change the reference standards from House/Professed to pharmacopoeial
  • Conditions to be Fulfilled: 1
  • Supporting Data: 1-2
  • Reporting Category: Annual Notification
24. Qualification of a new lot of reference standard against the approved reference standard
  • Conditions to be Fulfilled: 1
  • Supporting Data: 2
  • Reporting Category: Annual Notification
25. Extension of reference standard shelf life
  • Conditions to be Fulfilled: None
  • Supporting Data: 3
  • Reporting Category: Annual Notification
Conditions
  1. Qualification of the reference standard is performed according to the approved protocol (i.e. no deviation from the approved protocol).
Supporting Data
  1. (1.3) Revised Product monograph to reflect the change in reference standard.
  2. (P.6) Information demonstrating qualification of the proposed reference standards or materials [e.g., source, characterization, certificate of analysis].
  3. (P.8.1) Summary of stability testing and results to support the extension of reference standard shelf life.
3.2.P.7 Container Closure System
26. Change in the primary container closure system, involving:
  1. replacement or addition of a container closure system
    • Conditions to be Fulfilled:
      • None
      • 1,3-6
    • Supporting Data:
      • 1-5
      • 1,3-5
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. deletion of a container closure system
    • Conditions to be Fulfilled: None
    • Supporting Data: 1
    • Reporting Category: Annual Notification
27. Change in the package size, involving:
  1. change in the fill weight/fill volume total radiactivity
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2,4-5
    • Reporting Category: Notifiable Change
  2. a change in the number of units (e.g. vials) per package
    • Conditions to be Fulfilled:
      • None
      • 1-6
    • Supporting Data:
      • 1-2,4-5
      • 1,3
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
Conditions
  1. No change in the type of container closure or materials of construction.
  2. No change in the shape or dimensions of the container closure.
  3. The change does not concern a container closure that functions to meter the drug product.
  4. No change in the principle of the sterilization procedures of the drug product.
  5. The change does not negatively impact the stability of the drug product.
  6. The change is within the range of approved package sizes.
Supporting Data
  1. (1.3) Product Monograph [e.g., Title Page, Storage and Stability (Part I), Dosage Forms, Composition and Packaging (Part I)] and Inner and Outer Labels.
  2. (P.3.5) Process validation and/or evaluation studies.
  3. (P.7) Information on the proposed container closure system [e.g., description, materials of construction of primary packaging components, specifications, including results of transportation studies, if appropriate].
  4. (P.8.1) Stability Summary and Conclusions.
  5. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment.
28. Change in the materials of construction of any primary or functional secondary container closure component
  • Conditions to be Fulfilled:
    • None
    • 1-4
  • Supporting Data:
    • 1-7
    • 1-5
  • Reporting Category:
    • Supplement
    • Notifiable Change
Conditions
  1. The change does not affect negatively the shelf-life of the drug product.
  2. The change does not affect negatively the chemical or radiochemical purity of a reconstituted final drug product or radiopharmaceutical.
  3. No change in the principle of the sterilization procedures and no impact on the apyrogenicity of the drug product.
  4. The change does not increase the amount of adsorption of radioactivity or reconstituted solution.
Supporting Data
  1. (1.3) Product Monograph [e.g., Title Page, Storage and Stability (Part I), Dosage Forms, Composition and Packaging (Part I)] and Inner and Outer Labels.
  2. (P.3.5) Process validation and/or evaluation studies.
  3. (P.7) Information on the changed container closure system [e.g., description, materials of construction of primary packaging components, specifications, including results of transportation or interaction studies, if appropriate].
  4. (P.7) Data demonstrating product compatibility with the vial/stopper material when in close contact.
  5. (P.7) Applicable data demonstrating acceptability of the packaging for the purpose intended [e.g., extractable/leachable testing, permeation testing, light transmission]. For changes to functional packaging, data to demonstrate that the functioning of the new packaging is equivalent to that previously approved.
  6. (P.8.1) Stability Summary and Conclusions.
  7. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment.
29. Change in the supplier for a primary container closure component, involving:
  1. replacement or addition of a supplier
    • Conditions to be Fulfilled:
      • None
      • 1-6
    • Supporting Data:
      • 1-6
      • 1
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. deletion of a supplier
    • Conditions to be Fulfilled: None
    • Supporting Data: None
    • Reporting Category: Annual Notification
Conditions
  1. No change in the type of container closure, materials of construction, shape, dimensions or specifications outside of the approved ranges.
  2. The change does not concern a sterile container closure component.
  3. The change does not affect negatively the shelf-life of the drug product.
  4. The change does not affect negatively the chemical or radiochemical purity of a reconstituted final drug product or radiopharmaceutical.
  5. No change in the principle of the sterilization procedures and no impact on the apyrogenicity of the drug product.
  6. The change does not increase the adsorption of radioactivity or reconstituted solution.
Supporting Data
  1. (P.3.5) Process validation and/or evaluation studies.
  2. (P.7) Information on the proposed container closure system [e.g., description, materials of construction of primary packaging components, specifications, including results of transportation or interaction studies, if appropriate].
  3. (P.7) Data demonstrating product compatibility with the vial/stopper material when in close contact.
  4. (P.8.1) Stability Summary and Conclusions.
  5. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment.
  6. Declaration that consistency of quality is maintained.
30. Change in the specifications used to release a primary or functional secondary container closure component, involving:
  1. deletion of a test
    • Conditions to be Fulfilled: 1-2
    • Supporting Data: 1-2
    • Reporting Category: Annual Notification
  2. addition of a test
    • Conditions to be Fulfilled: 3
    • Supporting Data: 1-2
    • Reporting Category: Annual Notification
  3. replacement of an analytical procedure
    • Conditions to be Fulfilled: 6-8
    • Supporting Data: 1-3
    • Reporting Category: Annual Notification
  4. minor changes to an analytical procedure
    • Conditions to be Fulfilled: 4-8
    • Supporting Data: 1-3
    • Reporting Category: Annual Notification
  5. relaxation of an acceptance criterion
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2
    • Reporting Category: Notifiable Change
  6. tightening of an acceptance criterion
    • Conditions to be Fulfilled: 9
    • Supporting Data: 1
    • Reporting Category: Annual Notification
Conditions
  1. The deleted test parameter has been demonstrated to be redundant with respect to the remaining tests or is no longer a pharmacopoeial requirement.
  2. The change to the specifications does not affect the functional properties of the container closure component nor result in a potential impact on the performance of the drug product.
  3. The change is not necessitated by recurring events arising during manufacture or because of stability concerns.
  4. No change in the acceptance criteria outside of the approved ranges.
  5. The new analytical procedure is of the same type.
  6. Results of method validation demonstrate that the new or modified analytical procedure is at least equivalent to the approved analytical procedure.
  7. The new or modified analytical procedure maintains or tightens precision, accuracy, specificity and sensitivity.
  8. The change does not concern sterility testing.
  9. The change is within the range of approved acceptance criteria or has been made to reflect new pharmacopoeial monograph specifications for the container closure component.
Supporting Data
  1. (P.7) Updated, QC approved copy of the proposed specifications for the primary container closure (or where applicable, the final version of the specifications to be signed by QC after HC approval).
  2. (P.7) Rationale for the change in specifications for a primary container closure component.
  3. (P.7) Description of the analytical procedure and, if applicable, validation data.
3.2.P.8 Stability
31. Change in the shelf life for the drug product such as kit, reconstituted final product or radiopharmaceutical, involving:
  1. extension
    • Conditions to be Fulfilled:
      • None
      • 1-5,7-9
    • Supporting Data:
      • 1-2,6-7
      • 1-2,5,7
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. reduction
    • Conditions to be Fulfilled:
      • None
      • 6
    • Supporting Data:
      • 1-5,7
      • 2-4
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
Conditions
  1. No significant changes to the container closure system in direct contact with the drug product or to the recommended storage conditions of the drug product.
  2. The approved shelf life is at least 24 months for the kit and eight (8) hours for the reconstituted final product or three (3) days for the radiopharmaceutical.
  3. Full long term stability data are available covering the proposed shelf life and are based on stability data generated on at least three (3) commercial scale batches.
  4. Stability data were generated in accordance with the approved stability protocol.
  5. Significant changes (as defined in ICH's Q1A guideline) were not observed in the stability data.
  6. The reduction of the shelf life is not necessitated by recurring events arising during manufacture or because of stability concerns (i.e. problems arising during manufacturing or stability concerns should be reported for evaluation).
  7. Stability data for reconstituted product was generated with the approved quantity of radioisotope in approved volume of final product.
  8. Stability data for the radiopharmaceutical was generated post calibration with the quantity of radioisotope in approved volume of final product.
  9. The change does not affect the specific activity, injection volume, chemical or radiochemical purity/impurity of the reconstituted final drug product or radiopharmaceutical.
Supporting Data
  1. (P.8.1) Summary of stability testing and results [e.g., studies conducted, protocols used, results obtained].
  2. (P.8.1) Proposed storage conditions and shelf life, as appropriate.
  3. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment.
  4. (P.8.2) Justification of the change to the post-approval stability protocol or stability commitment.
  5. (P.8.3) Results of stability testing on both upright and inverted samples, except for lyophilized products (i.e., full real time/real temperature stability data covering the proposed shelf life generated on at least three (3) commercial scale batches).
  6. (P.8.3) Interim stability testing results and a commitment to notify Health Canada of any failures in the ongoing long term stability studies. Extrapolation of shelf life should be made in accordance with ICH Q1E guideline.
  7. (P.8.3) For reconstituted final product or radiopharmaceutical, test data up to the proposed expiry for three (3) commercial scale batches in vial orientation of upright and inverted.
32. Change in the post-approval stability protocol of the drug product, involving:
  1. major change to the post-approval stability protocol or stability commitment such as deletion of a test, replacement of an analytical procedure, change in storage temperature
    • Conditions to be Fulfilled:
      • None
      • 1-2
    • Supporting Data:
      • 3-6
      • 1-2,4-5
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. addition of time point(s) into the post-approval stability protocol
    • Conditions to be Fulfilled: None
    • Supporting Data: 4-5
    • Reporting Category: Annual Notification
  3. addition of test(s) into the post-approval stability protocol
    • Conditions to be Fulfilled: 3
    • Supporting Data: 4-5
    • Reporting Category: Annual Notification
  4. deletion of time point(s) from the post-approval stability protocol beyond the approved shelf life
    • Conditions to be Fulfilled: None
    • Supporting Data: 4-5
    • Reporting Category: Annual Notification
  5. deletion of time point(s) from the post-approval stability protocol within the approved shelf life
    • Conditions to be Fulfilled: 4
    • Supporting Data: 4-5
    • Reporting Category: Annual Notification
Conditions
  1. For the replacement of an analytical procedure, the results of method validation demonstrate that the new analytical procedure is at least equivalent to the approved analytical procedure.
  2. For the replacement of an analytical procedure, the new analytical procedure maintains or tightens precision, accuracy, specificity and sensitivity.
  3. The addition of test(s) is not due to stability concerns or to the identification of new impurities.
  4. In the case of kits, the approved shelf life is at least 24 months.
Supporting Data
  1. (P.5.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  2. (P.5.3) Copies or summaries of validation reports, if new analytical procedures are used.
  3. (P.8.1) Proposed storage conditions and or shelf life, as appropriate.
  4. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment.
  5. (P.8.2) Justification of the change to the post-approval stability protocol or stability commitment.
  6. (P.8.3) If applicable, stability testing results to support the change to the post-approval stability protocol or stability commitment [e.g., data to show greater reliability of the alternate test].
33. Change in the labelled storage conditions for the drug product or the reconstituted final drug product or radiopharmaceutical, involving:
  1. addition or change of storage condition for the drug product [e.g., relaxation or tightening of a temperature criterion]
    • Conditions to be Fulfilled:
      • None
      • 1-2
    • Supporting Data:
      • 1-6,8
      • 1,3-5
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. addition of a cautionary statement
    • Conditions to be Fulfilled:
      • None
      • 1
    • Supporting Data:
      • 1-3,5-6
      • 1-3,5-6
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  3. deletion of a cautionary statement
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-3,5,7
    • Reporting Category: Annual Notification
Conditions
  1. The change is not necessitated by recurring events arising during manufacture or because of stability concerns.
  2. The change consists in the tightening of a temperature criterion within the approved ranges.
Supporting Data
  1. (1.3) Revised Product Monograph [e.g., Where applicable, Title Page, Composition and Packaging (Part I), and Pharmaceutical Information (Part II) section] and Inner and Outer Labels, as applicable.
  2. (P.8.1) Summary of stability testing and results [e.g., studies conducted, protocols used, results obtained].
  3. (P.8.1) Proposed storage conditions and shelf life, as appropriate.
  4. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment.
  5. (P.8.2) Justification of the change in the labelled storage conditions/cautionary statement.
  6. (P.8.3) Results of stability testing (i.e., full real time/real temperature stability data covering the proposed shelf life generated on one (1) commercial scale batch).
  7. (P.8.3) Results of stability testing (i.e., full real time/real temperature stability data covering the proposed shelf life generated on at least three (3) commercial scale batches).
  8. (P.8.3) For reconstituted final product or radiopharmaceutical, test data up to the proposed expiry for three (3) commercial scale batches in vial orientation of upright and inverted.

3.2.P Drug Product (Generators)

3.2.P.1 Description and Composition of the Generator
1. Addition or modification of radioactive strength (total radioactivity of the generator)
  • Conditions to be Fulfilled:
    • None
    • 1-6
  • Supporting Data:
    • 1-9
    • 1-4,8-9
  • Reporting Category:
    • Supplement
    • Notifiable Change
Conditions
  1. No change in the origin or supplier of parent radionuclide.
  2. No change in the formulation.
  3. No change in generator shelf-life.
  4. No change in elution methodology.
  5. No change in radiochemical purity and/or impurity specifications outside of the approved ranges.
  6. No change in column, elution vial, tubing, needle and other generator accessories.
Supporting Data
  1. Supporting comparative Batch Analyses data for chemical equivalence.
  2. (1.3) Revised Product Monograph (title page, ''Dosage Forms, Composition, and Packaging'' section).
  3. (1.3) All applicable Labels.
  4. (P.3) Batch formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates, Process Validation and/or Evaluation Studies.
  5. (P.5) Specification(s), Analytical Procedures (if new analytical methods are used), Validation of Analytical Procedures (if new analytical methods are used), Batch Analyses (certificate of analyses for one (1) production scale batch to be provided in section 3.2.R.3).
  6. (P.5) Description of elution and quality control procedure, if these procedures have changed.
  7. (P.7) Discussion (including description, materials of construction, summary of specifications) on the container closure system, if any of the components have changed.
  8. (P.8.1) Stability data, Summary and Conclusions. Bracketing and matrixing for multiple strength products, container sizes and/or fills may be acceptable if scientifically justified (refer to ICH Q1D).
  9. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment.
2. Change in the formulation
  • Conditions to be Fulfilled:
    • None
    • 1-8
  • Supporting Data:
    • 1-8
    • 2-8
  • Reporting Category:
    • Supplement
    • Notifiable Change
Conditions
  1. No change in the origin or supplier of parent radionuclide.
  2. No change in generator shelf-life.
  3. No change in elution methodology.
  4. No change in column, elution vial, tubing, needle or other generator accessories.
  5. No qualitative change in the formulation.
  6. No change in the specifications of the proposed excipient(s) outside of the approved ranges.
  7. The change does not affect negatively the physicochemical characteristics of the eluate [e.g., pH, appearance, parent radionuclidic breakthrough, radionuclidic and radiochemical purity of the daughter radionuclide].
  8. No change in the principle of the sterilization procedures.
Supporting Data
  1. Supporting comparative Batch Analyses data for chemical equivalence.
  2. (1.3) Revised Product Monograph (title page, ''Dosage Forms, Composition, and Packaging'' section).
  3. (P) Confirmation that the information on the parent radionuclide has not changed as a result of the change [e.g., cross reference(s) should be provided to the previously approved parent radionuclide, including brand name of the drug product, manufacturer's/sponsor's name, submission type, control number, date approved] or revised information on the parent radionuclide, if any of the attributes have changed.
  4. (P.2) Description of the proposed formulation of the generator.
  5. (P.4) Control of Excipients, if new excipients are proposed [e.g., specifications, confirmation that none of the excipients are prohibited by the Food and Drug Regulations].
  6. (P.5) Specification(s), Analytical Procedures (if new analytical methods are used), Validation of Analytical Procedures (if new analytical methods are used), Batch Analyses (certificate of analyses for three (3) commercial scale batches to be provided in section 3.2.R.3).
  7. (P.8.1) Stability data, Summary and Conclusions. Bracketing and matrixing for multiple strength products, container sizes and/or fills may be acceptable if scientifically justified (refer to ICH Q1D).
  8. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment.
3.2.P.2 Pharmaceutical Development

Health Canada is in the process of adopting ICH Q8 "Pharmaceutical Development". Establishment of a design space or modification of an approved design space requires the filing of an Supplement. Sponsors are encouraged to contact Health Canada for further guidance.

3.2.P.3 Manufacture
3. Replacement or addition of a generator component manufacturer/manufacturing site involving:
  1. supplier of parent radionuclide
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-7
    • Reporting Category: Supplement
  2. primary packaging (including generator casing, lead shielding and other materials used in the manufacture of the generator)
    • Conditions to be Fulfilled: 1-3
    • Supporting Data: 2-3
    • Reporting Category: Notifiable Change
  3. secondary packaging (if any)
    • Conditions to be Fulfilled: 1-3
    • Supporting Data: 2-3
    • Reporting Category: Annual Notification
  4. labelling
    • Conditions to be Fulfilled: 2
    • Supporting Data: 2-3
    • Reporting Category: Notifiable Change
  5. testing [e.g., calibration, release, stability]
    • Conditions to be Fulfilled: 1-3
    • Supporting Data: 2-6
    • Reporting Category: Notifiable Change
  6. storage and distribution
    • Conditions to be Fulfilled: 1-3
    • Supporting Data: 2-3,5
    • Reporting Category: Annual Notification
  7. deletion of generator component manufacturer/ manufacturing site including supplier of parent radionuclide
    • Conditions to be Fulfilled: None
    • Supporting Data: None
    • Reporting Category: Annual Notification
Conditions
  1. No change in the Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates, or generator Specifications outside of the approved ranges.
  2. No significant change in the container closure system.
  3. No change in the generator shelf-life, including the shelf-life of eluate (if applicable).
Supporting Data
  1. (1.2.5) GMP and EL information.
  2. (P) Confirmation that information on the generator has not changed as a result of the submission [e.g., other than change in site] or revised information on the generator, if any of the attributes have changed.
  3. (P.2.2) Comparative full release test data for one (1) batch of each of the approved and proposed generators. This should include data from radiolabelling of kits that contain ligands that are anionic, cationic and neutral.
  4. (P.3) Name, address, and responsibility of the proposed production site or facility involved in manufacturing and testing.
  5. (P.3.5) Process validation and/or evaluation studies. The proposed validation protocol may be sufficient, but data could be requested.
  6. (P.5.4) Batch Analyses (certificate of analyses for three (3) commercial scale batches to be provided in section 3.2.R.3).
  7. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment.
4. Change in the generator manufacturing process
  • Conditions to be Fulfilled:
    • None
    • 1-5
  • Supporting Data:
    • 1-7
    • 1-5,7
  • Reporting Category:
    • Supplement
    • Notifiable Change
Conditions
  1. The same standard operating procedures (SOPs), process controls and formulation are used on the approved and proposed generator. The equipment used to produce the proposed generator may vary in capacity, but are of the same design and operating principles.
  2. The change is not the result of recurring events arising during manufacture or because of stability concerns.
  3. The change does not involve the packaging or labelling.
  4. No change in the principle of the sterilization procedures and no impact on the apyrogenicity of the generator.
  5. The change does not affect the shelf-life of the generator.
Supporting Data
  1. (P.2.2) Comparative full release test data for one (1) batch of each of the approved and proposed generator and eluate. For eluate, test should include appearance, pH, parent radionuclide breakthrough, radionuclidic and radiochemical purity/impurity, sterility and apyrogenicity.
  2. (P) Confirmation that the information on the parent radionuclide has not changed as a result of the change.
  3. (P.2) Discussion of the development of the manufacturing process for the approved and proposed generator.
  4. (P.3) Batch Formula, Description of Manufacturing Process and Process Controls, Controls of Critical Steps and Intermediates, Process Validation and/or Evaluation Studies.
  5. (P.5) Specification(s) (if specification(s) have changed), Batch Analyses (certificate of analyses for three (3) commercial scale batches to be provided in section 3.2.R.3).
  6. (P.8.1) Stability Summary and Conclusions.
  7. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment.
5. Change in the controls (in-process tests and/or acceptance criteria) applied during the manufacturing process or on intermediates, such as:
  1. deletion of an in-process test
    • Conditions to be Fulfilled: 4-5
    • Supporting Data: 4
    • Reporting Category: Annual Notification
  2. replacement or addition of an in-process test
    • Conditions to be Fulfilled: 1-4,6
    • Supporting Data: 1-3,5
    • Reporting Category: Annual Notification
  3. relaxation of an acceptance criterion
    • Conditions to be Fulfilled: None
    • Supporting Data: 1,4-5
    • Reporting Category: Notifiable Change
  4. tightening of an acceptance criterion
    • Conditions to be Fulfilled:
      • None
      • 2
    • Supporting Data:
      • 1,4-5
      • 1
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
Conditions
  1. The change is not necessitated by recurring events arising during manufacture or because of stability concerns.
  2. The change is within the range of approved acceptance criteria.
  3. Any new analytical procedure does not concern a novel, non-standard technique or a standard technique used in a novel way.
  4. No change in the principle of the sterilization procedures and no impact on the apyrogenicity of the generator or its eluate.
  5. The deleted test has been demonstrated to be redundant with respect to the remaining analytical tests.
  6. The replaced or added analytical procedure maintains or tightens precision, accuracy, specificity and sensitivity.
Supporting Data
  1. (P.3.3) Description of the proposed process controls or acceptance criteria.
  2. (P.3.5) Method validation for any new analytical procedures.
  3. (P.5.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  4. (P.5.4) Release data for at least one (1) commercial scale batch to show that the relaxation has no negative impact on the quality of the batch.
  5. Rationale for the change supported by data.
6. Major change to the following process validation protocols used during the manufacture of the generator: introduction of product into an approved mutli-product facility, protocol for the cleaning of equipment [e.g., change in the worst-case scenario during cleaning validation process]
  • Conditions to be Fulfilled: None
  • Supporting Data: 1-2
  • Reporting Category: Notifiable Change
Conditions

None

Supporting Data
  1. (P.3.5) Proposed validation protocol. Process validation and/or evaluation studies could be requested.
  2. Rationale for the change in the validation protocol.
3.2.P.4 Control of Parent Radionuclide
7. Change in the standard/monograph (i.e. specifications) claimed for the parent radionuclide
  • Conditions to be Fulfilled:
    • None
    • 1-5
  • Supporting Data:
    • 1-4
    • 1-4
  • Reporting Category:
    • Notifiable Change
    • Annual Notification
8. Change in the specification for the parent radionuclide to comply with an updated Schedule B pharmacopoeial standard/monograph
  • Conditions to be Fulfilled: 2-3
  • Supporting Data: 1-2,4
  • Reporting Category: Annual Notification
Conditions
  1. The change is from a House/Professed to a Schedule B pharmacopoeial standard/monograph.
  2. The change is made exclusively to comply with a Schedule B pharmacopoeial standard/monograph.
  3. The change to the specifications does not affect negatively the radionuclidic or chemical purity of the parent radionuclide.
  4. No deletion of tests or relaxation of acceptance criteria of the approved specifications, except to comply with a Schedule B pharmacopoeial standard/monograph.
  5. No deletion or change to any analytical procedures, except to comply with a Schedule B pharmacopoeial standard/monograph.
Supporting Data
  1. (P.4.1) Updated excipient specifications.
  2. (P.4.3) Where a House analytical procedure is used and a Schedule B standard/monograph is claimed, results of an equivalency study between the House and compendial methods.
  3. (P.4.4) Justification of the proposed specifications for the parent radionuclide [e.g., demonstration of the suitability of the monograph to control the parent radionuclide and potential impact on the performance of the drug product].
  4. Declaration that consistency of quality and of the production process of the parent radionuclide is maintained.
9. Change in the specifications used to release the parent radionuclide, involving:
  1. deletion of a test
    • Conditions to be Fulfilled: 2
    • Supporting Data: 1,3
    • Reporting Category: Annual Notification
  2. addition of a test
    • Conditions to be Fulfilled: 4
    • Supporting Data: 1-3
    • Reporting Category: Annual Notification
  3. replacement of an analytical procedure
    • Conditions to be Fulfilled: 4,7-9
    • Supporting Data: 1-2
    • Reporting Category: Annual Notification
  4. minor changes to an approved analytical procedure
    • Conditions to be Fulfilled: 4-5,7-9
    • Supporting Data: 1-2
    • Reporting Category: Annual Notification
  5. change from a House/Professed analytical procedure to a Schedule B analytical procedure
    • Conditions to be Fulfilled: 4-9
    • Supporting Data: 1-2
    • Reporting Category: Annual Notification
  6. to reflect a pharmacopoeial monograph update
    • Conditions to be Fulfilled: 4
    • Supporting Data: 1
    • Reporting Category: Annual Notification
  7. relaxation of an acceptance criterion
    • Conditions to be Fulfilled: 3
    • Supporting Data: 1,3
    • Reporting Category: Annual Notification
  8. tightening of an acceptance criterion
    • Conditions to be Fulfilled: 1
    • Supporting Data: 1
    • Reporting Category: Annual Notification
Conditions
  1. The change is within the range of approved acceptance criteria or has been made to reflect new pharmacopoeial monograph specifications for the parent radionuclide.
  2. The deleted test has been demonstrated to be redundant with respect to the remaining tests or is no longer a pharmacopoeial requirement.
  3. The change to the specifications does not negatively affect the radionuclidic purity or radiochemical purity of the parent radionuclide.
  4. The change does not concern sterility testing.
  5. No change in the acceptance criteria outside of the approved ranges.
  6. The method of analysis has not changed.
  7. Results of method validation demonstrate that the proposed analytical procedure is at least equivalent to the approved analytical procedure.
  8. The replaced analytical procedure maintains or tightens precision, accuracy, specificity and sensitivity.
  9. The change does not concern test for radionuclidic or radiochemical purity.
Supporting Data
  1. (P.4.1) Updated specifications of the parent radionuclide.
  2. (P.4.3) Where a House analytical procedure is used and a Schedule B standard is claimed, results of an equivalency study between the House and compendial methods.
  3. (P.4.3) Justification of the proposed specifications for the parent radionuclide.
10. Addition or replacement of the source of a parent radionuclide
  • Conditions to be Fulfilled: None
  • Supporting Data: 1-6
  • Reporting Category: Supplement
11. Deletion of the source of a parent radionuclide
  • Conditions to be Fulfilled: 1
  • Supporting Data: 7
  • Reporting Category: Annual NotificationFootnote 6
Conditions
  1. The deletion does not affect the physicochemical properties or specifications of the generator.
Supporting Data
  1. (S) Detailed information of facility, radioisotope production, quality control and transportation procedure from the manufacturer/supplier of the parent radionuclide or Letter of Access from the supplier to access any existing file with Health Canada for the above information.
  2. (S) Detailed information on storage, processing, and manufacturing process, or confirmation that these steps remain unchanged (cross-reference to the existing information of the same generator approved by Health Canada (File number, Control number, date of approval, product name, sponsor name).
  3. (S.3.1) Information demonstrating comparability in term of physicochemical characterization and impurity profile of the proposed parent radionuclide with the approved parent radionuclide.
  4. (P.5.4) Comparative release test data for the proposed generator eluate and the approved eluate to demonstrate chemical equivalence.
  5. (P.5.4) Batch analyses data for at least three (3) commercial scale batches of the proposed generator.
  6. (P.8.3) Stability test data to support the claimed expiry of the proposed generator.
  7. Rationale for the deletion of the source of a parent radionuclide.
3.2.P.5 Control of Generator
12. Changes affecting the quality control (QC) testing of the generator, involving:
  1. transfer of the QC testing activities for a non-pharmacopoeial assay (in-house) to a new company or to a different facility within the same company
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2
    • Reporting Category: Notifiable Change
  2. transfer of the QC testing activities for a pharmacopoeial assay (in-house) to a new company not listed on the Establishment Licence of the manufacturer/sponsor
    • Conditions to be Fulfilled: 1
    • Supporting Data: 1-2
    • Reporting Category: Annual Notification
Conditions
  1. The transferred QC test is not a potency assay.
Supporting Data
  1. (P.3.5) Information demonstrating technology transfer qualification.
  2. Evidence that the new company/facility is GMP compliant.
13. Change in the standard/monograph (i.e. specifications) claimed for the generator product, involving:
  1. a change from a Schedule B pharmacopoeial standard/monograph to a House standard
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-5
    • Reporting Category: Notifiable Change
  2. a change from a House/Professed standard to Schedule B pharmacopoeial standard/ monograph or from one Schedule B standard/monograph to a different Schedule B standard/monograph)
    • Conditions to be Fulfilled: 1-4
    • Supporting Data: 1-3
    • Reporting Category: Annual Notification
14. Change in the specifications for the generator to comply with an updated Schedule B pharmacopoeial standard/monograph
  • Conditions to be Fulfilled: 1-2
  • Supporting Data: 1-3
  • Reporting Category: Annual Notification
Conditions
  1. The change is made exclusively to comply with a Schedule B pharmacopoeial standard/monograph.
  2. The change to the specifications does not result in a potential impact on the performance of the eluate.
  3. No deletion of tests or relaxation of acceptance criteria of the approved specifications, except to comply with a Schedule B pharmacopoeial standard/monograph.
  4. No deletion or change to any analytical procedures, except to comply with a Schedule B pharmacopoeial standard/monograph.
Supporting Data
  1. (1.3) Product Monograph [e.g., Where applicable, Title Page, Composition and Packaging (Part I), and Pharmaceutical Information (Part II) section] and Inner and Outer Labels.
  2. (P.4.3) Copies or summaries of validation reports, if new analytical procedures are used.
  3. (P.5.1) Updated, QC approved copy of the proposed generator specifications and its eluate specifications (or where applicable, the final version of the specifications to be signed by QC after HC approval).
  4. (P.5.3) Where a House analytical procedure is used and a Schedule B standard is claimed, results of an equivalency study between the House and compendial methods.
  5. Justification of specifications with data.
15. Change in the specifications for the generator, involving:
  1. replacing the sterility test with process parametric release for ultra short lived daughter radionuclide
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2,5-6
    • Reporting Category: Supplement
  2. deletion of a test
    • Conditions to be Fulfilled: None
    • Supporting Data: 2,6
    • Reporting Category: Notifiable Change
  3. addition of a test
    • Conditions to be Fulfilled: 1-2
    • Supporting Data: 2-4,6
    • Reporting Category: Annual Notification
  4. replacement of an analytical procedure
    • Conditions to be Fulfilled: None
    • Supporting Data: 2-4,6-7
    • Reporting Category: Notifiable Change
  5. minor changes to an approved analytical procedure
    • Conditions to be Fulfilled: 5-8
    • Supporting Data: 3-4,7
    • Reporting Category: Annual Notification
  6. change from a House/Professed analytical procedure to a Schedule B analytical procedure or change from an approved compendial analytical procedure to an harmonized compendial procedure
    • Conditions to be Fulfilled: 5,7-9
    • Supporting Data: 2-4
    • Reporting Category: Annual Notification
  7. relaxation of an acceptance criterion
    • Conditions to be Fulfilled: None
    • Supporting Data: 2,6-7
    • Reporting Category: Notifiable Change
  8. tightening of an acceptance criterion
    • Conditions to be Fulfilled: 3-4
    • Supporting Data: 2
    • Reporting Category: Annual Notification
Conditions
  1. No change in the limits/acceptance criteria outside of the approved ranges for the approved assays.
  2. The addition of test is not to monitor new impurity species.
  3. The change is within the range of approved acceptance criteria.
  4. Parent radionuclide breakthrough in the eluate is within the acceptance limit specified by Health Canada.
  5. No change in the acceptance criteria outside of the approved ranges.
  6. The modified analytical procedure maintains or tightens precision, accuracy, specificity and sensitivity.
  7. The change does not concern sterility testing.
  8. The change does not concern test for radionuclidic identity or purity or radiochemical purity.
  9. The change does not concern tests for parent radionuclide breakthrough or pH for the eluate.
Supporting Data
  1. (P.3.5) Process validation and/or evaluation studies or validation protocol of the proposed generator.
  2. (P.5.1) Updated, QC approved copy of the proposed generator specifications (or where applicable, the final version of the specifications to be signed by QC after HC approval).
  3. (P.5.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  4. (P.5.3) Copies or summaries of validation reports, if new analytical procedures are used.
  5. (P.5.4) Description of the batches, certificates of analyses, and summary of results, of a sufficient number of batches to support the process parametric release.
  6. (P.5.6) Justification of the proposed generator specifications [e.g., demonstration of the suitability of the monograph to control the generator and its eluate, including parent radionuclide breakthrough].
  7. (P.5.6) Justification of the proposed drug product specifications [e.g., demonstration of the suitability of the monograph to control the drug product, including degradation products].
3.2.P.6 Reference Standards or Materials
16. Change the reference standards from pharmacopoeial to House
  • Conditions to be Fulfilled: None
  • Supporting Data: 1-2
  • Reporting Category: Notifiable Change
17. Change the reference standards from House/Professed to pharmacopoeial
  • Conditions to be Fulfilled: 1
  • Supporting Data: 1-2
  • Reporting Category: Annual Notification
18. Qualification of a new lot of reference standard against the approved reference standard
  • Conditions to be Fulfilled: 1
  • Supporting Data: 2
  • Reporting Category: Annual Notification
19. Extension of reference standard shelf life
  • Conditions to be Fulfilled: None
  • Supporting Data: 3
  • Reporting Category: Annual Notification
Conditions
  1. Qualification of the reference standard is performed according to the approved protocol (i.e. no deviation from the approved protocol).
Supporting Data
  1. (1.3) Revised Product monograph to reflect the change in reference standard.
  2. (P.6) Information demonstrating qualification of the proposed reference standards or materials [e.g., source, characterization, certificate of analysis].
  3. (P.8.1) Summary of stability testing and results to support the extension of reference standard shelf life.
3.2.P.7 Generator Accessories
20. Change in the container closure system, involving:
  1. replacement or addition of elution or collection container closure system
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-5
    • Reporting Category: Notifiable Change
  2. deletion of elution or collection container closure system
    • Conditions to be Fulfilled: None
    • Supporting Data: 1
    • Reporting Category: Annual Notification
21. Change in chromatography column and tubing, involving:
  1. a change in chromatography column
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-5
    • Reporting Category: Notifiable Change
  2. a change in the column tubing, elution needle
    • Conditions to be Fulfilled:
      • None
      • 1-5
    • Supporting Data:
      • 1-5
      • 1,3-5
    • Reporting Category:
Conditions
  1. No change in the type of container closure or materials of construction for chromatography column, column tubing or elution needle.
  2. No change in the shape or dimensions of the vial, stopper, chromatography column, column tubing or elution needle.
  3. No change in the principle of the sterilization procedures and no impact on the apyrogenicity of the eluate.
  4. The change is within the range of approved package sizes.
  5. All the accessories of the generator, such as vial, stopper, chromatography column, column tubing and elution needle, are compatible with the eluate.
Supporting Data
  1. (1.3) Relevant sections of the Product Monograph and Inner and Outer Labels affected by the proposed change.
  2. (P.3.5) Process validation and/or evaluation studies.
  3. (P.7) Information on the changed components such as vial, stopper, chromatography column, column tubing and elution needle [e.g., description, materials of construction, specifications, including results of compatibility studies].
  4. (P.8.1) Stability Summary and Conclusions.
  5. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment (if any).
22. Change in the supplier for vial, stopper, chromatography column, column tubing or elution needle involving:
  1. replacement or addition of a supplier
    • Conditions to be Fulfilled:
      • None
      • 1-2
    • Supporting Data:
      • 1-2
      • 2
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. deletion of a supplier
    • Conditions to be Fulfilled: None
    • Supporting Data: None
    • Reporting Category: Annual Notification
Conditions
  1. No change in the type of container closure, materials of construction, shape, dimensions or specifications.
  2. The change does not concern a sterile container closure component.
Supporting Data
  1. (P.3.5) Process validation and/or evaluation studies.
  2. (P.7) Information on the proposed components such as vial, stopper, chromatography column, column tubing or elution needle [e.g., description, materials of construction, specifications, including results of compatibility studies].
3.2.P.8 Stability
23. Change in the shelf life for the generator, involving:
  1. extension
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2,5
    • Reporting Category: Notifiable Change
  2. reduction
    • Conditions to be Fulfilled: 1-3
    • Supporting Data: 1-5
    • Reporting Category: Annual Notification
Conditions
  1. No change to the recommended storage condition of the generator.
  2. Change does not affect the parent radionuclide breakthrough, radionuclidic or radiochemical purity of the eluate.
  3. The reduction in the shelf life is not necessitated by recurring events arising during manufacture or because of stability concerns.
Supporting Data
  1. (P.8.1) Summary of stability testing and results [e.g., studies conducted, protocols used, results obtained].
  2. (P.8.1) Proposed storage conditions and shelf life.
  3. (P.8.1) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment.
  4. (P.8.2) Justification of the change to the post-approval stability protocol or stability commitment.
  5. (P.8.3) Results of stability testing (i.e., full long term stability data covering the proposed shelf life generated on at least three (3) commercial scale batches).
24. Change in the post-approval stability protocol of the generator, involving:
  1. major change to the post-approval stability protocol or stability commitment such as deletion of a test, replacement of an analytical procedure, change in storage temperature
    • Conditions to be Fulfilled:
      • None
      • 1-2
    • Supporting Data:
      • 3-6
      • 1-2,4-5
    • Reporting Category:
      • Notifiable Change
      • Annual Notification
  2. addition of time point(s) into the post-approval stability protocol
    • Conditions to be Fulfilled: None
    • Supporting Data: 4-5
    • Reporting Category: Annual Notification
  3. addition of test(s) into the post-approval stability protocol
    • Conditions to be Fulfilled: 3
    • Supporting Data: 4-5
    • Reporting Category: Annual Notification
  4. deletion of time point(s) from the post-approval stability protocol within or beyond the approved shelf life
    • Conditions to be Fulfilled: None
    • Supporting Data: 2-3
    • Reporting Category: Annual Notification
Conditions
  1. For the replacement of an analytical procedure, the results of method validation demonstrate that the new analytical procedure is at least equivalent to the approved analytical procedure.
  2. For the replacement of an analytical procedure, the new analytical procedure maintains or tightens precision, accuracy, specificity and sensitivity.
  3. The addition of test(s) is not due to stability concerns or to the identification of new impurities.
Supporting Data
  1. (P.5.2) Copies or summaries of analytical procedures, if new analytical procedures are used.
  2. (P.5.3) Copies or summaries of validation reports, if new analytical procedures are used.
  3. (P.8.1) Proposed storage conditions and or shelf life, as appropriate.
  4. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment.
  5. (P.8.2) Justification of the change to the post-approval stability protocol or stability commitment.
  6. (P.8.3) If applicable, stability testing results to support the change to the post-approval stability protocol or stability commitment [e.g., data to show greater reliability of the alternate test].
25. Change in the labelled storage conditions for the generator, involving:
  1. addition or change of storage condition for the generator [e.g., relaxation or tightening of a temperature criterion]
    • Conditions to be Fulfilled: 1-5
    • Supporting Data: 1-5,7
    • Reporting Category: Annual Notification
  2. addition of a cautionary statement
    • Conditions to be Fulfilled: 4
    • Supporting Data: 1-2,5-6
    • Reporting Category: Annual Notification
  3. deletion of a cautionary statement
    • Conditions to be Fulfilled: None
    • Supporting Data: 1-2,5,7
    • Reporting Category: Annual Notification
Conditions
  1. Full stability data for the generator are available and covers the proposed shelf life and are based on stability data generated on three (3) commercial scale batches.
  2. Stability data was generated in accordance with the approved stability protocol.
  3. Stability data for the generator was generated post calibration with the approved quantity of parent radionuclide.
  4. The change is not necessitated by recurring events arising during manufacture or because of stability concerns.
  5. The change consists in the tightening of a temperature criterion within the approved ranges.
Supporting Data
  1. (1.3) Revised Product Monograph [e.g., Where applicable, Title Page, Composition and Packaging (Part I), and Pharmaceutical Information (Part II) section] and Inner and Outer Labels, as applicable.
  2. (P.8.1) Summary of stability testing and results [e.g., studies conducted, protocols used, results obtained].
  3. (P.8.1) Proposed storage conditions and shelf life, as appropriate.
  4. (P.8.2) Updated, QC approved post-approval stability protocol (or where applicable, the final version of the protocol to be signed by QC after HC approval) and stability commitment.
  5. (P.8.2) Justification of the change in the labelled storage conditions/cautionary statement.
  6. (P.8.3) Results of stability testing (i.e., full real time/real temperature stability data covering the proposed shelf life generated on one (1) commercial scale batch).
  7. (P.8.3) Results of stability testing (i.e., full real time/real temperature stability data covering the proposed shelf life generated on at least three (3) commercial scale batches).

Appendix 5: Recommendations for Conducting and Assessing Comparative Dissolution Profiles

Below are recommendations when conducting comparative dissolution profiles:

  • The resulting comparative dissolution profiles should be considered similar using the following equation which defines a similarity factor (f2):
    • Equation - Comparative dissolution profiles
      where Rt and Tt are the percent dissolved at each time point. An f2 value between 50 and 100 suggests the two dissolution profiles are similar.
  • At least 12 units should be used for each profile determination. Mean dissolution values can be used to estimate the similarity factor, f2. To use mean data, the % coefficient of variation at the earlier point should be not more than 20% and at other time points should be not more than 10%.
  • The dissolution measurements of the two products (e.g., test and reference, pre- and post- change, two strengths) should be made under the same test conditions. The dissolution time points for both the profiles should be the same, e.g., for immediate release products: 15, 30, 45 and 60 minutes, for extended release products: 1, 2, 3, 5 and 8 hours.
  • Adequate sampling should be performed until either 90% of drug from the drug product is dissolved or an asymptote is reached. A surfactant may be used with appropriate justification.
  • Because f2 values are sensitive to the number of dissolution time points, only one measurement should be considered after 85% dissolution of the product.
  • If the individual data for both the test and reference products show more than 85% dissolution within 15 minutes, the profiles are considered similar (no calculations are necessary).
  • When multi-media dissolution profiles are recommended, these studies should be performed in at least three (3) media covering the physiological range (pH 1.2 - 6.8), e.g., water, 0.1N HCl, and pharmacopoeial buffer media for the test and reference products.
  • When delayed-release products (e.g., enteric coated) are being compared, it is acceptable to consider either multi-point testing in the acid phase as one of these media, or alternatively for coated products, to compare testing in 3 media once the coating disintegrates (e.g., pH 4, 5 and 6.8).

Summary of Dissolution Documentation

Case A: High Permeability,High Solubility Drugs
Dissolution of 85% in 15 minutes in 900 mL of 0.1N HCl. If a drug product fails to meet this criterion, the applicant should perform the tests described for Case B or C (below).
Case B: Low Permeability, High Solubility Drugs
Multi-point dissolution profile should be performed in the submission/compendial medium at 15, 30, 45, 60 and 120 minutes or until an asymptote is reached. The dissolution profile of the proposed and currently used product formulations should be similar.
Case C: High Permeability, Low Solubility Drugs
Multi-point dissolution profiles should be performed in at least three (3) media covering the physiological range (pH 1.2 - 6.8), e.g., 0.1N HCl, and pharmacopoeial buffer media for the proposed and currently accepted formulations. Adequate sampling should be performed at 15, 30, 45, 60, and 120 minutes until either 90% of drug from the drug product is dissolved or an asymptote is reached.
Solubility
Solubility is calculated based on the minimum concentration of drug, milligram/millilitre (mg/mL), in the largest dosage strength, determined over the physiological pH range (pH 1.2 to 6.8) and temperature (37 0.5°C). Highly water soluble drugs are those with a dose/solubility volume of less than or equal to 250 mL.
  • Example: Compound A has as its lowest solubility at 37 0.5°C, 1.0 mg/mL at pH 6.8, and is available in 100 mg, 200 mg, and 400 mg strengths. This drug would be considered a low solubility drug as its dose/solubility volume is greater than 250 mL (400 mg/1.0 mg/mL = 400 mL).
Permeability
Evidence should be provided to justify the degree of permeability claimed for the drug substance. This could include information from published literature and/or data from experimental and/or clinical studies.

Appendix 6: Changes to Excipients

Excipient
Percent excipient (w/w) out of total target dosage form core weight

Table 1 footnotes

Table 1 footnote 1

Where the film coat is for appearance only and not intended affect the release rate or stability characteristics of the drug.

Return to table 1 footnote 1 referrer

Filler 5.0
Disintegrant
Starch 3.0
Other 1.0
Binder 0.5
Lubricant
Ca or Mg Stearate 0.25
Other 1.0
Glidant
Talc 1.0
Other 0.1
Film CoatTable 1 footnote 1 1.0

Notes

  • These percentages are based on the assumption that the drug substance in the product is formulated to 100.0% of label/potency. The total additive effect of all excipient changes should be not more than 5.0%.
  • Multi-functional Excipients: If an excipient provides multiple functions (e.g., microcrystalline cellulose as a filler and as a disintegrant), then the most conservative recommended range should be applied (e.g., 3.0% for microcrystalline cellulose should be applied in this example). If a wider range is proposed, scientific justification, including supporting data to demonstrate that the wider range will not affect the other function of the excipient should be provided.
  • Bracketing: If different strengths of an immediate release solid oral dosage form have differences in the proportion of excipients which exceed those in the above table, but within the progression of strengths, the changes are incremental, a comparative bioavailability study should be performed on the lowest and highest strengths. Incremental changes are those in which proportions of excipients increase or decrease successively from the lowest to the highest strengths in the range.
    If different strengths contain different excipients, or if the differences in the proportion of excipients exceed those defined in the above table and are not incremental within the progression of strengths, comparative bioavailability studies should be performed on each strength.
  • Pharmacokinetic Considerations: It should be noted that the pharmacokinetic characteristics of the medicinal ingredient (e.g., linear kinetics or non-linear kinetics with greater than or less than proportional increases in area under the curve (AUC) with increasing dose), will also be taken into consideration during the evaluation of a request for a waiver of the requirement to conduct clinical or comparative bioavailability studies on the basis of proportionality of additional proposed strength(s) to the strength used in the in vivo studies.

Appendix 7: Examples of Level IV changes

  • Non-critical changes to the licensed application including spelling mistakes, editorial changes made to documents such as Validation Summaries and/or Reports, Analytical Procedures, SOPs, Production Documentation Summaries, QOS, for added clarity that have no impact to affect the safety, efficacy and quality of the product.
  • Change in stopper cap colour for an injectable product.
  • Modification to pretreatment stages of a WFI system, including purified water systems used solely for pretreatment in WFI production.
  • Change in the floor plan that does not affect production process or contamination precautions.
  • Addition of vial reject chute.
  • Change in the in-process controls performed at non-critical manufacturing steps or change to a non-critical manufacturing area (see Glossary).
  • Rooms upgrades, such as installation of improved finishes on floors/walls.
  • Addition of a new GMP storage warehouse for raw materials, master and working cell banks and drug substance.
  • Installation of non-process-related equipment or rooms to improve the facility, such as warehousing refrigerators or freezers.
  • Replacement of equipment with an identical equipment.
  • Introduction of additional laboratory facility in a facility to perform drug substance or drug product testing.
  • For biologics and radiopharmaceuticals, with the exception of a potency assay or a bioassay, transfer of the QC testing responsibilities for a pharmacopoeial assay to a different facility within the same company.
  • For biologics and radiopharmaceuticals, with the exception of a potency assay or a bioassay, transfer of the QC testing responsibilities for a pharmacopoeial assay to a different company listed on the sponsor's establishment licence.
  • Change in supplier for non-critical excipients.
  • Change in tertiary packaging components of drug substance or drug product that do not affect stability.

Appendix 8: Glossary

Acronyms

ANDS
Abbreviated New Drug Submission
BGTD
Biologics and Genetic Therapies Directorate
BSE
Bovine Spongiform Encephalopathy
CPSFI
Changes in Product-Specific Facility Information
CTD
Common Technical Document
DMF
Drug Master File
DPIF
Drug Product Information Form
EDQM
The European Directorate for the Quality of Medicines of the Council of Europe
EL
Establishment Licence
GMP
Good Manufacturing Practices
ICH
International Conference on Harmonisation
INN
International Non-proprietary Name
IVIVC
in-vitro, in-vivo correlation
NC
Notifiable Change
NDS
New Drug Submission
NOC
Notice of Compliance
Q1A
ICH guideline entitled "Stability testing of New Drug Substances and Products"
Q1D
ICH guideline entitled "Bracketing and Matrixing Designs for Stability Testing of New Drug Substance and Drug Product".
Q1E
ICH guideline entitled "Evaluation of stability data"
Q5E
ICH guideline entitled "Comparability of biotechnological / biological products"
SUPAC-MR
Scale-up and Post-approval Changes - Modified Release Solid Oral Dosage Forms (United States FDA guideline)
SANDS
Supplement to an Abbreviated New Drug Submission
SNDS
Supplement to a New Drug Submission
TSE
Transmissible Spongiform Encephalopathy
VDD-CPID
Veterinary Drugs Directorate Certified Product Information Document.
VDD-QOS
Veterinary Drugs Directorate Quality Overall Summery
VICH
International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products
WHO
World Health Organization

Definitions

Adjuvant
Component that potentiates the immune responses to an antigen and/or modulates it towards the desired immune responses. Adjuvant may be of pharmaceutical origin (chemical/synthetic adjuvant) or of biological origin (biological adjuvant).
Batch
A quantity of drug in dosage form, a raw material, or a packaging material, homogeneous within specified limits, produced according to a single production order and as attested by the signatories to the order. In the case of continuous manufacture, a batch corresponds to a defined fraction of the production, that is characterized by its intended homogeneity. It may sometimes be necessary to divide a batch into a number of sub-batches, which are later brought together to form a final homogeneous batch.
Biological auxiliary material
Raw material from a biological source which is intended to be used as a processing aid in the fabrication of the drug. It may be absent from the drug or may remain as an impurity in the drug at the end of the manufacturing process (e.g., biological additives used to supplement cell culture medium in production fermenter, human antithrombin III used to complex and remove human thrombin).
Biological starting material
Raw material from a biological source which is intended to be used in the fabrication of a drug and from which the active ingredient is derived either directly (e.g., plasma derivatives, ascitic fluid, bovine lung, etc.) or indirectly (e.g., cell substrate, host/vector production cells, eggs, viral strains, etc.).
Carrier
An edible material (e.g. calcium carbonate, rice hull, corn cobs, gluten) to which drug substances are added to form a homogenous drug premix or is used to dilute the drug premix (or medicated premix) to form medicated feed.
Certificate of suitability (CEP)
A certificate of compliance of a substance with the relevant requirements of the European Pharmacopoeia monographs for use in medicinal products issued by the European Directorate for the Quality of Medicine of the Council of Europe (EDQM).
Container closure system
The sum of packaging components that together contain and protect the dosage form. This includes primary packaging components and secondary packaging components, if the latter are intended to provide additional protection to the drug product. A packaging system is equivalent to a container closure system.
Change-over procedure
A logical series of validated steps that ensures the proper cleaning of suites and equipment before the processing of a different product begins.
Closed process/closed system
Process equipment or process step in which the product is not exposed to the external environment. A closed system requires that the quality of materials entering or leaving the system and the manner in which these materials are added/removed from the system is carefully controlled.
Critical manufacturing step
A manufacturing process/step that may result in a potential change in the purity/impurity profile or due to the nature of the starting materials or resulting product/intermediate, requires containment within a specially designed manufacturing area or production facility, for example, the development and preparation of cell banks and seed lots, initial propagation, scale-up, blood and plasma pooling and fractionation, fermentation, harvesting, inactivation, purification, addition of adjuvants or preservatives, the conjugation and pooling of bulk concentrates and the final preparation of drug product including concentration/diafiltration, formulation, sterile filtration, filling and lyophilization.
Critical process parameter
A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality.
Delayed release
Release of a drug (or drugs) at a time other than immediately following oral administration.
Dilute drug premix
A drug for veterinary use that results from mixing a drug premix with a feed as defined in section 2 of the Feeds Act, to such a level that at least 10 kg of the resulting mixture is required to medicate one tonne of complete feed, as defined in section 2 of the Feeds Regulations, 1983, with the lowest approved dosage level of the drug.
Design space
The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval.
Different host/media-type
Mammalian cells or any micro-organisms involved in the manufacture of a drug substance which are different from the existing hosts in the facility or use a cell culture or fermentation medium with significantly differing composition.
Discrete chemical entity
A single molecular entity with a known chemical structure.
Dosage form
A drug product that has been processed to the point where it is now in a form in which it may be administered in individual doses.
Drug product
The dosage form in the final immediate packaging intended for marketing.
Drug substance
The unformulated drug substance that may subsequently be formulated with excipients to produce the dosage form.
Equivalency of method
The proposed analytical method has been validated and demonstrated to be equivalent to the approved method in term of suitability for its intended use.
Equivalent equipment
Equipment with similar design and same operating principle and fabricated with product-contact material of same or higher grade quality. Equivalent equipment should give a product of same quality as the one processed by the previous equipment.
Excipient
Anything other than the drug substance in the dosage form.
Extended release
Extended release products are formulated to make the drug available over an extended period after ingestion. This allows a reduction in dosing frequency compared to a drug presented as a conventional dosage form (e.g., as a solution or an immediate release dosage form).
Facility
A building in which a specific manufacturing operation or multiple operations take place.
Feed ingredient
Any substance or mixture of substance that is assessed or evaluated as being acceptable for use in feeds.
Feed microtracers
Microtracers are uniform stainless steel particles coloured with codified food dyes and incorporated into a drug premix (medicated premix). Microtracers are used in feed assays to establish correlation between drug and microtracer recoveries to give an easy and rapid method for semi quantitative detection of the medicated premix in the medicated feed, and the validation of mixing process in a field environment.
Fermentation train
Equipments and conditions involved in the stepwise expansion of the cell culture process.
Functional secondary packaging
Packaging material not in direct contact with the product that provide additional protection or serve to deliver the product.
HVAC (Heating, Ventilation, and Air Conditioning)
Industry term for the systems and technology responsible for the heating, ventilation, and air conditioning in buildings. HVAC systems regulate comfort (temperature and humidity), energy efficiency, and air quality.
Immediate release dosage forms
Dosage forms that allow the drug to dissolve in the gastrointestinal contents, with no intention of delaying or prolonging the dissolution or absorption of the drug.
In-process control
Check performed during production in order to monitor and, if necessary, to adjust the process to ensure that the finished product conforms to its specifications. The control of the production environment or equipment may also be regarded as part of in-process control.
Interchangeable
Where such status is indicated, any of the official texts from JP, EP, or USP can be substituted one for the other (appropriately referenced) in the ICH regions for purposes of the pharmaceutical registration/approval process. Using any of the interchangeable methods, an analyst will reach the same accept or reject decisions irrespective of which PDG pharmacopeia is used.
Medicated feed
A mixed feed that contains a medicating ingredient [2.(1) of the Feeds Regulations, 1983].
Medicated premix (or drug premix)
A drug for veterinary use to which a drug identification number has been assigned, where the directions on its label specify that it is to be mixed with feed as defined in section 2 of the Feeds Act. (C.01A.001 of the Food and Drugs Regulations). It is a veterinary drug product prepared in advance with a view to the subsequent manufacture of medicated feeds.
Modified release dosage forms
Dosage forms whose drug-release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as a solution or an immediate release dosage form. Modified release solid oral dosage forms include both delayed and extended release drug products.
Multi-product facility
A facility where more than one product of the same type or products from different classes are fabricated (e.g., pharmaceutical and biological drugs).
Non-critical area
Area that does not encompass process steps.
Non-critical excipient
Excipient with no active function, e.g., solution used to adjust pH.
Non-critical manufacturing step
A manufacturing process/step that has no impact upon purity and impurity profile or requires no specific facility considerations, for example, buffer and media preparation, storage of intermediates, and packaging (note that some biological drugs may require critical temperature and/or light control during packaging).
Open system
Any steps in a manufacturing process where in-process materials or components are exposed to the external environment.
Pilot scale
A batch of a drug substance or drug product manufactured by a procedure fully representative of and simulating that to be applied to a full production scale batch. For solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is the larger.
Presentation
Container that contains the drug product. The container may be used directly or indirectly in the administration of the drug (e.g., vials, pre-filled syringes, pre-filled pens).
Primary container closure component
Packaging material in direct contact with the product.
Proposed drug substance/drug product
Drug substance and/or drug product manufactured using a process incorporating the proposed change(s).
QC approved documents
"QC approved" means approved by the person in charge of the quality control department.
Reprocessing
Subjecting all or part of a batch or lot of an in-process drug, a bulk process intermediate (final biological bulk intermediate) or a bulk drug of a single batch/lot to a previous step in the validated manufacturing process due to failure to meet predetermined specifications.
Schedule B pharmacopoeia
Pharmacopoeia listed in Schedule B of the Food and Drugs Act (e.g., United States Pharmacopeia, European Pharmacopoeia).
Shelf life (also referred to as expiration period)
The time period during which a drug product is expected to remain within the approved shelf life specification, provided that it is stored under the conditions defined on the container label.
Strength
Quantity of medicinal ingredient in a particular dosage form. For solution, concentration of the active pharmaceutical ingredient multiplied by the fill volume.
Release controlling excipient (or agent)
An excipient in the final dosage form whose primary function is to modify the duration of release of the active drug substance from the dosage form.
Unexpected events
"Unexpected events arising during manufacture or because of stability concerns" refers to unexpected events resulting in a failure to meet specifications.
Validation
The documented act of demonstrating that any procedure, process, and activity will consistently lead to the expected results. Includes the qualification of systems and equipments.
Withdrawal period
The length of time between the last administration of a drug to an animal and the time when tissues or products collected from the treated animal for consumption as food contain a level of residue of the drug that would not likely cause injury to human health.

Footnotes

Footnote 1

The Veterinary Drugs Directorate (VDD) should be consulted to determine if the submission constitutes a veterinary biotechnological drug under the Food and Drug Act.

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Footnote 2

Health Canada is in the process of adopting International Conference on Harmonisation Q8 and Q8 Annex.

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Footnote 3

This application consists of the review of the CPID-B only.

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Footnote 4

Change in a component of a biological adjuvant system may require the filing of a NDS. Sponsors are encouraged to contact Health Canada for further guidance.

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Footnote 5

Note that a biological diluent is considered itself a drug product.

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Footnote 6

Notification is required immediately after the change is made.

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Footnote 7

Notification is required immediately after change has been made.

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