Draft Guidance for Industry - Impurities in Existing Drug Substances and Products

2005-09-06
Our file number: 05-119427-760

Help on accessing alternative formats, such as Portable Document Format (PDF), Microsoft Word and PowerPoint (PPT) files, can be obtained in the alternate format help section.

Contact: Bureau of Pharmaceutical Sciences (BPS) Enquiries

Notice

Health Canada is pleased to announce the release of the draft Guidance for Industry Impurities in Existing Drug Substances and Products for Stakeholder consultation.

The purpose of this document is to provide guidance on the identification, qualification, and control of impurities for existing drug substances and associated drug products. In 1999, Health Canada released a draft guidance document entitled Identification, Qualification, and Control of Impurities in Existing Drugs for Stakeholder consultation. The finalization of this document was delayed due to maintenance activities of the International Conference on Harmonization (ICH) guidelines Impurities in New Drug Substances (Q3A) and Impurities in New Drug Products (Q3B). The conclusion of the ICH maintenance activities and the release of the Q3A(R) and Q3B(R) guidelines allows for further development of this Health Canada guidance document, now entitled Impurities in Existing Drug Substances and Products. As a number of changes have been introduced as a result of the maintenance of the ICH Q3A and Q3B guidelines, this Health Canada guidance document is being re-released as a draft document for Stakeholder consultation.

Comments on the draft guidance document should be forwarded (preferably in electronic format quoting the applicable line references) no later than December 1, 2005 to:

Gary Condran
Senior Scientific Advisor,
Bureau of Pharmaceutical Sciences,
Therapeutic Products Directorate, Health Canada
1^st Floor, Room D-122, Finance Building, Tunney's Pasture
(Address locator: 0201D)
Ottawa, Ontario, K1A 0K9

Telephone: (613) 941-3192
Facsimile: (613) 957-3989
Internet: gary_condran@hc-sc.gc.ca

Foreword

Guidance documents are meant to provide assistance to industry and health care professionals on how to comply with the policies and governing statutes and regulations. They also serve to provide review and compliance guidance to staff, thereby ensuring that mandates are implemented in a fair, consistent and effective manner.

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 scientific 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 information or material, or define conditions not specifically described in this guidance, 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 guidances.

Table of Contents

• 1. Introduction
  • 1.1 Objective
  • 1.2 Scope
  • 1.3 Background
• 2. Impurities in Existing Drug Substances
  • 2.1 Preamble
  • 2.2 Classification of Impurities
  • 2.3 Rationale for the Reporting and Control of Impurities
    • 2.3.1 Organic Impurities
    • 2.3.2 Inorganic Impurities
    • 2.3.3 Solvents
  • 2.4 Analytical Procedures
  • 2.5 Reporting Impurity Content of Batches
  • 2.6 Listing of Impurities in Specifications
  • 2.7 Qualification of Impurities
• 3. Impurities in Existing Drug Products
  • 3.1 Rationale for the Reporting and Control of Degradation Products
  • 3.2 Analytical Procedures
  • 3.3 Reporting Degradation Products Content of Batches
  • 3.4 Listing of Degradation Products in Specifications
  • 3.5 Qualification of Degradation Products
• 4. Glossary
• Attachment 1A: Thresholds for Impurities in Existing Drug Substances
• Attachment 1B: Thresholds for Degradation Products in Existing Drug Products
• Attachment 2A: Illustration of Reporting Impurity Results for Identification and Qualification in an Application
• Attachment 2B: Illustration of Reporting Degradation Product Results for Identification and Qualification in an Application
• Attachment 3A: Decision Tree for Identification and Qualification of an Impurity
• Attachment 3B: Decision Tree for Identification and Qualification of a Degradation Product

1. Introduction

1.1 Objective

This guidance is an extension of the previously released ICH¹/Health Canada guidance documents entitled Impurities in New Drug Substances (Q3A(R)) and Impurities in New Drug Products (Q3B(R)) and provides guidance on the identification, qualification, and control of impurities for existing drug substances and associated drug products.

An "existing drug" is one that does not contain a new medicinal ingredient (also known as a new active substance), but requires the filing of a New Drug Submission (NDS), an Abbreviated New Drug Submission (ANDS) or a Supplement (e.g., generic products). This would include, for example, submissions for new dosage forms, new strengths, and other changes to approved products.

1.2 Scope

This guidance document addresses recommendations for the impurity information to be included in applications that are filed with the Therapeutic Products Directorate of Health Canada for existing drug substances produced by chemical syntheses and their associated drug products.

This would include those impurities in existing drug substances or drug products classified as degradation products of the drug substance or reaction products of the drug substance with an excipient and/or immediate container closure system (collectively referred to as "degradation products" in this guidance document). Generally, impurities present in the existing drug substance need not be monitored or specified in the existing drug product unless they are also degradation products (see ICH Q6A guidance document on specifications).

Impurities arising from excipients present in the existing drug product or extracted or leached from the container closure system are not covered by this guidance document. This guidance does not apply to existing drug substances or existing drug products used during the clinical research stages of development. The following types of drug substances or drug products are not covered in this guidance document: biological/biotechnological products, peptides, oligonucleotides, radiopharmaceuticals, fermentation products and semi-synthetic products derived therefrom, herbal products, and crude products of animal or plant origin. Also excluded from this document are: (1) extraneous contaminants that should not occur in existing drug substances or existing drug products and are more appropriately addressed as good manufacturing practice (GMP) issues, (2) polymorphic forms, and (3) enantiomeric impurities.

¹ International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use.

1.3 Background

The ICH guidelines Impurities in New Drug Substances (Q3A) and Impurities in New Drug Products (Q3B) were originally adopted as Health Canada guidance documents in 1995 and 1999, respectively. These ICH guidelines have since been the subject of the ICH maintenance process and were finalized in 2002 and 2003, respectively, and subsequently adopted by Health Canada in 2003.

In 1999, Health Canada released a draft guidance document entitled Identification, Qualification, and Control of Impurities in Existing Drugs for Stakeholder consultation. The purpose of this guidance document was to outline recommendations for the control of impurities for products that are outside of the scope of the current ICH impurity guidelines (e.g., existing drugs). The finalization of this document was delayed due to maintenance activities of the aforementioned ICH Q3A and Q3B guidelines. The conclusion of the ICH maintenance activities and the release of the finalized Q3A(R) and Q3B(R) guidelines allows for further development of this Health Canada guidance document, now entitled Impurities in Existing Drug Substances and Products. As a number of changes have been introduced as a result of the maintenance of the ICH Q3A and Q3B guidelines, this Health Canada guidance document is being re-released as a draft document for Stakeholder consultation.

In the interests of international harmonization, wherever possible, this guidance conforms to the text and principles of the ICH Q3A(R) and Q3B(R) guidance documents. The text from the Q3A(R) and Q3B(R) guidance documents has been merged into this single document, with changes necessary to reflect the recommendations for existing drugs indicated by text. This approach is consistent with that taken with similar Health Canada guidance documents (e.g., Stability Testing of Existing Drug Substance and Products).

This guidance document should be read in conjunction with other applicable ICH and Health Canada guidance documents and the applicable portions of the various pharmacopoeias.

2. Impurities In Existing Drug Substances

2.1 Preamble

Impurities in an existing drug substances are addressed from two perspectives:

Chemistry Aspects include classification and identification of impurities, report generation, listing of impurities in specifications, and a brief discussion of analytical procedures; and

Safety Aspects include specific guidance for qualifying those impurities that were not present, or were present at substantially lower levels, in batches of an existing drug substance used in safety and clinical studies.

2.2 Classification of Impurities

Impurities can be classified into the following categories:

• Organic impurities (process- and drug-related)
• Inorganic impurities
• Residual solvents

Organic impurities can arise during the manufacturing process and/or storage of the existing drug substance. They can be identified or unidentified, volatile or non-volatile, and include:

• Starting materials
• By-products
• Intermediates
• Degradation products
• Reagents, ligands and catalysts

Inorganic impurities can result from the manufacturing process. They are normally known and identified and include:

• Reagents, ligands and catalysts
• Heavy metals or other residual metals
• Inorganic salts
• Other materials (e.g., filter aids, charcoal)

Solvents are inorganic or organic liquids used as vehicles for the preparation of solutions or suspensions in the synthesis of an existing drug substance. Since these are generally of known toxicity, the selection of appropriate controls is easily accomplished (see ICH Guidance Document Q3C on Residual Solvents).

2.3 Rationale for the Reporting and Control of Impurities

2.3.1 Organic Impurities

The applicant should summarise the actual and potential impurities most likely to arise during the synthesis, purification, and storage of the existing drug substance. This summary should be based on sound scientific appraisal of the chemical reactions involved in the synthesis, impurities associated with raw materials that could contribute to the impurity profile of the existing drug substance, and possible degradation products. This discussion can be limited to those impurities that might reasonably be expected based on knowledge of the chemical reactions and conditions involved.

In addition, the applicant should summarise the laboratory studies conducted to detect impurities in the existing drug substance. This summary should include test results of batches manufactured during the development process and batches from the proposed commercial process, as well as the results of stress testing (see ICH Guidance Document Q1A on Stability) used to identify potential impurities arising during storage. The impurity profile of the drug substance batches intended for marketing should be compared with those used in development, and any differences discussed.

The studies conducted to characterise the structure of actual impurities present in the existing drug substance at a level greater than (>) the identification threshold given in Attachment 1A (e.g., calculated using the response factor of the drug substance) should be described. Note that any impurity at a level greater than (>) the identification threshold in any batch manufactured by the proposed commercial process should be identified. In addition, any degradation product observed in stability studies at recommended storage conditions at a level greater than (>) the identification threshold should be identified. When identification of an impurity is not feasible, a summary of the laboratory studies demonstrating the unsuccessful effort should be included in the application. Where attempts have been made to identify impurities present at levels of not more than (≤) the identification thresholds, it is useful also to report the results of these studies.

Identification of impurities present at an apparent level of not more than (≤) the identification threshold is generally not considered necessary. However, analytical procedures should be developed for those potential impurities that are expected to be unusually potent, producing toxic or pharmacological effects at a level not more than (≤) the identification threshold. All impurities should be qualified as described later in this guidance document.

2.3.2 Inorganic Impurities

Inorganic impurities are normally detected and quantified using pharmacopoeial or other appropriate procedures. Carry-over of catalysts to the existing drug substance should be evaluated during development. The need for inclusion or exclusion of inorganic impurities in the existing drug substance specification should be discussed. Acceptance criteria should be based on pharmacopoeial standards or known safety data.

2.3.3 Solvents

The control of residues of the solvents used in the manufacturing process for the existing drug substance should be discussed and presented according to the ICH Q3C Guidance Document for Residual Solvents.

2.4 Analytical Procedures

The registration application should include documented evidence that the analytical procedures are validated and suitable for the detection and quantification of impurities (see ICH Q2A and Q2B Guidance Documents for Analytical Validation). Technical factors (e.g., manufacturing capability and control methodology) can be considered as part of the justification for selection of alternative thresholds based on manufacturing experience with the proposed commercial process. The use of two decimal places for thresholds (See Attachment 1A) does not necessarily reflect the precision of the analytical procedure used for routine quality control purposes. Thus, the use of lower precision techniques (e.g., thin-layer chromatography) can be acceptable where justified and appropriately validated. Differences in the analytical procedures used during development and those proposed for the commercial product should be discussed in the registration application.

The quantitation limit for the analytical procedure should be not more than (≤) the reporting threshold.

Organic impurity levels can be measured by a variety of techniques, including those that compare an analytical response for an impurity to that of an appropriate reference standard or to the response of the existing drug substance itself. Reference standards used in the analytical procedures for control of impurities should be evaluated and characterised according to their intended uses. The drug substance can be used as a standard to estimate the levels of impurities. In cases where the response factors of the drug substance and the relevant impurity are not close, this practice can still be appropriate, provided a correction factor is applied or the impurities are, in fact, being overestimated. Acceptance criteria and analytical procedures used to estimate identified or unidentified impurities can be based on analytical assumptions (e.g., equivalent detector response). These assumptions should be discussed in the registration application.

2.5 Reporting Impurity Content of Batches

Analytical results should be provided in the application for all batches of the existing drug substance used for clinical, bioequivalence/bioavailability, safety, and stability testing, as well as for batches representative of the proposed commercial process. Quantitative results should be presented numerically, and not in general terms such as "complies", "meets limit" etc. Any impurity at a level greater than (>) the reporting threshold (see Attachment 1A) and total impurities observed in these batches of the existing drug substance should be reported with the analytical procedures indicated. Below 1.0%, the results should be reported to two decimal places (e.g., 0.06%, 0.13%); at and above 1.0%, the results should be reported to one decimal place (e.g., 1.3%). Results should be rounded using conventional rules (see Attachment 2A). A tabulation (e.g., spreadsheet) of the data is recommended. Impurities should be designated by code number or by an appropriate descriptor, e.g., retention time. If a higher reporting threshold is proposed, it should be fully justified. All impurities at a level greater than (>) the reporting threshold should be summed and reported as total impurities.

When analytical procedures change during development, reported results should be linked to the procedure used, with appropriate validation information provided. Representative chromatograms should be provided. Chromatograms of representative batches from analytical validation studies showing separation and detectability of impurities (e.g., on spiked samples), along with any other impurity tests routinely performed, can serve as the representative impurity profiles. The applicant should ensure that complete impurity profiles (e.g., chromatograms) of individual batches are available, if requested.

A tabulation should be provided that links the specific existing drug substance batch to each safety study, bioequivalence/bioavailability, and clinical study in which the existing drug substance has been used.

For each batch of the existing drug substance, the report should include:

• Batch identity and size
• Date of manufacture
• Site of manufacture
• Manufacturing process
• Impurity content, individual and total
• Use of batches
• Reference to analytical procedure used

2.6 Listing of Impurities in Specifications

The specification for an existing drug substance should include a list of impurities. Stability studies, chemical development studies, and routine batch analyses can be used to predict those impurities likely to occur in the commercial product. The selection of impurities in the existing drug substance specification should be based on the impurities found in batches manufactured by the proposed commercial process. Those individual impurities with specific acceptance criteria included in the specification for the existing drug substance are referred to as "specified impurities" in this guidance document. Specified impurities can be identified or unidentified.

A rationale for the inclusion or exclusion of impurities in the specification should be presented. This rationale should include a discussion of the impurity profiles observed in the safety, bioequivalence/bioavailability, and clinical development batches, together with a consideration of the impurity profile of batches manufactured by the proposed commercial process. Specified identified impurities should be included along with specified unidentified impurities estimated to be present at a level greater than (>) the identification threshold given in Attachment 1A. For impurities known to be unusually potent or to produce toxic or unexpected pharmacological effects, the quantitation/detection limit of the analytical procedures should be commensurate with the level at which the impurities should be controlled. For unidentified impurities, the procedure used and assumptions made in establishing the level of the impurity should be clearly stated. Specified, unidentified impurities should be referred to by an appropriate qualitative analytical descriptive label (e.g., "unidentified A", "unidentified with relative retention of 0.9"). A general acceptance criterion of not more than (≤) the identification threshold (Attachment 1A) for any unspecified impurity and an acceptance criterion for total impurities should be included.

Acceptance criteria should be set no higher than the level that can be justified by safety data, and should be consistent with the level achievable by the manufacturing process and the analytical capability. Where there is no safety concern, impurity acceptance criteria should be based on data generated on batches of the existing drug substance manufactured by the proposed commercial process, allowing sufficient latitude to deal with normal manufacturing and analytical variation and the stability characteristics of the existing drug substance. Although normal manufacturing variations are expected, significant variation in batch-to-batch impurity levels can indicate that the manufacturing process of the existing drug substance is not adequately controlled and validated (see ICH Q6A Guidance Document on Specifications, Decision Tree #1, for establishing an acceptance criterion for a specified impurity in an existing drug substance). The use of two decimal places for thresholds (See Attachment 1A) does not necessarily indicate the precision of the acceptance criteria for specified impurities and total impurities.

In summary, the existing drug substance specification should include, where applicable, the following list of impurities:

Organic Impurities

• Each specified identified impurity
• Each specified unidentified impurity
• Any unspecified impurity with an acceptance criterion of not more than (≤) the identification threshold
• Total impurities

Residual Solvents

Inorganic Impurities

2.7 Qualification of Impurities

Qualification is the process of acquiring and evaluating data that establishes the biological safety of an individual impurity or a given impurity profile at the level(s) specified. The applicant should provide a rationale for establishing impurity acceptance criteria that includes safety considerations. The level of any impurity present in an existing drug substance that has been adequately tested in safety and/or clinical studies would be considered qualified. Impurities that are also significant metabolites present in animal and/or human studies are generally considered qualified. A level of a qualified impurity higher than that present in an existing drug substance can also be justified based on an analysis of the actual amount of impurity administered in previous relevant safety studies.

Additional qualification options for specified impurities in existing drug substances include:

• An impurity present in an existing drug substance can be qualified by comparing the analytical profiles of the drug substance with those in an approved human drug product using the same validated, stability-indicating analytical procedure (e.g., comparative HPLC studies). This approved human drug product is generally the Canadian Reference Product (CRP). However, the profile may also be compared to a different drug product with the same route of administration and similar characteristics (e.g., tablet versus capsule) if samples of the Canadian Reference Product are unavailable. It is recommended that the studies be conducted on comparable samples (e.g., age of samples) to get a meaningful comparison of the impurity profiles.
• Levels of impurities generated from studies under accelerated or stressed storage conditions of the approved human drug product are not considered qualified.
• An impurity present in the existing drug substance is considered qualified if the amount of the impurity in the existing drug substance reflects the levels observed in the corresponding approved human drug product.

If data are unavailable to qualify the proposed acceptance criterion of an impurity, studies to obtain such data can be appropriate when the usual qualification thresholds given in Attachment 1A are exceeded.

Higher or lower thresholds for qualification of impurities can be appropriate for some individual drugs based on scientific rationale and level of concern, including drug class effects and clinical experience. For example, qualification can be especially important when there is evidence that such impurities in certain drugs or therapeutic classes have previously been associated with adverse reactions in patients. In these instances, a lower qualification threshold can be appropriate. Conversely, a higher qualification threshold can be appropriate for individual drugs when the level of concern for safety is less than usual based on similar considerations (e.g., patient population, drug class effects, clinical considerations). Proposals for alternative thresholds would be considered on a case-by-case basis.

The "Decision Tree for Identification and Qualification" (Attachment 3A) describes considerations for the qualification of impurities when thresholds are exceeded. In some cases, decreasing the level of impurity to not more than the threshold can be simpler than providing safety data. Alternatively, adequate data could be available in the scientific literature (e.g., a specified identified impurity in a Schedule B monograph) to qualify an impurity. If neither is the case, additional safety testing should be considered. The studies considered appropriate to qualify an impurity will depend on a number of factors, including the patient population, daily dose, and route and duration of drug administration. Such studies can be conducted on the existing drug substance containing the impurities to be controlled, although studies using isolated impurities can sometimes be appropriate.

Although this guidance is not intended to apply during the clinical research stage of development, in the later stages of development the thresholds in this guidance document can be useful in evaluating new impurities observed in drug substance batches prepared by the proposed commercial process. Any new impurity observed in later stages of development should be identified if its level is greater than (>) the identification threshold given in Attachment 1A (see the "Decision Tree for Identification and Qualification" in Attachment 3A). Similarly, the qualification of the impurity should be considered if its level is greater than (>) the qualification threshold given in Attachment 1A. Safety assessment studies to qualify an impurity should compare the existing drug substance containing a representative amount of the new impurity with previously qualified material. Safety assessment studies using a sample of the isolated impurity can also be considered.

Although Quantitative Structure Activity Relationships (QSAR) programs may be used for prediction of toxicity of an individual impurity or a given impurity profile, the results are not generally considered conclusive for qualification purposes.

3. Impurities In Existing Drug Products

3.1 Rationale for the Reporting and Control of Degradation Products

The applicant should summarise the degradation products observed during manufacture and/or stability studies of the existing drug product. This summary should be based on sound scientific appraisal of potential degradation pathways in the existing drug product and impurities arising from the interaction with excipients and/or the immediate container closure system. In addition, the applicant should summarise any laboratory studies conducted to detect degradation products in the existing drug product. This summary should also include test results of batches manufactured during the development process and batches representative of the proposed commercial process. A rationale should be provided for exclusion of those impurities that are not degradation products (e.g., process impurities from the drug substance and impurities arising from excipients). The impurity profiles of the batches representative of the proposed commercial process should be compared with the profiles of batches used in development and any differences discussed.

Any degradation product observed in stability studies conducted at the recommended storage condition should be identified when present at a level greater than (>) the identification thresholds given in (Attachment 1B). When identification of a degradation product is not feasible, a summary of the laboratory studies demonstrating the unsuccessful efforts to identify it should be included in the registration application.

Degradation products present at a level of not more than (≤) the identification threshold generally would not need to be identified. However, analytical procedures should be developed for those degradation products that are suspected to be unusually potent, producing toxic or significant pharmacological effects at levels not more than (≤) the identification threshold. In unusual circumstances, technical factors (e.g., manufacturing capability, a low drug substance to excipient ratio, or the use of excipients that are crude products of animal or plant origin) can be considered as part of the justification for selection of alternative thresholds based upon manufacturing experience with the proposed commercial process.

3.2 Analytical Procedures

The registration application should include documented evidence that the analytical procedures have been validated and are suitable for the detection and quantitation of degradation products (see ICH Q2A and Q2B guidance documents on analytical validation). In particular, analytical procedures should be validated to demonstrate specificity for the specified and unspecified degradation products. As appropriate, this validation should include samples stored under relevant stress conditions: light, heat, humidity, acid/base hydrolysis, and oxidation. When an analytical procedure reveals the presence of other peaks in addition to those of the degradation products (e.g., the drug substance, impurities arising from the synthesis of the drug substance, excipients and impurities arising from the excipients), these peaks should be labeled in the chromatograms and their origin(s) discussed in the validation documentation.

The quantitation limit for the analytical procedure should be not more than (≤) the reporting threshold.

Degradation product levels can be measured by a variety of techniques, including those that compare an analytical response for a degradation product to that of an appropriate reference standard or to the response of the existing drug substance itself. Reference standards used in the analytical procedures for control of degradation products should be evaluated and characterised according to their intended uses. The drug substance can be used to estimate the levels of degradation products. In cases where the response factors are not close, this practice can still be used if a correction factor is applied or the degradation products are, in fact, being overestimated. Acceptance criteria and analytical procedures, used to estimate identified or unidentified degradation products, are often based on analytical assumptions (e.g., equivalent detector response). These assumptions should be discussed in the registration application.

Differences between the analytical procedures used during development and those proposed for the commercial product should also be discussed.

3.3 Reporting Degradation Products Content of Batches

Analytical results should be provided in the registration application for all relevant batches of the existing drug product used for clinical, bioequivalence/bioavailability, safety, and stability testing, as well as batches that are representative of the proposed commercial process. Quantitative results should be presented numerically, and not in general terms such as "complies", "meets limit" etc. Any degradation product at a level greater than (>) the reporting threshold (see Attachment 1B), and total degradation products observed in the relevant batches of the existing drug product, should be reported with the analytical procedures indicated. Below 1.0%, the results should be reported to the number of decimal places (e.g., 0.06%) in the applicable reporting threshold; at and above 1.0%, the results should be reported to one decimal place (e.g., 1.3%). Results should be rounded using conventional rules (see Attachment 2B). A tabulation (e.g., spreadsheet) of the data is recommended. Degradation products should be designated by code number or by an appropriate descriptor, e.g., retention time. If a higher reporting threshold is proposed, it should be fully justified. All degradation products at a level greater than (>) the reporting threshold should be summed and reported as total degradation products.

For each batch of the existing drug product described in the registration application, the documentation should include:

• Batch identity, strength, and size
• Date of manufacture
• Site of manufacture
• Manufacturing process
• Immediate container closure
• Degradation product content, individual and total
• Use of batch (e.g., clinical studies, bioequivalence/bioavailability studies, stability studies)
• Reference to analytical procedure used
• Batch number of the drug substance used in the existing drug product
• Storage conditions for stability studies

3.4 Listing of Degradation Products in Specifications

The specification for an existing drug product should include a list of degradation products expected to occur during manufacture of the commercial product and under recommended storage conditions. Stability studies, knowledge of degradation pathways, product development studies, and laboratory studies should be used to characterise the degradation profile. The selection of degradation products in the existing drug product specification should be based on the degradation products found in batches manufactured by the proposed commercial process. Those individual degradation products with specific acceptance criteria included in the specification for the existing drug product are referred to as "specified degradation products" in this guidance document. Specified degradation products can be identified or unidentified. A rationale for the inclusion or exclusion of degradation products in the specification should be presented. This rationale should include a discussion of the degradation profiles observed in the safety, bioequivalence/bioavailability, and clinical development batches and in stability studies, together with a consideration of the degradation profile of batches manufactured by the proposed commercial process. Specified identified degradation products should be included along with specified unidentified degradation products estimated to be present at a level greater than (>) the identification threshold given in (Attachment 1B). For degradation products known to be unusually potent or to produce toxic or unexpected pharmacological effects, the quantitation/detection limit of the analytical procedures should be commensurate with the level at which the degradation products should be controlled. For unidentified degradation products, the procedure used and assumptions made in establishing the level of the degradation product should be clearly stated. Specified unidentified degradation products should be referred to by an appropriate qualitative analytical descriptive label (e.g., "unidentified A", "unidentified with relative retention of 0.9"). A general acceptance criterion of not more than (≤) the identification threshold (Attachment 1B) for any unspecified degradation product and an acceptance criterion for total degradation products should also be included.

For a given degradation product, its acceptance criterion should be established by taking into account its acceptance criterion in the drug substance (if applicable), its qualified level, its increase during stability studies, and the proposed shelf life and recommended storage conditions for the existing drug product. Furthermore, each acceptance criterion should be set no higher than the qualified level of the given degradation product.

Where there is no safety concern, degradation product acceptance criteria should be based on data generated from batches of the existing drug product manufactured by the proposed commercial process, allowing sufficient latitude to deal with normal manufacturing and analytical variation and the stability characteristics of the existing drug product. Although normal manufacturing variations are expected, significant variation in batch-to-batch degradation product levels can indicate that the manufacturing process of the existing drug product is not adequately controlled and validated (see ICH Q6A guidance document on specifications, decision tree #2, for establishing an acceptance criterion for a specified degradation product in an existing drug product).

In this guidance document, the use of two decimal places for thresholds (See Attachment 1B) does not necessarily indicate the precision of the acceptance criteria for specified degradation products and total degradation products.

In summary, the existing drug product specification should include, where applicable, the following list of degradation products:

• Each specified identified degradation product
• Each specified unidentified degradation product
• Any unspecified degradation product with an acceptance criterion of not more than (≤) the identification threshold
• Total degradation products.

3.5 Qualification of Degradation Products

Qualification is the process of acquiring and evaluating data that establishes the biological safety of an individual degradation product or a given degradation profile at the level(s) specified. The applicant should provide a rationale for establishing degradation product acceptance criteria that includes safety considerations. The level of any degradation product present in an existing drug product that has been adequately tested in safety and/or clinical studies would be considered qualified. Therefore, it is useful to include any available information on the actual content of degradation products in the relevant batches at the time of use in safety and/or clinical studies. Degradation products that are also significant metabolites present in animal and/or human studies are generally considered qualified. Degradation products could be considered qualified at levels higher than those administered in safety studies based on a comparison between actual doses given in the safety studies and the intended dose of the existing drug product. Justification of such higher levels should include consideration of factors such as: (1) the amount of degradation product administered in previous safety and/or clinical studies and found to be safe; (2) the increase in the amount of the degradation product; and (3) other safety factors, as appropriate.

Additional qualification options for specified degradation products in existing drug products include:

• A degradation product present in an existing drug product can be qualified by comparing the analytical profiles of the drug product with those in an approved human drug product using the same validated, stability-indicating analytical procedure (e.g., comparative HPLC studies). This approved human drug product is generally the Canadian Reference Product (CRP). However, the profile may also be compared to a different drug product with the same route of administration and similar characteristics (e.g., tablet versus capsule) if samples of the Canadian Reference Product are unavailable. It is recommended that the studies be conducted on comparable samples (e.g., age of samples) to get a meaningful comparison of the degradation product profiles.
• Levels of degradation products generated from studies under accelerated or stressed storage conditions of the approved human drug product are not considered qualified.
• A degradation product present in the existing drug product is considered qualified if the amount of the degradation product in the existing drug product reflects the levels observed in the corresponding approved human drug product.

If the qualification thresholds given in (Attachment 1B) are exceeded and data are unavailable to qualify the proposed acceptance criterion of a degradation product, additional studies to obtain such data can be appropriate (see Attachment 3B).

Higher or lower thresholds for qualification of degradation products can be appropriate for some individual existing drug products based on scientific rationale and level of concern, including drug class effects and clinical experience. For example, qualification can be especially important when there is evidence that such degradation products in certain existing drug products or therapeutic classes have previously been associated with adverse reactions in patients. In these instances, a lower qualification threshold can be appropriate. Conversely, a higher qualification threshold can be appropriate for individual existing drug products when the level of concern for safety is less than usual based on similar considerations (e.g., patient population, drug class effects, and clinical considerations). Proposals for alternative thresholds would be considered on a case-by-case basis.

The "Decision Tree for Identification and Qualification of a Degradation Product" (Attachment 3B) describes considerations for the qualification of degradation products when thresholds are exceeded. In some cases, reducing the level of degradation product (e.g., use of a more protective container closure or modified storage conditions) to not more than (≤) the threshold can be simpler than providing safety data. Alternatively, adequate data could be available in the scientific literature (e.g., a specified identified degradation product in a Schedule B monograph) to qualify a degradation product. If neither is the case, additional safety testing should be considered. The studies considered appropriate to qualify a degradation product will depend on a number of factors, including the patient population, daily dose, and route and duration of existing drug product administration. Such studies can be conducted on the existing drug product or substance containing the degradation products to be controlled, although studies using isolated degradation products can sometimes be appropriate.

Although this guidance is not intended to apply during the clinical research stage of development, in the later stages of development the thresholds in this guidance can be useful in evaluating new degradation products observed in existing drug product batches prepared by the proposed commercial process. Any new degradation product observed in later stages of development should be identified (see the "Decision Tree for Identification and Qualification of a Degradation Product" in Attachment 3B) if its level is greater than (>) the identification threshold given in (Attachment 1B). Similarly, qualification of the degradation product should be considered if its level is greater than (>) the qualification threshold given in (Attachment 1B).

Safety studies should provide a comparison of results of safety testing of the existing drug product or drug substance containing a representative level of the degradation product with previously qualified material, although studies using the isolated degradation products can also be considered.

Although Quantitative Structure Activity Relationships (QSAR) programs may be used for prediction of toxicity of an individual degradation product or a given degradation profile, the results are not generally considered conclusive for qualification purposes.

4. Glossary

Canadian Reference Product

Refer to Section C.08.001.1 of the Food and Drug Regulations.

Chemical Development Studies

Studies conducted to scale-up, optimise, and validate the manufacturing process for a new or existing drug substance. Q3A(R)

Degradation Product

An impurity resulting from a chemical change in the drug substance brought about during manufacture and/or storage of the existing drug product by the effect of, for example, light, temperature, pH, water, or by reaction with an excipient and/or the immediate container closure system. Q3B(R)

Degradation Profile

A description of the degradation products observed in the drug substance or drug product. Q3B(R)

Development Studies

Studies conducted to scale-up, optimise, and validate the manufacturing process for a drug product. Q3B(R)

Enantiomeric Impurity

A compound with the same molecular formula as the drug substance that differs in the spatial arrangement of atoms within the molecule and is a non-superimposable mirror image. Q3A(R)

Existing Drug

one that does not contain a new medicinal ingredient (also known as a new active substance), but requires the filing of a New Drug Submission (NDS), an Abbreviated New Drug Submission (ANDS) or a Supplement (e.g., generic products). This would include, for example, submissions for new dosage forms, new strengths, and other changes to approved products.

Extraneous Contaminant

An impurity arising from any source extraneous to the manufacturing process. Q3A(R)

Herbal Products

Medicinal products containing, exclusively, plant material and/or vegetable drug preparations as active ingredients. In some traditions, materials of inorganic or animal origin can also be present. Q3A(R)

Identified Degradation Product

A degradation product for which a structural characterisation has been achieved. Q3B(R)

Identified Impurity

An impurity for which a structural characterisation has been achieved. Q3A(R)

Identification Threshold

A limit above (>) which an impurity or degradation product should be identified. Q3A(R)/Q3B(R)

Impurity

Any component of the existing drug substance or existing drug product that is not the chemical entity defined as the existing drug substance or an excipient in the drug product. Q3A(R)/Q3B(R)

Impurity Profile

A description of the identified and unidentified impurities present in an existing drug substance or drug product. Q3A(R)/Q3B(R)

Intermediate

A material produced during steps of the synthesis of an existing drug substance that undergoes further chemical transformation before it becomes an existing drug substance. Q3A(R)

Ligand

An agent with a strong affinity to a metal ion. Q3A(R)

New Drug Substance

The designated therapeutic moiety that has not been previously registered in a region or member state (also referred to as a new molecular entity or new chemical entity). It can be a complex, simple ester, or salt of a previously approved drug substance. Q3A(R)

Polymorphic Forms

Different crystalline forms of the same drug substance. These can include solvation or hydration products (also known as pseudo-polymorphs) and amorphous forms. Q3A(R)

Potential Impurity

An impurity that theoretically can arise during manufacture or storage. It may or may not actually appear in the existing drug substance. Q3A(R)

Qualification

The process of acquiring and evaluating data that establishes the biological safety of an individual impurity or degradation product or a given impurity profile or degradation profile at the level(s) specified. Q3A(R)/Q3B(R)

Qualification Threshold

A limit above (>) which an impurity or degradation product should be qualified. Q3A(R)/Q3B(R)

Reagent

A substance other than a starting material, intermediate, or solvent that is used in the manufacture of an existing drug substance. Q3A(R)

Reporting Threshold

A limit above (>) which an impurity or degradation product should be reported. Reporting threshold is the same as reporting level in Q2B. Q3A(R)/Q3B(R)

Schedule B Monograph

A monograph appearing in a pharmacopoeia listed in Schedule B of the Food and Drugs Act (e.g., United States Pharmacopeia, European Pharmacopoeia).

Solvent

An inorganic or an organic liquid used as a vehicle for the preparation of solutions or suspensions in the synthesis of an existing drug substance. Q3A(R)

Specified Degradation Product

A degradation product that is individually listed and limited with a specific acceptance criterion in the existing drug product specification. A specified degradation product can be either identified or unidentified. Q3B(R)

Specified Impurity

An impurity that is individually listed and limited with a specific acceptance criterion in the existing drug substance specification. A specified impurity can be either identified or unidentified. Q3A(R)

Starting Material

A material used in the synthesis of an existing drug substance that is incorporated as an element into the structure of an intermediate and/or of the existing drug substance. Starting materials are normally commercially available and of defined chemical and physical properties and structure. Q3A(R)

Unidentified Degradation Product

A degradation product for which a structural characterisation has not been achieved and that is defined solely by qualitative analytical properties (e.g., chromatographic retention time). Q3B(R)

Unidentified Impurity

An impurity for which a structural characterisation has not been achieved and that is defined solely by qualitative analytical properties (e.g., chromatographic retention time). Q3A(R)

Unspecified Degradation Product

A degradation product that is limited by a general acceptance criterion, but not individually listed with its own specific acceptance criterion, in the existing drug product specification. Q3B(R)

Unspecified Impurity

An impurity that is limited by a general acceptance criterion, but not individually listed with its own specific acceptance criterion, in the existing drug substance specification. Q3A(R)

Attachment 1A: Thresholds for Impurities in Existing Drug Substances

Maximum Daily Dose1	Reporting Threshold2,3	Identification Threshold3	Qualification Threshold3
≤2 g/day	0.05%	0.10% or 1.0 mg per day intake (whatever is lower)	0.15% or 1.0 mg per day intake (whichever is lower)
>2 g/day	0.03%	0.05%	0.05%

¹ The amount of drug substance administered per day
² Higher reporting thresholds should be scientifically justified
³ Lower thresholds can be appropriate if the impurity is unusually toxic

Attachment 1B: Thresholds for Degradation Products in Existing Drug Products

Reporting Thresholds

Maximum Daily Dose1	Threshold2,3
≤1 g	0.1%
> 1 g	0.05%

Identification Thresholds

Maximum Daily Dose1	Threshold2,3
< 1 mg	1.0% or 5 µg TDI, whichever is lower
1 mg - 10 mg	0.5% or 20 µg TDI, whichever is lower
>10 mg - 2 g	0.2% or 2 mg TDI, whichever is lower
> 2 g	0.10%

Qualification Thresholds

Maximum Daily Dose1	Threshold2,3
< 10 mg	1.0% or 50 µg TDI, whichever is lower
10 mg - 100 mg	0.5% or 200 µg TDI, whichever is lower
>100 mg - 2 g	0.2% or 3 mg TDI, whichever is lower
> 2 g	0.15%

¹ The amount of drug substance administered per day
² Thresholds for degradation products are expressed either as a percentage of the drug substance or as total daily intake (TDI) of the degradation product. Lower thresholds can be appropriate if the degradation product is unusually toxic.
³ Higher thresholds should be scientifically justified.

Illustration of Thresholds for Reporting, Identification, and Qualification of Degradation Products in Existing Drug Products as a Function of Maximum Daily Dose¹

¹ Note: Actual threshold values should be taken from the preceding table in this attachment.

Attachment 2A: Illustration of Reporting Impurity Results for Identification and Qualification in an Application

'Raw' Result (%)	Reported Result (%)	Action
		Identification (Threshold 0.10%)	Qualification (Threshold 0.15%)
0.066	0.07	None	None
0.0963	0.10	None	None
0.12	0.12*	Yes	None*
0.1649	0.16*	Yes	Yes*

^* After identification, if the response factor is determined to differ significantly from the original assumptions, it may be appropriate to re-measure the actual amount of the impurity present and re-evaluate against the qualification threshold (see Attachment 1A).

Attachment 2B: Illustration of Reporting Degradation Product Results for Identification and Qualification in an Application

50 mg Maximum Daily Dose

'Raw' Result (%)	Reported Result (%) (Reporting Threshold = 0.1%)	Total Daily Intake (TDI) of the Degradation Product (rounded result in µg)	Action
			Identification Threshold 0.2%	Qualification Threshold 200 µg TDI (equivalent to 0.4%)
0.04	Not reported	20	None	None
0.2143	0.2	100	None	None
0.349	0.31	150	Yes	None1
0.550	0.61	300	Yes	Yes1

1.9 gram Maximum Daily Dose

'Raw' Result (%)	Reported Result (%) (Reporting Threshold = 0.05%)	Total Daily Intake (TDI) of the Degradation Product (rounded result in mg)	Action
			Identification Threshold 2 mg TDI (equivalent to 0.11%)	Qualification Threshold 3 mg TDI (equivalent to 0.16%)
0.049	Not reported	1	None	None
0.079	0.08	2	None	None
0.183	0.181	3	Yes	None1,2
0.192	0.191	4	Yes	Yes1

¹ After identification, if the response factor is determined to differ significantly from the original assumptions, it can be appropriate to re-measure the actual amount of the degradation product present and re-evaluate against the qualification threshold (see Attachment 1B).
² Although the reported result of 0.18% exceeds the calculated threshold value of 0.16%, in this case the action is acceptable since the TDI (when rounded) does not exceed 3mg.

Attachment 3A: Decision Tree for Identification and Qualification of an Impurity

Notes on Attachment 3A

1. If considered desirable, a minimum screen (e.g., genotoxic potential), should be conducted. A study to detect point mutations and one to detect chromosomal aberrations, both in vitro, are considered an appropriate minimum screen.
2. If general toxicity studies are desirable, one or more studies should be designed to allow comparison of unqualified to qualified material. The study duration should be based on available relevant information and performed in the species most likely to maximise the potential to detect the toxicity of an impurity. On a case-by-case basis, single-dose studies can be appropriate, especially for single-dose drugs. In general, a minimum duration of 14 days and a maximum duration of 90 days would be considered appropriate.
3. Lower thresholds can be appropriate if the impurity is unusually toxic.
4. For example, do known safety data for this impurity or its structural class preclude human exposure at the concentration present?
5. For example, is the impurity a metabolite or qualified by scientific literature?

Attachment 3B: Decision Tree for Identification and Qualification of a Degradation Product

Notes on Attachment 3B

1. If considered desirable, a minimum screen (e.g., genotoxic potential), should be conducted. A study to detect point mutations and one to detect chromosomal aberrations, both in vitro, are considered an appropriate minimum screen.
2. If general toxicity studies are desirable, one or more studies should be designed to allow comparison of unqualified to qualified material. The study duration should be based on available relevant information and performed in the species most likely to maximise the potential to detect the toxicity of a degradation product. On a case-by-case basis, single-dose studies can be appropriate, especially for single-dose drugs. In general, a minimum duration of 14 days and a maximum duration of 90 days would be considered appropriate.
3. Lower thresholds can be appropriate if the degradation prouct is unusually toxic.
4. For example, do known safety data for this degradation product or its structural class preclude human exposure at the concentration present?
5. For example, is the degradation product a metabolite or qualified by scientific literature?