Draft Help Notes for Completing the Quality Information Summary-Biologicals (QIS-B) and Certified Product Information Document- Biologicals (CPID-B) Templates

Date 2001-08-09

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.

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Nom du contact : CERB/CBE

Biologics and Genetic Therapies Directorate

Memorandum - Health Canada Protected

These draft help notes were written to provide some assistance to sponsors while completing the draft Quality Information Summary- Biologicals (QIS-B) and Certified Product Information Document- Biologicals (CPID-B) electronic templates, as part of preparing their drug submission. An official Biologics and Genetic Therapies Directorate (BGTD) Guidance Document will be available for the final version of the templates.

A) Quality Electronic Templates Available:

1. The updated quality (chemistry and manufacturing) electronic templates for biological (Schedule D) products: the draft Quality Information Summary- Biologicals (QIS-B) and Certified Product Information Document- Biologicals (CPID-B) (August 8, 2001) are available (in Wordperfect 8.0) from the Health
   Canada Internet site at http://www.hc-sc.gc.ca/hpb- gps/therapeut/htmleng/template.html under the blnkqisb.zip and blkcpidb.zip files respectively OR printed copies of the documents and a disk copy of the
   template files can be obtained by sending your name and address by mail or facsimile to:
   Submissions Management Division (SMD)
   Centre for Policy and Regulatory Affairs (CPRA)
   Biologics and Genetic Therapies Directorate (BGTD)
   L.C.D.C. Building#6, Locator# 0601E3
   Tunney's Pasture, Ottawa, Ontario K1A 0L2
   FAX# (613) 957-0364
2. The entire QIS-B template consists of four main parts:
   (The file name of each part is identified in brackets. All of these files are found within the blnkqisb.zip file.)
   Part 1: G. General Information (1gi_all.wpd)
   Part 2: S. Drug Substance (2ds_bld.wpd), (2ds_gen.wpd), (2ds_rdna.wpd), and (2ds_vac.wpd)
   Part 3: P. Drug Product (3dp_all.wpd)
   Part 4: O. Other Information (4oi_all.wpd)
   
   Parts 1, 3, and 4 apply to all types of biological products, whereas, Part 2 has been specifically designed for certain types of biological products, to address considerations unique to their chemistry and manufacturing.
   The following Part 2 versions are currently available (with their specific file names identified in brackets):
   QIS-B-BLD- applies to Submissions of Blood Products (2ds_bld.wpd)
   QIS-B-GEN- applies to Submissions of General Biological Product Lines (2ds_gen.wpd)
   QIS-B-rDNA/MAbs- applies to Submissions of Recombinant DNA Products and Monoclonal Antibodies (2ds_rdna.wpd)
   QIS-B-VAC- applies to Submissions of Vaccines (2ds_vac.wpd)
3. Also available on the Health Canada Internet site, is a draft Quality Information Summary- Pharmaceuticals (QIS-P) electronic template for non-Schedule D products and a draft Quality Information Summary- Radiopharmaceuticals (QIS-R) electronic template for Schedule C products, which may be used, either solely OR in combination with the QIS-B, if appropriate.
4. The CPID-B template is provided as one file named cpidb.wpd and it is found within the blkcpidb.zip file.
5. French translations of the draft templates are not currently available.

B) Application and Use of the Electronic Quality Templates:

1. Sponsors are encouraged to use the draft, electronic QIS-B templates for summarizing their quality information when filing a New Drug Submission (NDS), a Supplementary New Drug Submission (S/NDS), a Notifiable Change (N/C), an Investigational New Drug Submission (IND) and/or a Record and Notice of Change for a biological (Schedule D) product. Sponsors should also complete the draft, electronic CPID-B template, when filing a NDS and if required, for a S/NDS, N/C or a Record and Notice of Change. (Ref: Policy Issues from the Drugs Directorate "A Comprehensive Summary of Chemistry and Manufacturing Information and Certified Product Information Document"- June 30, 1995).
   
   Depending on the past experience of the sponsor and on the biological product, the use of the QIS-B and CPID-B electronic templates for summarizing the quality information of a submission may be looked upon as a new process or an improved one. This change will be kept as simple and as flexible as possible, with the understanding that during the transition period, the use of the draft templates may not always be practical for every situation (e.g. where preceding quality (chemistry and manufacturing) information for a NDS, S/NDS, or N/C was submitted without a completed electronic template or using the CS(CM-rDNA) template).
   
   It should be noted that based on Health Canada experience with previous versions of chemistry and manufacturing electronic templates (i.e. July 28/95 and April 1/96 versions of the CS(CM-rDNA) and CPID), that the quality of a drug submission is expected to be considerably improved if the QIS-B and CPID-B templates are properly completed, and subsequently, this will result in fewer deficiencies being issued and will expedite the submission review process.
   
   The final version of the QIS-B-rDNA and CPID-B templates will likely phase out the previous CS(CM-rDNA) and CPID templates (April 1996), once they are completed. If an electronic quality template will be used, it is recommended that the draft QIS-B and CPID-B templates be chosen because they have been designed along current Canadian regulations and current developments in terms of international harmonization. A sponsor should only complete one of the QIS-B or the CS(CM) template, preferably, the QIS-B.
2. If the sponsor decides to include a summary of the quality information electronically, the following parts of the QIS-B (and CPID-B, if applicable) should be completed as part of the submission, depending on the type of submission filed:
   
   For an Investigational New Drug Submission (IND):
   
   Upon initial filing of an IND, the sponsor is required to complete ONLY those subsections or parts of a table, which are identified with a check mark (i.e. U) to the left of the heading under Parts 1-4 of the QIS-B template. Since the IND template is a subset of the NDS template, within the QIS-B, it is possible for a sponsor to complete other subsections under Parts 1-4 of the QIS-B which are without a check mark (i.e. U) to the left of the heading, as information becomes available during the course of drug development or as advance preparation for a NDS submission.
   
   Note that under some subsections, where there is a specific subheading for an IND submission (e.g. "If filing an IND submission, submit..."), the sought IND information should be provided instead. It is understandable that depending on the stage of drug development, a limited amount of information may be available for the IND submission; in which case, the sponsor should provide whatever data is available.
   
   With subsequent IND submission filings for the same drug (e.g. Phase II or III clinical trials), where much of the quality information may be similar, the sponsor is encouraged to build upon the previously completed QIS-B template (e.g. Phase I clinical trial), by making any necessary revisions or adding relevant information to update the submission and clearly identifying the changes with the use of coloured text or a different font. A chronology of the changes made to the manufacturing process through drug development should be maintained from each IND phase to the NDS stage. However, if very significant or substantial chemistry and manufacturing changes have been made through drug development, it may be more practical to complete a blank QIS-B template instead, although a chronological account of the chemistry and manufacturing changes should still be documented and a summary should be provided by the sponsor.
   
   If applicable, it would be acceptable to cross-reference any relevant quality information from a previous IND submission, rather than resubmitting this information, unless a direct comparison was being made.
   
   The sponsor is not required to complete a CPID-B template or a Product Monograph for an IND submission.
   
   For a New Drug Submission (NDS):
   
   Upon initial filing of a NDS, the sponsor should complete Parts 1-4 of the QIS-B template in its entirety (white or unshaded areas only). The completion of a Product Monograph (section O.3) is required for all New Drugs.
   
   Near the end of the review process (or upon request by the Biologics and Genetic Therapies Directorate (BGTD)), the sponsor should complete the CPID-B template, and include any necessary revisions addressed from the review up to that point.
   
   For a Supplementary New Drug Submission (S/NDS) or a Notifiable Change (N/C):
   
   If a QIS-B had not been used previously for a drug submission (e.g. NDS, other S/NDS or N/C submission) for that product, upon initial filing of the S/NDS or N/C, the sponsor should complete and submit Part 1 of the QIS-B AND ONLY those affected sections/subsections of Parts 2-4 of the QIS-B, which contain new or updated chemistry and manufacturing information about or in support of the change(s) of the S/NDS or N/C submission.
   
   It would be acceptable to cross-reference any relevant quality information from a previous submission (e.g. NDS, other S/NDS or N/C), if applicable, rather than resubmitting this information, unless a direct comparison was being made. However, in order to facilitate the review process, a sponsor is encouraged to submit as complete a template as possible, with the new or updated chemistry and manufacturing information about or in support of the change(s) of the S/NDS or N/C submission, clearly distinguished from the other information with the use of coloured text or a different font.
   
   On the other hand, if a QIS-B had been used previously for a drug submission (e.g. NDS, other S/NDS or N/C submission) for that product, the sponsor should revise/update and submit Part 1 of the QIS-B, and ONLY those affected sections/subsections of Parts 2-4 of the QIS-B, which contain new or updated chemistry and manufacturing information about or in support of the change(s) of the S/NDS or N/C submission, by clearly identifying this information with the use of coloured text or a different font. The information which still applies should remain.
   
   If necessary, the sponsor should submit a current CPID-B, reflecting information relevant to the change(s) of the S/NDS or N/C submission and including any necessary revisions addressed through the BGTD review up to that point. If a QIS-B and CPID-B were used previously for a drug submission (e.g. NDS, other S/NDS or N/C submissions) for that product, an updated CPID-B, with the changes clearly identified using coloured text or a different font, should be resubmitted electronically. In the case where a CPID-B is being completed for the first time and where a QIS-B has not been completely filled out, the instructions provided within [square brackets] under sections S. Drug Substance, P. Drug Product, and O. Other Information of the CPID-B, may be ignored and the CPID-B template should be completed with the appropriate information.
   
   For a Record and Notice of Change:
   
   For any Record and Notice of Change which affects quality information detailed in the Certified Product Information Document (CPID), an updated CPID-B must be resubmitted electronically, with revised/ additional information identified clearly, using coloured text or a different font.
   
   If a QIS-B and CPID-B were used previously for a drug submission (e.g. NDS, other S/NDS, N/C, or Notice of Change submission) for that product, an updated CPID-B, with the changes clearly identified using coloured text or a different font, should be resubmitted electronically. In the case where a CPID-B is being completed for the first time and where a QIS-B has not been completely filled out, the instructions provided within [square brackets] under sections S. Drug Substance, P. Drug Product, and O. Other Information of the CPID-B, may be ignored and the CPID-B template should be completed with the appropriate information.
3. During the review process, when preparing a response to solicited information requested through a Notice of Deficiency (e.g. issued from the review of a NDS or S/NDS), a Notice of Noncompliance (e.g. issued from the review of a NDS or S/NDS), a Clarifax (e.g issued from the review of a NDS, S/NDS, IND, or a Record and Notice of Change), or a Not Satisfactory Letter (e.g. issued from the review of an IND or a Notifiable Change):
   1. the sponsor may make any necessary revisions or include additional information to the QISB initially submitted, with the changes/ additional information identified clearly using coloured text or a different font and resubmit electronically, a revised Part 1 and Parts 2-4 of the QIS-B, only if they have been revised. The accompanying covering letter should identify the exact location within the template that contains the answer for each question/concern addressed by BGTD, OR
   2. the sponsor may electronically submit a Question-Answer- type response (with appended information, if necessary) and a revised Part 1 of the QIS-B (but not necessarily, with electronic updates made to Parts 2-4 of the QIS-B).
      
      In either case, the sponsor should make relevant cross-referencing, wherever appropriate (e.g. under G.1- Prior Related Submission(s), under a specific subsection, etc.)
   Should revisions be required for the CPID-B (INDs excluded), an updated CPID-B must be resubmitted electronically, with revised/ additional information identified clearly using coloured text or a different font.
   
   Similarly, should revisions be required for the Product Monograph (PM) (may be applicable to a NDS or S/NDS), an updated PM must be resubmitted electronically, with revised/ additional information identified clearly using highlighting, coloured text, or a different font.
4. If a Part 2 (S. Drug Substance) of the QIS-B needs to be completed, the most appropriate Part 2 template(s) should be used, depending on the type of biological product and/or biological source. (See list of available Part 2 templates under A) 2. For example:
   
   
   • for a human plasma-derived product, the QIS-B-BLD template (or 2ds_bld.wpd file) should be used;
   • for a bacterial, viral, recombinant or other type of vaccine, the QIS-B-VAC template (or 2ds_vac.wpd file) should be completed;
   • for any biological product derived from a recombinant DNA origin (vaccines excluded), any monoclonal antibody, or any gene therapy, the QIS-B-rDNA/MAbs template (or 2ds_rdna.wpd file) should be used;
   • the QIS-B-GEN template (or 2ds_gen.wpd file) should be used, with specific modifications made to the template, as required, if none of the other specifically-designed Part 2 QIS-B templates are appropriate (e.g. products extracted from tissues or organs).
     
     With more complex products, for example:
   • for a radiolabelled monoclonal antibody, the Part 2 QIS-B-rDNA/MAbs template (or 2ds_rdna.wpd file) should be completed for the monoclonal antibody-related drug substance information, the Part 2 QIS-R template should be filled out for the isoTope-related drug substance information, AND a single Part 3 (P. Drug Product) of the QIS-R template should be completed for the conjugated final product. (The QIS-R template and files will be posted when available);
   • for a non-biological immunotoxin (e.g. a chemically-derived toxin coupled to a monoclonal antibody), the Part 2 of the QIS-P template (or 2drugsub.wpd file) should be completed for the toxin-related drug substance information, the Part 2 QIS-B-rDNA/MAbs template (or 2ds_rdna.wpd file) should be completed for the monoclonal antibody-related drug substance information, AND a single Part 3 (P. Drug Product) of the QIS-B template (or 3dp_all.wpd file) should be completed for the conjugated final product;
   • for a biological immunotoxin, which is not used as a vaccine (e.g. a diptheria toxin attached to a monoclonal antibody), a separate Part 2 QIS-B-rDNA/MAbs template (or 2ds_rdna.wpd file) should be completed for the toxin-related drug substance information, as well as for the monoclonal antibody-related drug substance information, AND a single Part 3 (P. Drug Product) of the QIS-B template (or 3dp_all.wpd file) should be completed for the conjugated final product;
   • for a combined vaccine, a separate Part 2 QIS-B-VAC template (or 2ds_vac.wpd file) should be completed for each drug substance component, AND a single Part 3 (P. Drug Product) of the QIS-B template (or 3dp_all.wpd file) should be completed for the combined final product.
5. The QIS-B is intended to serve both as a sponsor's Comprehensive Summary of the quality information AND as a BGTD Reviewer's Evaluation Report. The unshaded (white) areas of the QIS-B (and CPID-B) are for the sponsor's use, whereas the shaded (blue) areas are for BGTD use only.
6. Using the draft QIS-B template, the sponsor is encouraged to summarize their quality information as accurately, as concisely, and as consistently as possible, and ensure that the information is reflective of the supporting detailed information (e.g. raw data, Standard Operating Procedures, Test Protocols, validation study reports, chromatograms, diagrams, original photographs of gels, detailed discussions, reference literature, etc.) which is appended separately in electronic format and/or in hardcopy in a submission volume(s). Misuse of the template may prolong the review process unnecessarily.
7. The sponsor should ensure that ALL quality information submitted pertains to the Drug Product which is intended to be marketed in Canada.

C) Useful Tips for Authoring In the Quality Electronic Templates:

1. The sponsor is encouraged to author in WP 8.0 whenever possible, to avoid any potential conversion and formatting problems. However, it may be possible to author in other software (e.g. MS Word) and convert back to WP 8.0. Although the conversion from WP 8.0 to MS Word has been successfully tested by Health Canada, sponsors who exercise this option, should note that some minor formatting adjustments (e.g. ensuring that tabled headings or data tables are not located close to page breaks) may be required prior to converting from WP 8.0 to MS Word. In addition, sponsors should ensure that all formatting, symbols, and syntax are properly converted from MS Word back to WP 8.0, before submitting the electronic files to BGTD. It should be noted that conversions from WP 8.0 to other software have not been tested by Health Canada at this time.
2. The sponsor should "edit" "Header A" on the first page of Parts 1-4 (file) of the QIS-B and on the first page of the CPID-B, by overwritting "[Brand Name]" and "[Submission Sponsor]" with the appropriate Brand Name of the drug and the Name of the Submission Sponsor, respectively. The proper headers should automatically be transcribed on all subsequent pages within that Part (file).
3. The sponsor should avoid deleting any headings or subsections of the QIS-B and CPID-B, which are not applicable. If subsections are not applicable, the sponsor should indicate this instead.
4. The sponsor may add a subheading for other information, which is not covered elsewhere within the template and which may be considered pertinent or unique to their product.
5. Under applicable subsections of the QIS-B, the sponsor should specify at the "Volume: /Page(s): " prompt(s), the exact location(s) where relevant and detailed supporting information is appended. The prompt(s) may be found either after a subheading or within a table.
6. The sponsor is encouraged to avoid using the identical font features which are used in the template design (i.e. Univers, bold), so that the sponsor's text is easily differentiated from the template subheadings. Simple is best.
7. The sponsor may use any of the predesigned tables of the QIS-B to summarize the sought information, as outlined by the headings of the predesigned tables provided under specific sections. The sponsor should avoid deleting any headings, columns or rows of the pre-designed tables which are not applicable, but rather, the size of these fields may be minimized within the table to create more space for other fields, and the sponsor should indicate "Not Applicable" in the entry field. In order to best accommodate the amount of available data, the parameters of a table may be modified using the properties found under the "Table" feature found on the menu bar (e.g. inserting additional blank rows, adjusting column widths, etc.) or an entire table may be duplicated using the "copy" and "paste" features found on the tool bar. Use of a "hard return" in a table, will create another line within the same cell. Most headings and some information contained within the tables have been intentionally "locked" so that by using the "Tab" key (or 4-directional arrow keys), the cursor will move directly into the fields that require data entry. In addition, this design allows headers to be automatically included for lengthy tables that run over page breaks. However, if absolutely necessary, the tables can be temporarily "unlocked" by "highlighting" the table areas that need to be "unlocked" and marking the "disable cell locks" option found under the "table" "format" feature and/or "demarking" the "lock" option found under the "cell" "format" feature, listed under the "Table" feature found on the menu bar. The table should be "relocked" after editting.
   
   Alternatively, a sponsor may opt to design their own table(s) OR use another method to better summarize the sought information, as outlined by the headings of the predesigned tables provided under specific sections. However, if a sponsor chooses to design their own tables, they should ensure that all table formatting is problem-free (e.g. columns do not realign, table headers remain intact across page breaks, etc.), prior to submitting the electronic files to BGTD.
8. Section O.5-References and O.6-Appendices under Part 4:O. Other Information, should be a summary of all references or appendices mentioned anywhere in the QIS-B (Parts 1-4). A copy of the reference papers and appended information, including analytical method descriptions, validation reports, raw data, etc., should be appended separately, rather than incorporated into the body of the QIS-B summary. This would not only allow each Part of the QIS-B to be more manageable in size, but it would allow the summary of the quality information to be more readable for the BGTD evaluators.
9. The sponsor should complete the CPID-B (if necessary-see B.1) after the satisfactory completion of the QIS-B. In this way, the appropriate information sought, as indicated in [square brackets] on the CPID-B template under each heading, can be "copied" from the appropriate subsection/Part of the completed QIS-B and "pasted" to the appropriate section of the CPID-B. The instructions provided in [square brackets] may be deleted once the section is completed. In the case where a QIS-B or parts of it are incomplete, the sponsor will need to fill out the CPID-B with the necessary information.
10. The Sponsor should note that the draft QIS-B and CPID-B templates are potentially subject to future revision, particularly under sections G.1 and G.2. The most current version should be used, whenever possible.
11. Any questions, problems, concerns, and/or comments regarding the draft quality electronic templates available for Biological (Schedule D) Products, should be forwarded to Ms. Hing Chong at the Centre for Biologics Evaluation by fax: (613) 954-4514 or e:mail: Hing_g@hc-sc.gc.ca.

D) Drug Submission Contents:

The sponsor should refer to either the Health Canada Guideline "Preparation of Human New Drug Submissions" (1991) (for a NDS or S/NDS submission filing) OR the Policy Issues from the Health Canada "Clinical Trial Review and Approval" (March 1997) and the Health Canada Guideline "Preparation of an Investigational New Drug Submission" (1991) (for an IND submission filing), in order to obtain detailed information on the drug submission content requirements. For more detailed data requirements, the sponsor may also refer to the Help Guide available for completing the CS(CM-rDNA) template (cscmhelp.wpd file found within the cs_schd.zip file of the Comprehensive Summary-Chemistry and manufacturing for Biological Products of Recombinant DNA Origin (CS(CM-rDNA)) and Certified Product Information Document (CPID)- April 1, 1996 link of the Health Canada Internet site listed under A.1). It should be noted that although this document is specific for recombinant products, to a certain degree, it may be applied to other biological products as well.

With the preparation of an electronic quality document (QIS-B), the sponsor is not obviated of their responsibility to file the necessary unabridged quality information, as two hardcopies, in submission volumes. However, it would be acceptable to organize the quality information provided in submission volumes according to the chronology and structure used in the QIS-B, rather than as outlined in the above Health Canada Guidelines or policy, with the exception that, for a NDS or S/NDS submission, the draft Package Insert (O.2.4), draft labels (O.2.5), and draft Product Monograph (O.3), if applicable, should be appended under Part I: Master Volume of the submission, rather than with the other appended information pertaining to Part 4: O. Other Information of the QIS-B. The sponsor should ensure that the hardcopies clearly identify any updated or revised information by using highlighting, a different font, or margin annotations.

Two electronic copies of the completed QIS-B (or the necessary Parts of it, depending on the type of submission) should be submitted, with each completed Part of the QIS-B saved as a separate file in WP 8.0. Each file should be assigned with a different file name from its original blank template file name, yet the assigned file name should somehow identify the content of that file. File names should contain a maximum of 8 characters and include the "wpd" extension. The electronic copies should be saved onto IBM-compatible, formatted, 3.5", certified virus-free diskettes. Each electronic copy should be labelled as either "original" or "working copy", and include the name of the submission sponsor, the brand name, the date of the submission, and if each electronic copy comprises of more than one diskette, the diskettes should be sequentially numbered. All diskettes, including a separate diskette each for the draft Product Monograph and the CPID-B, should be inserted in a 3-ring binder diskette holder inserted at the front of Part 1: Master Volume.