Yearly Biologic Product Report Template - annotated version

Context

Yearly Biologic Product Report (YBPR) is a requirement that applies to Schedule D (biologic) drugs assigned to Evaluation Groups 2, 3, and 4, as defined in Health Canada guidance Lot Release Program for Schedule D (Biologic) Drugs. The content of YBPR is itemized in Section 5.1 of the guidance. However, these instructions are open to interpretation, resulting in inconsistent quality of the submitted documents. The iterative process currently used to prepare and review YBPR submissions is inefficient, challenging both the sponsor and the regulator.

Purpose

The intent is to facilitate both the preparation and the review of YBPR, primarily by minimizing superfluous information, information gaps, and time to locate specific information through consistent presentation.

Objective

The goal is to develop a template (attached) that reflects the consensus by the BGTD reviewers on the interpretation of the YBPR guidance, focusing on the type of information required, the level of detail, preferred presentation of the data, and overall organization.

Yearly Biologic Product Report (YBPR)

Note 1. All items in the template should be addressed. Items that do not apply should be clearly identified.

Note 2. Include in the report every (i) approved5 product4 associated with the above proprietary/brand name, (ii) facility involved in the manufacture or testing of each approved product, (iii) batch/lot of approved product, initiated during the current reporting period, whether intended for Canadian or international market, and (iv) test performed, during the current reporting period, for lot release, in-process, or stability assessment of each approved product.

Note 3. Where a product is manufactured by multiple approved processes (e.g. drug substance at 5,000 L and 10,000 L scale, 100 mg in vial and pre-filled syringe) or at multiple facilities (e.g. 100 mg vial at ABC and XYZ), the information must be reported separately and clearly identified using the product type and/or facility name, respectively (e.g. "Drug product (100 mg vial / ABC)".

Note 4. Product is drug substance (i.e. formulated or pre-formulated bulk drug), drug product units (i.e. formulated drug in primary packaging), and drug product kits (i.e. drug product units incorporated into secondary packaging containing e.g. packages comprising vials of lyophilized product and vials of diluent or packages containing multiple single-dose units).

Note 5. Product is considered approved if every aspect of its manufacture (e.g. facility, equipment, manufacturing) and testing has been documented, submitted by the sponsor for review by Health Canada, and in response received before the end of the current reporting period a No Objection Letter (NOL) or a Notice of Compliance (NOC).

Section 1: Facilities Information

Note 6. For each facility provide the associated address and a brief description of responsibilities (e.g. manufacturing, analytical testing). This information serves to confirm the accuracy of Certified Product Information Document (CPID) currently on file at Health Canada, and to establish the scope for information to be provided in this report.

1.1. Drug substance

1.2. Drug product

1.2.1. Drug product unit

1.2.2. Drug product kit (if applicable)

Section 2: Production Information on Drug Substance and Drug Product Lots

2.1 Drug product lots sold on Canadian market

2.2 Lot disposition

Note 7. For each manufacturing facility and product type, indicate on a separate line the number of aborted11, quarantined12, rejected13, and released14 lots.

Note 8. For trending purposes, provide information concerning the current and previous (if available) reporting period.

Note 9. For each product lot that was aborted, quarantined, and/or rejected during the current reporting period provide a brief discussion, which includes (i) lot number, (ii) manufacturing step where event occurred, (iii) overview of the event, and (iv) reference to Section 2.5 of this template, which describes associated deviation(s) and corrective and preventive action(s).

Note 10. For lots indicated as quarantined during the previous reporting period, discuss current status (i.e. disposition).

Note 11. Aborted lot is a lot of process intermediate whose processing was not completed, e.g. due to a non-conforming in-process test result, equipment failure.

Note 12. Quarantined lot is a product lot whose processing was completed but final recommendation regarding its disposition is pending, e.g. due to incomplete analytical testing, ongoing batch record review.

Note 13. Rejected (failed) lot a product lot whose processing was completed but which was not deemed by competent quality assurance personnel as suitable for commercial distribution, e.g. due to non-conforming test result of analytical quality assessment, a critical deviation identified during batch record review.

Note 14. Released (passed) lot is a product lot deemed by competent quality assurance personnel as suitable for commercial distribution.

2.2.1 Drug substance

Details on aborted, quarantined, and rejected lots:

2.2.2. Drug product

• Facility name / Product type
• Current reporting period
  • Aborted
  • Completed
    • Quarantined
    • Rejected
    • Released
• Previous reporting period
  • Aborted
  • Completed
    • Quarantined
    • Rejected
    • Released

Details on aborted, quarantined, and rejected lots:

2.3 Reprocessed lots

Note 15. For each manufacturing facility and product type, list in a separate sub-section the corresponding lots of approved product initiated during the current reporting period and subjected to reprocessing17.

Note 16. For each affected lot provide (i) lot number, (ii) facility name, (iii) product type, (iv) reason for reprocessing, (v) overview of reprocessing steps, (vi) regulatory status in Canada, and (vii) whether lot sold in Canada.

Note 17. Reprocessing is procedure, developed, validated, approved, and documented in a batch record for use under anticipated extraordinary circumstances, whereby a lot of process intermediate or finished product is re-introduced into the routine manufacturing process and subjected to one or several steps.

2.3.1 Drug substance

(a) [Facility name - product type]

(b) [Facility name - product type]

2.3.2. Drug product

(a) [Facility name - product type]

(b) [Facility name - product type]

2.4 Reworked lots

Note 18. For each manufacturing facility and product type, list in a separate sub-section the corresponding lots of approved product initiated during the current reporting period and subjected to reworking20.

Note 19. For each affected lot provide a (i) lot number, (ii) facility name, (iii) product type, (iv) reason for reworking, (v) overview of reworking steps, (vi) regulatory status in Canada, (vii) quality assessment of reworked lot, and (viii) whether lot sold in Canada.

Note 20. Reworking is a procedure, developed in response to a specific unanticipated event, whereby a lot of process intermediate or finished product is subjected to one or several steps that may differ from the routine manufacturing process. If deemed appropriate, additional studies are performed to confirm that the quality of reworked material was not compromised (e.g. extended product characterization, stability studies).

2.4.1 Drug substance

(a) [Facility name - product type]

(b) [Facility name - product type]

2.4.2. Drug product

(a) [Facility name - product type]

(b) [Facility name - product type]

2.5. Critical deviations and non-conformances

Note 21. For each manufacturing facility and product type, provide in a separate sub-section a list of critical25 deviations23 and non-conformances24.

Note 22. For each event include an overview of associated investigations with root cause analysis, resolution with corrective and preventative actions (CAPA), and resulting product lot disposition.

Note 23. Deviation is a failure to follow established procedures (e.g. manufacturing, analytical). A deviation may be deliberate (i.e. planned and pre-approved by quality assurance department) or inadvertent (i.e. unplanned).

Note 24. Non-conformance is a failure of an analytical test result to meet established acceptance criteria.

Note 25. Critical deviation or non-conformance is likely to compromise product quality with a potential impact on its safety and/or efficacy.

2.5.1 Drug substance

(b) [Facility name - product type]

• Description of event
• Date investigation initiated
• Root cause
• Resolution and corrective and preventative action (CAPA)
• Product disposition

2.5.2. Drug product

(b) [Facility name - product type]

• Description of event
• Date investigation initiated
• Root cause
• Resolution and corrective and preventative action (CAPA)
• Product disposition

Section 3: Information on Analytical Method Performance

3.1 Invalid lot release and stability tests

Note 26. For each test facility, provide in a separate sub-section a list of associated test methods.

Note 27. For each test method provide (i) the total number of tests performed, (ii) the number or percentage of invalid tests, and (iii) a summary of causes resulting in invalid tests, including the associated corrective and preventative actions.

Note 28. For trending purposes, provide information concerning the current and previous (if available) reporting period.

Note 29. Invalid tests are test runs aborted due to events deemed to compromise the reliability of acquired test results (e.g. equipment failure, operator error, non-conforming analytical system suitability control).

(b) [Facility name - product type]

• Test name
• Current reporting period
  • Total number of tests performed
  • Percentage of invalid tests
  • Explanation/cause and any corrective/preventive actions
• Previous reporting period
  • Total number of tests performed
  • Percentage of invalid tests

3.2 Retesting due to out-of-specification (OOS) test results

Note 30. For each test facility, provide in a separate sub-section a list of associated test methods.

Note 31. For each test method provide (1) the total number of tests performed, (2) the number of tests resulting in an out-of-specification (OOS) test result, (3) number of OOS results confirmed by retesting, and (4) a summary of causes resulting in unconfirmed (false) OOS test results, including the associated corrective and preventative actions.

Note 32. For trending purposes, provide information concerning the current and previous (if available) reporting period.

(b) [Facility name - product type]

• Test name
• Current reporting period
  • Total number of tests performed
  • Number of OOS
  • Number of confirmed OOS
  • Details
• Previous reporting period
  • Total number of tests performed
  • Number of OOS
  • Number of confirmed OOS

Section 4: Summary of Changes

Note 33. For each manufacturing facility and product type, provide in a separate sub-section a list of changes implemented during the reporting period that have a potential impact on product quality (i.e. Level I, II, and III changes), including those to the manufacturing process and controls, raw material suppliers and non-compendial specifications, and to analytical methods. Duplicate subsections as necessary.

Note 34. For each Level I and Level II change provide the control number of the relevant Canadian submission and its regulatory status. For each Level III change provide the date of the relevant Annual Notification.

4.1 Manufacturing process and controls

4.1.1 Drug substance

(b) [Facility name - product type]

• Brief description
• Rationale
• Change level
• Regulatory status

4.1.2 Drug product

(b) [Facility name - product type]

• Brief description
• Rationale
• Change level
• Regulatory status

4.2 Raw material suppliers and non-compendial specifications

4.2.1 Drug substance

(b) [Facility name - product type]

• Brief description
• Rationale
• Change level
• Regulatory status

4.2.2 Drug product

(b) [Facility name - product type]

• Brief description
• Rationale
• Change level
• Regulatory status

4.3 Analytical methods

(b) [Facility name - product type]

• Brief description
• Rationale
• Change level
• Regulatory status

Section 5: Test Results

Note 35. For each manufacturing facility and product type, provide in a separate sub-section a list of critical in-process control tests (as defined in CPID) and lot release tests.

Note 36. For each test provide associated acceptance criteria, the range of result values, and identify any overall shifts or trends.

Note 37. For each test provide in the Appendix control charts (indicating acceptance limits, mean, and standard deviation) representing all lots manufactured during the current reporting period. If fewer than ten lots were manufactured during the current reporting period, provide data on the last 30 lots (including lots from previous reporting periods) or all available lot data, whichever is less.

Note 38. If trend or shift is detected, provide in the Appendix tabulated summary of the data, including the status of relevant investigations.

5.1 In-process test results

5.1.1 Drug substance

(b) [Facility name - product type]

• Process step
• In-process control
• Acceptance criteria / Action limits
• Range of results (n)
• Observed shifts or trends

5.1.2 Drug product

(a) [Facility name - product type]

• Process step
• In-process control
• Acceptance criteria / Action limits
• Range of results (n)
• Observed shifts or trends

(b) [Facility name - product type]

• Process step
• In-process control
• Acceptance criteria / Action limits
• Range of results (n)
• Observed shifts or trends

5.2 Lot release test results

5.2.1 Drug substance

(b) [Facility name - product type]

• Lot release test
• Acceptance criteria
• Range of results (n)
• Observed shifts or trends

5.2.2 Drug product

(a) [Facility name - product type]

• Lot release test
• Acceptance criteria
• Range of results (n)
• Observed shifts or trends

(b) [Facility name - product type]

• Lot release test
• Acceptance criteria
• Range of results (n)
• Observed shifts or trends

Section 6: Stability Studies

Note 39. For each manufacturing facility and product type, provide in a separate sub-section a list of lots assessed in stability studies (due to e.g. annual commitments, manufacturing process changes, reworking), whether initiated, ongoing, or completed during the current reporting period.

Note 40. For each lot provide in the Appendix a graphical representation of available stability data (one figure for each test), including acceptance criteria, the regression line, and suitable confidence intervals.

Note 41. If a trend is detected, provide in the Appendix tabulated summary of the data.

Note 42. Where appropriate, provide a statement regarding current stability program commitments, and changes to shelf-life, cross-referencing relevant submission control number.

6.1 Stability lots

6.1.1 Drug substance

(b) [Facility name - product type]

• Lot number
• Batch size
• Enrolment date
• Storage condition
• Completed (and proposed) test intervals
• Study type / purpose

6.1.2 Drug product

(b) [Facility name - product type]

• Lot number
• Dosage form & strength
• Enrolment date
• Storage condition
• Completed (and proposed) test intervals
• Study type / purpose

6.2 Stability test results

6.2.1 Drug substance

(a) [Facility name - product type]

(b) [Facility name - product type]

6.2.2 Drug product

(a) [Facility name - product type]

(b) [Facility name - product type]

Section 7: Analysis of Adverse Drug Reaction Reports Attributable to Product Quality

Note 43. Provide a list and an assessment of Canadian and international adverse drug reaction (ADR) reports received by the sponsor during the current reporting period and deemed to be linked or potentially linked to product quality; or provide a clear statement confirming that no ADR reports related to product quality were received during the reporting period.

Section 8: Product Recall and Corrective Actions

Note 44. Provide a list of product recalls issued during the current reporting period, including for each (1) the cause, (2) the issue date, (3) the list of implicated product lot numbers identifying those distributed in Canada, and (4) a summary of resulting corrective actions; or provide a clear statement confirming that no product recalls were issued during the current reporting period.

Section 9: Certified product Information Document (CPID)

Note 45. Provide a confirmation that changes implemented during the current reporting period are captured in CPID that is currently on file at Health Canada, cross-referencing the version number and relevant submission control number; or provide an annotated and a clean copy of the revised CPID; or provide a commitment to providing the revised CPID at a future date (e.g. upon the completion of scheduled annual CPID revision cycle).