Summary of changes: Lot Release Program for Schedule D (biologic) drugs for implementation

On this page

• Background
• Administrative edits
• Terminology edits
• Clarifying edits
• Regulatory authority
• Operational updates
• Other updates
• Replacement of documents

Background

Health Canada has revised the Guidance document on the Lot Release Program for Schedule D (biologic) drugs to capture administrative, terminology and operational changes or updates. Clarifying edits and more details about Health Canada's regulatory authority are also included.

Stakeholder comments on this revised guidance document were considered. We also considered comments previously received concerning lot release during the consultation on proposed amendments to Division 4 of Part C of the Food and Drug Regulations (regulations).

This is a summary of edits made before and after the stakeholder consultation, which are included in the final guidance.

Administrative edits

Administrative edits include updates to the names of 2 organizations:

• Biologics and Genetic Therapies Directorate (BGTD) to Biologic and Radiopharmaceutical Drugs Directorate (BRDD)
• Regulatory Affairs Division (RAD) to Office of Regulatory Affairs (ORA)

We have added a new document name:

• DIN-B: Drug Identification Number-Biologics (DIN-B drugs)

We have added an abbreviation:

CTA-A: clinical trial application amendment

The fax-back process is now a notification process by email. The Group 1A Lot Notification Form and Group 4 Lot Notification Form replace the fax-back forms.

Terminology edits

The following terms have been edited or added:

• a definition for manufacturer/sponsor is added to align with the Guidance on management of drug submissions and applications
• biochemical replaces chemical
• notifications replaces fax-back
• documentation review replaces protocol review
• Schedule D is mentioned once, then the document refers to biologic drugs
• pre-market testing replaces consistency testing and a definition is provided
  • supplements to new drug submissions now specifies (containing chemistry and manufacturing changes)
• lot documentation replaces protocol of tests and protocol
  • lot documentation is a more general term that can include the protocol, certificate of analysis or any other supporting documentation (for example, in-process test results, gel images or chromatograms) that we might ask for to support the release of a given batch
  • the definition now aligns with C.04.007 by stating suitable for sale
• special replaces exceptional in regard to expedited release in special cases for Group 2 (also, for prophylactic vaccines, in special circumstances, BRDD will contact a sponsor if we require more information and/or samples for testing)
• documented product shortage in Canada replaces product shortage
• periodic quality report (PQR) replaces yearly biologic product report (YBPR)

Clarifying edits

Edits have been made to:

• give a targeted timeframe for a BRDD release decision
• add guidance about foreign marketed products used in clinical trials
• clarify when a sponsor does not need to submit a Group 1A lot notification form
• provide more guidance for prophylactic vaccines and the certificate of analysis (CoA)
• describe production history factors when assigning a drug product to an evaluation group
• describe a scenario where a subset of lots manufactured in a new facility may be in 1 evaluation group while another subset of lots of the same product may be in another group

Regulatory authority

When a biologic drug is placed in the lot release program, each lot of the biologic drug is subject to the lot release program before sale in Canada.

The guidance provides more details about Health Canada's regulatory authority to:

• request information about specific lots of a biologic drug

Coming into force of the Division 4 regulatory amendments:

• Under section C.04.007 of the regulations, on request by BRDD the regulated party must provide information, samples or materials supporting lot release.
  • For Groups 2 and 3 a formal release letter from BRDD is required before each lot is sold. For Groups 1A and 4, the sponsor notifies the BRDD through a Notification process.
• Under section C.04.008 of the regulations a Periodic Quality Report (PQR) may be required for biologic products with a DIN.
• The Appendix is updated
  • The periodic quality reporting frequency is on an annual basis or longer, as specified by the Minister. The requirements may vary depending on the product. The BRDD will communicate this to the manufacturer.

Operational updates

The guidance clarifies operational updates:

• BRDD reviews lot release activities on an ongoing basis. As the level of product oversight may change based on benefit and risk considerations, a product may be moved to a different evaluation group over its lifecycle.
• After receiving the notice of compliance (NOC) or decision letter (DIN-B), the sponsor should follow the process for the post-approval evaluation group assigned to the product.
• For prophylactic vaccines: Where BRDD has requested the submission of lot documentation, a written approval in the form of a release letter is required.
• Due to the coming into force of C.04.007, BRDD will continue responding to Group 1A and Group 4 notifications.
• The BRDD aims to respond to Group 1A and Group 4 notifications within 2 business days. This is a change from the 48 hours in the 2005 version of the guidance.
• Updates to the information requirements for the different evaluation groups are summarized in the summary of requirements for evaluation groups

Other updates

BRDD is harmonizing the process for movement between evaluation groups. Products are continuously being assessed with respect to their evaluation group. BRDD uses information from the PQR to confirm or reassign to the appropriate lot release category.

The evaluation groups introduction is updated:

• After receiving the Post-Decision Letter following a notice of compliance (NOC), No Objection Letter (NOL), or decision letter (DIN-B and Periodic Quality Reports), the sponsor should follow the process for the post-approval evaluation group assigned to the product.
• Notifications are made by sponsors

Refer to:

• Group 1A lot notification form
• Group 4 lot notification form

Group 1: Pre-approval stage is updated to include a DIN-B submission.

Group 1A: Clinical trial materials is updated:

• Group 1A consists of clinical trial materials associated with authorized CTAs.
• Note: If a clinical trial product is out of specification, the sponsor should contact the Biologic and Radiopharmaceutical Drugs Directorate's Office of Regulatory Affairs (BRDD-ORA) immediately by email at brdd_faxback_dmbr@hc-sc.gc.ca.

Group 1A: Clinical trial materials, prophylactic vaccines is updated. To assess whether a lot is suitable for sale, BRDD may request a sponsor to provide more information and/or samples for testing.

Groups 2 to 4: Post-approval stage is updated. Evaluation Groups 2 to 4 apply to biologic products for which an approval letter has been issued.

Factors when assigning products to evaluation groups is updated. In addition, BRDD may reassign a product to a different evaluation group at any time.

Pre-market testing replaces consistency testing and is defined. Group 1B guidance text is updated and includes the following statement: "Sponsors must follow the requirements for the assigned evaluation group post-authorization."

An update to targeted testing to indicate that not all tests are applied to all lots. Added product stability profile and shelf life as a consideration in the targeted testing regime.

Periodic testing is updated. Lot samples are selected based on risk assessment of factors such as production history, site history, testing history and other related factors.

If BRDD has requested lot samples for periodic testing, the targeted timeframe for release is 6 weeks from the date that all required information and samples are received.

BRDD has included the drug identification number-biologics (DIN-B) within the lot release process.

The following changes include reducing the scope for notifications:

• Change in scope for other biologics: "Other biologics" are clinical trial materials associated with authorized clinical trial applications (CTAs). Sponsors must complete and file a Group 1A lot notification form for lots derived from human plasma or containing human-derived excipients, such as albumin.
• Group 1A notification process is required for products derived from human plasma or those containing human-derived excipients
  • Group 1A Lot Notification Form with updated fields replaces the CTA Fax-back Form Clinical Trial Materials.
  • Before using the lot in the related Clinical Trial, the sponsor must send in the completed Group 1A notification form. The sponsor must wait for a signed response from BRDD before using the lot in the clinical trial.
  • The Group 1A Lot Notification Form no longer has check boxes for testing specifications, as out of specification for Group 1A can no longer be sent as a fax-back notification.
• Group 4 notification process is required for products containing human-derived excipients
  • Group 4 Lot Notification Form with updated fields replaces the Fax-back Form Group 4 Products and Group 4 Products containing human-derived excipients
  • When a biologic drug is assigned to Group 4, the manufacturer of that drug must notify BRDD when a lot containing human-derived excipient(s) is to be sold in Canada. To do so, use the Group 4 Lot Notification Form. The manufacturer must wait for a signed response from BRDD prior to use of the lot.
• The Yearly Biologic Product Report (YBPR) is replaced by periodic quality reporting
  • Submitting the periodic quality report section is updated to reflect the new scope and application.
  • Periodic quality reporting is risk-based. For example, BRDD may issue a product specific communication to the manufacturer for a product or group of products. In some cases, the PQR may be for more than 1 product under the same DIN holder.
  • As an alternative, you may submit a report prepared for another competent regulatory authority that has similar information as the periodic quality report. If you do, ensure it is updated with Canadian-specific information that includes:
    • Information in the PQR template
    • Lots sold in Canada, including lot numbers
  • You may coordinate the date of submission with BRDD to coincide with the submission of a similar report to another regulatory authority.
  • If no lots are sold or manufactured for Canada or no lots are sold or produced internationally, the manufacturer should submit the PQR indicating this.
  • If the DIN has not been cancelled, then the manufacturer should submit a PQR, unless the periodic quality reporting requirement does not apply.
  • The periodic quality reporting frequency is on an annual basis or longer, as specified by the Minister. The requirements may vary depending on the product. BRDD will communicate this to the manufacturer.
  • The details about information that should be part of the PQR is removed from the guidance document. An annotated version of the PQR template is available instead.
  • During our review of the PQR, we may ask you to clarify or provide additional information via Clarification Request (with a 30-day target).
  • There is no Approval Letter or Decision Letter issued following review of the PQR.
  • BRDD will notify the manufacturer if there is a change resulting from our review of the periodic quality report, such as:
    • an approved CPID-B
    • feedback to provide to the manufacturer and/or
    • a change to the lot release evaluation group for the product
• The Note referencing the interpretation of C.02.011 and C.02.012 from the Annex 2 to the Good manufacturing practices guide – Manufacture of biologics (GUI-0027) is removed because it is not the current text.
• The Appeals section is replaced with Reassessment:
  • Once a product has been assigned to an evaluation group, sponsors may request a reassessment by writing to the Office of Regulatory Affairs.

Replacement of documents

Relevant text from the "Frequently asked questions – Guidance for sponsors: Lot Release Program for Schedule D (biologic) drugs" and "Yearly biologic product reports: Questions and answers" is edited and merged into the revised guidance document.

This final guidance will replace the following documents:

• Changes to notification requirements for biologic drugs: Notice to industry
• Guidance for sponsors: Lot Release Program for Schedule D (biologic) drugs
• Frequently asked questions – Guidance for sponsors: Lot Release Program for Schedule D (biologic) drugs
• Yearly biologic product reports: Questions and answers