FDA Guidelines for Post-Approval CMC Changes, Part Two: Contents of Comparability Protocol Submissions

Additional information on FDA's draft guidance is available in our preceding FDA News article, entitled "FDA Guidelines for Post-Approval CMC Changes, Part One: Overview of the Updated Draft Guidance."

In February 2003, FDA published a draft guidance entitled "Comparability Protocols: Chemistry, Manufacturing, and Controls Information." Last month, the Agency replaced the 13 year old draft guidance with a revised and updated document. The new draft guidance, entitled "Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information," will provide more flexibility with regard to the implementation of advanced control approaches and includes recommendations for applicants submitting a comparability protocol (CP) to FDA.

Although the draft guidance touches on a number of different topics, an emphasis is placed on the content recommendations for CP submissions. As such, the draft guidance states that CP submissions should provide FDA with the applicant's plan for the implementation of proposed changes, and should include the following information:

Summary

The summary should provide a brief description of the following:

• A description of and rationale for the proposed change(s)
• Supporting information and analysis
• Comparability protocol for the proposed change(s)
• Proposed reduced reporting category
• Other information

Description of & Rationale for the Proposed Change(s)

"The proposed change(s) should be described in sufficient detail to enable the Agency to evaluate the relevancy and adequacy of the CP."

Supporting Information & Analysis

"Supporting information submitted with the CP should demonstrate your understanding of those aspects of the product, manufacturing process, and control strategy that are relevant to the proposed change(s)."

In addition, FDA also states that "the amount of supporting information that should be provided will depend on, and be commensurate with, the complexity of the product and the planned change. For any information that is already submitted in the same NDA, ANDA, or BLA, simply indicate where this information can be found (e.g., provide the volume and page number)."

Comparability Protocol for the Proposed Change(s)

"The CP for the proposed change(s) should describe, in sufficient detail for FDA to assess the CP, the specific tests and studies to be performed, including analytical procedures to be used and criteria to be achieved, to demonstrate the lack of adverse effect on the product quality. These tests and studies should be performed at commercial manufacturing scale."

FDA recommends that the following items be included:

• A comparative assessment of product's quality attributes before and after the change(s).
• Scientific justification for the design of studies, selection of the tests, and analytical procedures.
• Description of the analytical procedures.
• Information to support that the methods are appropriate for their intended purpose.
• Criteria to ensure the quality of the product after implementation of the CMC change(s).
• Relevant and clearly defined acceptance criteria that must be met to demonstrate that the change was successful (for each characterization test and study).
• Acceptance criteria related to the success of the change for impurity profiles, stability studies, and any other studies, where applicable.

Proposed Reduced Reporting Category

In its draft guidance, FDA states that following:

"We recommend that you propose an appropriate reduced reporting category for implementation of each change (i.e., an annual report, CBE, or CBE-30). FDA will evaluate your proposed reporting category as part of its review of the CP submission and communicate any concerns about your proposal. FDA approval of the submission containing the CP will include your proposed reporting category, if appropriate, for each of the specified CMC changes."

In addition, FDA notes that in some cases, the appropriate review division may recommend that the changes be submitted in a regular Prior Approval Supplement (PAS) rather than a CP. The division may suggest this if the complexities associated with the change(s) pose an unacceptably high risk to the product's quality.

Other Information

The draft guidance also provides the following recommendations concerning the content of a CP submission:

• "Indicate whether the CP is for a one-time change(s) or will be used repeatedly for a specified type of change over the life cycle of the product."
• "Provide that the site will not distribute product manufactured with the change(s) until the site's quality control unit has confirmed that the criteria specified in the protocol have been met and approved the implementation of the change."
• Provide an estimated timeline for the changes to be implemented.
• Biological products that are not specified biological products "should provide the qualification studies to be completed for new or modified manufacturing equipment and facilities, and the criteria to be met."

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