Comparability protocols: Final guidance incorporates ICH Q12, allows for API supplier changes

Regulatory NewsRegulatory News | 17 October 2022 |  By 

The US Food and Drug Administration’s (FDA) last week released a final guidance to assist the pharmaceutical industry in submitting comparability protocols for postapproval manufacturing changes.
The final guidance contains several changes from the draft version issued in April 2016. (RELATED: Postapproval CMC Changes: FDA Updates Guidance, Regulatory Focus 19 April 2016)
Among the changes are the incorporation of the International Council on Harmonisation (ICH) Q12 principles for postapproval changes, allowing manufacturers to change API suppliers though the use of a comparability protocol instead of requesting this change through the more burdensome prior approval supplement (PAS) reporting category and expanding the scope of the guidance to address CPs for drug master files (DMFs) and drug-device combination products.
The final guidance defines a comparability protocol as a “comprehensive plan, prospectively written plan for assessing the effect of a proposed postapproval CMC change(s) on the identity, strength, quality, purity and potency of a drug product, including a biological product.” The protocol may be submitted as part of the original application or in a PAS.
Positive response to draft guidance
Several large pharmaceutical trade groups, such as the Biotechnology Innovation Organization (BIO) and the Parenteral Drug Association (PDA) expressed their support for the guidance when it was released in draft form.
BIO said that it finds the guidance “to be thorough and well-considered. It takes into account several approaches to utilizing change protocols for postapproval changes.”
For its part, PDA said it “applauds this new draft and feels this guidance is an improvement on what was previously available and appreciates the options provided. It clearly portrays FDA’s intent to work, and partner, with applicants to achieve positive outcomes for patients. It is very helpful to have details on what information to submit. The acknowledgement and opportunity to utilize risk assessments to provide sound scientific justification to discuss post‐approval changes with the agency introduces needed flexibility to the review process and is considered very helpful.”
Final guidance incorporates ICH Q12 principles
At industry’s suggestion, the guidance was revised to include reference the newly adopted ICH Q12 guideline. The guidance now states that postapproval changes should be made in alignment with the principles of ICH Q9, ICH Q10, ICH Q11, and now Q12.
The ICH guideline was adopted in November 2020 and aims to faultuaite the management of postapproval chemistry, manufacturing and controls (CMC) changes for new and marketed pharmaceuticals and drug substances. The FDA made available the ICH guidance on 11 May, which is now being implemented by regulators. (RELATED: FDA issues ICH Q12 final guidance on postapproval changesRegulatory Focus 11 May 2021).

BIO, PDA, Novartis, Biogen and GSK had urged FDA to adopt these principles in their comments. Novartis said “it would be useful to add the reference to ICH Q12, once finalized” in the text of the guidance, or a footnote.
API supplier changes
FDA also accepted industry’s request to allow API supplier changes to be made through comparability protocols.
The draft guideline called these changes as “too high or uncertain” risk and recommended these changes be made through a PAS, not a comparability protocol.
BIO commented that “changes in API supplier for a small molecule product are not likely to result in unacceptably high or uncertain risk to product quality. This position is supported by the fact that other FDA guidances allow changes in API supplier to be submitted as a CBE-30, provided that the site has had a GMP inspection (see Guidance for Industry Changes to an Approved NDA or ANDA). Also, industry experience reflects those changes to an API supplier generally is not a high-risk CMC change.”
Revised guidance addresses combination products, DMFs
The final version also addresses the handling of comparability protocols for combination products and DMFs.
For combination products, a comparability protocol “can be submitted for changes to a drug-device or biologic-device combination product where CDER or CBER is the lead center. The nature of the proposed change to the device constituent part would need to be considered in determining if a [comparability protocol] CP would be suitable.”
Additionally, DMFs “can be cross-referenced in a [comparability protocol] CP that provides for postapproval CMC changes (e.g., changes to the information about excipients or materials used in the preparation of drug substance, drug substance intermediate, or drug product), except if the information in the master file is drug substance, drug substance intermediate, or drug product information.”
Final guidance


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