On April 19, 2016, FDA released a revised and updated draft guidance entitled “Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information,” which provides various recommendations concerning the use of a comparability protocol (CP) to implement chemistry, manufacturing, and controls (CMC) postapproval changes.
The revised document replaces the Agency’s February 2003 draft guidance, entitled “Comparability Protocols: Chemistry, Manufacturing, and Controls Information.”
According to FDA, “a CP is a comprehensive, prospectively written plan for assessing the effect of a proposed CMC postapproval change(s) on the identity, strength, quality, purity, and potency of a drug product or a biological product (i.e., product), as these factors may relate to the safety or effectiveness of the product (i.e., product quality).” Furthermore, a CP describes the specific tests and studies to be performed as well as the acceptance criteria used to demonstrate that the proposed CMC change(s) do not adversely affect the product’s quality.
The submission of a CP is optional, and they may be submitted to the Agency as part of an original marketing application (e.g. NDA, ANDA, BLA), or as a Prior Approval Supplement (PAS) after the original application has been approved. Once approved, a CP “can be for a one-time change(s), or be used repeatedly for a specified type of change over the life cycle of a product. A CP can also be submitted to cover an identical change(s) that affects multiple applications (grouped supplements, trans-BLA).”
After the original application or PAS containing the CP has been submitted and approved, 21 CFR 314.70(e) and 601.12(e) state that any proposed modifications or additions to the CP are considered an amendment and must be submitted as a new PAS.
Nonetheless, “as provided for in 21 CFR 314.70(a)(3), and 601.12(a)(3) to make CPs more useful and flexible, this guidance provides for a less burdensome notification of certain types of modifications to an approved CP.” The draft guidance provides a number of examples, which demonstrate the types of modifications to an approved CP that may be considered to have a moderate potential to have an adverse effect on the product quality.
If the planned modifications listed below are included in the scope of the original CP submission, FDA states that they can be submitted as a CBE-30 supplement:
In addition, if the scope of the original CP submission includes the following planned modifications, they must be submitted as a CBE supplement:
When implementing the change(s) of an approved CP, FDA recommends the following:
The draft guidance states that, “regardless of the reporting category in the approved CP, ongoing verification beyond that reported can and should be performed under your pharmaceutical quality system to continue to evaluate and ensure that there is a lack of adverse effect of the change(s) on product quality.”
Title 21 of the Code of Federal Regulations part 314.70 requires that applicants “notify FDA about each change in each condition established in the approved application beyond the variations already provided for in the application.” Applicants must notify FDA of the change(s) in a supplement or by including the information in the annual report, as described in 314.70(b)-(d).
According to 21 CFR 601.12, all applicants are required to “inform the FDA about each change in the product, production process, quality controls, equipment, facilities, responsible personnel, or labeling established in the approved license application(s).”
However, with an approved CP, FDA states that the approved reporting category can be used once the applicant has successfully completed its plan to implement the change(s) described in the CP. “The level of detail of the information provided should be commensurate with the change(s) and reduced reporting category. This submission should begin with a heading that identifies the change(s) as being made under an approved CP and should include the following:
Any new information concerning the change(s) that is generated after implementation should be included in the next annual report.
The draft guidance provides a number of suggestions regarding the content to be included in a CP submission.
Interested in learning more about FDA’s recommendations? Stay tuned… Part two is coming soon with everything you need to know about the content of CP submissions.
Are you developing an NDA, ANDA, BLA, or other FDA submission? Do you need to submit a PAS to FDA? We can help. To learn more about our services and how we can help you achieve a successful interaction with FDA, contact us today.
May 3, 2016
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...
May 3, 2016
On Wednesday, June 29th the FDA issued a draft guidance, entitled “Gifts to the Food and Drug Administration: Evaluation and Acceptance: Draft Guidance for the Public and Food and Drug Administration...
May 3, 2016
On April 13, 2022, FDA published a new draft guidance for industry entitled “Considerations for Waiver Requests for pH Adjusters in Generic Drug Products Intended for Parenteral, Ophthalmic, or Otic...