FDA Guidelines for Post-Approval CMC Changes, Part One: Overview of the Updated Draft Guidance

May 3, 2016

On April 19, 2016, FDA released a revised and updated draft guidance entitled "Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information," which provides various recommendations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The revised document replaces the Agency's February 2003 draft guidance, entitled "Comparability Protocols: Chemistry, Manufacturing, and Controls Information."

What is a comparability protocol (CP)?

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)."

Modifying an Approved CP

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 The draft guidance provides a number of examples, which demonstrate the types of modifications to an approved CP that may be considered to have a moderate potential to have an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:

  • "Replacement or modification of a test, study or acceptance criterion specified in an approved CP that provides for the same or increased level of rigor of the CP for assessing the effect of the change(s) on the product quality
  • Inclusion of an additional approved application in a previously approved CP which covers an identical change(s) that affects multiple applications"

In addition, if the scope of the original CP submission includes the following planned modifications, they must be submitted as a CBE supplement:

  • "Addition of a test, study, or acceptance criterion not specified in an approved CP that provides for the same or increased level of rigor of the CP for assessing the effect of the change(s) on product quality"

Implementing Changes to an Approved CP

When implementing the change(s) of an approved CP, FDA recommends the following:

  • Applicants should review and compare the risk assessment provided in the initial CP submission with current knowledge.
    • This will ensure that the outcomes of the risk assessment continue to be valid as they pertain to the planned change(s). Any fundamental differences between the previously described level of risk associated with the change(s) may affect the reporting category for the change specified in the approved CP. In this case, FDA recommends that the applicant "contact the appropriate FDA review division because it may be necessary to modify the CP, the proposed reporting category, or both."
  • Applicants should confirm that the "control strategy will continue to ensure that the product will be produced consistently after implementation of the change(s)."
  • Applicants are expected to implement the change(s) outlined in the approved CP within their change management system as part of their overall pharmaceutical quality system.
    • This includes "ensuring that the facility(ies) where the change is to be made is capable of implementing the change in accordance with current good manufacturing practice (CGMP)."
    • "If any impacted facility is not capable of implementing the change in accordance with CGMP, the approved CP should not be implemented."

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."

Reporting Changes Made in Accordance with an Approved CP

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:

  • A reference to the number and date of approval for the approved original application or supplement containing the CP
  • If the approved CP provided for a reporting category other than a PAS, a statement that all approved criteria for the findings were met and that the change(s) was successfully implemented under the site's pharmaceutical quality system, which includes approval by the quality control unit
  • Details regarding the implementation of the change(s), a summary and analysis of the data (e.g., tables, graphs, charts), and any changes to the risk assessment
  • Specific data if indicated to be necessary in the approved CP
  • Update of the risk assessment provided with the approved CP submission (if any), or statement that risk assessment has not changed
    • As indicated above, if the updated risk assessment indicates a substantive change in the level of risk associated with the change, this may impact the previously approved reporting category. In this case, you should contact the appropriate FDA review division.
  • Unexpected results that may have affected the tests or studies (if any)
  • A summary of deviations and investigations performed (if any)
  • Evaluation of the impact of the change on product quality
  • Conclusions reached after evaluation of studies conducted to support the change"

Any new information concerning the change(s) that is generated after implementation should be included in the next annual report.

Content Recommendations for CP Submissions

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.


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