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Regulatory Focus™ > News Articles > Postapproval CMC Changes: FDA Updates Guidance

Postapproval CMC Changes: FDA Updates Guidance

Posted 19 April 2016 | By Zachary Brennan 

Postapproval CMC Changes: FDA Updates Guidance

Drug and biologics manufacturers looking to implement a chemistry, manufacturing and controls (CMC) postapproval change through the use of a comparability protocol (CP) should take note of an updated US Food and Drug Administration (FDA) draft guidance released Tuesday.

The revised draft provides recommendations to drug manufacturers on implementing CMC postapproval change(s) through the use of a CP. Companies that fall within the scope of this guidance will not have to submit commercial scale CMC information on post-change products to FDA before making the proposed changes, FDA says.

The draft document replaces draft guidance from February 2003 -- called Comparability Protocols: Chemistry, Manufacturing, and Controls Information -- and is intended to establish a framework to promote continuous improvement in the manufacturing of quality drugs and biologics by encouraging applicants to employ:

  • Effective use of knowledge and understanding of the product and manufacturing process
  • A robust control strategy
  • Risk management activities over a product’s life cycle
  • An effective pharmaceutical quality system

FDA noted in the Federal Register on Tuesday that the guidance was revised in order to provide more flexibility regarding filing procedures for a notification of change in a condition established in an approved application, to include current pharmaceutical quality concepts and to add an appendix to address commonly asked questions.


A CP describes the specific tests and studies to be performed and the acceptance criteria that can demonstrate the lack of adverse effects of one or more proposed CMC changes on product quality.

The description of the specific tests and studies to be performed should also include the analytical procedures to be used or reference, FDA says, noting that analytical procedures should include regulatory analytical procedures and those used for characterization studies.

The drivers for such changes include business needs, expanding markets, process improvements, potential for drug shortage and accelerated manufacturing development for drugs subject to expedited programs.

CP Submissions

FDA says it recommends companies consider a CP submission that proposes a reduced reporting category for particular changes only if a company has a sufficient understanding of the product and manufacturing process to assess the associated risks.

The CP submission should provide a plan for the implementation of a proposed change(s) and include:

  • Summary, including tabular, narrative, or graphic representations
  • Description of and Rationale for the Proposed Change(s), with sufficient details
  • Supporting Information and Analysis demonstrating a company’s understanding of the product, manufacturing process and control strategy
  • Comparability Protocol for the Proposed Change(s), which should describe 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.
  • Proposed Reduced Reporting Category, which should include proposals for implementation of each change. FDA will evaluate the proposed reporting category as part of its review of the CP submission and communicate any concerns
  • Other information, particularly on whether the CP is for a one-time change(s) or will be used repeatedly for a specified type of change over a product’s life cycle. FDA also recommends that the CP 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.

“Seeking approval of a CP as part of the original application may facilitate the applicant’s ability to prospectively plan to optimize the manufacturing process or otherwise adjust the control strategy rapidly and predictably in the immediate postapproval period as manufacturing experience is gained,” FDA says. “If the product and process understanding available at the time of the original application approval is not sufficient to support the risk analysis for future changes, a CP can also be submitted in a PAS [post-approval study] once additional commercial manufacturing experience is gained.”

FDA Draft Guidance: Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information

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