FDA releases draft guidance on the use of comparability protocols for post approval changes

On April 19, 2016, the US Food & Drug Administration (FDA) released a draft guidance for industry "Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information". Comments and suggestions regarding the draft guideline should be submitted within 60 days of publication.

The guidance replaces the draft guidance published in February 2003. It provides recommendations on implementing postapproval changes through the use of comparability protocols (CPs). A CP is a comprehensive, prospectively written plan for assessing the effect of proposed CMC postapproval changes on the identity, strength, quality, purity, and potency of a drug product or a biological product. Using a CP in an original application or prior approval supplement (PAS) will, in many cases, facilitate the subsequent implementation and reporting of CMC changes. This could result in moving a product into distribution or facilitating a proactive approach to reinforcing the drug supply chain sooner than without a submitted protocol.

The guidance emphasizes that it is intended to establish a framework to promote continuous improvement in the manufacturing of quality products by encouriging applicants to employ tools of  ICH Q8 to Q11:

  • 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.

An FDA approved submission containing a CP provides an applicant with an agreed-upon plan to implement the proposed change(s), and in many cases, justification to report the implementation of the proposed change(s) in a reduced reporting category.

FDAs recommendations for the CP content: The CP submission should provide a comprehensive, detailed plan for the implementation of proposed changes and should include the information described below:

  • Summary;
  • Description of and Rationale for the Proposed Changes;
  • Supporting Information and Analysis (based on knowledge and risk assessments, information from development);
  • Comparability Protocol for the Proposed Change(s) - the CP should describe the specific tests and studies to be performed, including analytical procedures to be used and criteria to be achieved for the expected results. The level of detail that should be provided will depend on the complexity of the change and the specific risks associated with the change to product quality;
  • Proposed Reduced reporting category (i.e., an annual report, CBE, or CBE-30);
  • Other Information.

Additionally, the draft guidance provides a "Questions and Answers" section on CPs in the Appendix, which covers general questions and questions regarding formulation, manufacturing site and process, specification (including analytical methods), packaging, and process analytical technology (PAT) changes.

CPs together with "established conditions" may be effective tools for the overall product life cycle management. They can also facilitate the management of post-approval CMC changes in a more predictable and efficient manner, as it is the intention of the planned ICH Q12 Guideline "Lifecycle Management". Steps 1 and 2 a/b of ICH Q12 are expected for June 2017.

For more information please visit the ICH website and see the FDA draft guidance for industry "Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information".

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