FDA Draft Guidance for Industry

Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls (CMC) Information

April 2016
Pharmaceutical Quality/CMC

This guidance provides recommendations to holders of applications for human drugs and biologics on implementing a chemistry, manufacturing, and controls (CMC) postapproval change through the use of a comparability protocol (CP).

It replaces the draft guidance that published in February 2003, titled Comparability Protocols: Chemistry, Manufacturing, and Controls Information.

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).

Submission of a CP in an original application or prior approval supplement (PAS) allows the agency to review a description of one or more proposed CMC postapproval changes, supporting information including any analysis and risk assessment activities, a plan to implement the change(s), and, if appropriate, a proposed reduced reporting category for the change(s).

This guidance is intended to establish a framework to promote continuous improvement in the manufacturing of quality products 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

Download FDA Guidance in PDF

Download “Comparability Protocol” ucm496611.pdf – Downloaded 394 times – 200 KB

Can a comparability protocol be used to describe a wide range of potential parameter changes to a manufacturing process?

A CP can be appropriately used to provide for a wide range of potential parameter changes to a manufacturing process using a risk-based approach, if you have a high level of process and product understanding.

A risk assessment should be conducted on the potential for product and/or  intermediate critical quality attributes (CQAs) to be affected by parameter changes. In many cases, it  may be possible to group unspecified parameter changes by individual unit operation or groups of unit operations. Often, pilot or smaller scale data can be used to identify the potential risks to product quality and help devise a suitable evaluation plan. The specific tests and studies proposed to evaluate the change should address how quality could be assured for the product, including each of the product and/or intermediate CQA.

The risk assessment should also consider how multiple manufacturing changes can result in combined effects that might not arise from individual changes. The risk of adverse effects as a result of such multiple changes should be addressed during manufacturing process development and included in the supporting information for the CP.

Last Updated: 2016-04-27

Comparability Protocols for Human Drugs and Biologics CMC
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