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 It replaces the draft guidance that published in February 2003, titled Comparability Protocols: Chemistry, Manufacturing, and Controls Information.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). Approval of the original application containing the CP or a subsequent PAS containing the CP can provide an applicant with an agreed-upon plan to implement the specified change(s), and in many cases, a justification to report the change(s) in a reduced reporting category, contingent upon the applicant’s analysis of the data from the implementation of the change. In many cases, using a CP will facilitate the subsequent implementation and reporting of CMC changes, which could result in moving a product into distribution or facilitating a proactive approach to reinforcing the drug supply chain sooner than if a protocol were not submitted. 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

This guidance applies to CPs submitted to new drug applications (NDAs), abbreviated new drug applications (ANDAs), and biologics license applications (BLAs), and supplements to these applications regulated by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). The scope of this revised draft guidance does not include animal drugs.

This guidance incorporates the modern regulatory concepts stated in FDA’s guidance for industry on PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, the Pharmaceutical Current Good Manufacturing Practices for the 21st Century, the Critical Path Initiative, and the quality-by-design principles described in the International Conference on Harmonisation (ICH) guidance for industry on Q8(R2) Pharmaceutical Development. These principles are also incorporated in the following ICH guidances: Q9 Quality Risk Management, Q10 Pharmaceutical Quality System, and Q11 Development and Manufacture of Drug Substances.

Posted on the FDA website on 19 April 2016