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The guidance discusses the implementation of CMC postapproval changes through a comparability protocol.
On April 19, 2016, FDA issued guidance on how to implement a chemistry, manufacturing, and controls (CMC) postapproval change by using a comparability protocol (CP). The guidance replaces previous guidance, Comparability Protocols: Chemistry, Manufacturing, and Controls information, published in February 2003.
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).” When a CP is submitted in an original application or prior approval supplement (PAS), the agency can review proposed CMC postapproval changes and any supporting information. If the original application with the CP is approved, the applicant will have an agreed-upon plan to implement the specified change. FDA states that, “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.”
In the guidance, FDA establishes a framework to improve quality by encouraging applicants to effectively use knowledge of the manufacturing process, have a robust control strategy, perform risk-management activities over a product’s lifecycle, and have an effective quality system. An appendix offers answers to CP questions.
The agency recommends that applicants submit a CP that “proposes a reduced reporting category for particular changes only if you have a sufficient understanding of the product and manufacturing process to assess the risks associated with implementing the proposed change(s).” Such understanding should come from prior knowledge, development of the drug and manufacturing process, pharmaceutical development, process validation, commercial-scale production, and quality risk management.
FDA recommends the CP have a summary, a description of and rational for the proposed change, supporting information and analysis, a comparability protocol for the change, proposed reduced reporting category, and other information. The guidance details steps for implementing changes according to the approved CP and for modifying an approved CP.
The guidance applies to CPs submitted to new drug applications, abbreviated new drug applications, and biologics license applications, as well as applications regulated by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER).