FDA draft guidance seeks to address ‘lack of clarity’ around CMC changes

The guidance comes as FDA seeks to help companies understand what CMC changes require reporting to the agency and what changes can be made solely under a company’s Pharmaceutical Quality System (PQS).  

“Clarification regarding which elements of the CMC information constitute established conditions and where in an application these elements are generally expected to be described, should lead to a better understanding that certain CMC changes can be made solely under the Pharmaceutical Quality System (PQS) without the need to report to FDA,” ​the agency says.

FDA defines “established conditions​” as the description of the product, manufacturing process, facilities and equipment, and elements of a control strategy that assure process performance and quality of an approved product. Changes to these conditions must be reported to the FDA.

“Although the reporting mechanism for many CMC changes is clear, FDA is concerned that there is confusion regarding which elements of an application are considered to be established conditions. This confusion could have a negative impact on change management activities and could discourage continual improvement in product manufacturing processes, lead to unnecessary submission of post-approval supplements to FDA for changes that could be managed solely by a manufacturer’s PQS, or, upon inspection, lead to Form 483 observations for hanges that should have been reported to FDA​,” the agency says.

In terms of which elements of the control strategy that are submitted in an application and may be considered established conditions, the FDA lists:

• DS/DP (drug substance/drug product) manufacturing and testing facilities, including in-process materials;
• Source of and specifications for starting materials for biological products;
• Process, including in-process tests and sequence of operations, equipment, and process parameters and their ranges;
• Specifications, including the tests, analytical procedures and acceptance criteria, including specifications for the DS, other components, in-process materials, and the DP;
• Container closure system, components, and specifications; and
• Maintenance strategy for chemometric and/or multivariate models (e.g., for models that may have a high impact on product quality).

And in cases where the relevance of the established conditions will depend on manufacturing site specific capabilities, such as on-line, real-time attribute monitoring, the FDA says “certain elements of established conditions may need to be specific to a particular facility or facilities should the application have multiple facilities approved for the same intended function​.”

The applicant should also provide an updated summary of the established conditions and supportive information (e.g., validation data, batch analysis) for any new or modified established conditions in a manufacturing supplement or the next annual report, the agency adds.

Alternatively, if an established condition is no longer necessary to assure process performance and quality, the applicant may remove such a condition by submitting a supplement or annual report, where the submission type is based on the recommendations found in FDA regulations and post-approval change guidance documents or in an approved protocol.