FDA’s Draft Guidance Helps Clarify Which Changes to Established Conditions are Reportable CMC Changes; Describes Process for Setting Out Established Conditions at Approval

By James E. Valentine* & Jay W. Cormier –

On June 1, 2015, FDA announced the availability of a draft guidance for industry entitled “Established Conditions: Reportable CMC Changes for Approved Drug and Biologic Products.” The draft guidance is intended to address a “lack of clarity” about when chemistry, manufacturing, and controls (CMC) changes must be reported to FDA. 

By way of background, FDA regulations require marketing applications for drugs and biologics to contain a CMC section that describes information such as the composition of the drug product, manufacture of the drug substance, and manufacture of the drug product.  Regulations also require all changes after approval of an application to be managed and executed in conformance with current Good Manufacturing Practices (cGMP).  Only a subset of these changes, however, must be reported to FDA.  Changes must be reported “in each condition established in an approved application beyond the variations already provided for in an application” 21 C.F.R. § 314.70(a)(1)(i) (emphasis added).

Although the substantive elements of the draft guidance are not surprising and are expected to be relatively non-controversial, FDA is interested in clarifying what constitutes a “condition established” for purposes of mandatory reporting to FDA so that sponsors have confidence that other changes do not require reporting.  FDA hopes that such clarification will alleviate confusion that it fears may “discourage continual improvement in product manufacturing processes” or result in unnecessary submissions to FDA. 

Established conditions include the description of the product, the manufacturing process, facilities and equipment, and elements of the associated control strategy, as defined in the marketing application, that assure process performance and quality of an approved product.  The guidance provides “control strategy” elements that are submitted in an application which may be considered established conditions, including:

• Drug substance and drug product manufacturing and testing facilities(including in-process materials);
• Source of and specifications for starting materials for biological products.;
• Process and process parameters and their ranges, including in-process tests and sequence of operations, equipment;
• Specifications, including the tests, analytical procedures and acceptance criteria, including specifications for the drug substance, other components, in-process materials, and the drug product;
• 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).

There are other elements of a “control strategy” that are not “conditions established in the marketing application” and, therefore, can be managed through the pharmaceutical quality system without having to be reported.  For example, although a control strategy is generally supported and verified by batch records, development data, characterization data, validation data, and batch analysis data, these elements are generally not considered established conditions.  The draft guidance also provides product manufacturers which section of the Common Technical Document (CTD) contain elements of the CMC information that constitute established conditions.  

The draft guidance provides that applicants should provide a summary of the proposed established conditions in applications (in Module 2, section 2.3 of the CTD, Introduction to the Quality Overall Summary), as well as a brief description or identification of the established condition with a reference to its specific location (in Module 3 of the CTD or with a hyperlink if in eCTD format).  This will allow FDA to assess the proposed established conditions as part of the review process.  For products whose applications did not include a clear delineation of the established conditions, the draft guidance states that FDA will develop a process for obtaining clarification.  To add, modify, or remove an established condition based on information learned during commercial manufacturing, such changes can be made through a manufacturing supplement (if needed) or the next annual report.

Whether the guidance, in draft form or if finalized, will actually increase manufacturing process improvements or reduce FDA’s workload with respect to post-approval supplements is unclear.  As with all draft guidance documents, FDA asks that comments be submitted to FDA so that it can incorporate such comments into its final version.  Comments can be submitted directly to the docket electronically via www.regulations.gov.

*Admitted only in Maryland. Work supervised by the Firm while D.C. application pending.