Combination products: FDA finalizes list of CGMP alternatives, streamlined mechanisms

The US Food and Drug Administration (FDA) has released a finalized list of alternatives and streamlined mechanisms for current good manufacturing practice (CGMP) of combination products.

Initially, FDA released a proposed list of alternative or streamlined mechanisms for compliance with CGMP for combination products in June 2018. This proposed list was intended to meet the requirements of the 21st Century Cures Act, which directed FDA to post such a list to the Federal Register and update it periodically. (RELATED: Combination Products: FDA Proposes Alternative Mechanisms to Comply with GMP Requirements, Regulatory Focus 13 June 2018)

During the public comment period, industry stakeholders requested more clarity on what FDA wants from manufacturers of combination products in terms of applying CGMP alternatives and streamlined mechanisms described in the list. The agency said it also added more details on requesting feedback from FDA regarding combination products.

Many of the mechanisms from the proposed list remain the same in the final version. The final list describes mechanisms for sample testing and distribution of representative samples that aren’t themselves combination products but still representative of the finished product to determine final specifications, combination product stability studies that use bracketing and matrixing approaches as well as use of stability data for a combination product already on the market and the storage of representative reserve samples for combination products. The final list also describes special testing requirements mechanisms such as defining a batch as a drug constituent part during special testing of pyrogens and endotoxins instead of the finished combination product.

Compliance mechanisms are also described similarly in the final list, with FDA elaborating on manufacturers using existing pharmaceutical development practices and documentation for design controls of combination products as well as exception of products from some device Quality System Regulation provisions, which “will most frequently apply to co-packaged combination products” like an oral dosing syringe,” FDA noted.

The agency anticipates manufacturers of combination products will need to discuss CGMP specifics with FDA and might need to contact the agency in the event of a manufacturing change or to seek approval. Manufacturers are “encouraged to interact early with FDA on any such contemplated use of alternative or streamlined CGMP mechanisms for combination products,” FDA said. The pre-submission and meeting requests required will depend on the type of combination product. “Regardless of the type of submission or meeting, such interactions should be focused on a general discussion of the CGMP approach the [combination product] manufacturer wishes to pursue and associated justification to support the approach,” they wrote.

Based on industry feedback, FDA has created a list of guidances for manufacturers of combination products on what information is appropriate to submit as part of a CGMP mechanism to FDA. “When submitting information on a CGMP mechanism, [combination product] manufacturers should refer to applicable guidance as the primary reference regarding what information to provide,” the agency wrote.

All content submissions for CGMP mechanisms should also include the applicable CGMP regulation, the applicable product, prior related interactions with the agency, justification and scientific data, and the justification for exemption from 21 CFR part 820. From there, FDA said they may decide on whether the rationale provided by the manufacturer of combination products is acceptable.

“In such cases, FDA generally will notify the [combination product] manufacturer and/or applicant regarding acceptability of the mechanism, consistent with existing policies and practices for the submission type and, if the Agency finds the approach insufficient, FDA intends to provide the scientific and/or regulatory basis for this determination,” they said.

Federal Register Notice

Combination products: FDA finalizes list of CGMP alternatives, streamlined mechanisms

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