On January 22, 2013, FDA published its final rule on cGMP requirements for combination products under 21 CFR Part 4. Specifically Part 4.4 provides two mechanisms for combination product manufacturers to comply with the cGMP requirements: either by complying with all the cGMP requirements of both constituent parts, or by complying with all the cGMP requirements of one constituent part and then complying with a streamlined list of cGMP requirements for the other constituent part, as listed in 21 CFR Part 4.4(b).
It appears as though Congress found this approach to be too burdensome for combination product manufacturers so, in the Cures Act that was signed into law in December of 2016, Congress included subsection 3038(c), which compels FDA to identify types of combination products and manufacturing processes for which cGMPs can be adopted even if they vary somewhat from the requirements of 21 CFR Part 4.4:
(c) VARIATIONS FROM CGMP STREAMLINED APPROACH.—Not later than 18 months after the date of enactment of this Act, the Secretary of Health and Human Services (referred to in this subsection as the ‘‘Secretary’’) shall identify types of combination products and manufacturing processes with respect to which the Secretary proposes that good manufacturing processes may be adopted that vary from the requirements set forth in section 4.4 of title 21, Code of Federal Regulations (or any successor regulations) or that the Secretary proposes can satisfy the requirements in section 4.4 through alternative or streamlined mechanisms. The Secretary shall identify such types, variations from such requirements, and such mechanisms, in a proposed list published in the Federal Register. After a public comment period regarding the appropriate good manufacturing practices for such types, the Secretary shall publish a final list in the Federal Register, notwithstanding section 553 of title 5, United States Code. The Secretary shall evaluate such types, variations, and mechanisms using a risk-based approach. The Secretary shall periodically review such final list. [Emphasis added]
On June 13th, FDA published its proposed list in the Federal Register for single-entity and co-packaged combination products that “…can satisfy requirements in section 4.4 through alternative or streamlined mechanisms.” It is relevant to note that while Congress gave the agency the opportunity to propose good manufacturing processes that vary from the requirements in Part 4.4 or that can satisfy the requirements in Part 4.4 through alternative or streamlined mechanisms, the agency chose to only list the latter.
This list includes the mechanisms identified below as a means to demonstrate compliance with the specified Part 211 requirements:
- Section 21 CFR 211.165 – Testing and Release for Distribution: Manufacturers may be able to use product samples that are not finished combination products when performing the required testing, but they would need to establish that any differences in the manufacturing process for the sample used, as compared to the finished combination product, do not affect the drug constituent part.
- Section 21 CFR 211.166 – Stability Testing: Manufacturers may be able to leverage stability data for an already marketed combination product, for example, when the new combination product is a modification of an already marketed product and the modification does not impact the stability of the drug constituent part.
- Section 21 CFR 211.167 – Special Testing Requirements: Manufacturers may be able to define “batch” based on the drug constituent part rather than the finished combination product for purposes of special testing requirements involving pyrogens and endotoxins.
- Section 21 CFR 211.170 – Reserve Samples: Manufacturers may be able to use validated surrogates as representative samples to meet the requirements of this regulation, provided the surrogate is appropriate.
FDA requests comments from stakeholders who believe that there are additional types of combination products and/or manufacturing processes where different approaches may be appropriate.