On January 22, 2013, FDA issued a final rule on CGMP requirements for combination products (see 78 FR 4307 and part 4, subpart A (21 CFR part 4, subpart A)) (CGMP Rule). The drugs, devices, and biological products included in combination products are referred to as “constituent parts” of the combination product. Combination products include “single-entity” combination products, the constituent parts of which are physically, chemically, or otherwise combined or mixed and produced as a single entity (see § 3.2(e)(1) (21 CFR 3.2(e)(1))) ( e.g., prefilled syringes and drug-eluting stents), and “co-packaged” combination products where the constituent parts are packaged together in a single package or as a unit (see § 3.2(e)(2)) ( e.g., a surgical or first-aid kit).[1] Section 4.4 (21 CFR 4.4) outlines how manufacturers of single-entity and co-packaged combination products (hereafter “CP manufacturers”) can demonstrate compliance with applicable CGMP requirements, including through implementation of a streamlined approach to meet the requirements of both the drug CGMP and the device quality system (QS) regulations.
In December 2016, the Cures Act (Pub. L. 114-255) was signed into law. Section 3038(c) of the Cures Act mandated that FDA publish in the Federal Register a list identifying types of combination products and manufacturing processes for which “good manufacturing processes” may be adopted that vary from the requirements set forth in § 4.4, or that FDA proposes can satisfy the requirements in § 4.4 through “alternative or streamlined mechanisms,” and to review this list periodically. In accordance with this statutory mandate, FDA published a proposed list on June 13, 2018 (83 FR 27609).
FDA received six comments on this proposed list, has considered them, and is now publishing a list after such consideration (see section II of this document). In response to the comments, FDA added and refined examples and provided additional clarity regarding FDA’s expectations for CP manufacturers when applying mechanisms presented in this list. FDA also added reference to a guidance on how to request FDA feedback on combination products, which provides additional detail on interacting with FDA, including with respect to CGMP issues addressed in this list.
While FDA has provided examples in this notice of the types of mechanisms that may be appropriate, CP manufacturers should consider the suitability of an approach in the context of their product and manufacturing process. For these examples, we have recommended engaging the Agency before adoption of some, whereas others may be evaluated on inspection as appropriate. Additional approaches may be permissible as well for evaluation on a case-by-case basis for a particular product and CP manufacturer. FDA continues to apply a risk-based approach to evaluating alternative or streamlined mechanisms for ensuring the quality of combination products, and as FDA and CP manufacturers develop additional data and rationales, this list may be expanded, including to provide additional examples or to identify types of combination products for which alternative or streamlined mechanisms may be applicable.
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