15/16 February 2022
As of 22 July 2013, cGMP requirements on combination products will apply in the USA as 21 CFR Part 4. But what are combination products? These are composed of a medical device, a medicinal product, and/or a biological product. A combination product comprises two or more of all these products as a single entity.
The FDA has developed own GMP regulations for each single product named above: requirements regarding medicinal products are laid down in 21 CFR 210/211, for medical devices in 21 CFR 820, for biological products in 21 CFR 600-680, and for tissue-based products in 21 CFR 1271. So far, there had been no standalone GMP regulations for combination products. This has now changed with the publication of FDA'S 21 CFR Part 4. The question of combination products had only been dealt with in a "Draft Guidance" from 2004 and in a draft on 21 CFR 4 from 2009. Comments received on the draft from 2009 have now flowed into 21 CFR 4. In the GMP regulations, a distinction is made between for combination products between "single-entity" and "co-packaged combination products". Less stringent rules apply to the latter. In the announcement of the new rules it is explicitly explained that when using GMPs for medicinal products (21 CFR 210/211) or GMPs for medical devices (21 CFR 820) for these products almost all requirements of 21 CFR 4 are met. Additional provisions are listed in § 4.4 (see below).
The final "regulation" - which is equivalent to a national order - is largely identical to the draft from 2009. The regulation is divided into 4 sections in a "question-and-answer" style:
The answer - reduced to a bit more than a DIN-A 4 page - doesn't provide much information. The content of § 4.3 is particularly disappointing and only refers to the respective regulations applicable to the constituents of the combination products. The references made in § 4.4 are interesting. They define which additional aspects of 21 CFR 820 have to be considered when a GMP system for medicinal products (21 CFR 210/211) is already available. In this case, it would be: 21 CFR 820.20, 21 CFR 820.30, 21 CFR 820.50, 21 CFR 820.100, 21 CFR 820.170, and 21 CFR 820.200. Reciprocally, if a system already exists according to the Quality System Regulations (21 CFR 820), the following regulations on medicinal products should be implemented: 21 CFR 211.84, 21 CFR 211.103, 21 CFR 211.132, 21 CFR 211.137, 21 CFR 211.165, 21 CFR 211.166, 21 CFR 211.167, 21 CFR 211.170.
Conclusion: The cGMP regulations on combinations products (21 CFR 4) will be effective as of 22 July 2013. Their presentation as questions and answers is interesting but the content is rather vague with regard to combination products. Useful recommendation is given for "single-entity" and "co-packed combination products".
Detailed explanations on 21 CFR 4 and the document itself can be found in the Federal Register, Vol. 78, No 14.