New guidance issued by the US Food and Drug Administration (FDA) offers an extensive set of recommendations on how members of the pharmaceutical industry can comply with a rule regarding the proper manufacture of combination products.
Combination products are, as their name implies, a combination of two or more product classes, such as a medical device, biologic and a pharmaceutical product. They are typically regulated by analyzing their constituent parts to determine their primary mode of action, which is then analyzed by the appropriate regulatory center. A pre-filled syringe containing a vaccine, for example, might be regulated by FDA's Center for Biologics Evaluation and Research (CBER), while a drug-coated stent might be regulated by the Center for Drug Evaluation and Research (CDER).
Combination products might also be two devices that are physically separate but are specifically indicated for use with one another or are packaged together ("co-packaged").
Because the devices combine two or more products that on their own might be regulated, they are subject to careful scrutiny in regard to their manufacturing.
Recent Regulatory Development
In January 2013, FDA released a long-sought regulation, Current Good Manufacturing Practice Requirements for Combination Products.
The rule, as reported by Regulatory Focus, is intended to illustrate which sets of current Good Manufacturing Practices (cGMPs) must be followed by a manufacturer of a combination product.
The problem is that different sets of CGMPs cover different types of products. The manufacture of pharmaceutical and biological products is regulated under 21 CFR 210-11 and 600-680, while medical devices are manufactured under Quality Systems Regulation (QSR) regulations (21 CFR 820) and blood- and tissue-based products are regulated under 21 CFR 1271.
The question faced by combination product manufacturers was often: Should I only follow the set of CGMPs for my product's primary mechanism of action (PMOA), or do I need to follow CGMPs for all constituent parts of the combination product?
FDA's latest guidance is a sort of quick-reference guide to the regulation.
FDA notes, for example, that the final rule "offers two ways to demonstrate compliance with CGMP requirements."
"Under the first option, manufacturers demonstrate compliance with all CGMP regulations applicable to each of the constituent parts included in the combination product. Under the second option, manufacturers implement a streamlined approach, demonstrating compliance with either the drug CGMPs (21 CFR part 211) or the quality system (QS) regulation (21 CFR part 820) rather than demonstrating full compliance with both, when the combination product contains both a drug and a device, under certain conditions. These conditions include demonstrating compliance with specified provisions from the other of these two sets of CGMP requirements. In addition, for a combination product that includes a biological product, the CGMP requirements for biological products in parts 600 through 680 (21 CFR parts 600 through 680) would apply, and, for a combination product that includes any HCT/Ps, the regulations in part 1271 (21 CFR part 1271)—including the current good tissue practice (CGTP) requirements and donor eligibility requirements—would apply."
In other words, FDA allows a manufacturer to establish its own CGMP process—within reason. Companies will still need to demonstrate compliance with their quality process, and will need to justify which quality measures they decided to adopt—and which they didn't.
The guidance, Current Good Manufacturing Practice Requirements for Combination Products, is available for comment for the next 60 days.