FDA Issues Draft Guidance for Combination Product cGMP Compliance

By Jay W. Cormier & Allyson B. Mullen –

Two years ago, FDA promulgated the Part 4 regulations that specify how manufacturers of combination products are to comply with current good manufacturing practice (cGMP) when making products whose constituent parts are from more than one type of product. Recently, FDA issued a draft guidance document that put a bit more color on these regulations.

For those who are unfamiliar, each type of FDA-regulated product (e.g., drug, biologic, device, etc.) has its own set of regulations that govern what constitutes cGMPs. For single-category products, this makes sense – while the types of manufacturing issues that a medical device and, a biologic present do overlap, there are some differences in how to approach these issues, both technically and in the existing regulations. As if compliance with cGMPs isn’t difficult enough even for companies with big budgets, add in the wrinkle of manufacturing a product that, for example, is both a medical device and a drug at the same time, and things get messy in a hurry.

Part 4 was intended to come to the rescue. At a high-level, Part 4 is rather straight-forward. The analysis begins with the general rule that each constituent part of a combination product must be manufactured in compliance with its respective cGMP requirements. 21 C.F.R. § 4.3. For combination products that are either co-packaged (i.e., two or more separate products that are packaged together) or single-entity (i.e., comprised of parts that are physically, chemically, or otherwise combined into a single product) combination products, Part 4 provides an alternative to the general rule: a facility can elect to fully comply with the cGMP requirements for one of the constituent types and supplement certain specified provisions of the other constituent type cGMP requirements. See 21 C.F.R. § 4.4. Such a manufacturing facility has three options:

1. Fully comply with each of Parts 210 and 211 with respect to the drug constituent and with Part 820 for the device constituent;
2. Comply fully with Parts 210 and 211 for the combination product and with 21 C.F.R. §§ 820.20 (management responsibility), 820.30 (design controls), 820.50 (purchasing controls), 820.100 (CAPAs), 820.170 (installation), and 820.200 (servicing) for all constituent device parts; or
3. Comply fully with Part 820 for the combination product and 21 C.F.R. §§ 211.84 (component and container-closure testing), 211.103 (yield calculations), 211.132 (OTC tamper-evident packaging), 211.137 (expiration dating), 211.165-211.167 (final product release and stability testing), and 211.170 (reserve samples) for all constituent drug parts.

At 46 pages in length, the Draft Guidance helps to put some additional details onto this regulatory scheme. For readers who are interested in specifically how to apply device QSR provisions to drug components (when using option 2, above) or how to apply drug GMP provisions to device components (when using option 3, above), the majority of the Draft Guidance is dedicated to walking through each of these cross-product type issues. These summaries may be particularly helpful to companies that are unfamiliar with the cGMPs for the other regulatory product types (e.g., a device company that does not currently follow drug cGMPs). Rather than summarizing the many statements made by FDA on these specific issues, this post will provide a few highlights of the general concepts and clarifications provided by the Draft Guidance.

• Options 2 and 3, above, only apply to those manufacturing steps that occur after the first instance where the two separate product-type constituent parts are first co-packaged or combined into a single product. Prior to this point in time, the individual constituent parts are subject to their respective cGMP requirements.
• With respect to inspections, if a manufacturer elects one of these “streamlined” approaches (options 2 and 3), FDA recommends that the manufacturer notify FDA of which approach it intends to adopt in their premarket submissions as well as at the time that an inspection begins. A 510(k) premarket notification typically would not discuss manufacturing.
• A manufacturer may elect either streamlined approach for a co-packaged or single-entity combination product, without regard to which product center has been assigned as the lead review center or what primary mode of action has been designated for the combination product.
• Part 4 does not change FDA’s expectations for cGMP compliance for investigational products: drugs are generally exempt from cGMPs during Phase 1 studies and investigational devices are generally exempt from Part 820 with the exception of design controls.
• Part 4 does not change the analysis of whether a device component manufacturer is subject to Part 820 requirements. The guidance does a good job of explaining the difference between a device component (as defined in Part 820) and a device constituent part of a combination product.
• As with all other cGMP regulations, only those regulations that are applicable to the manufacturing operations must be followed.
• Specific procedures designed to implement one set of requirements (e.g., discrepancy investigations under 21 C.F.R. § 211.192) can be used to satisfy part or all of the relevant additional requirement s (e.g., CAPA requirements under 21 C.F.R. § 820.100).

The Draft Guidance includes detailed hypotheticals for pre-filled syringes, drug-coated meshes, and drug-eluting stents. While these hypotheticals each only cover one of the available options under Part 4, they are illustrative of what FDA expects combination product manufacturers to do when designing and implementing their manufacturing processes.

As always, general agency guidance cannot anticipate every scenario used by industry, so while applying the Draft Guidance to many products may seem to be straightforward, undoubtedly there will be instances where reducing agency guidance to practice is anything but clear.

Comments on the Draft Guidance are due to FDA by March 30th.