FDA Issues Final Rule on CGMP Requirements for Combination Products; Requirements for “Convenience Kits” Defined

By Carmelina G. Allis –

The FDA has issued a final rule on the current good manufacturing practice (CGMP) requirements applicable to combination products.  78 Fed. Reg. 4307 (Jan. 22, 2013).  This rule finalizes a proposed rule issued on September 23, 2009.  The new rule, which appears in a newly added section to Title 21, 21 C.F.R. Part 4, sets forth the CGMP requirements that apply when drugs, devices, and biological products are combined to create combination products.  This new rule also applies to manufacturers of “single-entity” and “co-packaged” combination products.  The scope of “manufacturing” activities that fall within the scope of Part 4 include, but are not limited to, repackaging, holding, storage, testing, and designing combination products.

The new regulations are based upon the premise that constituent parts of a combination product retain their regulatory status after they are combined.  In other words, the manufacturing requirements that apply to each of the constituent parts continue to apply when the parts are combined into the combination product. 

In general, the new regulations in Part 4 require that:

• drug CGMPs in 21 C.F.R. Parts 210 and 211 apply to a combination product that includes a drug constituent part;
• device CGMPs (Quality System Regulation or QSR) in Part 820 apply to a combination product that includes a device constituent part; and
• biological product CGMPs in Parts 600 through 680 apply if the combination product includes a biological product constituent part.

For “single-entity” or “co-packaged” combination products, the manufacturer can follow one of two requirements:

1. it may comply with the requirements applicable to each constituent part, or
2. it may choose to comply with the manufacturing requirements applicable to one constituent part, but must implement certain provisions set forth in the newly added section 4.4(b) applicable to the other constituent part.  For example, a manufacturer of a “co-packaged” drug-device combination product may choose to fully implement both the drug CGMPs and device QSR requirements.  Alternatively, the manufacturer may choose to comply with the drug CGMPs, but would be required by the new regulations to also comply with specific QSR requirements, such as, for example, the requirements in 21 C.F.R. § 820.20 regarding management responsibility, § 820.30 regarding design controls, and § 820.200 on servicing.  Given the burden that would entail having to comply with all the requirements applicable to each constituent part, the second choice seems more appealing.

Regarding “convenience kits,” although the new regulations in Part 4 do not address or define “convenience kits,” FDA specifically discussed those products in the preamble to the final rule.  In the preamble, FDA defined “convenience kits” as “kits that solely include products that are: (1) also legally marketed independently and (2) included in the kit as already packaged for independent marketing and with the same labeling as for independent marketing.”  78 Fed. Reg. at 4310-11.  FDA explains that no additional CGMP requirements generally would apply to the products in a convenience kit other than those applicable to the assembly, packaging, labeling, or sterilization of the kit.  However, the agency clarified that the new requirements under Part 4 would apply to the kit if any of the products included in the kit are “repackaged, relabeled or otherwise modified for purposes of their inclusion in the kit.”  Id.  In that case, the kit would no longer be deemed a “convenience kit” and the CGMP requirements under the new rule for combination products would apply.

The newly added Part 4 says it does not change or alter the definitions or jurisdictional requirements applicable to combination products as set forth in 21 C.F.R. Part 3.

Manufacturers of combination products have six months to comply with the new rule, which will become effective on July 22, 2013.