On January 22, 2013, the U.S. Food and Drug Administration (FDA) published its final rule implementing current good manufacturing practice (CGMP) requirements for combination products, which will take effect on July 22, 2013. FDA promulgated the rule in response to comments the agency received on its CGMP Guidance for Combination Products that described the need to develop a clear regulatory framework to account for the variety of combination products that can contain drug, device and/or biologic components.

As a starting point, the preamble states that the rule is “not intended to change existing CGMP requirements,” but to clarify that firms are to comply with CGMP requirements for combination products. The relevant CGMP requirements are still in effect for each constituent part of a combination product (e.g., 21 C.F.R. pts. 210, 211 for drugs; 21 C.F.R. pt. 820 for devices). FDA, however, noted that because of the overlap between drug CGMPs and device Quality System (QS) regulations, firms are currently required to comply with redundant standards, which is unnecessary and inefficient in certain situations, such as with constituent parts of single-entity and co-packaged combination products, which are defined under 21 C.F.R. § 3.2(e)(1), (2). These parts are not individually packaged and are not necessarily manufactured under a separate manufacturing system. Accordingly, the new rule develops practical applications for CGMPs for those types of combination products.

The general approach of the rule is "(1) [t]o demonstrate compliance with the specifics of all CGMP regulations applicable to each of the constituent parts included in the combination product or (2) to demonstrate compliance with the specifics of the drug CGMPs or the QS regulation, rather than both...." The second, streamlined approach would require some standards to be applicable regardless of whether the firm follows drug CGMPs or QS regulations to demonstrate compliance. In other words, if a firm chooses to follow drug CGMPs, they would be required to still comply with certain QS regulations that are absent from drug CGMPs, such as management responsibility, design controls and purchasing controls. Similarly, if a firm chooses to follow the device QS regulations, it would need to also follow certain drug CGMPs, such as requirements related to container closure systems, expiration dating and stability testing. In addition, any combination product containing a biological constituent must also satisfy 21 C.F.R. pts. 600-680. Moreover, compliance with 21 C.F.R. pt. 1271 would have to be met if the product contains human cells, tissues or cellular and tissue-based products (HCT/Ps).

The preamble notes that these CGMPs apply to all combination products regardless of when they were approved, a rejection of requests to apply these CGMPs only to combination products approved or cleared after the effective date of the final rule. FDA indicated that it will be issuing guidance on how to comply with the new rules and how to bring pre-manufacturing design control requirements into compliance for products already on the market. While FDA clarified that the rules will apply to specification developers and contract manufacturers, since both are engaged in “manufacturing” activities, FDA noted that these rules will not apply to manufacturers of the underlying components even if those components are later included in a combination product or constituent part of a combination product at another facility.

Some other highlights of the preamble include:

  • Drug containers and closures will continue to be regulated under 21 C.F.R. pts. 210 and 211; however, syringes do not constitute drug containers or closures and prefilled syringes are subject to this combination product CGMP final rule.
  • FDA declined to revise the definition of “constituent part” or to issue a definition for “component” in the final rule (noting that previously issued definitions exist and will continue to apply).
  • Not all of the combination product CGMPs will apply to all product types; e.g., only combination products with an over-the-counter (OTC) drug must comply with the tamper-evident packaging requirements. Similarly, not all combination product CGMPs will apply to all facility types as many, but not all, CGMP requirements are facility specific. Therefore, manufacturers must ensure compliance with all applicable provisions and requirements for their facilities.
  • FDA rejected one commenter’s proposal that the CGMP requirements applicable to a constituent part come into effect only after that constituent part has been formed. FDA noted that the “trigger” for compliance is whether a facility is conducting manufacturing operations that would be subject to the underlying CGMP requirements.
  • Out-of-specification (OOS) investigations for combination products should appropriately address FDA’s considerations for OOS investigations articulated in pts. 211 and 820, as applicable.
  • FDA will discuss batch release testing in future guidance.
  • FDA will also provide further information on compliance with stability testing and expiration dating requirements in future guidance. In other combination product news, FDA issued a Draft Guidance on Submissions for Postapproval Modifications to a Combination Product Approved Under Certain Marketing Applications (approved under a BLA, NDA or PMA). The Draft Guidance provides “tables” to help sponsors determine what type of submission to provide for changes to constituent parts of combination products. The comment period on the Draft Guidance will be open until April 22, 2013.

It would be prudent for companies manufacturing constituent parts of single-entity and co-packaged combination products to begin reviewing their existing CGMP programs to identify any gaps under FDA’s final CGMPs for combination products. Companies have until July 22, 2013 to establish and implement updated or new procedures, as applicable to their facilities.