On January 22, 2013, the Food and Drug Administration (FDA) issued a final rule on current good manufacturing practice (CGMP) requirements applicable to combination products. The purpose of the rule is to clarify which CGMP requirements apply when drugs, devices, and biological products are combined to create combination products. In addition, the rule sets forth a regulatory framework for firms to use when demonstrating compliance with CGMP requirements for “single-entity” [a product comprised of two or more regulated components, (e.g., drug/device, biologic/device) that are physically, chemically, or otherwise combined or mixed and produced as a single entity] and “co-packaged” (two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products) combination products.

The regulated entities must become compliant under the new rule before its effective date of July 22, 2013. The final rule emerges from the FDA’s draft guidance issued in October 2004 entitled “Current Good Manufacturing Practices for Combination Products” and the proposed rule issued on September 23, 2009. This final rule will apply to both existing and future combination products. The FDA acknowledges that the CGMP requirements for constituent parts of a combination product that are manufactured and marketed separately are fairly straight forward. Such constituent parts are subject only to the CGMP regulations applicable to that type of constituent part (e.g., drug or device). Consequently, the rule expressly addresses CGMP requirements applicable to single-entity and co-packaged combination products.

The final rule offers two options for demonstrating compliance with the CGMP requirements to a co-packaged or a single-entity combination product:

  1. To demonstrate compliance with the specifics of all CGMP regulations applicable to each constituent part included in the combination product
  2. To demonstrate compliance with the specifics of either the drug CGMP or the QS regulation, rather than both, when the combination 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 included 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 included any human cell, tissue, and cellular and tissue-based products (HCT/Ps), the regulations in part 1271 (21 CFR part 1271) would apply. The rule further states that in the event of a conflict between CGMP requirements applicable to a combination product, the regulations most specifically applicable to the constituent part at issue shall prevail.

The FDA received several comments on the proposed rule from regulated entities, trade associations, and individuals. In response to the comments, the FDA discussed its position (among other things) on the development of written procedures and maintenance of records to demonstrate compliance under the rule and applicability of the rule (among other things) to: different stages of production, investigational products, products that produce another product at site of care (device producing drug), convenience kits, drug containers and closures, and off-the-shelf devices. We have reviewed the final rule and are analyzing it for our different clients’ needs and particular circumstances. Stay tuned for our further discussion as we continue to analyze the rule and crease-out issues to make our clients compliant before July 22, 2013.