Yesterday, FDA issued two new items to help clarify combination products: 1) a Final Rule published in the Federal Register entitled, "Current Good Manufacturing Practice Requirements for Combination Products" and 2) a Draft Guidance entitled, "Guidance for Industry and FDA Staff:
Submissions for Postapproval Modifications to a Combination Product Approved Under a BLA, NDA, or PMA", also announced in the Federal Register.
The Final Rule is intended to clarify which good manufacturing practice ("CGMP") requirements apply when drugs, devices, and biological products are combined to create combination products. The Rule also provides a mechanism that FDA describes as "transparent and streamlined regulatory framework" for companies to use when demonstrating compliance with CGMP requirements for "single-entity" and "co-packaged" combination products. "Single-entity" combination products are two or more regulated components, e.g., drug/device, biologic/device, drug/biologic/device, which are physically, chemically, or otherwise combined or mixed and produced as a single-entity. Two or more separate products packaged together in a single package or as a unit and comprised of two or more regulated products is a "co-packaged" combination product. The Final Rules started as a Draft Guidance announced on October 4, 2004 (69 FR 59239), entitled "Current Good Manufacturing Practices for Combination Products." Based on comments and FDA's own internal review, FDA decided that "rulemaking was warranted" and issued Proposed Rules on September 23, 2009 (74 FR 48423).
The concept behind the CGMP Rule is simple for parts that are separately manufactured and marketed: each of the constituent parts of a combination product are subject only to the CGMP regulations applicable to that part, e.g., drug, biologic, or device. The two categories of combination products mentioned above, however, "single-entity" and "co-packaged" are slightly different due to the possibility for overlapping CGMP requirements for the different regulated components. Companies have two basic options for these types of products: 1) demonstrate compliance with the specifics of all CGMPs to each of the parts, or 2) demonstrate compliance with the specifics of either the drug CGMPs at 21 C.F.R. Parts 210 and 211 or the quality system ("QS") regulation at 21 C.F.R. Part 820 rather than both, for drug/devices under certain conditions. For combination products including biologics, the specific regulations are 21 C.F.R. parts 600 through 680, and for product including any human cell, tissue, and cellular tissue-based products, the regulations are 21 C.F.R. Part 1271.