FDA Issues Proposed Rule on cGMPs for Combination Products

September 29, 2009

By Jeffrey K. Shapiro
FDA’s Office of Combination Products (“OCP”) recently issued a proposed rule (74 Fed. Reg. 48,423) setting forth current good manufacturing practice (“cGMP”) requirements for combination products.    

The proposed rule does not independently establish new requirements; rather, it clarifies which set of existing cGMP regulatory requirements apply when drugs, devices, and biological products are combined to create a combination product.  Because FDA has separate cGMP regulations for each type of product, there has been confusion as to which regulations apply when the various products are combined.  The confusion has been particularly acute for combination products where the constituents are physically combined into a single entity or in co packaging.  In the proposed rule, FDA offers a streamlined option to avoid having to establish duplicative drug and device quality systems.

FDA describes the rationale for the proposed rule as follows (74 Fed. Reg. at 48,429):

The proposed rule has two related purposes. The first is to clarify the cGMP requirements that apply to combination products, and the second is to help ensure the consistent and appropriate application and enforcement of these requirements. Constituent parts and manufacturing practices vary among combination products; different cGMP requirements apply depending upon the constituent parts in the combination product and what manufacturing practices are used. Second, the proposed rule attempts to streamline the practical implementation of cGMP requirements for co packaged and single-entity combination products. 

FDA estimates that approximately 300 manufacturers of combination products will be affected by the proposed rule.  Id.

FDA’s Definition of Combination Products

A “combination product” is defined as a product comprised of two or more FDA regulated components. 

The regulated components could include drugs, biologics (including blood and blood components), medical devices or human cell and tissue products (called “361 HCT/Ps” or just “HCT/Ps”).  FDA regulates drugs and devices under the Federal Food, Drug, and Cosmetic Act (“FDCA”), biological products under section 351 of the Public Health Service Act (“PHS Act”), and HCT/Ps under section 361 of the PHS Act.

A combination product can be created either:

  • by physically combining during manufacture to create a single entity product or by placing two separate components in the same package (known as “co packaging”), or

  • by cross labeling, where the components are separately manufactured and packaged, but are expressly labeled for use with one another. 

The full regulatory definition of a combination product is set forth in 21 C.F.R. § 3.2(e)(1)-(4).

Which Current Good Manufacturing (CGMP) Regulations Apply?

FDA has cGMP regulations for drugs, biologics, medical devices and HCT/Ps:

  • cGMP for drugs (21 C.F.R. Parts 210 and 211),
  • cGMP for biological products, including blood and blood components (21 C.F.R. Parts 600 through 680),
  • Quality System Regulation (“QSR”) for medical devices (21 C.F.R. Part 820), and
  • Donor eligibility screening and Good Tissue Practice (“GTP”) for HCT/Ps (21 C.F.R. Part 1271).

A long standing question has been how these various regulations apply to combination products.  In 2004, the OCP issued a draft guidance on this question, but did not finalize it.  Now, the OCP has decided not to finalize the guidance, but rather, to create a new regulation that is similar in form to the approach proposed in the draft guidance.  Thus, the agency has issued a proposed rule, with a preamble that describes some of the commentary on the draft guidance.  Comments are due by December 22, 2009.

If the usual administrative process is followed, FDA will review the comments and issue a final rule, which may be somewhat revised as compared to the proposed rule, to address the various comments.  The agency proposes to make the final rule effective 180 days from the date of publication.  From an administrative law standpoint, the issuance of a regulation is a much more solid foundation for agency action than issuing non binding guidance.

The Proposed Rule

The proposed rule would create new 21 C.F.R. Part 4 in FDA’s regulations that would specify how to determine which cGMP requirements apply to a combination product.

Here is a brief section by section analysis of the proposed rule:

Sec.  4.1.  This section simply explains that the regulation establishes which cGMP requirements apply to combination products. 

Sec.  4.2.  This section defines the terms used in the regulation.

Sec.  4.3.  This section identifies the cGMP regulations that apply to the constituent parts of any combination product.  For example, FDA identifies the drug cGMP regulations (21 C.F.R. Parts 210 and 211) as applicable to drug constituents of a combination product.  As another example, FDA identifies the QSR for devices (21 C.F.R. Part 820) as applicable to device constituents of a combination product.

FDA takes the position that this section is all that is needed to determine cGMP requirements for combination products created by cross labeling.  The reason is that the constituent parts of such combination products are manufactured and packaged separately.  Therefore, it is fairly straightforward to apply the relevant cGMP regulation to each constituent part.

Sec.  4.4.  In general, FDA takes the position that the constituent parts of a combination product retain their regulatory status (as a drug or device, for example) even after they are combined.  Accordingly, the cGMP requirements that apply to each of the constituent parts continue to apply when they are physically combined in a single entity or co packaged product.

Thus, if a drug and device are combined in a single entity or via co packaging, then theoretically the manufacturer must comply with both the drug cGMPs for the drug constituent and the QSR for the device constituent.  Section 4.4(a) requires such duplicative compliance for each applicable cGMP regulation, unless the manufacturer elects to follow the streamlined compliance in section 4.4(b).  Such compliance might require the manufacturer to establish complete cGMP and QSR operating systems at a single facility.  Obviously, this requirement is onerous.

In section 4.4(b), FDA offers an option to help manufacturers avoid such duplicative cGMP operating systems.   A manufacturer may demonstrate an operating system in primary compliance with either the drug cGMPs or QSR for devices, and then need only demonstrate compliance with selected provisions from the other regulation.  FDA specifies these provisions in section 4.4(b) based upon its analysis as to areas in which there is not an overlap. 

For example, a manufacturer who demonstrates primary compliance with the drug cGMPs must still show compliance with the design controls provision in the QSR (21 C.F.R. § 820.30) to the extent it is applicable, based upon FDA’s view that there is not a comparable provision in the drug cGMPS.  But the manufacturer avoids having to operate under both cGMPs and QSRs for the same product.

If there is a biological component, the manufacturer would still have to show compliance with the cGMPs for biologics (21 C.F.R. Parts 600 through 680).  If there is an HCT/P component, the manufacturer would still have to show compliance with donor screening and GTPs (21 C.F.R. Part 1271).

Section 4.4(c) prescribes that when manufacture of a constituent part occurs at a separate facility, the cGMP requirements for that constituent part apply, and the streamlined approach is not available. 

Under section 4.4(d), however, the streamlined approach is available whenever the constituent parts arrive at the same facility or are being processed there.

Section 4.4(e) indicates that the regulations in the proposed rule do not supersede the specific cGMP regulations whenever there is a conflict.