FDA recently published the long awaited proposed rule on good manufacturing practices for combination products. The proposed rule is very similar to the Current Good Manufacturing Practice Draft Guidance that has been posted on the Office of Combination Products’ Web site for the last five years, but contains additional information that may be useful when designing good manufacturing systems for combination products.

As with all proposed rules, FDA is seeking your comments. This is your opportunity to influence the agency's approach on this important issue. Comments may be submitted until December 22, 2009. A copy of the proposed rule, containing instructions for submitting comments can be obtained at: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a29c7a&disposition=attachment&contentType=html.

The proposed rule is based on the idea that components of a combination product retain their status as a drug, device or biologic throughout the manufacturing process and after approval. Therefore, the drug Current Good Manufacturing Practice (CGMP) regulations (21 CFR Parts 210 and 211) apply to drug components of combination products; the device Quality System (QS) regulations (21 CFR Part 820) apply to device components of combination products. The additional good manufacturing requirements imposed on biological products (21 CFR Parts 600 through 680), and on human cells, tissues, and cellular- and tissue-based products (HCT/P's; 21 CFR Part 1271) apply where appropriate. In short, all combination products are subject to at least two sets of good manufacturing requirements.

This may not be as burdensome as it sounds. The proposed rule contains two approaches to meeting this requirement. Under the first approach, manufacturers may design a process that meets all the specifics of all relevant good manufacturing practice systems.

Alternatively, manufacturers may use the "streamlined" approach. The streamlined approach is based on observation that with a few specific exceptions, the drug cGMP regulations and the device QS regulations are really very similar. According to the proposed rule, compliance with one system will satisfy almost all requirements of the other system. The proposed rule identifies eight provisions of the drug cGMP regulations that would not be met by complying with device QS regulations. Similarly, the proposed rule identifies six provisions of the device QS regulations that would not be met by complying with the drug cGMP regulations. Manufacturers can meet the requirements of both systems by meeting the requirements of one system, plus the identified additional requirements from the other system.

The proposed rule contains several helpful illustrations. For example, if the drug and device components of a combination product are manufactured at different facilities, then before the components are combined or co-packaged, each component should be manufactured according to its usual good manufacturing practice scheme. Once the components are brought together for combining or co-packaging, a manufacturer may comply with the specifics of all requirements of all relevant current good manufacturing systems, or it may choose a "streamlined" approach. Under the streamlined approach, one manufacturing system (drug or device) would be selected, and the manufacturer would also be required to implement the identified additional regulations from the other scheme.

In an inspection, if a manufacturer chooses to use the streamlined approach by implementing the device quality system regulations supplemented by specific drug cGMP's, then the inspection would focus on compliance with the QS regulations and the specified drug cGMP's. Similarly, if the manufacturer implements the drug cGMP's with the addition of specified device QS regulations, the inspection would focus on the drug cGMP's and the additional specified device QS regulations. In either event, by complying with these regulations, the manufacturer would be in compliance with both device QS regulations and the drug cGMP regulations.

Manufacturers responsible for combining or co-packaging combination products who choose to use a streamlined approach will have to consider whether to comply with all the requirements of drug cGMP regulations or device QS regulations. There may be many factors that go into this decision. You may wish to consult with appropriate advisors to develop the most appropriate streamlined system.