FDA Inspection Compliance Program for Combination Products

Combination products are products that are subject to different sets of regulations. Such products may, for example, consist of a drug and a medical device, or a biological component may be added. Because of the different product components, special inspection procedures are required.

In the USA, these products are regulated by independent GMP rules. However, the regulations of the individual components are still relevant. These are, for example, 21 CFR 211 for drugs and 21 CFR 820 for medical devices. These different sets of regulations are also assigned to different "centers" in the USA. For drugs, the Center for Drug Evaluation and Research (CDER), and for medical devices, the Center for Devices and Radiological Health (CDRH). In the event of an inspection, an organised approach must be taken here. The FDA therefore issued a compliance program that describes inspections of combination products last year.

The program is relatively extensive with a total of 46 pages and 3 appendices. The focus of the program is on packaging units ("single entity") and enclosed combination products, consisting of drug and medical device or biological product or device constituent parts. The program begins by describing how it is to be implemented. A separate chapter is then dedicated to the different types of inspections:

  • Pre-approval inspections (PAI)
  • Surveillance inspections
  • Post-approval/Post-market inspections
  • Inspections due to special situations

For the first two types of inspections, tables show what FDA should look for in an inspection of combination products, based on the regulations selected as the basis (21 CFR 211 for drugs or 21 CFR 820 for medical devices). 

Other chapters cover sampling, expectations for analytics, an administrative strategy, and elaborations on the responsibilities of each "center."

With a total of 20 pages, the final 3 appendices are very comprehensive. Appendix A goes into great detail about the requirements in 21 CFR 211, starting with a QM system based on 21 CFR 820. Addressed are

  • 21 CFR 211.84,
  • 21 CFR 211.103,
  • 21 CFR 211.132,
  • 21 CFR 211.137,
  • 21 CFR 211.165,
  • 21 CFR 211.166,
  • 21 CFR 211.167

and

  • 21 CFR 211.170

which are to be specifically verified during an FDA inspection of a manufacturer of combination products.

Appendix B, similar to Appendix A, addresses the requirements in 21 CFR 820 in detail, starting from a QM system based on 21 CFR 211. Addressed are

  • 21 CFR 820.30,
  • 21 CFR 820.50

and

  • 21 CFR 820.100

which are to be specifically verified during an FDA inspection of a manufacturer of combination products.

Appendix C includes definitions and acronyms.

You can view the entire document on the FDA website.

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