The Food and Drug Administration (FDA) has just issued its long-awaited Draft Guidance on Current Good Manufacturing Practice (CGMP) Requirements for Combination Products. According to the FDA, the Draft Guidance (which is 46 pages long) “describes and explains” the final rule on CGMPs that was published in the Federal Register two years ago — on January 22, 2013.

“Combination products” are products composed of any combination of a drug, a device, or a biological product, and include the following:  

  1. Products that are physically, chemically, or otherwise combined or mixed and produced as a single entity;
  2. Two or more separate drugs, devices, or biological products packaged together in a single package;
  3. Two or more such products packaged separately that, according to an investigational plan or the proposed labeling, are intended for use only with an approved, individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where, upon approval of the proposed product, the labeling of the approved product would need to be changed; or
  4. Any investigational drug, device, or biological product packaged separately that, according to its proposed labeling, is for use only with another product where both are required to achieve the intended use, indication, or effect.  

In the Draft Guidance, the FDA “clarifies” that the CGMP requirements that apply to each of the constituent parts of the product apply to the combination product as a whole as well. But the “clarification” here is that the FDA is now offering two options to meet these requirements:  

  1. Under the first option, manufacturers can demonstrate compliance with both the drug and device CGMP regulations applicable to each of the constituent parts.
  2. Under the second option (which will no doubt be adopted almost universally), manufacturers can implement a “streamlined approach,” demonstrating compliance with either the drug CGMPs or the device CGMPs (as set forth in the Quality System Regulation [QSR]) along with specified provisions from the other set of CGMP requirements.  

The second option is a bit complex but, in brief, the FDA is saying that a manufacturer can meet its CGMP requirements if it demonstrates compliance with either of the following:  

  1. Full compliance with the drug CGMPs and compliance with the following provisions of the Device QSR:  management responsibility; design controls; purchasing controls; corrective and preventive action; installation; and servicing; or
  2. Full compliance with the device QSR and compliance with the following provisions of the drug CGMPs: testing and approval or rejection of components, drug product containers, and closures; calculation of yield; tamper-evident packaging requirements for OTC drugs; expiration dating; testing and release for distribution; stability testing; special testing requirements; and reserve samples.  

For product approval purposes, a combination product is assigned to a FDA Center that will have primary jurisdiction (i.e., the lead) for that product’s premarket review and regulation. However, the FDA is now saying that, for purposes of compliance with CGMPs, a manufacturer adopting the streamlined approach can choose either set of requirements, not just the set of requirements that would be applicable to the lead Center.

The Draft Guidance also discusses combination products that contain a biological product or a Human Cells, Tissues, and Cellular and Tissue-Based Product (HCT/P) and requires that a manufacturer must comply with the requirements that would apply to the biological product or the HCT/P if it were not part of a combination product.