FDA Issues Draft Guidance on Combination Product Manufacturing

Two years after issuing a final rule on current good manufacturing practice (cGMP) requirements for combination products, FDA has announced the availability of draft guidance that explains the final rule and further clarifies how manufacturers can comply with cGMP requirements. Following the rule’s issuance, industry requested additional guidance from FDA about the rule’s implementation, and FDA promised to provide such guidance. FDA has now made good on that promise. The draft guidance reviews the definition of a combination product and reiterates that the final rule on cGMP requirements applies to all combination products. Accordingly, the final rule applies to: (1) a “single entity” combination product, meaning a product comprised of two or more regulated components, that are physically, chemically, or otherwise combined or mixed and produced as a single entity (e.g., a prefilled syringe); (2) a “co-packaged” combination product, meaning two or more separate products that are packaged together as a unit and comprise drug and device, device and biological, or biological and drug products (e.g., a surgical kit); and (3) a “cross-labeled” combination product, meaning a drug, device, or biological product that is intended for use only with another separate drug, device, or biological product, where both are required to achieve the intended use, indication, or effect (e.g., a light-emitting device and a light-activated drug). Manufacturers of drug-device single entity or co-packaged combination products can demonstrate compliance with the cGMP requirements in two ways. First, manufacturers can demonstrate compliance with all cGMP regulations and Quality System Regulations (QSR) applicable to each of the constituent parts of the combination product. Alternatively, a manufacturer can demonstrate compliance via a streamlined approach, either by demonstrating compliance with the drug cGMPs and a subset of device QSRs (a cGMP-based streamlining approach) or by demonstrating compliance with device QSRs and a subset of drug cGMPs (a QS regulation-based streamlining approach). The guidance emphasizes that, should a manufacturer prefer the streamlined procedure, the manufacturer is not obligated to implement the streamlined approach for the constituent part that provides the primary mode of action (PMOA) of the combination product. For example, even if the drug constituent part of the drug-device combination product provides the PMOA, the manufacturer is still free to implement the QS-regulation based streamlining approach. The draft guidance also states that FDA intends to apply the same policies when inspecting combination products, regardless of the manufacturer’s compliance approach, but urges manufacturers to clearly identify in their premarket submissions and indicate at the beginning of an inspection if they are operating under a streamlined procedure (and if so, which one).