The Code of Federal Regulations 21 CFR 3.2 (e) defines a combination product as a product comprised of any combination of a drug and a device; a biological product and a device; a drug and a biological product; or a drug, device, and a biological product. Below are frequently asked questions about FDA inspections of combination products.
Combination products are therapeutic and diagnostic products that combine drugs, devices and/or biological products. A helpful reference is FDA’s Office of Combination Product’s (OCP) website, which contains guidance as well as regulatory and jurisdictional information. Specific information on combination-product Current Good Manufacturing Practices (cGMPs) is located on OCP’s intranet (access limited to FDA employees only). Various offices within the Office of Regulatory Affairs (ORA) — specifically, the Office of Medical Device and Radiological Health Operations (OMDRHO), Office of Pharmaceutical Quality Operations (OPQO), Office of Biologics Program Operations (OBPO) — and the national Official Establishment Inventory (OEI) Coordinator work together, along with other FDA offices and centers (i.e., OCP, Center for Devices and Radiological Health (CDRH), Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER)), to ensure that:
- All combination-product firms are easily identifiable;
- There are trained investigators to perform inspections of these firms; and
- A compliance program is established to ensure consistency in conducting, reviewing, and classifying the inspections.
Frequently Asked Questions (FAQs)
- What is a combination product?
- How does ORA determine which ORA program is the lead for a combination-product inspection?
- Are there regulations specifically covering combination products?
- Will a Consumer Safety Officer (CSO) from each ORA program for a given combination product be required to participate in the inspection?
- Is a combination-product inspection eligible for pre-announcement?
- Can ORA perform a surveillance inspection of a combination product at a firm participating in the Medical Device Single Audit Program (MDSAP)?
- Is there a Compliance Program for combination products?
- How is it determined which Center and ORA program is the lead for a recall?
- What if I have additional questions related to combination products?
A combination product is comprised of two or more types of medical products (e.g., drug and device, drug and biological product, device and biological product, or all three types). There are three categories of combination products:
- Single-entity: The constituent parts are physically or chemically combined (e.g., a prefilled syringe, transdermal system, drug-eluting stent, or drug-coated catheter or implant)
- Co-packaged: The constituent parts are packaged together (e.g., a surgical or first-aid kit containing devices and drugs, a delivery device packaged with a container of drug product)
- Cross-labeled: The constituent parts are distributed separately (e.g., a light-activated drug product and a separately distributed laser activation device). Manufacturers of constituent parts of cross-labeled combination products need only comply with the requirements otherwise applicable to that type of product (see 21 CFR Parts 210 and 211 for a drug constituent part; and see 21 CFR Part 820 for a device constituent part).
See list of combination-product examples.
A combination product is assigned to an agency center that will have primary jurisdiction (i.e., the lead) for a combination product’s premarket review and regulation. Assignment of a combination product to a lead center is based on a determination of which constituent part makes the greatest contribution to the product’s effects (i.e., provides the “primary mode of action” or “PMOA”) of the combination product. For additional information on product assignment, see Frequently Asked Questions about Combination Products.
For a pre-approval inspection, the ORA program aligned with the lead center will be the lead on the inspection. For example:
- For CDRH-led combination products (e.g., Premarket Approval (PMA)), the ORA device program will be the lead, unless the device is approved under CBER’s authority.
- For CDER-led combination products (e.g., Abbreviated New Drug Application (ANDA), New Drug Application (NDA), CDER-led Biologics License Applications (BLA)), the ORA pharmaceutical program will be the lead.
- For CBER-led combination products (e.g., CBER-led BLA, CBER-led PMAs or 510(k)s), the ORA biologics program will be the lead.
For surveillance inspections, OMDRHO, OBPO, and OPQO work together to determine the lead. ORA’s decision on the inspection approach takes into account the risk associated with the product and the complexity of the manufacturing process.
Yes, 21 CFR Part 4 addresses the Regulation of Combination Product current good manufacturing practices and postmarketing safety reporting requirements. And, 21 CFR Part 3 describes product jurisdiction (i.e., how products are assigned to a lead center).
A guidance document for Current Good Manufacturing Practice Requirements for Combination Products is available. View other Combination Products Guidance Documents for more information.
ORA assigns as many qualified and trained staff as needed in consideration of the following:
- Product complexity and new technologies
- Risk associated with the product, complexity of the manufacturing process, and CSO expertise
- Requests by the CSO identifying the need for expertise from another program during an inspection (if this occurs, another CSO may join or otherwise support the inspection after it begins)
Pre-announcement typically applies to pre-approval inspections (PAI), consistent with the existing process for the ORA program aligned with the lead center. Pre-announcement will apply to surveillance inspections, as appropriate.
Yes, ORA can conduct surveillance inspections because, combination products are excluded from MDSAP.
The Office of Combination Products is working with ORA, CDRH, CBER, and CDER on a Compliance Program for inspections of CDER- and CDRH-led combination products.
The lead for the combination product is the lead for a product recall.
For questions related to the status of a product as a combination product or cross-cutting combination product policy questions, email firstname.lastname@example.org.