United States: New FDA Compliance Program Details FDA Expectations For Inspections Of CDER- Or CDRH-Led Combination Product Manufacturers

On June 4, 2020, the U.S. Food & Drug Administration (FDA) implemented a compliance program (No. 7356.000), which explains how CGMP requirements are to be applied to combination products, the subject of a final guidance issued in January 2017. In particular, the new program document focuses on providing a framework for conducting inspections of manufacturers of single-entity and co-packaged finished combination products—led by either the Center for Drug Evaluation and Research (CDER) or the Center for Devices and Radiological Health (CDRH)—that include both (i) drug and device; or (ii) biological product and device constituent parts. While the compliance program applies to combination products regulated by CDER and CDRH, the final guidance referenced above was issued by OCP, ORA, CDER, CBER and CDRH. Therefore, ORA would likely apply the principles set forth in the compliance program to medical products where the lead agency is CBER.

Options for Demonstrating Compliance with Combination Products cGMPs

Combination products, as the program document explains, are products comprised of two or more different types of medical products (that is, a product that includes both a drug and a device, a drug and a biological product, a biologic product and a device, etc.). Examples of combination products include prefilled syringes and implants coated in antimicrobial drugs. A single-entity combination product is one in which all constituent parts are physically or chemically combined (e.g., a prefilled syringe). A co-packaged combination product, on the other hand, has its constituent parts packaged together but not already combined.

By way of background, a manufacturer can demonstrate compliance with cGMP requirements in two ways. First, the manufacturer can show compliance with all of the cGMP regulations applicable to each of the individual constituent parts included in the combination product. Second, manufacturers of combination products that include both (i) a drug; and (ii) a device or a biological product can take what FDA termed a "Streamlined Approach," laid out in the 2017 final guidance. Under the streamlined approach, manufacturers can demonstrate cGMP compliance concerning the combination product by demonstrating compliance with either (a) the drug cGMPs and certain select provisions of the device quality system (QS) regulation; or (b) the device QS regulation and certain select provisions of the drug cGMPs.

Guidelines for Inspectors in Evaluating Compliance

Planning

The compliance program contains a number of instructions about what sorts of information FDA inspectors should collect in connection with the combination product facility inspection. For example, FDA inspectors should confirm which type of cGMP operating system—the streamlined approach or the "full compliance" approach—the manufacturer has adopted. While most combination product manufacturers have opted to take the streamlined approach, inspectors should determine which approach the given manufacturer has adopted. FDA inspectors, according to the compliance program, should also request information about the facilities involved in the manufacturing of the combination product and which activities take place at which facilities. Finally, for pre-announced inspections, FDA inspectors should make sure to confirm with the facility personnel that the relevant documents (including those materials which demonstrate compliance) will be made available.

Instructions Based on Type of Inspections

FDA also provides instructions to inspectors based on the types of inspections taking place. For example:

For Pre-Approval Inspections, "the focus of the inspection should be on the combination product for which marketing approval is sought."

For Surveillance Inspections where inspectors conduct combination product coverage, inspectors should prioritize combination products that were recently approved, cleared or significantly changed (in design) or those that include complex technology or manufacturing considerations. The compliance program makes clear that abbreviated inspections should not be used if the facility has a history of noncompliance, there have been significant changes in management or organizational producers or new technologies or equipment requiring new expertise have been implemented since the prior inspection. Comprehensive (full) inspections will be performed under certain circumstances—"as resources permit" based on a risk-based determination—including for the first inspection of a combination product manufacturer.

For-Cause and Risk-Based Inspections are typically initiated at the request of the lead center for the combination product (here, either CDER or CDRH) and intended to address specific issues. As such, inspectors are advised that For-Cause Inspections may require additional expertise for more complex products, or when an inspection involves known defects that could pose a significant health hazard. Because of the tailored nature of these inspections, inspectors may not need to require coverage of all constituent parts of the combination product or cGMP requirements applicable to the combination product.

Finally, Post-approval/Postmarket Inspections may be conducted for combination products to ensure continued compliance—this includes monitoring changes in the manufacturing processes that occur after the product was initially approved. The program document explains that for this type of inspection of both CDER- and CDRH-led combination products, the coverage should include an assessment of the combination product—and not simply a constituent part—as may be appropriate. The program document provides an example: If process validation for the specific combination product is covered during the inspection, process validation for any device, drug or combination product manufacturing processes occurring at the facility should be assessed.

These tips and explanations provided above are not comprehensive; the full compliance program document contains instructions and evaluation guidelines based on types of combination products, inspections and manufacturers.

For More Information

If you have any questions about this Alert, please contact Frederick R. Ball, Patrick C. Gallagher, Ph.D., Justin M. L. Stern, any of the  attorneys in our Life Sciences and Medical Technologies Industry Group or the attorney in the firm with whom you are regularly in contact. 

Originally published by Duane Morris, on June 2020

Disclaimer: This Alert has been prepared and published for informational purposes only and is not offered, nor should be construed, as legal advice. For more information, please see the firm's full disclaimer.