Manufacturers have been given direction by the U.S. Food and Drug Administration on how they can best comply with the agency’s current good manufacturing practice (CGMP) requirements for combination drug/device products.
In a Final Notice published in the Federal Register on Sept. 13, “Alternative or Streamlined Mechanisms for Complying With the Current Good Manufacturing Practice Requirements for Combination Products,” the FDA explains how companies can use such mechanisms to meet regulatory obligations. It also describes how firms can interact with the agency on the topic.
The Notice satisfies a mandate found in the 21st Century Cures Act of 2016, which directed the FDA to develop a list of mechanisms for complying with the agency’s CGMPs for pharmaceuticals under 21 CFR, Part 211, and its Quality System Regulation (QSR) for medical devices under 21 CFR, Part 820. It also finalizes a proposed list the agency put out as a Federal Register Notice in 2018.
Kim Trautman, MEDIcept’s Managing Director and VP, says the Notice doesn’t change the agency’s requirements around combo products under 21 CFR, Part 4, the 2013 rule that regulates them.
Rather, the Notice “simply discusses how to practically approach some specific requirements called out in the streamlined approach in a fashion that makes good science sense without undue burden or unneeded expensive testing of the entire combination product in certain circumstances,” Trautman explains.
The FDA says these mechanisms can be used by combo product companies to demonstrate compliance:
- 211.165, “Testing and Release for Distribution”: Use of samples that aren’t finished combo products, but are representative of the finished product;
- 211.166, “Stability Testing”: Use of bracketing and matrixing approaches to stability studies for combo products;
- 211.167, “Special Testing Requirements”: Defining “batch” based on the drug constituent part rather than the finished combo product for purposes of special testing requirements for pyrogens and endotoxins;
- 211.170, “Reserve Samples”: Keeping reserve samples that are representative of the finished combo product; and
- 820.30, “Design Controls”: Using existing pharmaceutical development practices and documentation that align with design control principles and requirements.
A sixth mechanism on the FDA’s list is for the exemption of combo products from Part 820 requirements. This can happen when the device constituent part of a product is already exempt from the QSR.
While these mechanisms have been given the thumbs-up by the FDA, the agency says in its Notice that makers of combo products should nevertheless “consider the suitability of an approach in the context of their product and manufacturing process.”
Further, companies can choose to use a different type of mechanism than those on the FDA’s list if it works best for them. “Additional approaches may be permissible … for evaluation on a case-by-case basis for a particular product and CP [combination product] manufacturer,” the Notice says. The agency adds that it will use a risk-based approach to evaluate “alternative or streamlined mechanisms for ensuring the quality of combination products.”
The FDA also says it will add additional mechanisms to its list in the future if necessary.
For each mechanism, makers of combo products “should consider what documentation would be sufficient to support that the mechanism, including the specific approach for implementing it, assures appropriate control of the manufacture of the combination product to ensure safety and effectiveness,” the agency says.
MEDIcept’s Kim Trautman says examples given by the FDA in its Notice are “practical discussions in how a manufacturer can meet the requirements of the GMP streamlined approach in a sensible scientifically sound manner – there are no changes in the requirements or fundamental FDA expectations. The Federal Register document provides clarifying discussions and examples while highlighting the need for manufacturer communication with FDA when there are scientific questions on how to comply with FDA requirements.”
In its Notice the FDA recognizes that there will be times when manufacturers of combination products must interact with the agency, including when a manufacturing change is made, or when a company needs to discuss using of any of the mechanisms listed above.
Combo product makers are “encouraged to interact early with FDA on any such contemplated use of alternative or streamlined CGMP mechanisms,” the agency says.
Such interactions include pre-submissions and meetings, pre-market review, and post-market supplements or notifications. Meanwhile, for its part, the FDA says it “may review information from a CP manufacturer” during those types of interactions, as well as during facility inspections.
“FDA may determine whether the data and rationale presented by a CP manufacturer for a particular mechanism are sufficient to demonstrate that the mechanism, as proposed or implemented, is acceptable,” the Notice says. “If the agency finds the approach insufficient, FDA intents to provide the scientific and/or regulatory basis for this determination.”
If you’re stumped by the FDA’s CGMP requirements for combination drug/device products, let MEDIcept’s team of longtime industry experts help. Learn more by visiting www.medicept.com or emailing firstname.lastname@example.org.