27 June, 2017 by Dr. Karl M. Kapp, Department of Instructional Technology, Bloomsburg University
At the beginning of this year, the FDA & issued final guidance for Current Good Manufacturing Practice (CGMPs) Requirements for Combination Products. This guidance is for therapeutic and diagnostic products that combine drugs, devices, and/or biological products. This guidance has become increasingly necessary due to the rapid pace of technological advances in the life science industry where product types continue to merge and blur lines of traditional separation.
As the FDA has indicated, the differences in regulatory pathways for each component can impact the regulatory processes for all aspects of product development and management, including preclinical testing, clinical investigation, marketing applications, manufacturing and quality control, adverse event reporting, promotion and advertising, user fees, and post-approval modifications.
The growing list of combination products includes such examples as the combination of surgical mesh and antibiotic coatings, an absorbable collagen sponge with genetically engineered human protein and even a drug or biological product packaged with a delivery device.
The assignment of a combination product to a lead center is based on a determination of which constituent part provides the Primary Mode of Action (PMOA) of the combination product. A PMOA is defined in the Federal Registry as the single mode of action of a combination product that provides the most important therapeutic action of the combination product.”
As an example, if the PMOA of a device-biological combination product is attributable to the biological product, the Agency component responsible for premarket review of that biological product would have primary jurisdiction for the combination product.
However, in some cases, the PMOA can be difficult to determine or the combination product may have two independent modes of action and neither are subordinate to the other. In these situations, the final rule describes an algorithm the FDA will follow to determine the center assignment. The algorithm directs a center assignment based on consistency with other combination products raising similar types of safety and effectiveness questions, or to the center with the most expertise to evaluate the most significant safety and effectiveness questions raised by the combination product.
It is important to note that the FDA has indicated that the lead center for premarket review of the combination product has the lead for ensuring compliance with CGMP regulatory requirements. Regardless of the PMOA, Agency components will coordinate as appropriate to enable efficient, effective CGMP regulatory oversight, including appropriate CGMP inspections.
To demonstrate compliance with applicable CGMPs for a combination product, the FDA has indicated that manufacturers must demonstrate compliance with each applicable CGMP requirement for constituent parts and combination products. The FDA has also indicated that if a streamlined approach is used, the manufacturer must demonstrate compliance with all of the relevant provisions of either the drug CGMPs or device QS regulation, and the provisions specified in 21 CFR 4.4(b) for the other set(s) of CGMP requirements applicable to the product.
Additionally, any facility that manufacturers a constituent part of a combination product or a complete combination product must be compliant with the CGMP requirements applicable to each manufacturing process that occurs at that specific facility. The combination product owner (the holder of the marketing authorization for the product) retains overall responsibility for the product, even if the owner is not directly engaged in its manufacture.
Karl M. Kapp, Ed.D.
is a professor of Instructional Technology in Bloomsburg University’s Department of Instructional Technology in Bloomsburg, PA. He has been working within the life sciences industry for over 20 years helping professionals understand the convergence of technology, science and learning. He spends a great deal of his time writing, consulting and speaking with pharmaceutical, insurance, biotech and medical device companies. He sits on the advisory board of several technology companies. Karl has spoken at dozens of industry events and has been a keynote speaker at the industry’s professional association for pharmaceutical, biotech, medical device trainers and educators called LTEN. Karl is a TEDx speaker who has presented internationally at life science events and for private organizations.
He is currently working on a grant with the National Institute of Health (NIH) and is the author of six books.