Adonna Blasko, Marketing Manager, Pilgrim Quality Solutions
Combination products bridge medical devices, pharmaceuticals, and biotech products. Each of these areas has its own respective pre and post-market regulatory requirements, making combination products all the more complex to juggle while adhering to FDA requirements and guidance. (21 CFR parts 3 and 4, 210/211, 820, and 606)
I recently attended a session presented by Frank Davis, Regulatory Director, Pharmaceuticals with RCA Associates where he covered this topic extensively for a group of SmartSolve LifeScience EQMS users and Pilgrim employees. The ideas presented below are snippets from his session.
When it comes to how to position your combination product to the FDA when seeking market approval, many things to consider are common sense. Here are 3 key QMS considerations for combination products.
What don’t you know that you’ll need to know? Identify product development precursors.
Device developers of a drug product may not realize key considerations in product development. This includes how drugs are impacted by types of containers or how the device and drug or biologic will interact overtime.
Likewise, drug manufacturers may not consider usability factors that are common to device companies. For example, would a glass syringe work for a drug used in an emergency situation, or would the syringe potentially break in the heat of the moment? Adding a new part or component to your new product development process means you need to learn what you don’t necessarily know already.
Another example, during Frank Davis’s Fusion session, a question and brief discussion on whether using a drug or component with a monograph was enough to count for stability testing. This question shows something a device manufacturer may be inclined to assume since the drug component has already gone through extensive testing to receive a USP monograph. But the answer of course, is no.
A monograph is a written standard from the United States Pharmacopeia to describe a finished drug, a drug ingredient, or a food chemical.
When submitting a combination product for premarket approval, using a drug component with a USP monograph is not enough to count for premarket development testing, nor for stability testing requirements once your combo product is well into production.
Why not? Well, USP’s role typically begins after FDA approvals. When an existing drug with a USP monograph is part of a combination product, there are other factors to consider. Such as, does the drug interact with its container? Does the drug lose water overtime, and therefore become more potent within the proposed device portion, or does it lose efficacy? These examples illustrate reasons explicit stability testing for the drug and its device or bio component must be conducted prior to FDA approval of a combination product, regardless of the drug’s prior history.
Are you down with OCP? Designate your PMOA.
The FDA’s Office of Combination Products plays a critical role in getting any combination product to market. OCP will review the application, assign the review board, designate the lead center (CDRH, CBER, CDER), and assign the primary mode of action (PMOA).
The PMOA is the action that is “expected to make the greatest contribution to the overall intended therapeutic effects of the combination product” according to the guidance.
Positioning your PMOA is limited to a 15 page document called a Request for Designation that explains your product’s intended use, how it works, and your recommendation for assignment of a lead center. Although your application will ultimately go to CDRH, CDER, or CBER (depending on the PMOA), the OCP plays the critical role of determining the lead center. How you position your PMOA and describe your product in the Request for Designation is key.
Again, this is common sense that you’d want the lead center to be that which you are most familiar, be it CDRH for devices or CDER for pharmaceuticals. Thinking through and positioning your product’s PMOA to the OCP can help simplify your application reviews, your quality system reviews, and your overall processes in the long run by positioning your product and your quality system for success in meeting all applicable requirements.
This leads us perfectly into the next tip, , the third of our QMS considerations for combination products, as once the PMOA is set, you must adapt your quality system documents and processes to include appropriate requirements for each product type (e. g. drug, device, and/or biotech and/or device).
More GMPs and SOPs? The answer is always: document; document; document.
“The lead center for premarket review of the combination product also has the lead for ensuring compliance with CGMP regulatory requirements.” II C Draft Guidance, Current Good Manufacturing Practices for Combination Products.
Whether your PMOA falls in the drug or device category, you will have new additions to your quality management system requirements to consider the secondary industry (pharma if your PMOA aligns with CDRH / device if your product is assigned to CDER , etc.). Your device company will need to speak cGMP for drug and vice versa. There will need to be a language translation so that both sides of the combination product can live harmoniously.
For example, if you consider a drug-device combination product, you will need to update SOPs on investigating product complaints, reporting adverse events (eMDR), and more.
Likewise, if your PMOA is the device, you will need your quality system to meet 21 CFR Part 211 requirements including testing, yield calculations, expiration dating, and reserve samples to name a few. In addition, a new SOP to detail your sampling plan for stability testing of the drug portion.
Great, but what exactly does this mean for you? According to Deb Kacera, Pilgrim’s in-house regulatory expert, “companies will have to learn how to co-exist across the combination product chasm, to understand how each speak, breakdown regulatory silos.”
From the quality perspective, when you’re continuing to manufacture and support the product, you have to share the GMP requirements. Therefore the quality system needs to share.
Thinking through these key pieces ahead of time can help your organization avoid missteps and get your combination product to market sooner. Although this is high-level information, it should help you get your wheels spinning if you’re working toward marketing a combination product and keeping your QMS compliant.
Tips and QMS considerations for combination products? Please share.
If you are looking to venture into combination products or have successfully done so, please share your tips and QMS considerations for combination products in the comments below.
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