Kari Miller, Regulatory and Product Management Leader, Pilgrim Quality Solutions, an IQVIA company
The road to regulatory compliance for Combination Products has been a long one, and we’ve not yet arrived at our final destination.
At a recent AdvaMed Workshop in Washington DC, Pilgrim Quality Solutions, alongside FDA experts, had the privilege to present a Past, Present and Future perspective on Combination Products, diving into topics such as Product Registration (PMA, 510K); the De Novo pathway for Combination Products; Requests For Designation (RFD); Primary Mode of Action (PMOA); Labeling and Cross Labeling of Combination Products; CGMP; Adverse Event Reporting and Post Market Safety Reporting; and, Combination Product Inspections and Quality System Regulations.
The workshop demonstrated how far the industry has come, and yet, how far we still have to go. Attendees came armed with questions from myriad angles, and many of their questions were answered with: “That is decided on a case-by-case basis.” While combination products have been around awhile, innovation is taking place in this sector, and in response, the FDA has evolved as the Combination Products market evolves. This three-part blog series will look at the past, present, and future of combination products.
Defining a Combination Product
Before looking at the history of combination products, where they are today and where they’re headed, it is important to understand what constitutes a “Combination Product.” A true combination product is a compound of two or more different products, called constituent parts, that are different product types, and can be combined in multiple ways. For more detailed information on the definition of combination products, reference 21 CFR Part 3.2.
Combinations of different products (constituent parts)
- Drug and Device
- Drug and Biologic
- Device and Biologic
- Drug and Device and Biologic
How constituent parts are combined
- Physically or chemically into a single-entity
- Sold separately – labeled for use together as both are required to achieve the intended use, indication, or effect (referred to as Cross-labeled products)
Combination products are not combinations of like products: drug and drug; device and device; biologic and biologic; food and drug/device/biologic; or, cosmetic and drug/device/biologic. So, a box of bandages of different sizes, co-packed or kitted together, is not a combination product. Neither would a kit with aspirin and a small bottle of water be considered a combination product. One would think with clarification on what constitutes a true combination product, it would be simple to determine what is and what isn’t a combination product, and in many cases it is; however,there are still many cases where it is not clear a clear-cut designation. Cross-labeled products often fall into this category, as they are the least clearly defined combination product types.
The History of Combination Products
The first combination products to fall under FDA regulatory authority were developed in the 1970s and included radio-biologics and in vitro diagnostics. Over the next two decades, combination products were regulated by the Agency on an ad hoc basis, which included the use of inter-agency agreements. During the 1990s, the Safe Medical Devices Act (SMDA), which included a provision for the regulation of combination products, was adopted. It designated that the FDA have primary jurisdiction. It’s also important to note that 1991 is when the product jurisdiction regulation, 21 CFR Part 3 (mentioned above) was introduced. Eventually this regulation fell under the FDA Modernization Act (FDMA), which was fully enacted in 1997. The FDMA addressed pre-market approval, notification, classification, labeling, tracking, surveillance, and establishment registration, to name a few of the areas of focus.
In 2002, the Office of Combination Products (OCP) was established as required by SEC 204 of the Medical Device User Fee and Modernization Act of 2002 (MDUFMA).
By 2002, the FDA had been engaged for over two decades in trying to regulate in a methodical and thorough manner, products that weren’t just devices, and they weren’t just drugs, but truly combinations. Therefore, in 2002 the Office of Combination Products (OCP) was established. With the OCP established, in 2004 we saw the draft cGMP for Combination Products and the Final Rule issued in 2013. Combination Products now had their own Current Good Manufacturing Practice Guidance with 21 CFR Part 4.
The Evolution of cGMP for Combination Products
Prior to the issuance of the final rule, cGMPs were in place for devices, drugs, biologics, and blood and tissue, but not for combination products, nor was there any guidance on how to apply cGMPs to them. This meant that organizations were left to their own devices (no pun intended). So it should be no surprise that organizations at which drugs were the primary competence were complying with 21 CFR Parts 210/211, and those organizations whose primary competence was devices referenced Part 820, etc. However, while there are commonalities between the cGMPs, they are not all the same. Each cGMP was developed to address the specific characteristics of the products to which they pertain.
With each cGMP being written to address the characteristics of the devices they serve, when a manufacturer of combination products is using either 210/211 or 820, there is high potential for gaps to exist in good manufacturing practices. In fact, as the OCP takes root, and as each of the centers — CDRH, CDER, and CBER — gain experience in inspecting combination products, it is going to be critical for organizations to explore, assess, and adjust their cGMP practices for combination products if they haven’t already.
To aid in that process, part two of this blog series, Combination Products: Past, Present and Future, will address the current state of combination products, including a look at the overlap and differences in cGMP, and examine the areas of weakness in Quality Management Systems that are based solely on either 210/211 or 820. Additionally, we’ll review how jurisdictional lines are established based on primary mode of action, and how 21 CFR Part 4 is being enforced, along with some key concepts used by the FDA in the regulation of combination products. Finally, in part three of this blog series, we’ll address the impact of the 21st Century Cures Act on Combination Products.
We look forward to your comments and feedback.
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