What should U.S. based pharmaceutical companies consider when seeking to commercialize their combination products in Europe?
It should be understood that the term “combination product” can be subject to misinterpretations in Europe. Unlike in the U.S., where the FDA clearly defines what a combination product is in 21 CFR 3.2(e), Europe has no such clear definition. The term is applied when referring to products having both a device and a drug element. In Europe, such combinations are regulated as either a medical device or a medicinal product, with the regulatory route being determined by the principle mode of action of the product.
What are the regulatory differences between the US and EU for combination products?
I will begin by pointing out the similarity that in both the US and EU, the regulation of drug-device combinations is an implicit part of a legislative framework. The primary difference is the way the products are categorized for review by the relevant divisions of the regulatory agencies. In the US, the FDA enacted a system in 2002 when it established the Office of Combination Products to facilitate the review of these products amongst the different FDA centers (CBER, CDER and CDRH). Generally, the primary mode of action for the intended purpose of the device will determine which center takes the lead on the review process. In the EU, however, these products are categorized as either a drug delivery device, or a device incorporating medicinal substances with ancillary action, and the review is conducted as either a medicinal product or as a medical device respectively.
What are the challenges for combination product manufacturers?
Most manufacturers have a biased familiarity with the processing and regulations of one constituent of a combination product over the other. For example, pharmaceutical companies are often more familiar with the requirements of drugs than devices, and vice versa. When the two are brought together, however, each constituent retains its regulatory status (either as a drug or device) and therefore, the cGMP requirements that apply to each part continue to apply when it is combined. The cGMP final rule, which became effective in 2013, addresses how to satisfy these cGMP requirements for combination products in a manner that ensures manufacture of a safe and effective product, and to avoid duplication of regulatory requirements.
Are there any current “Hot Topics” that regulators are focused on?
Extractables and Leachables are becoming a cause of major concern, as combination products become increasingly complex in their design and materials of construction. Combination products such as inhalers and pens, as well as more sophisticated medical devices such as insulin pumps and implants, all have the potential to leach unwanted chemicals.
… and these leached compounds could pose a safety risk?
Yes, of course. There are actually two separate concerns related to leached compounds. The first is the interaction of these compounds with the active pharmaceutical ingredients, which could result in a loss of activity or impact the efficacy of the drug. The other concern is obviously the potential toxicity that an unwanted compound, such as a residual plasticizer or processing agent, could have on a patient. These risks could include toxicity, immunogenicity, and endocrine disruption.
Does following the ISO standard ensure a manufacturer’s combination products will be safe?
ISO 10993 and the FDA’s recent guidance document on its use provide a framework for assessing the biological compatibility of medical devices, including constituent components to combination products though a “one size fits all” approach is not feasible due to the diversity of the combination products and the diversity of the global regulations. A thorough understanding of the intricacies of each combination product and the impact of potential interactions between the constituent components is critical to ensuring patient safety.
With more than 25 years of experience in Medical Device Testing and regulatory affairs, Dr. Poth oversees laboratory operations, quality assuarance and regulatory procedures for Eurofins’ Medical Device Testing laboratories across Europe. He currently serves as Chairman of ISO TC 194 Technical committee for Clinical and Bological Evaluation of Medical Devices and is Head of the working group for ISO TC 194 Genotoxicity, Carcinogenicity and Reproductive Toxicology. He also serves as Chairman of the German National Committee DIN M12 for Clinical and Biological Evaluation of Medical Devices. Dr. Poth earned a PhD in Toxicology and a master’s degree in Biology from the Technical University Darmstadt.