Extractables Study Principles for Drug-Device Combination Products

The use of medical devices in combination products has increased greatly in the past 15 years and is expected to continue to increase for the foreseeable future. This has been bolstered by an industry push to fill a demand for patients to have access to at-home therapies with the use of self-dosing and on-body wearable solutions. Companies that decide to use devices like these to deliver their drugs have plenty to consider with regards to extractables, leachables, and the overall chemical safety of their product. A strong understanding of the risks that leachables may pose during the use of a combination product first requires thoughtful and informed design of extractables studies as part of chemical characterization of both the device and container closure system, with the appropriate application of industry guidance. 

There are two main sources of guidance for drug-device combination products. First is USP <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems, which is primarily applied to drug container closure systems. Second is ISO 10993-18 Chemical characterization of medical device materials within a risk management process. This is part of the broader evaluation of biocompatibility of medical devices that this ISO standard covers. Although there are some basic principles shared between these two sources, there are distinctions that must be understood so that the design of the extractables study keeps you on the path of success in your E&L program. 

Extractables and leachables evaluations of drug-device combination products must be done through risk assessment and start with breaking down the product into the two main items: one being the packaging system of the drug and the other being the device. The container closure is the source of, in general, the greatest risk of leachables due to two critical parameters: the composition of the drug which influences the types of organic compounds that may leach and the storage conditions and duration of the product. Due to this, performing an extractables study of the packaging components is a critical step in the evaluation of the overall product. This should be done with the goal of determining the overall extractables profile of the container closure to enable the selection of leachables to target and monitor in later leachables studies. The process and considerations are explained in USP <1663> and the Product Quality Research Institute's (PQRI) parenteral drug product recommendations, but some critical parameters of an extractables study includes things like the selection of extraction media, the extraction conditions, the types of analyses employed, and concentration at which the extract is analyzed.

For the device portion of the product, ISO 10993-1, 10993-12, and 10993-18 offer many considerations and encourage a risk-based approach. Just like with container closure components, understanding the chemistry of the components and their materials of construction is vital in successfully characterizing the whole device and the risks it poses during normal use. In most cases, even after gathering all available information on the chemical characteristics of the materials, an extractables study will be needed to get the complete picture. The critical parameters of such a study take into account the materials of construction of the components of the device, the solvent compatibility of these components with various potential extraction media, and the clinical use of the combination product, with the latter being focused on patients' exposure time and conditions to any drug- and patient-contacting device components. The study should be performed by extracting individual components at conditions, and with extraction media, that exaggerate their actual use. For example, if a combination product is used only once, the extractables study conditions will be relatively mild. However, if a combination product is used periodically, but long-term, the total accumulation of potential leachables must be considered and extraction conditions selected that will describe this accumulation, leading to harsher extractions compared to one-time use.

This example barely scratches the surface, and overall, there are more considerations and details that go into an extractables study for the device in a combination product, so a thoughtful and thorough study design is necessary for success. 

Our experts have the knowledge and experience to guide customers through E&L programs for their combination products, and have been performing these studies for 25 years. Learn more about our Extractable and Leachables Testing support here. Contact West today to learn how we can help simplify your combination product journey.

Note: West's SmartDose® drug delivery platform is not independently cleared or approved by any Regulatory Body for general healthcare professional or patient use, nor is it available for general commercial purchase. Its distribution and use are subject to applicable regulatory requirements for clinical investigation, and for marketing authorization, as used in combination with a specific drug or biological product. Each constituent part of a combination product is subject to the requirements established by the Regulatory Body for that type of constituent part (drug, biologic or device) and when evaluating products that utilize a specific drug delivery system or device the Regulatory Body is expected to evaluate the characteristics of that delivery system and its functionality, as well as the potential for undesirable interactions between the drug or biologic and the delivery system. The regulatory process can be more complicated for combination products. As a result, we note that the SmartDose® drug delivery platform's compatibility with any particular drug or biologic must be confirmed, and its ability to achieve the desired patient benefits must also be confirmed, on a case-by-case basis in a manner sufficient to meet Regulatory Body requirements.

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