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Introduction 
Léa Sorret
Assessing the clinical in-use compatibility of biotherapeutics is a critical step toward developing a stable and safe drug product (DP). It is also a regulatory requirement to provide data to support the procedures for administering products during clinical testing in a clinical trial application submitted to a Health Authority to seek approval for clinical testing. In addition, commercial applications for products to be marketed must contain information to support the directions for handling and administration of the product. Data obtained from testing to support the administration of the product includes stability and compatibility studies spanning the clinical in-use time frame for the DP (comprising of the dose preparation, storage, and simulated administration). Data obtained from clinical in-use testing should demonstrate that the handling and administration procedures result in the delivery of DP that is safe, potent, and at the intended strength.
Clinical in-use testing of biotherapeutic DPs for parenteral delivery faces numerous challenges that the drug developer must consider and address. In this article, we include the technical challenges associated with clinical in-use testing and potential strategies for biopharma companies to address these.
Compatibility with infusion diluents and material
DP formulations are commonly optimized to ensure their stability, allowing for an appropriate shelf life. However, the DP is often diluted with a diluent prior to administration to patients. The compatibility of this diluent with the DP should be assessed, as incompatibility could result in drug quality and efficacy issues and raise potential patient safety concerns. Furthermore, the DP and the prepared product do come into contact with many new materials during dose preparation and administration, such as syringes, filters or filter-needles, closed system transfer devices (CSTDs), intravenous (IV) bags, in-line filters, administration lines, and catheters. Contact with these materials can have a critical impact on drug stability, quality, efficacy¬ and safety. A stringent assessment to ensure compatibility with the contact materials during dose preparation using a wide range of supportive analytical testing is recommended to identify potential incompatibilities. These studies should be conducted early in product development to prevent delays in the initiation of clinical testing.
The presence or generation of particles and leachables from administration materials can also represent patient safety and immunogenicity risks. This should be tightly controlled during in-use administration. Particles can be introduced when handling and administering the DP and can also be generated due to incompatibility of the drug during in-use procedures.
“Clinical in-use testing is a regulatory requirement of health authorities worldwide to ensure patient safety and accurate dose delivery”
Dose accuracy and analytical challenges
Dose escalation studies are often performed in First-In-Human (FIH) and early clinical trials. In addition, highly potent biotherapeutics are often effective at extremely low doses. These scenarios pose challenges when performing clinical in-use testing as protein-based therapies may adsorb to administration material interfaces, leading to potential product loss and subsequent under-dosing of patients. Another issue around dose accuracy is that the available analytical methods may face limitations in accurately quantifying the lowest effective dosing solution, making it difficult to precisely predict potency and purity levels. An evaluation of the concentration of the dosage levels during simulated in-use testing is therefore paramount because no analytical assessment is typically performed in the clinic to ensure correct dose delivery to the patient.
Clinical and regulatory challenges
The complexity of the clinical set-up is difficult to control, as multiple procedures are available to administer drugs in clinics, and there is no universal global standard for clinical in-use testing. Regulatory authorities may accept various approaches during simulated administration testing as long as there is a clear technical and scientific rationale to support the approach. As such, relying on the experience and knowledge of an experienced Contract Development and Manufacturing Organization (CDMO) to propose suitable material and procedures to help ensure suitable clinical in-use data for regulatory submissions is key.
Conclusions
Clinical in-use testing is a regulatory requirement of health authorities worldwide to ensure patient safety and accurate dose delivery. Providing high-quality guidance, information, and testing is key to enabling safe in-use administration procedures for patients and healthcare personnel and ensuring a successful regulatory filing with health authorities to support the conduct of clinical trials and market applications. Partnering with a CDMO that has vast experience with in-use simulated administration testing can help support better decision-making on the appropriate study set-up, which could result in more effective and faster preparation of the relevant chemistry manufacturing and controls
