Ensuring that patients receive the highest quality treatment under the best possible conditions is a fundamental priority in drug development. When a patient requires treatment, they are already facing a health challenge, and drug developers have an obligation to ensure that the drug they receive is safe, stable, effective, and appropriately administered. This is where in-use stability and compatibility testing play a critical role by making sure that biologic drug products (DP) remain stable not just during manufacturing and storage but also throughout handling and administration.
In my current role at Lonza, I focus on evaluating the in-use stability of biologic drug products, particularly their compatibility with administration components. This work is essential in defining handling instructions that preserve drug quality, ensuring that by the time a treatment reaches a patient, it has retained its critical quality attributes to ensure its safety and efficacy. Beyond assessing stability, we also seek solutions that make drug administration easier for healthcare providers and more comfortable for patients. A treatment should not only be effective but also designed for ease of use, minimizing physical strain so that patients, regardless of their condition, can receive treatment as smoothly as possible.
What motivates me in this work is knowing that each step we take contributes to both our customers' success and, ultimately, patient well-being. Through daily discussions and problem-solving, I see firsthand how in-use stability considerations shape the safe and efficient delivery of biotherapeutics. Being part of this process means ensuring that every treatment reaches patients in the best possible condition - because when it comes to their health, every detail matters.
Importance and challenges of in-use stability and compatibility testing
Looking at the continuum of steps from manufacturing, testing and distribution of drug products, the very last stage is the administration to the patient. Beyond safety and efficacy, further considerations, such as patient tolerance or delivery logistics, are often highly relevant when selecting the best administration route for a given therapy. As a result, there is a variety of administration routes available, together with a selection of devices, handling, and preparation steps to find the optimum administration approach for each product.
The target dosage for a drug is evaluated throughout clinical trials. As a result, the final product concentration and administration volume may not be selected until later in clinical development. As a result, a wide range of concentrations, volumes and even different diluents and administration routes need to be evaluated and optimized, often pushing the limits of what is possible from a development perspective.
Ensuring the effectiveness and stability of the active pharmaceutical ingredient (API) in the final formulation up to the point of administration to a patient comes with challenges to be considered during formulation development and selection of an administration device including:
- Looking at intravenous administration, a 1000-fold dilution is common, particularly in early-phase programs and for highly potent drugs. This need for a dilution creates several challenges, starting with the dilution of the formulation excipient, which can lose its stabilizing effect. In addition, the process may include multiple handling steps and exposure to large surface areas from materials such as lines, filters, syringes, and IV bags, which may lead to an increased risk of aggregation due to interfacial stress or a loss of API due to adsorption.
- From an analytical perspective, highly diluted DPs often cannot be evaluated using concentration and purity methods traditionally used for DPs with standard concentrations due to the low protein concentration or high salt load.
- The rise of new complex protein modalities, such as fusion proteins, bi-/tri-specific antibodies, and antibody-drug conjugates, has been steadily increasing since the early 2000s. Their complex nature brings numerous challenges, as previous learnings and approaches obtained for standard IgG-type antibodies cannot always be applied. Challenges also lie in additional safety concerns for clinical administration. For example, the introduction of closed system transfer devices (CSTDs) intends to improve the safety of healthcare providers by preventing accidental needle sticks and contamination. However, compared to drug administration using a vial and a syringe, CSTDs are more complex, and their use may lead to the formation of visible and subvisible particles, leading to efficacy and safety concerns.
Lonza’s approach to simulated clinical administration to assess in-use stability and delivery device compatibility studies
As the names indicate, in-use stability studies and administration components compatibility testing of biological DPs encompass simulating dose preparation, storage in the clinical setting, handling, and administration of drug products. Data from these studies aim to demonstrate that the final DP is delivered at the intended strength and is safe. In addition, state of the art technology is used to support troubleshooting for issues that may arise during administration of biological DPs, such as particle characterization.
At Lonza, our teams of formulation development, regulatory, and analytical testing experts work alongside our customers to achieve development of suitable, stable, and safe DP formulations, and identify the compatible devices for delivery of the DP. Working with an experienced team with the right expertise can streamline regulatory submissions, reduce timelines, and ensure patient safety and accurate dose delivery.