De-risking Combination Product Development Through Early Data-Driven Evaluation of Container Closure Systems
Functional performance of the combination product is significantly influenced by the interactions between the drug product and its primary container closure system. Ana Rusetski, Senior Manager, Device Development at Astria Therapeutics discusses Astria Therapeutic’s data-driven strategy to evaluate drug-container compatibility in early development to de-risk potential future issues.
Can you tell us about the selection strategy you used to evaluate syringe systems to deliver your drug product?
As combination products have become more complex and sensitive, especially with more high concentration formulations and biologics, we recognized that there was a lack of systematic approach to early-stage drug container compatibility testing from a functional perspective. Our idea was to put in the work beforehand: to evaluate different container closure systems so that we can minimize the potential for failures in later stages by identifying these risks as early as the feasibility stage. We assessed these functional parameters, and we primarily assessed break loose and glide forces as our critical quality attributes, as well as characterized the silicone layer, viscosity particulates, etc, and whether our formulation was compatible with the primary container.
Tell us more about the upfront approach you took to testing.
Unlike other drug container compatibility studies, and unlike conventional approaches which focused primarily on chemical compatibility (stability, extractables, leachables), we emphasized functional performance of the combination product under stress conditions and over time.
We layered both short-term mechanical stressors like mechanical agitation and accelerated aging with both the drug and the placebo formulations to assess whether the degradation of functional performance was due to excipients or the molecule itself. We also conducted comparative testing across multiple syringe systems to create a performance profile for each system over time to make our decision.
"Our idea was to put in the work beforehand: to evaluate different container closure systems so that we can minimize the potential for failures in later stages by identifying these risks as early as the feasibility stage."
How is this different from how other companies test and evaluate syringe systems?
In general, it is uncommon for companies to evaluate the container closure systems on such a holistic basis. Often, it is treated as more of a procurement step and not necessarily something that integrates into your entire strategy and requires evaluation beforehand.
This reflects a holistic strategy to not only evaluate individual components but also examine their interdependencies to better understand underlying mechanisms. By doing so we potentially avoided costly resource-intensive fixes later in the process.
What therapies is Astria Therapeutics developing?
Astria Therapeutics focuses on the development of life changing therapies to treat allergic and immunologic diseases. Our lead program centers on navenibart, a monoclonal antibody inhibitor of plasma kallikrein in clinical development for the treatment of hereditary angioedema. For this biologic formulation, selecting the optimal container that demonstrates consistent performance over time was critical to ensuring quality and usability. We prioritized device engineering and decided upon our data-driven container selection strategy in the early stages with the goal of mitigating future risks.
What kinds of risks generally come up and how can companies address them proactively?
From a risk management perspective, it is important for us to choose a mature and proven delivery platform when possible and to pay close attention to the drug product and primary container compatibility testing when selecting that primary container.
Additionally, engaging in the cross-functional team and ensuring that we had an integrated product development plan that aligned across the drug timelines, the device timelines and the regulatory timelines, so that the device design controls and risk management processes were fully integrated with the overall drug development plans.
A lot of the risks in combination product development come from timelines not being fully aligned or lack of cross-functional collaboration. We tried to align across these different timelines and do things as early as possible so that the device wasn’t a roadblock to these other timelines.
"Early data generation and integration of device considerations set the foundation for long-term product success."
Why aren’t other companies doing this risk management earlier in development?
Often, issues pop up later in development and then you need to do risk mitigation and rework a lot of things.
I would recommend considering combination product selection and challenges before first-in-human studies. Starting the process earlier and expanding to other kinds of compatibility testing and involving the cross-functional teams earlier on can de-risk development.
How can companies de-risk combination product development?
We approached this by defining the performance attributes that matter from a patient and use case perspective and then generated comparative data across multiple systems in both active drug product and placebo formulations. This allowed us to assess whether differences in performance were formulation-driven or inherent to the container closure system and how that variability fared on mechanical stress or accelerated aging. Our goal extended beyond selecting the highest performing container closure system at initial testing; we aimed to understand each system’s performance over time with the goals of ensuring sustained compatibility and functionality, culminating in its data-driven specificity to our drug product.
Anything else?
The importance of fundamental understanding and how rigorous testing can clarify and streamline the rest of development is not necessarily in the forefront of a lot of teams as they bring on the device development portion of the drug development team. Early data generation and integration of device considerations set the foundation for long-term product success.
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