Moving the development of oral solid dosage medicines along the clinical development stages requires an aligned CMC strategy and drug product capabilities that have different aspects in focus for First-In-Human (FIH) as compared to phase III clinical trial material. Initially speed, flexibility, and API consumption are predominant factors, without neglecting limiting oral absorption conditions like they are encountered in the case of low solubility or permeability compounds. As the development path progresses, more focus is placed on formulation refinement and expanding batch volumes – all while ensuring path to commercial scalability. Ultimately commercial-ready processes based on process understanding, with full regulatory documentation and validation-ready protocols, are designed to serve as basis to reach filing readiness.
OSD Drug Products for First-in-Human Trials: Fast & Flexible from Concept & Prototypes to Clinical Supply
With new approaches to tackle previously undruggable pharmacological targets, the molecular and material properties of new molecules like PROTACs or generally beyond-rule-of-5 molecules show a strong tendency towards unfavorable properties that limit oral absorption, with solubility and permeability being the main reasons. For many compounds, the question isn’t whether you can technically make a formulation, it’s whether you can achieve reliable in vivo performance and scale the process without losing control.
Therefore, it is of utmost importance to assess the developability ahead of FIH clinical trials and to answer the question of what type of formulation is required to observe sufficient systemic exposure. Developability always considers the predicted human dose for pharmacological action in relation to the solubility in biorelevant media as well as the permeability. From a pharmaceutical development perspective, the biopharmaceutic developability assessment will provide guidance to investigate and develop appropriate dosage forms that can be conventional, enhanced via the use of multicomponent solid-state forms, or enabled via advanced formulation principles. By far the most prominent variant of enabled formulations are Amorphous Solid Dispersions (ASD), where the API and a polymer are processed into an amorphous Drug Product Intermediate (DPI) prior to being further processed into a drug product.
Be it the multicomponent solid-state form or the enabled formulation approach, both exploit the ability of having more API dissolved in the intestine, which results in a higher flux and more drug uptake into the systemic circulation. This higher dissolved amount is referred to as supersaturation, which naturally tends to go back to the natural solubility, a phenomenon described as the “spring and parachute effect”. Finding the right spring and parachute that provides sufficient oral absorption is a key endeavor best conducted in the screening mode. CordenPharma has established a holistic approach for enhanced and enabled formulations, combining the expertise of our Solid State & Crystallization, and Drug Product Innovation Centres of Excellence.
Our structured approach encompasses:
Phase Appropriate Development, Manufacturing for Clinical Phases and Reaching Filing Readiness
Drug product related development activities will strongly depend on the chosen strategy and the outcomes of the FIH clinical trials. In the case of conventional formulation with no solubility or permeability challenges, multiple options on how to continue are available. For the ASD type of formulations, the DPI, i.e., the part of the formulation that brings the desired spring and parachute effect, is generally not to be modified. Aspects like formulation fine tuning, scaling and industrialization, processing and the identification of critical process parameters and process characterization will capture more attention when progressing along the clinical development path. The Phase III drug product should ideally be already representative of the to-be-marketed drug product. Full implementation of Quality by Design (QbD), a data-driven and risk-based approach, helps to structure and prioritize the necessary activities to reach this milestone for filing readiness.
When preparing for a New Drug Application (NDA) or Marketing Authorization Application (MAA) submission you need reliable data. This means that you need to generate the necessary data in a robust manner. Comprehensive analytical capabilities and expertise are needed to develop appropriate methods that can reliably monitor quality attributes of choice with fast turnaround times.
Generating process understanding is not limited to the infrastructure foreseen for manufacturing. Nowadays downscaled instruments that mimic large scale infrastructure, or simulation with mechanistic models, are becoming more and more popular. They are a real help in generating comprehensive process understanding that is the basis for the establishment of robust processes, all backed by analytical capabilities that include in process controls that e.g., may probe the solid-state nature of the API and demonstrate the fate of the solid-state form along all unit operations.
Technology Transfer
To implement a fully developed and validated process successfully in a new facility, a structured and well-defined process is key. Next to general technology transfer recommendations, CordenPharma follows a systematic, risk-based QbD approach that has proven how thorough risk assessment and gap analysis helps to define mitigation activities as needed and focus first on the prioritized activities.
Having a good physical understanding of pharmaceutical unit operations helps to focus on the main process parameters that may be investigated using design of experiment approaches with multivariate analysis of the results. Such an approach will lead to a comprehensive data basis that serves the implementation of robust processing and delivers sufficient data for any kind of regulatory documentation.
Next to a structured approach and physical unit operations knowledge, a further factor for successful technology transfers is the analytical support and capability to provide detailed analytics that may be used as supporting information. To summarize, sound analytical support, combined with robust methods, strong Manufacturing Science and Technology (MSAT) understanding, and a structured data-driven and risk-based approach, will strongly contribute to a successful technology transfer.
Commercial Manufacturing and Packaging
While strong development capabilities are needed to bring a drug product from drug discovery to filing readiness, or to onboard a product via a technology transfer, commercial manufacturing looks at different metrics. A good knowledge of the infrastructure combined with the engineering support for maintenance will help to maintain throughput. Strong planning, coupled with execution, and related administrative processes involving quality assurance and quality control are now more in focus. Supply chain specialists help with launch in multiple markets, or supply to established markets.
Move Your OSD Projects from Development to Commercialization with Confidence
CordenPharma provides expert OSD guidance and execution across every phase, including preclinical and clinical supply, late-stage validation, full-scale manufacturing and packaging. By incorporating biopharmaceutic principles for early-phase formulation screening, compatibility for formulation development, robust process development, risk-based technology transfer, and appropriate process characterization to reach filing readiness, our experts support your molecule from FIH to successful market launch and commercial supply.
Christian Schmitt
VP, Global Commercial Head - OSD Drug Products
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