An Interview With Richard Castledine

The pharmaceutical industry is facing significant challenges and opportunities when it comes to active pharmaceutical ingredient (API) sourcing and manufacturing. To gain insight into these critical issues, we spoke with Richard Castledine, Head of Drug Substance and Translational Pharmaceutics Operations, Quotient Sciences about the current landscape and future outlook for API production. Our discussion covered topics ranging from supply chain resilience to emerging technologies that are reshaping synthesis processes. Read on for his perspective on the most pressing concerns, regulatory hurdles, and promising innovations that will shape API manufacturing in the coming years.

What do you consider to be the most critical issues facing the pharmaceutical industry regarding API sourcing and manufacturing today?

The need to simultaneously increase the speed and sustainability of API supply, while working within increasingly tight regulatory frameworks, often against a background of reduced budgets presents a significant challenge for organizations developing APIs. At the same time, a range of emerging and recently emerged technologies offer the potential for a paradigm shift in the development of APIs from candidate selection to commercial launch putting pressure on suppliers to embrace new modes of working or be left behind. The availability of a small-molecule API is often on the critical path for initiating a range of drug development activities. When transitioning from candidate selection to first-in-human (FIH) clinical trials, defining a safe, cost-efficient, regulatory-compliant, and sustainable route for the API earlier rather than later can save time, costly repeat activities, and bridging studies in later phases of development.

This creates great opportunities for organizations at the forefront of technological innovation and regulatory adoption.

How are new technologies like continuous flow manufacturing and biocatalysis impacting API synthesis processes and scalability?

A steady increase in the number of processes developed for a continuous mode of operation has been boosted by the 2023 adoption of ICH Q13 by the FDA and EMA which has resolved any remaining regulatory uncertainty in the development of regulated continuous processes. I think that the adoption of continuous manufacturing has now moved past the point where it is only used to address specific process issues, for instance, substrate stability or process safety issues. Now a more agnostic approach to process development prevails whereby the best approach for an individual synthetic stage or sequence is selected based on the underlying fundamentals of the chemistry be that batch, semi-batch, or full continuous. This leads to a greater reliance on steady-state process monitoring and controls to ensure product quality rather than sole reliance on end-of-batch testing. Consequently, we are seeing many more multistep (telescoped) syntheses of complex molecules conducted in a continuous mode of operation, which reduces manufacturing timelines and also allows for rapid increases in production volumes. I think that this trend will continue, which overall will lead to increased process sustainability and efficiency.

What regulatory challenges are API manufacturers encountering as quality expectations increase, even for early-phase clinical trial materials?

The recent adoption by ICH of M7 highlights the importance of an early understanding of the toxicity profile of your API. This means that work often previously completed later in development is taking place earlier at Phase 1/2A. This places a responsibility on drug substances manufacturers to understand the potential of API synthesis routes to generate, for example, nitrosamines and other potentially mutagenic impurities. As such, a greater and earlier understanding of the identity of process and degradation impurities and some understanding of their ultimate fate and control points in the synthesis are essential. Effective early process and analytical method design can circumvent many of these issues, particularly for Phase 1. When these factors aren’t considered early enough it can lead to delays in clinical trial approval and the requirement for additional work often requiring specialized knowledge and equipment.

How can pharmaceutical companies build more resilience and redundancy into their API supply chains?

Maintaining a secure supply chain can place pharmaceutical companies in a dilemma between onboarding more on the synthesis, often increasing costs and lead-times, or relying on outside vendors. When choosing a CDMO pharmaceutical companies can de-risk their selection by working with established providers who are aligned with their values and have a passion for delivery.

Irrespective of the vendor selected a secure supply chain starts at route selection. It relies on the development of a robust manufacturing process, avoiding long linear synthetic sequences and starting from readily available commercial materials, which can be sourced from multiple suppliers ideally located in different geographical regions.

Looking ahead, what emerging technologies or approaches do you think will have the biggest impact on addressing API synthesis challenges in the next 5-10 years? I think we will see increasing integration of technologies that already exist being used to complement one another. For instance, the use of semi-autonomous systems for process optimization could become routine by bringing together gravimetric and volumetric robotic dispensing systems, flow chemistry, Process Analytical Technology (PAT), and predictive software (DoE) to rapidly screen and iterate experimental designs.

I think that we will also increasingly see closer and earlier integration of drug substance development with solid state development and characterization, in part driven by more insoluble drug substances and a reliance on complex formulations, but also by a desire to reduce development times and to fully characterize the drug substance. The trend towards more complex small molecule drug substances is also likely to continue, driven by the emergence of novel modes of action such as Proteolysis Targeting Chimeras (PROTACs). More complex synthetic routes will in turn increase the cost and time-saving benefits which can be accessed by early high-quality route design.

Finally, I think that sustainability will increasingly become a metric by which an API synthesis is assessed, which in turn will drive further adoption of technologies and approaches such as aqueous-based chemistries, biocatalysis, and continuous manufacturing.

Author Details 

Richard Castledine- Head of Drug Substance and Translational, Pharmaceutics Operations, Quotient Sciences

Publication Details