David O’Connell, director of Scientific Affairs at PCI Pharma Services, Tredegar site, shares insight on how CDMOs, like PCI, can provide end-to-end solutions in the growing demand of high potency manufacturing.
Drug products containing high potency active pharmaceutical ingredients (HPAPIs) continue to be a major driving force in the global pharmaceutical market. Consequently, Contracted Development and Manufacturing Organisations (CDMOs) that are able to provide end-to-end solutions for the development and manufacture of highly potent solid oral dosage forms remain a vital part of the pharmaceutical outsourcing industry.
Recent data suggest that between 2021 and 2026, the small molecule drug discovery market will register a compound annual growth rate (CAGR) of 8.05 percent, indicating a growing need for these dosage forms. Oncology remains at the forefront of this demand, accounting for approximately 38% of all new small molecule drug candidates, with around three‑quarters containing HPAPIs.
For an active pharmaceutical ingredient (API) to be considered highly potent, it requires an operational exposure limit (OEL) of less than 10 μg/m3. Whereas, it can be safely assumed that many, if not all, small molecule oncology therapies may fall within this category, in reality many HPAPIs in development register a potency far greater than this. The greater the potency, the more targeted the medicine becomes, which is understandable given the innate complexity of oncology-related diseases, for example.
PCI has developed and manufacture potent products since the 1980s, and in 2013 the Contained Manufacturing Facility (CMF) in Tredegar, South Wales was launched to increase our capabilities in this field. The CMF was originally built to fulfil a relatively unmet need for highly potent solid oral dosage forms, and was designed in accordance with the latest safety, scalability and regulatory guidelines.
After gaining almost a decade of operational experience with the first CMF, PCI has now expanded the Tredegar facility with a second CMF, essentially doubling their capacity for high potent development and manufacture. Combined with a new high potent packaging facility, the Tredegar site is well-placed to deliver precision small molecule therapies to the market at commercial scale.
Using oncology as an example, such medicines are often classified as extremely potent, which means they would fall within operational exposure band (OEB) 4 or 5. A molecule with an OEB 5 classification would register an OEL of less than 1 μg/m3. The design of the CMF, which prioritised engineered containment systems, allows for the safe handling of HPAPIs down to an OEL of 0.01 μg/m3. This ensures not just the safety of operators when handling these molecules, but also the protection of their clients’ products. In order to on-board such potent drug substances with confidence, PCI routinely partners with recognised industry expert groups such as Affygility and Safebridge for the assignment of OELs to new molecules. By performing robust assessments of new molecules, PCI ensures the safe handling of the product throughout its lifecycle.
Like many CDMOs, PCI is a multi-product facility. In order to prevent cross-contamination when using their equipment for development and manufacturing activities, a robust approach to cleaning verification and validation is essential. Establishing permitted daily exposure (PDE) cleaning limits – known in the US as acceptable daily exposure (ADE) – early in the product lifecycle ensures no significant API carry over to the next product on the equipment train. An accurate risk assessment would include an understanding of the PDE/ADE, equipment contact areas, batch sizes, API concentration and maximum carry over (MACO) data. Experience with the original CMF places PCI in a strong position to ensure a strong NPI process.
In the current market, there is a strong desire to work with fewer outsourcing partners throughout a product’s lifecycle. The top 5 CDMOs occupy just 15% of the market share, with the remaining 85% experiencing a high level of fragmentation. With this fragmentation comes a large number of CDMOs who are not able to offer end-to-end services, from clinical development to commercial launch. PCI’s ability to support clients by scaling-up from development to commercial volumes is of central importance when positioning as a true commercial CDMO. By utilising geometrically similar equipment and mathematical scaling models, this provides a greater success rate during this phase of process development.
As the market continues to evolve with increasing numbers of highly potent molecules in development, it is important to understand the requirements for the safe processing of such molecules, the differing regulatory requirements across the world, and – above all – the safety of employees and the environment. For pharmaceutical developers looking to outsource the development and manufacture of products containing HPAPIs, the challenge is finding a CDMO with the right technical capabilities, knowledge and experience to successfully manage the project.