P H A R M AC EU T I CAL S
HPAPI GROWTH PROSPECTS The recent acquisition of Ash Stevens by Piramal Pharma Solutions has provided Piramal with in-house expertise for managing the many challenges of HPAPIs. Challenges of HPAPI Oncology drugs generally comprise Highly Potent APIs (HPAPIs), which present unique development challenges relative to other therapeutic areas. Development and manufacturing processes for such compounds require a greater level of physical containment. Moreover, due to the serious nature of the therapeutic area, these products are usually on the fast track regulatory approval path by the US Food and Drug Administration (FDA). However, the FDA still expects a comprehensive understanding of the development process, as well as the analytical and validation packages. In this regard, the development team has the responsibility of developing a robust and reproducible process that also emphasizes safety and complies with regulatory requirements.
Scientific expertise Piramal recently acquired US-based contract development and manufacturing organization (CDMO) Ash Stevens, which has extensive experience in handling highly potent compounds and regularly sees increased demands for its offerings. This FDA-licensed cGMP facility located in Riverview, USA, specializes in cancer APIs and has a longstanding relationship with the National Cancer Institute. Cancer agents are typically classified as ‘highly potent’. Companies that develop and manufacture potent compounds have to be cognizant and willing to adopt the latest technologies to minimize potential hazards. It is imperative that they understand the likely hazards of production at the commercial scale, such as worker exposure during chemical operations. Once these have been assessed, appropriate engineering controls and personal protective equipment to mitigate risks can be implemented. One of the first approaches in assessing exposure control bands was published in 1996 by researchers at Merck.1 They proposed a five-band system based on their products’ toxicological and pharmacological properties. The criteria assigned potent compounds into performance-based exposure
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bands, based on the degree to which exposure impacted human health. Such assignations also dictated the engineering controls, handling and safety practices associated with each product. The scientists at Ash Stevens have worked on several high potent APIs in Band 4. This band represents the working environment within 1-10μg of API per m3, mandating minimal exposure, stringent engineering controls and storage of the product in a clean environment. Hence it is desirable to conduct the final processing in a particulate free environment to ensure that foreign particles are not introduced into a patient’s circulatory system.
Case study: Busulfan A highly potent API manufactured at Ash Stevens in Riverview was busulfan, used for the treatment of chronic myeloid leukemia (CML).2 An injected form of this drug was launched as Busulfex in the US in 1999. Consideration of the therapeutic dose and the size of the patient population suggested that manufacturing a multi-kilo batch was required to meet market need. As this was to be formulated into an injectable drug, the product needed to be manufactured in a clean environment free of particulate matter. The goal was therefore to develop a process that both minimized operator exposure to the product and product exposure to the environment. The chemistry was a straightforward sulfonylation of an alcohol. Operationally, the process involved the treatment of butanediol with methanesulfonyl chloride in the presence of a base in an appropriate solution, followed by precipitation of the isolated crude solid which was then purified by recrystallization and the final API was air-dried, vacuum-dried and packaged. Busulfan is relatively safe from operator exposure when it is in solution. The most problematic steps of the process are when busulfan is present as a dry solid rather than in solution. This is especially the case when the API is being dried and packaged, and danger of exposure to the operator as dust is at its highest.