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8 Pharmaceutical Technology APIs, EXCIPIENTS, AND MANUFACTURING eBOOK 2021 P h a r mTe c h . c o m APIs Michael Stanek, vice president, commercial operations, API global, pharma services, Thermo Fisher Scientific. "On the contrary, the biggest barriers to using vaccines containing large molecules like mRNA [messenger RNA] or proteins, such as the Pfizer and Moderna vaccines, are transportation and storage, which can be particularly problematic in countries with poor infra- structure. The AstraZeneca and Johnson and Johnson vaccines also require refrigeration." Jamie Grabowski, PhD, MBA, vice president, portfolio and sourcing, Curia (formerly AMRI), emphasizes the importance of understanding the usage of small-molecule APIs. "Small molecules are used in more traditional pharmaceuticals—drugs like aspirin that have, in many instances, been around for more than a hundred years. Large-molecule pharmaceuticals, on the other hand, started with insulin usage for the treatment of diabetes and then, over time, be- came synonymous with monoclonal antibodies, ADC [antibody-drug conjugate] drugs, etc.," says Grabowski. "The advantage of a small molecule is the versatility in dosage forms such as tablets, thin films, inhalation powders, solutions, oral or inject- able suspensions, transdermal patches, etc. With large molecules, the applications are more limited." Between dosage form versatility, product stabil- ity, lack of storage restrictions or need to refrigerate, and an easier means of purification, small-molecule APIs present an appealing, and strongly growing, market segment. Clinical vs. commercial API manufacturing The challenges faced during clinical-trial API manu- facturing differ from commercial supply API manu- facturing. Turnaround times, especially, can be leaner for clinical trial manufacturing. "The vast majority of clinical trial APIs are or- dered by small and emerging pharma companies. These organizations operate within tight budgets and focus on speed, an approach that often does not allow for proper manufacturing preparation and overlooks the needs of commercial supply. This fre- quently leads to unexpected challenges during scale- up from labs to large glassware to pilot plants," says Stanek. "As a result of this fast-tracked approach, we may end up with a commercial process that is rather costly. Driving down the cost of goods by stepwise learning, which is typical in most industries, is lim- ited due to GMP [good manufacturing practice] requirements in a validated process. Changes are possible, but they can only be implemented slowly, oftentimes involving authorities' approval and piv- otal clinical trials. This is in comparison to the car industry, for example, where changes can be imple- mented within days or weeks." According to Grabowski, chemistry and/or scale-up issues can become more complex and multidimen- sional as clinical trials progress. "In clinical supply, processes aren't typically vali- dated until Phase III; so, at that point, customers face unknown and sometimes difficult chemistry and/or scale issues," says Grabowski. "Handling Between dosage form versatility, product stability, lack of storage restrictions or need to refrigerate, and an easier means of purification, small-molecule APIs present an appealing, and strongly growing, market segment.