Issue link: https://www.e-digitaleditions.com/i/1468049
24 Pharmaceutical Technology TRENDS IN MANUFACTURING 2022 eBOOK P h a r mTe c h . c o m Biologics used must be advanced, user-friendly, efficient, and applicable from development to scale-up, notes Rosenbaum. The increasing demand for biologics requires smaller batch sizes and greater f lexibility in manufacturing solutions, which necessitates frequent line and equipment changes, Rosenbaum observes. The requirement for smaller batch sizes and manufacturing f lexibility is leading to a shift from large manufacturing areas to small and f lex- ible footprints. As a result of the shift towards bio- logics, there is also a growing trend towards the use of single-use technology, he adds. "The driving forces are not only cost reduction and improved production efficiency, but also the ability to process potent compounds and produce smaller batch sizes," says Rosenbaum. Rosenbaum goes on to discuss some of the man- ufacturing challenges in the lyophilization of bio- logic drug product. "Freeze-dried and liquid drug vials for biologics are filled in a similar manner, but the different formulations present different manufacturing challenges," he says. Liquid products, for instance, require less time for development and therefore have shorter lead times. The lead time for lyophilized products ac- counts for the lyophilization cycle and the charac- terization of that cycle. Characterization is impor- tant because the parameters of the lyophilization cycle affect the production of a cake with high integrity, and the production of a cake without collapse, re-melting, or shrinkage requires addi- tional development, Rosenbaum explains. "In both cases, it is necessary to understand the stability of the formulation, but for freeze-dried products, we need to develop the cycle through calorimetric measurements, refine the process parameters, and optimize the cycle. The freeze-dried product needs to be characterized and the stability profile needs to be established," Rosenbaum states. Meanwhile, a major technical challenge lies in the development work that takes place before a clinical batch is filled, as freeze-dried products require more preparation in selecting the right excipients, fillers, and cryoprotectants, as well as in cycle development. "It is also important to note that some of the COVID-19 vaccines are multi- dose and require the use of an evaluated preserva- tive," Rosenbaum says. By way of example, Rosenbaum points out that messenger RNA (mRNA) vaccines use nanopar- ticle technology to increase stability, as opposed to the aqueous-soluble molecules typical of standard biologics. Recombinant protein vaccines may also require the use of an adjuvant to stimulate the im- mune response, and there are unique differences between live and attenuated or inactivated vaccines. "These differences require considerations related to plant classification and engineering controls, as live viruses must be separated from other types of vac- cines. At the end of the day, COVID-19 vaccines are no more difficult than other biologics from a filling/ manufacturing perspective. However, the real prob- lem lies in managing the time that vaccines are out of controlled storage," Rosenbaum cautions. He does note that transferring liquid formulations to freeze-dried products can improve thermal sta- bility and reduce the need for cold chain handling. There are already results showing that freeze-drying The lead time for lyophilized products accounts for the lyophilization cycle and the characterization of that cycle.