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PharmTech.com Bio/Pharma Outsourcing Innovation eBook 2023 Pharmaceutical Technology ® 31 Biologics considerable time ensuring product stability in all development stages, further truncating timelines. This shift of focus increased pressure for additional and specialized capabilities. In response to t he pandem ic, CDMOs began to adapt and expand their capacities and broaden their capabilities. Achieving this was no simple task and presented many difficulties. With caref ul organi- zation, expertise, and applying the right strategies, many companies are now well placed for the future. mRNA paves way for future technologies With relatively simple editing, mRNA can offer "plug- and-play" applications. This characteristic has opened the door to their use in various therapeutic areas. mRNA technologies currently in the development pipeline include those targeting rare diseases, autoim- mune disorders, and various cancers (3). Consequently, the global market for mRNA therapeutics is predicted to continue to rise—increasing from $46.7 billion in 2021 to $101.3 billion by 2026, at a compound annual growth rate of 16.8% (4). As a result, those organizations that responded to meet rising fill/finish and cold chain capability de- mands are well-positioned to handle the predicted rise in mRNA production needs in the future. CDMOs with these adapted capabilities will also be aligned to support another area in biopharma expected to see ex- pansion: the cell and gene therapy (CGT) space. Strategies for new drug modalities The flexibility and adaptations manufacturers had to offer in response to the demand for vaccines during the pandemic were not easy to achieve. Tackling the chal- lenge of global vaccine production relied on strategies incorporating three key areas. Firstly, manufacturers had to solve the challenges of implementing and/or expanding vital cold chain and fill/finish capabilities. While doing so, CDMOs had to maintain a transparent relationship with their sponsor to help build an under- standing of a novel technology. Considering cold chain capabilities. As the types of cold chain capabilities required for each individual biotherapeutic project can vary greatly, manufacturers embracing the challenge of producing mRNA technol- ogies had to carefully determine how certain factors could impact cold chain processes. Selecting the right primary packaging. There are many types of containers that are used during cold chain processes, from bottles and vials to bags and cryovials. When determining the right container, the decision will primarily rely on the product owner's platform. However, the chosen container must also align with the operations of the CDMO partner. When working with mRNA technologies, manufacturers had to offer flexibility to their clients, potentially offering the use of an array of different containers to ensure the success of the project. Another important consideration was how the con- tainer materials could influence the product. Whether containers were made from plastics or glass, manufac- turers had to determine the extractables and leach- ables that could be expected and anticipate how they could be removed. Handling multiple types of freezing and storage. In biologics production, there are typical ranges for freezing products. However, being able to handle multiple t y pes of storage capabilities and having the necessary standard operating procedures (SOPs) for each is often key to success when working with new technologies. Despite generally standardized freezing tempera- tures, the rate of freezing required can vary depend- ing on the product. For some biologics, it has been reported that slower freezing rates can cause high levels of cr yoconcentration, leading to molecular structures becoming damaged. Cryoconcentration is a particular problem when using blast rate freezers, which tend to have slow freezing rates throughout the bulk of liquid products. As a result of compression of the core volume by a slowly advancing solid-frozen phase, the stability of sensitive products within the bulk can be affected. Alternatively, control-rate freezers can minimize potential damage by controlling the cooling rate at specific points of freezing. Although these types of freezers can offer consistency between batches in certain parameters (including the degree of super- cooling), control-rate freezers can be difficult to work with, requiring the manipulation of various probes and containers. Validating cold chain capabilities. The global nat u re of t he pa ndem ic mea nt t hat it wa s v it a l t hat m a nu fac t u rers con sidered bot h st at ic a nd dynamic handling validations of cold chain capa- bilities during storage and transport. The US Phar- macopeia (USP) <1079> "Good Storage a nd Sh ip- ping Practices for Qualification" offers guidance in this area, describing best-practice procedures for maintaining storage environments to safeguard a preparation's integrity. St a t ic v a l id a t ion s a r e r e q u i r e d f or t he h a n- dling of the drug substance (DS) on-site. In these env iron ments, temperat ure excursions a re t y pi- cally less likely due to more robust temperature con- trols. On the other hand, dynamic validations, which are associated with off-site DS handling, are more complex. This is because temperature exposures will generally be within a greater range; for exam- ple, seasonal temperatures will have a larger impact on products during transpor t as compared w it h those in on-site storage.