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www.biopharminternational.com Partnerships for Outsourcing eBook May 2023 BioPharm International ® 31 Fill/Finish DS handling, are more complex. This is because tem- perature exposures will generally be within a greater range; for example, seasonal temperatures will have a larger impact on products during transport as compared with those in on-site storage. It is also essential that the controls for temperature and humidity during manufacturing, storage, and transportation are considered. Temperature and hu- midity need to be monitored in real-time, with risk management systems and continuity plans in place in case of control failures. Preliminary measures to avoid temperature deviation, such as immediately responsive 24/7 control centers that can access alternative storage options in response to alarms, can further limit the im- pact of temperature excursions. Rising fill/finish and sterility needs As with most parenteral therapeutics, ensuring the sterility of the mRNA vaccines has been essential. In- jectable products must be pure with no contaminant particles that could ultimately impact patient safety. Manufacturers must carefully consider where potential contamination could manifest—from raw materials to stoppers to other equipment—to minimize the risk. Ensuring sterility of biotherapeutics is most often achieved using sterile filtration, as this is often the only method that can suitably sterilize the product without affecting its stability. Typically, sterile filtra- tion is achieved using two in-line filters during fill/fin- ish that are placed in Grade A environments as close to the filling points (needles) as possible. In this way, the product is sterilized as it f lows through the lines to a container closure. Building technology understanding One of the biggest challenges in producing a global supply of COVID-19 mRNA vaccines was the fact that few in the biopharma industry, or those working to support development and manufacturing, had expe- rience with these types of molecules. Manufacturers that previously worked with drugs that were water-soluble had to quickly familiarize themselves with mRNA products that were encapsu- lated with lipid nanoparticles. As these technologies can be unpredictable, the potential for fill/finish con- ditions to change mRNA product characteristics had to be quickly determined. Having a thorough understanding of the potential challenges likely to be encountered was vital to en- sure the success of the mRNA projects. Achieving this understanding relied on the development of a strong relationship with clear communication between the CDMO and the sponsor. With a relationship built on trust, important informa- tion such as critical process parameters could be shared quickly and easily between parties, enabling rapid un- derstanding and optimization of the processes involved. Additionally, by adopting an "ownership mindset," many CDMOs were able to be proactive in deciding how the product should be processed and launched, offering advice based on their unique experience and expertise. With this approach and implementing dedication and discipline, critical milestones could be reached on time, ensuring essential vaccines reached the public at speed. Looking to the future In a feat of global research, development, and manufac- turing, the success of the COVID-19 mRNA vaccine roll- out was remarkable. CDMOs quickly responded to offer their support in the production of these critical products by expanding their capabilities and broadening their expertise into a new and rapidly expanding area. When examining the lessons from the early years of COVID-19's onset, it is clear that flexibility and adapt- ability were essential for CDMOs to successfully pro- vide cold-chain and fill/finish capabilities for mRNA vaccine production. mRNA technologies will continue to expand into new therapeutic areas, further increas- ing production facility requirements. Additionally, the need for CDMOs with experience working with new and previously unfamiliar products will grow as more CGTs enter the space. By reflecting on these lessons, manufacturers can be confident in their approach to supporting mRNA proj- ects under pressure and be prepared for a variety of new challenges that could be predicted on the horizon. References 1. Bloomberg, More Than 12.7 Billion Shots Given: Covid-19 Tracker. www.bloomberg.com, Oct. 6, 2022. 2. IMarc, Global mRNA Vaccines and Therapeutics Market to Reach US$ 40.55 Billion by 2027, Spurred by Increasing Investments in Biotechnology. Press Release, Aug. 21, 2020. 3. Da mase T.R.; Suk hoversh in R.; Boada C.; et a l. The Limitless Future of RNA Therapeutics. Front Bioeng Biotechnol. 2021, 9, 628137. DOI: 10.3389/ f bioe.2021.628137. 4. Thakur, R., mRNA: Therapeutics and Global Markets, BCC Research, October 2021. ■ As with most parenteral therapeutics, ensuring the sterility of the mRNA vaccines has been essential.