The COVID-19 pandemic continues to shape bioprocess development trends, and many lessons have been learned from industry’s response to and preparedness for dealing with a public health crisis. However, the focus in 2021 shifted beyond the pandemic to optimization and scaling up adeno-associated virus (AAV) production, process workflows and considerations for messenger RNA (mRNA) therapeutics and vaccines, and efficiencies in processes development.
As we move into 2022, let’s take a look back at some of the most popular 2021 articles from the Bioprocess Development Forum.
Next-Generation Therapeutics: Improvements & Challenges
Advanced therapeutic medical products (ATMPs)—which are based on genes, tissues, or cells—continue to gain traction. They are further categorized into gene and cell therapies that use vectors such as AAVs, adenoviruses, and lentiviruses for delivery; oligo-based therapeutics such as anti-sense DNA, siRNA, mRNA, splice-switching oligonucleotides, and immune-stimulatory oligonucleotides; extracellular vesicles and exosomes such as inherent therapeutic products and drug delivery vector; and plasmids, phages, and microbiome and microbiota. But many challenges are associated with the process development for the downstream purification of these molecules.
Peter Guterstam, Ph.D., product manager of next generation resins & technologies at Cytiva, said one of the biggest challenges with ATMPs is the diversity of entities and the lack of established platforms. In terms of product development, it’s difficult to get enough material for proper product development. Further, in terms of manufacturing, because many of these molecules are so large, they are not only sensitive, but they also require closed processing.
AAV is quickly becoming the most flexible and useful vector in gene therapy. But, according to Anki Magnusson, staff research engineer, protein and viral production, and Åsa Hagner-McWhirter, PhD, senior scientist, bioprocess applications R&D, both at Cytiva, it has its own set of unique challenges when it comes to process development, both from an upstream perspective—such as which development platform to use and scalability—and a downstream perspective—such as cell lysis and the polishing step for full capsid enrichment. Nonetheless, it was evident in a roundtable discussion of industry experts that this field is full of opportunities to treat both rare and common diseases, and it will continue to evolve and advance with technologies that enable faster and cheaper production.
There was strong interest in 2021 in mRNA processing workflows for therapies and vaccines. mRNA therapies offer manufacturing advantages over recombinant proteins, and they are more cost-effective and faster to produce than most therapeutics, not to mention their flexibility. This infographic takes you through, step by step, the mRNA manufacturing workflow process—from plasmid linearization and buffer exchange to polishing and drug product. Because of its manufacturing perks, mRNA is advantageous for infectious diseases and personalized medicines. And thanks to the spotlight COVID-19 vaccines put on mRNA therapies, they are being studied for use in cancers, including cancer vaccines, and other vaccinations such as the flu and bacterial infections.
And beyond the vaccine, lessons learned from COVID-19 are now being applied to help improve process development for non-pandemic development programs, including the role that an influx of financial investment played in advancing process development, technologies that can accelerate this process, and the industry’s adoption of these more time-efficient processes.
Implementing Titers, Compliance, Mechanistic Modeling of Chromatography for Smarter Process Development
Bioprocessing has evolved over the past 30 years, and readers how curious how to navigate the complexities of the biologic manufacturing process. According to Peggy Lio, senior director of global cell culture services at Cytiva, over the past 20 years, there has been a significant increase in titers of bioprocess, especially for monoclonal antibodies (mAbs). In the 1980s and 1990s, mAb titers were only 0.5 g/L. From the 1990s onward, the average mAb titers have increased a full order of magnitude; today, it’s common to reach 3–10 g/liter as a result of high-producing cell lines, advanced technologies, and media, feeds, and process optimization. Lio details the manufacturing process, both cell line development and upstream cell culture process development, and provides parameters for developing cell culture media, and what media optimization really means.
Another aspect of this is the manufacturing process and its robustness as it pertains to compliance with process validation requirements set forth by the FDA and ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use). To help with this, an independent structured assessment process that uses data to develop insights into product sustainability and risks is proposed. It focuses on the evaluation of intra- and inter-batch variability and can be applied to both large- and small-molecule pharmaceuticals.
Bioprocess Development Forum readers also focused on efficiency as a key part of process development. Being able to increase process understanding and create process efficiency is important. One way to do this is with the implementation of mechanistic modeling of chromatography—although an older technique, it is new to biopharmaceuticals, and there isn’t an established skill base. Gunnar Malmquist, senior principal scientist, and Nick Whitelock, sales specialist, both at Cytiva, provide readers practical tips for how to implement mechanistic modeling into their process development work—the dos and the don'ts.