Pratima Cherukuri, chief scientific officer at Genezen answers some of most pressing questions about developments in biologics processing.
Q: Bioprocessing at commercial scale is becoming industrial in scope. Given your offerings and capabilities, what protein/gene expression or chemistry platforms are offering developers and sponsors better yields, efficiencies, and programme success?
A: Producer cell lines offer an attractive alternative to transient transfection when it comes to larger-scale manufacturing. They reduce or eliminate the need for plasmid transfection, which decreases process complexity and the risk of batch-to-batch variation or human error. Producer cell lines also use less expensive raw materials and labour as compared with transient transfection, resulting in lower associated costs.
However, using producer cell lines for viral vector production can be a challenge as some of the gene products required for vector generation are toxic to cells, and cell lines do not necessarily continue to produce a high titer of vectors upon expansion. Despite this, the technologies and strategies required to address these challenges continue to improve rapidly.
Suspension platforms are preferred wherever viable as they allow for substantially more cells to be grown to increase yield. Organisations are increasingly looking to outsource this to partners with the required niche expertise as adaptation to new mediums can be tricky.
Q: What aspects of biopharmaceutical technical transfer and scale-up are proving challenging? What sets a biotechnical transfer apart from a small molecule drug?
A: Unlike small-molecule drugs, biologics and cell and gene therapies (CGTs) are inherently variable. They are also much larger in size and structurally more complex as they are living entities.
The inherent variability of CGT products makes them impractical to replicate. Their heterogeneity is influenced both by biological processes inside the cells that are used to express them and by the manufacturing process used to produce them.
The complexity of CGT products can best be described by the properties that define them. These include their physical (size, structure), chemical (charges and ability to bond/clump), and biological properties (activities, interactions). These properties are known as quality attributes. Each product, including retroviruses and adeno-associated viruses, can differ in its attributes.
A subset of these quality attributes will have a direct impact on the efficacy and safety of the product, and these are known as critical quality attributes (CQAs). In process, these attributes need to be identified and analysed to ensure biological activity is maintained.
Q: Continuous, and continuous flow manufacturing is being promoted to improve the quality outcomes of drug manufacturing and processing. Are you introducing any of these principles into your cGMP manufacturing environment?
A: Genezen continuously explores ways to further improve quality outcomes. Our equipment and processes allow for closed and semi-automated manufacturing of viral vectors wherever this is technologically possible. We are also investing in research and development to ensure that innovation is continued, and we can fully realise the potential of any CGT product that we support.
Q: There is an adage in biopharma that says: “The process is the product.” Does this still hold true?
A: CGT products are highly complex molecules produced in live cells through a multistep manufacturing process. The key characteristics of these molecules (CQAs) can vary based on the cellular environment or during the process of manufacturing.
If changes to CQAs occur during the manufacturing process, even small modifications can alter the critical characteristics of the CGT product. These changes can go on to impact clinical effectiveness and safety.
Therefore, yes, the process defines the product. As a result, CGT processes need to be built, innovated, and evolved continuously to consistently make the highest quality products.