Biologic medicines are continuing to change the lives of an increasing number of people all over the world. However, as molecules become increasingly complex, it means that it isn’t easy to develop the right manufacturing process. I have spent more than 15 years working within the industry on therapeutic proteins, anti-drug antibody, and viral vaccines, focusing on cGMP (current good manufacturing practice) manufacturing, scale-up and upstream process development. I have developed processes for more than a dozen molecules.
I frequently think about what makes an “optimised” or “good” process – and where are the pitfalls. In my opinion, an optimised process generates highly purified materials in a minimum number of batches that meet clinical timelines and prepares for your commercial launch, while managing supply, quality and cost. Also, an optimised process needs to minimise the chance for failures, improve consistency and robustness, and streamline operations. Engineering controls also need to be considered in order to prevent introducing adventitious agents or contamination events. This should all result in long-term success in manufacturing.
Of course, this is all easier to say than do! With so many crucial areas involved in the bioprocessing workflow, it can be hard to know where your efforts should be focused. I think that success tends to involve taking a measured approach while balancing trade-offs that are associated with process optimisation and speed-to-clinic, which are tailored to your molecule’s specific needs.
There are many different areas that can be focused on to get the performance of your upstream process optimised. However, balance is also very important. It isn’t always having the highest titer. For example, developing a process that can reproducibly achieve a 5 g/L titer might be more sensible rather than identifying the ideal set of conditions that are needed to achieve a 7 g/L. If it is necessary for the process to run exactly right, even just a small deviation may lead to titers that are much lower than that initial 5 g/L, and could potentially fail.
I believe that overall there are three questions that need to be asked throughout your optimisation process:
How can the process be simplified?
Something that can be run easily in a lab at a small-scale might result in variability and unnecessary risk in large-scale GMP (good manufacturing practice) environments. If a complicated feeding strategy is replaced with a more simplified approach, you might be able to lower your risk of failure. Using closed systems instead of open manipulations might also reduce the risk of contamination. Variability might be reduced by streamlining media preparation or cell expansion.
What can I do to ensure that performance is consistent?
The closer you become to having a commercial manufacturing process, the higher number of batches will need to run. At that point, robustness and consistency are key – particularly if your goal is to commercially manufacture multiple batches a month, or maybe dozens every year.
How is downstream being impacted by upstream?
Considering the downstream implications for the upstream process is essential to ensure that the material being made can be purified downstream on a consistent basis.
Managing supply and quality
The need for having quality raw materials is tied to another important consideration as well: assurance of consistent supply. No one – including supplier and biopharmaceutical companies – want to have to deal with stock-outs. While a biological process is being developed, you need to consider how reliable the supply chain is for your raw materials. Supply continuity is critical. Companies need to have strategies for mitigating the disruption of supplies. Transparency in the requirements of raw material supplies is necessary for redundant site qualification, safety stocks and other means to prevent supply interruption.