Biologic medicines continue to change the lives of more and more people across the world. However, with molecules becoming increasingly complex, that means developing the correct manufacturing process is not easy. I have worked within the industry for over 15 years on viral vaccines, anti-drug antibodies, and therapeutic proteins. I have focused on current good manufacturing practice (cGMP) manufacturing, upstream process development, immunoassay, and scale-up. I have been able to develop processes for over one dozen molecules.
I often think about what makes a process “good” or “optimised” – and where the pitfalls are. An optimised process, in my opinion, produces highly purified materials from a minimum amount of batches. Clinical timelines are met and you are prepared for commercial launch, while cost, quality, and supply are managed. An optimised process also must minimise chances of failure, streamline operations, and improve robustness and consistency. Engineering controls must be considered as well, to prevent contamination events or the introduction of adventitious agents. All of this should result in long-term successful manufacturing.
This is of course easier said than done. The bioprocessing workflow involves so many different crucial areas, so it can be difficult to know where you should focus your efforts. I believe that success usually comes taking a more measured approach as well as balancing the trade-offs that come with speed-to-clinic and process optimisation that are customised to meet your specific molecule needs.
You can focus on a number of different areas in order to optimise your upstream process performance. However, balance is quite important as well. Achieving the highest titer is not always key. For example, it might be sensible to develop a process where a 5 g/L titer can be achieved instead of an ideal set of conditions being identified that are necessary for achieving a 7 g/L. If that is necessary for the process to operate exactly right, then even a small deviation might result in titers that are a lot lower than the initial 5 g/L and they may possibly fail.
Overall, I think that throughout the optimisation process there are three main questions that must be asked:
How can we simplify the process?
Something that can be easily run on a small scale in a lab may result in unnecessary variabiliy and risk within large-scale GMP environments. If a complex feeding strategy is replaced with one that is more simplified, it may help to reduce the risk of failure. When closed systems are used rather than open manipulations, it can also help to lower the risk of contamination. When cell expansion or media preparation is streamlined, it can help to reduce variability.
What can be done to ensure consistent performance?
When a commercial manufacturing process is used, more batches need to be run. At this point, consistency and robustness are key – especially if your goal is commercially manufacturing multiple batches each month, or perhaps dozens each year.
How does the upstream impact the downstream?
It is essential to consider the downstream implications on your upstream process to make sure the material that is being produced can be purified downstream consistently.
How to manage quality and supply
Needing to have quality raw materials is associated with another important thing that needs to be considered: assurance of having a consistent supply. Having to deal with a stock-out is something no one wants – including biopharmaceutical companies and suppliers. Throughout biological process development, you must consider how reliable your raw material supply chain is. It is critical to have supply continuity.