Biologic medicines are not just changing lives around the world but doing so in increasing numbers with each passing year. On the other hand, molecules quickly get very complicated, so developing the best manufacturing process isn’t always something that’s simple to accomplish. I’ve been working in the industry for more than 15 years. In that time, I’ve worked on immunoassay anti-drug antibodies, viral vaccines, and therapeutic proteins, always with an eye on current good manufacturing practise (or cGMP), upstream process development, and scaling-up. I’ve personally developed the process for over a dozen different molecules.
I think frequently about what constitutes a ‘good’ or ‘optimised’ process, as well as the potential pitfalls. I personally think that an optimised process will generate highly purified materials in the minimum number of overall batches that adhere to clinical timelines while preparing for a commercial launch in ways that manage cost, supply, and quality. Also, a truly optimised process has to minimise the odds of failures while streamlining operations and enhancing the strength and consistency of said molecules. Engineering controls should also be considered if they are going to prevent contamination events or the introduction of adventitious agents. All of this should add up to long-running manufacturing success.
Then again, it’s a lot easier to say all this than actually do it. Given how many crucial areas are involved in the workflow of bioprocessing, knowing where to focus your efforts can be really hard to figure out. Success often involves taking a rather measured approach that balances trade-offs in terms of speed-to-clinic and process optimisation. Many factors have to be customised to meet the specific needs of your particular molecule in question at the time.
If you want to optimise the performance of your overall upstream process, then you need to focus on multiple areas. Still, balance is always crucial to the whole enterprise. It’s not always about having the highest possible titer. For instance, if you can develop a process that achieves a 5 g/L titer over and over consistently, then that might make more sense than trying to find perfect conditions for a 7 g/L titer. If it’s crucial for a process that will run just right, the smallest deviations might result in titers far lower than 5 g/L. They could even fail.
I think that three questions in particular stand out that should be asked and answered all throughout an optimisation process:
How can a process be made simpler?
Something that you run with ease in your lab on a small scale could wind up with needless risk and variability when tried in larger-scale GMP environments. You can possibly reduce your odds of failure if you replace a rather complicated feeding strategy with an approach that is far more simple. You can also prevent contamination risks if you use closed systems instead of open manipulations. Variability can be reduced if you streamline cell expansion or media preparation.
What can you do to be sure you get consistent performance?
The closer you get to your commercial manufacturing process, the more batches you’re going to need to run. When this happens, consistency and robustness are both crucial. This is especially true if you intend to manufacture multiple commercial batches per month, or even dozens each year.
How does upstream impact the downstream?
Considering any downstream implications on an upstream process is crucial to making sure you can purify your materials downstream consistently.
Quality and supply management
Another crucial consideration is having enough quality raw materials. This is called assurance of consistent supply. Nobody, be they a supplier or a biopharmaceutical company, ever wants to put up with stock-outs. During the time that your biological process is still undergoing development, you should analyse the supply chain for its reliability in providing you raw materials. Continuity of the supply is crucial.