Process Development: How To Plan For Comparability At Commercial Scale

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

I love bite-sized pieces of advice, so I was grateful to garner some from the Business of Biotech Podcast Cell & Gene series, hosted by my fantastic colleagues Erin Harris (Cell & Gene) and Matthew Pillar (BioProcess Online).

In a recent episode, Pillar and Harris sat down with Bobby Gaspar, the CEO of Orchard Therapeutics on the company’s efforts and goals for the future for its HSC therapies. In particular, Pillar asked Gaspar for a bite-sized piece of advice for organizations working to establish commercial scale manufacturing with CDMO partners. Gaspar replied:

Try and start with what you want to use at the end. So even if you can go to a CDMO that can manufacture at commercial scale, try to keep the process you start with the same the whole way through. Because once you start making changes, the comparability exercise that you have to go through can be quite significant. It’s doable, but it does involve cost, transfer of technology and processes, etc. So, the fewer changes you can make along that path, the smoother that path will be. 

This piece of advice goes nicely hand-in-hand with some of the news coming out from biotechs that have had to slow their progress through clinical trials to backstep and better demonstrate the comparability of their larger scale processes to the FDA.

But while the end-goal is to have a well-understood and highly controlled processes at the end of the day, it’s important to emphasize that the progress towards that final process is and will be nuanced.

In January, I attended the Phacilitate Advanced Therapies Connect virtual conference. During one panel focused specifically on process development, some advice from a Dark Horse consultant really resonated with me. As Sara Mills shared, the adage “the process is the product” is commonly used throughout the ATMP space. But this adage can be more harmful than helpful because it inadvertently encourages companies to avoid changing their process throughout the development cycle. This reticence to change processes early on will only lead to the accumulation of barriers that will become exceptionally more problematic the farther the product moves through development.

Instead of trying to avoid comparability altogether — which, frankly, will be unavoidable for most if not all companies — she emphasized that companies should always be thinking and planning for comparability. In fact, for some products — particularly allogenic or stem cell-based — she proposed building a comparability program into the regulatory filings. This way, a company won’t need to pursue formal FDA meetings to gain buy-in from regulators prior to undertaking the comparability exercise.