CGT Manufacturing Resolution #4: "Work Backwards" When Capacity & Supply Chain Planning

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

In early December, I invited Katy Spink, COO and managing partner of Dark Horse Consulting, to sit down with me for a discussion on her expectations and predictions for CGT manufacturing paradigms in the new year. But because cross-industry collaboration, face-to-face communication, and transparency are critical in this burgeoning industry (and, let’s be honest, can be a lot of fun), Katy and I were also joined by a small group of CGT manufacturing experts from different companies across the industry.

Our conversation ultimately outlined five best practices — or, more fittingly, New Year’s Resolutions — that companies should embrace in 2022 that will (incrementally) help us define and achieve manufacturing maturity in the future.

In the fourth of this five-part article, Spink dives into resolution #4, outlining how companies can and should be approaching commercial-scale capacity planning from the earliest stages of development.  

Over the past few years, there have been a seemingly endless number of articles encouraging companies to think about the end goal — commercialization — from the very start. However, as Spink pointed out, for preclinical companies, the end goal (i.e., a commercial manufacturing paradigm) can easily be overlooked as teams face a seemingly more pressing question: “How do I get enough product for my Phase 1 clinical trials?”

Though this is (obviously) an important question/challenge for companies, Spink reasserts how critical it is to step back and plot out future commercial manufacturing needs — albeit, with big margins built in for error. Afterall, a company doesn’t need to make the product at scale from the start. But if it can identify its “wildest dreams” (i.e., treating the target population with the desired product market penetration), it can then identify the high-level, incremental steps to take to achieve commercial supply. In addition to forecasting the annual lot number/lot size, yield, and cell count, it’s also exceptionally important to think about the number of cell divisions required to achieve the desired commercial scale. A company must ensure that the cells can tolerate that many divisions without genomic instability or loss of critical functional characteristics.

“The industry has some well-established tools for capacity planning, but they’re not consistently applied,” Spink added. “You have to get your target product profile [TPP] and your quality target product profile [QTPP] in place from the start. You can then use these to fuel broader discussions on the manufacturing strategy(ies) that will reasonably achieve your commercial goals. Having this vision even at the preclinical stage can help a company more deliberately plan for long-term, resource-heavy evolutions in the manufacturing paradigm.”

In particular, she homed in on the likely burden and challenge of comparability that comes with making a technology or raw material change later in the development paradigm. By knowing the roadmap of technologies and GMP materials you’ll need to serve the commercial market, you can begin planning for and making smaller, more manageable changes earlier in the process.

For example, should a large bioreactor be necessary for a commercial-scale process, it makes more sense, comparability-wise, to introduce a small bioreactor into small-scale processes, as opposed to making a larger leap between technologies (i.e., from T-flasks to a bioreactor) later in development. The same can be said for the selection of raw materials. It’s not unusual to see companies relying on the phase-appropriate approach to raw material selection, starting with lower compliance materials and implementing GMP materials later in the process.

There are a few reasons why Spink encourages companies to start out using the higher quality materials — the time constraint and cost of proving comparability being big ones. “If it is possible to source the higher quality material now, choosing not to do so (i.e., falling back on the shortcut of the phase-appropriate approach) doesn’t make a lot of sense. It would just lock in one thing you’re guaranteed to have to change later,” she said.

Similarly, there is, in some instances, an increasing amount of pressure being applied on companies to secure higher quality ancillary materials that, historically, did not need to be GMP quality. One of the most notable — albeit still case-by-case — shifts Spink has noticed is in how even the secondary aspects of raw materials are being more heavily scrutinized. Not only are questions posed about the source of the raw material itself, but it’s also becoming more common to question whether the materials used in the manufacturing of each raw material are human- or animal-sourced.

“This is not a hard-and-fast rule,” she qualified, emphasizing that thorough risk assessments/additional testing to de-risk lower-grade raw materials is certainly still a possible approach. In fact, there may be instances in which the time constraints to secure GMP-grade materials will necessitate sourcing lower-grade materials. But from a cost standpoint, generally speaking, companies may find themselves in a “penny-wise but pound-foolish” situation, as the risks and costs of demonstrating comparability later in the process will greatly outweigh the cost of sourcing GMP-grade materials early.

You’re almost there! You’ve got four resolutions under your belt — the fifth and final is here (and it's another important one!)

Further Reading:

• In this Cell & Gene article, AVROBIO’s Chief Commercialization Officer Holly May outlines how to establish a commercialization mindset during early development.
• For a real-world perspective on forecasting raw material needs, check out this Cell & Gene Collaborative article featuring insights from Ludek Sojka, the CTO of SOTIO.