Manufacturing Strategies for Regenerative Medicine Success

Just a few years ago, my requests for manuscripts detailing logistical considerations for cell-therapy manufacturing were met with puzzlement. The assumption seemed to be that such processes already existed for commercial biopharmaceuticals and would simply be adapted later. In quite a few cases, adopting a commercial mind-set did not appear to be a goal at all, with hands-on practitioners used to applying procedures in hospital settings.

For those of us who remember early discussions about commercialization and cost-containment for protein products, who watched the fledgling biopharmaceutical industry struggle through ups and downs in the 1980s–1990s, the question was how many existing procedures could be applied easily to cell therapies. Many would need major adaptation and rethinking. Since BPI’s first cell-therapy issue, we’ve watched as equipment and methods for cell growth and process scale-up benefited from existing technologies and began to diverge in ways specific to the needs of this emerging segment.

Technical discussions abound regarding development of autologous and allogeneic therapies, as in our previous cell- therapy supplement issues. Identifying therapeutic goals and related processes — and adapting equipment for those specialized needs — has given us plenty of room to explore. But the manufacturing and logistics discussion finally seems necessary to explore in its own dedicated issue. Our decision to focus attention in a dedicated supplement on commercial preparation seemed to strike a chord with authors — as it continues to be a more frequent emphasis in regenerative medicine-related conference programs.

The point shared by all the articles in this issue sounds logical and simple enough: Know where you want to go (literally) with your cell-therapy product, and plan ahead for scale-up and logistics; and create processes that will be protected against contamination and acceptable, eventually, to reimbursement groups. The message to build development programs with the end in mind is still needed in the industry as a whole. But specific to regenerative medicines, we encounter it now as a sobering winnowing of expectations: Your product might offer a seemingly miraculous treatment option overall, and although personalized medicine is arguably the direction in which much of the industry is heading, if it doesn’t improve on existing standards of care, it may not be worth developing (financially, that is).

This issue begins with The Technology Partnership’s Edwin Stone emphasizing the importance of implementing current good manufacturing practice (CGMP) strategies for regenerative medicine. After a bit of a recap to set the stage, Stone heads directly into the issues at hand, concluding that “the biggest hurdles to a viable commercial model lie not in the biology, but in the underlying technologies and associated costs.”

From there, we offer two case studies that struck us as especially significant in their linking of process development to the needs for robustness, reproducibility, and cost containment — from the start. Behnam Ahmadian Baghbaderani and his group at Lonza show how all those considerations must come together under “defined, xeno-free, and CGMP conditions.” Adriana Lopes and her colleagues at Cobra describe their incorporation of single-use technologies and the closed, automatable systems they enable — again, looking at cost-containment from the very beginning of the process: in this case, development of plasmids for cell transfection.

Richard Grant and his colleagues at Invetech (“Needle-to- Needle Logistics”) and Bob Preti and his group at Caladrius (“Mapping Success for Commercial Cell Therapy Manufacturing”) then present practical considerations for working at commercial scale. This is that critical look at how cell-therapy companies can address the “go–no-go” decisions detailed in our main issue’s special report on “developability” this month. Some of these realities may be a bit difficult to hear. Not all promising therapies will succeed at large-enough scale to be worth developing commercially. I suppose that is a sign of a maturing market overall: Great expectations become tempered by limitations beyond any single company’s control.

Dan O’Donnell closes out this issue with supply-chain strategies specific to autologous cell therapies, offering a level of detail about shipping logistics that we have not seen often in BPI. These scale-up and scale-out approaches at the final distribution points are aspects that I especially want to pursue in our fall 2016 cell-therapy supplement. As time passes, first- adapter companies will have more specific guidelines and experiences for others to follow into the clinic and toward transforming human healthcare.

Finally, two other papers intended for this issue just didn’t make our schedule in time. I regret their absence here, but I am delighted to tell you to watch for them in our November and December issues, both brought to us by the multitalented David Brindley (of Harvard Stem Cell Institute, the University College London, and IP Asset Ventures), one of the cell-therapy industry’s most dedicated proponents. For November he teamed with authors from CASMI (Oxford-UCL Centre for Advancement of Sustainable Innovation) and Sartorius Stedim Biotech to present a quantitative risk assessment of extractable and leachable contaminants in cellular immunotherapy biomanufacturing. And in our December’s “bioexecutive” issue, he and other authors team with Rahul Rekhi (advisor to England’s Chief Medical Officer) to guide attention to decision support tools (the current landscape and development opportunities) for monoclonal antibodies and cell therapy bioprocessing. That latter topic especially emphasizes the merging of the familiar with the lesser-understood considerations and the fruitful results of continuing collaborations.

                        S. Anne Montgomery, editor in chief