Historically, cell and gene therapy medicinal products have been rare in the drug market. Meanwhile, ten cell and gene therapy products have been launched to the US market and thousands of advanced therapies are in the pipeline as of April 20221. Beyond doubt, many of these products will fail, but learning from the past, about 5% will become successful. In the often-quoted statement, the former commissioner of the Food and Drug Administration (FDA), Scott Gottlieb, predicted that by 2025, the FDA would approve between 10 and 20 cell and gene therapies per year2. Although developers currently reduce speed, the numbers are still impressive. But these numbers further challenge developers, who are already under pressure by limitations of current production methods and time-consuming and cost-intensive material sourcing. It is estimated that the viral vector-manufacturing capacity can cover just 5% – 10% of the capacity needed in the next ten years3. In addition, payers´ reluctance to accept the high prices for these boutique therapies put commercialization at risk. Most recently, Bluebird bio withdrew its gene therapy for a rare blood disorder from the German market after failing to reach an agreement with health authorities on the treatment’s price4.
To tackle the limitations, the industry has invested massively in centralized manufacturing to expand manufacturing capabilities. However, fixed factory-based manufacturing continues to struggle with complicated logistics, vein-to-vein time lags, and most significantly, with small batch sizes.
The strength of cell and gene therapies lies within personalization. At the same time, it is the cost-intensive personalization that keeps cell and gene therapies out of reach for many patients and payers. Centralized manufacturing might be suitable for allogeneic cell products or when targeting larger patient populations once the field expands from rare diseases to more common indications, but developers must explore alternative manufacturing models, especially when the batch is manufactured for a single patient (as is the case for CAR T-cell therapy,) to manage costs and resource limitations.
Decentralized manufacturing of cell and gene therapy products is an attractive proposition for high-value, low-volume medicines that require personalization. The recent advancement of continuous bioprocessing opens the doors for alternative manufacturing strategies. Integrated manufacturing systems allow for harmonization of both upstream and downstream unit operations. All production systems are designed to maintain a sterile, closed manufacturing environment and are automated to assure consistent operation and product quality. This would allow a process to run in exactly the same way each time. Provided incoming raw materials are well controlled, the process will routinely run at optimal productivity. Further efficiencies and consistency can be gained by using single-use consumables and their use can accelerate process development, simplify manufacturing processes, and safeguard quality.
Developers may build a hub-and-spoke decentralized manufacturing network. Decentralized manufacturing could be established at excellence centers which would work under the supervision of the hub. Cloud-based connection of all involved facilities would allow for the implementation of identical manufacturing protocol and the same in-process and batch release assays and quality attributes, thereby meeting strict regulatory requirements.
Acknowledging the need for affordable medicines, regulators are open to decentralized manufacturing. The FDA addresses decentralized manufacturing for the first time in the draft guidance document “Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products”5 which was released for industry comments in March 2022. Decentralized, multisite manufacturing may contribute to product variability, so developers are asked to demonstrate that products manufactured at each site and analytical assays are the same. The automatization and integration of operation units should enable developers to manufacture the comparable products at each site to meet regulators´ expectations at the same time. In addition, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) is currently seeking comments on the introduction of a new regulatory framework for decentralized manufacturing of innovative medicinal products6.
With these regulatory provisions on hand, decentralized manufacturing has great potential to contribute innovative medicines to all patients.
2: US FDA (Jan. 15, 2019). Statement from FDA commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies Accessed Sept. 9, 2020: Retrieved from US FDA (Jan. 15, 2019). Statement from FDA commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies Retrieved from https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologics.
3: van der Loo, J. C. & Wright, J. F. Progress and challenges in viral vector manufacturing. Human molecular genetics 25, R42-52 (2016).
4: Pagliarulo,N, Bluebird to withdraw gene therapy from Germany after dispute over price. BIOPHARMADIVE (Apr. 20, 2021): Retrieved from: https://www.biopharmadive.com/news/bluebird-withdraw-zynteglo-germany-price/598689/?utm_source=Sailthru&utm_medium=email&utm_campaign=Issue:%202021-04-20%20BioPharma%20Dive%20%5Bissue:33706%5D&utm_term=BioPharma%20Dive
Senior Consultant, Advanced Therapies, KCR
Dr. Karoline Hahn is a Senior Consultant for Advanced Therapies on KCR’s Trial Execution Consulting team with 20 years of experience in the biopharmaceutical industry – devising regulatory strategies and leading interactions with global health authorities. A geneticist by training, Dr. Hahn has extensive expertise in Advanced Therapies and provides top-tier strategic regulatory services in the area of ATMPs.