Issue:April 2018

EXECUTIVE INTERVIEW – MilliporeSigma: Accelerating the Development & Manufacture of Gene Therapies, Immunotherapies & Viral Vaccines

MilliporeSigma, a leader in the life science industry, works hand-in-hand with the global scientific community to develop, manufacture, and market products and solutions that bring customers one step closer to solving the toughest life science problems. With 19,000 employees and 65 manufacturing sites worldwide, MilliporeSigma has a portfolio of more than 300,000 products enabling scientific discovery. The company combines its expertise in biopharmaceutical manufacturing and high-technology products to accelerate the development of gene- and cell-based therapeutics. Drug Development & Delivery recently interviewed Dave Backer, Head of Virus & Gene Therapy Strategic Initiatives at MilliporeSigma, to discuss its expanding GMP capacity to speed development and manufacture of gene therapies, immunotherapies, and viral vaccines.

Q: MilliporeSigma recently expanded its GMP capacity for gene therapy, immunotherapy, and viral vaccine production by almost 90% What were the driving forces behind this expansion, and what new services/capabilities will you be offering?

A: The clinical manufacturing of intermediates and final products used in viral vaccines and gene therapies requires dedicated facilities, and there is significant demand for these services in the growing cell and gene therapy market. The Carlsbad expansion is designed to meet this growing demand. Our primary objective is to double our capacity for bulk drug manufacturing in response to customer demand. Our new suites were built with a modular design and can be used in a flexible way to meet both medium and larger scale production needs. This expansion will allow us to scale the manufacturing process for our customers as they prepare to commercialize their products.

Q: What are the biggest challenges facing development and manufacturing of gene therapies and immunotherapies?

A: One of the main challenges in this space is moving from clinical- to commercial-scale development. It’s important to plan early for a scalable production platform where you understand your critical process parameters. Gene therapy, in particular, has relied on processes developed for small-scale, academic settings that were appropriate for early stage clinical trials. Often, companies are hesitant to move away from these proven technologies, and this can be a challenge when it comes to scalability. It’s much more efficient to do two large production runs rather than 10 small runs, but this requires good planning, process development, characterization, and validation. Taking the time to generate sufficient data to define operating windows for critical process parameters and developing a robust, scalable process is key to commercial success.

Q: To what extent and how must manufacturing capabilities for these innovative therapies evolve in order to successfully bring them to large numbers of patients?

A: There have been a number of advances in gene therapy and gene-modified cell therapy space, particularly around the gene delivery vectors like adeno-associated virus and lentivirus that are very exciting scientifically and also leading to some very promising clinical results. But as these therapies are making their way through clinical trials and approaching commercialization, the field is beginning to realize that process engineering innovation must happen in parallel to enable commercial production to be robust, scalable, and cost effective. There are real opportunities to improve production yield as well as viral vector purity through the combination of cell line and media development, bioreactor-based expansion, and downstream processing improvements.

This is an area where we need to take the next big step forward to enable cell and gene therapy. We are certainly focused on this through the combination of our Carlsbad viral manufacturing experience and our MilliporeSigma product and process knowledge.

Q: What are some innovations that MilliporeSigma has incorporated into this facility and how are those innovations accelerating the progress of these therapies to the bedside?

A: The Carlsbad facility has been supporting the development of therapies for cancer, cardiovascular, and central nervous system disease for more than a decade. The new expansion will house twice the warehouse capacity and will incorporate both fixed- and single-use equipment in a flexible, scalable format. The expansion is necessary primarily to meet the increased demands of existing clients, but will allow for an expansion of services to new entries into the gene therapy field as well.

The Carlsbad campus features segregated fill/finish capacity for gene therapy, viral vaccine, and immunotherapy products. Our expanded capacity allows us to seamlessly support customers with a full offering from clinical to commercial scales, and is complemented by cell-banking services in Rockville, MD; viral and gene therapy manufacturing capacity in Glasgow, Scotland; and global BioReliance® biosafety testing offering.

Q: Manufacturing gene and immunotherapies appears to be quite different from manufacturing biologics, such as monoclonal antibodies or recombinant proteins. What are some of key differences, and how are they being addressed?

A: There are certainly differences in manufacturing gene and immunotherapies as compared to more mature biologic products, such as monoclonal antibodies, but there are similarities as well. The same principles apply, and the same cGMP requirements can be applied to determine process validation and compliance of the manufacturing facilities. Most of all, manufacturers face the same production issues, such as scalability, cost efficiency, and product stability. A highly reproducible, cost-effective manufacturing process is one of the major challenges for immunotherapy manufacturing, and the same holds true for biologics. We understand that as partners of drug manufacturers, we must engage in informed conversations about the entire production flow. In fact, the use of sterile, single-use disposable materials has always been part of our manufacturing platform. And now, as the industry moves more aggressively toward cell and gene therapies, there is definitely a continuing shift toward closed, pre-sterilized manufacturing systems, and particularly toward single-use bioreactors. On the downstream side, disposable single-use and pre-packed columns are also driving efficiency. Similar to our expansion, the move toward modular, single-use-based facilities is making manufacturing more flexible and able to be tailored to a drug product’s manufacturing needs.

As to differences, we have to treat each viral product as potentially infectious, even when they are fully attenuated. That requires specific facility designs, standard operating procedures, and dedicated areas in which to manufacture these products. Viral products also have wide variability in productivity, vector stability, and size. Thus, the site has developed a robust set of capabilities for these products, and we need to keep those skill sets while also scaling up and validating processes for commercialization. For cell therapy production, which our customers perform, but we do not perform at Carlsbad, autologous or personalized therapies are scaled out, while allogeniec, or off-the- shelf, therapies are scaled up. Scaling up and scaling out are quite different. When scaling out, you need good scale down models that can predict performance at a larger scale. You want to do the bulk of your process development at small scale to be economical and practical. However, you need confidence that the same process parameters will lead to the same product at large scale, with the same quality characteristics. With scale out, you need to be able to run the same process multiple times on a small scale, robustly and with the same result. With scale out, the biggest variable is often the starting materials, namely the autologous patient cells. Your process needs to be robust enough to handle variation in the starting cell population, or you need to be able to control for variation during your cell selection.

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Dave Backer
Head of Virus & Gene Therapy Strategic Initiatives