What needs to happen in order to bring the science and manufacturing in sync.

MilliporeSigma announced an expansion of its Carlsbad, California facility, which is scheduled to be completed in 2016. In order to meet the demand for viral and gene therapy products, the Carlsbad campus will increase from 44,000 square feet to 65,000 square feet, with 16 modular viral bulk manufacturing cleanroom suites, two fill/finish suites, and twice the warehouse capacity.

Martha S. Rook, Ph.D.—Head of Novel Therapies at MilliporeSigma—participated in an exclusive Q&A regarding their new facility as well as what needs to happen in order to bring science and manufacturing in sync.

Q: Congrats on the announcement of your recent expansion of your Carlsbad, California facility! I see that the expansion is primarily for gene therapy, immunotherapy, and viral vaccine production. Could you describe some of the events leading up to this decision?

Rook​: The SAFC Carlsbad facility has specialized in the clinical manufacturing of intermediates and final products used in viral vaccines and gene therapies since its inception in 1994. The manufacturing of these viral vectors 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.

Q: What are some of the things you hope to see/accomplish with the expansion of your California facility?

Rook​: 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: I also saw that the expansion will incorporate single-use equipment in a flexible, scalable format for clinical and commercial bulk drug production. Could you describe how your facility was previously arranged?

Rook​: The use of sterile, single use disposable materials has always been part of our manufacturing platform. However, historically the cell expansion in the facility was carried out using flat stock production, primarily multi-stack systems, which require large amounts of incubator space and manual handling. The new facility is designed to also incorporate single use bioreactors which can allow more efficient scale up and more closed, automated processing.

Q: In the current manufacturing environment, some people say that the science has gotten ahead of manufacturing capabilities. What are your thoughts on that?

Rook​: There have been a number of advances in gene therapy and gene modified cell therapy space, particularly around the gene delivery vectors like AAV and lentivirus that are very exciting scientifically and also leading to some very promising clinical results. As these therapies are making their way through clinical trials and approaching commercialization, the field is beginning to realize that there needs to similar process engineering innovation to enable commercial production to be robust 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 SAFC Carlsbad manufacturing experience and our MilliporeSigma product and process knowledge.

Q: What are some of the scientific advancements that are currently impacting pharmaceutical manufacturing? How have they gotten ahead of manufacturing capabilities?

Rook​: A number of the current manufacturing processes that we are involved with, particularly in the field of ex vivo gene therapy and adaptive T cell therapies, use lentivirus to deliver a gene of interest to autologous or patient cells. The technology has had impressive clinical results, but the manufacturing challenges along with logistics have put a strain on manufacturing entities more used to traditional batch based manufacturing processes used for “off-the-shelf” therapies. The need to manufacture on demand for a personalized therapy where the patient is in dire need of the expanded cells, coupled with the rapid biosafety and release testing required, is leading to multiple opportunities for manufacturing, logistics as well as rapid release testing innovation.

Q: In your experience, how long does it take to incorporate a new scientific technology into a manufacturing process? What are some of the things that might deter/slow down its integration? What are some of the things that might speed up its time to implementation?

Rook​: The time needed to implement new technology really depends on the technology. Something simple like implementing a new bioreactor system, particularly if you are changing from one suspension system to another, may take only a few months to a year. Developing something more fundamentally different, like a new way to produce a vector, could take multiple years. It’s also important not to underestimate the effort around process understanding, robustness and understanding your design space, followed by the requirements of validation. It’s one of the primary challenges in new therapeutic areas like gene therapy, time to the clinic is very important as a way of understanding the potential of the therapeutic. However, you also need to be planning for your commercial manufacturing process that may be incorporating new technology. How can you bridge the current, often traditional, manufacturing method that can meet a phase I clinical supply need with innovations required to manufacture efficiently at commercial scale? The earlier in your development process that you can start planning this, the better the outlook for a successful incorporation of new technology.

Q: From a manufacturing standpoint, what is one of the most difficult hurdles to overcome when moving from clinical to commercial-scale development?

Rook​: It’s really about planning early for a scalable production platform where you really understand your critical process parameters. Often companies are leery of moving away from proven technology. This can be a problem when it comes to scalability. It’s much more efficient to do two large production runs rather than ten small productions, 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: Is there a difference in scale up and scale out between various drug products?

Rook​: With regards to viral vector production, we perform batch production, so we are concerned with scaling up. For cell therapy production—which our customers perform but we do not at SAFC Carlsbad—autologous or personalized therapies are scaled out, while allogeniec or off-the-shelf therapies are scaled up. The two processes are similar in that you need to understand your manufacturing process. You need to understand the critical process and quality parameters and demonstrate robustness and repeatability. However, beyond that, scaling up and scaling out are quite different.

When scaling out, you need good scale down models that can predict performance at 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.

Q: How can the process of moving from clinical- to commercial-scale development be standardized? (Are there certain processes that are standardized already?)

Rook​: In the near term, standardization is being driven by using a master validation planning process; we consider this to be a customer’s roadmap to commercialization. Currently, the processes are quite unique to the client and the product they are generating. Going forward, the ideal is to move to more templated processes for the most common viral vectors like AAV and lentivirus, similar to the consolidation that led to the current template for monoclonal antibody manufacturing. This is going to require some process and product innovation but with the clinical promise these therapies it seems inevitable that this type of innovation will occur.

Q: Do you think the DSCSA regulations and various serialization requirements will impact the scientific technologies that are integrated in pharmaceutical/biopharmaceutical manufacturing?

Rook​: These regulations are having an impact in the pharma field in general and will need to be addressed for cell and gene therapy drug products as well. However, I don’t see it as an issue for manufacturing technologies, but more regarding how you track the final drug product. This is already an issue for autologous cell therapies more for safety reasons than the anti-counterfeiting that we generally think of with these regulations.

Q: What are some of the technologic trends you are seeing in pharmaceutical manufacturing space?

Rook​: There is definitely a continuing move towards closed, pre-sterilized manufacturing systems. Particularly with regards to cell and gene therapy, there has been a shift towards single-use bioreactors both for suspension but also adherent cells either through fixed bed reactors or microcarrier cultures. On the downstream side, disposable single-use and pre-packed columns are also driving efficiency. Similar to our expansion, the move towards modular, single-use based facilities is making manufacturing more flexible and able to be tailored to a drug products manufacturing needs.

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