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Manufacture Bioprocessing - Single Use Systems, Contract Manufacturing Services, Advanced Medicine

On the Cusp of Curing Disease

sponsored by MilliporeSigma

What is your role at the M Lab™ Collaboration Centers?

Elizabeth Goodrich: I lead the Application Engineering team worldwide, and most of our projects are run in the M Lab™ Collaboration Centers. We don’t work in product development, but we do work with products that are already launched to develop best practices and other useful information that we can deliver to customers to help them streamline their own process development efforts. Often, customers come into the M Lab™ Collaboration Centers so that we can address their specific concerns – they can also learn more about our products and test out different processing strategies. These labs are situated in nine different locations worldwide, so we can reach customers wherever they are.

Ranjeet Patil: I lead the vaccine and viral therapies group, which works with customers in a consulting capacity. Many customers come to the M Lab™ Collaboration Centers to look at our systems and hardware to get a feel for what would be a good fit for them. Gene therapy products are attracting a great deal of attention so my group talks to customers in this area.

What are the biggest needs of gene therapy manufacturers?

RP: There is now rapid growth in the pipeline and this translates to a need for speed. Speed to market is nothing new, but it resonates with gene therapy customers for a few different reasons. Firstly, many companies are targeting rare diseases – and, in many cases, patients won’t have long to live without treatment. Secondly, many of these drug programs qualify for expedited approvals and other companies may be chasing the same targets. You may not have a viable business because there isn’t a large population to go after if your competitor is first to market.

Given that companies want to get to market fast, many decide not to invest in a physical footprint and instead look for a CMO, but capacity at such companies is extremely limited given how many people are developing gene therapies. On the other hand, even if a company wanted to expand and have their own manufacturing capacity, it is extremely challenging to build and effectively operate spaces suitable for gene therapy manufacturing. Infrastructure for any kind of viral process is significantly more expensive than for other classes of biopharmaceuticals. Although there is clarity on the clinical aspects of the process, the manufacturing aspects are challenging because there is no template approach – every process is different and regulatory guidance isn’t straight forward.

What do the M Lab™ Collaboration Centers offer to customers?

EG: Many of the companies working on gene therapies are small – perhaps even virtual – so they have limited human and laboratory resources at their disposal. The M Lab™ Collaboration Centers can be an extension of their resources, giving them relevant tools to work with and a place where they can test new processing options.

We also have a full suite of single-use products available in the centers for customers to evaluate. Single use is a great option for gene therapy manufacturers because there is a huge need for sterility and eliminating the potential for cross contamination. Again, the M Lab™ Collaboration Centers are spaces where customers can visit to see what technology is available, receive hands-on experience, and test to see what will work for their process.

Finally, we offer a wide range of training for equipment , process strategies and manufacturing strategies, under different types of operating conditions. The M Lab™ Collaboration Centers can be used by the process development team to train new hires, and we also see training being delivered to manufacturing operators. If speed to market is critical, you don’t want to have a product approved and then have a delay in getting the product manufactured. There have also been instances where customers come to us and we work side by side with them to create and test their process.

“Single use is a great option for gene therapy manufacturers.”

And how have customers responded to the M Lab™ Collaboration Centers?

RP: Feedback from customers has been excellent. Many developers of gene therapies are still in small research labs (many have been spun out of academia) – and the teams will often under-estimate the real difficulties of manufacturing a therapy at scale. At the M Lab™ Collaboration Centers, the customer brings their understanding of their product and expectations for scale, and we contribute our expertise in each unit operation and our holistic understanding of the implications of certain processes for commercial scale manufacturing.

How is MilliporeSigma preparing for the future?

EG: Gene therapies could dramatically change world health, and will also cause a shift for companies like ourselves. We need to contribute product and application expertise to ensure that these therapies are manufacturable to high safety and quality standards. This also needs to be done in a cost-efficient manner so that patients can access these important treatments.

RP: Product and technology innovation is very important to MilliporeSigma. We are looking at purpose-built tools for gene therapy manufacturers, such as more productive cell lines, more efficient downstream tools, and the biosafety testing services to consistently satisfy regulatory expectations. We are also working to understand how we can become a better business partner for gene therapy developers, as well as other players in the ecosystem, such as other CMOs.

Elizabeth Goodrich is Director of Global Applications Engineering within Manufacturing Sciences and Technology, and Ranjeet Patil is Segment Head, Vaccines and Viral Therapies, both at MilliporeSigma.

Heading to the Clinic

With Michael Mercaldi, Ph.D, Director Purification Process Development at Homology Medicines.

Homology Medicines is a gene therapy and gene editing company that was started based on the discovery of 15 novel adeno-associated viruses (AAV) naturally found in human hemopoietic stem cells (AAVHSCs). This set of novel serotypes enables the selection of optimal AAVHSC capsids for genetic medicines that exhibit differentiated biodistribution, lower immunogenicity and enhanced potency compared to other AAV serotypes. We have discovered that AAVHSCs can perform nuclease-free gene editing in addition to gene transfer. The gene editing capability of these AAVs was shown to harness the mechanism of homologous recombination, the body’s natural DNA repair process. This is different than other gene editing technologies (i.e., CRISPR, ZFNs, etc.), which require a nuclease to cut the DNA and, in doing so, promote another DNA repair pathway called nonhomologous end joining, or NEHJ, a more common yet error prone process. Homologous recombinationbased gene editing has shown to be highly efficient and precise, and utilizes a single component system (i.e., one vector, one construct), making it a more straightforward method.

Currently, we are moving toward the clinic with our lead gene therapy construct, HMI-102. HMI-102 is designed to treat and potentially cure phenylketonuria (PKU) in adult patients.

There are many challenges in the gene therapy space. Leveraging the industry’s experience with proteins (mAbs) is a great start to manufacturing gene therapies, but it’s insufficient, and in some cases provides counterproductive directions. Unlike mAbs and recombinant proteins, where there is a 30 to 40-year bedrock of understanding on how to efficiently and effectively design and produce these therapies, the industry is only just beginning to learn how to do this with AAVs. To this, we feel that the big drivers to advance the field are to increase upstream and downstream productivity, develop more in-depth analytical methods, and to drive development of more specific AAV raw materials and equipment.

At Homology, we are building our own internal process development and GMP manufacturing capabilities and to this point we understand that it requires collaboration among Homology and key partners to solve the challenges in this field. We decided to visit the M Lab™ Collaboration Center this year to work with MilliporeSigma on developing some of our platform manufacturing processes for our AAV therapies. We found MilliporeSigma to be extremely helpful with identifying equipment and consumables that we are testing and may want to implement in our new facility. Their expertise and openness toward collaboration has been very valuable for us as we build out our pipeline and capabilities.

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About the Authors

Elizabeth Goodrich

Director of Global Applications Engineering within Manufacturing Sciences and Technology.

Ranjeet Patil

Segment Head, Vaccines and Viral Therapies.

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