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Protein Production of the Future

– A Q&A with Anthony Person, Ph.D.

Anthony Person is a protein expert whose roots were laid in academia and continued to grow in the biopharmaceutical industry. After obtaining his PhD from the University of Arizona in cell biology, he continued to pursue post-doctoral studies at the University of Minnesota in various fields; from discovering the molecular mechanisms of heart valve and kidney development to exploring the genetic cause of Robinow syndrome – a rare type of dwarfism.

An impressive career in industry followed; first in a role at R&D Systems – now a Bio-Techne brand - and subsequently at CellScript, in Madison, Wisconsin, where he focused on developing mRNA-based cellular transformation technologies. Upon returning to Bio-Techne as part of the bioassay unit in 2013, Anthony committed himself to the production and development of GMP proteins.

Now, as the Senior Director of the Protein Business Unit, Anthony has harnessed his skills to drive forward the growing protein division at Bio-Techne. In a recent interview, Anthony gives us his perspective on all things proteins – from his day-to-day and the proteins that support cell and gene therapy, to a brand-new, world-class protein manufacturing facility.

Bio-Techne is a leading manufacturer of proteins for research and clinical manufacturing, led by Protein Business Unit leader Anthony Person.

 

Hi Anthony! Could you tell us a bit about your role at Bio-Techne and how it has evolved this year?

 

I've been the Senior Director of the Bio-Techne protein business unit since 2018. I’m based in Minneapolis, where it all started as R&D Systems. R&D Systems started making recombinant proteins all the way back in the 1980s. We were one of the early pioneers in the field of making recombinant, as well as naturally-derived proteins.

My day-to-day involves managing new product development - I’m heavily involved in coming up with ideas for new protein products that customers really need, developing new products from a technical perspective and ultimately, bringing these products to market. I spend a lot of time meeting with clients to discuss their needs and to collaborate to develop new, custom proteins.

It’s been a really busy and exciting year for me and for Bio-Techne. In the last year, we've released over 200 different coronavirus-related protein products that enable pharmaceutical companies to make blocking antibodies against the spike protein, and for small-molecule therapeutics targeting the SARS-CoV-2 proteases.

On top of this, we've put significant effort into redeveloping our GMP portfolio for higher yields and scalability, which is a real focus for me because it’s such a rapidly growing space. Particularly, we’ve seen a massive growth in the cell and gene therapy market.

 

How has the growth in the cell and gene therapy market affected the demand for specialized proteins?

 

The advent of cellular therapies, which really didn't exist until the early 2000s, has created a whole new need and a new market for proteins. For example, CAR-T and CAR-NK therapies represent genetically modified T/NK-cells that can be used to, for example, fight B cell lymphomas. These therapies rely on proteins, such as our cytokines, for expansion in culture.

Bio-Techne proteins are used in a variety of other cell and gene therapy applications such as keeping induced pluripotent stem cells in their stem cell state, or to differentiate them into different cell lineages for transplantation. The cell and gene therapy field has greatly expanded since the mid-2000s and consequently, has driven increasing demand for GMP proteins as therapies come closer to scale up and commercialization.

As cell and gene therapy transitions through the discovery phase to clinical trials, manufacturing and commercialization, how do customers’ protein needs change?

 

As more cell and gene therapy products go from discovery to commercialization, scalable protein production is going to be necessary to get therapies to clinic. Additionally, accessibility to different grades – such as RUO, GMP, and animal-free variations

 

Moreover, as cell and gene therapies scale-up, ensuring the continuity of supply can become more challenging since larger volumes of proteins are required. This is critical, since disruption to supply chains can interrupt costly and time-consuming clinical trials. Ultimately, cell and gene therapies end up in a patient, so guaranteeing these larger lot sizes remain consistent is paramount to securing the quality and efficacy of a vital therapy.

Finally, the field of cell and gene therapy is a relatively new space, and is extremely diverse. Consequently, access to a diverse, and often custom, set of proteins can be a major hurdle to cell and gene therapy developers.

What can protein suppliers do to support cell and gene therapy developers as they scale-up production?

 

GMP protein manufacturing facility for supplying cell and gene therapy manufacturers with cytokines, such as IL-2, IL-7, IL-15 and IL-21.

Any supplier needs to ensure that they can meet the demands of growing cell and gene therapy manufacturing. To that end, we built a new $50 million world-class facility in St. Paul, Minnesota, which is now fully operational. We're very excited about the transition to the new facility; our lot sizes are going to be substantially larger and we're going to have capacity to scale our production to a much larger extent than we do at our current facility.

We’re re-developing key products from our established E. coli derived, animal-free GMP portfolio and bringing them into the new facility. We've redeveloped them to have much higher yields and to create processes that are scalable, to meet the growing requirements of our customers.

In the new facility, we will continue to provide various grades to match the customer’s needs in their development journey. This includes research use only (RUO), GMP, and animal free-GMP proteins at three different

cost points; corresponding to different levels of quality control, documentation and analytic testing. All grades are manufactured identically, which means they demonstrate comparable activities – making it easy to transition between the grades.

Additionally, we’ve designed the new facility with expanding capacity in mind. This means the potential for even larger bioreactors and protein purification suites, so we can expand in line with our customer’s needs. We have already begun releasing proteins manufactured in the new facility to the market. It's an extremely exciting time for us.

GMP is more expensive than RUO. When would you suggest it is financially justified to invest in GMP?

 

The latest we recommend that cell and gene therapy developers switch to a GMP raw material is when they are moving into a phase one clinical trial. GMP means the protein comes with more testing documentation and QC specifications that guarantees consistency and performance. Therefore, switching from RUO to GMP early in the process can help downstream steps, such as regulatory approval, to become more streamlined.

You have to remember these materials support the manufacture of cellular therapies that will ultimately be put into patients. So, the peace of mind that using a GMP product provides in terms of meeting strict regulations is worth the extra cost, in my opinion.

However, when you make the transition from RUO to GMP is dependent on your risk and cost sensitivity. We support customers through the transition by manufacturing RUO and GMP proteins side-by-side, and using the same process. Therefore, you know that the transition will be as seamless as possible and you won’t suffer the costs of having to switch supplier.

How are you ensuring that cell and gene therapy customers can trust in the quality, consistency and supply of proteins?

 

In regards to continuity of supply, we’ve thought thoroughly about contingency plans. For example, we’ve identified secondary vendors in case there is a disruption to our primary suppliers. This has been particularly important in the context of the pandemic where supply chains have been heavily disrupted.

Scalability, continuity of supply, and lot-to-lot consistency are at the center of what we do

 

To ensure lot-to-lot consistency, we have a range of over 1,000 robust bioassays that we use to QC test and pass our products to market. The exhaustive QC testing we perform ensures quality and truly differentiates us from other biotech companies. We run each new batch against other, previously QC’d lots as well as against a master lot to make sure we’re controlling for assay drift. In other words, to release a new GMP protein to market we have to manufacture three lots at the same scale that meet all the specifications we set forth in the design review process. This includes adhering to World Health Organization standards for activity, USP 71 sterility testing, among other stringent analytical and QC specifications.

We can discuss manufacturing protocols with customers, and we welcome on-site visits and/or audits. In the event there is proprietary information that we cannot share, we’ve submitted Drug Master Files (DMF) to regulatory authorities for some of our GMP proteins. These documents contain extensive detail about the manufacturing process, providing a mechanism for regulatory authorities to access the information, and for a customer to reference the DMF in a regulatory submission in the market of interest.

How does Bio-Techne ensure that cell and gene therapy developers have access to the right proteins for their therapeutic?

 

We have over 5,000 protein products in our catalogue right now, as well as 34 GMP proteins. We are continuing to invest heavily in the GMP protein space, and it is a rapidly growing part of our portfolio. Moreover, we do a lot of custom work with customers.

We have a dedicated custom group that works with customers to design tailored products. Oftentimes, customers have their own vectors or sequences that we can’t reverse engineer to maintain the exclusive/proprietary custom relationship with the customer. In those cases we can design a complete workflow for purifying their protein and optimizing yields to provide the mass quantities they need in the future. This type of collaboration has worked really well - we have various customers in clinical trials for completely customized, non-catalogue products. We can also take catalogue products and customize them per the customer's needs; whether it be specific bottlings, with specific activity units per bottling, different labeling, even extended stabilities.

GMP protein manufacturing begins in the inoculum prep room, at Bio-Techne’s GMP protein manufacturing facility

What do you think sets Bio-Techne apart from other biotechnology companies?

 

I think the number one thing is quality. We go above and beyond to provide the highest quality protein reagents in the business. We go at this from a robust analytical core to ensure consistent and quality proteins – every time. And we also really pride ourselves in having technical experts available, so that customers can always have conversations with the industry-leading technical experts that make the proteins. This gives our customers confidence in our abilities to reproducibly make their proteins. Of course, scalability, continuity of supply, and lot-to-lot consistency are also at the center of what we do. Ultimately, we partner with our customers to enable their cell and gene therapies to reach more patients.

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