In this podcast, we talk with Ratish Krishnan, Associate Director for Cell & Gene Therapy BioProcessing for the Americas with MilliporeSigma about the tremendous promise gene therapies have for changing the healthcare paradigm, challenges in manufacturing and solutions.

Show Notes:

We began the interview by discussing the tremendous promise that gene therapies have for changing the healthcare paradigm, and also the challenges in delivering on that promise. I asked Ratish if he could explain what he thinks the biggest challenges in gene therapy production are. He explained that he believes  companies are already delivering on the promise of the technology and this can be seen in the steady increase in approved gene therapy therapeutics. That said, challenges remain in manufacturing and he categorized the challenges into three primary areas.

1. Unique – Unlike monoclonal antibody production, viral vector processes have no recognized templates for process development, manufacturing capabilities or capacities. In addition, there are multiple AAV serotypes which have to be considered in process development and different dosing requirements based on the target indication. Lastly, there is an overall lack of established experience in viral vector production.
2. Urgent – This addresses supply and demand issues. Because these therapeutics are intended to cure rare diseases, the timelines for process development and manufacturing are compressed. The race to market encompasses not only process  and assay development, but also technology transfer and manufacturing time.
3. Uncertainty – Due to the lack of historical data and shorter history compared to monoclonal antibody counterparts, there is a focus on the evolving regulatory situation. Guidances are being drafted to accommodate these novel therapies, while still keeping patient safety in mind.

Next I asked if he could share MilliporeSigma’s role in providing solutions to these challenges. He described how MilliporeSigma leverages their 350 year history of success in other modalities such as small molecules, monoclonal antibodies, plasma and vaccines in support of their gene therapy customers. They believe in taking an integrated and holistic approach to gene therapy by providing customers with quality products, services, educational resources and collaborations.

Specifically, he discussed how they have created gene therapy products that are both fit for purpose and purposefully build for viral vector manufacturing. They provide analytical testing services and their routine platform testing methods provide clients with an alternative to developing time intensive custom methods for release testing. This is in addition to their CDMO manufacturing capabilities in Carlsbad, California where they have over 25 years of experience in viral vector manufacturing platforms.

He went on to say that they also have internal research and development labs dedicated to bioprocessing of novel modalities.  State of the art collaboration and innovation centers called M Labs are located globally that customers can leverage as well.

Ratish shared that he thinks that the most important ingredient in their recipe for success is the comprehensive expertise of colleagues in process and technology consulting, including complimentary process development support and technology management for each unit operation and single use and hardware teams. Customer education is another key asset with access to a variety of courses on bioprocess related topics including gene therapy. Lastly, he explained that MilliporeSigma has very close relationships with customers who view them as partners in their journey to commercialization of their therapies.

We then discussed manufacturing capacity and how it is estimated as 1-2 orders of magnitude lower than what we need to meet the demands for gene therapies in development. In addition, Covid-19 has added to the constraint. He explained how we are in a unique situation with gene therapy where the demand is far greater than supply and this has created a manufacturing capacity bottleneck at the moment.

The pandemic has made the availability of raw materials and products more challenging from the lens of product supply chain and delivery. He shared that several of their novel modality customers are focused on bringing a treatment, be it monoclonal antibody, plasma or vaccine to market to suppress the pandemic and they have observed that gene therapy clinical trials and regulatory filings are being delayed as a result. Critical lab activities are also taking a hit as companies comply with social distancing measures and there has been a halt of face to face engagement.

Regardless of the pandemic, patients are still awaiting these life saving treatments using viral vectors. From experience, Ratish believes we should be ensuring proactive communication and dialogue between customer procurement teams and vendor account managers. For in-house manufacturing, forecasting supply demands as accurately as possible is going to be critical. Conversely, for an outsource supply scenario, an upfront discussion with the CDMO on contingency plans must be established to ensure drug supply.

Pandemic aside, Ratish stressed that the use of templated processes and optimized processes will ensure timely scale up and avoid any surprises in technology transfer and manufacturing whether in-house or at a CDMO.

I then asked about what can be done about compressed timelines for gene therapies and how to enable a faster time to the clinic. Ratish said that there are several components that can enable faster time to clinic. Having a platform process for viral vectors during process development carries a lot of weight. Even if the entire process can be templated, individual unit operations can be platformized in sections such as upstream bioreactors, harvest step, depth filtration, chromatography, and fill and finish steps. At their CDMO in Carlsbad, Ratish said  they performed a study where they projected an estimated time savings of 14-18 months upon analysis using a templated process. Other catalysts that he discussed included better process understanding, risk mitigation of raw materials, and strategies such as virus and other residual clearance and quality profiles. Establishing and securing the supply of clinical material either in-house or at a CDMO is also very important.

Finally and perhaps most important, Ratish recommended leveraging the experience of vendors. Since vendors provide all the raw materials to make the drug product. It is key to engage with vendors early and often, as vendors like MilliporeSigma can help gene therapy manufacturers by doing the work for them, with them, or help them make the product themselves.

Next, I asked Ratish about what is critical to ensuring success with the regulatory process for gene therapy developers. He said that it is important to emphasize a quality first mindset. Yield is important, but quality outweighs yield any day. It is also important to design and develop a process that uses quality raw materials that are chemically defined or animal-origin free. He mentioned MilliporeSigma’s Benzonase^® endonuclease Safety Plus Emprove^® Expert product, which is completely animal-origin free starting from upstream raw materials used in the fermentation process. As regulatory guidelines are developing for viral vectors, the emphasis is on using quality raw materials in the process.

He went on to say that we should also design a process that is so robust that residual impurities such as host cell proteins, DNA and others are below detectable levels. A well defined quality profile of the drug product with appropriate adventitious agent control strategies, even if it is a gray space at the moment, is also important.

With AAV, it is also critical to keep in mind the remaining percentage of empty capsids in the drug product, even though today there isn’t a clear guideline on a defining number. Lastly, using qualified and validated assays for characterization of cell banks, process intermediates, and release testing from MilliporeSigma are steps in the right direction.

We moved on to talk about how to improve yield and scalability. Ratish said that he feels that there is always an opportunity for process improvement regardless of the stage of the program. Optimization is often deprioritized over speed, therefore keeping the strategy simple is key.

To improve yield, you need to produce more vector upstream and lose less vector downstream, he laughed and said that for anyone who has worked in bioprocessing, they know that this is easier said than done. There are trends in the industry to improve yield and scalability, such as using suspension cultures with cell lines and chemically defined media to maximize bioreactor production. He strongly recommends listeners take a look at MilliporeSigma’s VirusExpress™ platform for lentivirus production and their upcoming insect cell line platform for AAV production that is rhabdovirus negative.

There have also been advancements in synthetic media for filters used post harvest during depth filtration and clarification, such as the Millistak® pro filters enabling one-step clarification in most cases. Optimization of processes and avoiding losses in other unit operations, such as using Fractogels® and Eshmuno® ion exchange resins for chromatography steps, tangential flow filtration using Pelicon® membranes and capsules to minimize losses in ultrafiltration and diafiltration, and final filtration steps using Millipak® filters.

For scalability, getting an early start thinking about scale up activities while designing the process is important. For instance, considering the use of suspension upstream as opposed to adherent cells. Implementing a chromatographic approach to purification as opposed to ultracentrifugation. There are pros and cons to each and it is important to evaluate these options early in process development.

We then discussed how for many gene therapy developers there is limited time and expertise around moving a production process from research to clinical use and I asked Ratish what advice and suggestions he had for developers with these challenges. He said that there are two important success factors here, time and expertise. Not spending time on process optimization can come back to hurt a program. The process is the product in gene therapy, so it is critical to spend time on process development and optimize processes so they meet current and also future demands.

Looking back, he says the advice that would have helped him in previous roles would be that technological expertise matters and that as a customer it is important to fully understand the capabilities that vendors like MilliporeSigma bring to the table. These capabilities are sometimes overlooked, so it is good to think of vendors as partners in solving problems and to draw on their experience as it is a great source of knowledge. Very few vendors can bring the complete portfolio of products, services, resources and training as integrated services like MilliporeSigma can. The best way to accelerate programs and advance gene therapies from bench to the clinic is through partnerships and collaborations.

I closed by asking him if he had anything else he would like to add for listeners. He said that he could relate to customers working in gene therapies and gives them kudos for developing novel therapies at unprecedented speed. Gene therapies have provided hope to patients where there previously was none.

Viral vectors are complex with known unknowns and unknown unknowns. Some have placed gene therapy on the same pedestal as the iconic landing on the moon. Others have equated gene therapy development with running a marathon at sprint speeds or building a parachute while jumping out of an airplane. Ratish believes these are all true. He went on to say that the reality is that there may not be a silver medal in gene therapy and the winner could take all the market share for a specific indication. Products and services are important in the journey to commercialization, but the secret ingredient in the gene therapy success recipe is the expertise that comes with the people that you collaborate with to solve your toughest problems.

To learn more about MilliporeSigma’s Gene Therapy Product Line and services, please see EMDMillipore.com/genetherapy

The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada.