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Manufacture Advanced Medicine, Technology and Equipment

Technology Leads the Way

sponsored by Bio-Rad

Cell and gene therapies are rapidly establishing themselves as one of the most exciting areas within the biopharmaceutical sector. The number of cell and gene therapy clinical trials rose by 37 percent in the UK alone in 2018. However, as with any new therapeutic modality, there are challenges, and it’s fair to say that these advanced medicines are some of the most complex medicines to work on. Patient-specific cell and gene therapies need to be manufactured using a one-batch-per-patient method – success relies on the manufacturer’s ability to edit genetic material and manipulate the patient’s cells safely and in a time-critical situation. This leads to a lot of process and manufacturing challenges.

Access for all

The right technology and processes are essential to develop and deliver these therapies to patients – but often the solutions can be complex. One of our objectives is to make relevant technology as easy to use as possible. For example, one important technology for cell and gene therapy development is Droplet Digital PCR (ddPCR). At Bio-Rad, we believe in making technology accessible to everyone, not just the specialist. As such, ddPCR is accessible to a broader audience. If we can bring a little simplicity into an already complex system, the operators can concentrate less on technology and more on generating the biological results.

ddPCR technology is a high throughput and flexible technology which partitions target molecules into roughly 20,000 droplets per well. This yields a dynamic range of 0 to 150,000 copies per well, or higher by simply merging multiple wells. This high number of partitions yields greater precision and accuracy when checked against standard WHO reference materials. The methodology is particularly good for measuring exact copy numbers, especially in the lower copy ranges, which is critical for these therapies.

The precision of quantification can make a significant difference in manufacturing processes and help companies address concerns raised by regulators. Our ddPCR System is being used by drug developers to precisely and accurately measure the biological dose of an edited virus or cell, and establish how many genes per cell are successfully integrating on target. ddPCR is accurate at very low, “rare event” numbers, measuring down to between one in ten thousand and one in a million. The ability to perform precise rare event detection means ddPCR technology serves as a critical analytical QC assay for cell therapy bioprocessing through its ability to measure the amount of mycoplasma, bacteria or host cell contaminants in the manufacturing process, where ddPCR’s strengths in precise rare event detection will serve as critical QC assays for cell therapy bioprocessing.

Going with the flow

When manufacturing cell and gene therapies, it is critical to be able to measure the physical and chemical characteristics of a large volume of cells rapidly and consistently. Flow cytometry has been the standard method since the 1970s and has been constantly enhanced over the years, resulting in ever more sophisticated ways to analyze cells. Currently, high-end cytometers can measure more than 25 parameters per cell and between 10,000 and 30,000 cells per second. For example, at Bio-Rad, we have developed the ZE5 Cell Analyzer. This system can be configured with up to five lasers and 30 detectors, with an optional small particle detector. The ZE5 Cell Analyzer was designed for the translational biology and biopharmaceutical community with the ability to easily integrate automation. This allows our customers to perform multiple analyses including high-resolution immunophenotyping and exosome analysis.

It is critical to be able to measure the physical and chemical characteristics of a large volume of cells rapidly and consistently.

Getting highly specific

One of the challenges of CAR-T cell therapy development is the measurement of cellular kinetics in the patient. It is crucial to be able to discriminate between CAR-T cells and normal T cells at several stages, and this can be done with a specialized antibody. Our custom recombinant antibody service uses HuCAL technology to generate an antibody that is highly specific to the chimeric antigen receptor. This unique antibody is a critical reagent needed for the quantitative assessment and tracking of CAR-T cells in patient blood using flow cytometry. The provision of custom services using HuCAL technology is unique to Bio-Rad in the research antibody field. It is an in vitro technology, using phage display to select antibodies from a naive synthetic antibody library consisting of 45 billion antibodies. The in vitro method enables us to select antibodies that meet very specific criteria and deliver them in as little as eight weeks; antibody generation can take six to nine months using traditional animal immunization methods. Because we are not relying on the immune response of an animal, we can generate antibodies to challenging targets, such as drug antibody variable regions, post translational modifications, protein complexes, non-immunogenic proteins and toxins, as well as the more usual proteins and peptides. The sequence of every antibody is known from the outset, and this coupled with the recombinant production method means scientists can be confident of a long-term secure and consistent supply for research projects or clinical studies. Every custom project is designed in collaboration with the client, and carefully managed by our antibody experts from beginning to end.

Working with regulators

It is particularly important in these early days of cell and gene therapies that authorities, researchers and commercial companies work closely to provide a rational regulatory framework. We’ve been delighted to be invited to discussions with a number of different internal divisions at the FDA, regarding areas where our technologies can impact research and manufacturing processes. As the provider of a new technology that is being pulled into many research and manufacturing processes, we find ourselves partnering with both the regulators and the practitioners, and providing support and education to both. For us, being part of that dialogue early on has been extremely productive and we look forward to the outcomes from these discussions and being able to have a positive impact on the research and manufacturing of these important therapies.

As a company deeply embedded in this sector, it is exciting to see how rapidly the field is evolving in multiple ways. The notion that we are able to produce tailor-made treatments that originate from an individual patient took time to be accepted as a viable, commercial-scale option but the various challenges from R&D through to those now being faced in manufacturing and scalability have helped drive innovation in the field. We are proud to be part of this process by providing the field with innovative tools and technologies, and we expect to see the momentum continue to grow in the years to come. By providing systems that can be operated by anyone from entry-level to highly experienced researchers, we’re helping to bring next-generation technology to a wider audience – and ultimately helping manufacturers bring revolutionary new therapies to patients who desperately need them.

Dawne Shelton is Associate Director for ddPCR IVD products, and Eli Heffner is R&D Manager III, both at Bio-Rad Laboratories.

BIO-RAD, DDPCR, and Droplet Digital PCR are trademarks of Bio-Rad Laboratories, Inc. in certain jurisdictions. HuCAL is a trademark of MorphoSys AG in certain jurisdictions. All trademarks are used herein are the property of their respective owner.

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About the Authors

Dawne Shelton

Associate Director for ddPCR IVD products

Eli Heffner

R&D Manager III, both at Bio-Rad Laboratories

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