A Biotech Revolution

To celebrate the 20th anniversary of BioProcess International, Tony Hitchcock (technical director at Charles River Laboratories) participated in a supplier survey on important bioprocess innovations, technologies, and advancements over the past two decades. He has over 38 years of experience in the biotechnology industry, specifically in production of critical starting materials and complex biologics for clinical trials.

What is the most important bioprocessing innovation in the past 20 years? The emergence and adoption of single-use production systems has been important both for contract development and manufacturing organizations (CDMOs) and the sector overall. Although cross-contamination risk is a factor in the manufacturing of all biopharmaceutical products, that risk is especially significant for

Establishing reliable cleaning procedures for removing plasmid DNA (pDNA) and viral vectors is difficult because of the sensitivity of assays based on quantitative polymerase chain reaction (qPCR) to determine residual product levels. The bioprocess industry also lacks established acceptable levels of product carry-over by regulators or quality groups, to ensure patient safety.

About 20 years ago, biomanufacturers producing clinical-trial materials often resorted to regarding stainless-steel equipment as “single use” when product changeover was required. Such was the case for equipment for downstream processing, where product concentrations can be high and contamination removal can be difficult (e.g., in tangential-flow filtration (TFF) and chromatography flow paths). That approach was unsustainable and expensive because it sometimes required that all product-contacting parts be replaced (e.g., flow paths, vessels, and elastomers).

When single-use equipment became available, manufacturers such as Cobra Biologics (now integrated into Charles River) adopted those components, initially with bioprocessing bags and membrane systems and then with complex systems such as single-use fermentors and TFF systems. The adoption of single-use systems had profound effects on the operation of CDMO businesses because it reduced or eliminated the burden of cleaning and testing equipment and eliminated the risk of cross-contamination.

The implementation of single-use systems also changed approaches to process design and manufacturing scale. Those changes enabled process development for novel therapies, including advanced therapy medicinal products (ATMPs). Traditionally, such development required engagement with process engineers as well as significant capital investment (e.g., in equipment, cleaning systems) and in sterilization infrastructure. The use of single-use systems enabled process development and operations personnel to design and configure processes without those requirements. Timelines and costs for development also were reduced, enabling new processes or the updating of existing processes.

Thus, small CDMOs have become engaged in the production of pDNA and viral vectors for clinical trials with low levels of capital investment in facilities and equipment, supporting the establishment of multiproduct facilities to manufacture both clinical-study and commercial materials. Such advancements are important to facilities that manufacture clinical-trial materials because often only one or two batches are required. The use of single-use technologies also means that suppliers processing commercial materials of drug substances and/or drug products can perform rapid turnarounds between products. In turn, facility designs, site layouts, and build approaches changed. Simple facilities (in terms of capital equipment) were constructed, but they had significantly complex logistical requirements because of the number of consumables components required (>1,000 per batch).

CDMO capabilities have expanded in the bioprocessing space. Before single-use adoption, most CDMOs were established manufacturing facilities seeking to use unused capacity. Single-use platforms have enabled capacities to be established rapidly in purpose-built facilities for both antibodies and ATMPs. Single-use technologies have supported manufacturing platforms for new clinical entities (e.g., for pDNA, viral vectors, cell therapies, and exosomes). Although some large-scale commercial products will continue to be made in sites supported by stainless-steel equipment, single-use systems also will be a critical part of producing existing and future clinical entities.

What has been the regulatory development that has shaped the growth of your company? Introduction of the European Clinical Trials Directive (2001) has had a profound impact for European manufacturers. It has been a double-edged sword in placing significant costs onto manufacturers, including the need to be regularly inspected and licensed by member states national regulators. For small and start-up companies or academic centers establishing manufacturing capabilities, it is especially burdensome because there has been an increase in regulatory expectation around facility design and quality management systems. For product developers, however, it has created a level platform for the quality systems applied to the production of clinical trial materials and has meant that product manufactured under these regulations can be used for global clinical studies, which is important for developers wanting to access multiple clinical trials centers and global expertise.

What has been the most important development in bioprocess business strategy? An increasing number of mergers and acquisitions (M&A) in the sector has influenced the relationships between suppliers and producers significantly. Suppliers have grown through acquisitions of stand-alone single-use vendors and through investments based on the adoption of single-use systems for commercial and clinical production. Companies have become not only equipment or consumable suppliers, but also whole-process “solution providers” for antibodies, vaccines, and ATMPs. In turn, the bioprocess industry has increased its dependency on a few key suppliers, and some biomanufacturers are relying on a single supplier for much of their production equipment and consumables. That dependency has lead to both biomanufacturers and CDMOs facing delays caused by supply-chain issues.

The CDMO sector has experienced M&A activity to expand core capabilities for both established and new therapies. Although many CDMOs have emerged in the cell and gene therapy space, the manufacture of such products is complex. Part of that is a result of maintaining supply chains for critical starting materials (e.g., pDNA and viral vectors) and raw materials (particularly for cell therapies) as well as the need for complex testing and characterization of those products. Thus, it is not surprising that the bioprocess industry has experienced significant M&A in that area, with many companies developing “end-to-end” solutions.

For example, Charles River has integrated cell and gene therapy acquisitions Cognate BioServices, Cobra Biologics, Vigene Biosciences, Hemacare, Cellero, Distributed Bio, and Retrogenix to expand its impact along the drug development life cycle beyond existing industry-leading drug discovery, safety/toxicology assessment, and analytical development/testing portfolios. The company offers human cellular material, pDNA, and viral vector supply through cell modification, selection, release, supply, and broad access to patients.

Which of your company’s products or services have been most successful in the past 20 years? From my perspective, the key services that Charles River offers have been in the production of pDNA and gene therapy vectors. Early on, pDNA was used almost solely as a direct therapy and was deemed to be safer than viral-based gene delivery through human adenoviral vectors. Significant effort was invested into the development of DNA vaccines for HIV, but those vaccines were unsuccessful and interest in large-scale plasmid production fell during the mid-late 2000s. The market remained that way until around 2015 when an increasing number of clinical studies became successful with therapies based on adenoassociated virus (AAV) and lentivirus (LV). In turn, funding for developers increased, enabling them to bring those therapies to clinical trials and to the market. Thus, the pDNA industry is expanding rapidly, along with an upturn in the numbers of players in what is forecast to be a key market in the next 10 years.

Gene therapies have been a part of the biomanufacturing industry over the past 30 years. These products had an initial surge of interest during the 1990s, followed by technical and clinical setbacks and a reemergence over the past 10 years based on the clinical successes of AAV- and retro/LV-based therapies through transient production. Production of vectors through transient production routes requires manufacturing three or four plasmids for each viral vector. That requires biomanufacturers to commit to significant time and cost demands. To alleviate that, regulators recognized that there was not an absolute requirement for plasmid to be produced to GMP and that it should be produced to a “high quality.” Our team has developed phase-appropriate manufacturing strategies and now manufactures GMP/high-quality and non-GMP, research-grade pDNA.

The bioprocess industry needs highly robust production platforms that can produce multiple plasmids without extensive development with identical production equipment. The outcome will be standardized manufacturing platforms that can perform at different scales and under different quality systems to meet customer requirements for early to late-phase trials and commercial supplies. The Charles River Laboratories team continues to innovate, adapt, and expand to serve rapidly growing market spaces. For example, we are opening the Alderley Park site to expand our pDNA capabilities, tripling HQ plasmid production, and launching off-the-shelf plasmids.

The gene therapy market is likely to continue to have a high level of diversification in terms of use and routes of generation. I expect that production scales will need to increase to support commercial AAV vector production, which might require multihundred-gram amounts of key products. We also are seeing the emergence of personalized therapies and the production of plasmid or mRNA using synthetic approaches. Those technologies will create substantial near-term difficulties for manufacturing, regulatory, and quality groups to overcome, but they also will create significant opportunities for drug developers and equipment manufacturers in the future to advance patient treatment options for severe diseases and conditions.

Tony Hitchcock is technical director at Charles River, IC5, Innovation Way, Keele Science Park ST5 5NT; 44-1782-714181; [email protected].