August 1, 2016 PAP-Q03-16-CL-013
More than 500 companies are involved in cell therapy technology,1 while the market for gene therapy is predicted to be valued at greater than $200 billion by 2020.2 Globally, there are over 2300 gene therapy3 and 372 cell therapy4 clinical trials currently in progress targeting numerous cancers, hemophilia, diabetes, cardiovascular, neurologic, and many other acquired and inherited diseases.
The rate at which new positive results are reported for these clinical studies is accelerating. The evidence strongly suggests that these next-generation therapies have real potential to help patients with currently untreatable diseases. Not surprisingly, investment in the cell and gene therapy sectors has risen dramatically. Also to be expected, pressures are mounting to move these promising treatments from the clinic to the market.
While a limited number of non-modified cell therapies have been on the market for several years, until recently, there has not yet been a gene or modified cell therapy commercialized. As a result, the majority of activities in the field are at the discovery phase including in human clinical trials, and there is very little direct experience with large-scale and commercial manufacture of these novel drug products. Robust, routine-manufacturing operations that can support the launch and ongoing supply are therefore a significant hurdle to be overcome.
Scalability is one of the biggest challenges. Often, the processes developed for the production of gene and modified cell therapies for testing in animals or early clinical studies have been designed without considering the requirements for late-stage routine commercial supply. As a result, certain manipulations that are not scalable must be re-engineered in order to achieve scalability while preserving product quality (purity, potency, etc.) and yield. In addition, because these products are living organisms — whether viruses for gene transfer or cells — certain processes, such as freezing for cryopreservation and later thawing for patient administration, require manipulations and formulations that are able to maintain product potency.
New analytical methods are also required. Preservation of product strength, potency and other key attributes is crucial for the clinical and commercial success of gene and cell therapies. As production processes move toward late stage clinical trials and commercialization, better process characterization and ultimately validation is required. Rapid, cost-effective and accurate analytical methods will be crucial for not only process monitoring, but also product release and stability testing. Improvements are needed in current analytical techniques in terms of overall performance and automation, but also specificity, accuracy, and sensitivity.
Manufacturers will also need to meet regulatory requirements, which are evolving as our understanding of these next-generation treatments increases. Current regulatory guidance is fairly clear on how to manufacture cell and gene therapy products, but as the industry matures and progresses to large-scale operations, it is likely that additional regulations will be established. However, while traditional biological manufacturers work tirelessly to prevent viral contamination of processes, the production of viral vectors requires the use of viruses, which necessitates rigorous changeover and decontamination processes at a level that is not common for traditional manufacturers. This requires changes to facility designs including construction material choices, room classifications, and material and personnel flows to ensure product and personnel safety.
Regardless, there are requirements that must be met if any changes to processes developed for the production of clinical trial materials are made to facilitate large-scale manufacture. At a minimum, equivalency tests to demonstrate that product attributes are maintained must be conducted. In some cases, that may consist of analytical testing in the laboratory. In others, additional comparability studies in animals are needed. For a radical process change, the addition of another arm to a clinical trial in humans may be necessary.
Although gene and cell therapies consist of living organisms, manufacturers with extensive process understanding and knowledge of the capabilities of currently available manufacturing technologies can develop robust, well-controlled and cost-effective larger-scale processes. Equipment suppliers are also actively developing solutions specifically designed for the manufacture of cell and gene therapy products, with a greater reliance on single-use technologies.
Importantly, these next-generation products need to be manufactured in cleanroom environments that provide containment and minimize cross-contamination risk. The ability to rapidly switch between processes and manufacturing campaigns for different products is essential for cost-effective production of these next-generation products. Therefore, facilities and processes must be designed to ensure that the environment, equipment and all ancillary items can be quickly cleared or decontaminated/cleaned in situ.
As a result, single-use technologies, which are increasingly being adopted for the commercial-scale manufacture of recombinant proteins, antibodies and other conventional biologics, are essential for cell and gene therapy production. Not only reactors (stirred tank, wave, etc.), but newer, reliable chromatography skids with disposable flow paths will be key enablers of larger-scale cell and gene therapy manufacturing. It is also desirable to perform as many unit operations as possible in closed systems to provide additional protection to operators, the environment and the product.
Automated workstations for the manipulation of cells (e.g., transduction or transfection) for modified cell therapies and expansion in built-in bioreactors are also available. While there is a long way to go before this technology will facilitate larger-scale manufacturing, it can be deployed in a scaled-out fashion. Advances in the control and process analytical technologies for disposable bioreactors are also expected, that will allow for the development of more robust, large-scale processes, leveraging many of the advances in process monitoring and control that have been developed by traditional biologics’ manufacturers.
It is also worth noting that advanced analytical techniques will be important in late-stage cell and gene therapy manufacture. For instance, traditionally, viral transfer vectors are analyzed for purity using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE) and staining, but there is progress toward the use of high-performance liquid chromatography (HPLC) as an alternative platform for the determination of impurities and product profiles. New technologies, such as analytical centrifugation and dynamic light scattering (DLS) for the evaluation of product attributes and aggregates, are also finding applicability. These developments reflect a trend toward the enhancement of analytics to meet the unique needs for robust and cost-effective cell and viral vector production.
Successful scale-up of manufacturing processes for next-generation therapies requires a deep understanding of the science and biology of these classes of products. Without understanding the products, it is challenging to develop cost-effective, high-yielding, robust processes that include essential and effective sanitization and decontamination regimes.
Upfront investment in careful facility, equipment and process design with the goal of preserving the potency of these living products, while also achieving high yields and purity levels, is also important. Such an approach cannot be achieved, however, without an understanding of the critical product attributes and knowledge of the process parameters that must be controlled to preserve them.
Because gene and modified cell therapies are emerging technologies, and these will not be introduced into existing biologics facilities due to cross-contamination concerns, few pharma and biotech companies are positioned to invest in the manufacturing capabilities needed to move their promising candidates to phase II trials and on to commercialization. In particular, startup companies and more established C> platform firms that are focused on discovery and early phase work typically do not have internal manufacturing capabilities and are unlikely to make the capital and organizational investments to create these. While some large pharma and biotech companies are installing in-house development facilities, many have partnered with early stage companies and thus require external development and clinical manufacturing support.
In addition, there has been a significant shift in the strategic approach to product development for many companies. In the past, most innovator firms developing new gene and modified cell therapies focused primarily on demonstrating proof-of-concept through successful phase I/II trials and then sought to partner their initial programs. Today, an increasing percentage of these organizations are taking a much longer term view. They recognize that phase I/II studies represent the beginning, and that evolution of both processes and analytics will be required to reach phase III and ultimately the market. This shift can largely be attributed to the growing demands of investors for companies to have a perspective/plan in place that provides a clear path to commercialization.
While there are quite a number of academic/incubator-based organizations with technical experience in cell and gene therapy that can provide initial supplies, there are only a limited number of truly integrated contract development and manufacturing organizations (CDMOs) that can support client projects all the way through phase III, licensure and supply of commercial quantities and quality.
CDMOs like Brammer Bio that have these capabilities and expertise will play a major role in bringing many of the promising new cell and gene therapy products from early clinical trials to the market. Brammer Bio, for instance, has helped take over 100 projects from the lab, to animal testing, to the clinic, with the provision of over 200 batches of clinical trial materials, many of which have supported first in human trials. It also has a team of people with extensive experience applying QbD principles to traditional bioprocess development that can leverage that experience to qualify processes for licensure.
The collective learning gained during the completion of over 100 client projects for gene and cell therapies using a variety of platform technologies has provided Brammer Bio with a tremendous depth of knowledge regarding process development, analytical development, and the identification of optimal manufacturing solutions.
With this high level of experience in viral vector processes, modified cell therapies, and analytical development together with clinical supply and a leadership team that has managed the commercial manufacturing of over 20 traditional biologic drugs, Brammer Bio has the capability of designing and scaling processes that are robust and cost-effective because the needs for large-scale production are taken into consideration from the start. As a result, the company is a dependable source, at the forefront of helping the cell and gene therapy sector mature all the way through to sustainable commercial supply.
Mark Bamforth is the founder and President & CEO of Arranta Bio, which was established in May 2019. In 2015, Mr. Bamforth founded Brammer Bio, a viral vector CDMO supporting cell and gene therapy companies, which was acquired by Thermo Fisher Scientific in April 2019. In 2010, Mr. Bamforth founded Gallus BioPharmaceuticals, a CDMO supplying biopharmaceuticals. In September 2014, Gallus was sold to DPx Holdings B.V., which later became part of Thermo Fisher Scientific. He holds a bachelor’s degree in chemical engineering from Strathclyde University and an MBA from Henley Management College.