The proof-of-concept studies have shown promising results and bring a therapy a step closer to the clinic. But what is needed before this therapy can show its efficacy in a clinical trial?
Cell therapy is a promising treatment, but its development is challenging due to its complex technology and the regulatory framework in which it operates. Although many general concepts from traditional drug development apply, cell therapy requires tailormade development strategies as every drug is unique and many parameters in the manufacturing process are interconnected. Drug development is required to meet quality standards and justifies the safety and efficacy of the therapy.
This blog will give insights in early phase drug development to bring a cell therapy faster to a first-in-human clinical trial.
Is the manufacturing process GMP suitable?
From a regulatory point-of-view, the first clinical trial is about patient safety. To help ensure this, it is necessary to understand and control the manufacturing of your cell therapy. This is where GMP, Good Manufacturing Practice, comes in: GMP is a set of rules and guidelines that ensures a manufacturing process is controlled, resulting in a consistent process quality.
Batches for clinical trials will be manufactured in collaboration with external partners like hospitals or contract development and manufacturing organizations (CDMOs) according to GMP regulations. Transfer of the manufacturing process from a research laboratory to such a manufacturing site is a necessity. However, not all research processes are suitable for a technology transfer since they may contain activities that cannot be standardized or are not feasible in a GMP environment. This is where process development comes in: the development of a research process into a GMP-compliant process.
An ideal manufacturing process for technology transfer should be on a scale that is appropriate for the clinical trial being planned, has reduced manual and open handling steps to a minimum and is transferable to any manufacturing site. Independent of the origin of the transplanted cells, whether autologous or allogenic, it should be confirmed that the final GMP manufacturing process delivers a product comparable to that obtained at the research scale. Although sufficient material for proof-of-concept studies can be acquired by culturing at small scale, clinical studies due to their larger scale often require bioreactors, bags, or other large volume culture chambers to reach the requested yield for patient dosing. The larger scale may result in process differences e.g., differences in medium refreshment schedule, cell expansion rate, and cell concentration, and this may have an impact on the product quality and final yield. Development of a comparable small-scale model or manufacturing at clinical scale resolves these issues and results in a more easily transferable manufacturing process.
An automated and closed production system reduces deviations during clinical manufacturing. It ensures process robustness, avoids contamination, and will reduce the number of production failures. These failures can be costly: clinical trials may not receive the needed material and the ensuing investigation into the cause of the failure can take a long time. Process development, adapting a production protocol from a manual and open handling process to an automated and closed system, can require significant investments in terms of time and money. As both time and money can be limited in the early stages of development, a balance should be found between the investment in process development towards an automated and closed production system and the risk of manufacturing deviations.
A standardized process would make it possible to manufacture the product at any location in the world. Depending on the manufacturing strategy and the process scale, technical transfers to other clinical manufacturing sites will be more efficient with a GMP suitable process.
Used materials determines the quality of the product
Clinical manufacturing requires raw materials, materials used in the manufacturing process, that are of high quality, free of microbial contamination and preferably with small batch-to-batch variation. Common materials used for cell therapy manufacturing are blood products, culture media, sera, cytokines, RNA, DNA, and viral vectors. Quality of these materials is key for safety of the drug. When these materials are produced under GMP manufacturing, their quality is much more controlled and the use of GMP grade material is therefore highly desirable.
Many research processes have not been developed with GMP grade material. Switching from research-use-only to GMP grade material could have impact on the process due to change of supplier or change of material composition. For example, cytokines from different suppliers, although similar on paper, could have different biological activities and concentrations, and could impact e.g., cell expansion and efficacy. Direct comparison of the different cytokines within a clinical scale manufacturing on many parameters is the only way to assess comparability. Similarly, different culture media or media compositions could influence cell expansion and requires direct comparison studies as well.
While GMP-grade starting materials often have low batch-to-batch variability, this may not be the case in human-derived materials, such as blood products and human sera. These human-derived materials are prone to introducing a lot of variation while essential in some manufacturing processes. As donor variability cannot be prevented, an enhanced understanding of the impact of the variability on the manufacturing process can be obtained by increasing the number of tested donors during process development.
In the allogeneic setting, when upscaling is preferred, another issue introduces variation. Each donation from one individual is limited in the maximum number of cells that can be obtained. Several donations from the same donor or donations from different donors could be required to meet the final product quantity. Banking of donor cells from repeated donations could be a solution only when cryopreservation of the material does not have any impact on the quality of the product. The use of stem cells may be another way to circumvent this issue but could involve a complete change of the manufacturing strategy and bring the program back to the start of drug development.
Some manufacturing processes require human serum for cell expansion or formulation. As human serum is limited, expensive and comes with a high degree of batch-to-batch variation, its necessity should be investigated for every process step. Reduction of human serum required steps or serum replacement with for example human serum albumin would reduce the process variation tremendously. Although not always possible, a serum-free manufacturing process would be preferred.
In conclusion, materials can have a big impact on the quality of the final product and changing material requires reevaluation of the manufacturing process and preclinical studies. The use of GMP grade material as soon as possible during process development can overcome these difficulties and, in the end, reduces development time.
Analytical methods control the manufacturing process
Analytical methods are tools to monitor the product during manufacturing, characterize the final product and allow for product release. This helps build an understanding of which aspects of the product contribute to the mechanism of action and efficacy of the product. As the manufacturing process and its product are unique, cell therapy requires many process- and product-specific methods. Therefore, the panel of required analytical methods is rather a strategic decision than a standard prescribed list.
Although analytical methods for cell therapy products will be tailormade, commonly used methods are cell counting, flow cytometry and qPCR. These methods seem simple to apply, but the choice and setup of each may affect manufacturing process transfers to a GMP environment. Cell counting results could differ significantly between research labs and manufacturing locations due to differences in procedure, equipment, and use of different viability dyes. Automated cell counting aids in the reduction of variability and is key in the comparison of results obtained during initial discovery, process development and clinical batch manufacturing.
Flow cytometry is a general method for phenotypic assessment of a cell therapy product and a common method used for clinical batch release: the testing of a batch to ensure it complies with previously defined acceptance criteria. As clinical trials could take months to several years, the flow cytometry method should be controlled throughout the complete trial period. This means that all equipment and critical reagents, like the conjugated antibodies, should behave consistently at any time and that the analysis strategy should be suitable qualified. Therefore, a flow cytometry method should be designed to be as simple as possible to capture those aspects critical to the quality of the cell therapy and minimize difficulties during method development, qualification, and validation.
When the genome of a cell therapy product has been modified by viral vectors, qPCR is a common method to monitor the number of vector integrations. The vector integration number is an important value to control genomic modifications and thereby patient safety. Moreover, a qPCR method allows clinical monitoring of the adapted cell population in the patient’s circulation. Development and qualification of a qPCR method is challenging since the technical procedures requires accuracy and is vulnerable to matrix effects.
The most important assay during drug development is a potency assay: a method that provides answers on the biological activity of a product as it would be administered to patients and therefore can be related to the expected clinical outcome. A potency assay is related to the products’ mechanism of action and can sometimes be difficult to develop for cell therapy products due to its complex and multi-factorial mechanisms within the human body. However, a potency assay can be extremely valuable during all phases of drug development, since it will give insights in batch-to-batch consistency and measure the impact of manufacturing process changes.
The development of analytical methods may seem trivial during drug development. However, data generated during early development and clinical batch manufacturing is of high importance for the product life cycle, due its ability to compare batches, control the manufacturing process and release clinical batches. This can be only achieved when data has been generated based on standardized and high-quality analytical methods.
Process development of cell therapies is challenging as many factors are involved, but a definite requirement for a first phase clinical trial. Although the level of process development is phase-dependent, an early start in development and a plan for future manufacturing process changes is a successful strategy for cell therapy products.