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A look at using best practice tech transfer methods for CGTs to increase process and analytics robustness while being scalable.
Cell and gene therapies (CGTs) are reshaping multiple therapeutic areas, including oncology, rare diseases, bleeding disorders, and monogenetic disorders, giving patients new, potentially curative treatment options. The first commercial cell and gene therapies were approved in 2017. Through the end of 2022, there were 12 approved cell and gene therapies (CGTs) in the United States. So far in 2023, there have been five cell and gene therapy US approvals, another three have FDA decision dates in 2023 (1). The field continues to advance rapidly, and, at last count, there are nearly 1700 active CGT clinical trials worldwide (1). In the early days of CGT, there was a saying frequently spoken which has become a mantra for the field: “the process is the product,” meaning there is some tribal knowledge associated with manufacturing these therapies. This mantra can be detrimental to scaling manufacturing to meet the demand of larger patient populations. Since this mantra relies on specific operators having specialized tribal process knowledge, manufacturing processes can be difficult to transfer to other facilities.
Strengthening manufacturing processes and analytics are a priority and the field has begun to align on removing nuance as well as tribal knowledge from manufacturing in an effort to close, automate, and ensure processes are transferrable. The bedrock of this process is an efficient and effective technology transfer (tech transfer) process. A well-defined and robust technology transfer process involves a systematic approach to transferring manufacturing processes, protocols, and knowledge from the research and development phase to the clinical and potentially commercial manufacturing setting, as shown in Figure 1. This process ensures the developed cell and/or gene therapy can be produced consistently, efficiently, and in compliance with regulatory requirements. The same requirements exist for transferring analytical methods to contract development and manufacturing organizations (CDMOs) or equivalent.
How does one make a peanut butter and jelly sandwich? It is a simple enough question, but one might find that if a person follows those instructions literally, it is quite difficult to execute without a large amount of detail. This is what CDMOs within the CGT field confront frequently. CDMOs take, at times, manufacturing processes quite early in development and transform them into processes suitable for certified good manufacturing practices (CGMP) manufacturing. While true, to a degree CGT drug products must adhere to pre-defined specifications much like other drug products administered to patients. This article will describe the necessary steps and strategies, as shown in Figure 1, to transfer a R&D manufacturing and analytical suite to GMP for clinical and commercial manufacturing. As the authors describe this journey, they will describe the different elements of the journey, such as establishing critical quality attributes (CQAs), critical process parameters (CPP), and target product profile (TPP). The authors will also offer some commentary on where they believe CGT manufacturing is heading in the near, mid-term, and long-term future.
The planning stage is the critical first step in ensuring the success of a tech transfer into the manufacturing facility. This phase involves careful evaluation, strategic decision making, and comprehensive planning to lay the foundation for a smooth and effective transfer.
Risk assessments and mitigations play a crucial role during this phase by ensuring the success of the tech transfer. They help to identify potential challenges, uncertainties, and vulnerabilities that could impact the transfer process or the quality of the final product. By proactively addressing these risks and implementing mitigation strategies during the initial assessment and planning stage, organizations can enhance the efficiency, reliability, and safety of the transfers.
By conducting a thorough and strategic initial assessment and planning stage, organizations can set the stage for a successful tech transfer. This phase provides a solid framework for subsequent steps, ensuring that the transfer process is well-informed, well prepared, and positioned for success.
Knowledge transfer is the second and most involved step of a successful tech transfer. It involves the effective dissemination of expertise, protocols, and insights from the research phase to the manufacturing setting. Cross-functional collaboration between research, manufacturing, and quality assurance facilitates a smooth exchange of knowledge. Clear and comprehensive documentation, including detailed standard operating procedures (SOPs) and process descriptions, captures critical information for seamless replication.
A continuous feedback loop also encourages ongoing learning, incorporating insights from manufacturing teams into refining protocols. Regulatory alignment ensures compliance and adherence to guidelines. In essence, successful knowledge transfer ensures that the innovation harnessed in research is translated effectively, leading to consistent, high-quality outcomes in CGT manufacturing and accelerating the availability of transformative treatments to patients in need.
Training during tech transfer is critical in ensuring a seamless transition from research to practical applications, such as cell therapy. Structured training programs provide personnel with the essential knowledge and skills needed to effectively execute transferred processes. These programs encompass both theoretical understanding and hands-on experience, enabling individuals to grasp the intricacies of manufacturing protocols. Mentorship and shadowing opportunities offer direct exposure to the procedures, fostering a deeper understanding of practical implementation. Continual learning is encouraged through resources such as workshops, webinars and online courses, allowing teams to stay updated on best practices. The benefits of comprehensive training extend beyond initial implementation, as well-trained personnel contribute to enhanced process efficiency, minimized errors, and, ultimately, the consistent production of safe and effective cell therapies. Through training, technology transfer becomes a catalyst for knowledge acquisition and competence development, enabling organizations to fully leverage their scientific advancements for real-world impact.
Concurrent with the tech transfer of the manufacturing process is the transfer of the methods for assessing the CQAs required to release the final drug product. Each product is unique and complex. As such, method development of the requisite set of assays is typically necessary. Depending on the stage of the developer, analytical development can range from establishing new methods, to simply updating methods, to compliant instrumentation.
For early phase developers, assay development for release of final product is dependent on process development completion to obtain “final product” material for testing. This is often the case as early phase developers have not established their final product formulation, and do not have formulated material on hand for analytical development. For example, in the case of cell therapy identity assays, which are mainly performed via flow cytometry, this gap can be mitigated with the use of “like” final product materials in the formulated state of the final product for these early phase developers. Similarly, once the formulation is set, some purity assays can be developed and assessed by spiking in the potential impurities into the final product formulation buffer to determine whether the assay is fit for the intended purpose.
One important consideration to note in assay development is that potency assays do require final formulated product. With an orthogonal (matrixed) approach to early potency assay development, substantial material may be required. Many developers do not consider the amount of material required for proper assay development, so this point is critical for developers to understand. As a result of this oversight, assay development of potency assays often lags slightly behind process development during a transfer for the early phase developer.
Another area that is often overlooked during method development is establishing the appropriate assay control(s). Ideally, an assay control would be able to span multiple assays in the assessment suite. Method controls can be either a “reference material”, which are assay controls established from lots of manufactured final product material, or “control material”, that is, mass produced to meet exact specification ranges but not necessarily all the characteristics specified by the assay. As is the case with material needed for general development, early phase developers may not have stores of reference material to add to their assays. If reference material is available, developers generally prefer to dedicate such material for use in optimizing key release assays. For some early phase developers, off-the-shelf cellular kits or control materials have, and can be, used as assay performance controls provided these controls meet assay requirements.
Once the analytical method is shown to be fit for its intended purpose, the locked method is ready to be transferred from development to a routine testing lab in quality control (QC). Prior to initiating the transfer of the method, the transferring lab plans the tech transfer of the method. The transferring lab ensues that proper training of the analysts is provided, the materials are added to the bill of materials for use for this assay, and the necessary instruments and software are installed in the receiving lab.
Tech transfer of the method to the receiving lab will be considered complete once the receiving lab has successfully executed the validated method. The scope of the validation will be dependent on the stage of the developer, whether the method in question will be used for releasing product or for characterization of the product, and the method transfer strategy employed.
The validation model could employ a comparative testing strategy, a co-validation strategy, partial validation, or complete validation. Phase-appropriate stringency should be applied to the validation parameters assessed, given the characterization status of the method being transferred. While often overlooked for early phase developers, it is recommended that certain robustness measures be performed to provide validation data to support impact statements which may arise from potential perturbations that can be expected in the QC laboratory. The overall success of the tech transfer plan determines the method robustness needed to produce CQA analytics during early-phase and pivotal clinical trials by gathering analytical performance data.
As the CGT field continues to mature, a well-defined technology transfer process is critical to ensure manufacturing therapeutic consistency. A defined tech transfer process for both manufacturing and analytics can ensure that batch production records are properly constructed and the analytics are phase-appropriately qualified and validated. The result is a well-defined manufacturing process and analytical suite which should be transferrable to any other facility.
While other challenges continue, a proper technical transfer is key for CGTs to reach their full therapeutic potential. The field must find avenues to efficiently scale (up and out) manufacturing to meet the needs of larger patients populations. This is critical for patients with limited treatment options.
As such, organizations should not work as competitors in this area, but, rather, as collaborators much like the industry did in the early days of monoclonal antibodies.
1. Alliance for Regenerative Medicine, The Sector Snapshot: August 2023. alliancerm.org/the-sector-snapshot-august-2023 (accessed Oct. 16, 2023).
Matthew Hewitt is vice-president, technical officer, Cell & Gene Therapy & Biologics; Larry Bellot, PhD, is scientific advisor, Cell and Gene Therapy; and Chad Andersen is associate director, Manufacturing Sciences & Technology; all at Charles River Laboratories.
Volume 47, No.11
When referring to this article, please cite it as Hewitt, M.; Bellot, L.; Andersen, C. Best Practice Tech Transfer Methods for CGTs. Pharmaceutical Technology 2023, 47 (11), 39–41.