Three Decades of Advancements in Technical Transfer of Biologics: A Blueprint for Advanced Therapeutics

Technology transfer of the manufacturing process and associated analytical methods is a critical process in the lifecycle of biotech products. It enables the production of clinical material to test a hypothesis developed in the drug discovery environment, expansion of clinical supplies, and establishment of a robust platform for commercial production. It can also provide flexibility in the product lifecycle by adding additional manufacturing nodes to supplement supply or provide business continuity. In the early history of the development and manufacturing of biotech products, there was reticence to locate commercial manufacturing facilities too far from the locations where the processes were developed since the technology was viewed as complex and not easy to transfer successfully. Over time, as technology matured, and in some cases driven by a need to acquire capacity not available within the innovator, companies began to transfer processes around internal networks and to newly constructed purpose-built sites, as well as to business partners and contract manufacturing organizations (CMOs) that sprung up to meet the expanding needs of successful pipelines. Technology transfer is a complex multi-disciplinary activity involving process and analytical development, engineering, operations, quality, and increasing automation and IT, as facilities are designed with high levels of automation and control. Factors influencing success include the level of process understanding and the understanding of the relationship between the process, equipment, and automation. Effective project management is a critical enabler that ensures successful orchestration of multiple functions and effective decision-making in a very complex and dynamic environment. The typical pathway to a successful transfer will be through a facility fit and gap assessment between the donor and acceptor facility, design and execution of any facility and equipment modifications, raw material procurement, process trial lots, and ultimately process validation lot manufacture. All of these activities will also be dependent on the transfer and qualification of appropriate test methods. Technology transfer, while not explicitly regulated by health authorities, is described in International Council for Harmonisation (ICH) Q10 as “the transfer of product and process knowledge between development and manufacturing and within manufacturing sites to achieve product realization. This knowledge forms the basis for the manufacturing process, control strategy, process validation approach and ongoing continual improvement.” Additionally, it is widely appreciated that the outcome of validation and comparability studies is critically reviewed as part of the regulatory approval of the process in the new location. To this end, care must be taken to ensure data integrity and continued compliance with U.S. 21 code of federal regulations (CFR) Part 11 and Eudralex Volume 4, Annex 11 across all of the steps from the donor to acceptor site. Clear definition of protocols and success criteria is critical to ensure effective transfer and decision-making, especially when projects are under time pressure. The relationships between the donor and acceptor teams are sometimes overlooked. Generation of close, collaborative relationships with shared goals are major enablers of success. These cultural and behavioral enablers can be built into the program, and on-site presence and visits to facilities can enhance these relationships. In the past 30 or so years, the transfer of robust processes like those used to produce monoclonal antibodies has become extremely effective and can be achieved with relatively modest investment of expert resources and can be completed in a matter of months. Mature biopharma companies have made significant advances in the development of platform processes and, with the associated maturity of expertise and capability and knowledge management within these companies, can perform effective technology transfer in a matter of months in a clinical setting and less than one year in a larger-scale commercial setting. Leveraging modeling software and other digital tools has also enabled speed and robustness. Despite these advances, it should be acknowledged that the timeline and investment may be much longer and costly for tech transfers to new facilities (e.g., biotech to external contract manufacturing organizations [CMOs] or between external CMOs) (i.e., where an effective technology transfer platform process is not in place). Interestingly, in the emerging and advanced therapies environment, the situation is more like the early days of recombinant protein production where process knowledge is still under development and the expertise is often localized within a small number of companies. Nevertheless, the same principles of technology transfer can be applied and over time will result in a broader proliferation of skills and the same flexibility that applies now for monoclonal antibody production.