June 5, 2017 PAP-Q2-17-CL-003
Technology transfer of cell- and gene-therapy production processes is a complex undertaking that can occur at different stages of development. The reasons for transferring a process vary significantly and often correlate with the maturity of the process.
When companies initiate development programs for next-generation therapies, they often rely on assistance from university laboratories or other academic institutions for production of the small quantities of material required for early studies. They may find, however, that those organizations are unable or unwilling to license cell lines and other reagents used in manufacturing at later stages. Additionally, the cell lines may not be very well characterized or the pedigree is unknown, information that is necessary for an FDA biologics license application (BLA) filing and commercial production.
In these cases, the company must turn to a contract development and manufacturing organization (CDMO) that can help identify appropriate cell line platforms, create master cell banks, identify and source raw materials, and design production and purification strategies to generate products that meet purity and safety standards and other desired quality-attribute specifications. In some cases, both raw material and product specifications must be established. Processes and analytical methods must be developed and qualified using reliable standards and controls. Batch and test records also need to be drafted.
Companies further along in the development cycle may need a horizontal transfer of information to switch service providers in order to gain access to larger-scale production capabilities. There are currently a limited number of CDMOs that can provide support for the commercialization of these advanced therapies. Most projects, therefore, require the transfer from one outsourcing partner to another as they advance to phase III and beyond.
Clients who are in the midst of phase I/II studies often produce clinical material using less-than-optimal processes. Typically the process controls and methods need to be optimized to establish a process and analytics suitable for phase III trials. There are consequently opportunities in vertical transfer of information to incorporate improvements, not only in the processes themselves but also the analytical methods that support them.
Mature projects that are moving from phase III into commercial production can present challenges of their own. Difficulties may arise when client processes are not as characterized or controlled as would be expected based on client descriptions. It is essential that sponsor firms transferring next-generation technologies to
CDMOs be fully aware of the actual state of their processes and accurately describe them to their outsourcing partners prior to project initiation.
Pharmaceutical technology transfer as defined by the Parenteral Drug Association (PDA) “consists of planned and controlled actions that are based on well-defined acceptance criteria to convey a manufacturing process, analytical method, packaging component, or any other step or process along the pharmaceutical drug lifecycle from an originator site, known as a sending unit (SU), to a new site, the receiving unit (RU).”1
The goal of tech transfer as outlined in ICH Q10 is to “transfer product and process knowledge between development and manufacturing, and within or between manufacturing sites to achieve product realization.” This knowledge “forms the basis for the manufacturing process, control strategy, process validation approach and ongoing continual improvement.”2
Controls for transfer of processes, documentation and professional expertise are essential, according to the World Health Organization, which states that “Technology transfer embodies both the transfer of documentation and the demonstrated ability of the RU to effectively perform the critical elements of the transferred technology to the satisfaction of all parties and any applicable regulatory bodies.”3
Overall, technology transfer should be pursued using a science- and risk-based approach that achieves a balance between risk minimization and cost effectiveness while aligning with applicable regulatory expectations.4
Inefficiencies during technology transfer can have significant, negative time and cost consequences and may also lead to the need for additional process development
work.5 Personalized medicines such as cell and gene therapies in fact have the potential to suffer from greater manufacturing variability due to the increased influence of the underlying biology, which can lead to inefficiencies in technology transfer.6
Regardless of the maturation stage of a next-generation therapy project or the type of technology transfer to a CDMO, technology transfer should follow a highly structured approach,7 starting with robust information exchange through provision of a comprehensive technology transfer document package or technology transfer package that contains the process description, process parameters, process performance and a process development report.5 Any available information on the analytical requirements and processes should also be provided.7 Other aspects of an effective technology transfer program include an agreed-upon, detailed project transfer strategy with clearly delineated acceptance criteria for all steps of the tech transfer process, including final GMP manufacture;8,9 established project management procedures; small-scale runs to verify performance; and at least one pre-GMP engineering run.7
Technology transfer begins with sharing of all relevant information, including safety aspects (e.g., safety profile, material safety data sheets, biosafety level concerns, etc.) and process (e.g., cell line, manufacturing reagents, process conditions, purification methodology, etc.), and analytical (e.g., protocols, custom reagents, assay standards, etc.) details. In essence, the client must provide all of the available information that will enable the CDMO to design, develop, optimize or implement processes and resources depending on their level of maturity.
The CDMO must also ensure that its technology transfer team is closely aligned with the client’s team with regard to all facets of the project, including the development program, manufacturing requirements and product release requirements. Close collaboration with transparent, two-way communication facilitates a successful technology transfer and successful project completion. Direct communication between scientists and engineers at the SU and RU is essential to success.7 In addition to alignment of the SU and RU, alignment of the information technology and quality systems, culture, and project management and problem-solving approaches is equally important.10
As mentioned above, the range of support required during the transfer of projects focused on next-generation therapies varies from project to project, and along the product life cycle.
One of the most common issues is raw material sourcing. Many clients bring processes to CDMOs that use raw materials that are not appropriate for GMP manufacturing, such as uncharacterized animal-derived materials or chemicals of a lower grade than is suitable. CDMOs must have the capability to identify appropriate alternatives and perform the necessary comparability studies to show that they achieve similar process yields and similar product quality attributes.
It is also not unusual to have processes transferred to CDMOs that are not practical at a larger scale. For instance, the upstream cell-culture configuration may be inappropriate for the scales needed at later stages; early processes conducted on flat stock often do not scale easily to the lot sizes needed for later-stage clinical studies, and thus the process may need to be redesigned. One primary downstream processing example is centrifugation, where a CDMO will develop a filtration or chromatographic purification method as an alternative. Some clients require assistance with formulation development as well, such as determining the appropriate concentration, packaging (e.g., which vial to use) and fill volume to ensure delivery of the correct dose with minimal product loss.
With respect to analytical methods, protocols often need to be developed to support manufacturing processes. In many cases, characterized references standards for the analytical methods also need to be established. The assays need to be qualified and then fully validated to support release of the product at different stages of development.
ICH Harmonized Tripartite Guideline: Pharmaceutical Quality System Q10. Rep. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). 4 June 2008. Web.
WHO Guidelines on Transfer of Technology in Pharmaceutical Manufacturing, WHO Technical Report Series, No. 961, Annex 7. Rep. World Health Organization (WHO). Web.
ISPE Good Practice Guide: Technology Transfer (Second Edition). ISPE, 2014. Print.
Tembach, Michel B., Paul Ives, Tangir Ahamed. “Best Practices for Technology Transfer.” BioPharm International. 1 June 2011. Web.
Haigney, Susan. "Being Thorough When Transferring Technology.” BioPharm International. 1 Mar. 2017. Web.
Perry, Stephen. “Tech Transfer: Do It Right the First Time.” Pharmaceutical Manufacturing. 6 Jan. 2010. Web.
McIntyre, Catherine, Cenk Sumen. “Are You Ready for a Tech Transfer? Part 1: Challenges and Critical Factors for Success in Cell Therapy Development.” Bioprocess International. 14 Apr. 2015. Web.
McIntyre, Catherine, Cenk Sumen. “Are You Ready for a Tech Transfer? Part 2: Overcoming Obstacles and Implementing Best Practices for Cell Therapy Technology Transfer.” Bioprocess International. 16 June 2015. Web.
Markarian, Jennifer. “Technology Transfer Connections.” Pharmaceutical Technology. 2 Apr. 2016. Web.
Dr. Tate has over 10 years' experience purifying various biologics, including viruses, and has been integral in developing the technology transfer procedures at Brammer Bio. Dr. Tate received her doctoral degree in biology from The State University of New York at Buffalo, where she also received a BS and BA in chemistry and biology, respectively.