The pharmaceutical industry is constantly engaged in transferring processes between organizations or locations; these transfers are critical to get product to market. The number of transfers is expected to increase as countries act on the need to manufacture drug products locally. This activity is part of the normal lifecycle of a drug product, and it can range from very successful transfers to problematic ones, based on a myriad of factors. Among them are process and product robustness, the readiness of organizations to engage in transfer activities, availability of experts, and the timely execution of all the work needed to complete a transfer.
The pharmaceutical industry is constantly engaged in transferring processes between organizations or locations; these transfers are critical to get product to market. The number of transfers is expected to increase as countries act on the need to manufacture drug products locally (1).
This activity is part of the normal lifecycle of a drug product, and it can range from very successful transfers to problematic ones, based on a myriad of factors. Among them are process and product robustness, the readiness of organizations to engage in transfer activities, availability of experts, and the timely execution of all the work needed to complete a transfer.
The ICH Q10 (2) guidance states that a transfer of technology is an integral part of its product lifecycle model and identifies it as an activity that must be executed under GMP given its relevance to commercial manufacturing and impact on product quality. This emphasis is justified due to the complexities surrounding transfers of technology.
Overall, technology transfer can be characterized as a phase in the pharmaceutical product lifecycle and requires considerations for specific areas to focus on when planning and executing transfers of technology between organizations.
Technology Transfer in a Nutshell
There are many definitions that describe the technology transfer process for pharmaceuticals. Approaching this process as only transferring information (documents, lists of process parameters, etc.), however, is not a technology transfer. Per ICH Q10 (2), the objective of technology transfer is:
“…to transfer product and process knowledge between development and manufacturing, and within or between manufacturing sites to achieve product realisation. This knowledge forms the basis for the manufacturing process, control strategy, process validation approach and ongoing continual improvement.”
In summary, the goal is to transfer knowledge between organizations which will serve as the basis for a sustainable and controlled manufacturing of pharmaceutical products.
The process of transferring knowledge has recently received attention through the issuance of guidance documents that describe the expectations, approaches, and steps for executing transfers (2-5). These documents offer valuable guidance on how to plan, manage and execute a transfer for a pharmaceutical product.
A typical approach for a technology transfer can be summarized as follows:
Pretransfer — The organizations involved confirm that the process or product is well characterized, ready to be transferred, and a decision is made to initiate transfer activities. A transfer team is created, consisting of members from the sending organization (Sending Unit) and the receiving organization (Receiving Unit). The organizations involved then initiate information sharing between the Sending and Receiving Units. Project management tools are launched to support the transfer activities.
Knowledge Transfer Package — Information regarding materials, methods and procedures, process parameters, equipment requirements, training materials, systems, etc. is collected and prepared to support the knowledge transfer process.
Technology Transfer Planning — Risk assessments are conducted to analyze and manage the potential impact of limited information or differences between manufacturing sites (e.g., equipment, process, facility fit, systems, etc.). A transfer plan is created to identify key milestones and provide guidance regarding transfer scope, resource requirements, timelines and level of effort.
Transfer Execution and Verification — The transfer plan is executed. Process verification activities (e.g., small and full-scale verification runs, process qualification and conformance runs, etc.) are conducted to demonstrate successful information and process transfer. Data is collected to close transfer activities and to support technical reports, regulatory submissions and approvals.
Posttransfer Verification — Lessons learned are shared within the organizations. Continued process verification is implemented to demonstrate ongoing process control.
In many ways, each transfer is unique and requires integrated organizational structures, engaged team members, careful planning, effective communication and skillful execution to ensure the desired results.
Considerations for Tech Transfer Success
Some transfers are complex to execute due to unexpected constraints or challenges. The following areas are usually sources of issues if they are not anticipated and added to the overall transfer plan.
Organizational barriers, geography and culture: Transferring knowledge across cultural boundaries to other countries can be a challenging exercise if not planned carefully. To start, countries may have different safety and engineering standards that create the need for design changes and other adaptations as part of the transfer of processes and technical systems. These adaptations must be assessed for risks and documented as part of the transfer process for future reference.
The Receiving and Sending Units will most likely have different organizational structures. Finding the right role and function to engage in transfer activities will be critical to ensure knowledge is transferred to the right person. The Receiving Unit must have the human capital and infrastructure to receive the knowledge and technology. For example, in some projects, organizations use contractors to conduct the transfer of technology. This approach could weaken the completion of a robust knowledge transfer if these contracted personnel leave the Receiving Unit at the end of the project. Securing the transferred knowledge in the Receiving Unit should be one objective of the overall transfer plan.
Language and cultural behaviors will also play a significant role as transfer teams share design documents, qualification protocols, and reports or engage in active communication via online meetings or e-mails. Defining the documentation structure and language before initiating any transfer of information will save countless hours during execution and documentation closure.
The role of electronic systems: Electronic systems are pervasive in today’s pharmaceutical industry. In addition to distributed control systems, process control modules, data acquisition systems and manufacturing execution systems, there is an abundance of critical data elsewhere that may be relevant for a successful technology transfer. For example, electronic systems supporting supplier quality management, inventory systems, and material release processes most certainly contain important data and methods to be documented and transferred to the Receiving Unit. This transfer will need special consideration given that there are hardware and software elements that need to be defined and managed.
Of special importance to some biotech products is the process control software managing how process parameters are executed and controlled. Changes to how a process is controlled should be assessed for impact to process performance and product quality.
Scale-up, adaptations and small-scale verifications: In many cases, processes are scaled up or scaled down between transfers. Early in the planning stage, a detailed assessment of scale differences must be completed to evaluate these as part of the transfer. Ideally, process and equipment changes are avoided to increase the likelihood of a successful transfer. This, however, is usually not possible. Process adaptations are almost always needed; for example, to accommodate for different lengths of transfer lines (hold times) and different equipment features (control systems, gaskets, alarms, etc.).
Valid small-scale process verification models can be extremely useful for verifying some process aspects early, before initiating large-scale process verification or engineering runs. For complex processes, full scale verification should be completed prior to initiating process qualification or conformance runs. This will provide an opportunity to evaluate the effectiveness of the process transferred at a full scale.
Analytical methods: Analytical methods are needed early in technology transfer processes. Raw materials need to be purchased, tested and released to support process verification runs and process qualifications. There may be a need to conduct special technical studies to obtain data related to process adaptations. These studies will require analytical testing capabilities. Different quality control labs may need additional time to run side-by-side comparisons to detect and then correct lab-to-lab biases.
For example, a laboratory bias was detected during a method transfer for a biologics drug substance. Data from the Sending Unit laboratory was trended against data from the Receiving Unit laboratory, and a significant difference was observed between results for some methods. The investigation concluded that the handling of samples and sampling preparations between laboratory scientists was not equivalent. Additional side-by-side testing and training was conducted with technicians from both sites to define further requirements and share techniques for proper execution. This extra effort eliminated the biases between the labs in time to support the rest of the technology transfer efforts.
Change management: The adoption of a system that effectively tracks, evaluates and manages changes between the Sending Unit and the Receiving Unit will support future investigations as part of process of technology transfer execution and closure. The structured documentation of changes (planned or not) will help scientists and engineers interpret discrepancies between expected and actual values. A formal system is recommended to track these changes during the transfer process.
Technology transfer is a mature process in the pharmaceutical industry; however, it still provides many challenges for transfer teams. Each organization should adopt a policy or procedure to manage transfers of technology in a structured and consistent way. Some areas of the transfer process merit additional focus to ensure timely and successful transfers. Key recommendations include:
- Acknowledging cultural and geographical challenges
- Having a full understanding of all relevant data in electronic systems
- Verifying process transfer effectiveness via small-scale models and engineering runs
- Ensuring analytical testing capabilities early in the transfer process
- Tracking all changes to support investigations and future process optimizations
- Pharmaceutical Production and Related Technology Transfer, World Health Organization: 2011 http://www.who.int/phi/publications/Local_production_and_access_to_medicines.pdf
- Pharmaceutical Quality Systems Q10, International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2008.
- ISPE. ISPE Good Practice Guide: Technology Transfer. 2nd Ed. Tampa: ISPE, 2014.
- Gabriele, M., et al. PDA Technical Report No. 65: Technology Transfer. Bethesda: PDA, 2014.
- WHO. WHO Technical Report Series, No. 961, Annex 7, WHO guidelines on transfer of technology in pharmaceutical manufacturing. Geneva: WHO, 2011.
About the Author
Jose Caraballo is Director of Global Quality, Biotech Product Supply at Bayer HealthCare, where he is responsible for providing strategic planning and support for new and existing operations for biotech products. He serves as a quality assurance expert on strategic project teams related to the expansion of biotech manufacturing capabilities.