October 26, 2018 PAP-Q4-18-CL-008
Technology transfer is the bridge between phases of the value chain: between different stages of development, between development and commercial scale for new products and between manufacturing sites for commercial products. According to the World Health Organization, “Technology transfer embodies both the transfer of documentation and the demonstrated ability of the receiving unit to effectively perform the critical elements of the transferred technology to the satisfaction of all parties and any applicable regulatory bodies.”1
Technology transfer should result in the transfer of product and process knowledge into a new phase of the product’s life cycle. The goal, as outlined in the ICH Q10 guidance, is to “transfer product and process knowledge between development and manufacturing, and within or between manufacturing sites to achieve product realization.”2 The transfer activities should add to the existing knowledge base and demonstrate that the product can be manufactured successfully in its next phase.
It is important that technology transfer is pursued using a science- and risk-based approach that achieves a balance between risk minimization and cost-effectiveness, while aligning with applicable regulatory expectations, according to the International Society for Pharmaceutical Engineering (ISPE).3 Confirmation that projects are fit for the facility, equipment or capabilities must be the first step. Controls for transfer of processes, documentation and professional expertise are essential.1 It is imperative to establish reasonable timelines and deadlines for milestone completion and decision-making, as well as strategies for addressing problems that arise.
Effective technology transfer cannot be achieved without access to relevant information about the process being transferred. Outsourcing partners, such as CDMOs, rely on clients to provide much of this information. They possess all of the documented and undocumented product and process knowledge at the start of the project.
Physical document transfer must occur for practical, executable documents, such as specifications, analytical methods, master batch records, the process description, production protocols and a process development report. Executed batch records provide actual in-process data and the parameters that were used, which are more valuable than ranges and targets and convey more precise information on process capability and the adequacy of the manufacturing directions. Ideally, knowledge transfer from the client to the CDMO takes place through the provision of a technology transfer document package or technology transfer package.
In addition to hard data and documents and reports, it is important to transfer peripheral and soft, experiential knowledge. The CDMO tech transfer team should discuss manufacturing, analytical issues and any safety aspects with the product/process experts from the client’s analytical laboratory, manufacturing group, quality assurance, R&D and other operations at the start of the project. These same individuals should be on the joint project team so that they can provide continued review and input. It is also critical to clearly delineate all expectations and limitations and to establish a comprehensive project strategy.
The more information that is provided, the better positioned the CDMO will be to develop and implement an optimized process. Project timelines also often correlate inversely with the amount of information provided by the client. In-depth information sharing, however, requires the establishment of a high level of trust between the client and the CDMO. Pharmaceutical companies looking to transfer projects to CDMOs should seek outsourcing partners with track records of success in technology transfer.
Document creation and approval are rate-limiting steps for critical functions in the laboratory, in manufacturing and for regulatory filing and can thereby impact project timelines. Ineffective and inefficient technology transfer processes can cause extreme consequences: the need to repeat development work, missed deadlines and higher costs are just some examples.2 These complications can be avoided if the client has a clear regulatory strategy that allows the CDMO to design an appropriate technology transfer plan.
The plan of work lays out the steps to be implemented to generate all of the information and data necessary for successful regulatory filing. It must meet standard regulatory agency (e.g., the U.S. Food and Drug Administration) expectations for the application, as well as answer any potential questions specific to the product being transferred.
The transfer plan is dictated by the type of transfer, the type of product and the stage of the product in its life cycle. The two broad categories of tech transfer are pre-approval, typically with a change in manufacturing scale, and post-commercial approval, where the approved manufacturing process is translated and replicated in a new manufacturing site.
Planning for technology transfer is completed by the technology transfer team, which should comprise experienced representatives of the various departments that participate in the tech transfer process, including at a minimum development, production, engineering, quality assurance/quality control, qualification/validation and regulatory affairs.
The first task of the CDMO’s technology transfer team is to conduct risk and gap analyses. A deep initial product and process review is critical before developing the plan of work. The CDMO needs to evaluate the product’s formulation, manufacturing process, equipment train, stability and product history in order to develop a complete transfer plan and anticipate potential problems.
It is also critical to ensure that analytical assays are transferred and qualified before transfer of processes has begun. Many analytical assays are essentially processes themselves, and timely method transfer is critical for keeping the project on track.
In addition to an appropriate transfer plan, the CDMO provides project management and technical and analytical support, executes manufacturing and analytical processes, completes any needed technical writing, proposes and executes a validation strategy, performs stability studies and supplies support for the client’s regulatory filing. All of these activities must be performed with some level of client review and approval, and all need to be executed to meet the project timeline.
CDMOs can best facilitate these activities and processes when there is close alignment and collaboration between their technology transfer team and the client team. Such alignment and collaboration require transparent communication between the scientists and engineers across, within and between both teams.
A useful best practice is to have gate-keeping reviews before starting significant steps, such as the manufacture of registration batches or validation batches. The executed process development batch records and in-process and analytical data should be evaluated by the technology transfer team to ensure that all parties agree that the project is ready to move forward through the next significant steps. The more thoroughly that processes are challenged at earlier phases, the more robust those processes will be further down the line.
UPM Pharmaceuticals has an experienced group of scientists and engineers working on technology transfer, with strong backgrounds in formulation, manufacturing equipment, process development, scale-up and validation. We take a collaborative approach to our projects, with frequent internal discussions on technical issues and troubleshooting to leverage our knowledge and provide value-added services to our clients.
Most projects consist of approximately 85% routine and 15% problem-solving work. Given the nature of pharmaceutical manufacturing, it is expected that projects will not always proceed according to the technology transfer plan. While problems are expected to occur, the nature of those problems is often unexpected. In addition, they can affect the project timeline. With our experienced team and internal consulting approach, UPM is capable of rapidly investigating and effectively troubleshooting issues that do arise, enabling us to keep projects on track and meet timelines.
In addition, our technology transfer group has experience with a variety of modified-release technologies and dosage forms, which have their own special sets of problems for scale-up and technology transfer. We have worked on successful applications for particle coating, sustained-release matrix tablets, tablets with modified-release coatings and complex combination products.
Joseph Szczesiul serves as Director of Technical Services in UPM’s Manufacturing department. He has over 30 years experience as a manager and scientist in formulation, process development, technology transfer and manufacturing support, with expertise in a variety of tablet and capsule modified release technologies.