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Only careful planning can prevent problems that stem from differences between a sponsor’s and a CDMO’s equipment, practices, and culture. This article highlights best practices and case studies.
Technology scale-up and transfer are common-and crucial-biodevelopment activities. For any biopharmaceutical manufacturer, commercial success depends on being able to increase drug substance production volume quickly and effectively and to move production freely without being locked into one provider. Successful transfer is vital for product efficacy and patient safety, but the time and financial costs of failure can be significant.
Regulators expect manufacturers and their contract partners to take a methodical approach and provide all required documentation as they move a process to a new facility or convert it from demonstration to commercial scale. Tech transfer activities guide the transfer of product and process knowledge from development to manufacturing or between manufacturers.
As stated in the International Council for Harmonization’s (ICH) Q10 guidance document (1), tech transfer activities also form the basis for control strategies, process validation, and ongoing process improvement. A contract development and manufacturing organization’s (CDMO) skills and experience greatly affect the ease of transfer. Appropriate planning and execution on both the manufacturing company’s and the CDMO’s part can prevent issues from coming up that would impact tech transfer, which can stem from differences between sender and receiver, such as equipment, resources, and employee culture.
This article touches on some operational aspects of the tech transfer and scale-up processes and offers a systematic approach for negotiating them effectively, including a methodology designed to ease and accelerate process transfer from one bioreactor to another.
Laying the groundwork is key in tech transfer. Ensuring that those who are working on the transfer have the requisite experience and skills will help ensure success and avoid surprises. Process parameters and process knowledge may need to be transferred from development to pilot study to clinical production or to an internal or external commercial manufacturing facility. In all cases, final scale and success parameters, such as critical quality attributes, must be defined clearly, in writing, before the transfer begins.
Transfers between different companies demand extra care in planning and documentation. Given differences between facilities and equipment, standard operating procedures are unlikely to translate directly and will need to be reinvented for the target site.
Occasionally, the sending party has less stake in the project’s success than the recipient, making a disciplined approach imperative. High-level due diligence regarding capacity, facilities, current good manufacturing practice (CGMP) capability, and personnel will help teams assess feasibility in order to prepare for transfer. Planning ahead, for example, can allow teams to pre-order equipment with long lead times, if necessary. Note that transfer does not end with the completion of qualification lots or approval, but extends throughout the duration of manufacturing. Successful tech transfer follows an orderly progression to set expectations and ensure that all stakeholders are working toward the same goals. Teams should follow all of the following steps, explained in subsequent sections.
Form tech transfer teams and governance structures and define a project charter with goals and timelines. Setting clear expectations and responsibilities between partners in the tech transfer is crucial to avoiding confusion and/or conflict down the road. The initial charter agreed upon by both parties must include the scope of the project, transfer timelines, as well as the team structure, specifying clearly defined roles and responsibilities. The charter should also establish clear paths of communication and a government structure for addressing issues. Most importantly, success criteria must be clearly documented in the project charter.
Consolidate process knowledge into a tech transfer protocol. Communicating manufacturing challenges can be difficult; the sending personnel may be so close to the process that they no longer see the difficulties. Nonetheless, both sending and receiving teams must collaborate to create a detailed description of the process.
The process description document is an overview of each step and must include critical process parameters. Everything from facility and equipment requirements to raw materials and consumables to vendors to analytical methods must be outlined, focusing on intrinsic, site- and scale-independent process requirements. The sending team should provide as much potentially useful process information as possible, down to tacit knowledge of media color, etc.
Analyze gaps and risks to create a detailed project plan. The next step is a thorough process walk-through at the receiving site, based on the process description document. This is a great learning exercise for the receiving team and identifies areas where changes will be necessary-and what differences are acceptable. Information learned from this activity guides the project work plan by pinpointing needs for facility, equipment, training, procedure, or process modifications, so that gaps may be addressed.
Some process amendments are inevitable, based on major differences in facility, equipment, or operational practices, and risks are always inherent in technology transfers. To determine acceptability, changes may require specific new validation studies or may be covered in the process qualification validation. Pre-defined success criteria are essential for promptly accepting or rejecting changes.
Execute the tech transfer as planned. Once the transfer protocol and project plans are in place, the teams can perform the actual transfer, with a goal of being ready for process qualification. First, they must make the necessary equipment and facility modifications to mitigate identified risks. Next, they must execute the process at a small scale and qualify that model before progressing to a larger or full-scale process. Once the team has developed a successful process, they must author and approve manufacturing instruction documents and train production and support staff.
Transferring a process between brands and sizes of equipment is always problematic. An experienced CDMO can help drug developers navigate this step efficiently and successfully. Use of a comprehensive methodology for modeling and adapting the equipment can mitigate risk by making the transfer much faster and easier.
This methodology is based on an understanding of the important, systematic differences among brands and sizes of bioprocessing equipment. For example, mixing efficiency can vary from system to system because of impeller type, position or size, or size of tank. Similarly, sparging efficiency can vary with differences in sparger size, position, or bubble size. Temperature gradients are typically not comparable, and fluid dynamics can vary with baffle type, position, and interactions. All of these characteristics impact the growth of the cell line and may therefore affect titers or quality in the final batch-an unacceptable result. However, mass transfer modeling, which models the behavior of the bioreactors in use, can help determine the right equipment settings to achieve consistent titers and quality of end products.
Figure 1 is a spatial representation of the relationship between the following three parameters:
Note that bioreactor brands and sizes behave differently, as modeled by the variety of graph morphologies shown in Figure 2.
These graphs demonstrate how differently they all behave. These representations show why culturing a cell line in different bioreactors invariably achieves different results. But these graphs also hold the key to achieving consistent results: by toggling the variables P/V and Vs so that the volumetric mass transfer constant KL.a remains constant between bioreactors, equivalent titers and cell quality can be achieved.
In this case study, equipment knowledge led to successful tech transfer and scale-up of a Chinese hamster ovary (CHO) cell line. The transfer team was able to reproduce titers as a function of time in three different-sized bioreactors by using the above methodology, as shown in Figure 3.
Tech transfer may not only be a matter of transferring a process, but also of negotiating issues that come with it. In this case, during the planning and risk analysis stage, it became apparent that the sending lab had never actually run the process twice within the same template. Therefore, the robustness of the process was in question.
Experimentation showed that, in fact, the process was not robust and resulted in product with inconsistent quality attributes. In the end, the receiving lab decided that the most likely way to achieve success would be to redevelop the process. To maximize flexibility and control, the developers opted for single-use technologies. In the end, the process was able to meet the acceptance criteria set forth at the beginning of the transfer.
Demonstrate technical success: meet acceptance criteria (process qualification). Pre-defined success criteria, whether part of a validation protocol or not, are a must. Process qualification through a demonstration showing that the process is performing correctly at the receiving unit may be a formal validation exercise or a simple report following an early clinical campaign. Criteria should include key process performance metrics such as step yields, impurities, growth rates, and titers. They may also delineate product quality ranges or require success in formal validation. Advance agreement on success metrics speeds decision making at key go/no-go points.
Finalize the transfer, through documentation, support of regulatory activities, follow-up actions, and examining lessons learned.The last tasks of tech transfer are geared toward process performance review and regulatory support. If process issues still need correction, the receiving team must assign actions and complete the work. Recognized flaws in standard transfer procedures must be amended. The team must also prepare documents for regulatory submission; respond to questions; prepare for inspections and implement systems for ongoing technical support of manufacturing. Finally, the team must complete all required documentation.
First, it is paramount that success criteria be defined, ahead of time, in writing. Critical quality attributes must be identified, agreed upon, and recorded. All sides must agree on the measures of success. Second, regulations mandate that tech transfer be performed in a specific, organized way to avoid surprises. The best option is to follow the regulatory guidelines. Lastly, tech transfer is difficult for many reasons: the culture and vocabulary of people at the sending and receiving facilities may differ. The sending facility may be unmotivated or unable to cooperate with the receiving facility, and standard operating procedures will likely not apply after changes in equipment and facilities. To ensure the best outcomes, receiving teams must plan and organize transfers down to the last detail and maintain a disciplined approach at all times. A partner experienced in tech transfer can help ensure success and minimize expenditures in time and cost.
1. ICH, Q10, Pharmaceutical Quality System (ICH, June 2008).
Supplement: Partnering for Bio/Pharma Success
Pages: s10, s12–s13, s34
When referring to this article, please cite it as G. Plane, “A Systematic Approach to Tech Transfer and Scale-Up," Partnering for Bio/Pharma Success Supplement (February 2019).
Guillaume Plane is global development and marketing manager for MilliporeSigma’s BioReliance End-to-End Solutions.