Technology Transfer of Manufacturing Processes: Best Practices
ISPE Biotechnology Steering Committee Presents: Technology Transfer of Manufacturing Processes: Best Practices
This blog post will describe several best practices regarding technology transfer of manufacturing processes between several sending and receiving sites across a global network. The technology transfer process has been simplified into four stages described in more detail below.
Step 1: Process Development (Early)
The technology transfer process ideally starts early during the process development life cycle. Best practices can be incorporated into early stage development (Phase I) long before facility selection. In general, the development stage identifies the manufacturing process and can be made more efficient if “platform” processes are defined for selection and leveraged with historical knowledge. Ideally, a “toolbox” is available that defines the capabilities for unit operations and provides secondary choices when required (as an example: flow through columns versus bind and elute). The development process is an ongoing collaboration with the potential commercial facilities and utilizes a clinical manufacturing site (if possible) that has minimized differences with the commercial sites considering scales and equipment sets. The development process is most effective when risk reduction and management is discussed early, especially considering the availability of processing models, facility fit constraints, and previous experience that has identified opportunities for improvement. This step is also where legal advice is considered when handling intellectual property or potential hurdles that may delay development.
Step 2: Process / Facility Fit Assessment
The second step is the process and facility fit assessment. Ultimately the process must be transferred and manufactured at a commercial site. Effective teamwork and knowledge sharing between development and manufacturing considerably streamlines the transfer. Facility equipment constraints must be carefully considered in late phase development (very important when limited by commercial flexibility – only one site available). Ideally points of contact and working groups are well established for the facilities that understand manufacturing details, limitations, operational strategies, and flexibility for the facilities. During the facility fit assessment, development and manufacturing partner to identify improvements and resolve equipment limitations either via continuous process improvement or capital investment. Typically, formal summaries are provided to development from each facility to assess options for process changes and highlight issues before selection. While working to provide a process that best suits the facility, compromise from both the sending and receiving sites will be required in order to maintain the process robustness and its ability to achieve critical quality attributes. An effective data sharing solution, such as an informal facility fit spreadsheet, between manufacturing and development greatly aids in minimizing the facility fit scope and identifying potential major gaps early. Regulatory impact must also be considered at this stage especially if specific processes require changes in the control strategy for a facility. Additionally environmental/health and safety representatives are consulted for any potential issues before formal selection. Finally, a formal sourcing decision is made considering a wide variety of factors from business, operations, and production schedule and capacities.
Step 3: Process Transfer Team Selection and Define Deliverables
When selecting a team to deliver a process transfer, members are selected from both the sending and receiving sites with cross functional technical and operational expertise. All team members are aligned to the overall mission including the key deliverables for the process transfer. Team members are selected to provide technical expertise on the manufacturing process requirements including critical quality attributes (CQAs) and associated controls, unit operation fundamentals, facility and equipment capabilities/limitations, process performance qualification (PPQ), process performance history as well as requirements for analytical method transfer, product protection, compliance, regulatory, product supply chain, health and safety, and environmental regulations. Each team member from the sending and receiving sites is a subject matter expert with a clear role and responsibility to the team to deliver a successful process transfer. Once the team members are selected, an initial face to face meeting with all members is beneficial to align the team to the mission and team deliverables, build team relationships, provide overview of the process and facility fit, and to commence key technical discussions. This meeting is typically hosted by the receiving site. The team should focus initially to identify the following:
- Overall timeline for process transfer deliverables (Process Validation, Analytical Comparability Results, Regulatory Submissions)
- High level process control strategy and potential risks
- Long lead deliverables and scope (Facility/Equipment modifications, raw material procurement/release)
- Strategies for Process Performance Qualification (PPQ) and Analytical Comparability
A formal process transfer plan is useful to document and clarify the process transfer objectives, deliverables, timeline, process transfer team responsibilities, and provide an overview of the risks with associated mitigations. The process transfer plan ownership is shared between the sending and receiving site technical leaders, typically process scientist molecule leaders from each site. Risk based assessments inform the process transfer plan deliverables. Typical process transfer and PPQ risks may be mitigated by the following:
- Minimized Process Complexity & Consistent Historical Process Performance
- Platform processes
- Process Experience at Multiple Manufacturing Scales
- Facility and Equipment Process Experience (especially if associated with similar/platform process)
- Planned Process Batches prior to commencing PPQ (i.e. engineering / shakedown runs)
The process transfer team should meet often to ensure alignment and progress technical deliverables.
Step 4: Execution (Monitor/Progress)
New processes are transferred to the receiving site through the integration of process requirements into local business processes, and associated process and operational documentation. Early development of local process deliverables during the technology transfer process enable complete risk identification with agreed resolution by the process transfer team including:
- Process descriptions for each unit operation
- Process and operating control strategies
- Process and equipment risk assessments (e.g. FMEA)
- Subsequent product/process requirements (if applicable)
Quality agreements between sites are established to enable product batch release/disposition. Operational expertise from the receiving site included in the process transfer team ensures successful integration of process requirements and enables well-defined, functional manufacturing batch records and operating instructions that result in a successfully manufactured process. The process transfer team closely monitors the process execution, in process results, and operational observations during the first process batch manufacturing campaign. The process results provide early indication of the process transfer success and identify requirements for changes prior to subsequent batch manufacturing, if applicable. Continued manufacturing process performance, deviations, and post-approval changes from the receiving site continue to inform the technology transfer process (Step 1 and Step 2) for future process transfers. This feedback is key to continue to optimize and improve the technology transfer process.
Authors: Jessica Mayne, David Kahn, Dane Dorundo, and Brian Youchak Eli Lilly and Company