Process Validation Challenges for Technology Transfer
For a commercial technology transfer, the ultimate measure of success is regulatory approval of the transferred process at the new site. A major step in obtaining regulatory approval is the process validation package. Successful design and execution of process validation requires proactive planning for both technical as well as logistical challenges. This article will discuss some common challenges that are faced as well as strategies to overcome them.
Technology transfers inherently involve a number of technical as well as logistical challenges.
Overcoming these challenges successfully within project timelines requires careful planning. One major activity in technology transfer and licensure of the process at the new facility is the process validation which demonstrates that the new facility delivers product of comparable quality with consistent performance. Considerations and strategies to successful validation of a transferred process are discussed here.
FACILITY FIT ASSESSMENT
One of the first challenges to overcome in transferring a manufacturing process is to fit the process into the target facility. In the initial stages of the technology transfer, a comprehensive review of process requirements and comparison with facility capabilities should be performed. A thorough fit assessment up front can help avoid unexpected delays or hidden costs later. Common examples of process requirements to evaluate include the expected titer/scale for the process against available column sizes and loading densities; comparison of expected flow rates and pressures against equipment ranges; evaluation of expected product pool sizes against tank storage capacities and effective mixing ranges; review of process temperature ranges against equipment temperature control capability; and review of chemicals used in the process for any impacts on waste limits or chemical storage permits. Local regulations on discharge limits can vary widely, and care should be taken to ensure that the assessment is performed against the applicable regulations for the target site.
Any changes to the process to accommodate the facility fit may result in additional process validation requirements. Changes should be minimized as practically feasible, utilizing the same scale and equipment as the original site when possible. When scaling up to a larger facility, maintaining the same scale factor across the entire process train should be targeted. Practically, there will always be some differences between facilities. A remediation plan for any potential gaps should be prepared, along with a risk assessment of any potential changes or differences. Gaps can be addressed either by facility modifications, which may entail capital investment, or by changes to the process itself, which may require process validation or characterization to support. While an upfront capital investment may seem undesirable, the time and resources required for the additional validation activities should also be considered. The decision should also factor in the criticality or impact of the step on product quality. Minimizing process changes minimizes risk of unintended differences in process performance and product quality, and may also facilitate regulatory approval for the transfer.
Once the process fit into the facility is defined, a site-specific process description and process flow diagram help to document and communicate the implementation plan across the various functional groups involved in the transfer (e.g., Engineering, Manufacturing, Process Development, Quality, Regulatory). Highlighting facility differences or process changes between the originating site and the receiving site in these documents will also facilitate assembly of a process validation project plan. The process validation project plan should include not only those additional studies required to support process changes, but also those studies which will be used to demonstrate the comparability of the product quality and the process performance. In constructing the validation project plan, one should also consider which unit operations may require site-specific studies at full-scale even with no changes to the process. For example, differences in piping or valve configurations may need to be accounted for by full-scale validation. A risk-based approach can be used to determine and document whether a site-specific validation study is required.
Leveraging existing process validation studies can help to streamline the validation plan, but the rationale for the applicability of those previous studies to the transfer at hand should be clearly documented. In projects where timelines are critical or constrained, making use of document templates can prove effective. Templates can help to provide consistency as well as limit the amount of review required in later phases of the project when technical resources are needed for other activities associated with the process transfer. The templates can undergo initial review with placeholders for missing details, followed by a final review with the data once available. However, this approach also requires careful document management and project management to ensure critical information receives the appropriate review once populated. For example, drafting of regulatory submissions may begin prior to completion of all process validation and characterization studies. Final review of the submission should ensure that all stated process parameter ranges match the ranges supported by the validation.
Process validation activities require many manufacturing process samples beyond those typically needed for QC in-process and release testing. To ensure that all the samples needed to support validation are acquired during the manufacturing campaign, a comprehensive sampling plan should be developed. The sampling plan should include a list of samples required to support process validation activities, as well as details on sample container types, storage temperature requirements, the analytical testing to be performed for each sample, and the testing timeline. If the samples will require shipment, one must also consider what additional materials are required for shipment – for example, shipping containers, temperature monitoring devices, and documentation for chain of custody. Seemingly simple decisions such as container type can often have a big impact. For samples which will be stored frozen, the physical properties of the container material should be evaluated to ensure that the container will not become fragile or brittle at the intended storage temperature. For samples which will be shipped on dry ice, the gas permeability of the container should also be evaluated. Higher gas permeability may result in changes to the sample pH due to diffusion of carbon dioxide.
In addition to the samples required to support process validation studies, additional samples may also be desired for potential troubleshooting activities. For example, a sample of manufacturing feedstock can be processed in a lab-scale model to help determine if unexpected issues seen at full-scale are feedstock-related or facility-related. Having a lab-scale model available in which studies can be run in real-time, or as close to manufacturing production as possible, can be useful in such cases.
RESOURCES AND RESPONSIBILITIES
It is also critical to identify and gain agreement on who will execute the outlined studies, as well as a timeline for the activities involved. In the 2011case of process validation studies, these activities include who will author the protocol, obtain the samples, deliver samples, perform analytical testing, and prepare the summary report. The roles and responsibilities should be clearly defined for all activities. Technology transfers are inherently multi-functional projects involving more than one site, and one site may assume an activity is the responsibility of the other. Defining all activities up front ensures an activity is not overlooked later. Similarly, expected lead times should be reviewed and documented, as lead times for an activity may be different from site-to-site. Availability of raw materials or consumables, shift coverage, and analytical testing lead times are all examples of activities which should be examined for differences between sites. Close coordination and communication between all the resources involved is critical, as timelines often can shift during the course of the project.
LOGISTICAL CONSIDERATIONS FOR INTERNATIONAL TRANSFERS
Additional challenges are faced when the technology transfer is to a facility in a different country than the originating site. There are the additional communication challenges of a different culture, different language, and/or different time zone. Even in instances where English is spoken proficiently by all team members as the common language, different cultural influences can result in different interpretations for a given word or phrase. While technological networking advancements have made it far easier to hold teleconference meetings while viewing a common presentation in real-time, occasional face-to-face meetings are still invaluable in establishing relationships and developing an innate understanding of each team member’s communication style.
Technology transfers are highly complex, multi-functional projects, but anticipation of the challenges can help ensure success. Careful evaluation of the process fit with the facility and minimizing changes; clear documentation of the process and project plan; defined roles, responsibilities, and timelines; and an appreciation for cultural differences between originating and receiving sites are all considerations that, when accounted for up front, can help to ensure a successful technology transfer and validation