Successful Technology Transfer, Process Validation, and Partnership with a CMO

ABSTRACT

The use of contract manufacturing organizations (CMOs) for biopharmaceutical production offers many benefits, including deferred capital investment in building and validating a new facility for introducing new products to the market, bridging a technology gap, or as a second source of manufacturing for supply-risk mitigation.

Figure 1. Stages of Technology Transfer. (All figures are Courtesy of the Authors)

The use of CMOs for production of biopharmaceuticals is fairly commonplace in industry today (1). This allows companies to accelerate the introduction of new products to market without the delay and cost incurred by having to build and validate a new facility. CMOs also provide an attractive dual sourcing strategy to mitigate product supply risks. Both the sponsor and CMO can reap benefits from this relationship if it is thoughtfully developed. However, the onus of oversight responsibility is clearly with the sponsor company as outlined in FDA guidance for industry (2). 

This article looks at best practices for technology transfer (TT) based on lessons learned over the course of the TT of a cell culture biotherapeutic process to a CMO and the subsequent transition to commercial manufacturing operations. In this case study, the strategy for use of a CMO was to supplement existing internal production to meet expected product demand. The stages of TT shown in Figure 1 are outlined in the subsequent sections where the key aspects for a successful TT are discussed. 

Team formation, planning, and information transfer

Figure 2. Team structure for technology transfer encompasses strategic and tactical execution. The various technical teams shown are joint teams and include members from both the sponsor and CMO.

Following the decision to use a CMO, the TT begins with team formation, planning, and information transfer. It is imperative to clearly define the scope and strategy for the TT. For example, if the objective is to demonstrate process and product comparability between an existing process and the one being transferred to the CMO, the strategy would be to minimize process and analytical changes to only those that are essential for fit within the CMO facility. Alternatively, if the objective is to improve process yield or throughput, there may be a greater tolerance for process changes. In forming the team, it is essential to clearly define roles and responsibilities of the sponsor and CMO teams. Figure 2 illustrates the team structure used to ensure that all aspects of the TT are considered. The TT core team brings together all work streams to ensure that they are aligned from a strategy perspective and highlight any issues that require cross-functional discussion and decision making. In addition to the core and sub-teams, it is important to have a governance structure for oversight of the TT and also to provide a forum for issues to be escalated and resolved in a timely manner. Some of the key considerations during the team formation phase are as follows:

• Ensure that teams have effective tools for communicating between sites (e.g., web-based teleconferences, a web-based server for storing and sharing information). Details such as meeting frequency and expectations for communication between teams should be clearly outlined at the start.

• Ensure that team accountability is clearly defined. It is important to have a good mix of technical and business and project management support, which enables clear focus on core competencies. This allows the TT lead to focus on ensuring technical success while the business or project manager can focus on the framework and financial aspects to ensure overall TT success.

• Ensure direct, face-to-face contact; for example, during project kick-off and milestone reviews. In these days of greater economic stringency, this is an area that is often the first to be cut to help reduce project costs. However, we would recommend that this is seen as a 'must have' for ensuring success of the TT.

• Training for teams on cultural nuances and work styles when dealing with international transfers. Awareness of differences in corporate and regional attitudes to work are important to ensure that teams can achieve their common goal of a successful TT. For example, some companies and cultures tend to have a more hierarchical approach while others tend to have a more direct engagement style. There is no right or wrong in this regard. What is essential is that teams have awareness and respect the other's style and that, as a combined team, they find an effective middle ground.

• Training by the sponsor company for the CMO on their product-commercialization program so that expectations are clear from the start. There should be dialogue during this stage to ensure that CMO policies and practices will meet the sponsor company's quality and business expectations.

• The working team should be encouraged and empowered to try and work through issues as much as possible and within budgetary accountability. It is important to find the balance between empowering the TT team to make decisions versus escalating everything to the governance team as the latter could become overly cumbersome and result in delays to the TT timeline.

• Be mindful of changes in the key members of the TT team, especially for leadership roles. Ideally, once the TT team has been assembled, it is important to maintain continuity in the team through TT to maintain knowledge and momentum. This also allows a solid relationship to form between the sponsor and CMO.

In the planning phase, the work plan forms a key document to list the key goals, assumptions, activities, deliverables, project timelines, and key milestone expectations. The work plan is a legally binding document used in conjunction with Quality and Supply Agreements so that the sponsor and CMO have clarity on expectations for the project moving forward. Defining a team charter and roles and responsibilities document as a joint effort is useful in ensuring clarity and avoiding issues later in the project. In our experience, it is rare that a complex TT project would have all the right assumptions from the start. It is important that the teams be adept in their ability to foresee the need for changes and assemble data justifying the change required. The scope and cost of the change should be defined and reviewed with the governance team for approval so that the project can keep moving forward without delay. Key through all stages of the TT is the need to avoid revisiting decisions once they have been made. It is important to document the decisions made, assumptions at the time, identified risks, and the agreed-upon path forward.

The information transfer stage involves the exchange of a large number of technical reports detailing the process and analytical methods. However, it is essential that this is not just seen as the exchange of documentation. While the coordinated transfer of documentation is an essential part of TT, the availability of CMO staff to observe the process as operated at the sending site (manufacturing, pilot, and laboratory scale) is essential in ensuring that the nuances that may not be captured in the documentation are also identified and discussed. As mentioned below, face-to-face meetings provide the best forum for active discussion of potential issues and changes that may have to be made to facilitate the process fit within the facility.

It is also important to stress that the information transfer is not a one-way affair from sponsor to CMO. The CMO needs to provide relevant equipment and facility information and also provide documentation to ensure that they have correctly understood the process. This type of dialogue and information sharing is sometimes constrained under the guise of what is considered proprietary information so the confidentiality aspects should be appropriately covered in the contractual agreements to ensure that both sponsor and CMO are able to share necessary information. It is important that the teams not make poor assumptions that would otherwise be identified later during engineering or validation runs with serious consequences to the project success and timelines.

New Product Introduction (NPI) phase

During the NPI phase, the process is operated at the CMO prior to the formal validation campaign. Some CMOs have developed scaled-down laboratory and pilot models that allow them to gain familiarity with the process without tying up valuable commercial manufacturing facilities, which would add to project duration and cost to the sponsor. This allows the consistency and robustness of the process to be evaluated by the CMO at an early stage in the transfer. Process changes for facility fit purposes may be evaluated during this phase. Additionally, the availability of qualified scale-down models is vital for effective troubleshooting in manufacturing. Typically, if the sponsor company is leading process characterization, it would be responsible for evaluating and performing supplemental process characterization studies to confirm the impact of any required process changes to the product and process. However, this should be discussed, and the tech-transfer team should distribute workload between sending and receiving teams to best use technical expertise and effectively maintain project timelines. The laboratory and pilot runs allow an opportunity for testing the raw materials to be used in the process. Risk assessments based on historical knowledge may help classify raw materials as crucial, where sponsor and CMO must agree on the supplier, and non-crucial where the CMO may use an alternative vendor with similar specifications. However, it is important to stress that this should be tested at laboratory and pilot scales to confirm that the final raw materials selected do not have any impact on the process and product quality. Experiences from the laboratory- and pilot-scale studies as well as supplemental process characterization help to drive the scope for the next stage of the NPI at the commercial scale.

At the commercial manufacturing scale, automation-, wet-testing, and engineering runs should be executed prior to the validation campaign. These are performed under development protocols so there is clarity on the goals and success criteria as well as the methodology to be used. At this stage of the program a balance needs to be reached between desired engineering run rate that provides time for data analysis and adjustment between runs, available facility time, and campaign cost. The engineering runs (sometimes referred to as shake-down or test runs) are product runs performed as a means to ensure that the process performs as expected before commencing the process validation campaign. Key considerations for this stage are as follows:

• Should the engineering runs be done to GMP or non-GMP standards? The latter offers greater flexibility in making modifications to the process under the guidance of technical experts without being constrained by the GMP requirements for change control and batch-record approval. However, the material from this non-GMP engineering batch cannot be released for clinical or commercial use. Another consideration is with respect to use of raw materials, such as chromatography resins from the engineering to validation campaign. The high cost of the resin makes reuse attractive between campaigns. The requirements for allowing resin reuse should be outlined in a protocol. Following execution, the data should be summarized in a report confirming that the resin is fit for use in validation runs.

• The number and stagger between runs to allow evaluation of process data and any process or equipment modifications to be made. Conducting runs back to back leaves little time to identify a problem, investigate its root cause, and develop potential corrective action, so that the problem may affect multiple runs. This requires careful balancing of technical risks and the cost of running at a slower pace to allow for such process trouble-shooting.

• Availability of scale-down models to run the process concurrently and aid with potential trouble-shooting work.

• Ensuring that contingency plans are developed for high or medium risk issues identified during the information transfer and pilot-scale studies. This allows one to react quickly to potential technical problems that may arise during the execution of the engineering runs. Contingency plans should consider additional runs to confirm that corrective actions remediate any problems identified.

• On-site presence of technical experts from the sponsor company to ensure that the process is operated as originally designed and to aid in process troubleshooting. This also helps to ensure fast communication back to the sponsor company so there is transparency in operations.

The engineering campaign tends to be the most intensive phase of the TT. A readiness assessment is a key output from the engineering campaign to ensure that the process is operating as expected and that all issues identified during the campaign have been adequately addressed such that the team is ready to move forward to perform process validation.

Process validation

The culmination of the TT work is the execution of the process validation campaign. There may be differences in validation strategy between the sponsor and CMO, so early initiation of discussions between validation experts at both companies is recommended. The output of these discussions is documented in the Process Validation Master Plan (PVMP), and process validation study protocols. In addition to these, it is recommended that a process validation support plan is defined. The support plan details roles and responsibilities during the validation campaign, ensures that data are actively being monitored and verified so that issues can be identified and resolved rapidly without affecting the overall validation campaign. Both parties should agree at the beginning about how frequently they will meet to review performance parameter (process outputs) and operating parameter (process inputs) data. On-site presence from the sponsor company especially for critical steps in the process is recommended during the validation campaign. This also facilitates discussion to identify any parameters excursions to understand impact on the integrity of the validation study and if any additional runs are required.

Regulatory filing and preapproval inspection (PAI)

Following completion of the validation campaign, the data from the validation campaign are consolidated in process validation study reports. Sufficient time should be allowed to draft and review the Controls, Manufacturing, and Chemistry (CMC) sections of the regulatory dossier. The roles and timelines to write and review CMC sections should be clearly defined. It is necessary to ensure that the CMO is aware of timelines for responding to questions from regulatory agencies and that resources are made available for this activity. A clear communication plan is crucial to ensure that regulatory questions are answered by the appropriate individuals within a specified time. It is important to prepare early for the PAI so that problems are corrected before they delay approvals and licensure. Sponsors should consider performing mock audits and sending their subject matter experts and quality management on-site for the PAI.

Transition to commercial manufacturing

Figure 3. Team structure for technology transfer encompasses strategic and tactical execution. The various technical teams shown are joint teams and include members from both the sponsor and CMO.

During the transfer to commercial manufacturing operations, it may be necessary to make some adjustments to the team structure and level of engagement. One organizational approach that we have found to be effective is to have a virtual site-management structure as outlined in Figure 3. This consolidates the various sub-teams that were engaged during the TT into a more sustainable format. The core team is more operational and quality focused to ensure continued success in delivering product to target metrics for quality, speed, and cost. Oversight via a governance team is still maintained.

From a technical aspect, an important consideration for the transfer to commercial manufacturing is to finalize plans for process monitoring. The parties should share and document their expectations about which in-process controls will be monitored as well as the methodology for establishing statistical process control (SPC) limits and identifying process shifts and trends. They should also agree on how this information should link to quality systems for deviations, change control, and annual product reviews. It is also important for the parties to agree on the frequency of data review, and how the team responds to SPC signals so that appropriate corrective action is taken where necessary.

Conclusion

Key to successful TT and a mutual beneficial relationship between sponsor and CMO is clarity in communicating expectations. Clearly aligned objectives and deliverables and well-defined roles, responsibilities, and team structure from the onset will lay the foundation for a successful working relationship. There should be appropriate oversight and governance structures in place. Teams should be mindful of cultural and corporate nuances and use appropriate communication tools, including face-to-face meetings for milestone project reviews and to build a cohesive team. The need to periodically assess TT and operational risks and develop contingency plans helps to mitigate such risks. The level of engagement would be expected to evolve depending on the operational phase, for example, during the transition from TT to commercial manufacturing. Underlying all of this is a relationship that is built on trust, which improves the speed and cost of doing business and maximizes benefit for both sponsor and CMO.

Acknowledgments

The authors wish to thank Ali Siahpush and Jian Irish for their insightful comments and guidance in preparation of this manuscript.

SUSHIL ABRAHAM* is director of Process Development, and HOWARD BLAND is a director of Contract Manufacturing, both at Amgen, sushila@amgen.com.

References

1. E. Langer, Contract Pharma, May 2008.

2. FDA, Guidance for Industry: Cooperative Manufacturing Arrangements for Licensed Biologics (Rockville, MD, November 2008).