Successful Technology Transfer, Process Validation, and Partnership with a CMO - The authors present lessons learned from a case study of the transfer of a cell culture biotherapeutic process to a

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Successful Technology Transfer, Process Validation, and Partnership with a CMO
The authors present lessons learned from a case study of the transfer of a cell culture biotherapeutic process to a CMO.


BioPharm International Supplements
Volume 24, Issue 3, pp. s9-s13

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.


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