Additional benefits of covalidation
Table III. Click to EnlargeTroubleshooting and method understanding. The collaborative approach used during the covalidation workflow enhanced the knowledge transfer between the transferring and receiving laboratories. Regular communication ensured that both units were fully aligned in achieving the optimum outcome. This collaboration required a cultural change by both units, as the transferring unit needed to engage with the “customer” (receiving unit) during the method validation stage of the analytical method lifecycle, and the receiving unit needed to engage in method troubleshooting and optimization of the analytical method where required. This new mode of operation modified the traditional work practices and resource allocations within both units. For example, there was a greater requirement for technical expertise amongst the staff engaged at the receiving unit than would be typically required for a transfer using the comparative testing model.
Early input from the receiving unit identified potential roadblocks to the application of several analytical methods in their laboratory. A validation team was formed, including representation from both the transferring and receiving units who worked together to identify solutions to the issues and incorporate the changes into the validation exercise and final method.
One such issue arose during the covalidation of a method to determine residual solvents by GC that used headspace sampling and flame ionization detection. At the commencement of covalidation discussions between the two laboratories, an equipment list was created that indicated both laboratories had the same GC equipment. However, during familiarization trials at the receiving lab, when data from the two laboratories were compared, it was noted that early eluting peaks observed at the transferring unit were consistently larger than those obtained by the receiving unit. A thorough review of the make and models of the instrumentation confirmed that the instrumentation was the same in both laboratories, but the instrument configurations were different.
If a comparative testing approach had been used, this issue would have halted the technology transfer while the issue was being resolved. It could have resulted in additional validation testing by the transferring laboratory and would have lengthened the time required to qualify the commercial laboratory. The collaborative nature of the covalidation approach resulted in the validation team rapidly identifying the root cause of the issue and incorporating the different instrument configurations into the covalidation exercise and final method documentation with negligible impact to the overall timeline.
Additional benefit: effective planning. Another outcome of the more collaborative and intensive communication between the two units was the identification of a planning tool. Frequent meetings, phone calls, and e-mail correspondence between both units, in addition to a significant volume of duplicate/redundant work, were identified as inefficiencies within the transfer. A review identified a more streamlined and efficient process, which resulted in adoption of the Microsoft Project planning tool for managing the overall transfer. The planning tool was customized to reduce the number of meetings, streamline documentation and communication activities, and optimize the scheduling of transfer testing through the use of Gantt charts.
Key features of the tool included:
- Use of Gantt charts to link and track all project activities
- Identification of critical risk factors for the technology transfer via technical risk and associated risk assessment grading (RAG) columns
- Use of filters to facilitate efficient review of relevant tranfer activities
- Controlled write access to the tool to ensure all information is current and accurate
- Use of hyperlinks for access to controlled transfer documentation
- Centralized location for all relevant project information (e.g., test methods, validation documentation, project timelines).
Traditionally, analytical method qualification of receiving laboratories is performed using comparative testing technology transfers, which involve validation of the method at the transferring unit, followed by technology transfer to the receiving unit. Covalidation is an alternative technology transfer model that combines method validation and receiving unit qualification in one process. To reduce the business risk of potential covalidation failure, a decision tree was established with the key requirements outlined. The decision tree highlights the importance of robustness study of any method before proceeding with covalidation.
The primary impact of using the covalidation model is the expedited analytical method qualification of both the transferring and receiving laboratories. Covalidation of analytical methods also affords other benefits to both transferring and receiving units, namely through the earlier engagement by both units in the analytical method lifecycle, thereby ensuring the relevant test method will be optimized for operation in the receiving unit. This early engagement facilitates input from the receiving unit, supporting a more efficient subsequent covalidation and qualification of the receiving unit than the comparative testing model. This approach also results in more efficient knowledge transfer between both units through method optimization and troubleshooting activities.
A cultural change is required to optimize the output of the validation team, which is comprised of members from both the transferring and receiving laboratories. Additionally, resource allocation for covalidation is very different from the comparative model. The covalidation process requires the receiving laboratory to allocate resources at an earlier stage in the analytical method qualification process, and also potentially to a greater degree than the comparative transfer model. Additionally, covalidation requires efficient organization and planning at both laboratories to ensure simultaneous activities are coordinated and scheduled so that transfer deadlines can be met. Use of a tool, such as Microsoft Project, facilitates the planning of covalidation activities and scheduling of resources.
The covalidation pilot detailed in the case study was successful in ensuring qualified analytical methods were available to support the manufacturing validation campaign at the receiving site as part of the expedited launch of the new drug product. Application of the covalidation model and transfer waivers greatly reduced the cycle time for the analytical transfer element of product development. As a result, covalidation is the preferred mode of analytical technology transfer within BMS where early identification and engagement of the receiving site is required.
The authors wish to thank the various project team members in UK, US, and Ireland who actively participated in the pilot programs for covalidation.
- FDA Safety and Innovation Act (FDASIA) Section 902, 126 STAT. 993, Public Law (July 2012), pp. 112-144.
- S. Scypinski and J. Young, “Analytical Methodology Transfer” in Handbook of Modern Pharmaceutical Analysis, S. Scypinski and S. Ahuja Eds. (Elsevier, Amsterdam, Netherlands, 2nd ed., Vol 10, 2011), pp. 507-526.
- USP39-NF 34 General Chapter <1224> “Transfer of Analytical Procedures”, pp.1638.
- ICH, Q2 (R1) Validation of Analytical Procedures: Text and Methodology (1997).
Citation: When referring to this article, please cite it it as K. O’Conner, N. Hulme, and Y. Shi, “Covalidation Strategies to Accelerate Analytical Method Transfer for Breakthrough Therapies,” Pharmaceutical Technology 41 (4) 2017.
About the Authors Kieran O’Connor is a quality control systems technical specialist, Bristol Myers Squibb, Ireland, [email protected]; Nicola Hulme is a senior research scientist, Bristol Myers Squibb, UK, [email protected]; and Yueer Shi is group leader, Bristol Myers Squibb, USA, [email protected].