Adoption of quality-by-design (QbD) concepts in pharmaceutical development and manufacture is becoming increasingly well-established. QbD concepts are aimed at improving the robustness of manufacturing processes based upon adopting a systematic and scientific approach to development and implementing a control strategy based on the enhanced process understanding this provides. Many pharmaceutical companies have also recognized that QbD concepts can be used to improve the reliability of analytical methods. The authors describe how traditional approaches to analytical method transfer and validation also may benefit from alignment with QbD concepts and propose a three-stage concept to ensure that methods are suitable for their intended purpose throughout the analytical lifecycle: method design, method qualification, and continued method verification. This paper represents a refinement and enhancement of the concepts originally proposed in an article written by P. Nethercote, T. Bennett, P. Borman, G. Martin, and P. McGregor (1).
To help in implementation of the goals of FDA's Pharmaceutical cGMPs for the 21 st Century–A Risk-Based Approach (2), FDA recently issued guidance for industry describing the general principles and practice of process validation, which seeks to align process validation activities with product lifecycle concepts. This guidance (3) addresses some of the issues with traditional approaches to process validation where a focus on a one-time, three batch approach, with the use of the best talent during the day shift with the same lot of raw material does little to ensure that the manufacturing process is and will remain in a state of control. The traditional approach to process validation encourages a "do not rock the boat" mindset since the product is approved and the process is validated and fails to foster continuous improvement in quality or efficiency (4).
These issues have parallels in analytical method validation. Analytical methods for pharmaceutical products are validated in accordance with the International Conference on Harmonization (ICH) Q2 Guideline, Validation of Analytical Procedures: Text and Methodology, usually by the experts who have been involved in developing the method (5). Method validation is often treated as a one-time event with no guidance on how to ensure continuing focus on consistent method performance. There also is lack of guidance on how to demonstrate in practice that a method is fit-for-purpose (i.e., what are suitable acceptance criteria). There is potential for the validation process to seem more focused on producing validation documentation that will withstand regulatory scrutiny than on ensuring that the method will actually perform well during routine application. There is a risk that both regulatory authorities and industry use ICH Q2 in a check-box manner rather than its intent, which is to provide guidance on the philosophical background to method validation.After the method has been validated by the developing group, it may be transferred to another laboratory, which involves transferring the knowledge of how to operate the method to those who will use it routinely and documenting that both parties obtain comparable results. The routine operating environment, however, is not always considered during the method-development and validation exercise. The lack of an effective process for capturing and transferring the tacit knowledge of the development analysts can cause methods to fail to perform as intended in the receiving laboratory. Much effort is then expended on identification of the variables that are causing the performance issues and the exercise is repeated. As in the case of the initial method validation activity, the transfer exercise is typically performed as a one-off process. There is a risk that the exercise will focus more on producing the method-transfer report than on ensuring the ability of the receiving laboratory to run the method accurately and reliably and ensuring the continuity and integrity of analytical results.
The recognition that an analytical method can be considered a process that has an output of acceptable quality data led Borman et al. to take the QbD concepts designed for manufacturing processes and show how these could also be employed for analytical methods (6). It follows, therefore, that the concepts of lifecycle validation being developed for manufacturing processes might also be applicable to analytical methods. This concept aligns well with the lifecycle concept of equipment qualification in the United States Pharmacopeia (USP), consisting of equipment design, followed by operational and performance qualification, and with analytical method validation activities proposed by Ermer and Landy (7, 8).