During the lifecycle of a product, both the manufacturing process and the method are likely to experience a number of changes
through continuous improvement activities or the need to operate the method or process in a different environment. It is essential
that all changes to the method's operating conditions are considered in light of the knowledge and understanding that exists
on the method performance. For all changes, a risk assessment should be carried out and appropriate further validation activities
performed. (See Appendix 2 for examples of actions for different types of changes.)
If a change involves operation of the method in a new location, appropriate method-installation activities, including knowledge
transfer, need to be performed in addition to a method-performance verification exercise. Method installation focuses on ensuring
that the location at which the method is intended to be operated is adequately prepared to use the method. It includes ensuring
that the analytical equipment is qualified and appropriate knowledge transfer and training of analysts has been performed.
The method conditions and detailed operating controls along with all the knowledge and understanding generated during the
design phase are conveyed to the location in which the method will be used. Performing a method-walkthrough exercise with
the analysts in the original and new locations can be extremely valuable in ensuring all tacit knowledge about the method
is communicated and understood. The extent of the method-installation activities should be based on an assessment of risk
and should consider, for example, the level of preexisting knowledge of the analysts in the new location with the product,
method, or technique. As part of the initial qualification of a method, a second laboratory may be involved in producing
data to determine the method's reproducibility. In such a case, the second laboratory can be considered as being within the
method design space, and any subsequent operation of the method in that laboratory would not be considered a change. Nevertheless,
the described activities with respect to method installation would be performed before starting the reproducibility study.
This approach to method qualification focuses on activities that would typically be performed for a method that is developed
and used within a single company. Other scenarios exist in which a laboratory may need to use a method for which it has no
access to the original method design or qualification information, such as in a contract-testing laboratory. In these situations,
it is important that the performance requirements of the method are considered and an ATP is defined and documented. An appropriate
qualification study is then performed to demonstrate that the method meets its ATP.
Adopting a QbD approach to analytical-method lifecycle management would have significant implications for analytical scientists
in the pharmaceutical industry. Industry and regulatory authorities will need to modify the way they use ICH Q2, which, ideally,
would prompt a revision of this guidance to align it with the lifecycle-validation concepts promoted by ICH Q8, Q9, and Q10
(9, 14, 15). The need for a revision of ICH Q2 as a consequence of increasing adoption of QbD concepts and use of PAT has
also been identified by Criuzak (16).
The activities that were previously defined as method transfer (i.e., knowledge transfer and confirmation of equivalence)
would become intrinsic components of the lifecycle validation approach (i.e., they would be described as method installation
and method performance verification activities) and would be traced back at all stages to the ATP requirements, rather than
being treated as distinct from traditional method validation.
A key advantage of adopting the approach described in this article is the flexibility to perform all the validation stages
against the specific ATP defined for the intended method use. This would eliminate the approach of creating a validation document
against ICH Q2 in a check-box manner, which can lead to unnecessary and non-value-adding work. Because this approach could
be adopted for all users of analytical methods, it also offers the potential to standardize industry terminology and create
a harmonized method validation approach. This approach aligns terminology to that used for process validation and equipment
qualification, supports a lifecycle approach, removes existing ambiguities in validation terms (e.g., method validation, revalidation,
transfer and verification), and clarifies what is required for each part of the process. Table I summarizes this comparison of the traditional and lifecycle approaches to method validation.
Table I: Comparison of traditional and lifecycle approaches to analytical method validation.