The QbD approach to analytical methods also faces several barriers, including the following:
- Current expectations of analytical technology transfer and method validation must change because current validation guidance
does not lead to methods that can always be reliably operated
- Acceptance must be gained for registration of the method performance criteria rather than the method conditions
- External guidance must be developed in this area; ICH guideline Q2(R1) requires revision (or removal) and Center for Drug
Evaluation and Research guidance must be created for analytical methods
- A common language for some of the new terms is required, including analytical method design space, analytical method control
strategy, and method performance criteria
- Analysts must learn new tools and skills
- A consistent worldwide approach is required for this initiative to be effective.
Conclusion
The goal of a well-characterized method development effort is to develop a reliable method that can be demonstrated with a
high degree of assurance to consistently produce data meeting predefined criteria when operated within defined boundaries.
The process detailed in this article illustrates how QbD can be applied to the development and evaluation of analytical methods.
During method development, all potential factors (the inputs) and all critical analytical responses (the outputs) are studied
to determine the relationships. Critical analytical factors are identified in an approach that parallels what is described
for process development in ICH Q8 and Q9. The QbD process outlined in this article relies on an active partnership of analytical
scientists at both the development and operational laboratories as methods are developed and as factors that lead to potential
method failures are identified and controlled. A corporate knowledge repository is required throughout the process to ensure
critical information is captured that can be reviewed and added to in the future such that lesssons learned can be applied
to the specific method under consideration and also to other similar methods being applied to other products. Such a repository
(in line with concepts described in the draft ICH Q10) will enable continuous improvement and change control of the method
to take place throughout its lifecycle.
Rather than continuing to perform analytical technology transfer exercises and ICH validation, a QbD approach based on a risk-assessed
change control procedure should be adopted. Each time a method is changed, a risk assessment should be performed. Where the
change is identified as having a potential to take the method outside its known design space, a method evaluation and, if
appropriate, an equivalency exercise should be performed to ensure method performance criteria are still met. This will allow
for method improvements to be made via internal change control procedures, and even switches between different techniques
(e.g., HPLC versus NIR) may become much easier to implement.
A QbD approach for analytical methods that includes risk assessment, robustness testing, and ruggedness testing is much more
rigorous than ICH validation requirements (Q2(R1)). It also includes an assessment of method variability compared with the
specification limits, which is one of the most important method attributes to test when deciding whether the method is fit
for its purpose. The approach described herein suggests that ICH Q2(R1), while adding some value, must be substantially rewritten
to take account of the QbD risk-based approaches described in this article.
This new QbD process offers the opportunity for much greater regulatory flexibility in the future. The method performance
criteria could potentially be registered instead of the method itself. The method used could be referred to as an example
of how to attain the required method performance criteria. Any changes to this method would be covered by internal change
control procedures.
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