The Role of Analytical Science in Implementing Quality by Design - Pharmaceutical Technology

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The Role of Analytical Science in Implementing Quality by Design
The authors present topics discussed and conclusions that resulted from the PDA QbD workshop.

Pharmaceutical Technology
Volume 37, Issue 3, pp. 74-77, 80

Application of QbD concepts to analytical methods

The concepts of QbD as articulated in ICH Q8, Q9, Q10, and Q11 are aimed at improving the robustness of pharmaceutical manufacturing processes and enabling continual improvement. They focus on taking a systematic structured approach to identifying process variables and how these variables relate to the desired process outputs and pharmaceutical products. Such enhanced understanding combined with application of formal risk-assessment processes are used to identify the critical attributes and parameters that should be controlled to assure product quality. Lifecycle knowledge and change-management processes then ensure that control strategies remain effective through the lifecycle. By considering an analytical method as simply a process, it is possible to apply these same concepts to provide enhanced confidence of the robustness of analytical methods. As mentioned above, this increased focus on robust methods is becoming an increasing area of concern for analytical scientists as non-robust methods undermine the ability to plan manufacturing and related quality assurance activities with confidence. Increased regulatory scrutiny on out-of-specification (OOS) investigations and effective root cause analysis of these is another key driver for ensuring method variables are well understood and controlled.

In 2010, the European Federation of Pharmaceutical Industries and Associations (EFPIA) and the Pharmaceutical Research and Manufacturers of America (PhRMA) jointly issued a white paper aimed at stimulating discussion between industry, regulators, and pharmacopeias on the potential benefits and implications of applying QbD concepts to analytical methods (5). A number of companies are now adopting this approach as they are seeing benefits in terms of increased method understanding, robustness, and ruggedness. During a Parenteral Drug Association (PDA) workshop, held Mar. 6–7, 2012 in Liverpool, UK, it was acknowledged that there are no regulatory barriers to adoption of a QbD approach for analytical method development and validation; however, it was also recognized that thinking may need to change about approaches to analytical method validation (10).

A lifecycle approach to method validation has been proposed (11) and indeed some of the concepts behind application of QbD to method development and validation have started to be promoted, particularly by the United States Pharmacopeia (USP) (12, 13) and through ASTM guidance on validation of PAT methods (14). Recently, USP has established an expert panel to explore whether the chapters on method validation, method verification, and transfer of analytical procedures may become amalgamated into a single chapter describing how methods are assured to be fit for purpose through their lifecycle. Sample replication levels, criteria for agreement between replicates, system performance requirements, repeat testing required for OOS and equivalence testing criteria should all ultimately be able to be linked back to an understanding of the methods performance and the targets for accuracy and precision that are required.

As noted above, a common understanding between pharmacopeias, regulatory agencies, consensus standards organizations, and industry on the description, application and interpretation of QbD concepts as applied to analytical methods is essential if they are to be more widely adopted. The PDA workshop recognized that alignment of understanding was key and that better clarity was desired on some of the terminology and concepts being used (e.g., method operable design region [MODR] vs. analytical design space [ADS], analytical target profile [ATP] vs. procedure performance acceptance criteria [PPACs]), and participants proposed the development of case studies to better illustrate the concepts. A key point that arose during the workshop that needs further discussion is whether a method is validated to meet a target performance (which is defined from the specification limits) or whether the specification limits are set based on the method capability.


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