PAT & QbD SUPPLEMENT


This will be crucial, in order to cover not only future changes that can be anticipated, such as application of fast LC-methods or flow- injection analysis to cope with increase of scale in production. The technological progress as well as crises are not predictable (the latter a priori), as we well know from the ‘acetonitrile-crisis’ in 2008/9. Later, during development as well as throughout the lifecycle, it


has to be demonstrated for each applied analytical procedure that it conforms to the ATP requirements (see Figure 3 on page 20). The latter would correspond to traditional validation, but will take the lifecycle aspect better into account as well as the iterative character of method development and validation. Because the acceptance criteria are already defined in the ATP, information from method development and optimisation can easily be included in the demonstration of suitability. For illustration of the concept a rather simple ‘mock’-example of


water determination in a drug substance is selected and potential scenario are pursued trough the lifecycle (seeExample 1 opposite).


Justification of the ATP For justification of the ATP and especially the acceptance limits, safety considerations are fundamental, followed by requirements to adequately control the manufacturing process and by analytical performance. If no safety aspects are concerned, generally expected analytical performance can be considered (analytical state-of-the-art). With respect to specificity, interference from other substances


likely to be present must be negligible or at an acceptable level. Interference may originate from the drug substance itself as the primary matrix, from impurities, degradation products, residual solvents, etc. and should be evaluated based on the knowledge of the synthesis process. Acceptable specificity may also be achieved by an appropriate correction using analytical results obtained from other control tests. Concerning the performance parameters, specificity is covered by accuracy: if an acceptable accuracy is demonstrated, the procedure is automatically (sufficiently) specific. The range exceeds the acceptance limits of the specification for


20 per cent in order to guarantee a reliable identification of non acceptable results9


. The precision criterion of the ATP refers to the precision


of the analytical result which will be compared to the acceptance limits of the specification, i.e. the reportable result10


(see Example 2


on page 20). Concerning accuracy, one has to take both a true bias and a


random difference into account. A true bias would result from interference, i.e. lack of specificity. A random difference originates from the normal variability of the analytical result (of the accuracy investigation). Both are method specific, but the latter can be influenced by the analytical design, i.e. the number of determinations, at least to a certain degree. Fundamentally, the ATP refers to a true bias, as this is linked to the requirements. However, both types will be confounded in the experimental results (‘observed bias’), similar to the concept of measurement uncertainty12


. It will


depend on the requirements for the concerned CQA, how strict the accuracy criterion must be defined. If there is less risk, the acceptable accuracy range may be defined wide enough to include


European Pharmaceutical Review www.europeanpharmaceuticalreview.com Volume 16 | Issue 3 | 2011


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