PAT & QbD SUPPLEMENT
Table 3Validation acceptance criteria and results Parameter
Specificity Precision of the procedure
Accuracy Slope
Error of intercept (e1 Error of intersection (e2 Residual plot Mean recovery:
) )
Range: result uncertainty (95per cent) Lower limit (3.2 per cent) Upper limit (6.0per cent)
Equation 3:
Acceptance criteria See accuracy
≤ 2.5 per cent RSD
0.975 – 1.205 ≤ 2.5 per cent ≤ 2.5 per cent
Random distribution of residuals 97.5 – 102.5 per cent
≤ 2.5 per cent RSD ≤ 2.5 per cent RSD
intersection (of the extrapolated calibration line with x-axis) and percentage errors e1
and e2 are
calculated. In addition, for each standard addition step, the recovery was calculated (according to16
). An evaluation of the linear
response function by means of the residual plot was used to confirm the absence of interferences and side reactions. The range of water concentration below the authentic content has not been investigated experimentally. Instead, the result uncertainty
Results See accuracy 0.60 per cent (single titration) c0 = initial water content of the sample 1.006
0.22 per cent 0.60 per cent
Residuals are randomly distributed 100.7 per cent
0.43 per cent 0.17 per cent
was extrapolated to the lower range limit. The standard addition data were used and a linear regression of the overall water concentration (added and initially present in the sample) vs. the water content found was performed. The relative uncertainty was calculated from the 95 per cent prediction interval at the lower and upper limit of the range. In Table 3, the established acceptance criteria and the results of validation study are summarised.
EXAMPLE 4 As a pharmacopoeial standard method, development and optimisation of the Karl-Fischer titration would just focus on an inspection of the titration curve and drift behaviour in order to detect or exclude side reactions. The amount of sample is defined to obtain a titrant volume within the optimal range.
Specificity is given by the reaction stoichiometry and demonstration of absence of side reactions, which is (numerically) confirmed by the recovery investigations.
Equation 2 sg = between series variance
sr = repeatability variance 2
2 n = number of routine determinations, if the mean is the reportable result (otherwise n = 1)
The assay precision is composed of two major variance contributions, repeatability, and the between series variance, which includes the titrant factor determination (Equation 2)10
. As obvious from
Equation 2, the precision of the analytical procedure can be influenced by the number of repetitions. An intermediate precision study was performed using an authentic drug substance batch to determine the variance contributions. Four series of six determinations each were performed with a new factor determination each, two operators and two titration apparatus. The calculation was performed by means of an analysis of variances17
(see Table 2 on page 20). Using the variance
contributions and Equation 2, the method precision can be calculated. For single determinations as reportable results, the method precision corresponds to the intermediate precision of 0.60 per cent. If the mean is defined as reportable result, two and three titrations, for example, would result in a precision of the analytical procedure of 0.57 and 0.56 per cent, respectively. Because the major variance contribution originates from between-series factors, not much is gained from increasing the number of titrations (from the perspective of random variability). Therefore, an individual reportable result can be defined in the control strategy. In order to minimise risks outside the random variability, two titrations seem to be appropriate.
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European Pharmaceutical Review Volume 16 | Issue 3 | 2011
a = ordinate intercept of the regression line d = intersection of regression line with x-axis = intercept / slope
Transfer to production When the production of the drug substance is established at an industrial site, all information and knowledge with respect to the CQA, ATP, method selection, development and validation should be appropriately transferred to the industrial Quality Control unit. The implementation of the analytical procedure at the receiving site should be considered as a change control process. Depending on the complexity, variables likely to change as a consequence of operating the method in a new environment are risk assessed and if relevant included in an experimental study to assess primarily conformance to the ATP, secondly equivalence to the originating site. Formally, i.e. with respect to the requirements, equivalence is included if the ATP requirements are met. However, if continuity of CQA control is of importance, stricter assessment of equivalency may be of interest, for example quantification of a shift in the results between originating and receiving site. A wide range of activities are acceptable to
demonstrate the suitability of the analytical procedures at the receiving site: If it fits into the timelines, the receiving site could be included in the validation study of intermediate precision, as described above
A comparative precision study including originating and receiving site can be performed. Precision and accuracy criteria will be taken from the ATP, with the percentage difference between the mean results as relative bias
The industrial QC could also establish a new analytical procedure, performing the activities of method selection, development, validation as afore - mentioned. This will likely be limited to simple applications where knowledge generation and transfer are of less importance, for example if generic methods are established which only need to be adapted to the new application, such as GC determination of residual solvents
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