Appendix I
The following examples use risk assessment to determine actions to be taken as part of method performance verification. The
aim of the method performance verification exercise is to provide confidence that the modified method will produce results
that meet the established criteria defined in the analytical target profile (ATP), which may be assessed by considering each
of the method's characteristics and rating the risk that the change in the method will affect each of these characteristics.
Risk assessment tools can be used to provide guidance on what actions are appropriate to verify the method is performing as
required.
A1, Table I: Importance of change in column manufacturer for content and impurities by a high-pressure, liquid chromatography
method.
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A1, Table II: Importance of an increase in column equilibration time prior to next injection for content and impurities by
a high-pressure, liquid chromatography method.
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The following rating system was used for assessing the possibility of an impact in the two examples of risk assessment shown
in A1 Tables I and II:
- 0 - No possibility of an impact
- 1 - Very low possibility of an impact
- 3 - Slight possibility of an impact
- 5 - Possible impact
- 7 - Likely impact
- 9 - Strong likelihood of impact
If a risk to a certain method performance characteristic has been mitigated through other controls (e.g., system suitability),
the risk for that characteristic should be reduced accordingly. It should be noted that some methods do not need to be validated
for all characteristics; for example, an API assay method may not require sensitivity. In these cases, put a 0 or ''not applicable''
in that category.
Based on the scoring, a decision is made on which characteristics need to be demonstrated (i.e., verified) as meeting the
method performance criteria.
For the following examples, any individual score of 5 or above will require work to ensure the suitability of the modified
method. Where a score of 5 or above for accuracy is recorded, an equivalence study will be required. Other characteristics
that are scored equal to or greater than 5 will require appropriate verification.
Table I shows a risk assessment for a change in the high-pressure, liquid chromatography (HPLC) column manufacturer for a
content and impurities method. In this example, the only aspect of the method that is changed is the analytical column manufacturer.
The technique has not changed, nor has the basic chemistry driving the technique. The most likely impacts on the reported
values for the method are to the selectivity for impurities, which in turn has a potential effect on the accuracy of impurity
quantitation. Therefore, for the example situation presented in Table I, it is necessary to assess equivalence between the registered method and modified method for the impurity identification
and content. The modified method for impurities should also be verified for selectivity, because the rating for this parameter
is greater than or equal to 5. Unless the peak width and/or tailing factor are significantly adversely affected by the change,
the sensitivity, precision, and linearity of the method are not likely to be affected by a change in the chromatographic column
manufacturer. Moreover, sensitivity and precision are controlled in most methods through the use of system suitability requirements
and do not represent a significant risk to the method.
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