Chemistry Reference
In-Depth Information
7.2.2 I
mPurIty
m
ethod
v
AlIdAtIon
d
ocumentAtIon
Impurity method validation begins with the preparation of a validation protocol
that should be reviewed and approved by the appropriate departments (such as
Analytical Chemistry, Quality Control, and Quality Assurance) [(9); for an example
of a generic method validation protocol, see Appendix A]. The validation protocol
should describe the test method, performance parameters to be validated, exactly
how the performance parameters will be validated (i.e., descriptions of how test
samples will be prepared and analyzed), and validation results acceptance criteria.
The validation report should cross-reference the validation protocol, should describe
the results obtained, and the conclusions made (including the passing or failing of
predetermined acceptance criteria). Furthermore, deviations from the validation
protocol should be documented and justified as well. The HPLC (or other instru-
ment technique, e.g., GC, etc.) impurity method report (also referred to as the impu-
rity method SOP) should be attached to the validation protocol. It should describe
exactly how to execute the test method. It should include a list of instrumentation
and related supplies (i.e., column) to use (including acceptable instrument manufac-
turers and models), a list of the reagents and solvents for use (including the grade
and manufacturer), the exact sample preparation instructions (including blank, refer-
ence standard, system suitability, and test samples), a description of the instrument
operating conditions (sample injection volume, flow rate, gradient parameters and
column re-equilibration time [if applicable], detection wavelength, run time, etc.),
injection sequence, instructions for calculating system suitability and test sample
analysis results (with example calculations), system suitability acceptance criteria,
and figures of sample and blank chromatograms clearly indicating how to integrate
each impurity peak.
Although not an ICH or FDA requirement, experience has shown that it is also of
value to have HPLC impurity method reports reviewed and approved by an analyst and
supervisor in the department to which the method will be transferred. The value of this
review is that the method recipients have an early opportunity to review and provide
constructive feedback about the method well before it is ever transferred to their depart-
ment. This review has a significant and positive impact on method transfer (Chapter 8).
7.2.2.1 reporting Impurity content of ApI batches
Once an impurity method has been successfully validated and the validation report
has been written and approved, the method is suitable for use in the analysis of clini-
cal API batches. The ICH guidelines address reporting of impurity content in API
batches [6]. Organic impurity levels are typically determined by an HPLC impurity
assay. Patients must be protected from exposure to significant levels of impurities
whose toxicities have not been qualified (through biological testing). If the toxicol-
ogy lot is manufactured separately (as is often the case) from any of the clinical lots
(Phase I, II, or III), then the clinical lot impurity profile must be compared to that of
the toxicology lot. This is needed to ensure that patients are not exposed to unaccept-
able levels of unqualified impurities.
It is therefore very important to understand acceptable means of reporting API
batch impurity levels, because this information is used to determine, in many
