Introduction
This guideline provides guidance for the validation of analytical test methods. These analytical test methods include those tests which evaluate API Raw Materials, In Process samples (e.g. reaction monitoring), and early intermediate materials (prior to the introduction of the first critical intermediate).
Per ICH Q7A, the degree of analytical validation performed should reflect the purpose of the analysis and the stage of the API production process.
Common analytical test methods within the scope of this document include but are not limited to the following examples.
– Limit tests (impurity, solvent OVI, clarity or extraneous matter tests).
– Quantitative tests for impurity content.
– Reaction Completion.
– Residual solvent content (OVI).
– Potency (assay) method for raw materials or intermediates.
– Tests for physical properties.
– Identification tests.
– Dryness Completion (e.g. % LOD or KF).
– For new test methods, the type of test, speed of turnover of results, simplicity and criticality to the production process to which it supports should be considered during the validation test design.
Example: If the test is for monitoring an IPC reaction completion step, these factors should be pre-determined in order to properly select the validation experiment parameters before the test method is developed and the validation exercise is begun.
To begin the validation exercise, individual sites can determine from Appendix 1 and 2 what analytical elements should be evaluated for the particular test and sample of interest.
In the case that a limited set of elements are included in the validation, it is recommended that the Method Validation Summary or protocol should address the reasons for limiting the validation to the chosen elements.
Validation of the test procedures should take into account the reactivity of the sample. If the sample can change over time, the validating scientist should attempt to find a means to quench the reaction before analysis. While this is normally a method development activity, this consideration should be evaluated by the site if method validation should occur at the sites. Once execution of the method validation has begun, deviations and experimental failures should be documented in the method validation report.
In some instances a set of experiments may be able to satisfy several validation parameters i.e. robustness, intermediate precision and repeatability could be combined and studied together instead of as isolated effects.
For example, compendial physical tests such as LOD/ROI/pH where the analyst a sample amount are primary contributors to variation and the method is well defined in general chapters are ideal for this situation.
An experiment could be constructed such that variations in sample size, analyst and equipment could all be studied at once.
Documentation
It is recommended that sites have local site procedures for performing test method validation. For methods in the scope of this guideline, sites may choose to prepare a protocol and obtain approval prior to commencing validation. Alternatively an SOP containing pre-approved templates or acceptance criteria guidelines could be used Because these test methods are generally lower risk than those used to test final APIs, more flexibility in documentation of validation information (e.g. use of an SOP versus a protocol) is considered acceptable.
Suggested criteria are included in this guideline on this topic; however criteria should be directly linked to the method’s intended use.
Method Validation Summary Report:
It is recommended to analyse the experimental results and prepare a Method Validation Summary of the findings.
These method validation summaries may include but are not limited to:
The performance results against criteria listed within this guideline, site SOP, or separate pre- approved protocol.
For higher risk methods, at least two reviewer signatures are recommended to be obtained for the Method Validation Summary to be approved.
It is suggested that at a minimum one signatory should be a member of the Site Quality Team. This should be an independent reviewer, not involved in the validation activities for that test method, in order to avoid the potential for conflict of interest.
The author should be responsible for determining that all data are accurately transcribed into the Method Validation Summary.
The reviewing/ approvers should be responsible for
– Technical correctness and completeness,
– Regulatory Compliance – Practices,
– Compliance – Registration,
– Compliance with written site requirements, SOPs;
– Authorization to implement.
– Review of changes to methods and their impact on other quality systems (e.g. process validation, etc)
– Review of deviations and failures during the method validation and their impact on the conclusions, if any.
– Test Raw Data or Reference to Raw Data.
– Reference to method development data (e.g robustness) if not referenced in a protocol.
Equivalent Cleaning Procedures
Any plan to group products or equipment for the purpose of cleaning validation should be based on the premise that the items grouped share the same cleaning procedure. Use of the term ‘same’ in this context means equivalent and applies to the cleaning methodology and parameters. If two or more procedures or automated programs share the same methodology and parameters, but have different titles, document numbers or program identifiers then it should be possible to apply the results of the cleaning validation across all those procedures. When determining if two procedures are equivalent, the following points should be considered as to their criticality in achieving the final result:
– Cleaning agent and cleaning agent concentration
– Liquid used for rinsing
– Temperature
– Scrubbing, rinsing and drying times
– Flow rate
– Agitation
– The extent of manual intervention required to produce expected results
Validation of Pharmacopoeial Methods:
Pharmacopoeial methods included in a specific official monograph are generally considered as validated. However, the suitability of compendial analytical procedures must be verified under actual conditions of use. It is recommended to demonstrate absence of interference with the compendial method, thus specificity (if applicable) should be assessed. Intermediate precision and stability of the sample solution should also be investigated using the compendial method for the specific API. Demonstration of the applicability of the method for use in the analysis of the specific product/material should be accomplished by the analysis of the material using the pharmacopoeial method. System suitability requirements of the method should be met, and for raw materials the results should conform to the expected result for that grade of material.