What Is Method Validation?
Analytical method validation is the experimental demonstration that a method is fit for its intended use. ICH Q2(R2) defines the performance characteristics to be assessed: specificity, linearity and range, accuracy, precision (repeatability and intermediate precision), detection and quantification limits, and robustness.
Purpose of Method Validation
The purpose is to show the analytical data produced is reliable. A result produced by an unvalidated method is not accepted in the marketing authorisation dossier or under GMP.
Which Products Is Method Validation Applied To?
- Assay and impurity methods
- Dissolution test methods
- Cleaning verification methods
- Microbiological methods
- Bioanalytical methods
In Which Sectors Is Method Validation Used?
Standards Related to Method Validation
- ICH Q2(R2) (validation of analytical procedures)
- ICH Q14 (analytical procedure development)
- Ph. Eur. 5.21 (chemometric methods) and relevant general chapters
- USP <1225> (validation of compendial procedures)
- USP <1226> (verification of compendial procedures)
Method Validation Conditions
- Method type
- Identity, assay, limit test for impurities, or quantitative impurity testing; the required parameters vary accordingly
- Acceptance criteria
- Predefined in the validation protocol
- Forced degradation
- Required for stability-indicating methods as evidence of specificity
Equipment for Method Validation
- HPLC / UPLC / GC systems
- Spectrophotometers
- Reference standards and impurity standards
- Statistical evaluation software
Sample Requirements for Method Validation
- Active substance, product and placebo specimens
- Known impurity standards
- Forced degradation specimens
- The method draft and intended use description must be provided
Duration of Method Validation
A full validation study takes weeks because of the number of parameters and replicate requirements. Verification of a compendial method is shorter.
Method Validation Procedure
- 1The method's intended use and type are defined.
- 2The validation protocol and acceptance criteria are prepared.
- 3A specificity study is performed; forced degradation is applied if needed.
- 4The linearity and range study is carried out.
- 5Accuracy (recovery) and precision studies are performed.
- 6Detection/quantification limits and robustness are assessed; the report is prepared.
Method Validation Acceptance Criteria
Acceptance criteria are defined in the validation protocol BEFORE the study and are set according to the method's intended use. ICH Q2(R2) defines which parameters are to be assessed; the organisation sets the numerical acceptance thresholds with its own justification.
Evaluation of Results
Validation shows the method is fit for the defined use, not that it will work under every condition. Re-assessment is needed if the method is to be used in a different matrix or a different concentration range. For pharmacopoeial methods, verification may be sufficient instead of full validation.
Method Validation Report
- Method description and intended use
- Validation protocol and acceptance criteria
- Raw data and statistical evaluation for each parameter
- Comparison of results against the criteria
- Conclusion and the method's scope of validity
Accreditation
EUROLAB holds internationally recognised accreditation obtained from accreditation bodies party to the IAF and ILAC multilateral recognition arrangements, under ISO/IEC 17025 for laboratory testing, ISO/IEC 17020 for inspection and surveillance, and ISO/IEC 17021-1 and ISO/IEC 17065 for system and product certification. This chain ensures the reports and certificates issued are accepted worldwide.
Whether this test can be offered within accredited scope depends on your product and the standard applied; since accreditation is method-based, the scope is confirmed in writing at the quotation stage.
Scope and authorisationsRelated Regulations
- 2001/83/EC Directive on Medicinal Products for Human Use
- GMP Guide (EudraLex Volume 4)
Pharmaceutical Analysis — What Does This Testing Field Cover?
The section below describes the field that the Method Validation test belongs to; the conditions and acceptance criteria of this particular test are given in the sections above. The scope specific to your product is confirmed in writing at the quotation stage.
Pharmaceutical analysis determines the identity, purity, quantity and behaviour of an active substance and of the finished product. What sets this family apart is that the methods are largely defined in PHARMACOPOEIAS: the European Pharmacopoeia (Ph. Eur.) and the United States Pharmacopeia (USP) give both the method and the acceptance framework together.
The binding nature of the pharmacopoeial method shapes how the field works. In other sectors a laboratory can choose a suitable method, whereas here the method in the monograph governs; if an alternative method is to be used, its equivalence must be demonstrated. This is what makes results comparable worldwide.
Analyses are carried out in several groups. Identity and assay (HPLC, UV, titration) show what the product is and how much active substance it contains. The impurity profile and residual solvents look for unwanted compounds arising from the manufacturing process. Elemental impurities address metals originating from catalysts and equipment. Dissolution and disintegration behaviour is the most important in vitro indicator of how the drug will be released in the body.
The DISSOLUTION TEST is one of the most critical measurements in the field. It is not enough for a tablet to contain the right amount of active substance; that substance must dissolve at a suitable rate. The dissolution profile is used to assess the effect of formulation changes on bioavailability and holds a central place in generic drug licensing.
METHOD VALIDATION is a mandatory step in this family. If a pharmacopoeial method is used, it is verified that the method works properly under that laboratory's conditions. If an in-house method has been developed, it is validated against parameters such as linearity, precision, accuracy, specificity, limits of detection and quantification, and robustness. A result produced with an unvalidated method cannot be used in a licence dossier.
Stability studies determine shelf life and are the longest-running work in the field. The product is held under defined temperature and humidity conditions, analysed at set intervals, and the results become the basis of the shelf life and storage condition claims. Accelerated conditions give preliminary information but real-time data is what counts.
The microbiological side is a separate body of work: microbial enumeration, testing for specified microorganisms, sterility testing for sterile products and the bacterial endotoxin test. For sterile products, packaging integrity and sterilisation validation also come into play.
Data integrity has moved to the centre of inspections in recent years. It is not enough for the result to be correct; the raw data must be traceable, unalterable and auditable. Validation of electronic record systems has therefore become an inseparable part of analysis.
Method groups in this field
Identity and assay
HPLC, UPLC, UV-Vis spectrophotometry, titration, identity confirmation by FTIR.
Impurities and residues
Related impurities, degradation products, residual solvents (GC headspace), nitrosamine screening.
Elemental impurities
Determination of elemental impurities by ICP-MS and ICP-OES and the associated risk assessment.
Physicochemical
Dissolution and disintegration, hardness, friability, uniformity of dosage units, water content (Karl Fischer), particle size.
Microbiological
Microbial enumeration, specified microorganisms, sterility, bacterial endotoxin, preservative efficacy.
Stability
Real-time and accelerated stability studies; photostability and in-use stability.
Commonly confused in this field
- The pharmacopoeial method is binding; an alternative method may be used only by demonstrating its equivalence.
- A result produced without method validation cannot be used in a licence dossier.
- Accelerated stability does not replace real-time data; shelf life is supported by real-time results.
- The dissolution profile is sensitive to apparatus type, agitation rate and medium; the conditions must be complete in the report.
- A shortcoming in data integrity produces a non-conformity in an inspection even when the result is correct.
- A change of formulation or supplier requires analytical comparison and, where necessary, a new stability study.
Which decisions these results support
- The licence dossier and batch release
- Determining shelf life and storage conditions
- Method transfer and method validation
- Incoming raw material acceptance control from suppliers
- Assessing the effect of a formulation change on bioequivalence
Related Tests
Frequently Asked Questions About Method Validation
Is validation required for a pharmacopoeial method?
Full validation is usually not required, but verification is: it must be shown the method works with your specimen in your laboratory. USP <1226> defines this approach.
If we change the method, is re-validation mandatory?
It depends on the scope of the change. For minor changes, re-assessing the affected parameters may be sufficient; a change that alters the separation principle requires full validation.