Pharmaceutical Analysis · Short notes

Validation of Analytical Methods: Short Notes & Cheat Sheet

ICH Q2 validation parameters, typical acceptance criteria, which parameters each test type needs, and instrument qualification.

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Short notes

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ICH validation parameters

Not every method needs every parameter; the test's purpose decides which ones apply.

Validation parameters (ICH Q2)

Specificity: the method measures the analyte without interference from impurities, degradants or excipients.
Linearity: results are proportional to concentration, usually over at least 5 levels (r often ≥ 0.999).
Range: the interval with acceptable linearity, accuracy and precision; for an assay usually 80–120% of the test concentration.
Accuracy: closeness to the true value, shown by recovery (at least 9 determinations over 3 levels; often 98–102%).
Precision: closeness of repeated results. Repeatability (same analyst, same day), intermediate precision (different days, analysts, equipment) and reproducibility (between laboratories).
Detection limit (LOD = 3.3σ/S; signal-to-noise about 3:1) and quantitation limit (LOQ = 10σ/S; about 10:1). Robustness: resistance to small deliberate changes (pH, flow rate, temperature).

Which parameters for which test

Identification tests need specificity only.
Assays need specificity, linearity, range, accuracy and precision.
Quantitative impurity tests need all of these plus the quantitation limit.
Limit tests for impurities need specificity and the detection limit.
Compendial methods are verified (shown to work in your laboratory) rather than fully validated.

Instruments

Instrument qualification: design (DQ), installation (IQ), operational (OQ) and performance (PQ) qualification.
System suitability tests are run each time to confirm the system works on that day.
Revalidation is needed after significant changes to the method, the product formula or the synthesis of the drug substance.

Cheat sheet

High-yield facts in one place. Cover the right-hand column and test yourself.

Parameters and typical criteria

Parameter	Typical criterion
Linearity	≥ 5 levels, r ≥ 0.999
Range (assay)	80–120% of test concentration
Range (content uniformity)	70–130%
Accuracy	9 determinations over 3 levels; 98–102%
Precision	RSD ≤ 2%
LOD	3.3σ/S (S/N ≈ 3)
LOQ	10σ/S (S/N ≈ 10)

Test type → parameters

Test	Needs
Identification	Specificity
Assay	Specificity, linearity, range, accuracy, precision
Impurities (quantitative)	All of the above + LOQ
Impurities (limit test)	Specificity + LOD

Memory aids

3 to detect, 10 to quantify: LOD at signal-to-noise about 3:1 and LOQ at about 10:1.

Exam traps

Accuracy is closeness to the true value; precision is closeness of results to each other. A method can be precise but inaccurate.
Robustness is tested by deliberate small changes, not by moving to another laboratory (that is reproducibility).
An identification test needs only specificity.
Compendial methods are verified, not fully revalidated, by each user.

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