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IBC’s 7th International Conference on Stability Testing How to Select, Validate and Report Analytical Test Procedures Used to Monitor Stability Jean Gilliard Forte Posthouse Regent Park, London 6&7 February 2001 SGS Lab Simon S.A. Test procedures • Selection of the tests: “The testing should cover the features susceptible to change during storage and likely to influence quality, safety and efficacy”. • Validation of the tests: “Validated stability-indicating analytical procedures should be applied” SGS Lab Simon S.A. Selection of the test procedures • Stability testing should cover as necessary the organoleptic, physical, chemical and microbiological test characteristics. • In general, appearance, assay and degradation products determination should be evaluated whatever the dosage form. • Considerations for specific dosage forms SGS Lab Simon S.A. Tablets & Capsules • Physico-chemical stability appearance, average weight, moisture, hardness, friability, disintegration time, dissolution rate, assay and degradation products determination • Microbiological stability microbial limits SGS Lab Simon S.A. Creams & Ointments • Physico-chemical stability appearance, particle size, viscosity, consistency, pH, preservative content (if present), assay and degradation products determination • Microbiological stability microbial limits, preservative effectiveness SGS Lab Simon S.A. Injections • Physico-chemical stability appearance, particulate matter, pH, preservative content (if present), assay and degradation products determination • Microbiological stability sterility,pyrogenicity, preservative effectiveness SGS Lab Simon S.A. Stability-Indicating Methodology “Validated quantitative analytical methods that can detect the changes with time in the chemical, physical or microbiological properties of the drug substance or product and that are specific so that the contents of active ingredient, degradation products, and other components of interest can be accurately measured without interference.” SGS Lab Simon S.A. Stability-Indicating Methodology Requirements 3high specificity 3high sensitivity 3high precision SGS Lab Simon S.A. Stability-Indicating Methodology Quantitative Technique Titrimetry poor poor high Universal detection capability poor UV-vis spectrometry poor poor high good - HPLC good good acceptable good CE good + acceptable acceptable good + SGS Lab Simon S.A. Specificity Sensitivity Precision Alternative procedures (Q6A) • For formulation shown to be stable during manufacture, non separative techniques may be used at release with the chromatographic method as the official procedure • When conclusively demonstrated with a significant body of data that the formulation is stable, degradation product testing may be reduced or eliminated SGS Lab Simon S.A. ICH validation requirements (Q2A) Attribute Assay Related substances Specificity + + LOQ - + Linearity + + Accuracy + + Precision Repeatability Intermediate Precision + + + + SGS Lab Simon S.A. Specificity • For the main component(s) • For the related substances (impurities and degradation products) • Supported by stress testing studies SGS Lab Simon S.A. Stress testing • Conducted to demonstrate the stability indicating power of the analytical procedures • Should be performed on the drug substance and on the drug product • Should included the effects of temperature, moisture, pH, oxidation and light • Usually aim to achieve 10 to 20 % degradation SGS Lab Simon S.A. Stress testing • Results from stress testing studies should form an integral part of the information provided to regulatory authorities • Attention should be paid to reviewing the adequacy of the mass balance SGS Lab Simon S.A. Mass balance • The process of adding together the assay values and levels of degradation products to see how closely these add up to 100 % of the initial value with due consideration of the margin of analytical error • Good mass balance (assay + degradants = 100 %) can support validation • Poor mass balance can suggest an analytical problem SGS Lab Simon S.A. Mass balance • HPLC may fail to detect some components – – – – – retained on the column eluted late eluted under main peak eluted at solvent front eluted undetected SGS Lab Simon S.A. Mass balance • Extraction complete ? • Response factors of the secondary peaks ? SGS Lab Simon S.A. Stress testing • Should included consideration for excipients effect Tablet Tabletstress: stress:44weeks weeksatat60°C 60°C API + SGS Lab Simon S.A. Stress testing • Should included consideration for container effect Spectrum Index Plot Estradiol - 16.211 250.00 nm 300.00 250.00 16.21 Peak16 - 17.756 nm 300.00 260.3 a-Estradiol - 19.041 250.00 nm 300.00 17.75 221.5 19.04 Syringes Syringesfilled filledwith withgel gel stress: stress:24 24hours hoursatat 40°C/75%RH 40°C/75%RH 280.4 280.4 319.5 343.3 315.9 345.7 Estradiol - 16.211 0.30 0.25 0.15 Peak16 - 17.756 0.10 0.05 a-Estradiol - 19.041 AU 0.20 0.00 5.00 SGS Lab Simon S.A. 10.00 15.00 20.00 Minutes 25.00 30.00 SampleName In Use/1 Vial 24 Injection 1 Date Acquired 12/21/00 2:32:12 AM 35.00 40.00 Sensitivity: quantitation limit • Confidence that the method is capable of providing the level of sensitivity required • LOQ ≤ reporting threshold (Q3B) Maximum Daily Dose Reporting Threshold = 1g > 1g 0.1 % 0.05 % SGS Lab Simon S.A. Quantitation Limit (Q2A&B) • LOQ: “the lowest amount of analyte which can be quantitatively determined with suitable precision and accuracy” • Approaches: – SNR: 10:1 – SD of response and slope: 10 x σ / S S = slope of calibration curve, σ = SD of blank, RSD of regression line, SD of intercept • The estimate should be validated by the analysis of a suitable number of samples known to be near or prepared at the LOQ SGS Lab Simon S.A. Precision • Analysis repeatability • Intermediate precision: establish the effect of variations e.g. different days, analysts, equipment,… • Reproducibility: interlaboratory trial SGS Lab Simon S.A. Precision (Q2B) • Repeatability: – a minimum of 9 determinations over the range of the procedure (e.g. 3 replicates at 3 concentrations) – or a minimum of 6 determinations at 100 % of the test concentration • Recommended data: SD, RSD and confidence intervals SGS Lab Simon S.A. Precision • HPLC level of precision – Repeatability: 0.5 to 1 % – Intermediate precision: 1 to 2 % – Reproducibility: 2 to 5 % • Adequate to detect 2 to 3 % potency loss over a three year storage period ? SGS Lab Simon S.A. Reporting Stability Data Test Methodology Information: • Physical, chemical and microbiological attributes and regulatory specifications • Test methodology used • Information on accuracy, precision and suitability of the methodology SGS Lab Simon S.A. System suitability • Ensure method performs in-use as at the time of validation • Link between validation and routine testing – Selection of relevant parameters from validation – Setting of acceptance limits • Stability-indicating methodology: check adequate resolution, quantitation limit and precision at the time of use SGS Lab Simon S.A. Method transfer • To assure the integrity of the analytical data in recipient laboratory • To assess competency in recipient laboratory • To demonstrate the adequacy of equipment in recipient laboratory • To identify limitations of the method • Ensure good communication between development and recipient laboratories SGS Lab Simon S.A. Summary • Assays and related substance tests must be fully validated and demonstrate stability indicating • Specificity, sensitivity and precision are the most crucial attributes for a stability indicating methodology • System suitability testing must be carried out to demonstrate suitable method performance at the time of use • Consider other tests which may be useful for monitoring product stability SGS Lab Simon S.A.