SGS Lab Simon S.A.

IBCs 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 stabilityappearance, average weight, moisture, hardness, friability, disintegration time, dissolution rate, assay and degradation products determination

Microbiological stabilitymicrobial limits

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Creams & Ointments

Physico-chemical stabilityappearance, particle size, viscosity, consistency, pH, preservative content (if present), assay and degradation products determination

Microbiological stabilitymicrobial limits, preservative effectiveness

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Injections

Physico-chemical stabilityappearance, particulate matter, pH, preservative content (if present), assay and degradation products determination

Microbiological stabilitysterility,pyrogenicity, preservative effectiveness

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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 specificity3high sensitivity3high precision

SGS Lab Simon S.A.

Stability-Indicating Methodology

QuantitativeTechnique

Specificity Sensitivity Precision Universaldetectioncapability

Titrimetry poor poor high poor

UV-visspectrometry

poor poor high good -

HPLC good good acceptable good

CE good + acceptable acceptable good +

SGS Lab Simon S.A.

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 + +

PrecisionRepeatabilityIntermediate Precision

++

++

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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

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Mass balance

Extraction complete ?

Response factors of the secondary peaks ?

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Stress testing Should included consideration for excipients

effect

API +

Tablet stress: 4 weeks at 60CTablet stress: 4 weeks at 60C

SGS Lab Simon S.A.

Stress testing Should included consideration for container

effectSyringes filled with gel stress: 24 hours at 40C/75%RH

Syringes filled with gel stress: 24 hours at 40C/75%RH

Spectrum Index Plot

SampleName In Use/1 Vial 24 Injection 1 Date Acquired 12/21/00 2:32:12 AM

n m250.00

300.00

280.4

16.21

Estradiol - 16.211nm250.00

300.00

260.3

319.5 343.3

17.75

Peak16 - 17.756nm250.00

300.00

221.5

280.4

315.9 345.7

19.04

a-Estradiol - 19.041

AU

0.00

0.05

0.10

0.15

0.20

0.25

0.30

Minutes5.00 10.00 15.00 20.00 25.00 30.00 35.00 40.00

Est

radi

ol -

16.

211

Pea

k16

- 17.

756

a-E

stra

diol

- 1

9.04

1

SGS Lab Simon S.A.

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 %

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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 s / S

S = slope of calibration curve,s = 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

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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

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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 ?

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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

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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

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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