Supplementary Training Modules on Good Manufacturing Practice

Validation Part 4: QC-related validation

Module 1,, Part 4: QC-related validation

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Validation
Introduction
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Why is analytical monitoring necessary?

What is the purpose of analytical validation?

Module 1,, Part 4: QC-related validation

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Validation
Objectives
To introduce the concepts of :
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Protocol development Instrument qualification

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Analytical procedure
Extent of validation Method transfer

Chemical and physical, biological, and microbiological test validation

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Module 1,, Part 4: QC-related validation

Validation
Validation of analytical procedures requires:
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Qualified and calibrated instruments Documented methods Reliable reference standards Qualified analysts Sample integrity
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Module 1,, Part 4: QC-related validation

Validation
Validation protocol for analytical method
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Statement of purpose and scope Responsibilities Documented test method List of materials and equipment Procedure for the experiments for each parameter Statistical analysis Acceptance criteria for each performance parameter

Module 1,, Part 4: QC-related validation

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Qualification of the instrument
Make, model and makers manual Modifications

Installation and operational qualification

Calibration programs Maintenance schedules

Module 1,, Part 4: QC-related validation

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Validation
Characteristics of analytical procedures (1)
Accuracy

Precision
Repeatability Reproducibility

Module 1,, Part 4: QC-related validation

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Relationship between accuracy and precision

Inaccurate & imprecise

Accurate but Inaccurate but imprecise precise Module 1,, Part 4: QC-related validation Slide 8 of 28

Accurate AND Precise

WHO EDM 1/2002

Validation
Characteristics of analytical procedures (2)
Ruggedness Robustness Variability caused by:
Day-to-day variations Analyst-to-analyst Laboratory-to-laboratory Instrument-to-instrument Chromatographic column-to-column Reagent kit-to-kit Instability of analytical reagents
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Validation
Characteristics of analytical procedures (3)
Linearity and range
Specificity Sensitivity Limit of detection Limit of quantitation

Module 1,, Part 4: QC-related validation

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Validation
Calculated analyte in mg/mL
0.040 0.035 0.030 0.025 0.020 0.015 0.010 0.01

Linearity of an analyte in a material

Table of values (x,y)

x # 1 2
Reference material mg/ml

y
Calculated mg/ml

0.0100 0.0150

0.0101 0.0145

Reference material mg/ml

3
0.04

0.0200
0.0250

0.0210
0.0260

0.015

0.02

0.025

0.03

0.035

5
6
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0.0300
0.0400

0.0294
0.0410

WHO EDM 1/2002

Validation
Linearity Statistics
Intercept
Slope

-0.0002
1.0237
0.9978 0.9985

Limit of Linearity and Range 0.005 0.040 mg/mL

Correlation coefficient
Pearson Olkin and Pratt

Relative procedure standard deviation

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3.4%
WHO EDM 1/2002

Validation
LOQ, LOD and SNR
Limit of Quantitation
Limit of Detection Signal to Noise Ratio
Peak A LOD
Baseline noise

Peak B LOQ

Module 1,, Part 4: QC-related validation

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Different classes of analytical tests
Class A: To establish identity Class B: To detect and quantitate impurities Class C: To determine quantitatively the concentration Class D: To assess the characteristics

Module 1,, Part 4: QC-related validation

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Characteristic
Accuracy Precision A
quant.

B
Limit test

C X X

D X* X

X X

Robustness Linearity and range

Specificity Limit of detection Limit of quantitation
Module 1,, Part 4: QC-related validation

X
X

X X
X X

X
X X

X X
X

X X
X

* A degree of bias may be allowed

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Extent of validation
New methods require complete validation
Pharmacopoeial methods require partial validation (or verification)

Significant changes mean partial revalidation

equipment changes formula changed changed suppliers of critical reagents

Module 1,, Part 4: QC-related validation

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Validation
Analytical method transfer
Method transfer protocol and procedure
precision accuracy ruggedness

Written and approved specific test method Proficiency check

Formal acceptance by new laboratory

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Validation
Chemical laboratory validation requirements (1)
Balances
Chromatography HPLC, HPTLC, GC, TLC Dissolution or disintegration apparatus Karl Fischer moisture determination Melting, softening or freezing point apparatus Ovens, refrigerators, incubators

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Chemical laboratory validation requirements (2)
pH meter
Polarimeter - optical rotation Refractometer

Spectrophotometer UV/Vis, IR, FTIR, Raman, AA

Timers Viscometer Volumetric equipment
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Typical validation of HPCL assay (1)
System suitability (performance check)
system precision column efficiency symmetry factor capacity factor

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Typical validation of HPLC assay (2)
Method validation
specificity accuracy precision linearity robustness

Module 1,, Part 4: QC-related validation

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Biological assays
Can be difficult to "validate"
"Validity" on a case by case basis Strictly adhere to the Biological Testing monographs in pharmacopoeias

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Microbiological testing requiring validation
Microbial limit testing
Microbial count Sterility testing Preservative effectiveness testing Environmental monitoring program

Biological testing
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Validation
Validation of microbial test procedures (1)
Virtually impossible to completely validate test procedures for every microorganism Neutralize /inactivate inhibitory substances, or dilute

Periodic media challenge

Media QC Reliable methods

Module 1,, Part 4: QC-related validation

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Validation
Validation of microbial test procedures (2)
Incubation temperature and time
Media may not grow all microorganisms Variations in media may affect recovery Inhibitory disinfectants or preservatives Sample
procedures
handling, storage, transport
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Validation
Microbiological viable count method validation (1)
Methods
pour plate / spread plate membrane filtration Most Probable Number

Sample size Test dilution Inoculation size

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Validation
Microbiological viable count method validation (2)
Membrane filtration conditions Incubation conditions Acceptance criteria

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Sterility testing validation requirements
Media growth promotion, sterility, pH
Product validation Stasis testing Environmental monitoring Negative controls Challenge organisms
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