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Analytical Method and Processes

Validation

Presented by

Yub Raj Neupane

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TOPICS…. 

• INTRODUCTION.......

• TYPES OF ANALYTICAL PROCEDURES .....

• REFERENCE STANDARDS ......

• METHODS VALIDATION FOR INDS ..

• VALIDATION CHARACTERISTICS........

•METHODOLOGY.... 

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INTRODUCTION.......

• Process of demonstrating that analytical  procedures are suitable for their intended use.

• FDA, NDA or ANDA applicant must submitsamples of drug product , drug substance, non

compendial reference standards with

analytical procedures.

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Steps in Method Validation

• Protocol or operating procedure

• Application, purpose, and scope of themethod.

• Performance parameters and acceptancecriteria.

• Qualify materials (e.g., standards and

reagents).• Criteria for revalidation.

• Document validation experiments

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TYPES OF ANALYTICAL PROCEDURES 

A. Regulatory Analytical Procedure:

• To evaluate a defined characteristic of the drugsubstance or drug product.

•In the U.S. Pharmacopeia/National Formulary (USP/NF).

B. Alternative Analytical Procedure:

Proposed by the applicant for use instead of theregulatory analytical procedure.

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C. Stability-Indicating Assay:

• Can detect the changes with time in the

pertinent properties of the drug substance

and drug product.

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REFERENCE STANDARDS 

• Reference standard 

• Obtained from the USP/NF or other official

sources

Working standard:

• Is qualified against and used instead of the

reference standard.

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METHODS VALIDATION FOR INDs 

• Investigational new drug, sufficientinformation is required in each phase of aninvestigation to ensure proper identification,quality, purity, strength, and/or potency.

• Guidance on analytical procedures andmethods validation information to be

submitted for different phases of studies,sponsors should refer to the FDA guidance forindustry.

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PARAMETERS FOR METHOD

VALIDATION 

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SELECTIVITY AND SPECIFICITY 

•Specific:

-Method that produces a response for a single analyteonly

Selectivity:

• measure accurately an analyte in the presence of interference ( precursors, excipients, enantiomers) anddegradation products that may be expected to be.

• In LC selectivity is obtained by choosing optimal

columns and setting chromatographic conditions, suchas mobile phase composition, column temperature,and detector wavelength

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PRECISION AND REPRODUCIBILITY 

• Repeatability:• In one laboratory by one operator using one

piece of equipment over a relatively short

time span.• Precision of better than 1% RSD is easily

achieved.

• Intermediate precision:• Comparing the results of a method run within

a single laboratory over a number of weeks.

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• Reproducibility:

• Represents the precision obtained between

laboratories.

• Important if the method will be used in

different laboratories

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ACCURACY AND RECOVERY 

• Test results generated by the method and thetrue value agree.

• Compare the results of the method with

results from an established reference method.• By analyzing a sample with known

concentrations.

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LINEARITY AND CALIBRATION CURVE 

• Test results that are directly, or by means of well-defined mathematical transformation,

proportional to the concentration of analytes

in samples within a given range.

• A linear regression equation applied to the

results should have an intercept notsignificantly different from zero.

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RANGE 

•Interval between the upper and lower levels.

• Be determined with precision, accuracy, and

linearity using the method as written

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LIMIT OF DETECTION AND

QUANTITATION • Lowest concentration of an analyte in a sample

that can be detected but not necessarilyquantified.

•

In chromatography LOD is the injected amountthat results in a peak with a height at least twiceor three times as high as the baseline noise level

• LOQ is the minimum injected amount that gives

precise measurements, in chromatographytypically requiring peak heights 10 to 20 timeshigher than baseline noise.

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ROBUSTNESS 

• Examine the effect operationalparameters have on the analysis results.

• Flow rate, column temperature, injection

volume, detection wavelength, or mobilephase composition.

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METHODOLOGY 

• High-Pressure Liquid Chromatography (HPLC):

• Column:

-glass, stainless steel, plastic

- length, inner diameter

-Particle type of packing materials

• System Suitability Testing

-Relative retention

-Relative standard deviation (RSD)

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• Gas Chromatography GC:

• Column:

- length, internal diameter, external diameter.

-Stationary phase

• Gases: purity, flow rate, pressure

Temperatures: column, injector, detector

• Injection .e.g., split, splitless, on-column

•

Detector• Typical retention time and total run time

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• Capillary Electrophoresis (CE):

• Capillary:

- length, length to detector, internal diameter,

external diameter

-Capillary material- Running buffer

- Detector

- Voltage-Current

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