New USP Chapter: <1226> Verification of Compendial Procedures

Horacio N. Pappa, Ph.D. Senior Scientist Department of Standards Development

CVG-TPD 2006 INTERNATIONAL CONVENTION October 5-6, 2006 (Toronto, Ontario, Canada)

The Analytical Process

PROCESS Laboratory Sample

Sample preparation Aliquout

<1058> Analytical Instrument Qualification Measurement <1225> Validation of Compendial Procedures <1226> Verification of Compendial Procedures <1010> Analytical data - interpretation and treatment Reportable value
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Raw data

<1225> Validation of Compendial Procedures

Defines analytical performance characteristics (precision, accuracy, etc.) Recommends data for submissions to USP-NF Provides guidance on which analytical performance characteristics are needed based on the type of test Incorporates ICH guidelines Q2A and Q2B No guidance on verifying suitability for use
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<1225> Validation of Compendial Procedures

Performance Characteristic

Category I

Category II Quant Limit Test * No Yes Yes No No *

Category III Category IV

Accuracy Precision Specificity LOD LOQ Linearity Range

Yes Yes Yes No No Yes Yes

Yes Yes Yes No Yes Yes Yes

* Yes * * * * *

No No Yes No No No No
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* May be required, depending on the nature of the specific test

Why is <1226> needed?

21 CFR 211.194(a)(2): users of analytical methods described in USPNF are not required to validate the accuracy and reliability of these methods, but merely verify their suitability under actual conditions of use. Response to industry inquiries First draft published in PF31(2). Republished in PF32(4)

<1226> Summary

The intent of this chapter is to provide general information to laboratories on the verification of compendial procedures that are being performed for the first time to yield acceptable results utilizing the laboratories personnel, equipment, and reagents. Not intended for retroactive application to already successfully established laboratory procedures. Verification consists of assessing selected Analytical Performance Characteristics, such as those which are described in chapter <1225>, to generate appropriate, relevant data rather than repeating the validation process.
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<1226> Summary

Companion to <1225> Validation of Compendial Procedures Builds on information from <1225> Applies to drug substances, drug products, and excipients Biological tests are not included; General Chapter <111> Design and Analysis of Biological Assays and <1033> Validation of Biological Assays (in development) provides guidance for validations of these procedures
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<1226> Summary

Application: titrations, chromatographic procedures (related compounds, assay, limit tests), spectroscopic tests, etc. General tests do not typically require verification (water, heavy metals, residue on ignition, etc.)

<1226> Summary

Verification of microbiological procedures is not covered in this chapter because it is covered in other USP general chapters, <51> Antimicrobial Effectiveness <61> Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests <71> Sterility Tests <1227> Validation of Microbial Recovery From Pharmacopeial Articles
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Data Elements for Verification of Drug Substances and Excipients

This table was deleted in the current proposal
Technique Category I Category II Quantitative HPLC/GC Spectro. or colorimet. Titration TLC Gel Electro. P P P ----P, S, LOQ P, LOQ P S, LOQ S, LOQ Limit Test S, LOD S, LOD --S, LOD S, LOD ----------S S --S S
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Category III

Category IV

P=Precision; S=Specificity; L=Linearity; LOD=Limit of Detection; LOQ=Limit of Quantitation;

Data Elements for Verification of Dosage Forms

This table was deleted in the current proposal
Technique Category I Category II Quantitative HPLC/GC Spectro. or colorimet. Titration TLC Gel Electro. P, S, L P, S, LOQ Limit Test S, LOD P S Category III Category IV

P, L

P, LOQ

S, LOD

P, L -----

P S, LOQ S, LOQ

--S, LOD S, LOD

-------

--S S
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P=Precision; S=Specificity; L=Linearity; LOD=Limit of Detection; LOQ=Limit of Quantitation;

Verification process

There are no general Validation protocols There are no general Verification protocols

Verification

DEGREE OF VERIFICATION

Perform the test as written

Full validation
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Case study Sodium Chloride

Acidity or alkalinity To 20 mL of the solution prepared for the test for Appearance of solution, add 0.1 mL of bromothymol blue TS: not more than 0.5 mL of 0.01 N hydrochloric acid or 0.01 N sodium hydroxide is required to change the color of this solution. Loss on drying <731>Dry the test material at 105 for 2 hours: it loses not more than 0.5% of its weight, determined on about 1.000 g of sample. Limit of bromides To 0.5 mL of the solution prepared for the test for Appearance of solution, add 4.0 mL of water, 2.0 mL of pH 4.7 phenol red TS, and 1.0 mL of chloramine T solution (0.1 mg per mL), and mix immediately. After 2 minutes, add 0.15 mL of 0.1 N sodium thiosulfate, mix, dilute with water to 10.0 mL, and mix. The absorbance of this solution measured at 590 nm, using water as the comparison liquid, is not greater than that of a Standard solution, concomitantly prepared, using 5.0 mL of a solution containing 3.0 mg of potassium bromide per L and proceeding as above, starting with the addition of 2.0 mL of pH 4.7 phenol red TS (0.010%). Heavy metals, Method I <231>: 5 ppm
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Case study Sodium Chloride

AssayDissolve 50 mg of Sodium Chloride, accurately weighed, in water and dilute with water to 50 mL. Titrate with 0.1 N silver nitrate VS, determining the endpoint potentiometrically (see Titrimetry <541>). Each mL of 0.1 N silver nitrate is equivalent to 5.844 mg of NaCl.

Performance Characteristic Accuracy Precision Specificity LOD LOQ Linearity Range

Validation Yes Yes Yes No No Yes Yes

Verification No Maybe No No No No No

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Case study API

Identification IR, UV HPLC Purity test Loss on drying, residue on ignition, Heavy metals pH Related substances Assay Titrimetry HPLC

Performance Characteristic Accuracy Precision Specificity LOD LOQ Linearity Range

Validation No No Yes No No No No

Verification No No Maybe No No No No

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Case study API

Identification IR, UV HPLC Purity test Loss on drying, residue on ignition, Heavy metals pH Related substances Assay Titrimetry HPLC

Performance Characteristic Accuracy Precision Specificity LOD LOQ Linearity Range

Validation No No Yes Yes No No No

Verification No No No No No No No

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Case study API

Identification IR, UV HPLC Purity test Loss on drying, residue on ignition, Heavy metals pH Related substances Assay Titrimetry HPLC

Performance Characteristic Accuracy Precision Specificity LOD LOQ Linearity Range

Validation Verification Yes Yes Yes No Yes Yes Yes No Maybe Yes No Yes No No

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Case study API

Identification IR, UV HPLC Purity test Loss on drying, residue on ignition, Heavy metals pH Related substances Assay Titrimetry HPLC

Performance Characteristic Accuracy Precision Specificity LOD LOQ Linearity Range

Validation Verification Yes Yes Yes No No Yes Yes No Maybe Maybe No No No No

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Case study Dosage form

Identification HPLC Specific tests Particle in injections Uniformity Dissolution Impurities: related substances residual solvents Assay

Performance Characteristic Accuracy Precision Specificity LOD LOQ Linearity Range

Validation No No Yes No No No No

Verification No No Yes No No No No

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Case study Dosage form

Identification HPLC Specific tests Particle in injections Uniformity Dissolution Impurities: related substances residual solvents Assay

Performance Characteristic Accuracy Precision Specificity LOD LOQ Linearity Range

Validation Maybe Yes Maybe Maybe Maybe Maybe Maybe

Verification Maybe Yes Yes No Maybe No No

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Case study Dosage form

Identification HPLC Specific tests Particle in injections Uniformity Dissolution Impurities: related substances residual solvents Assay

Performance Characteristic Accuracy Precision Specificity LOD LOQ Linearity Range

Validation Yes Yes Yes No Yes Yes Yes

Verification Maybe Yes Yes No Yes No No

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Case study Dosage form

Identification HPLC Specific tests Particle in injections Uniformity Dissolution Impurities: related substances residual solvents Assay

Performance Characteristic Accuracy Precision Specificity LOD LOQ Linearity Range

Validation Yes Yes Yes No No Yes Yes

Verification Maybe Yes Yes No No No No

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Horacio N. Pappa hp@usp.org

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