Quality Assurance of Pharmaceuticals - A Compendium of Guidelines and Related Materials - Volume 1
(1997; 248 pages) [French] View the PDF document
Table of Contents
Open this folder and view contentsIntroduction
Open this folder and view contents1. National drug regulation
Open this folder and view contents2. Product assessment and registration
Open this folder and view contents3. Distribution
Open this folder and view contents4. The international pharmacopoeia and related activities
Close this folder5. Basic tests
View the documentCollaboration within the basic test programme1
Open this folder and view contents6. Laboratory services
Open this folder and view contents7. International trade in pharmaceuticals
Open this folder and view contents8. Counterfeit products
Open this folder and view contents9. Training
View the documentSelected WHO publications of related interest
View the documentBack cover
 

Collaboration within the basic test programme1

1 Who Expert Committee on Specifications for Pharmaceutical Preparations. Twenty-ninth Report. Geneva, World Health Organization, 1984 (WHO Technical Report Series, No. 704)

Introduction

In its twenty-eighth report, the WHO Expert Committee on Specifications for Pharmaceutical Preparations agreed that the prime objectives of basic (or simplified) tests for pharmaceutical products, which was the subject of preliminary discussions in the Committee’s twenty-sixth and twenty-seventh reports, should be as follows:

“(a) to provide simple and readily applicable methods for verifying the identity of active ingredients using a limited range of readily available reagents;

(b) to provide a practicable means for confirming the identity of a drug, where fully equipped laboratories are not available;

(c) to provide a means for rapid verification of the identity in cases where each container of a large consignment has to be identified (full quality assessment of such a consignment is usually carried out only on a mixed sample from various containers); and

(d) to indicate if gross degradation has occurred in certain substances that are known to decompose readily under adverse conditions.”

It was noted that basic tests are not, in any circumstances, intended to replace the requirements of pharmacopoeial monographs. The latter give an assurance of quality whereas basic tests merely confirm the identity.

The test procedures for pharmaceutical substances elaborated so far are contained in the unpublished document WHO/PHARM/81.506/Rev. 1.2 The procedures for the confirmation of the identity consist of one or more test-tube identification reactions based upon colour, precipitate, or fluorescence, and on data regarding the physical aspects of the substance, its melting characteristics, and frequently the melting point of eutectic mixtures.

2 Since this statement was made, two volumes of test procedures have been published and a third is in preparation (see Introduction, page 9).

The test procedures for the indication of gross degradation consist of one or more simple tests based on the description of physical aspects, solubility, or test-tube reactions. These tests have been developed during the course of stability testing carried out under standardized conditions in air at temperatures of 50 °C and 70 °C and 100% humidity, with light excluded. The tests are intended to provide evidence of degradation of 10% or more.

In addition to the test-tube reactions and melting point determinations, procedures based on thin-layer chromatography have been developed.

Attached is a protocol for guidance in the development and the verification of basic tests.

Protocol for the development and verification of basic tests

1. Development of tests

(a) Tests for each drug substance and the corresponding dosage forms should, whenever possible, be developed together by the same person. Only one person should be asked to develop tests for a specific drug substance and/or dosage form. Where suitable tests are contained in The international pharmacopoeia these should be given priority, and the description should not be unnecessarily modified.

(b) In order to secure appropriate distribution of work, each investigator should compile a list of locally available drug substances.

(c) When a proposed test proves to be inadequate in the course of validation in other laboratories, the information will be referred back to the prime investigator who will have the responsibility of devising an alternative test. To this end, all samples used in the course of validation of the tests should be supplied to the prime investigator, where appropriate through WHO. Priority should in each case be given to tests based on test-tube reactions and melting characteristics. The test-tube reactions can involve colour reactions, flurosecence, or precipitations.

The following methods are recommended in order to introduce some homogeneity among the reactions used in basic tests:

Element or active functional group

Principle of the reaction

chloride or hydrochloride

- precipitation with AgNO3

- in order to complete the characterization of the formed silver chloride it is always preferable to separate the AgCl before verifying its dissolution in ammonia (otherwise precipitation of the other bases may occur in alkaline medium)

bound chloride

- ignition with Na2CO3 then reaction with AgNO3 after acidification

fluoride and bound fluorine

- inhibition of wetting the inner wall of a tube containing a chromic acid/sulfuric acid mixture

sulfate

- precipitation with BaCl2

bound sulfur

- fusion with NaOH or Na2CO3, then reaction with BaCl2 after acidification with HCl

heterocyclic sulfur

- heating with Zn and HCl: formation of dihydrogen sulfide detected with lead acetate paper

sodium ion

- precipitation with magnesium uranyl acetate

potassium ion

- precipitation with sodium cobaltinitrite

saturated compounds

- absence of decolorization of bromine (obtained from KBr + KBrO3 + HCl)

reducing compounds

- formation of a red precipitate in a warm solution with potassio-cupric tartrate

- formation of a silver mirror in ammoniacal solution with silver nitrate

multiple bonds (double or triple)

- in alkaline medium permanganate changes to brown

glycol

- precipitation of silver iodate produced by the reaction of silver periodate

enolizable ketone

- coloration produced with nitroprusside and NaOH

phenol

- coloration produced with the diazonium salt of the sulfanilic acid in alkaline medium

- colorations with a ferric salt (various colorations) are also obtained with the same reagent, such as for: formate and acetate ions, benzoate ion, acetylacetone and enolizable ketones, phenazone, camphocarboxylic acid, colchiceine, phenylpyruvic acid, hydroxyacids, amino acids

- coloration produced by the reaction of a primary aromatic amine and hypochlorite

ortho diphenol

- coloration of the molybdate ion in acidic medium

aliphatic amine and amino acid

- coloration with triketohydrindene hydrate (ninhydrin) and pyridine

amino acid

- colored precipitate with cupric ion and NaOH

primary aromatic amine

- coloration with dimethylaminobenzaldehyde in acidic medium

- diazocoupling by action of nitrite ion in acidic medium followed by 2-naphthol in alkaline medium

- coloration produced with phenol and hypochlorite

aromatic nitro compounds

- reaction with zinc in acidic medium and identification of the amine using one of the reactions described above

ammonium salts or aliphatic amine

- reaction with NaOH, the vapours of the liberated base being detected with pH-indicator paper

alkaloid or nitrogenous bases with high molecular weights

- precipitate with potassio-mercuric acetate

ester

- reaction with hydroxylamine, then detection of the formed hydroxamic acid by coloration obtained by adding a ferric salt

- odour of ethyl acetate on heating with sulfuric acid and ethanol

complex polyhydroxylated or polyunsaturated structures

- coloration formed with phosphoric acid

- coloration formed with sulfuric acid alone, or with the addition of nitrous/nitric acid mixture, molybdate, dichromate, or formaldehyde

xanthine

- heating to dryness of the substance with HCl and hydrogen peroxide, then coloration produced with the reaction of ammonia on the residue

barbiturate

- coloration produced with a cobalt salt in ammoniacal solution

2. Verification of tests

(a) Drug substances: If a pharmacopoeial test is selected no verification is required. In other circumstances verification in one laboratory will suffice.

(b) Dosage forms: Verification must be undertaken, in each instance, in at least four different laboratories selected on a representative regional basis. Tests should be undertaken on locally available solid oral dosage forms, branded or generic, containing the substance in question.

3. Coordination

Responsibility for coordination and monitoring of the programme will reside with WHO, which will pay particular regard to reasonable distribution of work among the various collaborators.

 

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