WHO Expert Committee on Specifications for Pharmaceutical Preparations - WHO Technical Report Series, No. 885 - Thirty-fifth Report: Annex 1. List of available International Chemical Reference Substances 1

WHO Expert Committee on Specifications for Pharmaceutical Preparations - WHO Technical Report Series, No. 885 - Thirty-fifth Report
(1999; 168 pages) [Spanish]

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Good Manufacturing Practices: Supplementary Guidelines for the Manufacture of Pharmaceutical Excipients. WHO Technical Report Series, No. 885, 1999, Annex 5

Índice de contenido

WHO Expert Committee on Specifications for Pharmaceutical Preparations
1. Introduction
2. The international pharmacopoeia and related issues
	2.1 Quality specifications for drug substances and dosage forms
	2.2 Simple test methodology
3. International Chemical Reference Substances and Infrared Reference Spectra
	3.1 Establishment of International Chemical Reference Substances
	3.2 International Infrared Reference Spectra
	3.3 Use of International Chemical Reference Substances and Infrared Reference Spectra
	3.4 Guidelines for the establishment, maintenance and distribution of chemical reference substances
4. Quality control - national laboratories
	4.1 Good laboratory practices in government drug quality control laboratories
	4.2 Information on external quality assessment
5. Good manufacturing practices
	5.1 Adoption of additional guidelines
	5.2 Good manufacturing practices for sterile products
	5.3 Relationship between pharmacopoeial requirements and manufacturers' internal specifications
6. Quality systems and inspection
	6.1 Quality systems for GMP inspectorates
	6.2 Pre-approval inspection
	6.3 Guidelines for inspection of drug distribution channels
	6.4 Use of simple test methods by inspectors
7. Other quality assurance topics
	7.1 Compendia
	7.2 Packaging for pharmaceutical products
	7.3 Multisource pharmaceutical products
	7.4 Guidelines for good pharmacy practice
8. Nomenclature and terminology
	8.1 International Nonproprietary Names for pharmaceutical substances
	8.2 Terminology
9. Legal aspects of pharmaceuticals
	9.1 Drug regulatory legislation
	9.2 National implementation guidelines for combating counterfeit pharmaceuticals
10. Regulatory issues
	10.1 WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce
		10.1.1 Finished pharmaceutical products
		10.1.2 Active pharmaceutical ingredients
	10.2 WHO model system for computer-assisted drug registration
	10.3 Model guidelines for the international provision of controlled medicines for emergency medical care
11. Training activities
	11.1 Training programmes for drug regulators and related activities
	11.2 Training programmes for the detection of counterfeit pharmaceutical products
12. Pharmaceuticals contaminated with diethylene glycol
Acknowledgements
References
Annex 1. List of available International Chemical Reference Substances¹
Annex 2. List of available International Infrared Reference Spectra¹
Annex 3. General guidelines for the establishment, maintenance and distribution of chemical reference substances
	Introduction
	Part A. Primary chemical reference substances
		1. Assessment of need for the establishment of chemical reference substances
		2. Obtaining source material
		3. Evaluation of chemical reference substances
			3.1 Use in identification tests
			3.2 Use in purity tests
			3.3 Use in assays
			3.4 Use in the calibration of an instrument
		4. Chemical and physical methods used in evaluating chemical reference substances
			4.1 Methods used to verify the identity of chemical reference substances
			4.2 Methods used to determine the purity of chemical reference substances
		5. Assignment of content
		6. Handling and distribution of chemical reference substances
			6.1 Packaging operations
			6.2 Storage
			6.3 Stability
			6.4 Information to be supplied with chemical reference substances
			6.5 Distribution and supply
			6.6 Period of use
	Part B. Secondary chemical reference substances
	References
Annex 4. Good manufacturing practices: authorized person - role, functions and training
	1. The role and position of the authorized person in the company
	2. Implementation of the quality system
	3. Routine duties of an authorized person
	4. Education and training
	5. Selected references
Annex 5. Good manufacturing practices: supplementary guidelines for the manufacture of pharmaceutical excipients
	1. General considerations
	2. Glossary
	3. Self-inspection and quality audits
	4. Equipment
		4.1 Use of equipment
		4.2 Cleaning programme
			4.2.1 Detailed cleaning procedure
			4.2.2 Sampling plan
			4.2.3 Analytical methods/cleaning limits
	5. Materials
		5.1 General
		5.2 Starting materials
		5.3 Rejected and recovered materials
		5.4 Returned excipients
		5.5 Storage practices
	6. Documentation
		6.1 General
		6.2 Specifications
		6.3 Batch production records
		6.4 Other documents
	7. Good practices in production and quality control
		7.1 Change control and process validation
		7.2 Good practices in production
			7.2.1 Prevention of cross-contamination
			7.2.2 In-process blending/mixing
			7.2.3 Control of microbial contamination
			7.2.4 Water systems/water quality
			7.2.5 Packaging operations
			7.2.6 Delivery
		7.3 Good practices in quality control
			7.3.1 General
			7.3.2 Control of starting materials
			7.3.3 In-process testing
			7.3.4 Quality records and retention samples
			7.3.5 Stability studies
			7.3.6 Expiry/re-evaluation dating
			7.3.7 Calibration of measuring and test equipment
Annex 6. Guidelines for inspection of drug distribution channels
	Introductory note
	General considerations
	Glossary
	1. Drug inspectors
		1.1 Qualifications
		1.2 Organizational aspects
		1.3 Methods of inspection
		1.4 Reference/information sources
	2. Inspection of establishments in the drug distribution chain
		2.1 Broad objectives
		2.2 Establishments
		2.3 Inspections
		2.4 Special categories of drugs
	References
	Selected further reading
	Appendix 1. Checklist for inspection and the preparation of a report
	Appendix 2. Guidance on sampling
	Appendix 3. Guidance for inspection when pharmaceutical products are suspected to be counterfeit, spurious or substandard
	Appendix 4. Sample receipt form
Annex 7. Good pharmacy practice in community and hospital pharmacy settings
Annex 8. National drug regulatory legislation: guiding principles for small drug regulatory authorities
	Introduction
	Drafting national legislation: points for consideration
	Defining the scope of the marketing authorization procedure for medicinal products
	Example of a legislative scheme for regulating medicinal products
		General considerations
		Potential value of the scheme
		Model legislative text and commentary
			Part A. Administration
			Part B. Provisional registration/marketing authorization and inventory of medicinal products
			Part C. Screening of products and issuance of product licences/authorizations
			Part D. Other activities requiring authorization/licensing
			Part E. General provisions
			Part F. Interpretation
	References
	Selected bibliography
	Appendix 1. Provisional legislative scheme for registration of pharmacy personnel
	Appendix 2. Guidelines, documents and other regulatory instruments established by WHO to support drug regulatory authorities
Annex 9. Provisional guidelines for developing training programmes: inspection and examination of counterfeit pharmaceuticals
	1. General remarks
		1.1 Introduction
		1.2 Requirements and goals of the training programmes for inspection and examination
		1.3 Prerequisites
	2. Training programme for inspection
		2.1 Course objectives
		2.2 Types of training
		2.3 Educational background of trainees and trainers
		2.4 Course programme items
		2.5 Duration of training course
		2.6 Reiterative training
		2.7 Assessment
		2.8 Certificate
		2.9 Evaluation of the programme
	3. Training programme on examination
		3.1 Course objectives
		3.2 Types of training
		3.3 Educational background of trainees and trainers
		3.4 Course programme items
		3.5 Duration of course
		3.6 Reiterative training
		3.7 Assessment
		3.8 Certificate
		3.9 Evaluation of the programme
	References
	World Health Assembly resolutions
	Appendix 1 The practical issues of organizing and implementing the programme
	Appendix 2 Thin-layer chromatography and its application
World Health Organization Technical Report Series
Selected WHO Publications of Related Interest
Back Cover

Annex 1. List of available International Chemical Reference Substances¹

¹As updated at the thirty-fifth meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations, 21-25 April 1997.

International Chemical Reference Substances (ICRS) are established on the advice of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. They are supplied primarily for use in physical and chemical tests and assays described in the specifications for quality control of drugs published in The international pharmacopoeia or proposed in draft monographs. The ICRS are mainly intended to be used as primary standards to calibrate secondary standards.

Directions for use, and analytical data required for the use described in the relevant specifications of The international pharmacopoeia, are given in the certificates enclosed with the substances when distributed. More detailed analytical reports on the substances may be obtained from the WHO Collaborating Centre for Chemical Reference Substances.

ICRS may also be used in tests and assays not described in The international pharmacopoeia. However, the responsibility for assessing the suitability of the substances then rests with the user or with the pharmacopoeia commission or other authority that has prescribed this use.

It is generally recommended that the substances should be stored protected from light and moisture and preferably at a temperature of about +5°C. When special storage conditions are required, this is stated on the label or in the accompanying leaflet. It is recommended that the user purchase only an amount sufficient for immediate use.

The stability of the ICRS kept at the Collaborating Centre is monitored by regular re-examination, and any material that has deteriorated is replaced by new batches when necessary. Lists giving control numbers for the current batches are issued in the annual reports from the Centre and new yearly lists may also be obtained on request.

Orders for the ICRS should be sent to:

WHO Collaborating Centre for Chemical Reference Substances
Apoteket AB
Produktion & Laboratorier Centrallaboratoriet, ACL
Prismavägen 2
S-141 75 Kungens Kurva
Sweden
(Telefax: +46 8 740 60 40)

The ICRS are supplied only in the standard packages indicated in the following list:

Reference substance			Package size	Control number
aceclidine salicylate			100 mg	172048
p-acetamidobenzalazine			100 mg	290042
acetazolamide			100 mg	186128
allopurinol			100 mg	287049
amidotrizoic acid			100 mg	196205
2-amino-5-nitrothiazole			25 mg	186131
3-aminopyrazole-4-carboxamide hemisulfate			100 mg	172050
3-amino-2,4,6-triiodobenzoic acid			100 mg	196206
amitriptyline hydrochloride			100 mg	181101
amodiaquine hydrochloride			200 mg	192160
amphotericin B			400 mg	191153
ampicillin (anhydrous)			200 mg	390001
ampicillin sodium			200 mg	388002
ampicillin trihydrate			200 mg	274003
anhydrotetracycline hydrochloride			25 mg	180096
atropine sulfate			100 mg	183111
azathioprine			100 mg	172060

bacitracin zinc			200 mg	192174
beclometasone dipropionate			200 mg	192175
bendazol hydrochloride			100 mg	173066
benzobarbital			100 mg	172051
benzylamine sulfate			100 mg	172052
benzylpenicillin potassium			200 mg	180099
benzylpenicillin sodium			200 mg	280047
bephenium hydroxynaphthoate			100 mg	183112
betamethasone			100 mg	183113
betamethasone sodium phosphate			100 mg	196203
betamethasone valerate			100 mg	190145
betanidine sulfate			100 mg	172053
bupivacaine hydrochloride			100 mg	289054

caffeine			100 mg	181102
calcium folinate (leucovorin calcium)			100 mg	194188
carbamazepine			100 mg	189143
carbenicillin monosodium			200 mg	383043
chloramphenicol			200 mg	486004
chloramphenicol palmitate			1 g	286072
chloramphenicol palmitate (polymorph A)			200 mg	175073
5-chloro-2-methylaminobenzophenone			100 mg	172061
chloroquine sulfate			200 mg	195201
2-(4-chloro-3-sulfamoylbenzoyl)benzoic acid			50 mg	181106
chlorphenamine hydrogen maleate			100 mg	182109
chlorpromazine hydrochloride			100 mg	178080
chlortalidone			100 mg	183114
chlortetracycline hydrochloride			200 mg	187138
cimetidine			100 mg	190150
clomifene citrate			100 mg	187136
clomifene citrate Z-isomer see zuclomifene
cloxacillin sodium			200 mg	274005
colecalciferol (vitamin D₃)			500 mg	190146
cortisone acetate			100 mg	167006

dapsone			100 mg	183115
desoxycortone acetate			100 mg	167007
dexamethasone			100 mg	388008
dexamethasone acetate			100 mg	288009
dexamethasone phosphoric acid			100 mg	192161
dexamethasone sodium phosphate			100 mg	192158
diazepam			100 mg	172062
diazoxide			100 mg	181103
dicloxacillin sodium			200 mg	174071
dicolinium iodide			100 mg	172055
dicoumarol			100 mg	178077
diethylcarbamazine dihydrogen citrate			100 mg	181100
digitoxin			100 mg	277010
digoxin			100 mg	587011
N, N'-di-(2,3-xylyl) anthranilamide			50 mg	173067
dopamine hydrochloride			100 mg	192159
doxorubicin hydrochloride			100 mg	196202

emetine hydrochloride			100 mg	187134
4-epianhydrotetracycline hydrochloride			25 mg	288097
4-epitetracycline hydrochloride			25 mg	293098
ergocalciferol (vitamin D₂)			500 mg	190147
ergometrine hydrogen maleate			50 mg	277012
ergotamine tartrate			50 mg	385013
erythromycin			250 mg	191154
erythromycin B			150 mg	194186
erythromycin C			25 mg	194187
estradiol benzoate			100 mg	167014
estrone			100 mg	279015
etacrynic acid			100 mg	281056
ethambutol hydrochloride			100 mg	179081
ethinylestradiol			100 mg	291016
ethisterone			100 mg	167017
ethosuximide			100 mg	179088
etocarlide			100 mg	172057

flucloxacillin sodium			200 mg	195194
flucytosine			100 mg	184121
fludrocortisone acetate			200 mg	195199
fluorouracil			100 mg	184122
fluphenazine decanoate dihydrochloride			100 mg	182107
fluphenazine enantate dihydrochloride			100 mg	182108
fluphenazine hydrochloride			100 mg	176076
folic acid			100 mg	388019
3-formylrifamycin			200 mg	190149
framycetin sulfate (neomycin B sulfate)			200 mg	193178
furosemide			100 mg	171044

gentamicin sulfate			100 mg	194183
griseofulvin			200 mg	280040

haloperidol			100 mg	172063
hydrochlorothiazide			100 mg	179087
hydrocortisone			100 mg	283020
hydrocortisone acetate			100 mg	280021
hydrocortisone sodium succinate			200 mg	194184
(-)-3-(4-hydroxy-3-methoxyphenyl)-2-hydrazino-2-methylalanine (3-O-methylcarbidopa)			25 mg	193180
(-)-3-(4-hydroxy-3-methoxyphenyl)-2-methylalanine (3-O-methylmethyldopa)			25 mg	179085

ibuprofen			100 mg	183117
imipramine hydrochloride			100 mg	172064
indometacin			100 mg	178078
o-iodohippuric acid			100 mg	171045
isoniazid			100 mg	185124

lanatoside C			100 mg	281022
levodopa			100 mg	295065
levonorgestrel			200 mg	194182
levothyroxine sodium			100 mg	189144
lidocaine			100 mg	181104
lidocaine hydrochloride			100 mg	181105
liothyronine sodium			50 mg	193179
loperamide hydrochloride			100 mg	194185

mebendazole			200 mg	195195
mefenamic acid			100 mg	173068
melting point reference substances
	azobenzene	(69°C)	4g	192168
	vanillin	(83°C)	4g	192169
	benzil	(96°C)	4g	294170
	acetanilide	(116°C)	4g	192171
	phenacetin	(136°C)	4g	192172
	benzanilide	(165°C)	4g	192173
	sulfanilamide	(166°C)	4g	192162
	sulfapyridine	(193°C)	4g	192163
	dicyanodiamide	(210°C)	4g	192164
	saccharin	(229°C)	4g	192165
	caffeine	(237°C)	4g	192166
	phenolphthalein	(263°C)	4g	192167
metazide			100 mg	172058
methaqualone			100 mg	173069
methotrexate			100 mg	194193
methyldopa			100 mg	179084
methyltestosterone			100 mg	167023
meticillin sodium			200 mg	274024
metronidazole			100 mg	183118

nafcillin sodium			200 mg	272025
neamine hydrochloride (neomycin A hydrochloride)			0.5 mg	193177
neomycin B sulfate see framycetin sulfate
neostigmine metilsulfate			100 mg	187135
nicotinamide			100 mg	179090
nicotinic acid			100 mg	179091
nifurtimox			100 mg	194189
niridazole			200 mg	186129
niridazole-chlorethylcarboxamide			25 mg	186130
norethisterone			100 mg	186132
norethisterone acetate			100 mg	185123
nystatin			200 mg	191152

ouabain			100 mg	283026
oxacillin sodium			200 mg	382027
oxytetracycline dihydrate			200 mg	189142
oxytetracycline hydrochloride			200 mg	189141

papaverine hydrochloride			100 mg	185127
paracetamol			100 mg	195198
paromomycin sulfate			75 mg	195197
pheneticillin potassium			200 mg	167028
phenoxymethylpenicillin			200 mg	179082
phenoxymethylpenicillin calcium			200 mg	179083
phenoxymethylpenicillin potassium			200 mg	176075
phenytoin			100 mg	179089
praziquantel			100 mg	194191
prednisolone			100 mg	389029
prednisolone acetate			100 mg	289030
prednisolone hemisuccinate			200 mg	195196
prednisolone sodium phosphate			200 mg	194190
prednisone			100 mg	167031
prednisone acetate			100 mg	169032
probenecid			100 mg	192156
procaine hydrochloride			100 mg	183119
procarbazine hydrochloride			100 mg	184120
progesterone			100 mg	167033
propicillin potassium			200 mg	274034
propranolol hydrochloride			100 mg	187139
propylthiouracil			100 mg	185126
pyrantel embonate (pyrantel pamoate)			500 mg	192157
pyridostigmine bromide			100 mg	182110

reserpine			100 mg	186133
retinol acetate (solution)			5 capsules¹	791038
riboflavin			250 mg	382035
rifampicin			200 mg	191151
rifampicin quinone			200 mg	190148

sodium cromoglicate			100 mg	188140
spectinomycin hydrochloride			200 mg	193176
sulfacetamide			100 mg	196200
sulfamethoxazole			100 mg	179092
sulfamethoxypyridazine			100 mg	178079
sulfanilamide			100 mg	179094
sulfasalazine			100 mg	191155

tamoxifen citrate			100 mg	196208
tamoxifen citrate E-isomer			10 mg	196209
testosterone enantate			200 mg	194192
testosterone propionate			100 mg	167036
tetracycline hydrochloride			200 mg	180095
thioacetazone			100 mg	171046
4,4'-thiodianiline			50 mg	183116
thyroxine sodium see levothyroxine sodium
tolbutamide			100 mg	179086
tolnaftate			100 mg	176074
toluene-2-sulfonamide			100 mg	196204
trimethadione			200 mg	185125
trimethoprim			100 mg	179093
trimethylguanidine sulfate			100 mg	172059
tubocurarine chloride			100 mg	170037

vincristine sulfate			9.7 mg/vial	193181
vitamin A acetate (solution) see retinol acetate (solution)

warfarin			100 mg	168041

zuclomifene			50 mg	187137

¹Each containing about 9 mg in 250 mg of oil.

Annex 1. List of available International Chemical Reference Substances1

Annex 1. List of available International Chemical Reference Substances¹