Quality Assurance of Pharmaceuticals - A Compendium of Guidelines and Related Materials - Volume 1: 4. The international pharmacopoeia and related activities: List of available International Chemical Reference Substances 1

Quality Assurance of Pharmaceuticals - A Compendium of Guidelines and Related Materials - Volume 1
(1997; 248 pages) [French]

Table des matières

Introduction
	National drug regulation
	Product assessment and registration
	Good manufacturing practices and inspection
	Distribution
	The international pharmacopoeia and related activities
	Basic tests
	Laboratory services
	International trade in pharmaceuticals
	Counterfeit products
	Training
	Conclusion
1. National drug regulation
	Guiding principles for small national drug regulatory authorities^1,2
		1. General considerations
			1.1 The scope of drug control
			1.2 Basic responsibilities
			1.3 Licensing functions
			1.4 Product licences
			1.5 Manufacturers’ and distributors’ licences
			1.6 New drug assessments
			1.7 Authorization of clinical trials
			1.8 Terms of reference of the regulatory authority
			1.9 Powers of enforcement
			1.10 Technical competence
			1.11 Advisory bodies
			1.12 Independence of operation
		2. Administrative aspects of the licensing process
			2.1 Provisional registration of existing medicinal products
			2.2 Screening of provisionally registered products
			2.3 New product licences
			2.4 Renewal and variation of licences
		3. Technical aspects of the licensing process
			3.1 General considerations
			3.2 Products containing long-established chemical entities
			3.3 Products containing new chemical entities
			3.4 Herbal products
			3.5 Combinations of potent, therapeutically active substances
			3.6 Generic products
2. Product assessment and registration
	Guidelines for the assessment of herbal medicines^1,2
	Stability of drug dosage forms¹
		1. Introduction
		2. General considerations
		3. Responsibility of parties involved in the assurance of drug stability
			3.1 Manufacturers
			3.2 Drug regulatory authorities
			3.3 Procurement agencies
			3.4 Pharmacists and other workers in the supply system
		4. Use of terms
		5. Less stable drug substances
		References
	Guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms¹
		General
		Definitions
		1. Stability testing
		2. Intended market
		3. Design of stability studies
		4. Analytical methods
		5. Stability report
		6. Shelf-life and recommended storage conditions
		References
		Official, international and national guidelines
		Appendix 1. Survey on the stability of pharmaceutical preparations included in the WHO Model List of Essential Drugs: answer sheet
		Appendix 2. Stability testing: summary sheet
	Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability¹
		Introduction
		Glossary
		Part One. Regulatory assessment of interchangeable multisource pharmaceutical products
			1. General considerations
			2. Multisource products and interchangeability
			3. Technical data for regulatory assessment
			4. Product information and promotion
			5. Collaboration between drug regulatory authorities
			6. Exchange of evaluation reports
		Part Two. Equivalence studies needed for marketing authorization
			7. Documentation of equivalence for marketing authorization
			8. When equivalence studies are not necessary
			9. When equivalence studies are necessary and types of studies required
		Part Three. Tests for equivalence
			10. Bioequivalence studies in humans
			11. Pharmacodynamic studies
			12. Clinical trials
			13. In vitro dissolution
		Part Four. In vitro dissolution tests in product development and quality control
		Part Five. Clinically important variations in bioavailability leading to non-approval of the product
		Part Six. Studies needed to support new post-marketing manufacturing conditions
		Part Seven. Choice of reference product
		Authors
		References
		Appendix 1. Examples of national requirements for in vivo equivalence studies for drugs included in the WHO Model List of Essential Drugs (Canada, Germany and the USA, December 1994)
		Appendix 2. Explanation of symbols used in the design of bioequivalence studies in humans, and commonly used pharmacokinetic abbreviations
		Appendix 3. Technical aspects of bioequivalence statistics
3. Distribution
	Quality assurance in pharmaceutical supply systems¹
		1. Introduction and general considerations
		2. Elements of quality assessment and assurance
			2.1 Legal base
			2.2 Regulatory elements
			2.3 Technical elements
		3. Pre-marketing quality assessment
			3.1 Drug notification, authorization and registration
			3.2 Drug nomenclature
		4. Drug quality surveillance during marketing
			4.1 Quality surveillance during manufacture
			4.2 Quality surveillance of imported drugs
			4.3 Quality surveillance during distribution
		References
4. The international pharmacopoeia and related activities
	Guidance for those preparing or commenting on monographs for preparations to be included in The international pharmacopoeia¹
	Validation of analytical procedures used in the examination of pharmaceutical materials¹
	General guidelines for the establishment, maintenance, and distribution of chemical reference substances¹
		1. Criteria for determining the need for the establishment of chemical reference substances
		2. Evaluation of reference substances
		3. Chemical and physical methods used in evaluating reference substances
			3.1 Methods useful for verifying the identity of reference substances
			3.2 Purity requirements for reference substances
			3.3 Methods used in determining the purity of reference substances
		4. Handling and distribution of reference substances
			4.1 Packing and storage
			4.2 Stability and periodic re-evaluation
			4.3 Information to be supplied with reference substances
			4.4 Expiry of reference substances
			4.5 Distribution problems
		5. Reference materials calibrated against International Chemical Reference Substances
		6. Means of promoting effective exchange of information and ensuring cooperation between organizations establishing reference substances
	General recommendations for the preparation and use of infrared spectra in pharmaceutical analysis¹
	List of available International Chemical Reference Substances¹
	List of available International Infrared Reference Spectra¹
5. Basic tests
	Collaboration within the basic test programme¹
6. Laboratory services
	National laboratories for drug quality surveillance and control¹
		1. Introduction
		2. First-stage laboratory for drug surveillance
		3. Medium-size drug control laboratory
			3.1 Capability
			3.2 Premises
			3.3 Staff
			3.4 Equipment
		4. Scope of activity
		5. Factors influencing the size and location of a laboratory
		6. Implementation of control laboratory projects
			6.1 Feasibility study
			6.2 Phasing of development
			6.3 Programme support
	Good laboratory practices in governmental drug control laboratories¹
		1. General
		2. Management and operational issues
			2.1 Organizational structure
			2.2 Staffing
			2.3 Incoming samples
			2.4 Analytical worksheet
			2.5 Testing
			2.6 Evaluation of test results
			2.7 Retention samples
			2.8 Specifications repertory
			2.9 Reagents
			2.10 Reference materials
			2.11 Instruments and their calibration
			2.12 Safety in drug control laboratories
		References
	Sampling procedure for industrially manufactured pharmaceuticals¹
		1. General considerations
			1.1 Purpose of sampling
			1.2 Types of controls
			1.3 Classes and types of materials
			1.4 Parties concerned with sampling procedures
		2. Use of terms
			2.1 Sampling operations
			2.2 Samples
			2.3 Quantities of material
			2.4 Personnel
		3. General precautions to be taken during sampling operations
		4. Packaging and labelling of samples
		5. Sampling during pharmaceutical inspections
		6. Sampling of pharmaceutical dosage forms in regular surveillance programmes on drug quality during marketing
		7. Sampling of pharmaceutical dosage forms for acceptance of consignments
		8. Sampling of starting materials
			8.1 General considerations
			8.2 Sampling plans for consignments of starting materials supplied in several sampling units
7. International trade in pharmaceuticals
	Guidelines for implementation of the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce¹
		1. Provisions and objectives
		2. Eligibility for participation
		3. Requesting a certificate
		4. Issuing a certificate
		5. Notifying and investigating a quality defect
		References
		Appendix 1. Model Certificate of a Pharmaceutical Product
		Appendix 2. Model Statement of Licensing Status of Pharmaceutical Product(s)
		Appendix 3. Model Batch Certificate of a Pharmaceutical Product
		Appendix 4. Glossary and index
	World Health Assembly resolution WHA50.3: Guidelines on the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce
	Guidelines on import procedures for pharmaceutical products¹
8. Counterfeit products
	Observations and recommendations on counterfeit drugs^1,2
9. Training
	Training programme in drug analysis^1,2
	Places of training in drug quality control offered by the International Federation of Pharmaceutical Manufacturers Associations¹
Selected WHO publications of related interest
Back cover

List of available International Chemical Reference Substances¹

¹WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-fourth Report. Geneva, World Health Organization, 1996 (WHO Technical Report Series, No. 863).

International Chemical Reference Substances 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.

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

International Chemical Reference Substances 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 their use.

It is generally recommended that the substances 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.

The stability of the International Chemical Reference Substances kept at the Collaborating Centre is monitored by regular re-examination, and materials that have deteriorated are replaced by new batches when necessary. Lists giving control numbers for the current batches are issued in the annual reports from the Centre and may be obtained on request.

Orders for International Chemical Reference Substances should be sent to:

WHO Collaborating Centre for Chemical Reference Substances
Apoteksbolaget AB
Centrallaboratoriet
S-105 14 Stockholm
Sweden
Telex: 115 53 APOBOL S
Fax: 46 8 740 60 40

International Chemical Reference Substances are supplied only in the standard packages indicated in the following list.

*Reference substance*		*Package* *size*

aceclidine salicylate		100 mg
p-acetamidobenzalazine		100 mg
acetazolamide		100 mg
allopurinol		100 mg
2-amino-5-nitrothiazole		25 mg
3-aminopvrazole-4-carboxamide hemisulfate		100 mg
amitriptyline hydrochloride		100 mg
amodiaquine hvdrochloride		200 mg
amphotericin B		400 mg
ampicillin (anhydrous)		200 mg
ampicillin sodium		200 mg
ampicillin trihydrate		200 mg
anhydrotetracycline hydrochloride		25 mg
atropine sulfate		100 mg
azathioprine		100 mg

bacitracin zinc		200 mg
beclometasone dipropionate		200 mg
bendazol hydrochloride		100 mg
benzobarbital		100 mg
benzylamine sulfate		100 mg
benzylpenicillin potassium		200 mg
benzylpenicillin sodium		200 mg
bephenium hydroxynaphthoate		100 mg
betamethasone		100 mg
betamethasone valerate		100 mg
betanidine sulfate		100 mg
bupivacaine hydrochloride		100 mg

caffeine		100 mg
carbamazepine		100 mg
carbenicillin monosodium		200 mg
chloramphenicol		200 mg
chloramphenicol palmitate		1 g
chloramphenicol palmitate (polymorph A)		200 mg
5-chloro-2-methylaminobenzophenone		100 mg
2-(4-chloro-3-sulfamoylbenzoyl)benzoic acid		50 mg
chlorphenamine hydrogen maleate		100 mg
chlorpromazine hydrochloride		100 mg
chlortalidone		100 mg
chlortetracycline hydrochloride		200 mg
cimetidine		100 mg
clomifene citrate		100 mg
clomifene citrate Z-isomer (see zuclomifene)
cloxacillin sodium		200 mg
colecalciferol (vitamin D₃)		500 mg
cortisone acetate		100 mg

dapsone		100 mg
desoxycortone acetate		100 mg
dexamethasone		100 mg
dexamethasone acetate		100 mg
dexamethasone phosphoric acid		100 mg
dexamethasone sodium phosphate		100 mg
diazepam		100 mg
diazoxide		100 mg
dicloxacillin sodium		200 mg
dicolinium iodide		100 mg
dicoumarol		100 mg
diethylcarbamazine dihydrogen citrate		100 mg
digitoxin		100 mg
digoxin		100 mg
N,N’-di-(2,3-xylyl)anthranilamide		50 mg
dopamine hydrochloride		100 mg

emetine hydrochloride		100 mg
4-epianhydrotetracycline hydrochloride		25 mg
4-epitetracycline hydrochloride		25 mg
ergocalciferol (vitamin D₂)		500 mg
ergometrine hydrogen maleate		50 mg
ergotamine tartrate		50 mg
erythromycin		250 mg
estradiol benzoate		100 mg
estrone		100 mg
etacrynic acid		100 mg
ethambutol hydrochloride		100 mg
ethinylestradiol		100 mg
ethisterone		100 mg
ethosuximide		100 mg
etocarlide		100 mg

flucytosine		100 mg
fluorouracil		100 mg
fluphenazine decanoate dihydrochloride		100 mg
fluphenazine enantate dihydrochloride		100 mg
fluphenazine hydrochloride		100 mg
folic acid		100 mg
3-formylrifamycin		200 mg
framycetin sulfate (neomycin B sulfate)		200 mg
furosemide		100 mg
griseofulvin		200 mg

haloperidol		100 mg
hydrochlorothiazide		100 mg
hydrocortisone		100 mg
hydrocortisone acetate		100 mg
(-)-3-(4-hydroxy-3-methoxyphemi)-2-hydrazino-2-methylalanine (3-O-methylcarbidopa)		25 mg
(-)-3-(4-hydroxy-3-methoxyphenyl)-2-methylalanine		25 mg
ibuprofen		100 mg
imipramine hydrochloride		100 mg
indometacin		100 mg
o-iodohippuric acid		100 mg
isoniazid		100 mg
lanatoside C		100 mg
levodopa		100 mg
levothyroxine sodium		100 mg
lidocaine		100 mg
lidocaine hydrochloride		100 mg
liothyronine sodium		50 mg

mefenamic acid		100 mg
melting point reference substances
	azobenzene (69 °C)	4g
	vanillin (83 °C)	4g
	benzil (96 °C)	4g
	acetanilide (116 °C)	4g
	phenacetin (136 °C)	4g
	benzanilide (165 °C)	4g
	sulfanilamide (166 °C)	4g
	sulfapyridine (193 °C)	4g
	dicyanodiamide (210 °C)	4g
	saccharin (229 °C)	4g
	caffeine (237 °C)	4g
	phenolphthalein (263 °C)	4g
metazide		100 mg
methaqualone		100 mg
methyldopa		100 mg
methyltestosterone		100 mg
meticillin sodium		200 mg
metronidazole		100 mg

nafcillin sodium		200 mg
neamine hydrochloride (neomycin A hydrochloride)		0.5 mg
neostigmine metilsulfate		100 mg
nicotinamide		100 mg
nicotinic acid		100 mg
niridazole		200 mg
niridazole-chlorethylcarboxamide		25 mg
norethisterone		100 mg
norethisterone acetate		100 mg
nystatin		200 mg

ouabain		100 mg
oxacillin sodium		200 mg
oxytetracycline dihydrate		200 mg
oxytetracycline hydrochloride		200 mg

papaverine hydrochloride		100 mg
pheneticillin potassium		200 mg
phenoxymethylpenicillin		200 mg
phenoxymethylpenicillin calcium		200 mg
phenoxymethylpenicillin potassium		200 mg
phenytoin		100 mg
prednisolone		100 mg
prednisolone acetate		100 mg
prednisone		100 mg
prednisone acetate		100 mg
probenecid		100 mg
procaine hydrochloride		100 mg
procarbazine hydrochloride		100 mg
progesterone		100 mg
propicillin potassium		200 mg
propranolol hydrochloride		100 mg
propylthiouracil		100 mg
pyrantel embonate		500 mg
pyridostigmine bromide		100 mg

reserpine		100 mg
retinol acetate (solution)		5 capsules¹
riboflavin		250 mg
rifampicin		200 mg
rifampicin quinone		200 mg

sodium cromoglicate		100 mg
spectinomycin hydrochloride		200 mg
sulfamethoxazole		100 mg
sulfamethoxypyridazine		100 mg
sulfanilamide		100 mg
sulfasalazine		100 mg

testosterone propionate		100 mg
tetracycline hydrochloride		200 mg
thioacetazone		100 mg
4,4’-thiodianiline		50 mg
L-thyroxine sodium see levothyroxine sodium
tolbutamide		100 mg
tolnaftate		100 mg
trimethadione		200 mg
trimethoprim		100 mg
trimethylguanidine sulfate		100 mg
tubocurarine chloride		100 mg
vitamin A acetate (solution) see retinol acetate (solution)
vincristine sulfate		9.7 mg/vial
warfarin		100 mg
zuclomifene		50 mg

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

List of available International Chemical Reference Substances1

List of available International Chemical Reference Substances¹