Quality Assurance of Pharmaceuticals - A Compendium of Guidelines and Related Materials - Volume 1: 2. Product assessment and registration: Stability of drug dosage forms 1 : 4. Use of terms

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

Table of Contents

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

4. Use of terms

The following working definitions or explanations are offered for a number of the terms used in this text.

Stability: The ability of a drug to retain its properties within specified limits throughout its shelf-life. The following aspects of stability are to be considered: chemical, physical, microbiological and biopharmaceutical.

Expiry (expiration) date: The expiry date placed on the container of a drug product designates the date up to and including which the product is expected to remain within specification if stored correctly. It is established for every batch by adding the shelf-life period to the manufacturing date.

Shelf-life (expiration dating period or validity period): The period of time during which a drug product is expected, if stored correctly, to remain within specification as determined by stability studies on a number of batches of the product. The shelf-life is used to establish the expiry date of each batch.

Provisional (tentative) shelf-life: The provisional shelf-life is determined by projecting results from accelerated stability studies.

Date of manufacture: A date fixed for the individual batch, indicating the completion date of the manufacture. It is normally expressed by a month and a year. The date of the release analysis may be taken as a date of manufacture, provided that the period between the beginning of production and the release of the product is not longer than one-twentieth of the shelf-life.

Normal storage conditions: Storage in dry, well-ventilated premises at temperatures of 15-25 °C or, depending on climatic conditions, up to 30 °C. Extraneous odours, other indications of contamination, and intense light have to be excluded.

Defined storage instructions: Drug products that must be stored under defined conditions require appropriate storage instructions. Unless otherwise specifically stated, e.g. continuous maintenance of cold storage, deviation may be tolerated only during short-term interruptions, for example during local transportation.

The following instructions are recommended:

On the label		Means:

“Do not store over	30 °C”	from +2 °C to +30 °C
“Do not store over	25 °C”	from +2 °C to +25 °C
“Do not store over	15 °C”	from +2 °C to +15 °C
“Do not store over	8 °C”	from +2 °C to +8 °C
“Do not store below	8 °C”	from +8 °C to +25 °C

“Protect from moisture”		no more than 60% relative humidity in normal storage conditions; to be provided to the patient in a moisture-resistant container

“Protect from light”		to be provided to the patient in a light-resistant container

Stability tests: The purpose of stability tests is to obtain information in order to define the shelf-life of the pharmaceutical product in its original container and to specify storage conditions.

Accelerated (stress) stability studies: Studies designed to increase the rate of chemical or physical degradation of a drug by using exaggerated storage conditions with the purpose of monitoring degradation reactions and predicting the shelf-life under normal storage conditions. The design of accelerated studies may include elevated temperature (e.g. 37-40 °C and up to 50-55 °C), high humidity and light.

Only a provisional shelf-life may be established on the basis of these studies. Therefore, accelerated studies should always be supplemented by real-time studies under expected storage conditions,

Utilization period: A period of time during which a reconstituted preparation or the preparation in an opened multidose container can be used.