WHO Expert Committee on Specifications for Pharmaceutical Preparations - WHO Technical Report Series, No. 863 - Thirty-fourth Report: Annex 5 - Guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms: General

WHO Expert Committee on Specifications for Pharmaceutical Preparations - WHO Technical Report Series, No. 863 - Thirty-fourth Report
(1996; 200 pages)

Table of Contents

1. Introduction
2. The international pharmacopoeia and related activities
	2.1. Quality specifications for drug substances and dosage forms
	2.2. Test methodology
	2.3. International Nonproprietary Names for pharmaceutical substances
	2.4. International Chemical Reference Substances and International Infrared Spectra
3. Simple test methodology
4. Stability of dosage forms
	4.1. Guidelines for the stability testing of pharmaceutical products containing established drug substances
	4.2. Joint WHO/UNICEF study on the quality of selected drugs at the point of use in developing countries
5. Good manufacturing practices for pharmaceutical products
	5.1. Adoption of additional guidelines
	5.2. Further guidance on good manufacturing practices
6. Legal and administrative aspects of the functioning of national drug regulatory authorities
	6.1. Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability
	6.2. The WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce
	6.3. Guiding principles for formulating national drug legislation
	6.4. Role of the pharmacist
	6.5. Model legislative provisions to update national legal texts to deal with counterfeit drugs
	6.6. Additional guidance
	6.7. Training activities
7. Quality assurance in the supply system
	7.1. Guidelines on import procedures for pharmaceutical products
	7.2. Guidelines for inspection of drug distribution channels
8. Terminology
Acknowledgements
References
Annex 1 - Guidelines for the graphic representation of chemical formulae
	1. Introduction
	2. Acyclic structures
	3. Cyclic structures
	4. Ionic structures
	5. Isotopically modified compounds
	6. Coordination compounds
	7. Stereochemistry
	8. Carbohydrates
	9. Steroids
	10. Terpenoids
	11. Prostanoids
	12. Alkaloids
	13. Antibiotics
	14. Polypeptides
	15. Polymers
	Acknowledgements
	References
Annex 2 - List of available International Chemical Reference Substances¹
Annex 3 - List of available International Infrared Reference Spectra
Annex 4 - General recommendations for the preparation and use of infrared spectra in pharmaceutical analysis
	1. Introduction
	2. Apparatus
	3. Method of verification of frequency scale and resolution
	4. Environment
	5. Use of solvents
	6. Preparation of the substance to be examined
	7. Identification by reference substance
	8. Identification by reference spectrum
	9. Reflectance techniques
Annex 5 - Guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms
	General
	Definitions
	1. Stability testing
	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
Annex 6 - Good manufacturing practices: guidelines on the validation of manufacturing processes
	Introduction
	Glossary
	General
	1. Types of process validation
	2. Prerequisites for process validation
	3. Approaches
	4. Organization
	5. Scope of a process validation programme
	6. Validation protocol and report
	References
	Bibliography
Annex 7 - Good manufacturing practices: supplementary guidelines for the manufacture of investigational pharmaceutical products for clinical trials in humans
	1. Introductory note
	2. General considerations
	3. Glossary
	4. Quality assurance
	5. Validation¹
	6. Complaints
	7. Recalls
	8. Personnel
	9. Premises and equipment
	10. Materials
	11. Documentation
	12. Production
	13. Quality control
	14. Shipping, returns, and destruction
	References
Annex 8 - Good manufacturing practices: supplementary guidelines for the manufacture of herbal medicinal products¹
	1. Glossary
	2. General
	3. Premises
	4. Documentation
	5. Quality control
	6. Stability tests
	References
Annex 9 - Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability
	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
			In vivo studies
			In vitro studies
	Part Three. Tests for equivalence
		10. Bioequivalence studies in humans
			Subjects
			Design
			Studies of metabolites
			Measurement of individual isomers for chiral drug substance products
			Validation of analytical procedures
			Reserve samples
			Statistical analysis and acceptance criteria
			Reporting of results
		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
Annex 10 - Guidelines for implementation of the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce
	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
Annex 11 - Guidelines for the assessment of herbal medicines^1,2
	Introduction
	Assessment of quality
	Assessment of safety
	Assessment of efficacy
	Intended use
	Utilization of these guidelines
Annex 12 - Guidelines on import procedures for pharmaceutical products
	1. Introductory notes
	2. Objectives and scope
	3. Legal responsibilities
	4. Legal basis of control
	5. Required documentation
	6. Implementation of controls
	7. Procedures applicable to pharmaceutical starting materials
	8. Storage facilities
	9. Training requirements
	References
	Glossary
	Appendix - Special import controls for narcotic drugs and psychotropic substances¹
Back Cover

General

The stability of finished pharmaceutical products depends, on the one hand, on environmental factors such as ambient temperature, humidity and light, and, on the other, on product-related factors, e.g. the chemical and physical properties of the active substance and of pharmaceutical excipients, the dosage form and its composition, the manufacturing process, the nature of the container-closure system and the properties of the packaging materials.

For established drug substances in conventional dosage forms, literature data on the decomposition process and degradability of the active substance (1) are generally available together with adequate analytical methods. Thus, the stability studies may be restricted to the dosage forms.

Since the actual stability of a dosage form will depend to a large extent on the formulation and packaging-closure system selected by the manufacturer, stability considerations, e.g. selection of excipients, determination of their level and process development, should be given high priority in the developmental stage of the product. The possible interaction of the drug product with the packaging material in which it will be delivered, transported and stored throughout its shelf-life must also be investigated.

The shelf-life should be established with due regard to the climatic zone(s) (see section 2) in which the product is to be marketed. For certain preparations, the shelf-life can be guaranteed only if specific storage instructions are complied with.

The storage conditions recommended by manufacturers on the basis of stability studies should guarantee the maintenance of quality, safety, and efficacy throughout the shelf-life of a product. The effect on products of the extremely adverse climatic conditions existing in certain countries to which they may be exported calls for special consideration (see section 6).

To ensure both patient safety and the rational management of drug supplies, it is important that the expiry date and, when necessary, the storage conditions are indicated on the label.