Quality Assurance of Pharmaceuticals - A Compendium of Guidelines and Related Materials - Volume 1: 2. Product assessment and registration: Guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms 1 : 2. Intended market

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

2. Intended market

The design of the stability testing programme should take into account the intended market and the climatic conditions in the area in which the drug products will be used.

Four climatic zones can be distinguished for the purpose of worldwide stability testing, as follows:

• Zone I: temperate.
• Zone II: subtropical, with possible high humidity.
• Zone III: hot/dry.
• Zone IV: hot/humid.

(See Schumacher P. Aktuelle Fragen zur Haltbarkeit von Arzneimitteln. [Current questions on drug stability.] Pharmazeutische Zeitung, 1974, 119:321-324.)

The mean climatic conditions, calculated data and derived storage conditions in these zones are summarized in Tables 2 and 3.

Table 2. Mean climatic conditions: measured data in the open air and in the storage room¹

¹ RH = relative humidity.

Climatic zone	Measured data in the open air		Measured data in the storage room
	°C	% RH	°C	% RH
I	10.9	75	18.7	45
II	17.0	70	21.1	52
III	24.4	39	26.0	54
IV	26.5	77	28.4	70

Table 3. Mean climatic conditions: calculated data and derived storage conditions¹

¹ Based on: Grimm W. Storage conditions for stability testing in the EC, Japan and USA; the most important market for drug products. Drug development and industrial pharmacy, 1993, 19:2795-2830.

Climatic zone	Calculated data			Derived storage conditions (for real-time studies)
	°C²	°C MKT³	% RH⁴	°C	% RH
I	20.0	20.0	42	21	45
II	21.6	22.0	52	25	60
III	26.4	27.9	35	30	35
IV	26.7	27.4	76	30	70

² Calculated temperatures are derived from measured temperatures, but all measured temperatures of less than 19 °C were set equal to 19 °C.

³ MKT = mean kinetic temperature (see p. 48).

⁴ RH = relative humidity.

Since there are only a few countries in zone I, the manufacturer would be well advised to base stability testing on the conditions in climatic zone II when it is intended to market products in temperate climates. For countries where certain regions are situated in zones III or IV, and also with a view to the global market, it is recommended that stability testing programmes should be based on the conditions corresponding to climatic zone IV.

In a stability study, the effect on the product in question of variations in temperature, time, humidity, light intensity and partial vapour pressure are investigated. The effective or mean kinetic temperature therefore reflects the actual situation better than the measured mean temperature; a product kept for 1 month at 20 °C and 1 month at 40 °C will differ from one kept for 2 months at 30 °C. Moreover, the storage conditions are often such that the temperature is higher than the average meteorological data for a country would indicate.

For some dosage forms, especially liquid and semi-solid ones, the study design may also need to include subzero temperatures, e.g. -10 to -20 °C (freezer), freeze - thaw cycles or temperatures in the range 2-8 °C (refrigerator). For certain preparations it may be important to observe the effects caused by exposure to light.