Quality assurance of pharmaceuticals

.A 'com,pelndiium of guidelines and related mater:ialls

Vo~ume1

The World Health Organization was established in 1948 as a specialized agency of the United Nations serving as the directing and coordinating authority for international health matters and public health. One of WHO's constitutional functions is to provide objective and reliable information and advice in the field of human health, a responsibility that it fulfils in part through its extensive programme of publications.

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Quality assurance of pharmaceuticals

A compendium of guidelines and related materials

Volume 1

Quality assurance of pharmaceuticals

A compendium of guidelines and related materials

Volume 1

World Health Organization Geneva

1997

WHO Library Cataloguing in Publication Data

Quality assurance of pharmaceuticals: a compendium of guidelines and related materials: volume 1.

1. Drug and narcotic control 2. Drug industry-standards 3. Legislation, Drug 4. Quality control 5. Guidelines

ISBN 92 4 154504 6 (NLM Classification: QV 33)

The World Health Organization welcomes requests for permission to reproduce or translate its publications, in part or in full. Applications and enquiries should be addressed to the Office of Publications, World Health Organization, Geneva, Switzerland, which will be glad to provide the latest information on any changes made to the text, plans for new editions, and reprints and translations already available.

© World Health Organization 1997

Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved.

The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.

The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.

Much of the material reproduced in this publication is extracted from the reports of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. These reports contain the collective views of an international group of experts and do not necessarily represent the decisions or the stated policy of the World Health Organization.

Printed in England 95/10460 - Clays - 8000

Contents

Introduction
National drug regulation 2
Product assessment and registration 3
Good manufacturing practices and inspection 6
Distribution 7
The international pharmacopoeia and related activities 7
Basic tests 9
Laboratory services 10
International trade in pharmaceuticals 12
Counterfeit products 15
Training 15
Conclusion 17
1. National drug regulation
Guiding principles for small national drug regulatory authorities 18
2. Product assessment and registration
Guidelines for the assessment of herbal medicines 31
Stability of drug dosage forms 37
Guidelines for stability testing of pharmaceutical products
containing well established drug substances in conventional
dosage forms 46
Multisource (generic) pharmaceutical products: guidelines on
registration requirements to establish interchangeability 62
3. Distribution
Quality assurance in pharmaceutical supply systems 105 v

CONTENTS

4. The international pharmacopoeia and related activities
Guidance for those preparing or commenting on monographs
for preparations to be included in The international
pharmacopoeia 116
Validation of analytical procedures used in the examination of
pharmaceutical materials 119
General guidelines for the establishment, maintenance, and
distribution of chemical reference substances 124
General recommendations for the preparation and use of infrared
spectra in pharmaceutical analysis 136
List of available International Chemical Reference Substances 142
List of available International Infrared Reference Spectra 148
5. Basic tests
Collaboration within the basic test programme 150
6. Laboratory services
National laboratories for drug quality surveillance and control 154
Good laboratory practices in governmental drug control
laboratories 162
Sampling procedure for industrially manufactured
pharmaceuticals 175
7. International trade in pharmaceuticals
Guidelines for implementation of the WHO Certification Scheme
on the Quality of Pharmaceutical Products Moving in
International Commerce 187
World Health Assembly resolution WHA50.3: Guidelines on
the WHO Certification Scheme on the Quality of
Pharmaceutical Products Moving in International Commerce 209
Guidelines on import procedures for pharmaceutical products 210
8. Counterfeit products
Observations and recommendations on counterfeit drugs 220
9. Training
Training programme in drug analysis 227
Places of training in drug quality control offered by the
International Federation of Pharmaceutical Manufacturers
Associations 235 vi

Introduction

The quality of pharmaceuticals has been a concern of the World Health Organization (WHO) ever since its inception. The setting of global standards is requested in Article 2 of the WHO Constitution which cites as one of the Organization's functions that it should "develop, establish and promote international standards with respect to food, biological, pharmaceutical and similar products".

Every government allocates a substantial proportion of its total health budget to drugs. This proportion tends to be greatest in developing countries, where it may exceed 40%.

Without assurance that these drugs are relevant to priority health needs and that they meet acceptable standards of quality, safety and efficacy, any health service is evidently compromised. In developed countries considerable administrative and technical effort is directed to ensuring that patients receive effective drugs of good quality. It is crucial to the objective of health for all that a reliable system of drug control be brought within the reach of every country.

The supply of essential drugs of good quality was identified as one of the prerequisites for the delivery of health care at the International Conference on Primary Health Care in Alma-Ata in 1978. Similarly, the Conference of Experts on the Rational Use of Drugs, held in Nairobi in 1985, and WHO's Revised Drug Strategy, adopted by the \'(:urld Health Assembly in May 1986, identified the effective functioning of national drug regulation and control systems as the only means to assure safety and quality of medicines. Yet the World Health Assembly continues to express great concern about the quality, safety and efficacy of medicines, particularly those products or active pharmaceutical substances imported into, or produced in, developing countries. In recent years counterfeit products have infiltrated certain markets in disquieting proportions. Since the founding of WHO, the World Health Assembly has adopted many resolutions requesting the Organization to develop international standards, recommendations and instruments to assure the quality of medicines, whether produced and traded nationally or internationally.

In response to these resolutions, the \X7HO Expert Committee on Specifications for Pharmaceutical Preparations, which was originally created to prepare The international pharmacopoeia, has made numerous recommendations relevant to quality assurance and control. Most of these recommendations, even if they

QUALIlY ASSURANCE OF PHARMACEUTICALS

were made several years ago, are still valid. Thus far, however, most have been available only as separate sets of recommendations contained in annexes to various WHO Technical Reports. The recommendations are essential to all concerned with the quality assurance of medicines, but separate publication over a period of years made it difficult to recognize them as complementary parts of a comprehensive system of quality assurance.

To provide easy access to this information, the appropriate annexes are being reproduced in the two volumes of this publication. They are supplemented with other material relevant to the quality assurance of pharmaceuticals, some already issued in the form of WHO documents. The information is not necessarily presented in chronological order of original issue. Instead it is presented in logical sequence as a series of administrative instruments and technical elements of an overall quality assurance system. Readers should bear in mind that, in certain previously published texts, reference is made to WHO guidelines and other documents that have since been updated. Some of these updated texts are themselves included in the compendium and others are mentioned in this introductory section or listed inside the back cover of the book. All material relating specifically to good manufacturing practices (GMP) and inspection of pharmaceutical manufacturers will appear in Volume 2 of this publication. The actual standards for analytical controls are contained in The international pharmacopoeia. Other relevant publications include Basic tests for pharmaceutical substances and Basic tests for pharmaceutical dosage forms.

WHO has addressed not only pharmaceutical aspects of the quality of medicines, but also the intrinsic safety and efficacy of pharmacologically active substances. Advice on this has been published in the reports of the WHO Expert Committee on Essential Drugs, the W1l0 model prescribing itiformation series, the W1l0 pharmaceuticals newsletter, and the quarterly W1l0 drug itiformation. From there relevant information is carried over into the regularly updated United Nations Consolidated list 0/ products whose consumption and/or sale have been banned, withdrawn, severelY restricted or not approved l?Y governments.

National drug regulation

The existence and functioning of a comprehensive drug regulatory system supported by legislation is a prerequisite for an overall quality assurance system. The first duty of a national regulatory authority is to register pharmaceutical products, thus defining the pharmaceutical market in the country. Only when this has been done will it be possible to distinguish between legally traded products and illegal and counterfeit ones.

The WHO Expert Committee on Specifications for Pharmaceutical Preparations addressed this issue in its thirty-first report and adopted guiding principles for small national drug regulatory authorities. These guiding principles, later endorsed by the World Health Assembly in resolution WHA47.17, are reproduced in Chapter 1. The text gives advice on how to

2

INTRODUCTION

organize national drug regulatory activities. The first section is devoted to general considerations such as the scope of drug control, basic responsibilities, licensing functions, product licences, manufacturers' and distributors' licences, new drug assessments, authorization of clinical trials, terms of reference of the regulatory authority, powers of enforcement, technical competence, advisory bodies and independence of operation.

The second and third sections of Chapter 1 address the administrative and technical aspects of the product registration or licensing process and give advice on the setting of priorities and on implementation by stages. It is anticipated that, once the initial drug registrations have been made, the registration process can be administered effectively if due advantage is taken of the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce, and prudence is exercised when accepting new chemical entities. It is recommended that developing countries do not register a new chemical entity before it has been on the market for at least five years in a country with a sophisticated drug regulatory system that includes postmarketing surveillance, unless the chemical entity presents a real therapeutic advance in combating a major endemic disease. If this approach is respected, the major work of the registration process will be the pharmaceutical evaluation of products that have not been registered in the country of export or that have been produced locally.

In some countries with large public sector procurement of essential drugs, major challenges will be to coordinate drug registration and procurement, making sure that only duly registered products are purchased. This is the only way to take real advantage of favourably priced generic products. If the purchase of generic products is allowed regardless of their registration status, there is no guarantee of the products' quality with regard to stability and bioavailability, since pharmacopoeial specifications do not necessarily address these features.

A model software package for computer-assisted drug registration has been developed by WHO's Division of Drug Management and Policies in collaboration with the Health System Information Unit of the Pan American Health Organization, and has now been field-tested in several countries. It can be obtained from the Division of Drug Management and Policies, WHO, 1211 Geneva 27, Switzerland.

Product assessment and registration

The WHO Expert Committee on Specifications for Pharmaceutical Preparations has on several occasions discussed and adopted guidelines and other texts concerned with the assessment of pharmaceutical products and with registration requirements.

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QUALITY ASSURANCE OF PHARMACEUTICALS

Herbal medicines

At its thirty-fourth meeting, the Expert Committee adopted guidelines for the assessment of herbal medicines. These guidelines, reproduced in Chapter 2, have been widely distributed to WHO Member States and were discussed at the Sixth International Conference of Drug Regulatory Authorities (ICDRA), held in Ottawa in October 1991. Their utility has been widely recognized.

Stability of pharmaceutical products

The problem of stability of pharmaceuticals has been addressed a number of times by the WHO Expert Committee on Specifications for Pharmaceutical Preparations. The introduction to this subject in the thirty-first report of the Expert Committee reads as follows:

Inadequate storage and distribution of pharmaceutical products can lead to their physical deterioration and chemical decomposition, resulting in reduced activity and, occasionally, in the formation of toxic degradation products. Degradation is particularly likely to occur under tropical conditions of high ambient temperature and humidity; and it is not widely recognized that, because of the potential for chemical interaction between the active ingredients and excipients, drug dosage forms can be more vulnerable to degradation than pure drug substances.

The stability of a specific product is thus dependent, in a large measure, on its formulation, and its expiry date should be determined on the basis of stability studies carried out by the manufacturer. Studies undertaken with a view to determining the stability of a product under temperate conditions, however, do not necessarily provide a reliable indication of its shelf-life in tropical climates. In such cases, additional proof of stability should be requested from the manufacturer, who should assume responsibility for formulating a product that is stable under the climatic conditions prevailing in the countries of destination. Relevant information should be specifically requested by the national regulatory authority in the importing country within the context of the WHO Certification Scheme ... It is obviously impossible to obtain satisfactory assurances when a product is purchased through an intermediary if its provenance is unknown to the purchaser. For domestically produced products, the regulatory authority should evaluate stability data furnished by the manufacturer. The procurement agencies and the pharmacists responsible for drug distribution should ensure that they are supplied with adequate information concerning the proper storage and handling of each product.

Specific guidelines on the stability of drug dosage forms were annexed to the Expert Committee's report and are contained in Chapter 2. They provide a comprehensive statement on both the technical aspects of the subject and the

4

INTRODUCTION

responsibilities that devolve upon the manufacturer and all agencies and individuals responsible for the product throughout the distribution chain up to the time of the drug's administration or delivery to the patient. The thirty-first report of the Expert Committee explains:

Within the distribution chain, the labelled expiry date on a pharmaceutical product has a dual significance: after this date, no formal assurance is provided regarding the condition of the product; and the manufacturer may no longer have legal liability for it. The Committee agreed that the use of timeexpired stock should be entertained only in the most exceptional circumstances, when to withhold the stock would have serious consequences for patients. In every instance, the proposal to release such a product must be channelled through a pharmacist or other professional experienced in quality assurance and, when appropriate, referred to the competent authority, which must decide on the necessity for analysis and the period of time during which the product may be used, having regard to all relevant circumstances. Doctors and other health professionals using the product may need to be alerted to the situation. Procurement procedures should be reviewed and, if necessary, modified to prevent such situations arising in the future.

Guidelines for stability testing of pharmaceutical products containing well

established drug substances in conventional dosage forms were adopted by the WHO Expert Committee on Specifications for Pharmaceutical Preparations at its thirty-fourth meeting, and are reproduced in Chapter 2. Recognizing that stability testing represents the evaluation of a pharmaceutical formulation in its final container, the Expert Committee emphasized that the same fundamental approach should be used for all products irrespective of whether the active ingredient was an established drug substance. Where sufficient information was already available on the chemical stability of the active ingredient, however, this could be taken into account. The availability of these guidelines was considered to be of special importance since they include advice on the stability testing of products for use in the more extreme climatic conditions found in many developing countries.

WHO has arranged for the conduct of accelerated stability studies on substances in the WHO Model List of Essential Drugs and has also sent out questionnaires to identify the products most likely to present stability problems. The accelerated stability studies are discussed in the twenty-eighth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. For newly introduced substances much information on stability is available, since in many countries this information is a mandatory requirement for registration of a new product and for determining expiry dates. By contrast, little information has been published on the degradation of long-established pharmaceutical substances (except for obviously unstable products) and, in many cases, their behaviour when exposed to extreme climatic conditions is uncertain.

For this reason, accelerated stability studies were carried out on long-

5

QUALITY ASSURANCE OF PHARMACEUTICALS

established essential drug substances under standardized conditions (e.g. 30 days' exposure to air at a temperature of 50°C and a relative humidity of 100%). The appearance of degradation products was detected by thin-layer chromatography, supplemented (as necessary) by spectrophotometry, fluorescence reactions, high-performance liquid chromatography and chemical determinations. The substances were additionally exposed to a temperature of 70°C under the same humidity conditions for a further 3-5 days. Negative results provided conclusive proof of the stability of the substance even under highly adverse conditions. All tests were carried out with light excluded since it is easy to protect substances from light during storage.

A document entitled "Accelerated stability studies of widely used pharmaceutical substances under simulated tropical conditions" (WHOjPHARMj 86.529) contains the results of these accelerated stability studies and is available on request from the Quality Assurance unit, Division of Drug Management and Policies, WHO, 1211 Geneva 27, Switzerland.

Interchangeability of multisource (generic) pharmaceutical products The final text in Chapter 2 provides guidance on registration requirements to establish the interchangeability of multisource (generic) pharmaceutical products. In adopting these guidelines at its thirty-fourth meeting, the WHO Expert Committee on Specifications for Pharmaceutical Preparations was pleased to note that they had already been adapted for local use by a number of WHO Member States and that positive feedback had been received especially with regard to the flexibility and clarity of the guidance. The guidelines were designed to allow a step-by-step approach tailored to the stage of development of a particular registration system and the needs and priorities of the national health authorities. They were intended to assist drug regulatory authorities and international organizations involved in the procurement of pharmaceutical products, and to provide manufacturers with an indication of the data required. It was recognized that these guidelines were a first step: they would need to be supported by training and advice on implementation.

Good manufacturing practices and inspection

The guidelines approved by the WHO Expert Committee on Specifications for Pharmaceutical Preparations on good manufacturing practices (GMP) for pharmaceutical products will be reproduced in Volume 2 of this compendium, together with supplementary guidelines for biological products, the validation of manufacturing processes and the manufacture of investigational pharmaceutical products for clinical trials in humans and of herbal medicinal products. This publication will also contain guidelines on the inspection of pharmaceutical manufacturers and of drug distribution channels.

6

INTRODUCTION

Distribution

The Twenty-eighth World Health Assembly, in resolution WHA28.66, enumerated a number of objectives relating to regulatory control of drugs. In consequence, in its twenty-seventh report, the WHO Expert Committee on Specifications for Pharmaceutical Preparations discussed the various elements of quality assurance in pharmaceutical supply systems (see Chapter 3).

Although parts of the elements described in Chapter 3 have been incorporated into or expanded in the guidelines for small national drug regulatory authorities, the text still provides a succinct review of quality assessment and assurance, premarketing quality assessment, and drug surveillance during marketing.

Pharmacists play an important role in the distribution of pharmaceuticals and must ensure that the service provided to patients is of appropriate quality. Guidelines on good pharmacy practice have been prepared by the International Pharmaceutical Federation in collaboration with WHO to encourage national pharmaceutical organizations to focus the attention of pharmacists in the community and hospital pharmacy sector on developing the elements of their services to meet changing circumstances. They provide a framework within which each country can set standards relevant to its own aspirations and needs.

The guidelines were presented in April 1997 to the WHO Expert Committee on Specifications for Pharmaceutical Preparations and will be included as an annex to the Committee's report. Copies of the text can be obtained from the Regulatory Support unit, Division of Drug Management and Policies, WHO, 1211 Geneva 27, Switzerland.

The international pharmacopoeia and related activities

The international pharmacopoeia provides internationally acceptable standards for the potency, purity and quality of pharmaceutical products moving in international commerce. These standards are available for adoption by Member States in accordance with Articles 21(d) and 23 of the Constitution of the World Health Organization and resolution WHA3.10 of the Third World Health Assembly.

Many national or regional pharmacopoeias rely increasingly on complex techniques of analysis that require expensive equipment and highly trained personnel. Such methods are inapplicable, however, in countries lacking these resources. For the most part, these methods merely permit analyses to be carried out more rapidly than by classical chemical methods.

Whereas earlier editions of Tbe international pharmacopoeia had relied heavily on material taken from certain national pharmacopoeias, the third edition, of which four volumes have been published so far, aims to accommodate the needs of developing countries by offering sound quality standards for essential drugs on the basis (wherever possible) of classical procedures. Volume 1, published in 1979, describes general methods of analysis. Volumes 2 and 3, published in 1981

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QUALl1Y ASSURANCE OF PHARMACEUTICALS

and 1988 respectively, contain quality specifications mainly for essential drug substances included in WHO's Model List of Essential Drugs. Volume 4 (1994) includes monographs on pharmaceutical substances, widely used excipients and dosage forms of essential drugs. Volume 5 (in preparation) will contain several new general requirements and additional test methods for substances and dosage forms, and a revised procedure for high-performance liquid chromatography. The volume will also contain specifications for the determination of more than 35 pharmaceutical substances and some 20 finished preparations in tablet form.

The role and objectives of The international pharmacopoeia are thus to a large extent to provide an alternative to some widely used national and regional pharmacopoeias that include sophisticated testing methods. Of course, if laboratory facilities permit use of advanced analytical methods, it is logical to analyse products according to the modern methods of such pharmacopoeias. Indeed, products may often be labelled as conforming to these pharmacopoeias. But where sophisticated testing is not possible, The international pharmacopoeia still allows verification of the quality of a product.

In its twenty-eighth report, the WHO Expert Committee on Specifications for Pharmaceutical Preparations summarized the functions and characteristics of The international pharmacopoeia and commented: "Inter alia, the production of The international pharmacopoeia helps to advance the setting of pharmacopoeial standards at national level, in that it fosters a valuable exchange of experiences gained in a wide variety of countries". At its thirty-fifth meeting, the Committee recommended that manufacturers in exporting countries be encouraged to use The international pharmacopoeia and to indicate such use in product information.

The international pharmacopoeia is developed in dose collaboration with members of the WHO Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations, other specialists from government authorities, industry, the academic world and WHO Collaborating Centres. Chapter 4 contains guidance for those preparing or commenting on monographs for inclusion in The international pharmacopoeia.

Analytical procedures used to control the quality of pharmaceutical substances and dosage forms must be adequately validated. Guidelines on validation, endorsed by the WHO Expert Committee on Specifications for Pharmaceutical Preparations, are included in Chapter 4. Since the extent to which validation is necessary is determined by the purpose of the analysis, judgement on the extent to which the guidelines need to be applied must be made on a case-by-case basis. These guidelines are directed primarily to the examination of chemical and physicochemical attributes, but many of the general principles are also applicable to microbiological and biological procedures.

Reference materials

Whenever necessary; monographs included in The international pharmacopoeia rely on the use of reference materials. These are provided either in the form

8

INTRODUCTION

of International Chemical Reference Substances and Melting-point Reference Substances or as International Infrared Reference Spectra. Chapter 4 provides general guidelines for the establishment, maintenance and distribution of chemical reference substances. These include a section on the need for national and/or regional collections of secondary reference materials that have been calibrated against International Chemical Reference Substances. The chapter also contains recommendations for the preparation and use of infrared spectra in pharmaceutical analysis.

The guidelines on reference substances reproduced in Chapter 4 were published in 1982. These guidelines were revised in 1996 in the light of developments in analytical chemistry and international collaboration and to take into account established practice in the use of chemical reference substances for pharmacopoeial purposes. The revised guidelines are not intended to be specific to International Chemical Reference Substances, but are general guidelines for all bodies issuing chemical reference substances, and give advice on the establishment of both primary and secondary reference substances. The revised text was presented in April 1997 to the WHO Expert Committee on Specifications for Pharmaceutical Preparations and will be included as an annex to the Committee's report. Copies can be obtained from the Quality Assurance unit, Division of Drug Management and Policies, WHO, 1211 Geneva 27, Switzerland.

Some 180 International Chemical Reference Substances and some 60 International Infrared Reference Spectra have been produced and are listed in Chapter 4. Information is also provided on how to obtain them. The establishment of International Chemical Reference Substances and International Infrared Reference Spectra is continuing and new lists will be annexed to the report of the thirty-fifth meeting of the \X;'HO Expert Committee on Specifications for Pharmaceutical Preparations.

A general list of reference substances for pharmacopoeial analysis is issued by the Quality Assurance unit, Division of Drug Management and Policies, WHO, 1211 Geneva 27, Switzerland, and is updated yearly. It provides current information on the availability and sources of reference substances. Most of these substances are prepared and issued by regional/national pharmacopoeial commissions or regional/national quality control laboratories on behalf of drug regulatory authorities. Each substance is generally established for a specific analytical purpose as defined by the issuing body. Use for any other purpose becomes the responsibility of the user and a suitable caution is included in the accompanying information sheet.

Basic tests

Simplified or basic tests for pharmaceutical substances have been published in Basic tests for pharmaceutical substalltes in 1986 and Basic tests for pharmaceutical dosage forms in 1991. In 1994, the WHO Expert Committee on Specifications for

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QUALIlY ASSURANCE OF PHARMACEUTICALS

Pharmaceutical Preparations suggested that the scope of the next publication on basic tests should be extended to include additional information on, and references to, other simple test methodologies. These are considered a valuable tool for primary screening and could play an important part in identifying counterfeit and spurious products. The third volume in the series of basic tests, which is in preparation for publication, will therefore refer to collections of simple tests other than those published by WHO. It will also contain details of basic tests for 23 additional pharmaceutical substances, 4 medicinal plant materials and 58 dosage forms. The substances covered by basic tests are mainly those included in WHO's Model list of Essential Drugs.

In its twenty-eighth report, the WHO Expert Committee on Specifications for Pharmaceutical Preparations stated: "Basic tests are not, in any circumstances, intended to replace the requirements of pharmacopoeial monographs. The latter give an assurance of quality whereas basic tests merely confirm the identity".

Basic tests do not need to be carried out by fully qualified pharmacists or chemists, but they should be performed by persons who have some understanding of analytical chemistry, such as required in courses for pharmaceutical assistants.

It is thus acknowledged that basic tests have a clearly defined but limited role. They have gained importance as screening tests to identify falsely labelled, spurious and counterfeit drugs.

Basic tests are developed in close collaboration with experts from all over the world and are tried in various laboratories to ensure their global applicability. Guidance on collaboration within the basic test programme, including a protocol for the development and verification of basic tests, was given in the twenty-ninth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations and is contained in Chapter 5.

Laboratory services

National laboratories for drug quality surveillance and control

An independent drug quality control laboratory is an indispensable element of a national drug quality assurance system, and is particularly important nowadays in the light of infiltration of distribution channels by counterfeit products. Laboratories are still missing in many developing countries. The reason for this is partly that, in the absence of any guidance on the basic requirements for such a laboratory, it was assumed for a long time that the COStS would be so exorbitant that it would be beyond the resources of most developing countries.

In its twenty-ninth report, the WHO Expert Committee on Specifications for Pharmaceutical Preparations stated that every country, regardless of its stage of development, should consider investment in an independent national drug

10

INTRODUCTION

quality control laboratory. The Expert Committee made recommendations directed to the many developing countries that have not yet created such a facility and do not have the resources to maintain a comprehensive system of control.

It should be recognized, in particular, that:

simple procedures, such as tablet disintegration tests, are frequently of critical importance in eliminating seriously substandard preparations;

a small laboratory directed by a competent, discerning individual will provide a persuasive deterrent to negligent or fraudulent manufacturing practices;

- the availability of complex automated equipment accelerates but does not necessarily raise the standard of analytical work. Moreover, such equipment performs reliably only when it is expertly maintained. Its operation may require the use of highly purified and expensive reagents.

Chapter 6 contains proposed models for a first-stage laboratory for drug surveillance, and a medium-size drug control laboratory. It provides advice on capabilities, premises, staff and equipment as well as on the scope of activities, factors influencing size and location of a laboratory, and the implementation of control laboratory projects. Even the smaller of the two model laboratories provides for the full pharmacopoeial analysis of more that 75% of WHO's Model List of Essential Drugs in accordance with the methods provided for in The international pharmacopoeia.

A document containing current prices for laboratory equipment is regularly updated and is available on request from the Quality Assurance unit, Division of Drug Management and Policies, \XiHO, 1211 Geneva 27, Switzerland.

Good practices for quality control laboratories

To complement its advice on setting up governmental drug control laboratories, the WHO Expert Committee on Specifications for Pharmaceutical Preparations included in its thirtieth report guidelines on good practices in governmental drug control laboratories. These, reproduced in Chapter 6, deal with management and operational issues affecting governmental drug control laboratories which analyse products for registration or during post-marketing surveillance. The scope of the guidelines ranges from organizational structure and staffing to advice on routines and management, documentation requirements, and the evaluation of test results. The sections on analytical work are primarily concerned with chemical and physicochemical analyses rather than 'with microbiological, pharmacological or other specialized test methods. The practices outlined are not fully applicable to quality control laboratories in manufacturing establishments, where test procedures and documentation may be different.

The guidelines are intended to be illustrative rather than prescriptive and need to be adapted to differing local circumstances such as the size of the laboratory. Alternative approaches to management are acceptable, provided that

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QUALl1Y ASSURANCE OF PHARMACEUTICALS

reliability of operations remains assured. In small laboratories many of the responsibilities lie with one qualified analyst, but the principles of management and operation are the same.

Sampling procedure for industrially manufactured pharmaceuticals Since analytical control procedures are often performed on only a small portion of the material under consideration, it is vital to ensure that the sample tested is reasonably representative of the whole batch or consignment. Many of the operations described in the guidelines on good laboratory practices in governmental drug control laboratories require the use of sound sampling procedures. It is for this reason that, in its thirty-first report, the WHO Expert Committee on Specifications for Pharmaceutical Preparations provided guidelines for sampling procedures for industrially manufactured pharmaceuticals. These are reproduced in Chapter 6.

No single sampling plan is applicable to all situations. Different considerations and methodologies apply to in-process control, to batch release by manufacturers, to routine control of consignments within the distribution chain, and to spot-sampling carried out by purchasers or government inspectors.

The guidelines on sampling procedures are intended primarily for use by national drug regulatory authorities and governmental procurement agencies, but the general principles and much of the advice are also applicable to manufacturers and wholesalers.

International trade in pharmaceuticals

WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce

The WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce was developed in response to concern raised in the World Health Assembly about import of substandard products into developing countries in the 1960s. The Certification Scheme is based on the concept of sharing of responsibilities between three partners. The pharmaceutical manufacturer in the exporting country has to produce in accordance with good manufacturing practices, the drug regulatory authority of the exporting country has to inspect the manufacturing plant to confirm that it complies with good manufacturing practices, and the drug regulatory authority of the importing country has to request from its counterpart in the exporting country information on the regulatory status of the product it intends to import and confirmation that the manufacturer complies with standards of good manufacturing practices. In normal circumstances the certified information issued by the drug regulatory authority in the exporting country, as provided for under the WHO Certification Scheme, reaches the drug regulatory authority

12

INTRODUCTION

of the importing country via the manufacturer, exporter or importer and is used as the basis for drug registration in the importing country. When there are problems or queries the Certification Scheme provides for a channel for direct communication between the regulatory authorities in the importing and exporting countries.

Some countries do not yet have effectively functioning drug registration systems. In such situations the procurement agency has to operate an unofficial de facto registration system in order to assure the quality of products it intends to purchase and makes use of the provisions of the Certification Scheme before importing a new pharmaceutical formulation. Provision of information as provided for under the Certification Scheme should be a precondition when tenders are submitted.

Where a legally based national drug registration system exists, all procurement agencies must comply with the law and limit their procurement to duly registered products. In the case of favourable conditions for a product not yet registered in the country, the procurement agency should submit all necessary information to the registration body. This may speed up the registration process for public sector procurement agencies, provided all elements necessary to guarantee quality have been properly and positively evaluated.

The Certification Scheme was first recommended by the World Health Assembly in 1969 in resolution WHA22.50. A revised version was recommended in 1975 in resolution WHA28.65. The Certification Scheme was evaluated in the 1980s and a further revised and expanded version was recommended to WHO Member States by the World Health Assembly in resolution WHA41.18 of 1988. The Scheme now includes provision of approved product information, certification of veterinary products when administered to foodproducing animals, and certification of starting materials in so far as they are subject to regulatory control in the country of export. Certification of starting materials, and particularly of active pharmaceutical ingredients, has become of particular relevance as many developing countries now produce the dosage forms themselves and are therefore more concerned to import raw materials of good quality. Parallel to this, there has been a shift in the production of active drug substances to developing countries, especially the more industrially advanced ones.

A country wishing to participate in the Certification Scheme must notify WHO of its intention to do so. The country must define both the extent to which it wishes to participate and the authority competent to issue and/or receive information as provided for in the Scheme. As of 1 January 1997, 140 of the 190 WHO Member States had informed the Organization officially of their intention to participate.

In order to facilitate the use of the Certification Scheme, the World Health Assembly endorsed provisional guidelines in 1992 in resolution \'<7HA45.29. These guidelines, which deal with certification of pharmaceutical products, were refined following field trials in a number of \1(!HO Member States and

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QUALITY ASSURANCE OF PHARMACEUTICALS

discussion during the sixth and seventh biennial International Conferences of Drug Regulatory Authorities. The revised guidelines were adopted by the WHO Expert Committee on Specifications for Pharmaceutical Preparations and published in its thirty-fourth report. Separate guidelines on certification of active pharmaceutical ingredients are under development.

Chapter 7 contains the text of the revised guidelines for implementing the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce. It also reproduces Resolution WHA50.3, adopted by the World Health Assembly in May 1997, which endorses the guidelines and urges Member States to implement them. A regularly updated list of Member States participating in the Scheme can be obtained from Regulatory Support, Division of Drug Management and Policies, WHO, 1211 Geneva 27, Switzerland, together with the addresses of the competent authorities of participating countries and details of any significant reservations expressed by countries regarding their participation in the Scheme.

Import procedures

Chapter 7 also contains guidelines on import procedures for pharmaceutical products, which take into account the needs of, and resources available in, developing countries. They are intended to provide a framework for the effective control of pharmaceutical products at specified ports of entry and a basis for collaboration between the various interested parties.

Arrangements for independent analysis of drug samples

In the case of disputes arising from an unanticipated adverse reaction to a drug or from physical signs of deterioration in the product, a country may need to turn to a foreign laboratory for analytical confirmation of a presumed defect. The solution should be first sought at the regional level, through the respective WHO Regional Office. Regional or subregional testing laboratories have been or are being established in the WHO Regions of Africa, the Americas and the Eastern Mediterranean. Exceptionally, an impartial retesting in a national laboratory of a European country may be arranged through WHO in Geneva. It should be noted, however, that in this case analyses will be expensive (over US$ 300 for a full pharmacopoeial testing) and may take one or two months (or more), depending on the workload of the laboratory approached. It is hoped that these arrangements can be extended to all products covered by the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce and that, when such analyses have undisputed implications for public health, directors of the testing laboratories will have discretionary authority to undertake them at reduced cost or even free of charge.

14

INTRODUCTION

Counterfeit products

Counterfeit pharmaceutical products present a new and serious threat to health care delivery. The alert was first given during the Conference of Experts on the Rational Use of Drugs, held in Nairobi in November 1985. In 1988, the Forty-first World Health Assembly adopted a resolution (WHA41.16) requesting governments and pharmaceutical manufacturers "to cooperate in the detection and prevention of the increasing incidence of the export or smuggling of falsely labelled, spurious, counterfeited or substandard pharmaceutical preparations" and requesting the Director-General "to initiate programmes for the prevention and detection of the export, import and smuggling of falsely labelled, spurious, counterfeited or substandard pharmaceutical preparations, and to cooperate with the Secretary-General of the United Nations in cases when the provisions of the international drug treaties are violated". A joint WHO/International Federation of Pharmaceutical Manufacturers Associations workshop on counterfeit drugs was organized in Geneva in April 1992. The observations and recommendations published in the report of the workshop are contained in Chapter 8. Apart from the need for coordination and exchange of information between all interested parties, the recommendations stress the need for overall regulatory control through the setting up and strengthening of national drug regulatory and control authorities.

In 1995 a project was started to develop means to combat counterfeit drugs.

Guidelines on drug inspection and the analysis of suspect samples have been prepared and a model training course on the application of these guidelines has been developed. A global workshop will be held at the end of 1997 to consider progress made and plan further activities.

Training

The establishment and development of pharmaceutical manufacturing facilities and national quality control laboratories in developing countries call for relevant training programmes for technical personnel. In particular, there is an evident need for group training of recent science and pharmacy graduates and for onsite individual training at more advanced level. The following advice on group training is taken from the twenty-ninth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations:

Ideally, all graduate personnel should undergo a six-month period of preparatory training in practical and theoretical aspects of drug analysis. Emphasis should be on the practical approach, although some provisions should be made for discussion of the theoretical basis of the work, and the experimental programme should be developed having regard to:

the structure and organization of the model laboratories [described in Chapter 6];

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QUALITY ASSURANCE OF PHARMACEUTICALS

- common practical problems encountered in the analysis of pharmaceutical products;

- the importance of selecting and validating appropriate analytical methods and of evaluating all results.

Following an introductory course lasting about 1 week, in which the general principles of drug quality control and analysis are presented, including an appreciation of their relevance to procurement and distribution, separate courses should be offered in chemical, microbiological, and biological control. It is important, however, that a trainee in one of these disciplines should have a general appreciation of the other aspects of control. A clear perception must be gained of all the duties and responsibilities of an analyst and of the need to institute good laboratory practice in the interests of both efficiency and safety.

Basic training in microbiological control should lay particular emphasis upon sterility testing, microbiological spoilage testing, and potency tests for antibiotics. Guidance is also required on the preparation and monitoring of culture media from locally available materials.

An introduction to biological control should be directed to pyrogen testing and other specific safety tests. Since the testing of biological products, including vaccines, blood products, and hormones, is usually undertaken in specialized institutions, this work falls outside the scope of a general introductory course.

A detailed model syllabus for such training programmes, which could be organized in many national quality control laboratories, is contained in Chapter 9. It covers both the practical and the theoretical aspects of drug analysis for regulatory purposes.

A primary objective is to teach students how to work efficiently and how to determine priorities for analyses so that limited resources can be used to best effect. This need is obviously most acute where facilities are most limited.

The syllabus provides for a general introduction to the objectives and principles of drug control and laboratory management, followed by separate parallel courses in chemical, microbiological and biological techniques of analysis. A sixmonth course is proposed for both chemical and microbiological analysis, and a course of three to four months for biological (pharmacological) techniques.

The sequence in which the subjects are listed is that in which the various analytical techniques are used in the control of specific categories of pharmaceutical raw materials and dosage forms, and it differs in this respect from the usual presentation of analytical methods.

Obviously trainees working in a first-stage laboratory, such as that described in Chapter 6, will not need practical experience in all the methods of analysis covered by the syllabus. If the training is to be used to best advantage, it is therefore important for the course organizer to obtain advance information on the facilities available to participants in their own countries.

16

INTRODUCTION

A simpler syllabus should also be drawn up for the training of laboratory technicians and courses should be organized for laboratory managers.

On-site training of persons already employed in national quality control laboratories is available through the scheme operated under the aegis of the International Federation of Pharmaceutical Manufacturers Associations, as described in Chapter 9.

Conclusion

Recommendations and guidelines provide an essential foundation for the development and maintenance of quality assurance of pharmaceutical products. But it is personnel who are crucial to quality assurance at all levels of pharmaceutical manufacture, regulation and distribution.

Pharmacists have an important contribution to make in public health and particularly in the field of medicines. WHO meetings on the role of the pharmacist in the health care system were held in New Delhi in 1988 and in Tokyo in 1993, and the World Health Assembly, in resolution WHA47.12, has stressed the key role pharmacists can play in the rational use and quality assurance of medicines.

By virtue of their training, pharmacists can playa part in drug regulation and control, particularly in the evaluation of pharmaceutical formulations at the time of product registration, and in the licensing and inspection of pharmaceutical manufacturing plants and distribution channels. In addition to their work in central medical stores, hospitals, pharmacies and other drug outlets, trained pharmacists may also contribute to quality assurance by assisting in pharmaceutical manufacture, in drug procurement and in distribution.

While quality assurance is founded on regulations and standards, it is the people who enforce the regulations or work to comply with the standards who make the difference between quality assurance and lack of it. The assurance of quality, safety and efficacy of medicines is a continuing concern of \Xi'Ho. This compilation of material is intended to assist all involved in the manufacture, regulation and distribution of pharmaceuticals to achieve these aims more effectively.

17

1.

National drug regulation

Guiding principles for small national drug regulatory
authorities 1,2·
1. General considerations 19
1.1 The scope of drug control 19
1.2 Basic responsibilities 19
1.3 Licensing functions 19
1.4 Product licences 20
1.5 Manufacturers' and distributors' licences 21
1.6 New drug assessments 21
1.7 Authorization of clinical trials 21
1.8 Terms of reference of the regulatory authority 22
1.9 Powers of enforcement 22
1.10 Technical competence 23
1.11 Advisory bodies 23
1.12 Independence of operation 23
2. Administrative aspects of the licensing process 24
2.1 Provisional registration of existing medicinal products 24
2.2 Screening of provisionally registered products 24
2.3 New product licences 26
2.4 Renewal and variation of licences 26
3. Technical aspects of the licensing process 27
3.1 General considerations 27
3.2 Products containing long-established chemical entities 27
3.3 Products containing new chemical entities 28
3.4 Herbal products 29 1 WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-first Report. Geneva, World Health Organization, 1990 (WHO Technical Report Series, No. 790).

2 Based on the report of a meeting convened by WHO in November 1987. with the following participants: Mr J. Y. Binka, Medicines Board, Medicsl and Health Department, Banjul, The Gambia; Dr J. L. Carrois, Cabinet International Carrois, Paris, France; Dr H. EI-Sheikh, Ministry of Health, Khartoum, Sudan; Dr G. Lewandowski, eiba-Geigy Ltd, Basle, Switzerland; Mr L. Prescod, Barbados Drug Service, St Michael, Barbados; Professor M. D. Rawlins. Department of Pharmacological Sciences. University of Newcastle-upon- Tyne, Newcastle-upon-Tyne. England; Mr J. Ruberantwari. Ministry of Health, Entebbe. Uganda; Dr P. N. Suwal. Ministry of Forest and Soil Conservation, Kathmandu, Nepal; Mr Tan Kiok K'ng, Pharmaceuticsl Department, Ministry of Health, Singapore; Mrs S. S. Tessema, Office of the Chief Pharmacist, Nairobi, Kenya.

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NATIONAL DRUG REGULATION

3.5 Combinations of potent, therapeutically active substances 29

3.6 Generic products 29

1. General considerations

Small countries which have yet to introduce comprehensive legal provisions for drug regulation can draw from a diversity of national systems in determining their own requirements. None the less, problems in establishing drug control in developing countries have too often resulted from the adaptation of provisions successful elsewhere but of a complexity that precludes their effective implementation in the country of adoption. It is of paramount importance that legislation and administrative practices are attuned to available resources and that every opportunity is taken to obtain and use information provided by regulatory authorities in other countries on pharmaceutical products and-substances moving in international commerce.

Channels of communication between national regulatory authorities are improving, as is evident from the information contained in WHO's monthly Pharmaceuticals newsletter, the quarterly journal WHO drug information, and the United Nations Consolidated List 0/ Products Whose Consumption and/or Sale have been Banned, Withdrawn, SeverelY Restricted or Not Approved by Govemments. Moreover, many difficulties inherent in storing, retrieving and analysing data that subserve the many facets of the regulatory process can now be overcome by the use of microcomputers and commercial software packages.

1 .1 The scope of drug control

To be effective, a small drug regulatory authority needs to operate within the context of a defined national drugs policy and to interrelate with other interested bodies, including organizations responsible for drug procurement in the public sector and the national formulary committee, where such exists.

1 .2 Basic responsibilities

The responsibilities of the regulatory authority are to ensure that all products subject to its control conform to acceptable standards of quality, safety and efficacy; and that all premises and practices employed to manufacture, store and distribute these products comply with requirements to ensure the continued conformity of the products to these standards until such time as they are delivered to the end-user.

1 .3 Licensing functions

These objectives can be accomplished effectively only if a mandatory system of licensing products, manufacturers, importing agents, and distributors is in place.

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QUALITY ASSURANCE OF PHARMACEUTICALS

A small authority has strictly limited capacity to undertake these tasks. For the assurances it requires in relation to imported pharmaceutical products and drug substances, it is vitally dependent on authoritative, reliable, and independent information generated in the exporting country. This information is most effectively obtained through the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce.

Before a formal licensing system can become operative, it is necessary:

(a) to adopt a precise definition of a drug product and of the various categories of licence-holders;

(b) to determine the content and format of licences, both for products and for licence-holders;

(c) to detail the criteria on which licence applications will be assessed; and

(d) to provide guidance to interested parties on the content and format of licence applications, and on the circumstances in which an application for renewal, extension or variation of a licence will be required.

The definition of a drug product is commonly contingent upon the claims that are made for it. Ideally, controls need to be applied to any product that is offered for sale for administration to human beings for treating, preventing and diagnosing disease, for anaesthesia, for contraception, and for otherwise altering normal physiological functions,' In practice, exemptions may need to be granted to various specific categories of products in order to address priorities effectively. It might be decided as an interim measure, for example, to require licences only for products listed in a national formulary. Ultimately, however, control needs to be extended not only to all products moving in the major distribution channels, but to those formulated in pharmacies and hospital dispensaries, to herbal preparations, and to other traditional medicines entering into local commerce.

Analogous priorities may also need to be accorded to the registration of licence-holders, although the ultimate objective should be to embrace all manufacturers, importing agents, wholesalers involved in repackaging, pharmacies, and hospital dispensaries in a system that imposes upon them relevant statutory obligations.

1 .4 Product licences

The issuance of product licences is pivotal to any system of drug control. The licence is a legal document that establishes the detailed composition and formulation of the product, the pharmacopoeial or other officially recognized specifications of its ingredients, its clinical interchangeability (in the case of

1 Veterinary products administered to food-producing animals may also fall into this category: see the revised WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce (WHO Technical Report Series, No. 790, 1990, Annex 5).

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NATIONAL DRUG REGULATION

multisource products), and its packaging, shelf-life and labelling. Of itself, this goes a long way towards establishing the assurances of quality, efficacy, and safety to which the system is directed. However, without a viable pharmaceutical inspectorate or access to an independent quality-control laboratory operating to standards that will ensure its credibility in the event of dispute, licensing provisions cannot be effectively enforced.

1.5 Manufacturers' and distributors' licences

The pharmaceutical inspectorate is responsible for ensuring that pharmaceutical products comply with conditions set out in the licence up to the time that they are delivered to the end-user. Its functions are:

(a) to establish, through periodic formal inspections and spot-checks, that all categories of licence-holder are operating in accordance with their licensed activities, prevailing standards of good manufacturing practice, and other prescribed regulations;

(b) to maintain oversight of distribution channels, either by inspection and monitoring or by arranging for pharmacopoeial analysis of selected samples, with a view to ensuring that products are not subject to unacceptable degradation during transit and storage at the periphery.

1.6 New drug assessments

Within highly evolved national drug regulatory authorities much effort is directed to establishing the efficacy and safety of new drug entities through pharmaceutical, biological, and clinical assessment and through subsequent surveillance of their performance in routine use after marketing. Premarketing assessment is dependent upon detailed multidisciplinary technical review, and postmarketing surveillance requires a highly developed health care infrastructure. Only in exceptional circumstances should a small regulatory authority contemplate allocation of scarce resources to these ends. Reliance must be placed primarily on information notified by other countries through the network of national information officers established by \,{THO.

1 .7 Authorization of clinical trials

A small authority may occasionally need to consider an application to conduct a clinical trial of an unregistered drug in the treatment of a condition that has a high local prevalence. To provide for this contingency, the registration system should include provision for the importation of the necessary materials, subject to appropriate controls. Such trials should only take place after formal clearance has been obtained from the competent registration authority and after assurances have been obtained that they will be conducted in conformity with the

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QUAUTY ASSURANCE OF PHARMACEUTICALS

principles contained in the World Medical Association's Declaration of Helsinki and the Proposed International Guidelines for Biomedical Research Involving Human Suo/ects issued by the Council for International Organizations of Medical Sciences.' WHO stands ready to offer independent technical advice to national authorities in these circumstances.

1.8 Terms of reference of the regulatory authority

The formal terms of reference of a national drug regulatory authority are determined by statute and regulation. Legislation relating to pharmaceutical products has developed piecemeal in many countries, and there are obvious advantages in bringing matters concerned with their regulation under one law. For example, it is important to correlate laws relating to the control of narcotic and psychotropic substances with requirements for product registration. If comprehensive overhaul of the legal system is impracticable, control within the existing framework through regulations specifically related to the registration of pharmaceutical products offers advantages of economy and time-saving. Whichever option is chosen, regulatory authorities require the flexibility to respond to changing circumstances imposed by the evolution of pharmaceutical science.

In general terms, the authority should be vested with legal powers to:

(a) issue, vary and revoke licences for pharmaceutical products on grounds of quality, safety, and efficacy;

(b) secure the subsequent safe and effective use of each product by controlling, through the terms of the licence, the content of all labelling (including package inserts, associated prescribing information and advertising) and the channels through which the product may legitimately be supplied; and

(c) inspect and license all manufacturing premises, importing agents, wholesalers and distributors, hospital dispensaries, independent pharmacies, and other retail outlets to ensure that they comply with prevailing regulations and guidelines.

1 .9 Powers of enforcement

In order to implement these responsibilities the authority must command powers of enforcement backed by legal provision for penal sanction against offenders.

In establishing administrative mechanisms for decision-making, the regulatory authority should not lose necessary flexibility. In particular, it should make provision for:

1 Council for International Organizations of Medical Sciences. Proposed international guidelines for biomedical research involving human subjects. Geneva, 1982 (also contains the Declaration of Helsinki as revised by the 29th World Medical Assembly, Tokyo, 1975).

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NATIONAL DRUG REGULATION

(a) implementing decisions regarded as urgent in the interest of public safety; and

(b) formal consultation (usually through representative bodies) with pharmaceutical companies and other interested parties, including pharmacists, doctors, nurses, and patients.

1.10 Technical competence

A small licensing authority will rarely, if ever, undertake comprehensive independent assessments of the safety and efficacy of individual products. The administrative and technical responsibilities that fall within its ambit are essentially of a pharmaceutical nature and they are directed primarily to quality assurance. The professional staff must include members with a thorough understanding and practical experience of the different facets of this work.

The responsible officer is accountable for the professional validation and assessment of licence applications and for the administrative aspects of licensing and, as such, should be involved in determining priorities and developing a timetable for implementation of controls. These activities require administrative and clerical support and premises sufficient to handle the large volume of documentation involved with appropriate confidentiality. Efficiency of operation is enhanced when the required information can be retrieved rapidly from a computerized data base.

1 .11 Advisory bodies

The responsible officer must also have access to a standing advisory committee or board of independent experts (including academic and practising health care professionals) for advice on technical issues. Consideration should also be given to the need for a multidisciplinary commission to advise on matters of general policy and administration and to ensure effective relations with bodies responsible for drug procurement in the public sector and with the national formulary committee.

1 .12 Independence of operation

To retain public confidence and respect, the authority must be seen to undertake its tasks in an independent, authoritative, and impartial manner. It should be concerned exclusively with the determination of standards and the implementation of controls. Although it will need to work closely with the authority responsible for drug procurement within the public sector, it should not itself be responsible for procurement and it should remain independent and autonomous in its operational activities and decisions.

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QUALITY ASSURANCE OF PHARMACEUTICALS

2. Administrative aspects of the licensing process 2.1 Provisional registration of existing medicinal products

Before any system of control can become effective, it is necessary to identify and catalogue all products already sold or otherwise supplied on the domestic market, in both the public and the private sectors, that qualify for control. To this end, all manufacturers and importing agencies must be given reasonable notice through official gazettes, the trade press and other media of their obligation to notify the authority by a specific date of all medicinal products that they currently distribute within the jurisdiction of the authority and that they intend to continue to supply after a duly appointed day, on which licensing requirements enter into operation. After the appointed day no medicinal product may lawfully be distributed or supplied unless its existence has been notified to the authority, and no new product may be introduced until a request for a product licence has been granted by the authority.

Effective administration of the provisional registration procedure is dependent upon:

(a) prior identification of all interested manufacturers and importers;

(b) a precise definition of a notifiable medicinal product based primarily on the

labelled claims and the indications for use;

(c) the issuance of guidelines on the procedure to be followed.

Each notified product must be identified by name (either brand or generic), the names and full addresses of the manufacturer and importing agent, a description of the dosage form, its composition-including active and inactive ingredients (using international nonproprietary names where appropriate)-the therapeutic class, the indications, a copy of all labelling, including any package insert, and a copy of any relevant certificates and warranties relating to the product or its components.

2.2 Screening of provisionally registered products

A rapid screening of notified products should be undertaken at the earliest opportunity with a view to securing the withdrawal of any products which, simply on the basis of a review of their ingredients and indications, are judged not to meet admissible standards of safety. This may be achieved by the withdrawal of permission to trade in specific notified products or the issuance of regulations imposing specified restrictions on precisely defined groups of products. After this preliminary review, a set of longer-term priorities needs to be set for the definitive assessment-of provisionally registered products. Consideration needs to be given to the resources required, both in manpower and information, if the review is to be adapted to a proposed time-schedule. Standards must be maintained and calls to accelerate the speed of implementation must be recognized as having resource implications.

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NATIONAL DRUG REGULATION

In planning priorities, consideration must be given to:

(a) the number of provisionally registered products to be processed; (b) the number of staff and/or consultants to be allocated to the task;

(c) the amount of relevant information available from other national authorities;

(d) the extent to which products can be reviewed in groups rather than individually;

(e) the extent to which a laissez-faire disposition can be adopted towards such products as herbal remedies and tonics that are without potent pharmacological activity and carry imprecise claims, but which satisfy an acknowledged public demand.

Considerations of safety require that particular attention be accorded to:

(a) products that either have been withdrawn or are the subject of restrictive regulatory action in other countries as notified in the United Nations Consolidated List of Products Whose Consumption and/or Sale have been Banned, Withdrawn, SeverelY Restricted or Not Approved l?J Governments, and in WHO's Pharmaceuticals newsletter to national drug regulatory authorities;

(b) products representing examples of irrational poly-pharmacy; and

(c) products for which exaggerated or spurious promotional claims are made in the labelling.

Subsequently, the review needs to be extended in a phased manner, gtvmg priority to drugs that are widely used, listed in nationally recognized formularies, or of a particularly important therapeutic class. An adequate documentation and information retrieval system is vital for this purpose. Some traditional products and particularly herbal preparations, because of their complexity, do not lend themselves to licensing on a product-specific basis. Control is then more readily applied through consideration of individual ingredients. Several regulatory authorities have devised administrative approaches to their licensing which are based on a three-category system of classification:

(a) all herbal ingredients, save for those items classified under (b) below, which may be dispensed for a specific, named patient by practitioners of herbal medicine who do not possess a formal medical qualification;

(b) ingredients such as digitalis leaf and atropine which, because of their pharmacological potency or their toxicity, need to be subjected to prescription control; and

(c) ingredients which, as a result of widespread, long-established and apparently innocuous traditional usage, are included, often within defined permissible limits, in labelled products for which limited claims are made and which are sold directly to the public from retail outlets other than pharmacies.

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QUALITY ASSURANCE OF PHARMACEUTICALS

2.3 New product licences

No product that is first proposed for authorization after the appointed day (see section 2.1 above) should be accorded a product licence without first having been submitted to technical assessment. Such products may not necessarily contain a new active ingredient: they may constitute a new combination of two or more established substances or they may merely represent a new dosage strength, a new dosage form, or a generic version of a pre-existing, nominally equivalent licensed product. In no case should the requirement for assessment be waived. A rationale for the formulation of every new product should invariably be provided, but the extent of the required review will vary considerably according to circumstances. The normal procedure for the authorization of a product is accomplished in three stages:

(a) the application is received from the manufacturer and is checked and assessed for completeness by the authority'S technical staff;

(b) it is submitted to the competent standing committee for advice on whether or not to authorize marketing of the product;

(c) the formal administrative action to grant or refuse a licence and to settle its

content is then taken by the authority.

The assessment of the product must be based primarily on its safety, quality, and efficacy, with regard to its intended use. In accordance with locally determined requirements, the assessment might also impinge upon comparative efficacy and/or safety and embrace economic factors, including price, cost-effectiveness, and other considerations determined by national policy.

For administrative convenience, the product licence should be as simple as possible. It should always describe the product by name, manufacturer and importing agent, identify the ingredients (preferably by their international nonproprietary names), and provide full details of the dosage form. It should also contain a serial number, the date of issuance of the licence, its date of expiry, and any special conditions to be observed. It is advisable to cite certain additional items in the licence for easy reference, such as shelf-life and sales category; but in other particulars it should refer to the information submitted by the licence-holder in the dated product application.

2.4 Renewal and variation of licences

Licences should never be regarded as immutable. Ideally, they should be reviewed at, say, five-year intervals. However, many national authorities do not have the capacity to undertake this task, particularly for as long as they remain engaged in the initial review of provisionally licensed products. In these circumstances many products fall to review on an ad hoc basis. Sometimes this is inspired by recently generated concern regarding safety. More frequently, a product attracts attention because the licence-holder has altered the formulation

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NATIONAL DRUG REGULATION

in some way-by changing, for instance, the source of the starting materials, the nature of the excipients, the route of synthesis of an active ingredient, or the claims made in labelling and promotional material. The precise circumstances in which licence-holders are required to apply for variations in a product licence differ from country to country. These circumstances should be clearly defined in all product licence documents, including provisional licences.

Licence-holders should be required, in all circumstances, to inform regulatory authorities immediately of unanticipated adverse effects that could possibly be associated with a licensed product and that might call for restrictive licensing action or the withdrawal of the product licence.

3. Technical aspects of the licensing process 3.1 General considerations

Although countries vary in their resources and priorities, advantage accrues from harmonizing documentary requirements to the fullest possible extent, since this simplifies registration procedures and reduces costs.

The most important starting-point for imported products is the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce.' This gives basic information on composition, an assurance that the product is manufactured in accordance with good manufacturing practices in premises subject to inspection, and information on the regulatory status of the product in the country of export. A certificate, issued in compliance with the model format recommended by WHO, should be required whenever application is made to license an imported product.

3.2 Products containing long-established chemical entities

For products indicated for standard uses and that contain established ingredients, the following elements of information usually suffice as the basis both for a product licence and for a computerized data retrieval system:

- name of the product

- active ingredient(s) [by international nonproprietary name(s)]

- type of formulation

- therapeutic category

- quantitative formula (including excipients)

- quality control specifications

- indications, dosage, method of use

contraindications, warnings, precautions - bioavailability data (ill IJitro/illl'h'o)

1 WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-first Report. Geneva, World Health Organization, 1990 (WHO Technical Report Series, No. 790), Annex 5,

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QUALITY ASSURANCE OF PHARMACEUTICALS

- stability data, shelf-life

- container, packaging, labelling

- intended method of distribution:

controlled drug; prescription item pharmacy sale; general sale

- manufacturer

- importer/distributor

- regulatory status in the exporting country.

If the dosage form is a novel one, such as a delayed-release tablet, or if a new route of administration is proposed, supporting data from clinical studies will be required.

3.3 Products containing new chemical entities

Considerably more extensive information is required to support a marketing application for a new drug substance in order to provide assurance of efficacy and safety as well as of quality. In particular, detailed accounts are required of:

(a) chemistry (structure, physical properties, synthesis, specification, impurities,

stability characteristics);

(b) pharmacological properties (in animals, in humans);

(c) toxicological data (short and long-term studies in animals, including car-

cinogenicity studies);

(d) reproductive and teratological studies in animals; (e) clinical studies.

Small regulatory authorities need to adopt caution in licensing newly developed products because they are likely not to possess the capacity to undertake the multidisciplinary assessment applied to them within large, highly evolved authorities, or to monitor their performance in use through postmarketing surveillance.

In general, a small authority is best advised to wait until this information has been generated and assessed elsewhere before authorizing such a product for use.

In the case of products intended exclusively for tropical parasitic diseases, much of this evidence may need to be built up in countries with limited resources. The expertise of the World Health Organization is at hand to offer advice in these circumstances. Once a decision is taken to authorize such a product for general use, the regulatory authority and the manufacturer share a responsibility to ensure that a monitoring mechanism is put in place to detect unanticipated reactions. A mutually acceptable plan for postmarketing surveillance should be settled in advance and included in the product licence as a condition of approval.

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3.4 Herbal products

The use of herbal and other naturally occurring substances is part of the fabric of traditional medicine. Because of the complex, and sometimes imprecise nature of the ingredients they contain and the paucity of scientific information on their properties, products containing these substances, often in combination, can rarely be reviewed on a rigorously scientific basis. Where time-honoured practices do no apparent harm, there is no urgency for regulatory intervention other than to set up a system for provisional registration.

However, prolonged and apparently uneventful use of a substance offers insecure testimony of its safety. In a few instances, recently commissioned investigations of the potential toxicity of naturally occurring substances widely used as ingredients in these preparations have revealed a previously unsuspected potential for systemic toxicity, carcinogenicity and teratogenicity. Small regulatory authorities need -to be quickly and reliably informed of these findings. They should also have the authority to respond promptly to such alerts, either by withdrawing or varying the licences of registered products containing the suspect substance, or by rescheduling the substance in order, for instance, to disallow its use by practitioners who are not medically qualified.

All regulatory authorities should also be alert to the practice of incorporating potent pharmacologically active compounds, such as steroids, into herbal preparations. When this is done clandestinely, it is a manifestly dangerous practice which demands immediate withdrawal of the products and a review of the manufacturer's licence.

3.5 Combinations of potent, therapeutically active substances

The justifications for formulating fixed combinations of potent, therapeutically active substances are few. All biologically active substances have a potential to induce harm as well as therapeutic benefit. The administration of two or more such substances, rather than one, increases the potential for adverse effects. Fixed-ratio combination products are consequently acceptable only when the dosage of each ingredient meets the requirements of a defined population group and when use of the combination provides a clear advantage over separate administration of the individual active compounds, in either therapeutic effect or compliance, or when it enhances safety-as in the case of multiple chemotherapy intended to reduce the emergence of resistant pathogens.

3.6 Generic products

In many countries, for reasons of economy, drugs destined for use in the public sector are purchased on open tender. This favours the use of generic products, and the practice in some countries is for tenders to be issued, bids examined, and

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QUALITY ASSURANCE OF PHARMACEUTICALS

contracts offered by the procurement authority without reference to the drug regulatory authority.

The licensing of generic products poses a challenge to all regulatory authorities, particularly when the product to be supplied is not registered in the country of origin. The need for expert assessment is accentuated because not all drug-exporting countries submit drugs intended exclusively for export to the same rigorous controls as drugs intended for the domestic market. Nominally equivalent generic products should contain the same amount of the same therapeutically active ingredients in the same dosage form and they should meet required pharmacopoeial standards. However, they are not necessarily identical and in some instances their clinical interchangeability may be in question. Differences in colour, shape and flavour, while obvious and sometimes disconcerting to the patient, are often inconsequential to the performance of the product, but differences in sensitizing potential due to the use of different excipients and differences in stability and bioavailability have obvious clinical implications. Regulatory authorities consequently need to consider not only the quality, efficacy and safety of such products, but also their interchangeability one with another and with the original innovative product. This concept of interchangeability applies not only to the dosage form but also to the instructions for use and even to the packaging specifications, when these are critical to stability and shelf-life.

Some highly evolved authorities require that every generic product must satisfy three sets of criteria of therapeutic equivalence. These relate to:

(a) manufacturing and quality control;

(b) product characteristics and labelling; and (c) bioequivalence.

Others adopt a more pragmatic approach to the need for experimental demonstration of bioequivalence. Study of the bioavailability of a dosage form is a costly undertaking that is demanding of human resources. It is clearly not a cost-effective requirement for highly water-soluble substances, when neither precise dosage nor consistency of response is a critical consideration. In developing countries the in vivo bioavailability testing of all domestically manufactured products would be impracticably costly. The regulatory authority should be in a position to help local manufacturers by advising them on drugs that pose potential bioavailability problems.

In the case of imported products, assurance should be obtained through the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce that the product has been produced in accordance with WHO's standards of good manufacturing practices and that, in the light of a full assessment, it has been authorized to be placed on the market in the country of origin.

30

2.

Product assessment and registration

Guidelines for the assessment of herbal medicines 1,2 Introduction

For the purpose of these guidelines, herbal medicines are defined as follows:

Finished, labelled medicinal products that contain as active ingredients aerial or underground parts of plants, or other plant material, or combinations thereof, whether in the crude state or as plant preparations. Plant material includes juices, gums, fatty oils, essential oils, and any other substances of this nature. Herbal medicines may contain excipients in addition to the active ingredients. Medicines containing plant material combined with chemically defined active substances, including chemically defined, isolated constituents of plants, are not considered to be herbal medicines.

Exceptionally, in some countries herbal medicines may also contain, by tradition, natural organic or inorganic active ingredients which are not of plant origin.

The past decade has seen a significant increase in the use of herbal medicines. As a result of WHO's promotion of traditional medicine, countries have been seeking the assistance of the Organization in identifying safe and effective herbal medicines for use in national health care systems.

In 1991, the Director-General of \X'HO, in a report to the Forty-fourth World Health Assembly, emphasized the great importance of medicinal plants to the health of individuals and communities. Earlier, in 1978, the Thirty-first World Health Assembly had adopted a resolution (\X!HA31.33) that called on the Director-General to compile and periodically update a therapeutic classification of medicinal plants, related to the therapeutic classification of all drugs; subsequently resolution WHA40.33, adopted in 1987, urged Member States to

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

2 Adapted from WHO document WHOITRM/91.4. These guidelines were finalized at a WHO consultation in Munich, Germany, 19-21 June 1991. The request for WHO to prepare the guidelines came from the Fifth International Conference of Drug Regulatory Authorities (ICDRA) held in Paris in 1989. The finalized guidelines were presented to the Sixth ICDRA in Ottawa in 1991.

31

QUALIfY ASSURANCE OF PHARMACEUTICALS

ensure quality control of drugs derived from traditional plant remedies by using modern techniques and applying suitable standards and good manufacturing practices; and resolution WHA42.43, of 1989, urged Member States to introduce measures for the regulation and control of medicinal plant products and for the establishment and maintenance of suitable standards. Moreover, the International Conference on Primary Health Care, held in Alma-Ata, USSR, in 1978, recommended, inter alia, the accommodation of proven traditional remedies in national drug policies and regulatory measures.

In developed countries, a resurgence of interest in herbal medicines has resulted from the preference of many consumers for products of natural origin. In addition, manufactured herbal medicines often follow in the wake of migrants from countries where traditional medicines play an important role.

In both developed and developing countries, consumers and health care providers need to be supplied with up-to-date and authoritative information on the beneficial properties, and possible harmful effects, of all herbal medicines.

The Fourth International Conference of Drug Regulatory Authorities, held in Tokyo in 1986, organized a workshop on the regulation of herbal medicines moving in international commerce. Another workshop on the same subject was held as part of the Fifth International Conference of Drug Regulatory Authorities, held in Paris in 1989. Both workshops confined their considerations to the commercial exploitation of traditional medicines through over-the-counter labelled products. The Paris meeting concluded that the World Health Organization should consider preparing model guidelines containing basic elements of legislation designed to assist those countries wishing to develop appropriate legislation and registration.

The objective of these guidelines is to define basic criteria for the evaluation of quality, safety and efficacy of herbal medicines and thereby to assist national regulatory authorities, scientific organizations and manufacturers to undertake an assessment of the documentation/submissions/dossiers in respect of such products. As a general rule in this assessment, traditional experience means that long-term use as well as the medical, historical and ethnological background of those products shall be taken into account. The definition of long-term use may vary according to the country but should be at least several decades. Therefore, the assessment should take into account a description in the medical/pharmaceutical literature or similar sources, or a documentation of knowledge on the application of a herbal medicine without a clearly defined time limitation. Marketing authorizations for similar products should be taken into account.

Prolonged and apparently uneventful use of a substance usually offers testimony of its safety. In a few instances, however, investigation of the potential toxicity of naturally occurring substances widely used as ingredients in these preparations has revealed previously unsuspected potential for systematic

32

PRODUCT ASSESSMENT AND REGISTRATION

toxicity, carcinogenicity and teratogenicity. Regulatory authorities need to be quickly and reliably informed of these findings. They should also have the authority to respond promptly to such alerts, either by withdrawing or varying the licences of registered products containing suspect substances, or by rescheduling the substances to limit their use to medical prescription.

Assessment of quality Pharmaceutical assessment

This should cover all important aspects of the quality assessment of herbal medicines. It should be sufficient to make reference to a pharmacopoeial monograph if one exists. If no such monograph is available, a monograph must be supplied and should be set out as in an official pharmacopoeia.

All procedures should be in accordance with good manufacturing practices.

Crude plant material

The botanical definition, including genus, species and authority, should be given to ensure correct identification of a plant. A definition and description of the part of the plant from which the medicine is made (e.g. leaf flower, root) should be provided, together with an indication of whether fresh, dried or traditionally processed material is used. The active and characteristic constituents should be specified and, if possible content limits should be defined. Foreign matter, impurities and microbial content should be defined or limited. Voucher specimens, representing each lot of plant material processed, should be authenticated by a qualified botanist and should be stored for at least a lO-year period. A lot number should be assigned and this should appear on the product label.

Plant preparations

Plant preparations include comminuted or powdered plant materials, extracts, tinctures, fatty or essential oils, expressed juices and preparations whose production involves fractionation, purification or concentration. The manufacturing procedure should be described in detail. If other substances are added during manufacture in order to adjust the plant preparation to a certain level of active or characteristic constituents or for any other purpose, the added substances should be mentioned in the manufacturing procedures. A method for identification and, where possible, assay of the plant preparation should be added. If identification of an active principle is not possible, it should be sufficient to identify a characteristic substance or mixture of substances (e.g. "chromatographic fingerprint'') to ensure consistent quality of the preparation.

33

QUALITY ASSURANCE OF PHARMACELfTICALS

Finished product

The manufacturing procedure and formula, including the amount of excipients, should be described in detail. A finished product specification should be defined. A method of identification and, where possible, quantification of the plant material in the finished product should be defined. If the identification of an active principle is not possible, it should be sufficient to identify a characteristic substance or mixture of substances (e.g. "chromatographic fingerprint'') to ensure consistent quality of the product. The finished product should comply with general requirements for particular dosage forms.

For imported finished products, confirmation of the regulatory status in the country of origin should be required. The WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce should be applied.

Stability

The physical and chemical stability of the product in the container in which it is to be marketed should be tested under defined storage conditions and the shelflife should be established.

Assessment of safety

This should cover all relevant aspects of the safety assessment of a medicinal product. A guiding principle should be that, if the product has been traditionally used without demonstrated harm, no specific restrictive regulatory action should be undertaken unless new evidence demands a revised risk-benefit assessment.

A review of the relevant literature should be provided with original articles or references to the original articles. If official monograph/review results exist, reference can be made to them. However, although long-term use without any evidence of risk may indicate that a medicine is harmless, it is not always certain how far one can rely solely on long-term usage to provide assurance of innocuity in the light of concern expressed in recent years over the long-term hazards of some herbal medicines.

Reported side-effects should be documented according to normal pharrnacovigilance practices.

Toxicological studies

Toxicological studies, if available, should be part of the assessment. Literature should be indicated as above.

34

PRODUCT ASSESSMENT AND REGISTRATION

Documentation of safety based on experience

As a basic rule, documentation of a long period of use should be taken into consideration when assessing safety. This means that, when there are no detailed toxicological studies, documented experience of long-term use without evidence of safety problems should form the basis of the risk assessment. However, even in cases of drugs used over a long period, chronic toxicological risks may have occurred but may not have been recognized. The period of use, the health disorders treated, the number of users and the countries with experience should be specified. If a toxicological risk is known, toxicity data must be submitted. The assessment of risk, whether independent of dose or related to dose, should be documented. In the latter case, the dosage specification must be an important part of the risk assessment. An explanation of the risks should be given, if possible. Potential for misuse, abuse or dependence must be documented. If long-term traditional use cannot be documented or there are doubts on safety, toxicity data should be submitted.

Assessment of efficacy

This should cover all important aspects of efficacy assessment. A review of the relevant literature should be carried out and copies provided of the original articles or proper references made to them. Research studies, if they exist, should be taken into account.

Activity

The pharmacological and clinical effects of the active ingredients and, if known, their constituents with therapeutic activity should be specified or described.

Evidence required to support indications

The indication(s) for the use of the medicine should be specified. In the case of traditional medicines, the requirements for proof of efficacy should depend on the kind of indication. For treatment of minor disorders and for non-specific indications, some relaxation in requirements for proof of efficacy may be justified, taking into account the extent of traditional use. The same considerations may apply to prophylactic use. Individual experiences recorded in reports from physicians, traditional health practitioners or treated patients should be taken into account.

\X!here traditional use has not been established, appropriate clinical evidence should be required.

35

QUALITY ASSURANCE OF PHARMACEUTICALS

Combination products

As many herbal remedies consist of a combination of several active ingredients, and as experience of the use of traditional remedies is often based on combination products, assessment should differentiate between old and new combination products. Identical requirements for the assessment of old and new combinations would result in inappropriate assessment of certain traditional medicines.

In the case of traditionally used combination products, the documentation of traditional use (such as classical texts of Ayurveda, traditional Chinese medicine, Unani, Siddha) and experience may serve as evidence.

An explanation of a new combination of well known substances, including effective dose ranges and compatibility, should be required in addition to the documentation of traditional knowledge of each single ingredient. Each active ingredient must contribute to the efficacy of the medicine.

Clinical studies may be required to justify the efficacy of a new ingredient and its positive effect on the total combination.

Intended use

Product information for the consumer

Product labels and package inserts should be understandable to the consumer or patient. The package information should include all necessary information on the proper use of the product.

The following elements of information will usually suffice:

• name of the product

• quantitative list of active ingredient(s)

• dosage form

• indications

- dosage (if appropriate, specified for children and the elderly)

- mode of administration

- duration of use

- major adverse effects, if any

- overdosage information

- contraindications, warnings, precautions and major drug interactions

- use during pregnancy and lactation

• expiry date

• lot number

• holder of the marketing authorization.

Identification of the active ingredient(s) by the Latin botanical name, in addition to the common name in the language of preference of the national regulatory authority, is recommended.

36

PRODUCT ASSESSMENT AND REGISTRATION

Sometimes not all information that is ideally required may be available, so drug regulatory authorities should determine their minimal requirements.

Promotion

Advertisements and other promotional material directed to health personnel and the general public should be fully consistent with the approved package information.

Utilization of these guidelines

These guidelines for the assessment of herbal medicines are intended to facilitate the work of regulatory authorities, scientific bodies and industry in the development, assessment and registration of such products. The assessment should reflect the scientific knowledge gathered in that field. Such assessment could be the basis for future classification of herbal medicines in different parts of the world. Other types of traditional medicines in addition to herbal products may be assessed in a similar way.

The effective regulation and control of herbal medicines moving in international commerce also requires close liaison between national institutions that are able to keep under regular review all aspects of production and use of herbal medicines, as well as to conduct or sponsor evaluative studies of their efficacy, toxicity, safety, acceptability, cost and relative value compared with other drugs used in modern medicine.

Stability of drug dosage forms 1

1. Introduction 37

2. General considerations 39

3. Responsibility of parties involved in the assurance of drug stability 41

3.1 Manufacturers 41

3.2 Drug regulatory authorities 41

3.3 Procurement agencies 42

3.4 Pharmacists and other workers in the supply system 42

4. Use of terms 42

S. Less stable drug substances 44

References 46

, WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-first Report. Geneva.

World Heanh Organization, 1990 (WHO Technical Report Series, No. 790).

37

QUALITY ASSURANCE OF PHARMACEUTICALS

1. Introduction

For industrially manufactured pharmaceutical products, especially those entering international commerce and/or distributed in territories with adverse climatic conditions, stability poses serious problems. Adequate stability may be achieved only through the combined efforts of all parties involved in product development, manufacture, registration, national quality surveillance, distribution, and use. It was pointed out at the Conference of Experts on the Rational Use of Drugs [Nairobi, 1985 (1)] that "no tests or certification schemes can prevent the gradual deterioration of products passing through a storage and distribution system and subjected to prolonged heat, humidity, rough handling and careless dispensing".

The stability and expiry date of a product depend on its formulation and conclusions from stability studies carried out by the manufacturer during product development and cannot be assessed by simple analysis of the final product. Mandatory use of the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce (2), which makes it possible to establish the true origin of the product and to distinguish between registered and unregistered products, can go a long way to providing assurance of product stability. The reason for this is that registration of a dosage form in the exporting country means that the formulation has been examined by an independent government authority for its pharmaceutical characteristics, including stability, based on submission of results of stability studies carried out by the manufacturer and, where applicable, of bioavailability studies. It is acknowledged, however, that stability studies conducted for temperate climates may not be fully relevant to storage and distribution in countries with extreme climatic conditions and that additional proof of stability under extreme conditions may need to be requested from the manufacturers. In the absence of registration in the exporting country buyers have to rely solely on the firm's assurance and on their own professional knowledge to assess relevant stability data submitted by the firm. When the product is purchased from a broker, the manufacturer is often not known at all. In these cases, it is virtually impossible to obtain reliable information on product stability.

In 1979 the WHO Expert Committee on Specifications for Pharmaceutical Preparations, in the text on quality assurance in the pharmaceutical supply system annexed to its report, noted that an important facet of quality assurance concerns storage. It pointed out further that "inadequate ... storage can lead to physical deterioration and chemical decomposition, resulting in a reduction in activity ... as well as the formation of possibly harmful degradation products" (3). At a later date other aspects, such as microbiological instability and impaired bioavailability, started to be considered.

The importance of factors related to storage, such as expiry dating (shelflife), has been recognized. The Twenty-fifth World Health Assembly requested the Director-General in 1972 to undertake a study of the most feasible means of

38

PRODUCT ASSESSMENT AND REGISTRATION

indicating, by a uniform system of marking, the limits of shelf-life of pharmaceutical products under the recommended conditions of their storage, as well as the date of manufacture and batch number (resolution WHA25.61).

In the past WHO has addressed some of the issues related to drug stability and storage. Recommendations have been formulated on the inclusion of the batch number, expiry date and date of manufacture in the text of drug labels (3-5). Results of accelerated stability studies and a manual for simplified tests permitting the detection of gross degradation of the least stable substances have been published (6).

The Organization is often asked for information and advice with regard to stability of finished pharmaceutical products. Particular interest in the issue of drug stability was expressed by many delegates at the Forty-first World Health Assembly, in 1988, during the discussion on the implementation of the revised drug strategy. The present document is an attempt to summarize basic principles in this area. It is addressed to policy-makers, health ministries, manufacturers, procurement agencies, and workers in the distribution system. It may be supplemented in future by technical advice in specific areas.

The document is concerned with industrially manufactured dosage forms and not with those prepared in the pharmacy or reconstituted in the hospital. Although many points discussed apply also to preparations of biological origin and radiopharmaceuticals, this document is not primarily intended for that purpose. The use of terms that occur most frequently in discussing these issues is explained in section 4.

2. General considerations

The most important factors that may influence the degree and rate of deterioration of drug products are the following:

(a) Environmental factors such as heat, moisture, light, oxygen and various other forms of physical stress and changes (for example, vibration or freezing).

(b) Product-related factors. These may include:

(i) the chemical and physical properties of the active drug substance and of the pharmaceutical aids (excipients) used (for example, the presence of certain impurities, the particular polymorphic or crystal form, the particle size and the possible presence of water or other solvents);

(ii) the dosage form and its composition;

(iii) the manufacturing process used (including environmental conditions and technological procedures);

(iv) the nature of the container or other packaging with which the product may be in direct contact or which may otherwise influence the stability.

39

QUALITY ASSURANCE OF PHARMACEUTICALS

All the above factors have to be considered when establishing the shelf-life of a product.

The stability of the finished product depends to a large degree upon the stability of the drug substance it contains. At the same time it should be noted that formulation and packaging may exert a positive or a negative influence on the stability of the active substance.' In section 5 drug substances are listed that were found to be less stable under simulated tropical conditions. All other factors being equal, finished products containing these substances require particular attention from the stability viewpoint.

For each product the shelf-life has to be established on the basis of stability testing. For practical reasons of commerce and distribution, a stated shelf-life exceeding five years is not recommended. Shorter shelf-lives may be expected for numerous active ingredients, e.g. antibiotics and vitamins, or for some types of dosage form, e.g. certain aqueous solutions, emulsions or creams. Products developed and packaged for a temperate climate may not necessarily be suitable for distribution in tropical zones.

The stability overage" is acceptable only in limited cases and on grounds of scientific and practical justification.

The use of time-expired drugs should be strongly discouraged. Only in exceptional cases, e.g. emergencies, should the use of such products be considered. The decision to utilize such products may be taken on a case-by-case basis by a responsible national health authority only, and then after careful weighing of all relevant factors by a competent professional. In such cases, samples of these products have to be retested against pharmacopoeial or similar standards by stability-indicating methods such as chromatography, attention also being paid to microbiological aspects. The economic loss and health hazards arising from the rejection of expired stock should be balanced against risks of impaired efficacy and safety. The availability of other appropriate medicines and/or the practicability of replenishing stocks should be taken into consideration. The eventual liability problems should be considered since the expiry date indicates the moment at which the manufacturer's liability for the product may be relinquished. Whenever feasible, such a decision should be taken after consultation with the manufacturer as well as with independent experts. When a decision is taken to use time-expired material, a new expiry date, well defined and as limited as practicable, has to be established.

1 It follows that the stability of a product is producer-specific.

2 An excess of the active drug substance in a dosage form, added at the time of manufacture to compensate for the expected loss of potency during storage.

40

PRODUCT ASSESSMENT AND REGISTRATION

3. Responsibility of parties involved in the assurance of drug stability

3.1 Manufacturers

As stated in Good Practices in the Mantifacture and Quality Control oj Drugs (4), it is the responsibility of manufacturers to ensure the quality of the drugs they produce. Similarly, they have the responsibility to develop appropriate dosage forms (including packaging) that are adequately stable under climatic conditions prevailing in the country or countries in which the preparations are intended to be used.

The manufacturer must establish the shelf-life of the product in relation to recommended storage conditions by using an appropriate stability-testing programme. Full details of the work carried out to establish the shelf-life should be made available to drug regulatory authorities. The expiry date and recommended storage conditions must be communicated to all involved in the pharmaceutical supply system and to patients; it is recommended that this information should be given on the label. Wben necessary, the utilization period must be determined and additionally specified on the label.

3.2 Drug regulatory authorities

Drug regulatory authorities must request adequate stability data from manufacturers in support of their claims concerning the shelf-life of registered products relevant to their countries. These data must be evaluated in the light of scientific knowledge and experience.

They should develop means to ensure that relevant information on shelflife and storage conditions is readily available to all concerned, for example by establishing regulations on labelling. They should ensure, when inspections of manufacturing establishments are carried out in accordance with the requirements of Good Practices in the Manufacture and Quality Control of Drugs (4), that appropriate stability-testing programmes for marketed products are being followed.

Guidelines and inspections are necessary to ensure that drug products are adequately handled and stored in the pharmaceutical supply system-for example, by requiring that the temperature regimen recommended by the manufacturer is followed, that there is appropriate control of other environmental factors, that a proper system of stock rotation ("first-in-first-out" rule) is maintained, and that expired products are destroyed. More detailed consideration of such factors is to be found in publications by FIP and IFPMA (7) and others (8,9). The importance of adequate storage facilities cannot be overemphasized. Experience in many countries proves that investment in warehouses is cost-effective. Products should be monitored by random visual inspection and where possible by laboratory testing at various stages in the distribution system (including hospital wards).

41

QUALITY ASSURANCE OF PHARMACEUTICALS

3.3 Procurement agencies

Procurement agencies should require sufficient information on the composition, the process of manufacture, stability, and provisions for appropriate labelling to be included in the drug procurement documents. Where possible, this information should be checked against data provided for registration purposes. In cases where the date of manufacture is not indicated on the label of a product, this information should be given in the accompanying documentation. In addition, the procurement agencies should inform potential suppliers of any extreme environmental conditions that might prevail.

3.4 Pharmacists and other workers in the supply system

Normally the supply system should be under the direct control of a pharmacist. When this is not possible, the responsible person should be under pharmaceutical supervision and have adequate training.

The responsible person should ensure that:

(a) Older stock is dispensed first and attention is paid to the expiry dates.

(b) Products are stored according to the recommended storage conditions, as stated on the label, etc.

(c) Products are observed for evidence of instability,'

(d) Products that are repackaged or further processed are properly handled and labelled.

(e) Products are dispensed in the proper containers with the proper closures. (f) Patients are educated and informed concerning the proper storage and use of the products, including the disposal of outdated or excessively aged prescriptions.

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.

1 General requirements for drug dosage forms will be published in The international pharmacopoeia.

42

PRODUCT ASSESSMENT AND REGISTRATION

Shelflife (expiration datingperiod 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.

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

Date if 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 ttorage 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 ttorage 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

.1Iea/ls:

"Do not store over 30°C" "Do not store over 25 °C" "Do not store over 15°C" "Do not store over 8 °C" "Do not store below 8 °C"

from +2 °C to +30 °C from +2 °C to +25 °C from +2 °C to +15 °C from +2 °C to +8 °C from +8 °C to +25 °C

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

"Protect from moisture"

"Protect from light"

to be provided to the patient in a light-resistant container

StabiliD' 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

43

QUALITY ASSURANCE OF PHARMACEUTICALS

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.

5. Less stable drug substances

The experimental conditions used to compile this list of less stable substances were the following: initial exposure for 30 days to air at 50°C and 100% humidity; if no degradation was demonstrable after this time, the temperature was raised to 70 °C for a further period of 3-7 days. All other factors being equal, finished products containing the following substances require particular attention from the stability viewpoint.'

acetylsalicylic acid aminophylline amitriptyline hydrochloride ammonium chloride amphotericin B

ampicillin sodium ampicillin trihydrate antimony sodium tartrate ascorbic acid

cefalexin chloral hydrate

chloramphenicol sodium succinate chlorphenarnine hydrogen maleate chlorpromazine hydrochloride chlortetracycline hydrochloride cloxacillin sodium (monohydrate) codeine phosphate

colecalciferol

bacitracin bacitracin zinc

benzathine benzylpenicillin benzylpenicillin potassium benzylpenicillin sodium bephenium hydroxynaphthoate

dapsone

dexamethasone sodium phosphate dicloxacillin sodium (monohydrate) diethylcarbamazine dihydrogen

citrate doxycycline hyclate

calcium gluconate

calcium para-arninosalicylate carbenicillin sodium

emetine hydrochloride ephedrine

ephedrine sulfate

1 For the report of the study on which this list is based, see Accelerated stability studies of widely used pharmaceutical substances under simulated tropical conditions. Geneva, World Health Organization, 1986 (unpublished document WHO/PHARM/86.529; available on request from Quality Assurance, Division of Drug Management and Policies, World Health Organization, 1211 Geneva 27, Switzerland).

44

epinephrine

epinephrine hydrogen tartrate ergocalciferol

ergometrine hydrogen maleate ergotamine maleate ergotamine tartrate ethosuximide

ethylmorphine hydrochloride

ferrous sulfate fluphenazine decanoate fluphenazine hydrochloride formaldehyde solution

gentamicin sulfate guanethidine sulfate

hexylresorcinol

hydralazine hydrochloride hydrocortisone sodium succinate hydroxocobalamin

hyoscyamine sulfate

imipramine hydrochloride ipecacuanha powder isoprenaline hydrochloride isoprenaline sulfate

lidocaine hydrochloride

melarsoprol

mercuric oxide yellow metrifonate

naloxone hydrochloride neomycin sulfate nystatin

orciprenaline sulfate oxytetracyline hydrochloride

paromomycin sulfate penicillamine

pethidine hydrochloride

PRODUCT ASSESSMENT AND REGISTRATION

phenobarbital sodium phenoxymethylpenicillin phenoxymethylpenicillin calcium phenoxymethylpenicillin potassium phentolamine mesilate phenylbutazone

pilocarpine hydrochloride pilocarpine nitrate

procainamide hydrochloride procaine benzylpenicillin

procaine hydrochloride procarbazine hydrochloride promazine hydrochloride promethazine hydrochloride pyridoxine hydrochloride

quinine bisulfate quinine dihydrochloride

retinol (vitamin A)

salbutamol sulfate senna leaf

silver nitrate

sodium calcium edetate sodium lactate

sodium nitrite

sodium para-amino salicylate sodium stibogluconate sulfacetamide sodium sulfadiazine sodium sulfadimidine sodium suxamethonium chloride

tetracaine hydrochloride tetracycline hydrochloride thiamine hydrochloride thiamine mononitrate thiopental sodium tolbutamide

undecylenic acid

warfarin sodium

45

QUALITY ASSURANCE OF PHARMACEUTICALS

References

1. WORLD HEALTH ORGANIZAl'ION. The rational use of drugs. Report of the conference of experts, Nairobi. 25-29 November 1985. Geneva, 1987.

2. WHO Technical Report Series, No. 790, 1990 (Thirty-first report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations), Annex 5.

3. WHO Technical Report Series. No. 645, 1980 (fwenty-seventh report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations), p. 27.

4. WHO Oifoial Records, No. 226. 1975, Annex 12, Part 1.

5. WHO Technical Report Series, No. 567, 1975 (Twenty-fifth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations).

6. WORLD HEALTH ORGANIZATION. Basic tests for pharmaceutical substances. Geneva, 1986.

7. DORNER, G. ET AL. Management of drugpurchasing, storage and distribution. Manua! for developing countries, 2nd rev. ed. 1985 (available from Federation internationale pharmaceutique (FIP), Alexanderstraat 11, 2514 JL The Hague; and from International Federation of Pharmaceutical Manufacturers Associations (IFPMA), 67 rue de St Jean, 1201 Geneva).

8. BATTERSBY, A. How to look qfter a health centre store. London, Appropriate Health Resources and Technologies Action Group, 1983.

9. Managing drug supplY. Boston, MA, Management Sciences for Health, 1982.

Guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms 1

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

47 47 49 51 52 54 55 55 56

1 WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-fourth Report. Geneva.

World Health Organization, 1996 (WHO Technical Report Series, No. 863).

46

PRODUCT ASSESSMENT AND REGISTRATION

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

57

58

61

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.

Definitions

The definitions given below apply to the terms used in these guidelines. They may have different meanings in other contexts.

47

QUALITY ASSURANCE OF PHARMACEUTICALS

accelerated stability testing

Studies designed to increase the rate of chemical degradation and physical change of a drug by using exaggerated storage conditions as part of the formal stability testing programme. The data thus obtained, in addition to those derived from real-time stability studies, may be used to assess longer-term chemical effects under non-accelerated conditions and to evaluate the impact of shortterm excursions outside the label storage conditions, as might occur during shipping. The results of accelerated testing studies are not always predictive of physical changes.

batch

A defined quantity of product processed in a single process or series of processes and therefore expected to be homogeneous. In continuous manufacture, the batch must correspond to a defined fraction of production, characterized by its intended homogeneity.

climatic zones

The four zones into which the world is divided based on the prevailing annual climatic conditions (see section 2).

expiry date

The date given on the individual container (usually on the label) of a drug product up to and including which the product is expected to remain within specifications, if stored correctly. It is established for each batch by adding the shelf-life period to the date of manufacture.

mean kinetic temperature

The single test temperature for a drug product corresponding to the effects on chemical reaction kinetics of a given temperature-time distribution. A mean kinetic temperature is calculated for each of the four world climatic zones according to the formula developed by Haynes (2). It is normally higher than the arithmetic mean temperature.

rea/-time «ong-term) stability studies

Experiments on the physical, chemical, biological, biopharmaceutical and microbiological characteristics of a drug, during and beyond the expected shelf-life and storage periods of samples under the storage conditions expected in the intended market. The results are used to establish the shelf-life, to confirm the projected shelf-life, and to recommend storage conditions.

shelf-life

The period of time during which a drug product, if stored correctly, is expected

48

PRODUCT ASSESSMENT AND REGISTRATION

to comply with the specification I 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.

stability

The ability of a pharmaceutical product to retain its chemical, physical, microbiological and biopharmaceutical properties within specified limits throughout its shelf-life.

stability tests

A series of tests designed to obtain information on the stability of a pharmaceutical product in order to define its shelf-life and utilization period under specified packaging and storage conditions.

supporting stability data

Supplementary data, such as stability data on small-scale batches, related formulations, and products presented in containers other than those proposed for marketing, and scientific rationales that support the analytical procedures, the proposed retest period or the shelf-life and storage conditions.

utilization period

The period of time during which a reconstituted preparation or the finished dosage form in an opened multidose container can be used.

1. Stability testing

The main objectives and uses of stability testing are shown in Table 1.

Table 1. Main objectives of stability testing

Objective

Type of study

Use

To select adequate (from the viewpoint of stability) formulations and containerclosure systems

To determine shelf-life and storage conditions

Accelerated

Development of the product

Accelerated and real-time

Development of the product and of the registration dossier

Registration dossier Quality assurance in general. including quality control

To substantiate the claimed shelf-life

To verify that no changes have been introduced in the formulation or manufacturing process that can adversely affect the stability of the product

Real-time Accelerated and real-time

1 "Shelf-life specification" means the requirements to be met throughout the shelf-life of the drug product (should not be confused with "release specification").

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QUALl1Y ASSURANCE OF PHARMACEUTICALS

1.1 In the development phase

Accelerated stability tests provide a means of comparing alternative formulations, packaging materials, and/or manufacturing processes in short-term experiments. As soon as the final formulation and manufacturing process have been established, the manufacturer carries out a series of accelerated stability tests which will enable the stability of the drug product to be predicted and its shelf-life and storage conditions determined. Real-time studies must be started at the same time for confirmation purposes. Suitable measures should be taken to establish the utilization period for preparations in multidose containers, especially for topical use.

1.2 For the registration dossier

The drug regulatory authority will require the manufacturer to submit information on the stability of the product derived from tests on the final dosage form in its final container and packaging. The data submitted are obtained from both accelerated and real-time studies. Published and/or recently obtained experimental supporting stability data may also be submitted, e.g. on the stability of active ingredients and related formulations.

Where the product is to be diluted or reconstituted before being administered to the patient (e.g. a powder for injection or a concentrate for oral suspension), "in use" stability data must be submitted to support the recommended storage time and conditions for those dosage forms.

With the approval of the drug regulatory authority, a tentative (provisional) shelf-life is often established, provided that the manufacturer has undertaken, by virtue of a signed statement, to continue and complete the required studies and to submit the results to the registration authority.

1.3 In the post-registration period

The manufacturer must carry out on-going real-time stability studies to substantiate the expiry date and the storage conditions previously projected. The data needed to confirm a tentative shelf-life must be submitted to the registration body. Other results of on-going stability studies are verified in the course of GMP inspections. To ensure the quality and safety of products with particular reference to degradation, national health authorities should monitor the stability and quality of preparations on the market by means of a follow-up inspection and testing programme.

Once the product has been registered, additional stability studies are required whenever major modifications are made to the formulation, manufacturing process, packaging or method of preparation. The results of these studies must be communicated to the competent drug regulatory authorities.

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PRODUCT ASSESSMENT AND REGISTRATION

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.] Phamlazeutische Zeitllllg, 1974, 119:321-324.)

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

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 1\: 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

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

Measured data Measured data
Climatic zone in the open air 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
1 RH = relative humidity. 51

QUALITY ASSURANCE OF PHARMACEUTICALS

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

II III IV

Derived storage conditions
Calculated data (for real-time studies)
°C2 °CMKT3 %RH4 °c %RH
20.0 20.0 42 21 45
21.6 22.0 52 25 60
26.4 27.9 35 30 35
26.7 27.4 76 30 70 Climatic zone

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

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.

(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.

3. Design of stability studies

Stability studies on a finished pharmaceutical product should be designed in the light of the properties and stability characteristics of the drug substance as well as the climatic conditions of the intended market zone. Before stability studies of dosage forms are initiated, information on the stability of the drug substance should be sought, collected and analysed. Published information on stability is available on many well established drug substances.

3.1 Test samples

For registration purposes, test samples of products containing fairly stable active ingredients are taken from two different production batches; in contrast, samples should be taken from three batches of products containing easily degradable active ingredients or substances on which limited stability data are available. The batches to be sampled should be representative of the manufacturing process, whether pilot plant or full production scale. Where possible, the batches to be tested should be manufactured from different batches of active ingredients.

In on-going studies, current production batches should be sampled in accordance with a predetermined schedule. The following sampling schedule is suggested:

- one batch every other year for formulations considered to be stable, otherwise one batch per year;

52

PRODUCT ASSESSMENT AND REGISTRATION

- one batch every 3-5 years for formulations for which the stability profile has been established, unless a major change has been made, e.g. in the formulation or the method of manufacture.

Detailed information on the batches should be included in the test records, namely the packaging of the drug product, the batch number, the date of manufacture, the batch size, etc.

3.2 Test conditions

3.2.1 Accelerated studies

An example of conditions for the accelerated stability testing of products containing relatively stable active ingredients is shown in Table 4.

For products containing less stable drug substances, and those for which limited stability data are available, it is recommended that the duration of the accelerated studies for zone II should be increased to 6 months.

Alternative storage conditions may be observed, in particular, storage for 6 months at a temperature of at least 15°C above the expected actual storage temperature (together with the appropriate relative humidity conditions). Storage at higher temperatures may also be recommended, e.g. 3 months at 45-50 "C and 75% relative humidity (RH) for zone IV.

Where significant changes (see below) occur in the course of accelerated studies, additional tests at intermediate conditions should be conducted, e.g. 30 ± 2 °c and 60 ± 5% RH. The initial registration application should then include a minimum of 6 months' data from a I-year study.

A significant change is considered to have occurred if:

the assay value shows a 5% decrease as compared with the initial assay value ofa batch;

any specified degradation product is present in amounts greater than its specification limit;

the pH limits for the product are no longer met;

the specification limits for the dissolution of 12 capsules or tablets are no longer met;

Table 4. Example of conditions for accelerated stability testing of products containing relatively stable active ingredients

Storage temperature (ee)

Relative humidity (Ufo)

Duration of studies (months)

Zone IV - For hot climatic zones or global market:

40±2 75±5 6

Zone 1/ - For temperate and subtropical climatic zones:

40 ± 2 75 ± 5 3

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QUALl1Y ASSURANCE OF PHARMACEUTICALS

- the specifications for appearance and physical properties, e.g. colour, phase separation, caking, hardness, are no longer met.

Storage under test conditions of high relative humidity is particularly important for solid dosage forms in semi-permeable packaging. For products in primary containers designed to provide a barrier to water vapour, storage conditions of high relative humidity are not necessary. As a rule, accelerated studies are less suitable for semi-solid and heterogeneous formulations, e.g. emulsions.

3.2.2 Rea/·time studies

The experimental storage conditions should be as close to the projected actual storage conditions in the distribution system as practicable (see Table 3). For registration purposes, the results of studies of at least 6 months' duration should be available at the time of registration. However, it should be possible to submit the registration dossier before the end of this 6-month period. Real-time studies should be continued until the end of the shelf-life.

3.3 Frequency of testing and evaluation of test results

In the development phase and for studies in support of an application for registration, a reasonable frequency of testing of products containing relatively stable active ingredients is considered to be:

- for accelerated studies, at 0, 1,2,3 and, when appropriate, 6 months;

- for real-time studies, at 0, 6 and 12 months, and then once a year.

For on-going studies, samples may be tested at 6-month intervals for the confirmation of the provisional shelf-life, or every 12 months for well established products. Highly stable formulations may be tested after the first 12 months and then at the end of the shelf-life. Products containing less stable drug substances and those for which stability data are available should be tested every 3 months in the first year, every 6 months in the second year, and then annually.

Test results are considered to be positive when neither significant degradation nor changes in the physical, chemical and, if relevant, biological and microbiological properties of the product have been observed, and the product remains within its specification.

4. Analytical methods

A systematic approach should be adopted to the presentation and evaluation of stability information, which should include, as necessary, physical, chemical, biological and microbiological test characteristics.

All product characteristics likely to be affected by storage, e.g. assay value or potency, content of products of decomposition, physicochemical properties

54

PRODUCT ASSESSMENT AND REGISTRATION

(hardness, disintegration, particulate matter, etc.), should be determined; for solid or semi-solid oral dosage forms, dissolution tests should be carried out.

Test methods to demonstrate the efficacy of additives, such as antimicrobial agents, should be used to determine whether such additives remain effective and unchanged throughout the projected shelf-life.

Analytical methods should be validated or verified, and the accuracy as well as the precision (standard deviations) should be recorded. The assay methods chosen should be those indicative of stability. The tests for related compounds or products of decomposition should be validated to demonstrate that they are specific to the product being examined and are of adequate sensitivity.

A checklist similar to that used in the WHO survey on the stability of pharmaceutical preparations included in the WHO Model List of Essential Drugs (Appendix 1) can be used to determine the other stability characteristics of the product.

5. Stability report

A stability report must be established for internal use, registration purposes, etc., giving details of the design of the study, as well as the results and conclusions.

The results should be presented as both a table and a graph. For each batch, the results of testing both at the time of manufacture and at different times during storage should be given. A standard form should be prepared in which the results for each pharmaceutical preparation can be summarized (see Appendix 2).

The stability of a given product, and therefore the proposed shelf-life and storage conditions, must be determined on the basis of these results.

6. Shelf-life and recommended storage conditions

Shelf-life is always determined in relation to storage conditions. Ifbatches of a product have different stability profiles, the shelf-life proposed should be based on the stability of the least stable, unless there are justifiable reasons for doing otherwise.

The results of stability studies, covering the physical, chemical, biological, microbiological and biopharmaceutical quality characteristics of the dosage form, as necessary, are evaluated with the objective of establishing a tentative shelf-life. Statistical methods are often used for the interpretation of these results. Some extrapolation of real-time data beyond the observed range, when accelerated studies support this, is acceptable.

A tentative shelf-life of 24 months may be established provided the

following conditions are satisfied:

the active ingredient is known to be stable (not easily degradable);

stability studies as outlined in section 3.2 have been performed and no significant changes have been observed;

55

QUALITY ASSURANCE OF PHARMACEUTICALS

supporting data indicate that similar formulations have been assigned a shelf-life of 24 months or more;

the manufacturer will continue to conduct real-time studies until the proposed shelf-life has been covered, and the results obtained will be submitted to the registration authority.

Products containing less stable active ingredients and formulations not suitable for experimental studies on storage at elevated temperature (e.g. suppositories) will need more extensive real-time stability studies. The proposed shelf-life should then not exceed twice the period covered by the real-time studies.

After the stability of the product has been evaluated, one of the following recommendations as to storage conditions can be prominently indicated on the label:

store under normal storage conditions!

store between 2 and 8°C (under refrigeration, no freezing); store below 8 °c (under refrigeration);

store between -5 and -20°C (in a freezer); store below -18 -c (in a deep freezer).

Normal storage conditions have been defined by WHO (3) as: "storage in dry well-ventilated premises at temperatures of 15-25 °c or, depending on climatic conditions, up to 30°C. Extraneous odours, contamination, and intense light have to be excluded."

These conditions may not always be met, bearing in mind the actual situation in certain countries. "Normal conditions" may then be defined at the national level. Recommended storage conditions must be determined in the light of the conditions prevailing within the country of designated use.

General precautionary statements, such as "protect from light" and/or "store in a dry place", may be included, but should not be used to conceal stability problems.

If applicable, recommendations should also be made as to the utilization period and storage conditions after opening and dilution or reconstitution of a solution, e.g. an antibiotic injection supplied as a powder for reconstitution.

References

1. Accelerated stability studies of widefy used pharmaceutical substances under simulated tropical conditions.

Geneva, World Health Organization, 1986 (unpublished document WHO/PHARM/ 86.529 available on request from Division of Drug Management and Policies, World Health Organization, 1211 Geneva 27, Switzerland).

2. HAYNES JD. World wide virtual temperatures for product stability testing. Journal of pharmaceutical sciences, 1971,60:927-929.

, This statement may not always be required for products intended for areas with a temperate climate.

56

PRODUCT ASSESSMENT AND REGISTRATION

3. WHO Expert CORm/ittee on Spedfications jor Pbarll/actlltica/ Preparations. Thirty-first report. Geneva, World Health Organization, 1990 (WHO Technical Report Series, No. 790).

Official, international and national guidelines Arbeitsgemeinschaft fUr Pharmazeutische Verfahrenstechnik e.V. Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.v. Richtlinie und Kommentar [Guidelines and commentary]. Pharmazeutische Industrie, 1985,47(6): 627-632.

European Community

Stability test on active ingredients and finished products. Note for guidance concerning the application of Part 1, Section F. Annex to Directive 75/318. In: The rules goveming medicinal products in tbe European Community r'oL 1) the rules governing medici/lal products for human use ill the Europea» Commuui()' (111/3574/92). Brussels, BEC Office for Official Publications of the European Community, 1991:50.

European Organization for Quality Control

Cartwright AC. The design 0/ stabililJl trials (memoralldum and condusions}. London, European Organization for Quality Control, Section for Pharmaceutical and Cosmetic Industries, 1986.

Food and Drug Administration, USA

Guidelines for stability studies for human drugs and biologics. Rockville, MD, Center for Drugs and Biologics, Office of Drug Standards, Food and Drug Administration, 1987.

Expiration datilzg and stabililJ' teslilzg_for bnman dmg produas. Inspeaion technical guide. Rockville, MD, Food and Drug Administration, 1985, No. 41.

Former German Democratic Republic

Testing of medicaments. lntemaiianal digest of health legislation, 1987, 38(2): 309-316. (For original reference, see: First regulations of 1 December 1986 for the implementation of the Medicaments Law; Testing, authorization, and labelling of medicaments intended for use in human medicine. Gesetzblatt der Destscben Demokratischen Repllblik, Part 1, 10 December 1986,37:479-483.)

Pharmacopoeia of the German Democratic Repllblic, English version. Berlin, 1988:99 (AB DDR85).

57

QUALITY ASSURANCE OF PHARMACEUTICALS

International Conference on Harmonisation

Stability testing of new drug substances and products. Harmonised tripartite guideline. 1993 (available from ICH Secretariat, c/o IFPMA, 30 rue de St-Jean, 1211 Geneva, Switzerland).

Japan

Draft poliry to deal with stability data required in applYing for approval to manufacture (import) drugs and draft guidelines for stability studies. Tokyo, Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, 1990.

Pharmaceutical Inspection Convention

Stability of pharmaceutical products: collected papers iven at a seminar, Sal:dJurg, 9-11 June 1976 (available from the Secretariat to the Convention for the Mutual Recognition of Inspections in Respect of the Manufacture of Pharmaceutical Products, c/o EFTA Secretariat, 9-11 rue de Varembe, 1202 Geneva, Switzerland).

Appendix 1. Survey on the stability of pharmaceutical preparations included in the WHO Model List of Essential Drugs: answer sheet

A checklist similar to that shown here can be used to determine the stability characteristics of a product.

Name of reporting person Address

Country Climatic zone

NAME OF ESSENTIAL DRUG:

Description of product Dosagejorm

1. tablet

2. capsule

3. injection

4. oral liquid

5. topical semi-solid

6. eye preparations

7. other (please state)

coated 0
hard 0
liquid 0
solution 0
cream D
liquid D
bottle 0
bottle 0
box 0
0
58 uncoated 0 soft 0 powder 0 suspension D ointment 0 semi-solid D

Packaging (material and type)

1. glass

2. plastic

3. paper

4. metal

vial 0 vial 0 bag 0

ampoule 0 ampoule 0 o

PRODUCT ASSESSMENT AND REGISTRATION

5. blister pack

6. other (please state)

o

State of packagin,g

intact 0 damaged 0

Storage conditions

according to the manufacturer's indications?

yes 0 noD

She!f-life (if at'fJilable)

claimed by the manufactuer percentage elapsed when tested

...... years months

%

Source of product tested

1. manufactured in country of use

2. imported from neighbouring country/countries

3. imported from distant country/countries

o o o

Problems encountered Occumnce

1. very frequent

2. occasional, but important

3. rare

Pharmacopoeial nOIl·compliance

o 1. identification

o 2. assay

o 3. purity tests

4. other pharmacopoeial test(s)

o o o o

Organoleptic

1. change of colour 0

2. visible changes, i.e. capping, 0

cracking, foam

3. inhomogeneous appearance 0

4. crystallization 0

5. particles, turbidity, precipitation 0

6. sedimentation, caking, agglomeration 0

7. smell, i.e. gas formation 0

8. rancidity 0

9. phase separation of emulsion 0

10. other interaction with packaging 0 material

11. other (please state)

Microbial

1. Microorganisms visible

2. tests for bacteria positive

3. tests for fungi positive

4. tests for pyrogens positive

5. other (please state)

o o o o

.Additiona! il/formatiol/

Date:

Instructions

1. The answer sheet is to be completed for drug products mentioned in the following list of essential drugs for which you have experienced stability problems:

acetylsalicylic acid aminophylline ampicillin

benzylpencillin

chloramphenicol

59

QUALITY ASSURANCE OF PHARMACEUTICALS

chloroquine chlorpromazine

nifedipine

epinephrine ergometrine ethinylestradiol

paracetamol phenoxymethylpenicillin propranolol

glyceryl trinitrate

spironolactone

sulfamethoxazole + trimethoprim suxamethonium bromide

ibuprofen indometacin isosorbide dinitrate

tetracycline thiamine

methyldopa

warfarin

2. A separate answer sheet should be completed for each of the above preparations in a specific finished dosage form, e.g. one for tetracycline capsules and another for tetracycline ointment.

Also applicable for other categories such as packaging material, source of drug product, etc.

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

zone I - temperate

zone II - subtropical with possible high humidity zone III - hot and dry

zone IV - hot and moist.

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PRODUCT ASSESSMENT AND REGISTRATION

Appendix 2. Stability testing: summary sheet

An example of a form in which the results of stability testing can be presented is shown below. A separate form should be completed for each pharmaceutical preparation tested.

Accelerated/real-time studies

Name of drug product .

Manufacturer .

Address .

Active ingredient (INN) .

Dosage form .

Packaging .

Batch number

1 .

2 ..

3 .

Shelf-life

Date of manufacture

../ .. /19 .. ../ .. /19 .. .. / .. /19 .. ... years(s)

Expiry date .././19 .. ../ .. /19 .. ../ .. /19 ..

... month(s)

Batch size

1 ..

2 ..

3 ..

Type of Batch (experimental, pilot plant, production)

Samples tested (per batch)

Storage/test conditions:

Temperature °C Humidity ..... %

Light cd

Results

1. Chemical findings

2. Microbiological and biological findings .

3. Physical findings .

4. Conclusions .

Responsible officer Date .. / .. /19 ..

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QUALITY ASSURANCE OF PHARMACEUTICALS

Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability 1

Introduction 63

Glossary 64

Part One. Regulatory assessment of interchangeable multisource

pharmaceutical products 66

1. General considerations 66

2. Multisource products and interchangeability 67

3. Technical data for regulatory assessment 68

4. Product information and promotion 69

5. Collaboration between drug regulatory authorities 69

6. Exchange of evaluation reports 69

Part Two. Equivalence studies needed for marketing

authorization 69

7. Documentation of equivalence for marketing authorization 69

8. When equivalence studies are not necessary 70

9. When equivalence studies are necessary and types of

studies required 71

In vivo studies 71

In vitro studies 72

Part Three. Tests for equivalence 72

10. Bioequivalence studies in humans 74

~~ ~

~~ ~

Studies of metabolites 78

Measurement of individual isomers for chiral drug substance

products 78

Validation of analytical procedures 78

Reserve samples 78

Statistical analysis and acceptance criteria 79

Reporting of results 80

11. Pharmacodynamic studies 80

12. Clinical trials 82

13. In vitro dissolution 82

Part Four. In vitro dissolution tests in product development

and quality control 83

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

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PRODUCT ASSESSMENT AND REGISTRATION

Part Five. Clinically important variations in bioavailability leading

to non-approval of the product 84

Part Six. Studies needed to support new post-marketing

manufacturing conditions 85

Part Seven. Choice of reference product 85

Aumo~ 85

References 87

Appendix 1

Examples of national requirements for in riio equivalence studies for drugs included in me WHO Model List of Essential Drugs (Canada,

Germany and me USA, December 1994) 88

Appendix 2

Explanation of symbols used in the design of bioequivalence studies in

humans, and commonly used pharmacokinetic abbreviations 103

Appendix 3

Technical aspects of bioequivalence statistics 104

Introduction

Multisource (generic) drug products must satisfy the same standards of quality, efficacy and safety as those applicable to the originator's product. In addition, reasonable assurance must be provided that they are, as intended, clinically interchangeable with nominally equivalent market products.

With some classes of product, obviously including parenteral formulations of highly water-soluble compounds, interchangeability is adequately assured by the implementation of good manufacturing practices (GMP) and evidence of conformity with relevant pharmacopoeial specifications. For other classes of product, including many biologicals, such as vaccines, animal sera, products derived from human blood and plasma, and products manufactured by biotechnology, the concept of interchangeability raises complex considerations that are not addressed here, and these products will consequently not be considered. However, for most nominally equivalent pharmaceutical products (including most solid oral dosage forms), a demonstration of therapeutic equivalence can and should be carried out, and should be included in the documentation submitted with me application for marketing authorization,

During the International Conference of Drug Regulatory Authorities (lCDRA) held in Ottawa, Canada, in 1991 and again in The Hague, The Netherlands, in 1994, regulatory officials supported the proposal that \X'HO should develop global standards and requirements for the regulatory assessment, marketing authorization and quality control of interchangeable multisource (generic)

63

QUALlIY ASSURANCE OF PHARMACEUTICALS

pharmaceutical products. On the basis of these suggestions, WHO convened three consultations during 1993 and 1994 in Geneva which led to the formulation of the present guidelines. Participants at the consultations included representatives of drug regulatory authorities, the universities, and the pharmaceutical industry, including the generic industry.

The objective of these guidelines is not only to provide technical guidance to national drug regulatory authorities and to drug manufacturers on how such assurance can be provided, but also to create an awareness that in some instances failure to assure interchangeability can prejudice the health and safety of patients. This danger has recently been highlighted in a joint statement by the WHO Tuberculosis Programme and the International Union against Tuberculosis and Lung Disease. This states, inter alia, that "studies of fixed-dose combinations containing rifampicin have shown that in some of the preparations the rifampicin was poorly absorbed or not absorbed at all". Fixed-dosage combinations containing rifampicin must therefore be "demonstrably bioavailable".

Highly developed national drug regulatory authorities now routinely require evidence of bioavailability for a very large majority of solid oral dosage forms, including those contained in the WHO Model List of Essential Drugs. WHO will assist small regulatory authorities, for whom these guidelines are primarily intended, in determining relevant policies and priorities - in relation to both locally manufactured and imported products - by compiling and maintaining a list of preparations that are known to have given rise to incidents indicative of clinical inequivalence. It will also work to promote a technical basis for assuring the interchangeability of multisource products within both an international and a national context by proposing the establishment of international reference materials as comparators for bioequivalence testing.

These guidelines apply to the marketing of pharmaceutical products intended to be therapeutically equivalent and thus interchangeable (generics) but produced by different manufacturers. They should be interpreted and applied without prejudice to the obligations incurred through existing international agreements on trade-related aspects of intellectual property rights (1).

Glossary

The definitions given below apply specifically to the terms used in this guide. They may have different meanings in other contexts.

bioavailability

The rate and extent of availability of an active drug ingredient from a dosage form as determined by its concentration-time curve in the systemic circulation or by its excretion in urine.

bioequivalence

Two pharmaceutical products are bioequivalent if they are pharmaceutically

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equivalent and their bioavailabilities (rate and extent of availability), after administration in the same molar dose, are similar to such a degree that their effects can be expected to be essentially the same.

dosage form

The form of the completed pharmaceutical product, e.g. tablet, capsule, elixir, injection, suppository.

therapeutic equivalence

Two pharmaceutical products are therapeutically equivalent if they are pharmaceutically equivalent and after administration in the same molar dose their effects, with respect to both efficacy and safety, will be essentially the same, as determined from appropriate studies (bioequivalence, pharmacodynamic, clinical or in vitro studies).

generic product

The term "generic product" has somewhat different meanings in different jurisdictions. In this document, therefore, use of this term is avoided as much as possible, and the term "multisource pharmaceutical product" (see definition below) is used instead. Generic products may be marketed either under the nonproprietary approved name or under a new brand (proprietary) name. They may sometimes be marketed in dosage forms and/or strengths different from those of the innovator products. However, where the term "generic product" has had to be used in this document, it means a pharmaceutical product, usually intended to be interchangeable with the innovator product, which is usually manufactured without a licence from the innovator company and marketed after the expiry of patent or other exclusivity rights.

innovator pharmaceutical product

Generally, the innovator pharmaceutical product is that which was first authorized for marketing (normally as a patented drug) on the basis of documentation of efficacy, safety and quality (according to contemporary requirements). When drugs have been available for many years, it may not be possible to identify an innovator pharmaceutical product.

interchangeable pharmaceutical product

An interchangeable pharmaceutical product IS one which IS therapeutically equivalent to a reference product.

multisource pharmaceutical products

Multisource pharmaceutical products are pharmaceutically equivalent products that mayor may not be therapeutically equivalent. Multisource pharmaceutical products that are therapeutically equivalent are interchangeable.

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pharmaceutical equivalence

Products are pharmaceutical equivalents if they contain the same amount of the same active substance(s) in the same dosage form; if they meet the same or comparable standards; and if they are intended to be administered by the same route. However, pharmaceutical equivalence does not necessarily imply therapeutic equivalence as differences in the excipients and/or the manufacturing process can lead to differences in product performance.

reference product

A reference product is a pharmaceutical product with which the new product is intended to be interchangeable in clinical practice. The reference product will normally be the innovator product for which efficacy, safety and quality have been established. Where the innovator product is not available, the product which is the market leader may be used as a reference product, provided that it has been authorized for marketing and its efficacy, safety and quality have been established and documented.

Part One. Regulatory assessment of interchangeable multisource pharmaceutical products

1 . General considerations

The national health authorities (national drug regulatory authorities) should ensure that all pharmaceutical products subject to their control are in conformity with acceptable standards of quality, safety and efficacy, and that all premises and practices employed in the manufacture, storage and distribution of these products comply with GMP standards so as to ensure the continued conformity of the products with these requirements until such time as they are delivered to the end user.

These objectives can be accomplished effectively only if a mandatory system of marketing authorization for pharmaceutical products and the licensing of their manufacturers, importing agents and distributors exists and adequate resources are available for implementation. Health authorities in countries with limited resources are less able to perform these tasks. To assure the quality of imported pharmaceutical products and drug substances, they are therefore dependent on authoritative, reliable, and independent information from the drug regulatory authority of the exporting country. This information, including information on the regulatory status of a pharmaceutical product, and the manufacturer's compliance with GMP (2) in the exporting country, is most effectively obtained through the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce [see pp. 187-209], which provides a channel of communication between the regulatory authorities in the importing and exporting countries (see World Health Assembly resolutions WHA41.18 and WHA45.29).

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The essential functions and responsibilities of a drug regulatory authority have been further elaborated by WHO in the guiding principles for small national drug regulatory authorities (3, 4).

2. Multisource products and interchangeability

Economic pressures often favour the use of generic products, and this can sometimes result in the purchase on contract of such products by procurement agencies without prior licensing by the appropriate drug regulatory authority. However, all pharmaceutical products, including generic products, should be used in a country only after approval by that authority. Equally, pharmaceutical products intended exclusively for export should be subjected by the regulatory authority of the exporting country to the same controls and marketing authorization requirements with regard to quality, safety and efficacy as those intended for the domestic market in that country.

Nominally equivalent interchangeable (generic) pharmaceutical products should contain the same amount of the same therapeutically active ingredients in the same dosage form and should meet required pharmacopoeial standards. However, they are usually not identical, and in some instances their clinical interchangeability may be in question. Although differences in colour, shape and flavour are obvious and sometimes disconcerting to the patient, they are often without effect on the performance of the pharmaceutical product. However, differences in sensitizing potential due to the use of different excipients, and differences in stability and bioavailability, could have obvious clinical implications. Regulatory authorities consequently need to consider not only the quality, efficacy and safety of such pharmaceutical products, but also their interchangeability. This concept of interchangeability applies not only to the dosage form but also to the instructions for use and even to the packaging specifications, when these are critical to stability and shelf-life.

Regulatory authorities should therefore require the documentation of a generic pharmaceutical product to meet three sets of criteria relating to:

- manufacture (GMP) and quality control;

- product characteristics and labelling; and

- therapeutic equivalence (see Part Two).

Assessment of equivalence ",,;11 normally require an in t'il'O study, or a justification that such a study is not required in a particular case. Types of in vivo studies include bioequivalence studies, pharmacodynamic studies, and comparative clinical trials (see sections 10-12). In selected cases, in oitro dissolution studies may be sufficient to provide some indication of equivalence (see section 13). The regulatory authority should be in a position to help local manufacturers by advising them on drugs that pose potential bioavailability problems so that in t'i,JO studies are therefore required.

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Examples of national requirements for in vivo studies for drugs included in the WHO Model List of Essential Drugs are given in Appendix 1.

3. Technical data for regulatory assessment

For pharmaceutical products indicated for standard, well established uses and containing established ingredients, the following information, inter alia, should be provided in the documentation submitted with the application for marketing authorization and for inclusion in a computerized data retrieval system:

- the name of the product;

- the active ingredient(s) (designated by their international nonproprietary

nametsj), their source, and a description of the manufacturing methods and the in-process controls;

the type of dosage form;

- the route of administration; the main therapeutic category;

a complete quantitative formula with justification and the method of manufacture of the dosage form in accordance with WHO GMP (2);

quality control specifications for the starting materials, intermediates and final dosage form product, together with a validated analytical method;

the results of batch testing together with the batch number and date of manufacture, including, where appropriate, the batch(es) used in bioequivalence studies;

- the indications, dosage and method of use;

- the contraindications, warnings, precautions and drug interactions;

- use in pregnancy and in other special groups of patients;

the adverse effects;

the effects and treatment of overdosage;

equivalence data (comparative bioavailability, pharmacodynamic or clinical studies and comparative in vitro dissolution tests);

stability data, proposed shelf-life, and recommended storage conditions;

- the container, packaging and labelling, including the proposed product information;

- the proposed method of distribution, e.g. as a controlled drug or a prescription item, and whether the product is intended for pharmacy sale or for general sale;

the manufacturer and the licensing status (date of most recent inspection, date of licence and the authority that issued the licence);

the importer/distributor;

the regulatory status in the exporting country and, where available, summary of regulatory assessment documents from the exporting country, as well as the regulatory status in other countries.

If the dosage form is a novel one intended to modify drug delivery, e.g. a

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prolonged-release tablet, or if a different route of administration is proposed, supporting data, including clinical studies, will normally be required.

4. Product information and promotion

The product information intended for prescribers and end users should be available for all generic products authorized for marketing, and the content of this information should be approved as a part of the marketing authorization. It should be updated in the light of current information. The wording and illustrations used in the subsequent promotion of the product should be fully consistent with this approved product information. All promotional activities should satisfy the WHO ethical criteria for medicinal drug promotion (see World Health Assembly resolution WHA41.17, 1988).

5. Collaboration between drug regulatory authorities

Bilateral or multilateral collaboration between drug regulatory authorities assists countries with limited resources. Sharing responsibilities in assessment and increasing mutual cooperation provide a wider spectrum of expertise for evaluation. Harmonization of the registration requirements for generics of the various drug regulatory authorities can accelerate the appro .... al process. Furthermore, an agreed mechanism of quality assurance in relation to the assessment work of collaborating agencies is vital.

6. Exchange of evaluation reports

When a company applies for marketing authorization in more than one country, the exchange of evaluation reports between drug regulatory authorities on the same product from the same manufacturer can accelerate sound decisionmaking at the national level. Such an exchange should take place only subject to the agreement of the company concerned. Appropriate measures for safeguarding data confidentiality must be taken.

Part Two. Equivalence studies needed for marketing authorization

7. Documentation of equivalence for marketing authorization

Pharmaceutically equivalent multi source pharmaceutical products must be shown to be therapeutically equivalent to one another in order to be considered interchangeable. Several test methods are available for assessing equivalence, including:

• Comparative bioavailability (bioequivalence) studies in humans, in which the active drug substance or one or more metabolites is measured in an accessible biological fluid such as plasma, blood or urine.

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• Comparative pharmacodynamic studies in humans.

• Comparative clinical trials.

• In vitro dissolution tests.

The applicability of each of these four methods is discussed in subsequent sections of these guidelines and special guidance is provided on assessing bioequivalence studies. Other methods have also been used to assess bioequivalence, e.g. bioequivalence studies in animals, but are not discussed here because they have not been accepted worldwide.

The acceptance of any test procedure in the documentation of the equivalence of two pharmaceutical products by a drug regulatory authority depends on many factors, including the characteristics of the active drug substance and the drug product, and the availability of the resources necessary for the conduct of a specific type of study. Where a drug produces meaningful concentrations in an accessible biological fluid, such as plasma, bioequivalence studies are preferred. Where a drug does not produce measurable concentrations in such a fluid, comparative clinical trials or pharmacodynamic studies may be necessary to document equivalence. In vitro testing, preferably based on a documented in vitro/in vivo correlation, may sometimes provide some indication of equivalence between two pharmaceutical products (see section 13).

Other criteria that indicate when equivalence studies are, or are not, necessary are discussed in sections 8 and 9 below.

8. When equivalence studies are not necessary

The following types of multisource pharmaceutical products are considered to be equivalent without the need for further documentation:

(a) products to be administered parenterally (e.g. by the intravenous, intramuscular, subcutaneous or intrathecal route) as aqueous solutions that contain the same active substance(s) in the same concentration(s) and the same excipients in comparable concentrations;

(b) solutions for oral use that contain the active substance in the same concentration and do not contain an excipient that is known or suspected to affect gastrointestinal transit or absorption of the active substance;

(c) gases;

(d) powders for reconstitution as a solution when the solution meets either criterion (a) or criterion (b) above;

(e) otic or ophthalmic products prepared as aqueous solutions that contain the same active substance(s) in the same concentration(s) and essentially the same excipients in comparable concentrations;

(f) topical products prepared as aqueous solutions that contain the same active substance(s) in the same concentration(s) and essentially the same excipients in comparable concentrations;

(g) inhalation products or nasal sprays that are administered with or without

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essentially the same device, are prepared as aqueous solutions, and contain the same active substance(s) in the same concentration(s) and essentially the same excipients in comparable concentrations. Special in vitro testing should be required to document comparable device performance of the multi source inhalation product.

For requirements (e), (t) and (g) above, it is incumbent on the applicant to demonstrate that the excipients in the multisource product are essentially the same as, and are present in concentrations comparable to, those in the reference product. If this information about the reference product cannot be provided by the applicant, and the drug regulatory authority does not have access to these data, in t'ivo studies should be performed.

9. When equivalence studies are necessary and types of studies required

Except for the cases listed in section 8, it is recommended in these guidelines that documentation of equivalence should be requested by registration authorities for multisource pharmaceutical products. In such documentation, the product should be compared with the reference pharmaceutical product. Studies must be carried out using the formulation intended for marketing (see also Part Seven).

In vivo studies

For certain drugs and dosage forms, in llivo documentation of equivalence, through either a bioequivalence study, a comparative clinical pharmacodynamic study, or a comparative clinical trial, is regarded as especially important. Examples include:

(a) oral immediate-release pharmaceutical products with systemic action when

one or more of the following criteria apply:

(i) indicated for serious conditions requiring assured therapeutic response; (ii) narrow therapeutic window/safety margin; steep dose-response curve; (iii) pharmacokinetics complicated by variable or incomplete absorption or

absorption window, non-linear pharmacokinetics, presystemic elimination/high first-pass metabolism> 70%;

(iv) unfavourable physicochemical properties, e.g. low solubility, instability, metastable modifications, poor perrneabilitv;

(v) documented evidence for bioavailability problems related either to the drug itself or to drugs of similar chemical structure or formulation; (vi) high ratio of excipients to active ingredients;

(b) non-oral and non-parenteral pharmaceutical products designed to act by systemic absorption (e.g. transdermal patches, suppositories);

(c) sustained-release and other types of modified-release pharmaceutical products designed to act by systemic absorption;

(d) fixed combination products (4) with systemic action;

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(e) non-solution pharmaceutical products for non-systemic use (oral, nasal, ocular, dermal, rectal, vaginal, etc.) and intended to act without systemic absorption. The concept of bioequivalence is then not applicable, and comparative clinical or pharmacodynamic studies are required to prove equivalence. This does not, however, exclude the potential need for drug concentration measurements in order to assess unintended partial absorption.

For the first four types of pharmaceutical products, plasma concentration measurements over time (bioequivalence) are normally sufficient proof of efficacy and safety. For the last type, as already pointed out, the bioequivalence concept is not applicable, and comparative clinical or pharmacodynamic studies are required to prove equivalence.

In vitro studies

For certain drugs and dosage forms (see also section 13), equivalence may be assessed by means of in vitro dissolution testing. This may be considered acceptable for example for:

(a) drugs for which in vivo studies (see above) are not required;

(b) different strengths of a multisource formulation, when the pharmaceutical products are manufactured by the same manufacturer at the same manufacturing site, and:

the qualitative composition of the different strengths is essentially the same;

the ratio of active ingredients to excipients for the different strengths is essentially the same or, for low strengths, the ratio between the excipients is the same;

- an appropriate equivalence study has been performed on at least one of the strengths of the formulation (usually the highest strength unless a lower strength is chosen for reasons of safety); and

- in the case of systemic availability, pharmacokinetics have been shown

to be linear over the therapeutic dose range.

Although these guidelines are concerned primarily with the registration requirements for multisource pharmaceutical products, it should be noted that in vitro dissolution testing may also be suitable for use in confirming that product quality and performance characteristics have remained unchanged following minor changes in formulation or manufacture after approval (see Part Six).

Part Three. Tests for equivalence

The bioequivalence studies, pharmacodynamic studies and clinical trials should be carried out in accordance with the provisions and prerequisites for a clinical trial, as outlined in the guidelines for good clinical practice for trials on pharmaceutical products (5) (see box), with GMP (2) and with good laboratory practice (GLP) (6).

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1. Provisions and prerequisites for a clinical trial 1.1 Justification for the trial

It is important for anyone preparing a trial of a medicinal product in humans that the specific aims, problems and risks or benefits of a particular clinical trial be thoroughly considered and that the chosen options be scientifically sound and ethically justified.

1.2 Ethical principles

All research involving human subjects should be conducted in accordance with the ethical principles contained in the current version of the Declaration of Helsinki. Three basic ethical principles should be respected, namely justice, respect for persons, and beneficence (maximizing benefits and minimizing harms and wrongs) or non-maleficence (doing no harm), as defined by the current revision of the International Ethical Guidelines for Biomedical Research Involving Human Subjects 1 or the laws and regulations of the country in which the research is conducted, whichever represents the greater protection for subjects. All individuals involved in the conduct of any clinical trial must be fully informed of and comply with these principles.

1.3 Supporting data for the investigational product

Pre-clinical studies that provide sufficient documentation of the potential safety of a pharmaceutical product for the intended investigational use are a prerequisite for a clinical trial. Information about manufacturing procedures and data from tests performed on the actual product should establish that it is of suitable quality for the intended investigational use. The pharmaceutical, pre-clinical and clinical data should be appropriate to the phase of the trial, and the amount of supporting data should be appropriate to the size and duration of the proposed trial. In addition, a compilation of information on the safety and efficacy of the investigational product obtained in previous and ongoing clinical trials is required for planning and conducting subsequent trials.

1.4 Investigator and site(s) of investigation

Each investigator should have appropriate expertise, qualifications and competence to undertake the proposed study. Prior to the clinical trial, the investigator(s) and the sponsor should establish an agreement on the protocol, standard operating procedures (SOP), the monitoring and auditing of the trial, and the allocation of trial-related responsibilities. The trial site should be adequate to enable the trial to be conducted safely and efficiently.

1.5 Regulatory requirements

Countries in which clinical trials are performed should have regulations governing the way in which these studies can be conducted. The pre-trial agreement between the sponsor and investigator(s) should designate the

1 These guidelines are updated regularly by the Council for International Organizations of Medical Sciences (ClaMS).

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parties responsible for meeting each applicable regulatory requirement (e.g. application to or notification of the trial to the relevant authority, amendments to the trial protocol, reporting of adverse events and reactions. and notifications to the ethics committee). All parties involved in a clinical trial should comply fully with the existing national regulations or requirements. In countries where regulations do not exist or require supplementation, relevant government officials may designate, in part or in whole. these Guidelines as the basis on which clinical trials will be conducted. The use of these Guidelines should not prevent their eventual adaptation into national regulations or laws. Neither should they be used to supersede an existing national requirement in countries where the national requirement is more rigorous.

2. The protocol

The clinical trial should be carried out in accordance with a written protocol agreed upon and signed by the investigator and the sponsor. Any change(s} subsequently required must be similarly agreed on and signed by the investigator and sponsor and appended to the protocol as amendments.

The protocol, appendices and any other relevant documentation should state the aim of the trial and the procedures to be used; the reasons for proposing that the trial should be undertaken on humans; the nature and degree of any known risks; the groups from which it is proposed that trial subjects be selected; and the means for ensuring that they are adequately informed before they give their consent.

The protocol, appendices and other relevant documentation should be reviewed from a scientific and ethical standpoint by one or more (if required by local laws and regulations) review bodies (e.g. institutional review board, peer review committee, ethics committee or drug regulatory authority). constituted appropriately for this purpose and independent of the investigator(s} and sponsor.

For additional information, see the guidelines for good clinical practice for trials on pharmaceutical products (5), from which the above text has been taken.

10. Bioequivalence studies in humans

Bioequivalence studies are designed to compare the in vivo performance of a test multisource pharmaceutical product with that of a reference pharmaceutical product. A common design for a bioequivalence study involves the administration of the test and reference products on two occasions to volunteer subjects, the second administration being separated from the first by a wash-out period of duration such as to ensure that the drug given in the first treatment is entirely eliminated before the second treatment is administered. Just before administration and for a suitable period afterwards, blood and/or urine samples are collected and assayed for the concentration of the drug substance and/or one or more metabolites. The rise and fall of these concentrations over time in each

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subject in the study provide an indication of how the drug substance is released from the test and reference products and absorbed into the body. To allow comparisons between the two products, these blood (including plasma or serum) and/or urine concentration-time curves are used to calculate certain bioequivalence metrics of interest. Commonly used metrics include the area under the blood (plasma or serum) concentration-time curve (AUC) and the peak concentration. These are calculated for each subject in the study and the resulting values compared statistically. Details of the general approach are given below.

Subjects

Selection of subjects

The subject population for bioequivalence studies should be as homogeneous as possible; studies should therefore generally be performed with healthy volunteers so that variability, other than in the pharmaceutical products concerned, is reduced. Clear criteria for inclusion/exclusion should be established. If possible, subjects should be of both sexes; however, the risk to women will need to be considered on an individual basis and, if necessary, they should be warned of any possible dangers to the fetus if they should become pregnant. They should normally be in the age range 18-55 years and of weight within the normal range according to accepted life tables. Subjects should preferably be non-smokers and without a history of alcohol or drug abuse. If smokers are included, they should be identified as such. Volunteers should be screened for suitability by means of standard laboratory tests, a medical history, and a physical examination. If necessary, special medical investigations may be carried out before and during studies, depending on the pharmacology of the drug being investigated.

If the aim of the bioequivalence study is to address specific questions (e.g. bioequivalence in a special population), the selection criteria will have to be adjusted accordingly.

Genetic phenotyping

Phenotyping and/or genotyping of subjects may be considered for safety reasons.

Patients versus healthy volunteers

If the active substance is known to have adverse effects and the pharmacological effects or risks are considered unacceptable for healthy volunteers, it may be necessary to use patients under treatment instead. This alternative should be explained by the sponsor.

Monitoring the health of subjects during the study

During the study, the health of volunteers should be monitored so that the onset of side-effects, toxicity, or any intercurrent disease may be recorded, and appropriate measures taken. Health monitoring before, during and after the study must be carried out under the supervision of a qualified medical practitioner licensed in the jurisdiction in which the study is conducted.

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Design

General study design

The study should be designed so that the test conditions are such as to reduce intra- and intersubject variability and avoid biased results. Standardization of exercise, diet, fluid intake and posture, and restriction of the intake of alcohol, caffeine, certain fruit juices, and drugs other than that being studied in the period before and during the study are important in order to minimize the variability of all the factors involved except that of the pharmaceutical product(s) being tested.

A cross-over design with randomized allocation of volunteers to each leg is the first choice for bioequivalence studies. Study design should, however, depend on the type of drug, and other designs may be more appropriate in certain cases, e.g. with highly variable drugs and those with a long half-life. In cross-over studies, a wash-out period between the administration of the test product and that of the reference product of more than five times the half-life of the dominant drug is usual, but special consideration will need to be given to extending this period if active metabolites with longer half-lives are produced, and also under certain other circumstances.

The administration of the test product should be standardized, i.e. the time of day for ingestion and the volume of fluid (150 ml is usual) should be specified. Test products are usually administered in the fasting state.

Parameters to be assessed

In bioavailability studies, the shape of, and the area under, the plasma concentration curve, or the profile of cumulative renal excretion and excretion rate are commonly used to assess the extent and rate of absorption. Sampling points or periods should be chosen such that the time-concentration profile is adequately defined so as to allow the calculation of relevant parameters. From the primary results, the bioavailability parameters desired, e.g. AVC"", AVC" Cm'x> tmax, At"" Ae" Me/dt, or any other necessary parameters, are derived (see Appendix 2). The method of calculating AVC-values should be specified. AVC", and Cmax are considered to be the most useful parameters for the assessment of bioequivalence. For urine excretion data, the corresponding parameters are Ae"" and dAe/ d/max• For additional information, tv, and MRT can be calculated, and for steadystate studies, AVC~, and the per cent peak-trough fluctuation. The exclusive use of modelled parameters is not recommended unless the pharmacokinetic model has been validated for the active substance and the products.

Additional considerations for complicated drugs

For drugs which would cause unacceptable pharmacological effects (e.g. serious adverse events) in volunteers or where the drug is toxic or particularly potent or the trial necessitates a high dose, cross-over or parallel-group studies in patients may be required.

Drugs with long half-lives may require a parallel design or the use of

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truncated area under curve (AVe,) data or a multidose study. The truncated area should cover the absorption phase.

For drugs for which the rate of input into the systemic circulation is impor-

tant, more samples may have to be collected around the time Imax' Multidose studies may be helpful in assessing bioequivalence for:

drugs with non-linear kinetics (including those with saturable plasma protein binding);

drugs for which the assay sensitivity is too low to cover a large enough portion of AUG,.;

- drug substance combinations, if the ratio of the plasma concentration of the individual drug substances is important;

- controlled-release dosage forms;

- highly variable drugs.

Number of subjects

The number of subjects required for a sound bioequivalence study is determined by the error variance associated with the primary parameters to be studied (as estimated from a pilot experiment, from previous studies or from published data), by the significance level desired, and by the deviation from the reference product compatible with bioequivalence, safety and efficacy. It should be calculated by appropriate methods (see p. 79) and should not normally be smaller than 12. In most studies, 18-24 subjects will be needed (7-9). The number of subjects recruited should always be justified.

Investigational products

The products (samples) used in bioequivalence studies for registration purposes should be identical to the projected commercial pharmaceutical product. For this reason, not only the composition and quality characteristics (including stability) but also the methods of manufacture should be those to be used in future routine production runs.

Samples should ideally be taken from industrial-scale batches. When this is not feasible, pilot- or small-scale production batches may be used provided that they are not less than one-tenth (10%) of the size of the expected full-scale production batches.

It is recommended that the potency and in ritro dissolution characteristics of the test and reference pharmaceutical products should be ascertained before an equivalence study is performed. The content of active drug substance(s) in the two products should not differ by more than ±5%. If the potency of the reference material deviates by more than 5% from that corresponding to the declared content of 100%, this difference may be used subsequently to dose-normalize certain bioavailability metrics in order to facilitate comparisons between the test and reference pharmaceutical products.

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Studies of metabolites

The use of metabolite data in bioequivalence studies requires careful consideration. The evaluation of bioequivalence will generally be based on the measured concentrations of the pharmacologically active drug substance and its active metabolite(s), if present. If it is impossible to measure the concentration of the active drug substance, that of a major biotransformation product may be measured instead, while measurement of the concentration of such a product is essential if the substance studied is a prodrug. If urinary excretion (rate) is measured, the product determined should represent a major fraction of the dose. Although measurement of a major active metabolite is usually acceptable, that of an inactive metabolite can only rarely be justified.

Measurement of individual isomers forchiral drug substance products A non-stereos elective assay is currently acceptable for bioequivalence studies. Under certain circumstances, however, assays that distinguish between the enantiomers of a chiral drug substance may be appropriate.

Validation of analytical procedures

All analytical procedures must be well characterized, fully validated and documented, and satisfy the relevant requirements as to specificity, accuracy, sensitivity and precision. Knowledge of the stability of the active substance and/or biotransformation product in the sample material is a prerequisite for obtaining reliable results (10). It should be noted that:

- validation comprises both before-study and within-study phases;

- validation must cover the intended use of the assay;

- the calibration range must be appropriate to the study samples;

- if an assay is to be used at different sites, it must be validated at each site and

cross-site comparability established;

- an assay which is not in regular use requires sufficient revalidation to show that it is performed according to the original validated procedures; the revalidation study must be documented usually as an appendix to the study report; - within a given study, the use of two or more methods to assay samples in the same matrix over a similar calibration range is strongly discouraged;

- if different studies are to be compared, the samples from these studies have been assayed by different methods, and the methods cover a similar concentration range and the same matrix, they should be cross-validated.

The results of validation should be reported.

Reserve samples

Sufficient samples of each batch of the pharmaceutical products used in the

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studies, together with a record of their analyses and characteristics, must be kept for reference purposes under appropriate storage conditions as specified by national regulations. At the specific request of the competent authorities, these reserve samples may be handed over to them so that they can recheck the products.

Statistical analysis and acceptance criteria General consideration

The primary concern in bioequivalence assessment is to limit the risk (0,) of a false declaration of equivalence to that which the regulatory authorities are willing to accept.

The statistical methods of choice at present are the two one-sided tests procedure (11) and the derivation of a parametric or non-parametric 100(1-20,)% confidence interval for the quotient ~/!J.R of the test and reference pharmaceutical products. The value of a is set at 5%, leading, in the parametric case, to the shortest (conventional) 90% confidence interval based on an analysis of variance or, in the non-parametric case, to the 90% confidence interval (12, 13).

The statistical procedures should be specified before data collection starts (see Appendix 3), and should lead to a decision scheme which is symmetrical with respect to the two formulations, i.e. it should lead to the same decision whether the new formulation is compared with the reference product or vice versa.

Concentration and concentration-related quantities e.g. AVC and Cm a: x s should be analysed after logarithmic transformation, but !max will usually be analysed without such transformation.

For tmax> normally descriptive statistics should be given. If tmax is to be subjected to a statistical analysis, this should be based on non-parametric methods. Other parameters may also be evaluated by non-parametric methods, when descriptive statistics should be given that do not require specific distributional assumptions, e.g. medians instead of means.

The assumptions underlying the design or analysis should be addressed, and the possibility of differing variations in the formulations should be investigated. This covers the investigation of period effects, sequence or carry-over effects, and homogeneity of variance.

The impact of outlying observations on the conclusions should be reviewed.

Medical or pharmacokinetic explanations for such observations should be sought.

Acceptance ranges

For AVC, the 90% confidence interval should generally be within the acceptance range 80-125%. For drugs with a particularly narrow therapeutic range, the AUC acceptance range may need to be smaller; this should be justified clinically.

Cmax does not characterize the rate of absorption particularly well in many cases, but there is no consensus on any other concentration-based parameter

79

QUALl1Y ASSURANCE OF PHARMACEUTICALS

which might be more suitable. The acceptance range for Cmax may be wider than that for AVC (see Appendix 3).

Reporting of results

The report on a bioequivalence study should give the complete documentation of its protocol, conduct and evaluation in compliance with the guidelines on good clinical practice (GCP) for trials on pharmaceutical products (5). The responsible investigator(s) should sign the respective section(s) of the report .. The names and affiliations of the responsible investigator(s), the site of the study and the period of its execution should be stated. The names and batch numbers of the pharmaceutical products used in the study, as well as the composition(s) of the tests product( s), should also be given. The analytical validation report should be attached. The results of in vitro dissolution tests should be provided. In addition, the applicant for registration should submit a signed statement confirming that the test product is identical with the pharmaceutical product submitted.

All results should be clearly presented. The procedure for calculating the parameters used (e.g. AUC) from the raw data should be stated. Deletion of data should be justified. If results are calculated using pharmacokinetic models, the model and the computing procedure used should be justified. Individual plasma concentration-time curves should be drawn on a linear/linear scale, and may also be shown on a linear/log scale. All individual data and results should be given, including those for any subjects who have dropped out of the trial. Drop-out and withdrawal of subjects should be reported and accounted for. Test results on representative samples should be included.

The statistical report should be sufficiently detailed to enable the statistical analyses to be repeated, if necessary. If the statistical methods applied deviate from those specified in the trial protocol, the reasons for the deviations should be stated.

11. Pharmacodynamic studies

Pharmacodynamic measurements in healthy volunteers or patients may be used for establishing equivalence between two pharmaceutical products. This may be necessary if the drug and/or its metabolite(s) in plasma or urine cannot be determined quantitatively with sufficient accuracy and sensitivity. Furthermore, pharmacodynamic studies in humans are required if measurements of drug concentrations cannot be used as surrogate end-points for the demonstration of the efficacy and safety of the particular pharmaceutical product; this applies, for example, to topical products where it is not intended that the drug should be absorbed into the systemic circulation.

If pharmacodynamic studies are used, the conditions under which they are performed must be as rigorously controlled as those of bioequivalence studies, and the requirements of the guidelines for good clinical practice (GCP) for trials on pharmaceutical products (5) must be satisfied.

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PRODUCT ASSESSMENT AND REGISTRATION

The following requirements must be taken into account in planning, conducting and assessing the results of a study intended to demonstrate equivalence by means of measurements of pharmacodynamic drug responses:

the response measured should be a pharmacological or therapeutic effect relevant to the claims of efficacy and/or safety;

the methodology must be validated for precision, accuracy, reproducibility and specificity;

neither the test nor the reference product should produce a maximum response in the course of the study, since it may be impossible to distinguish differences between formulations given in doses that produce maximum or near-maximum effects; investigation of dose-response relationships may be a necessary part of the design;

the response should be measured quantitatively under double-blind conditions and be recordable by means of a suitable instrument on a repetitive basis to provide a record of the pharmacodynamic events which are substitutes for plasma concentrations; where such measurements are not possible, recordings on visual analogue scales may be used, and where the data are limited to qualitative (categorized) measurements, appropriate special statistical analysis will be required;

non-responders should be excluded from the study by prior screening, and the criteria whereby responders and non-responders are identified must be stated in the protocol;

where an important placebo effect can occur, allowance for this effect should be made in the study design by including placebo treatment as a third phase in that design;

the underlying pathology and natural history of the condition should be considered in the study design, and information on the reproducibility of baseline conditions should be available;

- where a cross-over design is not appropriate, a parallel group study design should be chosen.

In studies in which continuous variables can be recorded, the time course of the intensity of the drug action can be described in the same way as in a study in which plasma concentrations are measured, and parameters can be derived which describe the area under the effect-time curve, the maximum response and the time when that response occurred.

The statistical methods for the assessment of the outcome of the study are, in principle, the same as those outlined for bioequivalence studies. However, a correction should be made for the potential non-linearity of the relationship between the dose and the area under the effect-time curve, based on the outcome of a dose-response study. However, it should be noted that the conventional acceptance range as applied for bioequivalence assessment is usually too large and therefore not appropriate; for this reason, it should be defined on a case-by-case basis and described in the protocoL

81

QUALl1Y ASSURANCE OF PHARMACEUTICALS

12. Clinical trials

For certain drugs and dosage forms (see example (e), p.72) plasma concentration time-profile data are not suitable for use in assessing equivalence between two formulations. While pharmacodynamic studies can sometimes be an appropriate tool for establishing equivalence (see section 11), in other instances this type of study cannot be performed because of a lack of meaningful and measurable pharmacodynamic parameters; a comparative clinical trial must then be performed in order to demonstrate equivalence between two formulations. In such a clinical trial, the same statistical principles will apply as in bioequivalence studies. The number of patients to be included in the study will depend on the variability of the target parameters and the acceptance range, and is usually much higher than that required in bioequivalence studies.

The methodology to be used in establishing equivalence between pharmaceutical products by means of a clinical trial in patients in which there is a therapeutic end-point has not yet been discussed as extensively as that used in bioequivalence trials. However, the following are important and need to be defined in the protocol:

(a) The target parameters; these are usually relevant clinical end-points from which the intensity and the onset, if applicable and relevant, of the response can be derived.

(b) The size of the acceptance range; this must be defined on a case-by-case basis, taking into consideration the specific clinical conditions, for example the natural course of the disease, the efficacy of available treatments and the chosen target parameter. In contrast to bioequivalence studies (where a conventional acceptance range is used), the size of the acceptance range in clinical trials cannot be based on a general consensus on all the therapeutic classes and indications.

(c) The statistical method used; this is currently the confidence interval approach, the main concern being to rule out the possibility that the test product is inferior to the reference pharmaceutical product by more than the specified amount. A one-sided confidence interval (for efficacy and/or safety) may therefore be appropriate. The confidence intervals can be derived by either parametric or non-parametric methods.

Where appropriate, a placebo leg should be included in the design, and it is sometimes appropriate to include safety end-points in the final comparative assessments.

13. In vitro dissolution

Comparative in vitro dissolution studies may be useful in the documentation of equivalence between two multisource pharmaceutical products. However, because of the many limitations associated with the use of in vitro dissolution in

82

PRODUCT ASSESSMENT AND REGISTRATION

the documentation of equivalence it is recommended in these guidelines that its application for this purpose should be kept to a minimum. In vitro dissolution testing as the sole documentation of equivalence is therefore not applicable to the drugs and dosage forms listed as examples (a)-(e) on pp. 71-72, but should be reserved for rapidly dissolving drug products.' When the multisource test and reference products both dissolve with sufficient rapidity (e.g. >80% in 15 minutes), their in vivo equivalence may be presumed. Approval of multisource formulations by the use of comparative il1 uitro dissolution studies should be based on the generation of comparative dissolution profiles rather than singlepoint dissolution tests, as described in various pharmacopoeial compendia and other publications. Multiple dissolution test conditions and physiologically relevant media are recommended.

Part Four. In vitro dissolution tests in product development and quality control

In vitro dissolution tests are useful in product development and in monitoring the batch-to-batch consistency of the manufacturing process following approval of marketing. Such tests are also used to check the consistency of the release characteristics of a dosage form during storage. Dissolution testing may also provide a useful check on a number of characteristics of the dosage form, including:

the particle size distribution, state of hydration, crystal form and other solid state properties of the active ingredients;

the mechanical properties of the dosage form itself (water content, resistance to crushing force for tablets, integrity of the shell for capsules and coated tablets, etc.).

When used in product quality control, information on in uitro dissolution should be provided in the documentation submitted with the application for marketing authorization. In vitro dissolution tests and quality control specifications should be based either on suitable compendial specifications or on the in iitro performance of the test batches used to generate material for the equivalence study. Where sufficient full-scale process validation batches are not prepared in the immediate post-approval period, several batches (two or three are recommended) of the test product should be manufactured in the preapproval period in accordance with standard, consistent, well documented procedures. Two of these batches should contain at least 100000 units or 10% of the intended

1 Where a drug substance and drug product do not dissolve with sufficient rapidity, as noted above, in vitro dissolution methods may still be used to document equivalence using appropriately validated dissolution methodology including an in vitro/in vivo correlation, Sucih methodology should be derived from the development and application of specifications and statistical methods to define non-equivalence. This may require formulations with different in vivo performance characteristics. With such formulations, discriminatory in vitro dissolution tests for use in equivalence studies may be developed. With these additional requirements, however, a standard in vivo bioequivalence study as described in section 7 may be preferable.

83

QUALIlY ASSURANCE OF PHARMACEUTICALS

production batch, whichever is larger. The third, if prepared, may be smaller (e.g. 25000 units). The use of smaller batches should be justified. Material from these test batches is used to provide material both for dissolution studies and for equivalence testing. Physiologically relevant media and test conditions should be used for dissolution tests on these batches. When selecting the test methods to be used, it is recommended that widely used compendial methods ("paddle" and "basket'') should be used initially and other methods ("flow-through cell", etc.) tried if these fail to demonstrate sufficient discriminatory power. Dissolution profiles are recommended, even when a single-point compendial dissolution test is available. For immediate-release pharmaceutical products, a single-point dissolution test may be used for quality control purposes. Specifications for the dissolution performance of batches subsequently manufactured will be based on the results of the dissolution tests performed on the test batches. While it is undisputed that the value of dissolution testing will be increased if the test results can be shown by in vivo studies to reflect important changes in formulation and/or the manufacturing process, the practical problems involved are still under discussion. It is not recommended that the dissolution specification should be made less stringent on the basis of the performance of the test batches beyond the point where equivalence between the test material used in the equivalence study and production batches subsequently manufactured can no longer be assumed.

The following data should be recorded and included in the documentation submitted with the application for marketing authorization:

(a) comparative dissolution results for the test and reference pharmaceutical products after intervals appropriate for the products and conditions under investigation (a minimum of three sampling times is normal);

(b) for each sampling time, the observed data, individual values, the range and the coefficient of variation (relative standard deviation).

Part Five. Clinically important variations in bioavailability leading to non-approval of the product

A new formulation of bioavailability outside the acceptance range as compared with an existing pharmaceutical product is by definition not interchangeable. A marketing authorization for a formulation of lower bioavailability may not be approved because of efficacy concerns. In contrast, a formulation of higher bioavailability ("suprabioavailability'') may not be approved because of safety concerns. There are then the following two options:

1. The suprabioavailable dosage form, if reformulated so as to be bioequivalent to the existing pharmaceutical product, could be accepted as interchangeable with that product. This may not be ideal, however, as dosage forms of lower bioavailability tend to be variable in performance.

2. A dosage form of increased bioavailability in which the content of active

84

PRODUCT ASSESSMENT AND REGISTRATION

substance has been appropriately reduced could be accepted as a new (improved) dosage form, but this decision would normally need to be supported by clinical trial data. Such a pharmaceutical product must not be accepted as interchangeable with the existing pharmaceutical product, and would normally become the reference product for future interchangeable pharmaceutical products. The name of the new pharmaceutical product should be such as to preclude confusion with the older approved pharmaceutical product(s).

Part Six. Studies needed to support new post-marketing manufacturing conditions

With all pharmaceutical products, when post-marketing changes are made, extensive in vitro and/or in vivo testing may be required. Such changes may be in: (i) formulation; (ii) site of manufacture; (iii) manufacturing process; and (iv) manufacturing equipment. The types and extent of the further testing required will depend on the magnitude of the changes made. If a major change is made, the product might then become a new pharmaceutical product, if the national regulatory authorities so decide.

Part Seven. Choice of reference product

The innovator pharmaceutical product is usually the most logical reference product for related generics because, in general, its quality will have been well assessed and its efficacy and safety will have been securely established in clinical trials and post-marketing monitoring schemes. There is, however, currently no global agreement on the selection of reference products, which are selected at national level by the drug regulatory authority. Either the most widely used "leading" pharmaceutical product in the market or the product that was first approved in that market is normally chosen. It is therefore possible that significant differences may exist between the reference products adopted in different countries.

This being so, consideration needs to be given to the feasibility of developing reference products on a global basis. Representative bodies of the pharmaceutical industry and other interested parties should be invited to collaborate in the preparation, maintenance and international acceptance of a system of international reference standards for pharmaceutical products of defined quality and bioavailability.

Authors

The guidelines were developed during three meetings convened by the Division of Drug Management and Policies. \\'orld Health Organization, Geneva, Switzerland, on 18-19 February 1993, 23-27 August 1993, and 23-26 August 1994, attended by the following people:

85

QUALIlY ASSURANCE OF PHARMACEUTICALS

Professor J.-M. Aiache, University of Clermont-Ferrand, Clermont-Ferrand, France

Dr Andayaningsih, Ministry of Health, Jakarta, Indonesia

Dr N. Aoyagi, National Institute of Health Sciences, Tokyo, Japan

Dr E. Beyssac, University of Clermont-Ferrand, Clermont-Ferrand, France

Professor D. Birkett, Flinders Medical Centre, Bedford Park, Australia

Dr D. Blois, International Federation of Pharmaceutical Manufacturers Associations (lFPMA), Geneva, Switzerland

Professor H. Blume, International Pharmaceutical Federation (PIP), Eschborn, Germany

Professor A. Bondani, General Directorate for the Control of Health Inputs, Mexico City, Mexico

Miss M. Cone, International Federation of Pharmaceutical Manufacturers Associations (lFPMA), Geneva, Switzerland

Mr M. N. Dauramanzi, Drugs Control Council, Harare, Zimbabwe

Mr T. Fushimi, Ministry of Health and Welfare, Tokyo, Japan

Professor U. Gundert-Remy (Chairman), Department of Clinical Pharmacology, University of Gottingen, Gottingen, Germany

Dr C. G. Guyer, Food and Drug Administration, Rockville, MD, USA

Professor F. D. Juma, University of Nairobi, Nairobi, Kenya

Professor G. Kreutz, Federal Institute for Drugs and Medicinal Devices, Berlin, Germany

Dr L. Lacy, International Federation of Pharmaceutical Manufacturers Associations (lFPMA), Geneva, Switzerland

Dr I. J. McGilveray, Drugs Directorate, Ottawa, Canada

Dr o. Morin, International Federation of Pharmaceutical Manufacturers Associations (IFPMA), Geneva, Switzerland

Dr R. Nedich, Generic Pharmaceutical Industry Association, Washington, DC, USA

Dr A. Nijkerk, European Generic Medicines Association, Brussels, Belgium

Dr H. P. Osterwald, European Generic Medicines Association, Brussels, Belgium

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PRODUCT ASSESSMENT AND REGISTRATION

Professor T. L. Pail, National Institute of Pharmacy, Budapest, Hungary

Dr R. N. Patnaik, Food and Drug Administration, Rockville, MD, USA

Dr J. M. Peon, General Directorate for the Control of Health Inputs. Mexico City, Mexico

Miss M.-C. Pickaert, International Federation of Pharmaceutical Manufacturers Associations (IFPMA), Geneva, Switzerland

Professor L. Rago, State Agency of Medicines, Tartu, Estonia

Dr B. Rosenkranz, International Federation of Pharmaceutical Manufacturers Associations (IFPMA), Geneva, Switzerland

Dr H. Scheinin, Turku University Central Hospital, Turku, Finland

Mr N. Uemura, Ministry of Health, Tokyo, Japan

Professor B. Vrhovac, University Hospital Medical School, Zagreb, Croatia

Dr R. L. Williams, Food and Drug Administration, Rockville, MD, USA

Secretariat (WHO, Geneva, Switzerland)

Dr J. F. Dunne, Director, Division of Drug Management and Policies

Dr J. Idanpaan- Heikkila, Associate Director, Division of Drug Management and Policies

References

1. Annex 1 C. Article 39. In: Marrakc,h Agreement Establishing tile World Trade Organization.

Marrakesh, GATT, 1994.

2. Good manufacturing practices for pharmaceutical products. In: WHO Expert ConmJittee 011 Specifications for Pharmaceutical Preparations. Thirty-second report. Geneva, World Health Organization, 1992:14-79 (WHO Technical Report Series, No. 823).

3. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Tbirty-firs: report.

Geneva, World Health Organization, 1990:64-79 (\X'HO Technical Report Series, No. 790).

4. The use 0/ essential drugs. il-Iode/ List 0/ Essentia! Drugs (SetY!I1th l.istj. Fifth report 0/ the WHO Expert Conlmittee. Geneva, \'\orld Health Organization, 1992:62-74 (WHO Technical Report Series, No. 825).

5. Guidelines for good clinical practice (GCP) for trials on pharmaceutical products. In: The use 0/ essential drugs. Sixth report 0/ the WHO Expert Committee. Geneva, \,{;'orld Health Organization, 1995:97-137 (\X'HO Technical Report Series, No. 850).

6. Good laboratory practices in governmental drug control laboratories. In: WHO Expert

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QUALITY ASSURANCE OF PHARMACEUTICALS

Committee on Specifications for Pharmaceutical Preparations. Thirtieth report. Geneva, World Health Organization. 1987: 20-35 (WHO Technical Report Series, No. 748).

7. Diletti E, Hauschke D, Steinijans vw. Sample size determination for bioequivalence assessment by means of confidence intervals. International joumal 0/ clinical pharmacology, therapy and toxicology, 1991, 29: 1-8.

8. Hauschke D et al. Sample size determination for bioequivalence assessment using a multiplicative model. Journal 0/ pharmacokinetics and biopbarmaceutics, 1992, 20:559-563.

9. Phillips KE. Power of two one-sided tests procedure in bioequivalence. Journal o/pharmacokinetics and biopharmaceutics, 1990, 18: 137-144.

10. Conference report on analytical methods validation: bioavailability, bioequivalence and pharmacokinetic studies. Jouma! o/pharmaceutica/ sciences, 1992, 81:309-312.

11. Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. Jouma! 0/ pharmacokinetics and biopharmaceutics, 1987,15:657-680.

12. Hauschke D et al. A distribution-free procedure for the statistical analysis of bioequivalence studies. International journal 0/ clinical pharmacology, therapy and toxicology, 1990, 28:72-78.

13. Hollander M, Wolfe DA. Nonparametric statistical methods. New York, John Wiley, 1973:35-38.

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)

General

National requirements for equivalence studies for specific drug products differ from country to country. National requirements for equivalence studies of a specific drug product can be based on any of the following:

case-by-case study;

criteria established by a national advisory committee; or application of the national regulatory guidelines.

A list of examples is presented in Table 1. It is intended to be illustrative only, in accordance with the guidelines, and does not represent a formal recommendation.

The list is based on substances and products included in the WHO Model List of Essential Drugs (1), but only includes essential drugs for which in vivo studies are required because of the nature of the dosage form. Some dosage

88

PRODUCT ASSESSMENT AND REGISTRATION

forms, e.g. solutions and injections, have therefore been omitted from the list as they have not been identified as requiring studies in one of the three countries covered.

Examples of decisions on criteria taken by national authorities Canada

At present, demonstration of bioequivalence is required for those drugs which are not considered to have been marketed in Canada for their intended purpose(s) for sufficient time and in sufficient quantity to establish safety and efficacy (new drugs). Bioequivalence may be demonstrated by comparative bioequivalence studies or by clinical studies including, where applicable, acceptable surrogate models. Scientific criteria, similar to those of the European Community and Australia, are being developed for deciding in which situations in ~'ivo demonstration of bioequivalence is required for drugs that are not new.

Germany

Over the past years, the National Advisory Committee has taken the decision on the need for a comparative bioavailability/bioequivalence study as a requirement for marketing authorization. These decisions have been based on published data for the drug substance and its dosage form, and on the use of an algorithm. Details of the algorithm, the criteria and the resulting decisions have been published in the German Federal Register. In certain circumstances, the regulatory authority takes decisions on a case-by-case basis.

USA

Drug products introduced before 1938 in the USA do not require approval for marketing and therefore no in t'it,o equivalence study is needed. The majority of drug products, other than solution dosage forms, approved between 1938 and 1962, and known to have potential bioavailability problems, require in t'jIJo equivalence studies. Generally, drug products approved after 1962, with the exception of solution dosage forms, also require ill riro equivalence studies.

Table 1. Examples of national requirements for equivalence studies'
Drug substance Dosage form Canada Germany USA
acetazolamide tablet, 250 mg +b +b +b
acetylsalicylic acid suppository, 50-150 mg ? +b
tablet, 1 00-500 mg +b 1 +: in vivo studies required; -b: bioequivalence studies; +p: pharmacodynamic studies: -c: clinical trials; -: no in vivo studies required; ?: decision on the type of in vivo studies pending; 0: no information available, no final decision taken, or not available on national market. See also pp. 72-83.

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QUALITY ASSURANCE OF PHARMACEUTICALS

Table 1 (continued)
Drug substance Dosage form Canada Germany USA
albendazole tablet, 200 mg 0 +b 0
allopurinol tablet, 1 00 mg +b +b +b
aluminium hydroxide oral suspension, 320 mgl +p
5ml
tablet, 500 mg +p
amiloride tablet, 5 mg +b +b
hydrochloride
aminobenzoic acid cream ? +p+c
gel ? +p+c
lotion ? +p+c
aminophylline tablet, 100 mg, 200 mg ? 0 +b
amitriptyline tablet, 25 mg ? +b +b
hydrochloride
amoxicillin capsule, 250 mg, 500 mg +b +b +b
powder for oral +b +b +b
suspension, 125 mgt
5ml
tablet, 250 mg, 500 mg +b +b +b
ascorbic acid tablet, 50 mg ?
atenolol tablet, 50 mg, 100 mg +b +b
atropine sulfate solution (eye drops), 0.1 %, 0 +c
0.5%,1%
tablet,1 mg 0 ? 0
azathioprine tablet, 50 mg +b +b +b
bacitracin zinc ointment, 500 IU + 0 +c
neomycin sulfate,
5 mglg
beclometasone inhalation, 50 I-Igtdose ? +p+c +p
dipropionate
benzathine powder for injection, 1.44 9 0 +b
benzylpenicillin of benzylpenicillin (=2.4
million IU) in 5-ml vials
90 PRODUCT ASSESSMENT AND REGISTRATION

Table 1 (continued)
Drug substance Dosage form Canada Germany USA
benznidazole tablet, 1 00 mg 0 +b 0
benzoic acid cream, 6% + salicylic acid, +p+c 0
3%
ointment, 6% + salicylic +p+c
acid,3%
benzoyl peroxide cream,5% +p+c
lotion, 5% +p+c
benzyl benzoate lotion, 25% +p+c 0
betamethasone cream, 0.1 % of +p +p+c +p
valerate betamethasone
ointment, 0.1 % of +p +p+c +p
betamethasone
biperiden tablet, 2 mg +b +b +b
hydrochloride
calamine lotion +p+c
calcium folinate tablet, 15 mg +b 0 +b
captopril tablet, 25 mg +b +b
carbamazepine tablet, 100 mg, 200 mg +b +b +b
carbidopa tablet, 10 mg + levodopa, +b +b +b
100mg
25 mg + levodopa, 250 mg +b +b +b
chloramphenicol capsule, 250 mg ? +b +b
chloramphenicol oral suspension, 150 mg of ? +b +b
palmitate chloramphenicol/5 ml
chloramphenicol oily suspension, injection, 0 +b 0
sodium succinate 0.5 9 of
chloramphenicol/ml in
2-ml ampoule
chloroquine injection, 40 mg of 0
hydrochloride chloroquine/ml in 5-ml
ampoule
chloroquine tablet, 150 mg of chloroquine 0 +b
phosphate
91 QUALITY ASSURANCE OF PHARMACEUTICALS

Table 1 (continued)
Drug substance Dosage form Canada Germany USA
chloroquine sulfate tablet, 150 mg of 0 +b 0
chloroquine
chlorphenamine tablet, 4 mg ?
hydrogen maleate
chlorpromazine tablet, 100 mg ? +b +b
hydrochloride
ciclosporin capsule, 25 mg +b +b +b
cimetidine tablet, 200 mg +b +b
ciprofloxacin tablet, 250 mg of +b +b +b
hydrochloride ciprofloxacin
clofazimine capsule, 50 mg, 100 mg 0 +b +b
clomifene citrate tablet, 50 mg +b +b +b
clomipramine capsule, 10 mg, 25 mg +b 0 +b
hydrochloride
cloxacillin sodium capsule, 500 mg of ? +b +b
cloxacillin
codeine phosphate tablet, 10 mg, 30 mg 0
colchicine tablet, 500 IJg ? +b
cyclophosphamide tablet, 25 mg +b +b +b
dapsone tablet, 50 mg, 100 mg ? +b +b
desmopressin nasal spray, 10 IJg/metered +b+p +p+c ?
acetate dose
dexamethasone tablet, 500 IJg, 4 mg ? ? +b
diazepam scored tablet, 2 mg, 5 mg +b +b
diethylcarbamazine tablet, 50 mg 0 +b +b
dihydrogen citrate
digitoxin tablet, 50 IJg, 100 IJg ? +b
digoxin tablet, 62.5 IJg, 250 IJg ? +b
92 PRODUCT ASSESSMENT AND REGISTRATION

Table 1 (continued)
Drug substance Dosage form Canada Germany USA
diloxanide furoate tablet, 500 I-Ig 0 +b 0
dimercaprol injection, in oil, 50 mg/ml in +b+c +b'
2-ml ampoule
dioxybenzone cream ? +p+c 0
lotion ? +p+c 0
gel ? +p+c 0
dithranol ointment, 0.1-2% +p+c
doxycycline hyclate capsule, 100 mg of +b +b +b
doxycycline
tablet, 100 mg of +b +b +b
doxycycline
ergocalciferol capsule, 1.25 mg (50 000 0 +b
IU)
tablet, 1.25 mg (50 000 IU) 0 +b
ergometrine tablet, 200 I-Ig ? +b
hydrogen maleate
ergotamine tartrate tablet,2 mg 0 +b
erythromycin capsule, 250 mg of ? +b +b
ethylsuccinate erythromycin
powder for oral ? +b +b
suspension, 125 mg of
erythromycin ? +b +b
tablet, 250 mg of
erythromycin
erythromycin capsule, 250 mg of ? +b +b
stearate erythromycin
powder for oral ? +b +b
suspension, 125 mg of
erythromycin ? +b +b
tablet, 250 mg of
erythromycin
ethambutol tablet, 100-400 mg +b +b +b
hydrochloride
, "Depot" preparation for injection.
93