IPA/AAPS/FIP Workshop on Quality

Wednesday 20 and Thursday 21 February 2008The Hyatt Regency Hotel,

Mumbai, India

“Good manufacturing Practices for 21st Century ”

WHO-GMP Perspectives

By Dr Abdel Aziz SalehSpecial Adviser to the Regional Director

WHO/EMRO

WHO Constitution

International health standards

WHO Constitution Article 2:“to act as the directing and coordinating authority on international health work.”

FUNCTIONS OF WHOTo act as the directing and coordinating authority on international health workTo develop, establish and promote international standards with respect to food, biological, pharmaceutical and similar products.

Standards with respect to the safety, purity and potency of biological, pharmaceutical and similar products moving in international commerce;Advertising and labeling of biological, pharmaceutical and similar products moving in international commerce;

The Health Assembly shall have the authority to adopt concerning:

STANDARD SETTING FUNCTION

Strategy Components

Medicines policyAccessQuality and safetyRational use

ChallengesThree types of common imbalance have been identified in regulatory practice

Much more time is assigned to pre-marketing assessment than to post marketing surveillanceWhile product registration is considered a major responsibility by all the drug regulatory authorities, the regulation of drug distribution channels and information does not enjoy the same level of attentionIn many countries, GMP inspection receives more attention and resources than inspection of distribution channels

With the technical support of WHO, a postgraduate university degree course on pharmaceutical good manufacturing practices (GMP) was developed in the Islamic Republic of Iran which can be used for capacity-building for countries of the Region. Technical support was provided for training workshops on good manufacturing practices in several countries.

Some examples of WHO Technical Support

Technical support was provided for fellowships for different issues related to quality assurance and safety of medicines and vaccines, a in addition to Who publications on quality and safety of medicines.

The quality of pharmaceuticals has been a concern of the World Health Organization (WHO) 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 similarproducts.”

Quality of Pharmaceuticals

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 WHO 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.

The recommendations are essential to all concerned with the quality assurance of medicines, but separate publications over a period of years has made it difficult to recognize them as complementary parts of a comprehensive system of quality assurance.

Volume 1 of Quality assurance of pharmaceuticals: a compendium of guidelines and related materialswas published by WHO in 1997. Material relating to national drug regulations, product assessment and registration

Volume 2, first published by WHO in 1999, reproduces guidelines related to good manufacturing practices (GMP) and to theinspection of pharmaceutical manufacturers and drug distribution channels. This volume was updated in 2004, and the current version constitutes the second updated edition of Volume 2 including new texts and revisions adopted to date as WHO guidelines.

GMP are an important part of a comprehensive system of quality assurance. They also represent the technical standard upon which is based the WHO Certification Scheme on theQuality of Pharmaceutical Products Moving in International Commerce.

GMP WHO Perspectives

The first GMP text published by WHO was developed during 1967–69 upon request by WHO’s Member States and was revised in 1975. In the 1980s and early 1990s, several national and regional drug regulatory authorities issued or revised guidelines reflecting the ongoing elaboration of the concept of GMP.

WHO GMP Guidelines

Revised and expanded GMP guidelines were prepared during 1989–90, approved by the WHO Expert Committee on Specifications for PharmaceuticalPreparations in late 1990 and subsequently published by WHO.

WHO GMP Guidelines

GMP guidelines published by WHO areto be regarded as advisory in nature and may need to be adapted to addressspecific conditions in individual countries. However, if any departures fromrecommended practices are introduced, the equivalence of such alternativeapproaches should be validated.

WHO GMP Guidelines

The GMP guidelines for biological productsThe GMP guidelines for the manufacture of investigational pharmaceutical productsThe specialized GMP guidelines for the manufacture of herbal medicinal productsRadiopharmaceuticals close collaboration with the International Atomic Energy Agency (IAEA).“Guidelines for inspection of drug distribution channels”

Specialized GMP Guidelines

WHO Basic Training Modules on

GMPA resource and study pack

for trainers

GMP VIDEO.Video Supplementary Document

The video shows GMP “compliant” and “non-compliant” practices. The “compliant” part contains “non-compliant” aspects that should be identified by participants during training.

Lack of reference or identification of responsibility of key personnel

final product release for distributionvalidation not referred to and others

Inspection is closely related to other elements of the overall medicines quality assurance system: GMP, licensing of manufacturing facilities, product registration.

WHO Guidelines on Inspection

“Provisional guidelines on the inspection of pharmaceutical manufacturers” was published by WHO in 1992 along with the core GMP guidelines.

Additional guidelines dealing with the quality system requirements for national good manufacturing practice inspectorates were adopted by the Expert Committee.

WHO good manufacturing practices: main principles for

pharmaceutical products

General considerationsLicensed pharmaceutical products (marketing authorization) should be manufactured only by licensed manufacturers (holders of a manufacturing authorization) whose activities are regularly inspected by competent nationalauthorities.

Glossary

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

Quality management in the drug industry

The basic elements of quality management are:

— an appropriate infrastructure or “quality system”, encompassing the organizational structure, procedures, processes and resources;

— systematic actions necessary to ensure adequate confidence that a product (or service) will satisfy given requirements for quality. The totality of these actions is termed “quality assurance”.

Quality assurance“Quality assurance” is a wide-ranging concept covering all matters that individually or collectively influence the quality of a product. It is the totality of the arrangements made with the object of ensuring that pharmaceuticalproducts are of the quality required for their intended use. Quality assurance therefore incorporates GMP and other factors, including those outside the scope of this guide such as product design and development.

Good manufacturing practices for pharmaceuticalproducts (GMP)

Good manufacturing practice is that part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization. GMP are aimed primarily at diminishing the risks inherent in any pharmaceutical production. Such risks are essentially of two types: cross-contamination (in particular of unexpected contaminants) and mix-ups (confusion) caused by, for example, false labels being put on containers.

Main Challenges

Legal framework Qualified national expertise in GMP inspectionTeaching GMP and Quality Assurance at universitiesContinued education and on job trainingQuality system

Legal Framework

Many developing countries do not have the national expertise to develop national legal framework for GMP standard and GMP national inspection system

Developing countries usually adopt one of the recognized national, regional, or global GMP rules. WHO/GMP are generally accepted.

The development of the National Inspection Manual and the Legal Framework of the GMP Inspection system needs additional technical support.

Qualified national expertise in GMP Inspection

Most of the national regulatory Authorities in developing countries lack the necessary personnel with the appropriate qualification and expertise in developing and running an efficient national system in GMP Inspection

The available facilities and working conditions do not attract competent personnel to work in the governmental sector

Teaching GMP and Quality Assurance System at

universitiesOnly recently schools of pharmacy in developing countries started teaching basic principles of medicines Quality Assurance System and GMP inspection to the pharmacy under-graduate students

Continued Education and on Job Training

Very few countries regularly organize continued education programmeand on job training courses to GMP inspectors and other quality assurance system staff

These activities are mainly dependent on external sources from donors and UN agencies

Recommendations and Conclusions:

Establishment of national quality systemPharmacy educationProfessional development Partnership and collaboration

Quality systems Requirements for National

Good Manufacturing Practice Inspectorates

Administrative StructureThe administrative structure, membership, operation and legal status of the GMP inspectorate should be described in the quality manual. The quality manual should show how all personnel working for the GMP inspectorate, including subcontracted staff or advisers, and persons serving on committees providing advice, can maintain their impartiality

Organizational structure

The GMP inspectorate should have an organization that enables it

to maintain the capability to perform its technical functions satisfactory

The GMP inspectorate should have:Documentation clearly identifying its legal statusAn organizational chart showing clearly the responsibility and reporting structure of the inspectorate and, in particular, the relationship between its inspection and authorization (licensing) functionsA description of the means by which the inspectorate obtains financial supportA description of the relationship between the GMP inspectorate and other departments within the drug regulatory authority and other government agencies, where they operate as separate bodies.

Inspection personnelThe credibility of the GMP inspection process will depend to a large degree on the technical competence and integrity of the inspectors. The quality manual should provide up-to-date details of the names, qualifications, experience and terms of reference (job description and duties to be performed) of each member of staff engaged in the GMP inspection process

Pharmacy Education

GMP and quality system courses should be part of the core

curriculum of undergraduate pharmacy education

Partnership and Collaboration

More technical support to developing countries is needed from UN agencies and other partnersBilateral, subregional and regional collaboration has proven to be very successful in improving the national quality assurance system

Thank You

Quality SystemMost developing countries lack the comprehensive set-up of a national quality system as defined by WHO “An appropriate infrastructure, encompassing the organizational structure, procedures, processes and resources necessary to ensure adequate confidence that a product (or service) will satisfy given requirements for quality”

Quality and Safety

The quality, safety and efficacy of all medicines assured by strengthening and putting into practice regulatory and quality assurance standards

Medicines regulation and quality assurance systems

WHO ObjectiveInstruments for effective drug regulation and quality assurance systems promoted in order to strengthen national drug regulatory authorities.

The quality of medicine Varies greatly-especially in low-and middle-income countries. While most countries have a medicines regulatory authority and formal requirements for registering medicines, one-third of WHO Member Sates have either no regulatory authority or only limited capacity to regulate the medicines market.

National Drug Quality Assurance System

IPA/AAPS/FIP Workshop on Quality

Wednesday 20 and Thursday 21 February 2008

The Hyatt Regency Hotel, Mumbai, India

“Good manufacturing Practices for 21st

Century ”WHO prequalification Scheme

By Dr Abdel Aziz SalehSpecial Adviser to the Regional Director

WHO/EMRO

Outline of the presentations

WHO Medicine strategyWHO Medicine Quality Assurance

ProgrammeWHO Prequalification Project

WHO Prequalification Scheme and Local Medicine Production

Recommendations

GOAL

WHO’s goal in medicines is to help save lives and improve

health by ensuring the quality efficacy, safety and rational use

of medicines, including traditional medicines, and by promoting

equitable and sustainable access to essential medicines,

particularly for the poor and disadvantaged

Strategy Components

Medicines policyAccess

Quality and safetyRational use

WHO Medicine Quality Assurance ProgrammeQuality and Safety

The quality, safety and efficacy of all medicines

assured by strengthening and putting into practice

regulatory and quality assurance standards

Medicines regulation and quality assurance systems

WHO Objective

Instruments for effective drug regulation and quality

assurance systems promoted in order to strengthen national drug regulatory authorities.

National Drug Quality Assurance System

The quality of medicine Varies greatly-especially in low-and middle-income

countries. While most countries have a medicines regulatory authority and formal requirements for registering

medicines, one-third of WHO Member Sates have either no regulatory

authority or only limited capacity to regulate the medicines market.

Quality System

Most developing countries lack the comprehensive set-up of a national quality

system as defined by WHO “An appropriate infrastructure, encompassing the

organizational structure, procedures, processes and resources necessary to

ensure adequate confidence that a product (or service) will satisfy given

requirements for quality”

Quality systems requirements

Administrative structure

The administrative structure, membership, operation and legal status

of the Quality system should be described in the quality manual. The quality manual should show how all

personnel working for the Quality system, including subcontracted staff or advisers,

and persons serving on committees providing advice, can maintain their

impartiality

Organizational structure

The Quality system should have an organization that enables it to maintain the capability to perform

its technical functions satisfactory

ChallengesThree types of common imbalance have

been identified in regulatory practice

Much more time is assigned to pre-marketing assessment than to post marketing

surveillanceWhile product registration is considered a

major responsibility by all the drug regulatory authorities, the regulation of drug distribution channels and information does not enjoy the

same level of attentionIn many countries, GMP inspection receives

more attention and resources than inspection of distribution channels

Fact sheet N°278May 2004

The WHO prequalification project

The Prequalification project, set up in 2001, is a service provided by the World Health Organization (WHO) to facilitate access to medicines that meet

unified standards of quality, safety and efficacy for HIV/AIDS, malaria and tuberculosis.

The availability of quality, safety and efficacy of medicines is a major concern of WHO. To ensure that quality pharmaceuticals are available, WHO sets norms and standards, develops guidelines

and advises Member States on issues related to quality assurance of medicines in national and

international markets. WHO assists countries in building national regulatory capacity through

networking, training and information sharing.

These activities have been endorsed and supported by Member States through

numerous World Health Assembly resolutions

The Prequalification project is part of these activities and mandate. It does not intend

to replace national regulatory authorities or national authorization systems for

importation of medicines. Prequalification draws from the expertise of some of the

best national regulatory authorities to provide a list of prequalified products that

comply with unified international standards

WHO PQ project

The project was supported by UNAIDS, UNICEF, UNFPA and the World Bank as a concrete contribution to the United Nations

priority goal of addressing widespread diseases in countries with limited access to

quality medicines

WHO PQ project HOW IT WORKSAny manufacturer wishing their medicines to be included in the prequalified products

list are invited to apply. Each manufacturer must present extensive information on the

product (or products) submitted to allow qualified assessment teams to evaluate its

quality, safety and efficacy

WHO PQ project HOW IT WORKS

The standards against which the assessment teams evaluate both the

quality specifications of medicines and the manufacturing sites are based on the

principles and practices agreed by the world’s leading regulatory agencies and adopted by the WHO Expert Committee

on Specification for Pharmaceutical Preparations

WHO PQ project HOW IT WORKS

The assessment teams evaluating the products and manufacturers include experts from some of

the national regulatory authorities of the European Union as well as Canada and Switzerland. These

teams ensure that high quality, international standards are respected. The teams work with

regulators from the developing countries where the medicines will be used to make sure that the process and results are at all times transparent

and trusted by the end-users

Dossier requirementsgeneral

The product dossier should include information on:

1. Details of the product2. Regulatory situation in other

countries3. Active pharmaceutical

ingredient(s)-API

Dossier requirementsgeneral

(3. API continue)

3.1 Properties of the API(s)3.2 Sites of manufacture

3.3 Route of synthesis3.4 Specification

API described in a pharmacopoeia API not described in a

pharmacopoeia3.5 Stability testing

Dossier requirementsgeneral

4. Finished product4.1 Formulation

4.2 Sites of manufacture4.3 Manufacturing procedure

4.4 Specifications for excipients4.5 Specifications for finished product

4.6 Container/closure system(s) and other packaging

Dossier requirementsgeneral

(4. Finished product continue )

4.7 Stability testing4.8 Container labeling

4.9 Product information4.10 Patient information and package

inserts4.11 Justification for any differences to the product in the country or countries

issuing the submitted WHO-type certificate(s)

Dossier requirementsgeneral

5. Interchangeability5.1 Bioequivalence study

5.2 Summary of pharmacology, toxicology* and efficacy of the

product (expert reports)

Bioequivalence dossier requirements for the

prequalification project

Basic guidelines

In vivo Bioequivalence studies areclinical trials in accordance with the

guidelines on:Good Clinical Practice

Good Manufacturing PracticeGood Laboratory Practice

Basic guidelinesAdditional guidance

WHO TRS No. 937, 2006, Annex 9Guidelines for organizations

performing in vivo bioequivalence studies. In: WHO Expert Committee on

Specifications for Pharmaceutical Preparations. Fortieth report. Geneva,

World Health Organization

Current Requirements of WHO for

Prequalification of Vaccines

World Health Organization, HTP/V&B/ATT. LBelgharbi

Source of vaccines, 2004Number of countries

Total = 192 countries

83

61

48

UN agency Procuring Producing

World Health Organization, HTP/V&B/ATT. LBelgharbi

Source of vaccines, 2004Number of countries

Total = 192 countries

83

61

48

UN agency Procuring Producing

43 %43 %43 %

Main source of vaccines for national immunization programmes in 2004

Producing

Procuring

UN agency

32 %32 %32 %

25 %25 %25 %

Prequalificationscheme

100% assured quality

CanadaFrance

SwitzerlandIndonesia

BrazilCuba

GermanyIndiaItaly

AustraliaUnited Kingdom

BelgiumSenegal

JapanRep.Korea

USABulgariaSweden

DenmarkUSA

Assured quality source of vaccine

Assured quality vaccines sourced through WHO prequalifed channel benefit 112 countries

80 countries are at high risk of not fully accessing assured quality vaccines(including 18 producing countries)

• 20 out of 48 producing countries• 65 pre-qualified vaccines produced by 24 manufacturers ( 14 industrialized & 6

developing countries) • NRA assessed in 13 out of 20

countries

The efficient National Vaccine Regulatory Authority should perform the following functions within an efficient Regulatory system:

•Marketing authorization & licensing activities,

•Post marketing: AEFI,•Lot release,•Laboratory access,•Regulatory inspections, and•Authorization & monitoring of Clinical

Trials.

Requirements for PQHighly reliant on NRA oversight, hence relevant NRA is

functional.PSF complete, and info compliant with WHO

requirements and UN tender specificationsResults of testing meet specifications and reflect a

consistent productProduction and control in accordance with WHO

requirementsClinical information relevant to target population and

schedulesLabels, inserts and packaging meet UN tender

specifications Compliance with GMP

Necessary commitments from NRAin order to accept the vaccine

Batch to batch release of the vaccines •Sharing reports of serious adverse events

with a prequalified vaccine•Sharing information on

-critical failure in compliance with GMP-failure to meet specifications-withdrawals or recall of products-suspension or non- renewal of license

Necessary commitments from manufacturer

•Communicate major variations immediately after approval by the NRA. If approval by NRA is not

required, then communicate to WHO before implementation

•Report serious adverse events immediately•Communicate minor variations annually (December)•Provide regular updates of safety profile of the

vaccine/s

Necessary commitments from manufacturer

•Inform on quality complaints if relevant to UN supply

•Inform of withdrawals or recalls of products•Inform suspension or non-renewal of

licenses in countries where the product is marketed

NOTE: Sharing of inspection reports is desirable and may lead to streamlining of WHO site visit

Prequalification: Manufacturers 'shortcomings52% applications submitted by vaccine manufacturers

failed WHO prequalification screening process

Absence of adequate/sufficient clinical data

Absence or insufficient/inadequate stability dataLack of proof of consistency of production

Commercial scale batches unavailable

30 out of 48 producing countries have a functional NRA (%)10 out of 61 procuring countries have a functional NRA (%)

Regulatory oversightNRA ' shortcomings

Evolution: Increasing number of applications and reassessments

0

5

10

15

20

25

30

2000 2001 2002 200 3 2004 2005*

Vaccine applications

Reassessments

Challenges

•More variety of products being assessed•Products of increased complexity (several sites)•More vaccines produced in DC•For products not marketed in Europe, no marketing

authorization in Europe, instead scientific opinion by EMEA. Registration and post- marketing regulatory

functions by receiving country •Registration for export purposes only. Post- marketing

regulatory functions by receiving country•Regulatory responsibility falls increasingly in DC

regulatory authorities

Consultation with Expert Group 2004

In April 2004, a consultation was held in Geneva to get advice from the experts'

committee on different aspects of the current prequalification procedure.

WORLD HEALTH ORGANIZATIONORGANISATION MONDIALE DE LA

SANTE

Procedure for Assessing the Acceptability, In Principle, of Pharmaceutical Products for Purchase by United Nations

Agencies

Annex 4Procedure for assessing the

acceptability, in principle, of quality control laboratories for use by United

Nations agencies

WHO Prequalification Scheme and Local

Medicine Production

Forty-fifth Session of the Regional Committee for the Eastern Mediterranean Region1998

Agenda Item 10

Technical discussions

Regional Self Sufficiency in Vaccine and Drug production

Self sufficiency in the production of essential drugs and vaccines faces considerable challenges.

Despite commitments to develop local production within the

Region, production volume in most facilities does not meet

national needs.

These guiding principles include the following:

Local production is an important component of national drug and vaccines policies and is one of the strategies for achieving equity in access to essential

drugs and vaccines.Quality is the leading priority in relation to decision-

makingAdvancing technology and changing global trade

arrangements have created a new reality which countries and manufacturers have to consider

Governments are responsible for creating an enabling environment that strengthens local

pharmaceutical and vaccine production industries.

Local State Production

An approach for Cost Containment

Vaccine Self-sufficiency in EMR

Strategy and action planbased upon a draft strategy paper

EMRO Strategy for Vaccine SelfEMRO Strategy for Vaccine SelfEMRO Strategy for Vaccine Self---sufficiencysufficiencysufficiency

The strategic goal

All the eligible persons in the member states of EMR have ensured access to

existing and new quality vaccines in accordance with the national

immunization schedules through nationally and/or regionally produced

vaccines.

EMRO Strategy for Vaccine SelfEMRO Strategy for Vaccine SelfEMRO Strategy for Vaccine Self---sufficiencysufficiencysufficiency

Fifth Strategic Objective

Commitment by non-vaccine producing countries

Apart from ensuring the supply of existing and new vaccines to their eligible populations it is also important for these countries to formally

commit in advance their markets to vaccine producers in the region. Without this

commitment any desire or drive to self-

sufficiency would remain a dream.

EMRO Strategy for Vaccine SelfEMRO Strategy for Vaccine SelfEMRO Strategy for Vaccine Self---sufficiencysufficiencysufficiency

Sixth Strategic Objective

Achieving WHO-prequalification status

Prequalification can act as a major booster for the producers in the region. This would not only bring credibility but would also act as a major stimulant for

increasing the production capacity, mobilizing investments and acting as

suppliers even beyond the region, after having met the regional needs.

Recommendations

(aDeveloping countries should develop clear national policies for local production

of essential medicines wherever appropriate and feasible;

(bLocal drug industries should give more attention to producing essential drugs;

and

(cCollaboration between WHO and developing countries should include

technical support for prequalification of locally produced medicines and vaccines

Thank You