who prequalification programme milan smid, m.d., ph.d. prequalification programme: priority...

WHO Prequalification WHO Prequalification ProgrammeProgramme

Milan Smid, M.D., Ph.D.Prequalification Programme: Priority Essential Medicines

WHO Prequalification Programme for Priority Medicines, Jakarta, October 20092 |

UN Prequalification Programme for Priority Essential MedicinesUN Prequalification Programme for Priority Essential Medicines

Action plan of UN from 2001 for expanding access of priority medicines to patients with

– HIV/AIDS

– Malaria

– Tuberculosis

– Reproductive health

– Influenza

– Acute diarrhoea

– Potentially other categories of products, if there is the need


Elements of Prequalification ProgrammeElements of Prequalification Programme

Objective: To ensure quality, efficacy and safety of medicines procured

using international funds (e.g. GFTAM, UNITAID)

Components: Evaluation of Quality, Safety and Efficacy of prioritised Essential

medicines, inspections of manufacturers and monitoring of the products after their prequalification.

Prequalification of quality control laboratories. Building capacity of regulators, manufacturers and quality control

laboratories.


How prequalification is organized?How prequalification is organized?

WHO manages and organizes the programme on behalf of the United Nations:

• provides technical and scientific support to assessment, inspections (GMP, GCP, GLP) and quality control (GPCL)

• involvement of qualified assessors and inspectors mostly from NRAs of ICH and associated countries and PIC/S inspectorates

• guarantees that international norms and standards are applied all through the process

• supports capacity of NRA in developing countries to evaluate, inspect and control the quality of medicines

• involvement of qualified assessors and inspectors from NRAs in developing countries

• by involvement of manufacturers from development countries into the project supports their capacity to produce according to international norms and standards


How prequalification is organized?How prequalification is organized?

WHO PQT working in co-operation with partners

• UNICEF• The Global Fund to Fight AIDS, Tuberculosis and Malaria• UN Population Fund (UNFPA)• UNAIDS• World Bank

• Anti-malarial and anti-TB products: Roll Back Malaria and Stop TB (Global Drug Facility); HIV/AIDS Department


Essential steps of PQ evaluation procedureEssential steps of PQ evaluation procedure

Need is specified and agreed by WHO treatment programmes Invitation for Expression of interest (EOI) is published Interested parties submit dossiersDossiers receive initial screeningFull dossiers are assessed Inspections are conducted at manufacturing sites and at CROsSamples are tested, if needed If outcome is positive, pharmaceutical product is listed on the

website, including product information (SPC, PIL), assessment report (WHOPAR) and inspection report (WHOPIR)


Essential steps of monitoring of PQ productEssential steps of monitoring of PQ product

Variations to the dossier of prequalified product

Sampling and Testing

Reinspections

Requalification

De-listing or suspension (if and when appropriate)


StandardsStandards

WHO standards as defined in WHO guidelines and International Pharmacopoeia are applied in prequalification process

If these not exist, ICH guidelines are applied

In case of need, guidelines of stringent regulatory authorities, which are involved in ICH process


IExpression

of Interest

Compliance

Additional informationand data

Corrective actions

Compliance

Assessment Inspections

Steps in prequalification

Prequalification

Maintenance and monitoring

Product dossierSMF


Evaluation procedureEvaluation procedure Assessment of product dossiers

(Quality specifications, pharmaceutical development, production, control, stability, bioequivalence etc).

Teams of professionals from national Drug Regulatory Authorities (DRA): Including Brazil, China, Canada, Denmark, Estonia, Finland, France, Germany, Hungary, Indonesia, Malaysia, Philippines, Spain, South-Africa, Sweden, Switzerland, Tanzania, Uganda, UK, Zimbabwe ...

Copenhagen assessment week

• 8 to 20 assessors together during one week at least every two months at UNICEF in Denmark

• Every dossier is assessed by at least four assessors. • An assessment report is issued - signed by assessors• Letter summarizing the findings and asking for clarification and

additional data if necessary is sent first by e-mail to the applicant followed by surface mail


Assessors participating in PQ assessment (all visits in 2001-2008, share of the WHO regions)

Assessors participating in PQ assessment (all visits in 2001-2008, share of the WHO regions)

34196

151

12

1

0 EURO

AMRO

AFRO

WPRO

SEARO

EMRO

In total 603 participations


Inspections:Inspections:

Team of inspectors for each inspectionWHO PQ inspector plus PIC/S member country plus local

country inspector (observer)Some cases – capacity building (recipient country)Preparation includes SMF, product information, inspection

reports, complaints etcAPIs, Finished products Clinical studies: Mostly Bioequivalence studies (generic

products


Prequalification assessmentPrequalification assessment

Innovator products• Accepted, if approved by stringent authorities like US FDA and

EMEA • Based on availability of assessment reports, WHO Certificate of

Pharmaceutical Product (CPP), batch certificate• Continuous update on product changes after prequalification

• Confidence in scientific expertise of well-established RAs


Alternative regulatory pathways

USA FDA tentative approvals linked to PEPFAR– Included in WHO PQ List – Confidentiality agreement with US FDA in place

EU Article 58– For products exclusively to be used outside EU

Canadian Access to medicines scheme– WHO cooperation with the above mentioned– Confidentiality agreement in preparation



Multisource products Assessment • Quality: information on starting materials and finished product,

(API details, specifications, stability data, formulation, manufacturing method, packaging, labelling etc.)

• Interchangeability with reference product (efficacy and safety): Report of bio-equivalence, biovaiwer or clinical study demonstrating interchangeability with reference product

• Inspection of manufacturers and CROs• Laboratory analysis in case of need

Monitoring after prequalification


Simplified assessmentSimplified assessment

Prequalification of Multisource (generic) Finished Pharmaceutical Products approved by Stringent Regulatory Authorities

– Assessment report (waived for anti-TB or antimalarial medicines with 30 years of therapeutic experience - including 15 years in ICH region)

– 5 years of continuous manufacturing experience

– last Annual Product Report



Combined products, new dosage forms, new indications

Assessment • May require safety and efficacy data

Monitoring after prequalification


Outcomes of PQ procedureOutcomes of PQ procedure

Information in public domain: http://who.int/prequal/

Lists of PQ medicinal products WHOPAR (SPC, PIL, labelling) WHOPIR (both FPP and API) Notices of Concern and Suspension Information on progress of assessment procedure and

inspections Supportive documents: WHO guidelines, description of PQ

procedure


www.who.int/prequal/www.who.int/prequal/


Same principals applied in prequalification as valid for national regulatory approvals by stringent authorities

Same principals applied in prequalification as valid for national regulatory approvals by stringent authorities

Benefits prevail the risks at a time of regulatory approval and nothing indicates that benefits will not prevail also during use of product in normal medical practice

– Available data about quality (Dossier)– Available data about efficacy and safety or interchangeability (Dossier)– Available data are credible and were eticaly obtained

• Good practices (GLP, GCP, GPhVP, …)– Existing reassurance about production in stable quality and quality assurance

mechanisms• GMP

– Way of use of medicine characterized for physicians and patients • Data sheets, SPCs, PILs, package labeling

– Lack of knowledge is be properly manged• Pharmacovigilance, risk management programmes

– Evaluations and inspections follow WHO and/or ICH standards


Difference between PQP and national approval procedures

Difference between PQP and national approval procedures

Only certain categories of products are accepted

Voluntary - no direct legal implications

Free of charge (yet)

Assessment and inspections done by multinational teams

Assessment and inspection outcomes are publicly available, no negative conclusions and findings published (yet)

Issues of IPP fully in responsibility of applicant / manufacturer

Definitive negative conclusions exceptional

Technical assistance and regulatory support possible


Prequalified priority essential medicinesPrequalified priority essential medicines(July 2009)

Prequalified priority essential medicinesPrequalified priority essential medicines(July 2009)

164

80

1112

6

10

11

10

0

50

100

150

200

250

Combination

Mono-component


0

50

100

150

200

250

HIV/AIDS Tuberculosis Malaria

Prequalification procedures

HC assessment

FDA assessment

Innovators

Multisourceproducts


194

33

1

6899

11

11

11

12

12 16

India

France

South Africa

UK

Germany

Switzerland

USA

Canada

Spain

Netherlands

China

Australia

Morocco

Pakistan

Countries where prequalified medicines are Countries where prequalified medicines are manufactured manufactured (July 2009)

Countries where prequalified medicines are Countries where prequalified medicines are manufactured manufactured (July 2009)


Prequalification of Quality Control Laboratories

Prequalification of Quality Control Laboratories

Invitation for expression of interest issued by WHO

Laboratory Information File submitted by interested QCLs

If needed, technical assistance is provided

Inspection is organised

Currently 10 QCLs is prequalified, 25 in process of prequalification (mostly from Africa)

More information PQP website


QCLs Prequalification ProcedureQCLs Prequalification Procedure (1) (1)June 2009

QCLs Prequalification ProcedureQCLs Prequalification Procedure (1) (1)June 2009

83

10

3

16

3

22

8

24

10

25

0

5

10

15

20

25

30

35

2004 2005 2006 2007 2008 Jun-09

QCLs Prequalified QCLs Interested

Prequalified QCLs:

South Africa, RIIP+CENQAM (2005)

Algeria, LNCPP (2005)

South Africa, Adcock Ingram (2007)

Morocco, LNCM (2008)

Kenya, NQCL (2008)

India, Vimta Labs (2008)

France, CHMP (2008)

Vietnam, NIDQC (2008)

Kenya, MEDS (2009)

Singapore, HAS (2009)


Contribution of PQ to capacity buildingContribution of PQ to capacity building

Organization of trainings– general and problem specific (HIV/AIDS, TB and antimalarial

products, pediatric dosage forms, BE, BE/BCS, GMP)

– Trainings of NRA staff and manufacturers frequently combined

Involvement of assessors from NRAs into PQ assessment

Involvement of inspectors from NRAs into PQ inspections

3 months rotations of experts from NRAs in WHO HQ – PQT


4

9

4

11

4

0

2

4

6

8

10

12

14

16

2006 2007 2008

Trainings organized or supported by PQP

PQP supported

PQP organized


Topics of training workshops2006-2008

Topics of training workshops2006-2008

8

10

53

3

4

42

Prequalification advocacyPrequalification requirementsGood manufacturing practiceQuality controlBioequivalence/BCS and GCPAssessment of medicinesPharmaceutical developmentPQ general


165

198

103

57

263

301

568

0

100

200

300

400

500

600

700

2007 2008

Participants in trainings organized or supported by PQP

Others

QCL staff

Regulators

Manufacturers


Technical AssistanceTechnical Assistance

Provision of expert consultants to– Manufacturers – Quality control laboratories– Regulators

Assistance focuses on – GMP, GCP or GLP compliance– Regulatory guidance

Assistance is separated from the assessment / inspections and may be followed by specific trainings


Technical assistances organized by WHO PQP 2006-2008Technical assistances organized by WHO PQP 2006-2008

2

1

3

2

10

3

8

0

2

4

6

8

10

12

14

2006 2007 2008

REG

GPCL

GCP

GMP


Conditions for provision of technical assistance

Conditions for provision of technical assistance

Manufacturers:Participation in the prequalification programme,Found to be capable and willing to improveLocation in a developing country

Products: Inclusion in the list of expression of interestHigh value for Public Health purpose Poor representation on the Prequalification list.


Thank you for attention

[email protected]

who prequalification programme milan smid, m.d., ph.d. prequalification programme: priority...

Documents

access of priority medicines

safety of medicines

evaluation of quality

essential steps of monitoring

developing countries

inspections of manufacturers

associated countries

development countries