who prequalification of medicines programme prequalification of medicines programme general overview...

WHO Prequalification of WHO Prequalification of Medicines ProgrammeMedicines Programme

General overview and update

Milan Smid, M.D., Ph.D.Slides benefiting from presentations of WHO PQP colleagues and BioBridge Strategies

WHO PQP tutorial, 27th September, 2012, Mumbai

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PQP updateMumbai, 27 Sept, 2012

UN Prequalification Programmefor Priority Essential Medicines

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

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

procured using international funds (e.g. GFTAM, UNITAID) to serve patients in developing countries

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

medicines (FPPs and APIs), 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.

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Categories of medicines invited• Primary categories of medicines:

– HIV/AIDS– Malaria– Tuberculosis

• Later added:– Reproductive health– Influenza– Acute diarrhoea– Neglected tropical diseases

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

• Prequalification also applicable for APIs!

• Published in invitations for Expression of Interest (EOI) on Prequalification website

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5th Invitation for EOI, May 2010Reproductive health medicines (1)

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3rd Invitation for EOIActive Pharmaceutical Ingredients

Invited Active Pharmaceutical IngredientsTherapeutic area

Abacavir, Atazanavir, Darunavir, Didanosine, Efavirenz, Emtricitabine, Etravirine, Lamivudine, Lopinavir, Nelfinavir, Nevirapine, Raltegravir, Ritonavir, Stavudine, Tenofovir, Zidovudine

HIV/AIDS

Amodiaquine, Artemether, Artesunate, Dihydroartemisinin, Lumefantrine, Mefloquine, Piperaquine, Pyrimethamine, Pyronaridine, Sulfadoxine

Malaria

Amikacin, Capreomycin, Cycloserine, Ethambutol, Ethionamide, Isoniazid, Kanamycin, Levofloxacin, Moxifloxacin, Ofloxacin, Para-Aminosalicylic Acid (PAS), Prothionamide, Pyrazinamide, Rifampicin, Streptomycin, Terizidone

Tuberculosis

Desogestrel, Estradiol, Ethinylestradiol, Etonogestrel, Levonorgestrel, Medroxyprogesterone, Mifepristone, Misoprostol, Norethisterone, Norgestrel, Oxytocin

Reproductive health

Diethylcarbamazine, MebendazoleNeglected tropical diseases

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Expression of Interest

Dossier and SMF submitted for assessment

Two prequalification routes

Medicine assessedby SRA

Medicine notassessed by SRA

WHO assessmentand inspections

organized

Compliance Prequalification Acceptance

Simplified review

Valid for innovators and generics

SRA registration (assessment and

compliance check)

Invitation for expression of Interest

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Essential 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 dossiers – 'Expression of interest'• Dossiers receive initial screening• Full dossiers are assessed• Inspections are conducted at manufacturing sites and at CROs• Samples 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)

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Expressionof Interest

Compliance

Additional informationand data

Correctiveactions

Compliance

Assessment Inspections

Steps in WHO prequalification

Prequalification

Maintenance and monitoring

Product dossierSMF

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Essential steps of monitoring of PQ product

• Variations to the dossier of prequalified product

• Sampling and Testing

• Re-inspections

• Requalification

• Management of complaints

• De-listing or suspension (if and when appropriate)

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Principles

• Same principles apply as for national regulatory approvals by stringent authorities

– Data on quality (FPP, API)

– Data on efficacy and safety or interchangeability

– Compliance with GMP (FPP, API), GCP/GLP (bioequivalence studies)

– Benefits prevail risks

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Assessment of product dossiers

• One week meeting at least every 2 months, team of professionals from NMRAs– Botswana, Canada, China, Congo, Ethiopia, France, Georgia, Germany,

Ghana, Israel, Italy, Kenya, Malaysia, Netherlands, New Zealand, Portugal, Singapore, Spain, South Africa, Sweden, Switzerland, Tanzania, Uganda, UK, Zambia, Zimbabwe ...

• Combined with capacity building• Quality assurance of outcomes

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Inspections• Team of inspectors for each inspection

• WHO 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 etc

• Inspections are product oriented and include data verification

• APIs and Bioequivalence studies inspected based on risk assessment

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Standards• WHO standards as defined in WHO guidelines are applied in

prequalification process

• If these not exist, ICH guidelines are applied

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

• Pharmacopoeias (Ph.Int., USP, BP, Ph.Eur., JP) as minimum standard – Depending on product, assessors may ask for additional tests or

tightening limits

• WHO GMP guidelines (compatible with PIC/S; references to pharmacopoeias, e.g. harmonized monographs)

• WHO GCP guidelines + Additional guidance for organizations performing in vivo bioequivalence studies (compatible with ICH)

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Adapting the CTD-NDS (new drug) to CTD-ANDS (generic)

RegionalAdmin

InformationModule 1

NonclinicalOverview

NonclinicalSummary

ClinicalOverview

ClinicalSummary

QualityOverall

Summary

Quality NonclinicalStudy Reports

ClinicalStudy Reports

Module 3 Module 4 Module 5

Module 2

Not Part ofthe CTD

The CTD

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Demonstration of bioequivalence

PD studies Clinicalstudies

In vitromethods

Bioequivalence study

ONLY EXCEPTIONAL!

or

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WHO BCS-based biowaiver

Active substances selected for biowaivingby WHO

HIV/AIDS:• Lamivudine (BCS 3)• Stavudine (BCS 1)• Zidovudine (BCS 1)• Abacavir sulphate

(BCS 3)• Emtricitabine (BCS 1)

TB:• Levofloxacin (BCS 1)• Ofloxacin (BCS 1)• Ethambutol ((BCS 3)• Isoniazid (BCS 3)• Pyrazinamide (BCS 3)

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Time to PQP Approval• The time to PQP approval can vary significantly but is influenced

principally by the quality of the application and company response time

• The mean time to approval in 2011 was 24 months– 8.4 months PQP processing time (35%)– 15.6 months manufacturer response time (65%)

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Outcomes of PQ procedureInformation in public domain:

http://www.who.int/prequal/• List of PQ medicinal products• WHOPAR (SPC, PIL, labelling)• WHOPIR (both FPP and API)• Notices of Concern and Suspensions• Information on progress of assessment procedure and

inspections • Supportive documents: WHO guidelines, description of

PQ procedure, training materials

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Prequalified medicines1 June 2012

+ 93 listed based on the– approval by US FDA = 16 (HIV only)– tentative approval by US FDA = 73 (HIV only)– approval within Canada's Access to Medicines Regime = 1 (HIV)– approval by EMA according to Article 58 = 3 (2 HIV + 1 Malaria)

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Prequalified medicines according to countries of manufacture (1 June 2012)

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Capacity building - objectives• Good quality submissions for PQ supported by

compliance with "good practices"– platform for improvement of drug development, manufacturing,

documentation and quality control• Fast regulatory approvals of PQ medicines in recipient

countries– technical education of regulators as a platform for strengthening

expertise, regulatory efficiency and networking• Reliable quality monitoring

– technical education of staff of QCLs to strengthen expertise, effectiveness of quality monitoring and networking

PQP standards and PQP example support strengthening of regulatory systems and capacity of manufacturers in general

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PQP updateMumbai, 27 Sept, 2012TBS

, Nov

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Technical Assistance• Provision of expert consultants to

– Manufacturers – Quality control laboratories– Regulators

• Assistance focuses on – GMP, GCP or GLP compliance– Dossier development

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

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Conditions for provision of technical assistance

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

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

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Technical assistances in countries

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Frequent misunderstandings• Manufacturers/manufacturing sites are

prequalified• PQP issues WHO GMP certificates• PQP provides direct financial support• Prequalification gives right to succeed in tenders• PQ substitutes national authorization

(registration) in recipient countries• All medicines used in treatment of HIV/AIDS and

tropical diseases are invited for PQ• Prequalified medicines may bear WHO logo

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Principles of proposed processPrinciples of proposed process• Availability of PQP assessment, inspection outcomes and

advice to facilitate national regulatory decisions making (registrations, variations, withdrawals)

• No interference with national legislation, decision making process and regulatory fees

• Co-operation among product manufacturer (PQP holder), NMRA in interested country and PQP to overcome confidentiality issues and assure information flow

• Procedure applicable for individual products

• Procedure voluntary for manufacturers and NMRAs

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Steps of the procedure: agreement Steps of the procedure: agreement

Interested NMRAs agree to participate in the procedure

PQP lists committed NMRAson its website

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Manufacturer informs PQP about national submission and

gives consent with information sharing

Participating NMRA confirms its interest to participate in procedure for specific product

PQP shares with participating NMRA outcomes of assessment and inspections

Participating NMRA reviews WHO PQP outcomes, decides within 90 days decides upon the national registration and informs PQP about its decision

Steps of the procedure: registrationSteps of the procedure: registrationPQ product is submitted for national registration

to NMRA participating in the procedureNMRA is informed about the interest to follow PQP

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WinWin--win outcomes for all stakeholderswin outcomes for all stakeholders• NMRAs

– Availability of WHO assessment and inspection outcomes to support national decisions

– Opportunity for learning from experienced assessors– Saving internal capacities– Demonstrating NMRA efficiency

• WHO– Prequalified medicines are faster available to patients

• Procurers– Faster start of procurement

• Manufacturers– Harmonized data for PQ and national registration– Facilitated interaction with NMRAs in assessment and

inspections– Accelerated registration

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• A panel of experts hosted by WHO since 2009• Assesses the potential risks/benefits associated with the

use of FPPs that are not yet WHO-prequalified or SRA-authorized

• Eligibility criteria for dossier submission: product manufactured in GMP compliant site and dossier submitted to and accepted for review by WHO PQP or a SRA

• Assesses abbreviated product dossiers submitted by manufacturers (questionnaire + annexes)

• Makes time limited recommendations: validity maximum 12 months-contracts can be signed any time up to one year

Expert Review Panel (ERP)Expert Review Panel (ERP)

ERP status does not replace WHO PQ/SRA approval ERP status does not replace WHO PQ/SRA approval but should be seen as a step towards WHO PQ/SRA approvalbut should be seen as a step towards WHO PQ/SRA approval

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Products reviewed by the ERP since 2009Data from Dec 2011

• 5 rounds completed

• 348 product dossiers were submitted and reviewed by ERP;

• 69 products were permitted for use for a one year period;

• during the ERP period validity:– 30 products have been WHO prequalified– 7 products have been authorized by an SRA

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Reported Procurement information http://www.theglobalfund.org/en/procurement/pqr/

• Products/Manufacturers distribution

ARV Anti-malarial

anti-TB

Branded: 34%

Branded: 70%

Branded: 22%

Generic: 66%

Generic: 30%

Generic:78%

Over 1, 400 million* US$ of transactions reported in the PQR system

Sophie Logez, GFATM, March 2011

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HIV / AIDS51 recipient countries

Malaria29 recipient countries

Tuberculosis76 recipient countries

> US$600 mil > US$300 mil- Cross cutting programs: US$109 m for PQ of drugs & diagnostics and transversal programs

> US$200 mil

COUNTRIES RECEIVING COMMODITIESUS$1.1Billion UNITAID funds

Lorenzo Witherspoon, UNITAID, March 2011

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What kind of investments does a company haveto make to in seeking prequalification of a product?

Bioequivalence

Formulation development

Stability studies

Dossier preparation

Capital

Clinical and analytical studies to validate the equivalence to the established comparator

If a company does not have a product on the market, it has to develop the formulation as specified by the EOI.

Stability studies have to be carried out on multiple batches of material for climatic zone IV

PQP requires CTD format of dossier and few additional specific documents and has well-defined requirements. The preparation and support require investment of personnel.

Money may be needed for investment in both R&D and manufacturing equipment as well as quality control systems. Capital is also needed for facilities upgrades and construction of new facilities.

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Investments varies depending on the experience of a company

Global companyBioequivalence Low

Dossier Preparation Low

Capital $ 0

InexperiencedBioequivalence High

Dossier Preparation High

Capital High

Local manufacturerBioequivalence Medium - High

Dossier Preparation Medium

Capital Low - Medium

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Potential benefits for manufacturers• Participation in tender procedures organized by national and

international procurers and financial profit• Recognition as being WHO listed company• Demonstration of social responsibility • Facilitated registration in some recipient countries• Reduction of inspections from recipient countries• Possibility to be assisted by expert consultants (GMP, dossier,

BE)• Learning process improving company's chance to succeed

with submissions to SRAs• Identified sources of quality assured APIs• Potential additional incentives (pro-export and pricing policies)

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Who should you contact at the WHO Prequalification of Medicines Programme• General enquiries: Jacqueline Sawyer, Liaison Officer,

[email protected]• Dossier submission and assessment: Dr Matthias Stahl, Head

of Assessments, [email protected]• Prequalification of APIs: Dr Antony Fake, [email protected]• Inspections: Ian Thrussell, Head of Inspections,

[email protected]• Training and technical assistance: Dr Milan Smid,

[email protected]• Prequalification of medicines quality control laboratories: Dr

Jitka Sabartova, [email protected]

mailto:[email protected]

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Thank you for the attention

[email protected]

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