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Prequalification ProgrammePrequalification Programme

Quality Control Laboratories

Olivier Gross, Jitka Sabartova

Prequalification Programme: Priority Essential Medicines

HTP/PSM/QSM

QCL Training | 26-29 novembre 2007, Rabat, Maroc 2 |

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– Potentially other categories of products

• Antiviral medicines efficacious for avian flue• Paediatric formulations


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

WHO PQ Team working in co-operation with partners

– UNICEF– UN Population Fund (UNFPA)– UNAIDS– UNITAID– The Global Fund– World Bank

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


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


Prequalification of QC laboratoriesPrequalification of QC laboratories

Need to increase the access to QC laboratories that

– meet recommended standards for testing of medicines

– are committed to provide a service of testing of medicines, including but not limited to HIV/AIDS, Tuberculosis and Malaria products to UN agencies

Procedure established in 2004

Participation of a QC laboratory is voluntary


Procedure for assessing the acceptability, in principle, of quality control laboratories for use by UN agencies

Procedure for assessing the acceptability, in principle, of quality control laboratories for use by UN agencies

Published in 2004 (WHO TRS, No. 917, Annex 4)

Revision published in 2007 (WHO TRS, No. 943, Annex 5)

Related documents– Good practices for national pharmaceutical control laboratories (WHO

TRS, No. 902 Annex 3)

– WHO GMP: main principles for pharmaceutical products. In: Quality assurance of pharmaceuticals. A compendium of guidelines and related materials. Vol. 2, 2nd updated edition. Good manufacturing practices and inspection (Geneva, World Health Organization, 2007)

– Guidelines for preparing a laboratory information file (WHO TRS, No. 917, Annex 5)


Based on the following principlesBased on the following principles

Reliance on the information supplied by the national drug regulatory authority

General understanding of the quality control activities of the laboratory

Evaluation of information submitted by the laboratory

Assessment of consistency in quality control through compliance with GMP(s) and WHO guidelines


Invitation for Expression of InterestInvitation for Expression of Interest

3rd EOI published in September 2007– http://www.who.int/prequal/info_applicants/eoi/EOI-QCLabsV3.pdf

Previous invitations limited to QC laboratories in Africa, currently no regional limitation

Priority in the assessment will be given to– National QC laboratories and laboratories providing testing

services to the government– QC laboratories in areas where UN agencies identify the need for

quality testing

Any laboratory (private or governmental) can participate


Steps of the procedureSteps of the procedure

1. Expression of interest

2. Submission of laboratory information− Laboratory Information File - LIF needed to get basic information on

laboratory's activities and suggested scope of prequalification

− A good LIF makes the procedure faster

− Guidelines for preparing LIF available• Documentation and QA system, Personnel, Handling of samples, Materials,

Premises, Equipment, Contract operations and activities, Out-of-specification investigation, Self-inspection

• Stability Testing, Microbiological testing, Water system, where applicable − Quality Manual can be submitted (amended as necessary)− Evidence of participation in proficiency testing schemes



3. Screening of submitted laboratory information− Formal completeness

− Amendment requested, if necessary

4. Evaluation of the laboratory information− WHO carries out evaluation of LIFs to assess the laboratory's

potential to pass successfully the inspection

− If the LIF indicates that the laboratory would comply - WHO starts arranging an inspection

– If the LIF is not adequate – WHO• Starts arranging an inventory audit or• Asks for more information or• Returns the LIF



5. Site inspection / inventory audit

− Planned and coordinated by WHO (normally for 2-3 days)

− Experts appointed by WHO preferably from regulatory authority inspectorates, experienced in quality control

• Required to sign declaration of interest and confidentiality declaration

− Compliance with WHO recommended standards• Good Practices for National Pharmaceutical Control Laboratories• Good Manufacturing Practices as recommended by WHO for such

laboratories– ISO certification encouraged and considered– However, GMP aspects to be taken into account during inspection



5. Site inspection / inventory audit (cont.)

− For the inspection representative(s) of the DRA of the country where the laboratory is located invited

− Inventory audit less formal, combined with discussions of problems and assessment of need of technical assistance



6. Report and outcome of evaluation− Final Report in the established WHO format communicated to the

laboratory and a copy sent to the national DRA– If corrective actions to be taken by the laboratory, WHO postpone

its final recommendations until the corrective action has been evaluated and found satisfactory

− In case of disagreement, possibility of an appeal− Ownership of the report lies with WHO

7. Results of assessment– Information is sent to the laboratory and national DRA– If compliant, laboratory is included in the published list and

WHOPIR is published– The list will be subjected to review at least once a year



8. Re-evaluation after prequalification

− On-going monitoring

Re-inspections at regular intervals (normally 3 years)

Evaluation of results from participation in proficiency testing schemes

− WHO External Quality Assurance Scheme, AFSSAPS network of Francophone African countries

− WHO may suspend or withdraw a laboratory from the list when there is evidence of noncompliance



9. Monitoring of complaints− WHO will investigate complaints concerning the results of

analysis or service provided by the laboratory• Written report and where appropriate recommendations for action • Copy of the report to the laboratory, manufacturer of the product and

DRA of the country where the manufacturing site is located• DRA could also be invited to participate in the investigation of the

complaint

10.Cost recovery– WHO reserves the right to charge for the quality assessment

procedure on a cost-recovery basis


Status of prequalification of QC LabsNovember 2007

Status of prequalification of QC LabsNovember 2007

4 QC laboratories prequalified– South Africa, CENQAM - 6/2005

– South Africa, RIIP - 7/2005

– Algeria, LNCPP - 10/2005

– South Africa, Adcock Ingram – 8/2007

2 QC laboratories near to PQ

11 QC laboratories audited, corrective measures proposed

6 QC laboratories expressed interest, but not send LIF yet


Frequent deficiencies and weak points (1)Frequent deficiencies and weak points (1)

Quality system– SOPs not covering, not properly maintained– No quality responsible– No or not enough self-audits

Personnel– No qualification system– Not enough training, no training programmes– Responsibilities and tasks not clearly defined on personal level,

vague organization

Premises– Too small and unfit– Limited and unfit storage areas (lot of cupboards etc. needed)– No regular environmental (at least temperature) monitoring– Archives not good, nor secured



Maintenance of the equipment – No proper or only partial qualifications– Documentation in general very deficient– Not adequate training by the suppliers in the beginning– No pre-maintenance programme

Reference materials and reagents – Maintenance system and records not efficient, nor clear– No working standards system

Instructions / methods – No clear system as to which pharmacopoeial or manufacturers'

method to use– Validations/ verifications of methods not sufficient or non-

existing



Waste management – Not properly organized

Safety – Fume hoods lacking or too few– No or insufficient protection of the personnel

(e.g. insufficient protective garments, no training, no safety sheets of the chemicals)

– No classification nor proper storage of dangerous chemical materials (e.g. toxics, caustic / volatile reagents etc.)


Technical assistanceTechnical assistance

Technical assistance provided to 5 national medicines quality control laboratories

– Assistance in implementation of quality system

– Assistance in microbiological testing

– 1 – 3 weeks

Capacity building and technical assistance provided to national QC laboratories out of the scope of the prequalification procedure


TrainingTraining

Participation in Quality Assurance training of OMCLs organized by EDQM

– October 2005, 5 participants from AFRO and EMRO

– September 2007, 12 participants from AFRO, EMRO and EURO

Trainings in Quality Assurance, Quality Control and Ph.Int. under preparation

– November 2007, Morocco, 40 participants from Francophone countries (AFRO, EMRO), cooperation with EDQM

– December 2007, Tanzania, 40 participants from Anglophone countries (AFRO, EMRO)

Trainings planned in 2008– Market surveillance projects, Networking of African laboratories


Sampling and Testing (1)Sampling and Testing (1)

Survey of the quality of antiretroviral medicines circulating in selected African countries

– Carried out in June-December 2005, report now finalized

– 7 countries (Cameroon, DR of Congo, Kenya, Nigeria, Tanzania, Uganda and Zambia)

– Monocomponent products (didanosine, efavirenz, lamivudine, nevirapine, stavudine, zidovudine), FDCs (lamivudine/zidovudine, stavudine/lamivudine, stavudine/lamivudine/nevirapine)

– 394 samples from official procurement and treatment centres, both private and public

– Testing according Ph.Int., USP, Indian Pharmacopoeia, validated in-house Swissmedic methods (laboratory Swissmedic)

– Tests performed - Appearance, Labelling, Identification, Uniformity of mass (capsules/tablets), Dissolution/disintegration, pH (oral solutions-depending upon the matrix), Related substances, Content of each active ingredient



Survey of the quality of antiretroviral medicines circulating in selected African countries - Findings

– Very low failure of 1.8%, no critical deficiencies• 1 sample with broken tablets, 2 samples insufficiently labelled,

1 sample with higher content, 1 sample failed to disintegrate in 30', 2 samples lower dissolution

• 53% prequalified products• In 3 countries found non-registered products, mostly in private

sector (12% of 394 samples)

– Positive effect of common efforts of NDRAs, WHO and others involved in prequalification and purchase policies

– Limited to official distribution points and treatment centres around the capital cities



Current activities– Quality survey of antimalarials

• ACTs, sulfadoxine-pyrimethamine in 9 African countries

– Quality monitoring within UNITAID projects• Paediatric ARV FDCs, cotrimoxazol, second line ARVs

– Dissolution of Coartem tablets

– Generic products containing nelfinavir• EMS/MMS impurity, dissolution

– Monitoring of quality of WHO prequalified products• Verification that WHO-prequalified products procured by agencies comply with the

specifications approved within PQ process

– Testing on request from countries• Arsuamoon tbl (co-blistered artesunate+amodiaquine), Guilin Pharma, China - from Indonesia• Diethylcarbamazine citrate tbl, Asian Pharmaceutical Company, Nepal – from Nepal


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