Prequalification Programme
Quality Control Laboratories
Olivier Gross, Jitka Sabartova
Prequalification Programme: Priority Essential Medicines
HTP/PSM/QSM
UN Prequalification Programme
for Priority Essential Medicines
 Action plan of UN from 2001 for expanding access of
priority medicines to patients with
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HIV/AIDS
Malaria
Tuberculosis
Reproductive health
Potentially other categories of products
• Antiviral medicines efficacious for avian flue
• Paediatric formulations
2 | QCL Training | 26-29 novembre 2007, Rabat, Maroc
UN Prequalification Programme
for Priority Essential Medicines
 WHO PQ Team working in co-operation with partners
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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
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Elements 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
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Prequalification 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
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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)
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Based 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
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Invitation 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
8 | QCL Training | 26-29 novembre 2007, Rabat, Maroc
Steps 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
9 | QCL Training | 26-29 novembre 2007, Rabat, Maroc
Steps of the procedure
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
10 | QCL Training | 26-29 novembre 2007, Rabat, Maroc
Steps of the procedure
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
11 | QCL Training | 26-29 novembre 2007, Rabat, Maroc
Steps of the procedure
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
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Steps of the procedure
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
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Steps of the procedure
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
14 | QCL Training | 26-29 novembre 2007, Rabat, Maroc
Steps of the procedure
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
15 | QCL Training | 26-29 novembre 2007, Rabat, Maroc
Status of prequalification of QC Labs
November 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
16 | QCL Training | 26-29 novembre 2007, Rabat, Maroc
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
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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
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Frequent deficiencies and weak points (2)
 Maintenance of the equipment
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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 nonexisting
18 | QCL Training | 26-29 novembre 2007, Rabat, Maroc
Frequent deficiencies and weak points (3)
 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.)
19 | QCL Training | 26-29 novembre 2007, Rabat, Maroc
Technical 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
20 | QCL Training | 26-29 novembre 2007, Rabat, Maroc
Training
 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
21 | QCL Training | 26-29 novembre 2007, Rabat, Maroc
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
22 | QCL Training | 26-29 novembre 2007, Rabat, Maroc
Sampling and Testing (2)
 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
23 | QCL Training | 26-29 novembre 2007, Rabat, Maroc
Sampling and Testing (3)
 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
24 | QCL Training | 26-29 novembre 2007, Rabat, Maroc
Thanks for your attention
25 | QCL Training | 26-29 novembre 2007, Rabat, Maroc