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WHO Sampling and Testing WHO Sampling and Testing ProgrammesProgrammes
Jitka SabartovaWHO Prequalification Programme: Priority Essential Medicines
HSS/EMP/QSM
Interregional Seminar for Quality Control Laboratories involved in WHO Prequalification Programme and/or participating in respective sampling and testing projects, Nairobi, Kenya, 23-25 September 2009
2-4
Sampling and testing for Quality Control Laboratories, Nairobi, September 20092 |
WHO Prequalification ProgrammeWHO Prequalification Programmemonitoring of medicines quality monitoring of medicines quality
WHO Prequalification ProgrammeWHO Prequalification Programmemonitoring of medicines quality monitoring of medicines quality
Policy– To monitor quality of medicines procured by UN agencies/
prequalified products
– To contribute to quality control of medicines, if requested by Member States
– To contribute to capacity building by cooperation with NDRAs
Sampling and testing projects– A tool for fulfilling the policy
Sampling and testing for Quality Control Laboratories, Nairobi, September 20093 |
Sampling and testing projectsSampling and testing projects
Conduct of projects
Plan+updates
P1 P2 P3
Actions Reports
InspectionsAssessment
PhV
Entryinformation
Quality concerns,complaints/defects ,
signals, inspectionsPQ procedures
…
Sampling and testing for Quality Control Laboratories, Nairobi, September 20094 |
Planning of projectsPlanning of projects
Commitments Signals
Evaluation ,discussion with experts, if needed Draft plan
Discussion with experts
Plan
Action needed?
Conduct of projects
NO
YES
Entry information
Urgent action?
End
YES
NO
Sampling and testing for Quality Control Laboratories, Nairobi, September 20095 |
Conduct of a project (1)Conduct of a project (1)
Setting OBJECTIVES of the project
Drafting protocol, its commenting and approval
Selection of the testing laboratory/ies and sampling organizationsAgreements, incl. financial arrangements
Collection of samples
Storage and dispatch of samples
1
Sampling and testing for Quality Control Laboratories, Nairobi, September 20096 |
Conduct of a project (2)Conduct of a project (2)
Receipt and check-in of samples by the laboratory
Testing of samples
Monitoring of quality of labels and package inserts,
if required
Evaluation of reported data and discussion with involved parties
Project report Actions
1
Conclusions and recommendations
Laboratory report Report
Sampling and testing for Quality Control Laboratories, Nairobi, September 20097 |
Project protocol (1)Project protocol (1)
Background information
Objectives (limitations)
Selection of countries and medicines– Procured volumes, existing regulation, stability of medicines
Selection of sample collection sites – cooperation with NDRAs– Levels of distribution, regions, transport and storage conditions
Instructions for sample collection - the more detailed the better– Definition of sample– Number of dosage units or multidose packages to be collected– Time period– Sample collection form (incl. monitoring storage conditions at collection sites)– Handling and storage of samples– Training of collectors
Sampling and testing for Quality Control Laboratories, Nairobi, September 20098 |
Project protocol (2)Project protocol (2)
Selection of tests to be conducted– Closely related to the project objectives– In principle
• Appearance• Identity and content of active ingredient/s, related substances• Uniformity of dosage units, dissolution/disintegration, pH• Sterility, bacterial endotoxins/ pyrogens
Selection of specifications– If products from more manufacturers collected – pharmacopoeial specs easier,
but it has to be taken into account when making conclusions– Differences in pharmacopoeial monographs to be considered
• Procaine Benzylpenicillin injection - PhInt spectrophotometry for total penicillins and titration for procain, no related substances; USP iodometric assay for antibiotics, no related substances; BP(Vet) HPLC for related substance and assay
– Laboratory validated method
Sampling and testing for Quality Control Laboratories, Nairobi, September 20099 |
Project protocol (3)Project protocol (3)
Content of the laboratory report
Monitoring of quality of labels and package inserts– Evaluation of the compliance with the national requirements
– Assessment of quality and completeness of essential information in package inserts
Handling of results– Non-compliant results pre-discussed with the respective NDRA and
manufacturer
– All results provided to NDRAs involved in the project and discussed
– Corrective actions recommended
– Adoption of the relevant measures in the responsibility of the respective NDRA
– Agreed outcomes and report from the project published
Sampling and testing for Quality Control Laboratories, Nairobi, September 200910 |
Quality control laboratories usedQuality control laboratories used
Importance of reliability
WHO Prequalified laboratories used, if available
If not, laboratories for which the evidence of reliability is available
– European OMCL network
– Inspection report
Sampling and testing for Quality Control Laboratories, Nairobi, September 200911 |
WHO QCLs Prequalification Procedure (1)
September 2009WHO QCLs Prequalification Procedure (1)
September 2009
83
10
3
16
3
22
8
24
11
24
0
5
10
15
20
25
30
35
2004 2005 2006 2007 2008 Sep-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, HSA (2009) Singapore, TÜV (2009)
Sampling and testing for Quality Control Laboratories, Nairobi, September 200912 |
WHO QCLs Prequalification Procedure (2)
September 2009WHO QCLs Prequalification Procedure (2)
September 2009
14
5
5
1
3
1
21
3
0
2
4
6
8
10
12
14
16
18
20
AFRO EMRO EURO SEARO WPRO
QCLs interested QCLs prequalified
9
26
National QCLs Other QCLs
Sampling and testing for Quality Control Laboratories, Nairobi, September 200913 |
Sampling and testing for Quality Control Laboratories, Nairobi, September 200914 |
Sampling and testing for Quality Control Laboratories, Nairobi, September 200915 |
WHO-PQ Capacity buildingWHO-PQ Capacity buildingWHO-PQ Capacity buildingWHO-PQ Capacity building
Capacity building focuses on national QC laboratories Organization of trainings
– Trainings in Quality Assurance, Quality Control and Ph.Int. (2007)• Morocco, 44 participants from 16 Francophone countries (AFRO, EMRO), cooperation with EDQM and
AFSSAPS• Tanzania, 46 participants from 23 Anglophone countries (AFRO, EMRO, PAHO/AMRO)
– Training on rational sampling and testing in quality control of medicines (2009)• Nairobi, 48 participants from 22 countries (AFRO, EMRO, WPRO)
– Participation in EDQM Quality Assurance training for OMCLs• 2005, 5 participants from AFRO and EMRO; 2007, 12 participants from AFRO, EMRO and EURO
Technical assistance provided to 8 national medicines QC laboratories – Focus on implementation of quality system and microbiological testing, inventory audits
Organization of proficiency testing for national quality control laboratories– WHO External Quality Assurance Scheme - free of charge
Sampling and testing for Quality Control Laboratories, Nairobi, September 200916 |
Survey of the quality of antiretroviral medicines circulating in selected African countries (1)
Survey of the quality of antiretroviral medicines circulating in selected African countries (1)
Carried out in 2005, report published – http://www.who.int/prequal/info_general/documents/ARV_survey.pdf
42 collection sites in 7 countries, cooperation with NDRAs
– Cameroon, DR of Congo, Kenya, Nigeria, Tanzania, Uganda and Zambia
394 samples of monocomponent products and FDCs
– didanosine, efavirenz, lamivudine, nevirapine, stavudine, zidovudine
– lamivudine/zidovudine, stavudine/lamivudine, stavudine/lamivudine/nevirapine
Sampling and testing for Quality Control Laboratories, Nairobi, September 200917 |
Survey of the quality of antiretroviral medicines circulating in selected African countries (2)
Survey of the quality of antiretroviral medicines circulating in selected African countries (2)
Testing in Swissmedic– Ph.Int., USP, Indian Pharmacopoeia, validated in-house
Swissmedic methods
– Appearance, identity and content of active ingredient/s, related substances, uniformity of mass, dissolution/disintegration, pH
Very low failure of 1.8%, no critical deficiencies– 1 sample higher API content, 1 sample failed to disintegrate in 30',
2 samples lower dissolution
Sampling limited to official procurement and treatment centres and capital cities
Positive effect of common efforts of NDRAs, WHO and others involved in prequalification and purchase policies
Sampling and testing for Quality Control Laboratories, Nairobi, September 200918 |
Quality monitoring of medicines funded by UNITAID (1)
Quality monitoring of medicines funded by UNITAID (1)
Strengthening quality control in close cooperation with NDRAs– Evaluation of the quality of medicines close to patients– Evaluation of compliance with national requirements for information on external
and primary packaging and in package inserts – Capacity building of NDRAs by involving them in organization of the project
Framework protocol supplemented by country specific sampling plans prepared by NDRAs
Pilot phase– Paediatric and second line ARVs + co-trimoxazole– Kenya, Tanzania, Uganda and Zambia– Samples collected mostly in treatment centres, throughout regions– 383 samples from 24 manufacturers– Majority of collected medicines registered in the country (for some information
missing)
Sampling and testing for Quality Control Laboratories, Nairobi, September 200919 |
ProductNo of samplesNo of manufacturers
No of countries
Lamivudine - Oral solution/ Tablets2433
Nevirapine - Oral suspension/ Tablets3423
Stavudine - Capsules/ Powder for oral solution2423
Zidovudine - Capsules/ Tablets/ Oral Solution3233
Lamivudine + Stavudine - Tablets821
Lamivudine + Zidovudine - Tablets211
Lamivudine + Stavudine + NevirapineDispersible tablets/ Tablets/ Tablets for oral suspension
5833
Abacavir - Oral solution/ Tablets2133
Didanosine - Dispersible tablet/ Enteric coated capsules /Powder for oral solution
1321
Efavirenz - Capsules/ Tablets2422
Tenofovir - Tablets1011
Emtricitabine + Tenofovir - Tablets2922
Lopinavir + Ritonavir - Tablets3413
Trimethoprim + Sulphamethoxazole - Oral suspension/ Tablets70144
Sampling and testing for Quality Control Laboratories, Nairobi, September 200920 |
Quality monitoring of medicines funded by UNITAID (2)
Quality monitoring of medicines funded by UNITAID (2)
Pilot phase - testing– Testing in MHRA (UK), AFSSAPS (France), NICPBP (China)– Tests performed
• Appearance• Identity• Content of active ingredient/s• Related substances• Uniformity of mass• Dissolution• pH
– Specifications
Sampling and testing for Quality Control Laboratories, Nairobi, September 200921 |
ProductSpecifications
Lamivudine - Oral solution/ Tablets
Ph.Int.Ph.Int., dissolution manufacturer
Nevirapine - Oral suspension/ TabletsUSP
Stavudine - Capsules / Powder for oral solution
Ph.Int., dissolution USPUSP
Zidovudine - Capsules/ Tablets / Oral Solution
Ph.Int., dissolution USPPh.Int.
Lamivudine + Stavudine - TabletsIndian Ph.
Lamivudine + Zidovudine - TabletsPh.Int., dissolution manufacturer
Lamivudine + Stavudine + NevirapineDispersible tablets/ Tablets/ Tablets for oral suspensionIndian Ph.
Abacavir - Oral solution/ TabletsPh.Int., dissolution manufacturer
Didanosine - Enteric coated capsules / Dispersible tablet/ Powder for oral solution
ManufacturerPh.Int., dissolution manufacturerPh.Int.
Efavirenz - Capsules/ TabletsIndian Ph.
Tenofovir - TabletsManufacturer
Emtricitabine + Tenofovir - TabletsManufacturer
Lopinavir + Ritonavir - TabletsLaboratory
Trimethoprim + Sulphamethoxazole - Oral suspension/ TabletsUSP
Sampling and testing for Quality Control Laboratories, Nairobi, September 200922 |
Quality monitoring of medicines funded by UNITAID (3)
Quality monitoring of medicines funded by UNITAID (3)
Pilot phase - results– Non-compliance
• 2 samples LAM+STA+NEV dispersible tablets collected in Zambia low stavudine content (83%)
(4 samples from the same batch OK, complaint to the manufacturer)• 1 sample Trimethoprim+Sulfamethoxazol collected in Kenya higher trimethoprim impurity
– Problems solved• All Didanosine dispersible tablets samples (2 manufacturers) additional peaks in related
substances test, placebo requested from manufacturers peaks due to excipients• All Nevirapine oral suspension samples (2 manufacturers) additional peaks in related
substances test, placebo requested from manufacturers peaks due to excipients• All LAM+STA+NEV tablets showed low nevirapine dissolution when tested according to
Indian Ph. Conditions, dissolution method requested from both manufacturers compliant results
– Majority of collected medicines WHO prequalified
Sampling and testing for Quality Control Laboratories, Nairobi, September 200923 |
WHO Prequalified priority essential medicines(September 2009)
WHO Prequalified priority essential medicines(September 2009)
164
80
11
12
6
10
1
26
0
0
50
100
150
200
250
HIV/AIDS
Tuberculosis
Malaria
Reproductive health
Influenza
Combination
Mono-component
Sampling and testing for Quality Control Laboratories, Nairobi, September 200924 |
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 WHO prequalified medicines are manufactured (July 2009)
Countries where WHO prequalified medicines are manufactured (July 2009)
Sampling and testing for Quality Control Laboratories, Nairobi, September 200925 |
Quality survey of antimalarial medicines in selected African countries (1)
Quality survey of antimalarial medicines in selected African countries (1)
ACTs (most sold and recommended by national guidelines), sulfadoxine-pyrimethamine, oral dosage forms
– Artemether/lumefantrine, artesunate/amodiaquine (both co-blistered and FDCs), sulfadoxine/pyrimethamine, sulfamethoxypyrazine/pyrimethamine
Cameroon, Ethiopia, Ghana, Kenya, Nigeria, Tanzania Collection of samples
– At all levels of distribution chain (private and public) and informal market, throughout the countries
– In cooperation of NDRAs with WHO country offices– 936 samples collected
Testing– Screening of all collected samples by Minilab– 305 samples then tested in RIIP, South Africa (296 samples) and USP laboratory,
USA (9 samples)
Sampling and testing for Quality Control Laboratories, Nairobi, September 200926 |
Quality survey of antimalarial medicines in selected African countries (2)
Quality survey of antimalarial medicines in selected African countries (2)
160
46
102
40
175
56
154
44
200
75
145
44
0
20
40
60
80
100
120
140
160
180
200
Cameroon Ethiopia Ghana Kenya Nigeria Tanzania
Samples collected Samples tested
Sampling and testing for Quality Control Laboratories, Nairobi, September 200927 |
Quality survey of antimalarial medicines in selected African countries (3)
Quality survey of antimalarial medicines in selected African countries (3)
No of samplestested
No of manufacturers
No of samplestested
No of manufacturers
No of samples tested
No of manufacturers
Artemether / LumefantrineArtesunate + Amodiaquine co-blistered
Artesunate + Amodiaquine FDC
Cameroon15210452
Ethiopia1520000
Ghana19917611
Kenya2341100
Nigeria21821974
Tanzania1510000
Sampling and testing for Quality Control Laboratories, Nairobi, September 200928 |
Quality survey of antimalarial medicines in selected African countries (4)
Quality survey of antimalarial medicines in selected African countries (4)
No of samplesNo of manufacturers
No of samplesNo of manufacturers
Sulfadoxine / PyrimethamineSulfamethoxypyrazine / Pyrimethamine
Cameroon16700
Ethiopia25500
Ghana191000
Kenya19511
Nigeria251311
Tanzania23374
Sampling and testing for Quality Control Laboratories, Nairobi, September 200929 |
Quality survey of antimalarial medicines in selected African countries (5)
Quality survey of antimalarial medicines in selected African countries (5)
Tests performed– Appearance– Identity and content of active ingredient/s– Artemether related substances– Uniformity of mass, dissolution, pH
Specifications
Results are currently evaluated Assessment of quality of product information (Labelling and PIL)
Artemether / Lumefantrine - TabletsPh.Int., dissolution manufacturer
Artesunate + Amodiaquine - Co-blistered tabletsArtesunate - Ph.Int., dissolution laboratoryAmodiaquine - USP
Artesunate / Amodiaquine - FDC tabletsLaboratory
Sulfadoxine / Pyrimethamine - TabletsUSP
Sulfamethoxypyrazine / Pyrimethamine - TabletsManufacturer
Sampling and testing for Quality Control Laboratories, Nairobi, September 200930 |
Quality survey of antituberculosis medicines (1)Quality survey of antituberculosis medicines (1)
First- and second-line anti-TB medicines to be collected close to patients
– Rifampicin capsules, Isoniazid tablets and injection, Rifampicin/Isoniazid tablets– Kanamycin powder for injection, Ofloxacin tablets and solution for infusion
Eastern Europe and NIS– Countries with high multidrug-resistant TB and extensively drug-resistant TB– Armenia, Azerbaijan, Belarus, Kazakhstan, Ukraine, Uzbekistan
Close cooperation with NDRAs and WHO EURO regional office
360 samples planned to be collected
Testing– OMCLs of Austria and Luxembourg, in EDQM, SGS (Belgium)– Comparative dissolution study of Rifampicin capsules and Rifampicin/Isoniazid
tablets at Goethe University, Germany (both conditions from Ph.Int. and USP)
Sampling and testing for Quality Control Laboratories, Nairobi, September 200931 |
Quality survey of antituberculosis medicines (2)Quality survey of antituberculosis medicines (2)
Tests performed– Appearance– Identity and content of active ingredient/s– Related substances (for rifampicin and ofloxacin only)– For tablets and capsules uniformity of mass, dissolution– For parenteral products volume in container, pH, sterility, bacterial endotoxins (for infusion only)
Specifications
ProductSpecification
Isoniazid - Tablets Injection
USP
Rifampicin - CapsulesPh.Int.
Isoniazid / Rifampicin - TabletsPh.Int.
Kanamycin - Powder for injectionUSP
Ofloxacin - Tablets / CapsulesSolution for infusion
USPUSP monograph for tablets
Sampling and testing for Quality Control Laboratories, Nairobi, September 200932 |
Specific quality monitoring projectsSpecific quality monitoring projects
Comparative dissolution study of Coartem tablets (2007)– Artemether / lumefantrine innovator - problems with dissolution reported
– 5 batches manufactured in different manufacturing sites and collected in Tanzania, tested in RIIP, South Africa
– Dissolution profiles compared to the mean of all data SIMILAR
Generic products containing nelfinavir (2007)– Triggered by Roche worldwide withdrawal of Viracept
– Test on EMS/MMS impurity using Roche method
– Samples of finished product from Cipla, Hetero, GPO Thailand and of API from Matrix, Hetero collected from manufacturers, as well as from markets, tested in Swissmedic
– All samples ≤ 0.5 ppm
– For the purposes of Ph.Int. monograph dissolution tested
Sampling and testing for Quality Control Laboratories, Nairobi, September 200933 |
Testing on request from countries/UN agenciesTesting on request from countries/UN agencies
Artesunate+Amodiaquine tablets (co-blistered), Guilin Pharmaceuticals, China – request from NGO in Indonesia
Diethylcarbamazine citrate tablets, Asian Pharmaceutical Company, Nepal – request from Ministry of Health in Nepal
Praziquantel tablets, Merck, Mexico – cooperation with WHO procurement and Neglected Tropical Diseases - Schistosomiasis control project
Artesunate tablets, Guilin Pharmaceuticals, China – request from WPRO
Miltefosin capsules, Popular Pharmaceuticals, Bangladesh - request from Ministry of Health in Bangladesh
Rifampicin capsules and Clofazimine capsules, Sandoz, India - cooperation with WHO procurement and Neglected Tropical Diseases – Leprosis elimination project
Sampling and testing for Quality Control Laboratories, Nairobi, September 200934 |
Thanks for your attentionThanks for your attentionThanks for your attentionThanks for your attention
[email protected] www.who.int/prequal