WHO Sampling and Testing Programmes Jitka Sabartova WHO Prequalification Programme: Priority Essential Medicines HSS/EMP/QSM Interregional Seminar for

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 projectsSampling and testing projects

Conduct of projects

Plan+updates

P1 P2 P3

Actions Reports

InspectionsAssessment

PhV

Entryinformation

Quality concerns,complaints/defects ,

signals, inspectionsPQ procedures

…


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


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


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


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



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



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


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


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)


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




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


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




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


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)


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




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


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




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


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


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)


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)




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




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




No of samplesNo of manufacturers

No of samplesNo of manufacturers

Sulfadoxine / PyrimethamineSulfamethoxypyrazine / Pyrimethamine

Cameroon16700

Ethiopia25500

Ghana191000

Kenya19511

Nigeria251311

Tanzania23374




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


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)


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


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


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


Thanks for your attentionThanks for your attentionThanks for your attentionThanks for your attention

[email protected] www.who.int/prequal

Documents

WHO Sampling and Testing Programmes Jitka Sabartova WHO Prequalification Programme: Priority Essential Medicines HSS/EMP/QSM Interregional Seminar for