Post-prequalification

activities:
Monitoring Projects

Dr Olexandr Polishchuk,
Technical officer, WHO EURO
15 – 16 August 2018
Cairo Egypt
The PQ QCL List (May 2018)
Currently
• 49 prequalified
o 2016 (5): Croatia, Iran, Ukraine, Belgium,
Thailand
o 2017 (2): South Africa, Vietnam
o 2018 (2): Ghana, China
• 49 in pipeline at various stages

2
PQT Inspections 2017

10
3
32
FPP
API
26
QCL
CRO

3
Technical Assistance, Capacity building and
Peer Audits

Technical assistance provided to national medicines QCLs

• 69 since 2006
• 2 conducted in 2017

Peer Audits as Technical Assistance

• 14 conducted since 2015 – Armenia, Cameroon, China, Cote d’Ivoire, Cuba,
Egypt, Ghana, Madagascar, Nigeria, Oman, Pakistan, Peru, Tanzania,
Zambia (2017 to date)

4
Training
Training on topics following critical and major observations noted during
PQ inspections
• Data Integrity will be main focus for 2018
• Post Proficiency or Interlaboratory Testing CAPA training (including
EQAAS)
• Microbiology testing
• Equipment trouble shooting and general maintenance (Germany since
March 2017)
• 3 months attachment
• Botswana, Burkina Faso, Cameroon, Malawi, Namibia, Senegal, Zambia, Zimbabwe.

5
Recommendations from recent WHO surveys

• For multi-country studies in-country testing should also be

considered as an element of PTS/ILT.
• During sample collection, non-destructive screening in-country
should be performed before testing at designated laboratories.
• WHO to facilitate set up of a sharing/repository platform for
NQCLs to share testing results and other relevant data.
• Countries should focus on PMS testing rather than pre-
registration testing.

6
 WHO current thinking and messages

• PMS should be part of the “Prevent, Detect and Respond”

strategy.
• WHO to focus on capacity building for the conduct of PMS
and encourage regional, multi-country PMS activities.
• PMS activities should be sustainable and risk based.
• Countries should improve on review and oversight on product
information.

7
 WHO survey of selected antibiotic and
anti-Malaria medicines circulating in
selected African countries 2018

Benin
Ghana
Nigeria
Sierra Leone
Togo
Uganda

8 |
 Main survey objectives (1)

Establish the quality of selected essential

medicines
• obtained from 3 levels of the distribution
chain in selected countries (including
unregulated, street vendors),
• using screening (NIR) and comprehensive
laboratory tests against quality criteria,
• review of product information for patient and
health professional.
9
 Survey Objectives (2)
To improve understanding of substandard and falsified (SF)
medical products and contribute to gather information on
their potential impact on Antimicrobial Resistance (AMR) by:
• Strengthening national post market surveillance and SF incident
management capacity

To verify suitability of NIR field and laboratory tools for:

• the detection of potentially substandard and falsified selected
products, and
• development of a fingerprinting spectral database for selected
prequalified pharmaceutical products (starting with ACT for malaria)

10
 Secondary Objectives
• To increase information sharing and reporting on SF medical
products using the GSMS.
• To train regulators and support capacity building on planning,
conduct, evaluation and follow up of risk-based market
surveillance.
• Initiate the development of a fingerprinting spectral database
for selected antibiotics and anti-malarials that were not
already included in reference library.

11
 Selection of products
Medicines for malaria (following PQT survey cycles) and antibiotics for AMR agenda

Products with suspected or documented inferior quality with actual/potential serious

implications for public health e.g. treatment failures & use in large volumes;

Exposure of patients to the medicine (availability at the lowest distribution level and
extent of exposed population);

Seriousness of potential harm (vulnerability of target population, risks related to

dosage form and route of administration, therapeutic index, risk of therapeutic failure,
acute versus chronic use, development of resistance);

Products with a high potential for diversity on the market, where various generic
alternatives are available

Products at risk of being SF due to potential high returns or demand in the

market.

12
 SF reporting

Antimalarials Artemisinin and derivatives

Antibiotics Beta lactam Penicillin

0 50 100 150 200 250 300

Most frequently reported antimalarials: Most frequently reported antibiotics:

Artemisinin and derivatives
Beta lactam Penicillins

Methanolquinolines
Sulfonamides

Cephalosporins: 1st, 2nd & 3rd generations

Diaminopyrimidines

Fluoroquinolones

Aminoquinolines

Macrolides

Etc..
Other antibacterials, incl. for TB treatment

Etc..

Data extract 11January 2018 Courtesy of WHO/MPV/EMP/SAV

Medicine Monograph

Amodiaquine (as hydrochloride)/ Artesunate tablets Ph.Int. (currently in draft)

Artemether/ Lumefantrine tablets Ph.Int.

Artemether/ Lumefantrine dispersible tablets Ph-Int.

Dihydroartemisinin/ Piperaquine (phosphate) tablets Chinese Ph.

Amoxicillin tablets, capsules USP

Amoxicillin dispersible tablets USP

Amoxicillin/ Clavulanate (Co-Amoxiclav) tablets BP

Sulfamethoxazole/ Trimethoprim tablets Ph.Int.

Ampicillin capsules BP

Phenoxymethylpenicillin (Penicillin V) tablets USP

Benzylpenicillin (Penicillin G) powder for injection Ph.Int.

Ciprofloxacin tablets BP

Ceftriaxone sodium powder for injection Ph.Int.

Cefuroxime Axetil tablets BP

14
Sample screening and testing
At the collection site or as near as possible (all collected
samples)
 Screening for suspected SF products
 NIR scanning using handheld device

At local laboratories in survey countries (selected samples)

 According to the testing protocol
 Results for comparison only

At WHO contracted laboratories (selected samples)

 NIR scanning using handheld device as well as bench equipment

 Comprehensive laboratory testing according to the protocol

15
 Sample distribution
500 samples collected per country
100% SF screening
100% NIR Scan

400 samples for local Assessment 100 samples to be shipped to WHO QCL
(option to split sample for LT)

10% PI review

100% NIR scan (Handheld +

Bench) + NLT 50% Lab testing at
Local Testing (suspected SF WHOQCL
100%) + X% other (including
subset of WHO QCL testing)

16
Laboratory testing

Test methods and specifications

 Compendial methods of the Ph.Int., BP or USP or exceptionally validated
in-house methods

• Enables testing and comparison of products from various

manufacturers.

• If a WHO prequalified product does not comply, it will be retested

using the method accepted at prequalification.

• Local laboratories may apply the same principles for locally registered
products.

17
 Pharmacopoeial methods to be used for ACTs

• Amodiaquine/artesunate tablets, Artemether/lumefantrine tablets and

Artenimol/piperaquine tablets Appearance, ID, Dissolution, Related substances,
Assay, Uniformity of Dosage Units

• For amodiaquine and artesunate tablets - monograph is currently under

development for inclusion in Ph.Int.
• Ph. Int contains a monograph for Artemether and lumefantrine tablets, ?
TLC method for artemether-related substances.
• Artenimol and piperaquine tablets monograph only in the Chinese
Pharmacopoeia 2015 (“Dihydroartemisinin and piperaquine phosphate
tablets”).
Guidance sought on tests to be conducted and specifications.

18
Survey of the Quality
of Anti-tuberculosis
Medicines Circulating in
Selected Newly Independent
States of the Former Soviet
Union

19
The countries of the former Soviet Union have the
highest MDR-TB rates in the world

Murmansk Oblast, Russian Federation (2008) 28.3

Pskov Oblast, Russian Federation (2008) 27.3

Arkhangelsk Oblast, Russian Federation (2008) 23.8

Baku city, Azerbaijan (2007) 22.3

Ivanovo Oblast, Russian Federation (2008) 20.0 13 top settings with >
15% MDR-TB among
Republic of Moldova (2006) 19.4 new TB cases, 2001-
2009
Kaliningrad Oblast, Russian Federation (2008) 19.3

Belgorod Oblast, Russian Federation (2008) 19.2

Dushanbe city and Rudaki district, Tajikistan (2009) 16.5

Mary El Republic, Russian Federation (2008) 16.1

Donetsk Oblast, Ukraine (2006) 16.0

Estonia (2008) 15.4

Tashkent, Uzbekistan (2005) 14.8

0 5 10 15 20 25 30
20
MDR-TB among new TB cases in 1994-2009

0-<3
3-<6
6-<12
12-<18
>=18
No data available
Subnational data only

Australia, Democratic Republic of the Congo, Fiji, Guam, New Caledonia, Solomon
Islands and Qatar reported data on combined new and previously treated cases.
21
MDR-TB among previously treated TB cases, 1994-2009

0-<6
6-<12
12-<30
30-<50
>=50
No data available
Subnational data only

Australia, Democratic Republic of the Congo, Fiji, Guam, New Caledonia, Solomon
Islands and Qatar reported data on combined new and previously treated cases.
22
Causes of drug resistance

Health care Patients Medicines

providers
Inadequate Inadequate Inadequate
regimens drug intake supply or
QUALITY

23
Can we rely on essential medicines against TB?

• Quality defects found in many countries

including: Botswana, Colombia, Estonia, India,
Latvia, Myanmar, Nigeria, Russia, South Africa
and Vietnam
• Few large scale-surveys and most information
anecdotal or from publications without scientific
evidence

24
Beijing and World Health Assembly 2009

Prevention and control of MDR-TB

requires:
1. Remove financial barriers
2. Ensure well trained and sufficient human
resources
3. Establish a network of labs where rapid tests are
also available
4. Ensure availability of quality drugs
5. Regulate the use of all anti-TB drugs
6. Introduce infection control
7. Establish proper surveillance
8. Promote Research & Development
9. Mobilize resources domestically and
internationally

25
Rationale of the survey

To investigate the extent and magnitude of

substandard or counterfeit anti-TB medicines
circulating in the countries with the highest
rates of MDR-TB in the world

26
Aim of the survey

Assess the quality of anti-tuberculosis medicines obtained at public

and private sector procurement and treatment sites in selected
countries of the former Soviet Union. To address:
• What proportion of anti-tuberculosis medicines samples, including
fixed-dose combination products, collected at approved procurement
and treatment centres fails quality testing?

• Are any of the deficiencies critical, i.e. could they affect treatment
efficiency and/or cause harm to the patient?

• Which specific quality tests do the samples fail, if any?

27
Survey benchmarks

First meeting March 2008

Questionnaire May 2008
NDRAs feedback September 2008
Invitation letters December 2008
Nominations March 2009
Minsk meeting May 2009
• National sampling plans June 2009
Sampling/sending October 2009
QC tests May 2010
Final meeting June 2010

28
Countries approached

11 countries from Eastern Europe

Armenia Latvia
Azerbaijan Moldova
Belarus Tajikistan
Estonia Ukraine
Kazakhstan Uzbekistan
Kyrgyzstan

29
Selection of medicines

• The final medicines selection was made based on the

information on medicines used in individual countries
• Apart of the availability:
• volumes and sources of medicines used in individual countries
• the susceptibility of medicines to quality deterioration such as low stability
was taken into account

30
Medicines selected for the survey

• Isoniazid tablets
300mg, 100mg, injection 10% (5ml)

• Rifampicin capsules 300mg, 150mg

• Isoniazid/Rifampicin tablets
150mg/300mg, 150/150mg, 75/150mg,
60/60 mg, 30/60mg

• Kanamycin powder for injection 1g

• Ofloxacin tablets/capsules 200 mg, 400mg, solution for injection 0.2% (200ml)

31
Survey protocol

• Introduction

• Glossary

• Objectives

• Methodology

• Data management

• Publication

• Annexes

32
Survey protocol. Annexes

• TB medicines Quality Survey

Questionnaire
• National Sampling Plan
• Sample Collection Form
• Testing Protocol
• Content of the Analytical Test Report

33
Training of country focal persons

• Presentation of the project to country focal

persons
• Training in development of national sampling
plan
• Draft National sampling plan for Kazakhstan
developed
• Sampling collection form and coding principles
• Instructions for sending samples

34
Samples collection form

35
Testing laboratory (I)

• Selection of appropriate laboratory for testing

• a prequalified laboratory should be used
• another laboratory could be chosen, where evidence of
reliability is available
• Appropriate arrangement with the laboratory has to be
made
• WHO guideline: Considerations for requesting analysis of drug
samples

36
Texting laboratory (II)
AGES - PharmMed (Austrian
Official Medicines Control
Laboratory) Vienna
(In cooperation with LNS
Luxembourg)
COUNCIL OF EUROPE
European Directorate For The
Quality Of Medicines &
Healthcare (European
Pharmacopoeia) Strasbourg
SGS Lab Simon S.A. Wavre
Isoniazid tablets, injection
Kanamycin powder for
injection
Ofloxacin tablets/capsules,
solution for injection
Testing for identity, assay,
related substances and
uniformity of mass:
• Rifampicin capsules
• Isoniazid + Rifampicin 37
Collected samples

Tablets 300mg, 100mg 54

Isoniazid 69
Injection 10% 15
Rifampicin 60 Capsules 150mg, 60
300mg
Isoniazid/Rifa 42 Tablets 75/150mg, 42
mpicin 150/150mg,
30/60mg,
60/60mg
Kanamycin 67 Powder for injection 1g 67
Tablets 200mg, 400mg 38
Ofloxacin 53 Capsules 200mg 2
Solution for infusion 13 38

0.2%
Number of manufacturers

33 manufacturers:

India -10
12

Ukraine - 5
10 11
Russia - 5
10
Kazakhstan – 3
8
8
Belarus – 2
6 7
China – 2

Cyprus – 1
4 5

France - 1
2
Palestine - 1
2 2
1
Syria - 1
0

Turkey - 1
l j l f
d tab zi d in c ap s ta bl de r in ta b ca p s c in in
Uzbekistan - 1
i w
n ia z s on ia pi cin p ic in i n po o x ac x ac in flo x a
Is o I
ifa m ifam m y c O fl O flo O
R / R n a
ia zi d K a
n
Is o

39
Collected samples

60 Ofloxacin inf
3
2
12
7 Ofloxacin caps
50
10
3 Ofloxacin tabl
12 12
40
12 13 12
Kanamycin
30 12 12 powder
4
12 6 11 12 Rifampicin/
Isoniazid tabl
20 3
12 12
3 5 Rifampicin
6 7
caps
10 4 4 2
12
14 Isoniazid inj
10 11
8 8
3
0
Isoniazid tabl
en i
a
aija
n ar us an ai n
e n
rm rb B el ak h st U kr
ek is ta
A Aze K az Uzb
40
Compliance with specifications
Failure rates by products

Non-compliant Compliant

100%

80%

43
60% 45 32
15 41 67 2 13
40%

20%
17
9 6
0% 1

l in j l p s in in f
t ab i d a ps b l de r t ab c a
z c a n c
n
id
ia z s o n ia i ci n ic in t w
po o xac
i
a cin flo xa
p n x
I so I
i f am f a m p m yci O fl O flo O
R R i a
a z id / K an
ni
Is o
41
Contribution of failures in individual tests
to total failure of product

20 Appearance

% 16
Assay

12
Related
substances
8
Dissolution
4
Mass
0 uniformity

a bl s ab l
id t ca p ta b
l n t
n ia z ic in
ic in ox aci
Is o a mp mp Of l
R if / Ri
fa
z i d
n ia
Is o 42
 Isoniazid (USP)

Isoniazid tablets (16.7% non-compliant of 54 samples) Manufacturers without failure:

• Broken tablets in 2 samples
 Cadila, India – 7 samples
o 2x - Luganskij, Ukraine, other 27 samples OK  Chimpharm, Kazakhstan – 1
sample
• Mass uniformity in 6 samples  Darnica, Ukraine – 1 sample
o 5x - Luganskij, Ukraine, other 24 samples OK  Pavlodarskij, Kazakhstan – 3
samples
o 1x - Borisovskij, Belarus, other 7 samples OK  Svizera, India – 4 samples
• Dissolution in 1 sample  Tyumenskij, Russia – 1 sample

o 1x - Luganskij, Ukraine - mean 70%, other 8 samples OK

Isoniazid injection (15 samples)  Borisovskij, Belarus - 4 samples

 Darnica, Ukraine - 11 samples
• No failure

43
 Rifampicin (Ph.Int.)

Rifampicin capsules (28.3% non-compliant of 60 samples)

Manufacturers without failure:
• Content of rifampicin in 12 samples

o 78.0%, 81.8%, 10x 85.1% - 89.6%  Cadila, India – 7 samples

 Belmedpreparaty, Belarus -
o 6 of them failed also in related substances test 17 samples
• Related substances in 11 samples
 Borshagovskij, Ukraine - 9
samples
o In all samples 3-formylrifampicin >0.5% (0.6-0.7%)  Darnica (bulk from Lupin
India) - 1 sample
o In 3 additional unknown impurity >1.5% (1.6, 1.9, 2.0%)
 Medochemie, Cyprus - 2
o In 2 sum of impurities >6.0% (7.5, 7.6%) samples
 Sandoz Private, India - 4
samples
• 5x Pavlodarskij Kazakhstan, 4x Lupin India (1 other OK), 2x Macleods India (2
other OK), 2x Troge India (2 other OK), 1x Shandong Reyoung China (3 other OK)

44
 Isoniazid / Rifampicin (Ph.Int.)

Manufacturers
without failure:
Isoniazid / Rifampicin tablets (2.4% non-compliant of 42 samples)
 Lupin, India - 18
• Related substances in 1 sample samples
o 1 unknown impurity >1.5% (4.9%)  Macleods, India - 3
o Pavlodarskij Kazakhstan, other sample from different batch OK samples
 Sandoz Private,
India - 17 samples
 Svizera, India - 2
samples

45
Dissolution of rifampicin containing products

• Different dissolution conditions in Pharmacopoeias (Ph.Int., BP, USP)

• Comparative dissolution study of one sample from each manufacturer and strength with
established comparator
• Contribute to clarification of differences in outcomes of dissolution tests performed under different
conditions

• Currently 2 sets of results for Rifampicin capsules, 1 set of results for

Isoniazid/Rifampicin tablets and 1 more ongoing – results not fully understood and
further investigation needed
• Results of dissolution testing were not considered as quality indicator and were not
included in the overall quality evaluation of rifampicin products
• Importance of
• Bioavailability/bioequivalence studies assessed within registration or procurement of not registered
products
• Appropriate quality specifications for API and finished product
• Continuous compliance of a manufacturer with standards of Good Manufacturing Practice

46
Kanamycin (USP)

Manufacturers without failure:

 Chimpharm, Kazakhstan - 11
Kanamycin powder for injection samples
 DHO Nika Pharm, Uzbekistan - 2
(67 samples) samples
• No failure  Kievmedpreparat, Ukraine - 29
samples
 OJSC "Biokhimik" Saransk, Russia -
1 sample
 Panpharma SA, France – 10 samples
 Shanghai Pharmaceutical Co. Ltd,
China - 4 samples
 Syntez Kurgan, Russia - 10 samples

47
 Ofloxacin (USP)

Ofloxacin tablets/capsules (15.0% non-compliant of

40 samples) Manufacturers without
failure:
• Related substances in 2 samples
 Holden Medical Laboratories,
o Individual unknown impurities >0.2% India – 2 samples
(0.4, 0.6, 0.7%) + Sum of impurities  Kaspar-Chabani Pharma, Syria
>1.0% (1.2, 1.3%) - 3 samples
o J.Duncan Healthcare India, Global  Kievmedpreparat, Ukraine - 1
Pharm Kazakhstan sample
 MacLeods Pharmaceuticals,
• Dissolution in 3 samples India - 4 samples
o 2x Borisovskij Belarus, the same batch  MU Pharmaceuticals Enibosna,
– mean 32% and 42%, individual tablets Turkey - 2 samples
17-99%; 9 other samples OK  OLA Ozon, Russia - 3 samples
o 1x Global Pharm Kazakhstan – mean
 Pharmacare Int. Co. Jerusalem,
78%, failed also in related substance, Palestine - 1 sample
the other sample OK  Pharmstandart - Lekarstva,
Russia - 2 samples
• Mass uniformity in 2 samples  Plethico Pharmaceuticals Ltd,
o 2x - Borisovskij, Belarus, other 9 India - 8 samples
samples OK
48
Registration status

 48 samples of not
registered products
Not registered Registered
 Supplied through GDF,
100%
MSF
90%
80%  2 of them non-compliant
70% 19 – Rifampicin caps, Lupin
30
60% 46
39
India (collected in
53
50% 53 Armenia, supplied by
40% MSF) – assay 87.1%,
30% related substances
20% 12
slightly above limit
12 14 – Rifampicin caps,
10%
7 6
0% Shandong Reyoung
China (collected in
Azerbaijan, supplied
before new legislation
came into force) –
assay 89.7%

49
Prequalification status

• 38 samples of WHO-prequalified products

• Isoniazid/Rifampicin tablets
• 75/150mg, Lupin India (18), Sandoz Private India (17)
• 30/60mg (2) and 60/60mg (1) Macleods Pharmaceuticals India

• None of WHO-prequalified products failed to

comply with specifications

50
 Interpretation of testing results

 Survey of quality of medicines available to patients

– Samples collected at treatment centres, dispensaries, pharmacies
– If failure found, it might be from a manufacture or might be caused by
improper/distributor handling during transport/storage
 Results obtained cannot predict the quality of the whole
production/manufacturer
– Laboratory testing itself cannot guarantee more than quality of
samples tested
• It cannot substitute regulatory system (GMP compliance, appropriate
quality specifications for API and finished product, continuous supervision
and random laboratory testing)
– Numbers of samples in the survey not representative

51
 Conclusions

• Not too many major failures but inconsistent quality found

• GMP issues evident

• Lower rifampicin content worrying

• Investigation of failures with manufacturers and follow-up

of corrective actions recommended

• Dissolution of rifampicin containing product does not

provide information on bioavailability ⇒ assessment of
bioequivalence study important

52
THANK YOU!

53