Transcript Antimalarial Drug Quality Monitoring in the Mekong Sub

USP Drug Quality and Information
Antimalarial Drug Quality Monitoring in
the Mekong Sub-region
Workshop on GMP and QA of Antimalarial Medicines
with Emphasis on Pre-qualification of ACTs
18-22 October, 2004
Bangkok, Thailand
S. Phanouvong, Pharm.D., Ph.D.
United States Pharmacopeia Drug Quality and Information Program
Presentation outline
USP Drug Quality and Information
1. Key points to alert us about poor quality
medicines
2. Antimalarial drug quality monitoring in Mekong
Sub-Region

Brief overview of the project

Progress to date

Preliminary results
3. Observation, action taken and closing remarks
Drug Quality  Definition
USP Drug Quality and Information
The suitability of a drug product for its intended use
is defined by WHO:
 Its efficacy weighed against safety (health risks)
according to a label claim or as promoted or
publicized; and
 Its conformity to specifications regarding identity,
strength, purity, and other characteristics.
Quality assessment─ compliance with established
pharmacopeial specifications and regulatory
requirements.
Poor quality medicines (contd)
USP Drug Quality and Information
Substandard
 A genuine product that does not conform to its
set pharmacopeial standards
 WHO definition “product with genuine
packaging with incorrect quantity of ingredient
(not deliberate).”
Poor quality medicines (contd)
USP Drug Quality and Information
Counterfeit
 Definition varies
 U.S. Federal FDA Act definition “a drug which, or
the container or labeling of which, without
authorization, bears the trademark, trade name, or
other identifying mark, imprint, or device, or any
likeness thereof, of a drug manufacturer, processor,
packer, or distributor other than the person or
persons who in fact manufactured, processed,
packed, or distributed such drug and which thereby
falsely purports or is represented to be the product
of, or to have been packed or distributed by, such
other drug manufacturer, processor, packer, or
distributor.”
Poor quality medicines (contd)
USP Drug Quality and Information
Counterfeit drug (continued)
 WHO definition “a product that is deliberately and
fraudulently mislabeled with respect to identity
and/or source; may include products with correct
ingredients, wrong ingredients, without active
ingredients, with incorrect quantity of active
ingredient or with fake packaging.”
Poor quality medicines – technical factors
USP Drug Quality and Information
1.
Poor manufacturing practices
2.
Counterfeiting
3.
Inappropriate procurement practices
4.
Inadequate storage, distribution, dispensing
and handling practices.
Poor quality medicines – other factors
USP Drug Quality and Information
1. Lack of adequate legislation and/or its enforcement
with weak penal sanctions
2. Absent or weak drug regulatory authority
3. Corruption and conflicts of interest
4. Trade involving many intermediaries
5. Demand exceeding supply and high prices
6. Inadequate regulation in exporting countries and
within free trade zones
7. Inefficient cooperation between stakeholders
Availability of poor quality medicines
USP Drug Quality and Information
They are widely available and are:
•
A constant threat to global health
•
Most affecting people living in countries with limited
regulatory capacity and resources
•
FDA estimated that up to 10% of drugs worldwide
are counterfeit, and in some countries more than
50% of the drug supply is made up of counterfeit
drugs
•
Costing about 22 billion USD per year, representing
about 7% of world-wide pharmaceutical sales
Antimalarial
quality
data in 9 selected
USAIDAvailability
ofdrug
poor
quality
medicines
assisted countries 1997-2003: % breakdown of data on
810 drug samples reported
USP Drug Quality and Information
Incorrect
amount of
API(s)
34%
Other
(incorrect
labeling,
unusual
appearance)
6%
No active
ingredient(s)
5%
Passed quality
testing
55%
Countries: Cambodia, Ghana, Laos, Myanmar, Nigeria, Senegal, Thailand, Tanzania, Vietnam
Source: Carpenter J P, 2003. Drug quality report matrix of USAID-assisted countries by the USP DQI Program
Consequences of using poor quality medicines
USP Drug Quality and Information
1. Trust into national programs credibility is
fading away
2. Waste of limited financial resources
3. Health is at risk, prolonged illness,
treatment failure, and some cases lead to
drug resistance
4. Death
Presentation outline
USP Drug Quality and Information
1. Key points to alert us about poor quality
medicines
2. Antimalarial drug quality monitoring in Mekong
Sub-Region

Brief overview of the project

Progress to date

Preliminary results
3. Observation, action taken and closing remarks
Aim and objectives of project
USP Drug Quality and Information
AIM: To strengthen country capability in drug
QA/QC systems at national and program levels
Objectives:
1. To obtain and document field evidence-based data
on quality of selected antimalarial drugs in Mekong
Sub-Region countries
2. To make suggestions to policy-makers/drug
regulators for developing and implementing
appropriate strategies to address the problems
Drug quality assurance structural components
USP Drug Quality and Information
Assured drug quality
Documentation, monitoring and evaluation
Pre-marketing
quality
assessment
(marketing
authorization/
licensing and
registration)
Regulatory
elements
(central
administration,
inspection, recall
and
gov. laboratory
services)
Technical
elements
(quality
specifications,
Basic tests, GMP,
GLP, GPP, GDP,
GSP)
Post-marketing
authorization
surveillance
(for quality,
adverse events,
and drug
promotion)
Adequate legislation and law enforcement
Methodological framework for monitoring
USP Drug Quality and Information
Review of malaria
and QA/QC
situation
Suggestions/
Recommendations for
policy development
and implementation by
country governments
Selection of
sentinel sites
Training in GLP,
basic testing,
sampling, data
management
Data analysis and
documentation
Field operation:
sample collection,
testing and
reporting
Performing TLC test
USP Drug Quality and Information
Mekong Sub-Region: Sentinel sites
USP Drug Quality and Information
Yunnan
Province of PR
of China
Laos
Vietnam
Mang La
Sayaburi
Lai Chau
Rui Li
Savannaketh
Quang Tri
Champasak
Daklak
Binh Phuoc
Cambodia
Thailand
Pursat
Mae Hong Son
Pailin
Kanchanaburi
Battambang
Chanthaburi/Trat
Preah Vihear
Ranong
17 sites participating
Testing – levels of current practice
USP Drug Quality and Information
Activity and requirements
Sample collection
Basic testing
Level of testing
Sentinel site
(physical/visual inspection,
simplified disintegration, TLC)
Verification
Basic test and/or
Pharmacopeial specifications
NDQC or
designated Labs
Confirmation
Pharmacopeial specification
Reference Labs
Quantity/number of samples
Test: 100% of samples collected.
Send:
1.
100% doubtful samples to NDQC
or designated Lab for verification
2.
100% of failed samples
3.
5-10% of passed samples
Test: 100% samples received from
sentinel sites.
Send:
1.
100% doubtful samples to
reference lab for confirmation
2.
100% of failed samples, where
possible
3.
5-10% of passed samples
Test: all samples received from
NDQC Lab/designated Lab
General Rules for Interpreting TLC Results
USP Drug Quality and Information
This simple guideline uses the percent Rf error, defined below, to determine the fate of a sample based on simple TLC.
Rf Sample Error = {|Rf (standard) – Rf (sample)| / Rf (standard)} x 100%
Example
From multiple TLC experiments, the following Rf values were obtained:
Rf (standard) = 0.55
Rf (sample) = 0.53
Then, Rf Sample Error = {(0.55 – 0.53)/0.55} x 100% = 3.6 %
Interpretation of TLC Results
Based on the typical Rf values, broadness of TLC spots and simple error analysis[1], some broad rules can be applied to
interpret TLC results. It is important to note that these rules should only be considered semi-quantitative and not
absolute.
When Rf Sample Error is 5% or less, the sample can be considered “Pass”
When Rf Sample Error is 10% or more, the sample can be considered “Fail”
When Rf Sample Error is between 5% and 10%, the sample can be considered “Doubtful”
Note:
If the TLC chamber and plates were not well saturated, or if the saturation has been disturbed the spots may not be horizontal
and this could give high Rf sample error.
Always make TLC in duplicate and compare the Rf of both runs.
When Rf sample error is more than 5%, always make another duplicate run under optimal conditions to double check the
doubt.
[1] Quantitative Chemical Analysis, 6th Edition. Daniel C. Harris, W. H. Freeman, New York, 2003.
Indicators used for monitoring
USP Drug Quality and Information
•
Background Indicators
•
Process Indicators
•
Outcome Indicators
•
Impact Indicators
Indicators used – core
USP Drug Quality and Information
OC 1: Number of batches or lots failing quality tests that
are removed from the National Malaria Program or
from the market .
OC 2: Administrative or regulatory actions taken against
providers or manufacturers that sell poor quality
antimalarial drugs
Progress to date
USP Drug Quality and Information
Training Round Round Round Remark
1
2
3





Laos


Thailand




To expand to +5
sites
Viet Nam




To expand to +2
sites
Yunnan of
China




Cambodia
Verification/confirmatory testing – on going
Sentinel sites by country and No. of samples
USP Drug Quality and Information
Country
Sentinel sites
R1
Sample/
Lot
R2
Sample/
Lot
R3
Sample/
Lot
Cambodia
Battambang; Pursat, Paillin; Preah
Vihar
179/85
175/82
123/75
Laos
Champasack; Savannakhet;
Sayaboury
108/95
-
-
Thailand
Chantaburi; Kanchaburi; Mae Hong
Son; Ranong
104/88
122/97
143/102
Vietnam
Binh Phuoc; Daklak; Lai Chau;
Quang Tri
75/47
60/38
-
Yunnan
Mengla; Ruili
39/36
78/64
-
Total
505/351
-
-
Preliminary data from countries
USP Drug Quality and Information
Lot/Batch failure percentage – Round 1 data (no. failed/total)
Cambodia
Laos
Thailand
Vietnam
Yunnan
ART
DIH
CHQ
MEF
QUI
23
(4/17)
0
(0/4)
4.5
(1/22)
0
(0/13)
NA
0
(13/26)
67
(2/3)
0
(0/9)
0
(0/16)
25
(2/8)
S/P
TET
43
(3/7)
NA
3.8
(1/26)
0
(0/3)
14
(3/22)
0
(0/10)
13
(4/31)
NA
0
(0/23)
0
(0/6)
3.8
(1/26)
0
(0/2)
3.8
(1/26)
NA
27
(3/11)
0
(0/1)
0
(0/9)
0
(0/10)
NA
NA
0
(0/14)
NA
0
(0/7)
0
(0/7)
NA
Preliminary data from countries
USP Drug Quality and Information
Lot/Batch failure rate percentage – Round 2 data (no. failed/total)
ART
DIH
CHQ
MEF
27
0
(0/8)
0
(0/32)
12
PRI
QUI
PYR
S/P
TET
Sites in
Cambodia
(4/15)
Thailand
14.3*
(1/7)
Vietnam
NA
(3/17)
NA
0
(0/15)
NA
?
(!1/27)
25
(1/4)
Yunnan
17.6
10
(1/10)
* Substandard (low API content
50
NA
(9/18)
0
(0/9)
NA
0
(0/14)
NA
0
(0/1)
NA
(1/8)
NA
5.9
NA
NA
(2/34)
NA
0
(0/3)
0
(0/23)
0
(0/10)
NA
0
(0/7)
NA
0
(0/16)
0
(0/7)
0
(0/4)
NA
Failure rates by drug in rounds 1 & 2 – Viet Nam
USP Drug Quality and Information
Name of drug samples
Chloroquine
tablet 250mg
No. of
samples
collected/L
ot
phosphate
Quinine sulfate 250mg
Quinine
500mg
Dihydrochloride
Artesunate 50mg
Mefloquine 250mg
Fansidar
tablet
500mg+Pri 25mg)
Primaquine
Total
(Sulf
Round 2
Round 1
No. of Lots tested
and failed using
basic tests at
sentinel sites or
failed at NIDQC
No. of
samples
collected/L
ot
No. of samples tested
and failed using basic
tests at sentinel sites
[verification test
results not yet
available]
14/11
3 (27%)
2 in Quang Tri
1 in Dak Lak
15/9
0
12/8
2 (25%)
10/6
0
1/1
0
0
0
27/16
0
21/16
1 (6.3%)
(1 out of 4 Lot failed
= 25% in Quang Tri
5/1
0
0
0
16/10
0
13/7
0
0
0
1/1
-
75/47
5 (10.6%)
60/39
1 (2.6%)
Test results summary in Cambodia
USP Drug Quality and Information
Test results summary in Cambodia (contd)
USP Drug Quality and Information
Test results summary in Cambodia (contd) –Round 1 by drug
USP Drug Quality and Information
USP Drug Quality and Information
Artesunate 50 mg 002-03
PVH lot 000902 of labeled as
“Guilin Pharmaceutical Co.”
Genuine
artesunate
hologram of
Guilin
Pharmaceutical
Co.
USP Drug Quality and Information
Artesunate 50 mg 002-03 PVH lot
000902 of labeled as “Guilin
Pharmaceutical Co.”
Genuine
artesunate
hologram of
Guilin
Pharmaceutical
Co.
USP Drug Quality and Information
Artesunate 50 mg 002-03
PVH lot 000902 of labeled as
“Guilin Pharmaceutical Co.”
Genuine
artesunate
hologram of
Guilin
Pharmaceutical
Co.
USP Drug Quality and Information
Artesunate 50 mg 071-03 PS
lot 010401ot of labeled as
“Guilin Pharmaceutical Co.”
Genuine
artesunate
hologram of
Guilin
Pharmaceutical
Co.
USP Drug Quality and Information
Genuine
artesunate
hologram of
Guilin
Pharmaceutical
Co.
Found after
1998 in Vietnam
and Cambodia
USP Drug Quality and Information
Genuine
artesunate
hologram
of Guilin
Pharmace
utical Co.
Fake found
in 2002/03 in
Laos and
Cambodia
Presentation outline
USP Drug Quality and Information
1. Key points to alert us about poor quality
medicines
2. Antimalarial drug quality monitoring in Mekong
Sub-Region

Brief overview of the project

Progress to date

Preliminary results
3. Observation, action taken and closing remarks
Observations
USP Drug Quality and Information
1.
It is clear that poor quality antimalarial medicines are
widely available and used in all countries – much to
be done
2.
Continuing support and commitments of Governments
and donors at all levels are needed



Financially – for project sustainability
Integrate into GFATM activities?
Law and regulations enforcement
Action taken by different parties
USP Drug Quality and Information
USP DQI
1. Contacted Yunnan of China (YIPD) and WPRO
on 2 lot-artesunates
2. Contacted Viet Nam NIMPE, NIDQC and DAV
3. In process of contacting CMPE, FDD and
FDQCC of Laos
4. In process of contacting CNM, FDD and
NLDQC of Cambodia
Closing thoughts
USP Drug Quality and Information
Even if these principles are followed
1. Qualified / trained health care provider consulted
2. Proper diagnosis made
3. STGs followed i.e.“correct” drug prescribed in
right dose and right route of administration
4. Objective information obtained
5. Treatment regimen complied
there will be no cure if the quality of medicines used is poor
Collaborative and persistent actions are required
from the responsible authorities at local, national
and regional levels