1. health and fitness
2. disease
3. aids and hiv

Overview
• Why counterfeit?
• What kinds of counterfeit products are out
there?
• What technologies are required to detect
them?
• How does SCMS protect its supply chains?
• How does SCMS plan to assist client
sovereign states to protect the follow-on
supply chains?
SCMS
Product Integrity Issues
Tom Layloff, Quality Assurance Advisor
Supply Chain Management System (SCMS)
“Providing Quality Medicines for People Living with and
Affected by HIV and AIDS”
www.scms.pfscm.org tlayloff@pfscm.org
The views expressed here are those of the author and may not be
those of USAID, SCMS, FDA, or MSH.
www.layloff.net tom@layloff.net
PEPFAR
Implementing Partner
Why Counterfeit??
What’s Out There
• Two Pharmaceutical Markets
• Legitimate Market
o
o
o
o
Products registered or formal waiver
Routine inspection of imports
GMP inspection of local manufacturers
Some pedigree control
• Gray Market
o Unregistered and no waiver
o No inspection or oversight
o Unknown pedigrees
PEPFAR
Implementing Partner
PEPFAR
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Some Counterfeiters Are Sophisticated Business People
Return on Investment? Repeat business?
Tiered Analytical Assessments
• Minimum Level Investment- One Off Sales -Local
• Flour in capsules
• To conserve resources the appropriate
technologies should be used to perform the
assessments. Tiered levels should be
instituted.
• In addition to capital costs maintenance costs
are estimated at 10% of capital costs per year
• In addition supply costs are estimated at 510% of capital costs per year
• Higher Level Investment- Return Markets -Internet
Sales-Cross Border Trafficking-International
• Impure drugs
• Undeclared therapeutic product substitution
• Sophisticated relabelers and manufacturers
• Highest Level Investments- Return Markets Diversions into Legitimate Supply ChainsInternational
• Designer Unapproved New Drugs
• Sophisticated relabelers and manufacturers
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Implementing Partner
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Level One Product Quality Assessments
Right Drug? About Right Amount?
Level Two Product Quality Assessments
Comply with legal standards?
• Technical Resources
• Technical Resources
• Thin Layer Chromatography
• Colorimetric Tests
• Near Infrared or Raman Spectroscopy
• Chromatography systems HPLC, GC , TLCDensitometry
• Spectroscopic procedures UV-Visible
• Personnel Qualifications
• Personnel Qualifications
• Trained laboratory personnel-GMP levels
• Basic Laboratory Skills
• Facility Requirements
• Facility Requirements
• Controlled temperature space
• Stable power required
• Good ventilation
• Minimal power requirements
• Capital Investment
• Capital Investment
• Tens to hundreds of thousands USD
• Tens of thousands USD
PEPFAR
Implementing Partner
PEPFAR
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Level Three Product Quality Assessment
New Drug? Impurities? Bioavailability?
Overview SCMS Supply Chain Product Integrity
• Technical Resources-Forensic Levels
• SCMS Support for Client Requirements
• Chromatography coupled Mass Spectrometry
• Near Infrared or Raman Spectroscopy
• Procurement
o Contracts
• Warehousing and Customs
• Distribution to Client Sites in Sovereign States
• Personnel Qualifications
• Highly trained personnel
• Ph.D. with experience
o Central Medical Stores--Most
o District Level--Few
• Facility Requirements
• Sovereign States
• Controlled temperature
• Stable power supplies
• Ministry of Health
o Regulatory Authority
o Internal Distribution System
o Health Care Delivery Workers
• Capital Investment
• Hundreds of thousands to millions USD
PEPFAR
Implementing Partner
PEPFAR
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The Need for Rapid Scale-up
What We Buy
• ARVs (including FDA tentatively approved generics)
• Rapid HIV test kits
• Laboratory equipment [e.g., Enzyme ImmunoAssay
(EIA), CD4, Nucleic Acid Amplification Testing
(NAT)]
• Drugs for Opportunistic Infections
• Drugs for Sexually Transmitted Infections
• Drugs for home care and palliative care
• Drugs for Tuberculosis
• Medical supplies
• Miscellaneous (e.g., vehicles)
Number of people in low- and middle-income
countries on antiretroviral therapy (in
8millions)
7
6
5
4
3
2
Global progress to date
1
2000
Dec. 2006
Source: UNAIDS
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Implementing Partner
PEPFAR
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2
SCMS Quality Assurance
SCMS has established routine and with-cause
sampling and testing procedures to pose a
creditable threat of detection to
unscrupulous suppliers.
• Routine sampling is conducted at SCMS
Regional Distribution Centers
• With-cause sampling is performed for
complaints or any deviation in processes.
Value of Commodities Delivered
Value of delivered commodities
$30,000,000
$25,908,823
$25,000,000
OTHER
$18,501,044
$20,000,000
Dollar
value
(USD)
OI/STI
LAB
$15,000,000
TEST KIT
$10,000,000
$5,000,000
ARV
$7,962,651
$3,213,304
$4,447,307
$0
Y1Q4
Y2Q1
Y2Q2
Y2Q3
Y2Q4
Quarter
PEPFAR
Implementing Partner
PEPFAR
Implementing Partner
Definition: The dollar value of commodities delivered to clients.
Where We Work
Regional Distribution Centers
PEPFAR
Implementing Partner
Botswana
Côte d’Ivoire
Ethiopia
Guyana
Haiti
Kenya
Mozambique
Namibia
Nigeria
Rwanda
South Africa
Tanzania
Uganda
Vietnam
Zambia
Zimbabwe
Regional Consolidation Centers
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Implementing Partner
Beyond the SCMS Supply Chain
• SCMS is establishing Regional Consolidation Centers
in India
• Rapid access to Indian generic products afforded
by the Tentative FDA-Approval process
• Inspection and sampling at RCCs prior to
consolidation and shipping.
• Chain of custody
• Controlled packing of shipments at the RCC and
unloading them at the RDC
• Customs inspections under SCMS observation
• Visibility of any in-transit security breaches (RFID
seals)
PEPFAR
Implementing Partner
• RDC Advantages:
• Efficiency and cost
• Smaller, regular
shipments to protect
local systems
• Timely, accurate and
safe transport including
cold/cool chain
• Delivery of drugs and
commodities door-to-door
• Physical security
• Chain of custody from
supplier to recipient
• Rapid response to
emergency requests
To protect their sovereign markets the
National Drug Regulatory Authorities
(NDRA) must have in place the basic
regulatory functions including: product
registration, product and premises
inspection, product testing, stringent
laws and regulation for standards
enforcement.
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Implementing Partner
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Registration
Just Looking Improves the Marketplace
• Defines what products may be legally
marketed in the country
• WHO prequalification Q&A states: “quality
assessment is product and manufacturing site
specific”
• Registration is product, manufacturer, and site
specific
PEPFAR
Implementing Partner
Registered 5.6%
Substandard
Standard
PEPFAR
Implementing Partner
Testing
Drug Registration Improves Drug Quality
•
Registered 5.6%
•
Product testing shows
that registered products
(5.6% substandard) are
much less likely to be
substandard than
unregistered products
(23.6% substandard).
•
Substandard
•
Standard
PEPFAR
Implementing Partner
Product testing is the most expensive tool in
the regulatory process.
Product testing is the only way to prove that
a product is substandard or is counterfeit.
Product testing results may be contested in
courts, so chain-of-custody and rigorous
adherence to good practices and legal
standards are essential.
PEPFAR
Implementing Partner
2007 WHO Survey of ARVs
in Seven African Countries
Survey Results Ports-of-Entry and Post-Marketing
Surveillance in Tanzania
• 394 ARV samples collected from seven African
countries
•
•
•
•
•
• Products not legally imported or marketed were
rejected or seized and not screened
• 1,257 samples of the targeted drugs were
screened; ca. 500 per annum
• 3.7% or 46 of the samples tested failed screening
tests.
1 failed appearance (NPQ)
2 failed labeling (NPQ)
1 failed disintegration (NPQ)
2 failed dissolution (1 NPQ, 1 PQ)
1 failed assay (PQ)
1.8% failure rate with no serious failures
84% of the products were registered in the country
60% were WHO pre-qualified
No samples were collected from unofficial sources or remote
sites
• Non-registered products primarily from the private sector
• 41sulfadoxine-pyrimethamine products failed
dissolution—all locally manufactured
• 5 samples failed screening test-wrong drug or
markedly sub-potent
•
•
•
•
PEPFAR
Implementing Partner
Not registered 23.6%
•A Comparison Study of
Testing Products
Registered and Not
Registered in Myanmar
and Vietnam 1996−1997
WHO Data
o 3 samples of quinine tablets
o 2 samples of erythromycin tablets.
Tanzania FDA Data in press
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Tanzania Pharmaceutical Market Defense
US FDA Counterfeit Detection Efforts
The following five slides concerning detection of
illegal Erectile Dysfunction (ED) drugs are
taken from a presentation by the US FDA
Forensic Chemistry Center in Cincinnati, Ohio.
• TZ surveillance focused on legal products which
had passed the registration requirements and were
stored in approved premises
• Upstream compliance activities: registration, record
inspection and physical examination are reflected in
improved quality of marketed products
• This overall regulatory activity provides a significant
deterrent.
• Therefore legitimate conscientious manufacturers
and distributors can compete.
PEPFAR
Implementing Partner
SCMS does not distribute ED drugs and these
slides are intended only to illustrate the level
to which some unscrupulous manufacturers
will go to sell products.
PEPFAR
Implementing Partner
VIAGRA Summary
“Counterfeit” and unapproved
Example Erectile Disfunction (ED) Drugs
FDA FCC Materials
•
•
•
•
FDA FCC Slide
The three approved products for ED treatment are:
Sildenafil Citrate (VIAGRA®) FDA approval - 1998
Tadalafil (CIALIS®)
FDA approval - 2003
Vardenafil HCl (LEVITRA®) FDA approval - 2003
Suspect Counterfeit Products
SubPotent
Potent
72
# of
Samples
SuperPotent
59
No
Active
30
Mixed Actives
1
3
Unapproved Products
Potent
# of Samples
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Implementing Partner
PEPFAR
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Cialis Summary
Levitra Summary
“Counterfeit” and unapproved
“Counterfeit” and unapproved
FDA FCC Slide
19
SuperPotent
No
Active
1
0
Mixed/Wrong
Actives**
15
FDA FCC Slide
Suspect Counterfeit Products
# of Samples
Suspect Counterfeit Products
Potent
SubPotent
SuperPotent
No
Active
Mixed/Wrong
Active
26
4
19
5
19/17
# of Samples
Potent
SubPotent
SuperPotent
No
Active
Mixed/Wrong Active
1*
0
0
1
16/19
# of Samples
* vardenafil polymorph
Unapproved Products
PEPFAR
Implementing Partner
34
SubPotent
Potent
SubPotent
SuperPotent
No
Active
Mixed/Wrong
Active
52
17
4
0
7/4
# of Samples
PEPFAR
Implementing Partner
Unapproved Products
Potent
SubPotent
SuperPotent
No
Active
Wrong Active
2
0
0
0
3
One sample was bulk powder declared as “sodium pyruvate”
contained 82% pure vardenafil
5
Analytical Approach at FCC
Scope of The Analog Analytical Problem
Sample
FDA FCC Data
Compound
M.W.
Rel Retention Time
Sildenafil
474.21
1.00
Homosildenafil
488.22
1.01
Supplement/Herbal
O
O
O
N
O
N
HN
S
Physical Characterization
(dimensions, markings, mass, color)
O
Not authentic
N
N
N
N
O
N
Authentic
LC-MSn
N
HN
S
N
N
O
Dosage Form
Approved API
Analog
LC-MSn
FTIR
HS GC-MS
O
LC Assay
sildenafil
(accurate mass)
homosildenafil
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Implementing Partner
PEPFAR
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US FDA Forensic Chemistry Center Summary
FTIR
LC Estimate
Authentic
Not authentic
Complete
LC Assay
Quality Products in the Marketplace
• The presence of ED drugs and numerous
analogs is widespread among herbal products,
supplements and dosage forms.
• Screening procedures that target only
approved APIs are inadequate.
• Preliminary results suggest that polymorphs
may also be a factor for this class of
compounds.
• Those who produce and market these illegal
products are becoming more clever. Those
trying to prevent it must adjust accordingly
PEPFAR
Implementing Partner
ICR FTMS
• Establish a strong well-publicized
regulatory posture including
enforcement
• Purchase products which are
approved AND marketed in ICH or
PIC/S countries or WHO prequalified
products
• Watch the pedigrees of incoming
products
PEPFAR
Implementing Partner
Client Countries
Inspection Levels
Technical Assistance to Strengthen National Drug
Regulatory Authorities
• Level One
• Strengthen level one drug product and
premises regulation-registration, inspection
• Strengthen level one assessment
technologies
• Technical assistance to strengthen level two
assessment technologies
• Assist in regional coordination of efforts to
strengthen level three assessment resources
• Technical assistance to strengthen regional
and international communications and alerts
• Product and premises compliance to
standards
• Level Two
• GMP inspection of manufacturers
• GLP inspection of testing laboratories
• Level Three
• Sterile operations
o Terminal sterilization
o Sterile filling
o Lyophilized products
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Implementing Partner
PEPFAR
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6
SCMS Internal Use Form to Report Product Quality Issues
Web Based Internal Reporting Form for SCMS Staff
• Report immediately issues relating to the
quality, safety, and/or efficacy of products to
the SCMS quality team. Your quick reporting
will help ensure the quality of products
procured and distributed by SCMS.
• Access Form on SCMS Intranet to report
issues, incidents, or complaints relating to
product quality.
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Implementing Partner
PEPFAR
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Things to Ponder
• “In a lawless world, the exigencies of
competition tended to drive commercial
practices toward the level of the most
unscrupulous.”
– James Harvey Young
• “If you have no defense you can’t defend
yourself.”
– Tom Layloff
PEPFAR
Implementing Partner
PEPFAR
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Requirements for Successful
Defense
Questions?
Society commitment
Political will
Financial resources
Thank You!!
Contacts tlayloff@pfscm.org tom@layloff.net
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Implementing Partner
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7