SCMS Product Integrity Issues Overview • Why counterfeit?

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 [email protected]
The views expressed here are those of the author and may not be
those of USAID, SCMS, FDA, or MSH.
www.layloff.net [email protected]
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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
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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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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
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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
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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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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
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Definition: The dollar value of commodities delivered to clients.
Where We Work
Regional Distribution Centers
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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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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)
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• 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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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
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Registered 5.6%
Substandard
Standard
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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
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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.
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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
•
•
•
•
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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.
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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.
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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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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
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34
SubPotent
Potent
SubPotent
SuperPotent
No
Active
Mixed/Wrong
Active
52
17
4
0
7/4
# of Samples
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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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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
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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
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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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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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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
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Requirements for Successful
Defense
Questions?
Society commitment
Political will
Financial resources
Thank You!!
Contacts [email protected] [email protected]
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