Detection of Counterfeit Drugs and Drugs in Dietary Supplements

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Detection of Counterfeit Drugs and Drugs in
Dietary Supplements

• Mark R. Witkowski, Ph.D.
• FDA Forensic Chemistry Center
• Organic Branch / Vibrational Spectroscopy
  Laboratory
• 6751 Steger Drive Cincinnati Ohio 45237
• email mark.witkowski_at_fda.hhs.gov

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FDA Office of Criminal Investigations (OCI)
ASCLD Accreditation 2004
FDA Forensic Chemistry Center (FCC) Cincinnati
Ohio
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Forensic Chemistry CenterUS Food and Drug
Administration

• Responsibilities
• Case work analysis and research related to
  product tampering, counterfeiting, fraud, drugs.
• Forensic laboratory service to the FDAs Office
  of Criminal Investigation (OCI).
• Laboratory support to traditional FDA
  investigations when necessary.
• Special health incidents and emergencies
  (national and international)
• Assistance to other regulatory and law
  enforcement agencies when appropriate.

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Products FDA Regulates FoodFoodborne Illness,
Nutrition, Dietary Supplements... DrugsPrescripti
on, Over-the-Counter, Generic... Medical
DevicesPacemakers, Contact Lenses, Hearing
Aids... BiologicsVaccines, Blood
Products... Animal Feed andDrugsLivestock,
Pets... CosmeticsSafety, Labeling... Radiation-Em
itting ProductsCell Phones, Lasers, Microwaves...
FY 2005 Biologics 39 Cosmetics 5 Drugs
391 Foods 89 Medical Devices 54 Supplements
34 Vet Drugs 11 Total 623
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Pharmaceutical Counterfeiting
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The public health significance of counterfeit or
unapproved drugs is that they may contain harmful
impurities, may be ineffective and/or have
altered bioavailability.

• Counterfeit medicines may cause
• Death
• Disease
• Disability
• Discomfort
• Dissatisfaction

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Initial Report http//www.fda.gov/oc/initiatives
/counterfeit/report02_04.html
FDA COUNTERFEIT DRUG TASK FORCE REPORT 2006
UPDATE http//www.fda.gov/oc/initiatives /counter
feit/report6_06.html
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• 1999 Counterfeit artesunate and mefloquine in
  Cambodia 30 people died.
• 2000 240,000 packs of medicines and 2 tons of
  raw materials worth
• 1 million US seized in Italy
• 2001 study in Southeast Asia (Cambodia,
  Laos,Myanmar, Thailand, Vietnam)
• 38 of 104 samples of artesunate found to
  contain no active ingredient.
• 2001 Counterfeit Serostim, Neupogen and
  Nutropin AQ found in USA.
• 2002 Counterfeit Viagra (Internet)
• 2003 Counterfeit Cialis
• May 2003 Counterfeit Lipitor Investigation
  (Supply Chain)
• July 2003 FDA Counterfeit Drug Task Force.
• Dec 2003 Counterfeit Surgical Mesh
• Oct 2004 Counterfeit Contact Lenses
• Feb 2004 FDA issues a report on combating
  counterfeit drugs

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COUNTERFEIT Dosage Form Drugs USA

• Naprosyn
• Pergonal
• Eldepryl
• Procrit
• Plavix

• Humatrope
• Metrodin
• Zyprexa
• Proprecia
• Lipitor

• Serostim
• Neupogen
• Nutropin
• Epogen

• Viagra
• Cialis
• Levitra
• Celebrex

• Tamiflu
• Percocet
• Phentermine
• Sertraline

• Singulair
• Reductil
  
• Steroids

COUNTERFEIT VeterinaryDosage Form Drugs USA

• Ivomec
• Baytril
• Nuflor

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Why Counterfeit ?

• Financial Gain
• Minimal Penalties
• Any Size Operations
• Small garage shops to large plants
• Demand
• Cheap Access to Digital Technology
• Access to Bulk Drug Actives
• Internet from China,Inda

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WHERE ARE COUNTERFEITS FOUND?
Counterfeiting can involve pharmaceuticals,
dietary supplements, cosmetics, medical devices.

• Black Market
• Internet
• Legal Distribution

An added dimension since September 11 2001
includes possible terrorism mainly for financial
gain.
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Types of Cases Analyzed

• Unapproved Drugs
• Generic or look-a-like versions of approved US
  drugs
• Products which contain drugs not approved for use
  in the US.
• Counterfeit Product
• Screening authentic vs. counterfeit
• Sourcing / Origin Analysis
• Diverted / Expired Product
• Right product, wrong packaging

Increasing Complexity of Analysis
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Chemical Fingerprinting Counterfeits
B. Chemical, Assay, Impurities
A. Formulation, Toolmarks, Trace Evidence
Chromatographic Techniques
HPLC Gas Chromatography Ion Chromatography
Headspace GC Capillary Electrophoresis Thin
Layer Chromatography GC-MS LC-MS
Elemental Analysis
AA ICP-MS
C. Physical
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Counterfeit Analysis

• Screening (rapid analysis)
• In general Does A B or A ? B
• Analysis may also include screening of suspect
  for other drugs, pharmaceuticals and/or poisons
• Sourcing / determination of origin
• In general does Counterfeit B Counterfeit C
  Counterfeit D or
• Counterfeit B Counterfeit C ? Counterfeit D
  etc.

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Pharmaceutical Product Manufacturing
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Drying and milling (grinding)
Mixing of drug active Ingredient with
excipient(s) water
Raw Materials Drug Active Ingredient Inactive
Ingredients (Excipients)
Blending
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Packaging
Tablet Compression
Tablet Coating
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Chemical information on oils of the individual
ridges
Physical Fingerprint
http//www.biometrics.gov/MediaRoom/fingerprint.as
px
A chemical pattern of the presence of oils for
ridges
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(A) Upper Punch (B) Compressed Tablet (C) Die
(D) Lower Punch
Examples of different tablet shapes Determined by
size/shape of upper Lower punches
Upper Punch with single score
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Boston Globe, 1/31/2001, By Naomi Aoki Serostim,
a human growth hormone used by about 6,000 AIDS
patients a year to fight the dangerous loss of
weight the disease can cause, costs about 21,000
for the recommended 12-week dose.
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Imported, Stuffed Teddy Bears!
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Stuffed with Counterfeit Viagra!
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Counterfeit Viagra 100 mg
Counterfeit Cialis 20 mg
Two different counterfeit products. Exhibit
same coating and core formulation and contain
sildenafil citrate.
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Authentic Tablet
Suspect 1
Suspect 2
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Authentic Tablet Manufacturing Site 1
Authentic Tablet Manufacturing Site 2
Counterfeit
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Counterfeit Label
Authentic Label from Pfizer
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A
B

• Authentic label adhesive (B) counterfeit
• Label adhesive

A
A
B
B
(A) Authentic white unprinted area (B)
counterfeit white unprinted area
(A) Authentic black Pfizer logo (B)
counterfeit black Pfizer logo
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Counterfeit Lipitor

• Within a 2 month period 20 submissions (66
  individual items) were received for analysis from
  6 OCI/FDA field offices and 2 FDA districts
  offices.
• The 20 submissions represented multiple lots of
  suspect counterfeit Lipitor products (10, 20, and
  40 mg).
• Screening determined 90 were counterfeit.
• Source analysis of the counterfeit product
  indicated a common source.

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Authentic Celebrex 200 mg
Counterfeit Celebrex 200 mg
Gross capsule weight of counterfeit ranged from
121 mg 340 mg. Gross Capsule weight of
authentic 328 mg.
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Capsule weights
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Suspect red fiber
Scale 1 mm
Rayon
Rice Chafe
Inorganic sulfate
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Testosterone Injection

• ? sample
• returned by
• customer to
• manufacturer
• sample
• suspected of
• being counter-
• feit
• manufacturer
• had not used
• labels with the
• suspects copy
• code since
• 1991

authentic suspect
product formulation cottonseed oil 560?g/mL
testosterone cypionate 202?g/mL benzyl
benzoate 20v/v benzyl alcohol 9?g/mL
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Haldol Tablets, Haloperidol
Item 1 was purchased over the internet through
a Canadian company and was mailed from Greece.
When one tablet was ingested it caused
numbness in the face and difficulty in breathing,
causing the person who took it to seek help at a
hospital.
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In addition to universal health concerns
regarding misuse of prescription drugs

• Pfizer, Eli Lilly, Bayer
• Their patents are being violated

• FDA
• Mislabeled products
• Unapproved drugs
• Herbals not evaluated as drugs

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Detection of Undeclared Pharmaceuticals In
Dietary Supplements
Dietary Supplement contents
Unapproved Product
Product contains tadalafil (API Cialis) assayed
at 9 mg/tablet
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His and Hers Dietary Supplement
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Analogs of Sildenafil
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Dinitrophenol History
Stanford Research
Weight Loss Clinics
FDC Act
Herbicide
Insecticide
1980s
1938
1925
1930
1892
Circa 1917
1990s
1935
1986

EPA Banned
Diet Pills
Munitions Factory WW I
Body Builders
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2,4-DinitrophenolAKA DNP, Dinitrophenol

• Unapproved Drug
• Increase in cases at FCC since 2000
• All involved bodybuilders
• Web sites promoting 2,4-DNP for wieght loss
• Detoxifies very slowly in humans
• 50 increase in metabolic rate

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Examples

• 7-day DNP Fat Loss Inferno Cycle
• Found in Elite Fitness News, May 30th, 2006
• United States vs. Sean Zang, plead guilty to
  introducing a misbranded drug into interstate
  commerce, resulting in two deaths.
• Recent submitted suspected steroids.

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Capsules containing fenproporex,
chlordiazepoxide HCl (Librium), fluoxetine HCl
Supplements/capsules for weight loss from Brazil.
The capsules were labeled as safe and were all
natural and did not contain amphetamines or any
other drugs.
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Acknowledgments
Fred Fricke (Laboratory Director) Dr. Doug
Heitkemper (Inorganic Branch Director) Dr. Duane
Satzger (Organic Branch Director) JaCinta
Batson John Crowe Nico Ranieri Sandy
Sterling Dr. Lorrie Lin Heather McCauley Dr.
Cheryl Flurer Dr. Sam Gratz (PDE-5
Analogs)