# Presentation: 085802

## 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@fda.hhs.gov

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## FDA Office of Criminal Investigations (OCI)

**FDA Forensic Chemistry Center (FCC)**
**Cincinnati Ohio**

- ASCLD Accreditation 2004

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Forensic Chemistry CenterUS Food and Drug Administration

***  ***

- Responsibilities
- Case work analysis and research related to product tampering, counterfeiting, fraud, drugs.
- Forensic laboratory service to the FDA’s 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.

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Products FDA Regulates

- _[Food](http://vm.cfsan.fda.gov/list.html)_*Foodborne Illness, Nutrition, Dietary Supplements...*
- _[Drugs](file:///D:/cder/)_*Prescription, Over-the-Counter, Generic...*
- _[Medical Devices](file:///D:/cdrh/index.html)_*Pacemakers, Contact Lenses, Hearing Aids...*
- _[Biologics](file:///D:/cber/index.html)_*Vaccines, Blood Products...*
- _[Animal Feed and_x000b_Drugs](file:///D:/cvm/default.htm)_*Livestock, Pets...*
- _[Cosmetics](http://vm.cfsan.fda.gov/~dms/cos-toc.html)_*Safety, Labeling...*
- _[Radiation-Emitting Products](file:///D:/cdrh/radhealth.html)_*Cell Phones, Lasers, Microwaves...*

- FY 2005
**Biologics ****	****39**
**Cosmetics ****	****5**
**Drugs ****	****	****391**
**Foods ****	****	****89**
**Medical Devices ****	****54**
**Supplements ****	****34**
**Vet Drugs ****	****11**
**Total****	****	****623**

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Pharmaceutical Counterfeiting

- Pharmaceutical Counterfeiting

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Slide 6

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Slide 7

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## 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

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## http://www.fda.gov/oc/initiatives

- Initial Report:
- /counterfeit/report02_04.html

- FDA COUNTERFEIT DRUG TASK FORCE
- REPORT: 2006 UPDATE
- /counterfeit/report6_06.html

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## 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
- 2005: Counterfeit Norvasc (Canada)
- Summer Fall 2005: Counterfeit Lipitor Celebrex (Mail Imports US, UK Supply Chain)
- December 2005: “Generic” Tamiflu

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## COUNTERFEIT: Dosage Form Drugs USA

- 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: **Veterinary**Dosage Form Drugs USA

- Ivomec
- Baytril
- Nuflor

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## 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

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## WHERE ARE COUNTERFEITS FOUND?

- Black Market
- Internet
- Legal Distribution

**An added dimension since September 11 2001 includes possible terrorism mainly for financial gain.**

**Counterfeiting can involve pharmaceuticals, dietary supplements, cosmetics, medical devices.**

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## 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

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Chemical Fingerprinting Counterfeits

-  HPLC
-  Gas Chromatography
-  Ion Chromatography
-  Headspace GC
-  Capillary Electrophoresis
-  Thin Layer Chromatography
-  GC-MS
-  LC-MS

- Chromatographic Techniques

- Elemental Analysis

- AA
- ICP-MS

- A. Formulation, Toolmarks, Trace Evidence

- B. Chemical, Assay, Impurities

- C. Physical

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## 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....

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Pharmaceutical Product Manufacturing

- 1

- Raw Materials
- Drug Active Ingredient
- Inactive Ingredients (Excipients)

**2**

- Mixing of drug active Ingredient
- with excipient(s) + water

- Drying and milling (grinding)

**3**

- Blending

**4**

- Tablet Compression

**5**

- Tablet Coating

- Packaging

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Physical Fingerprint

- http://www.biometrics.gov/MediaRoom/fingerprint.aspx

- Chemical information on oils
- of the individual ridges

- A chemical pattern of the
- presence of oils for ridges

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## (A) Upper Punch (B) Compressed Tablet 

- (A) Upper Punch (B) Compressed Tablet
- (C) Die (D) Lower Punch

- Upper Punch with single score

- Examples of different tablet shapes
- Determined by size/shape of upper
- Lower punches

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## 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.”

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Imported, Stuffed Teddy Bears!

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Stuffed with Counterfeit Viagra!

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Counterfeit Cialis 20 mg

- Counterfeit Viagra 100 mg

- Two different counterfeit products.
- Exhibit same coating and core formulation and contain sildenafil citrate.

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Authentic Tablet

- Suspect # 1

- Suspect # 2

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Authentic Tablet

- Manufacturing Site 1

- Manufacturing Site 2

- Counterfeit

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

##  Counterfeit Label

-  Counterfeit Label

- Authentic Label from Pfizer

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## A

- Authentic label adhesive **(B)  counterfeit**
**Label adhesive**

**A**

**B**

- (A) Authentic black Pfizer logo **(B) counterfeit**
**black Pfizer logo**

**A**

**B**

- (A) Authentic white unprinted area **(B)  counterfeit**
**white unprinted area**

**A**

**B**

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Counterfeit Lipitor 

- 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.

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## 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.

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Capsule weights

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Slide 31

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Scale 1 mm

- Suspect red fiber

- Rayon

- Rice Chafe

- Inorganic sulfate

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Slide 33

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Testosterone Injection

-   sample
-    returned by
-    customer to
-    manufacturer
-  sample
-   suspected of
-   being counter-
-   feit
-  manufacturer
-    had not used
-    labels with the
-    suspect’s copy
-    code since
-   1991

**authentic****        ****suspect**

- product formulation:
- cottonseed oil 560g/mL; testosterone cypionate 202g/mL;
- benzyl benzoate 20%v/v;  benzyl alcohol 9g/mL

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## 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.

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Slide 36

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

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

-      Their patents are being violated

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

- In addition to universal health concerns regarding misuse of prescription drugs...

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Detection of Undeclared Pharmaceuticals In Dietary Supplements

- Product contains tadalafil (API Cialis) assayed at 9 mg/tablet

**Dietary Supplement**
**contents**

**Unapproved Product**

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Slide 39

- FDA Forensic Chemistry Center

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## “His and Hers” Dietary Supplement

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Analogs of Sildenafil

- FDA Forensic Chemistry Center

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## Slide 42

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Dinitrophenol History

- 1892

- Herbicide

** **

- Insecticide

- Circa 1917

- Munitions Factory
- WW I

- 1930

- Stanford
- Research

- 1990’s

- Diet Pills

- 1935

- 1980’s

- Weight Loss
- Clinics

- Body
- Builders

- 1938

- FD&C
- Act

- 1925

- 1986

- EPA
- Banned

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## 2,4-DinitrophenolAKA: 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

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## 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.

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## Capsules containing: 

- fenproporex,
- chlordiazepoxide HCl (Librium),
- fluoxetine HCl

- The capsules were labeled as safe and were all
- natural and did not contain amphetamines or
- any other drugs.

- Supplements/capsules for weight loss from Brazil.

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium

## 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)

- FDA Forensic Chemistry Center

- 2007-06-USPHS Scientific and Training Symposium