1. TAMPERABILITY/EXTRACTABILITY OF PRESCRIPTION DRUGS
Pain Therapeutics Summit
October 3-4, 2012
San Jose CA
TAMPERABILITY/EXTRACTABILITY OF PRESCRIPTION DRUGS
Robert P. Bianchi
Prescription Drug Research Center - Fairfax, VA

2. BACKGROUND
Prescription drug abuse is the fastest rising category of drug abuse in the US, second only to cannabis and synthetic cannabinoids (ONDCP – Drug Control Strategy 2011).
Emergency department visits resulting from non-medical use of prescription analgesics increased 98.4 percent between 2004 and 2009 (NIDA 2011).
Seven of the ten substances most abused by high school seniors are legal drugs used non-medically. 2009, Monitoring the Future
According to DEA, 17 of the top 25 drugs most often examined by forensic laboratories in 2011, are available as prescription drugs. (DEA, NFLIS, 2011 mid year report)

3. BACKGROUND
An estimated (5%) 10.5 million Americans reported past year use of prescription drugs for non-medical purposes. (National Survey on Drug Use and Health, 2008).
Nearly 7 percent of youth between the ages of 12 
and 17 (1.7 million) have used such drugs which include pain relievers, sedatives, tranquilizers or stimulants, for non-medical purposes at some point.
(National Survey on Drug Use and Health,2008)

4. BACKGROUND What caused this phenomenon?
Prescription drugs do not fall under the clandestine cloud of illegal drugs such as heroin, ecstasy or methamphetamine
Prescription drugs are more available due to the development of new products and increased sales
Drugs are FDA approved
Friends and family use them
Drugs are frequently obtained free of cost

5. TYPES OF ABUSERS* Health care professionals – easy access, educated
Hard core opioid addicts – prefers heroin to Rx
Casual – low tolerance, alcohol & marijuana
Polydrug/Rave – uses anything available
Patient abuser – scammer, doctor shopper
SR Hard core Rx – converts to IR
* Sidney H. Schnoll, MD, PhD

6. DIVERSION METHODS Doctor shopping or other prescription fraud
Illegal online pharmacies
Theft and burglary (from residences, pharmacies, etc.)
Stereotypical drug dealing (selling pills to others)
Receiving from friends or family, often for little or no cost
Over prescribing (negligent or intentional over prescribing by physicians)

7. INFORMATION SOURCES
Most abusers do not have technical training and get their information on abuse and extraction methods from friends, publications or the Internet
Web sites
(good detail)
News group:
Alt.drugs, Alt.drugs.hard, Rec.drugs, Lycaeum
Amazon.com

8. INDUSTRY RESPONSE Development of abuse resistant delivery systems
Reformulation - Oxycontin
Oros® – osmotic pump (POLYOX)
Encapsulated pellets
Addition of antagonists
Capsules within capsules
Rel-Ease™ - Ionic complexes
Packaging
Reservoir transdermal patch
Pro-drugs
ADPREM
Dose counting devices
Benefit to industry
Enhanced corporate image
Fewer litigation actions
Increased market share
Lower schedule ? – more doctors will prescribe
Perceived as safer leading to increased prescriptions
Patient/Public Benefit
Reduced abuse and subsequent health care costs

9. SCHEDULING
The DEA in concert with FDA has been delegated the authority to add or transfer substances between schedules if the substance has a potential for abuse and meets the criteria for a particular schedule or remove them completely from scheduling
Scheduling based on eight factor analysis (combined to major three issues)
Potential for abuse and actual pattern of abuse and dependence (combines Factors 1, 4, 5, and 7). Ease of tampering or extracting.
Chemistry and pharmacological effect (combines Factors 3 and 2), including whether the substance is an immediate precursor of a controlled substance (Factor 8)
Public health risks (Factor 6)

10. EIGHT FACTORS
The 8 factors are specified in the Controlled Substance Act (CSA) as:
(1) The drug/substance actual or relative potential for abuse
(2) Scientific evidence of the drug/substance pharmacological effect, if known
(3) The state of current scientific knowledge regarding the drug/substance
(4) The drug/substance history and current pattern of abuse
(5) The scope, duration, and significance of abuse
(6) What, if any, risk there is to the public health
(7) The drug/substance psychic or physiological dependence liability
(8) Whether the drug/substance is an immediate precursor of a substance already controlled under this subchapter

11. ABUSE METHODS Physical – oral, snorting, smoking
Multiple doses
Heating patches
Crushing
Chewing
Grinding – hammer, coffee grinder, kitchen utensils
Removal of barrier – cut patch
Extraction –oral, nasal, smoking, IV
Solvent extraction to remove excipients and/or concentrate active ingredient

12. DEFINITIONS Tampering – physical manipulation
Crushing
Physical separation components (beads, layers, gel)
Heating, freezing, crisping, microwaving
Extractability – chemical manipulation of a product to remove, concentrate and/or purify the active ingredient performed using commonly available equipment and chemicals
Procedures may be used individually or in combination – crushing is frequently the first step in solvent extractions

13. EXTRACTION EXPERIMENTS
Standardized laboratory extractions must be developed for each type of dosage form, e.g. tablets, capsules, patches, liquids, IR, SR using solvents & equipment commonly available. All experiments must be conducted at least in triplicate to provide statistical validity. Controls and a comparator must included.

14. IN-VITRO EXPERIMENTS aka KITCHEN CHEMISTRY
Every product is different; therefore each requires a unique set of experiments to assess tamperability.
Sponsor knows product’s vulnerabilities and should develop experiments in concert with abuse experts based on product knowledge and current abuse methods of similar products using commonly available chemicals and equipment.
Consider testing all dosage strengths 14

15. IN-VITRO EXPERIMENTS
Develop written protocols that produce statistically valid, reproducible results.
Include related comparator product
Include controls
Include quality assurance procedures
Take photographs to illustrate results
Use graphs and charts to illustrate data 15

16. SOLVENT EXTRACTION EXPERIMENTS
Information I can share was presented at the American Pain Society annual meeting. Janssen sponsored study to compare the extractability of fentanyl from reservoir and matrix patches. All extractions were performed by NMS Laboratories using chemicals and equipment available to the general public. Identification and purity of extracts confirmed by GC/MS/MS

17. FENTANYL TRANSDERMAL SYSTEMS
The DURAGESIC reservoir patch is a form-fill-seal design that contains a suspension of fentanyl base in a water/ethanol and hydroxyethyl cellulose solution.
The matrix patch is a drug-in-adhesive formulation that contains fentanyl base dissolved in an adhesive.

18. FENTANYL TRANSDERMAL SYSTEMS
Generic
DURAGESIC®
Reservoir
Skin
Adhesive and Fentanyl Base
Backing Layer
Backing Layer
Fentanyl Base in Gel
Rate Controlling Membrane
Adhesive
Skin

19. FENTANYL TRANSDERMAL SYSTEMS
Products extracted
Duragesic® 10 mg/patch – 100μg/hr
Matrix mg/patch -100µg/hr
Solvents used
Water
Vodka (40% ethanol)
Bacardi 151 rum
Rubbing alcohol (IPA)
Vinegar
Methyl alcohol

20. EXTRACTION TECHNIQUES
Protective layers removed and intact patches subjected to extraction
“Room temperature Soak” (party punch): each patch left undisturbed in 500 ml of each solvent at RT.
“Elevated Temperature Soak”: each patch soaked in 500 ml of solvent at boiling point.
“3 Hour Percolation”: each patch percolated with 750 ml of each solvent.

21. ROOM TEMPERATURE SOAK Matrix Duragesic® Methanol Rum IPA Vodka Vinegar
Water
Duragesic®

22. IN-VITRO EXPERIMENTS
Particle size reduction is generally the first step.
Experiments should be attempted at RT and ET as well as after physical manipulation (heating, freezing, microwaving, crisping)
Use a variety of available manual and electric tools
Set practical time limits (Egalet study- 80% of subjects would spend 3-10 minutes tampering)
Smallest particle size generally produces the most desirable result.

23. SOLVENT EXTRACTION EXPERIMENTS
Solvents of different pH and polarity
Soaked and stirred
RT and elevated temperature (ET)
Ground and intact
Percolated
Single solvent (ingestible e.g. alcohol, water - non-ingestible e.g. paint thinner, acetone)
Multiple solvents - aqueous /pH adjustments & immiscible solvents

24. EXTRACTION EXPERIMENTS
All modes of abuse must be considered
Oral – the most commonly encountered
Nasal – crushing followed by snorting
Smoking – crushing/extracting -
IV – hard core abusers requiring immediate most intense result

25. Photos by permission, Egalet, Copenhagen DK, 2010.
INJECTABILITY
Photos by permission, Egalet, Copenhagen DK, 2010.

26. Photos by permission, Egalet, Copenhagen, DK 2010.
CRISPING
Photos by permission, Egalet, Copenhagen, DK 2010. 26

27. EXTRACTABILITY RATING
Neither the DEA nor FDA have objective criteria to measure/evaluate extractability.
Ideally, a rating system should be developed that would result in a quantitative score that regulators and industry officials could use to determine the relative extractability of any pharmaceutical product.
In February 2012, Dr. Douglas Throckmorton, deputy director of CDER, stated that the FDA will be releasing industry guidance on tamper-resistant formulations by the end of the 2012. 27

28. EXTRACTABILITY RATING
Objective metrics must be established -
Number of steps required
Amount of equipment and chemicals required
Amount of time expended
Percent recovery
Other active & inactive ingredients recovered
Physical characteristics of extract – viscosity, color, odor, syringability

29. EXTRACTION EXPERIMENTS
Although pharmaceutical companies and drug delivery development companies have their own laboratories, the objectivity of an independent laboratory is sought in addition to or instead of in house experiments. FDA guidance to industry recommends that in vitro experiments be conducted by an independent laboratory that is blinded to the fullest extent possible (after the May 2008 advisory committee meeting, FDA advised Purdue to utilize an independent laboratory to conduct in-vitro experiments of reformulated OxyContin).

30. Summary
No objective measure exists to measure Tamperability/extractability
Each product/system requires unique experiments designed to address vunerabilities
Use independent laboratory & abuse experts
Consider all modes of abuse & all strengths
Include photographs, graphs & charts where appropriate
No product has been proven to be tamper proof

31. Thank you Robert P. Bianchi
Vice-President and Chief of Scientific and Technical affairs Prescription Drug Research Center 134 N. LaSalle Street
Chicago, IL Office
– Cell