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

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)

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)

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

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

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)

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 http://www.courtinfo.ca.gov/opinions/revpub/A100018.DOC http://www.rhodium.ws/chemistry/ http://www.erowid.org/index.shtml http://www.totse.com/en/drugs/speedy_drugs/166004.html http://www.the-hive.ws/forum/forums.pl http://nepenthes.lycaeum.org/Drugs/DXM/extract.html http://www.erowid.org/chemicals/dxm/faq/dxm_chemistry.shtml (good detail) http://www.bluelight.ru/ News group: Alt.drugs, Alt.drugs.hard, Rec.drugs, Lycaeum Amazon.com

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

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)

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

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

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

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.

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

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

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

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.

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

FENTANYL TRANSDERMAL SYSTEMS Products extracted Duragesic® 10 mg/patch – 100μg/hr Matrix 18.4mg/patch -100µg/hr Solvents used Water Vodka (40% ethanol) Bacardi 151 rum Rubbing alcohol (IPA) Vinegar Methyl alcohol

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.

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

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.

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

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

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

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

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

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

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).

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

Thank you Robert P. Bianchi Vice-President and Chief of Scientific and Technical affairs Prescription Drug Research Center 134 N. LaSalle Street Chicago, IL 60602 312-726-8620 - Office 571-233-4780 – Cell RBianchi@pdrcllc.com RBConsulting700@AOL.com