Transcript PRE0005 - PDRC | Prescription Drug Research Center

TAMPERABILITY/EXTRACTABILITY
OF PRESCRIPTION DRUGS
Robert Bianchi – Prescription Drug Research Center, LLC
American Pain Society Meeting – Baltimore, MD May 8, 2010
Financial Disclosure
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Consulting services provided to :
Purdue Pharma L.P.
 Egalet®
 GW Pharmaceuticals
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Types of Abusers*
Health care professionals – easy access, educated
 Hard core opioid addicts – prefer heroin to Rx
 Hard core Rx – converts SR to IR
 Polydrug/Rave – uses anything available
 Casual – low tolerance, alcohol & marijuana
 Patient abuser – scammer, Rx forger, doctor
shopper
* Sidney H. Schnoll, MD, PhD
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Information Sources
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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
Other
Amazon.com
US Patent & Trademark Office (USPTO)
Definitions
Tampering – physical manipulation
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Crushing - most common & frequently the first step in
extractions
Physical separation components (beads, layers, gel)
Heating, freezing, crisping, microwaving
Extraction – the manipulation of a product to remove,
concentrate and/or purify the active ingredient using
commonly available equipment and chemicals
Procedures may be used individually or in combination
Scheduling
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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
three major issues)
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Potential for abuse and actual pattern of abuse and
dependence (combines Factors 1, 4, 5, and 7). Ease of
tampering/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)
Abuse Methods
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Tampering/Physical – oral, transdermal
 Crushing
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Chewing
Grinding – hammer, coffee grinder, kitchen utensils
Removal of barrier – cut patch
 Multiple
doses
 Heating patches
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Extraction/Chemical –oral, nasal, smoking, IV
 Solvent
extraction to remove excipients and/or
concentrate active ingredient
In-vitro Experiments
aka Kitchen Chemistry
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There is no standard battery of tests.
Every product is different; therefore each requires a
unique set of experiments to assess
tamperability/extractability.
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 all viable methods of administration, i.e.,
oral, IV, snorting, smoking.
Conduct in-house experiments and modify protocol as
data are generated.
Exercise due diligence
In-vitro Experiments
 Particle
size reduction is generally the first step
attempted by abusers. Smallest particle size generally
produces the most desirable result.
 Experiments should be attempted on “as is” formulation
as well as after physical manipulation (heating, freezing,
microwaving, crisping, grinding)
 Use a variety of manual and electric devices readily
available
 Set practical time limits (Egalet unpublished study - 80%
of subjects would spend a maximum of 3 to 10 minutes
tampering with an unspecified pharmaceutical product).
In-vitro Experiments
Soaked and stirred
 Ground and intact
 RT and elevated temperatures
 Solvents - Different pH and polarity
 Single solvent (ingestible e.g. alcohol, water &
non-ingestible e.g. paint thinner, acetone)
 Multiple solvents – aqueous/pH
adjustment/immiscible solvent extraction
 Smoking machine
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In-vitro Experiments
Develop written protocols that produce
statistically valid, reproducible results.
 Include related comparator product
 Include controls
 Include quality assurance procedures
 Engage an independent laboratory that is
blinded to the fullest extent possible.
 Use photographs and graphics to illustrate
results
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In-vitro Experiments
Coffee mills used to grind
Egalet® ADPREM tablets
• Shown lids have been used for approx 15 runs each
• Examples on broken blades from two mills
Photos by permission, Egalet, Copenhagen DK, 2010.
In-vitro Experiments
Grinding Egalet® ADPREM tablets results in broken lids and mills without destroying
the shell integrity and thereby the controlled release mechanism
Photos by permission, Egalet, Copenhagen DK, 2010.
•
Egalet® ADPREM tablets
• Preparing an IV solution from Egalet® ADPREM tablets results in a highly
viscous gel-like structure
Photos by permission, Egalet, Copenhagen DK, 2010.
SOLVENT EXTRACTION EXPERIMENTS
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Duragesic® 10 mg/patch – 100μg/hr
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Matrix
18.4mg/patch -100µg/hr
Solvents utilized
Water
 Vodka (40% ethanol)
 Bacardi 151 rum
(75.5% ethanol)
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Rubbing alcohol (IPA)
 Vinegar
 Methyl alcohol
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Room Temperature Soak
Methanol
Rum
IPA
100
Vodka
% yield
75
Vinegar
Matrix
50
25
Water
Duragesic®
0
0
50
100
minutes
150
200
Extractability Rating
Neither the DEA nor FDA have objective
criteria to 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.
Extractability Rating
Objective metrics must be established
 Number of steps required
 Amount of time expended
 Percent recovery
 Other active & inactive ingredients recovered
 Physical characteristics of extract – viscosity,
color, odor
 Syringability
Summary
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Each product/system requires unique
experiments designed to address vunerabilities
Engage independent laboratory & abuse experts
Consider all modes of abuse & all strengths
Include photographs & graphs where appropriate
No product has been proven to be tamper proof
No objective measure exists to measure
Tamperability/extractability
Thank you
Robert P. Bianchi
Vice-President and Chief
of Scientific and Technical Affairs
Prescription Drug Research Center
4031 University Drive, Suite 200
Fairfax, VA 22030
571-233-4780
[email protected]
[email protected]