In the recent years the life sciences industries worldwide are dealing with controlled substance compliance and the production and handling of these substances is highly regulated due to concerns regarding their negative effect on human health and the environment. Legislation at local, national and international levels is becoming increasingly complex and the R&D departments of pharmaceutical companies and other life sciences organizations are, of course, not exempt from these regulations. During the age of externalization and collaboration, when much of the R&D operations of the parent companies are being outsourced to Contract Research Organizations (CROs), often located in other countries, the controlled substance process becomes even more complicated. The responsible organizations need to make sure that their compounds satisfy the legislations of the countries where these CROs operate. Compliance Checker offers you a solution for this business management challenge. Compliance Checker is a web-based state of the art system using chemical intelligence that allows you to perform fast searches (by structure, names, SMILES strings, synonyms, CAS / DEA numbers, etc.) against a constantly maintained, high quality legislation database covering a wide geographical area, to verify if the compounds you produce, store or transport fall under any regulations described by law. In this talk the main functionality of Compliance Checker will be revealed, but also case studies on how easily it can be deployed in any type of organizations (eg. integrate it in third party applications like Electronic Laboratory Notebooks – ELN).

1. Compliance Checker
A Solution from Pre-Competitive Space

2. Compliance is important
The penalties for not maintaining compliance are real…
– Large Retail Pharmacy Pays $77 Million Fine
– DEA issues Two Year Suspension for Wholesale Distributor's Ability to Sell Controlled
Substances.
– Large Logistics Carrier Pays $40 Million Fine
– Large Retail Pharmacy Chain Pays $80 Million Fine DEA Inquiry
– 2008 ‘Major Pharmaceutical Company’ settles with United States over record keeping
of Controlled Substances - $511,000 in fines
– 2009 ‘Pharmaceutical Company’ was contacted by the U. S. Department of Justice
representing the Drug Enforcement Administration concerning alleged regulatory
violations of the Controlled Substances Act. The company paid a civil fine of $250,000
Source: Pistoia Alliance

3. Controlled Substances???
Gamma-hydroxybutyric acid
Chloral hydrate Ketamine Amphetamine
Piperonal Acetone
ALL ARE CONTROLLED !!!

4. Beyond Borders
• Each country’s legislative approach leads to different
sets of controlled substances
Salvinorin A
Germany but not US
Caffeine
Controlled in China
Tramadol
Controlled in US + Sweden

5. Working together with the
Pistoia Alliance!
CSCS Milestones :
• 2012 – Project starts
• Early 2013 – RFP published
• April 22, 2013 - Pistoia Alliance have chosen
ChemAxon + Patcore to develop Compliance
Checker
• End 2013 – UAT testing starts
• March 11, 2014 – UAT approval
– dataset of over 400 chemical structures
to challenge the system
– the dataset contained both controlled
and non-controlled structures across a
range of chemical classes and
legislative schedules
– team of experts drawn from major life
science organizations
AstraZeneca
Bayer
GlaxoSmithKline
Merck
Novartis
Roche

6. What is Compliance Checker?
Text, CAS #,
Name, etc.

7. Compliance Checker pedigree
• Marketed in Japan as
CRAIS Checker since 2006
and currently used by 30+
companies
• Powered by JChem’s
Markush technology
• Easily integratable
• Supported worldwide by
ChemAxon and Patcore
The Rotterdam Convention on the Prior
Informed Consent Procedure for Certain
Hazardous Chemicals and Pesticides in
International Trade (PIC)
Substances listed of the Montreal Protocol
on Substances that Deplete the Ozone Layer
United Nations Recommendations on the
Transport of Dangerous Goods
United Nations Single Convention on
Narcotic Drugs 1961
United Nations Convention on Psychotropic
Substances 1971
United Nations Convention Against Illicit
Traffic in Narcotic Drugs and Psychotropic
Substances 1988
EU REGULATION (EC) No 273/2004 OF THE
EUROPEAN PARLIAMENT AND OF THE
COUNCIL of 11 February 2004 on drug
precursors
US Controlled Substance Act Schedule I-V
US Chemical Diversion and Trafficking Act
List I-II Chemicals
CA Controlled Drugs and Substances Act
Schedule I-VIII
UK Misuse of Drugs Act Part I Class A-C
Drugs
UK The Misuse of Drugs Regulations 2001
Schedule I-IV
IN Narcotic Drugs and Psychotropic
Substance Act 1985
CH Swiss Controlled Substances Act
(BetmVV-EDI) Narcotics List A-G
FR Arrête du 22 fevrier 1990 fixant la listedes
substances classees comme stupefiants
ANNEXE I-IV
FR Arrête du 22 fevrier 1990 fixant la liste
des substances psychotropes PREMIERE-
TROISIEME PARTIE
DE Gesetz uber den Verkehr mit
Betaubungsmitteln (Betaubungsmittelgesetz
- BtMG) Anlage I-III
DE Gesetz uber den Verkehr mit
Arzneimitteln (Arzneimittelgesetz - AMG)
Anhang I-III
S Lakemedelsverkets foreskrifter om
forteckningar over narkotika Forteckning I-V
IRE MISUSE OF DRUGS REGULATIONS 1988
Schedule I-V
NL Opiumwet 12 mei 1928 Lijst I-II
IT Decreto del Presidente della Repubblica
del 9 ottobre 1990, n. 309 TABELLA I-II
BE Arrête royal reglementant les substances
soporifiques et stupefiantes, et relatif a la
reduction des risques et a l'avis
therapeutique
BE Arrête royal reglementant certaines
substances psychotropes, et relatif a la
reduction des risques et a l'avis
therapeutique
DK Bekendtgorelse om euforiserende stoffer
Liste A-E
E LEY 17/1.967, DE 8 DE ABRIL LISTA I-IV
E REAL DECRETO 2829/1.977, DE 6 DE
OCTUBRE LISTA I-IV
Full Japanese coverage, etc…

8. Use Cases
Check that…
… what you already hold is legal
… what you plan to synthesize is legal
… what you play to buy is legal
… what you plan to ship is legal over there
Departments need
Compliance Checker!
… AND know this before new legislation becomes active
Chemical Weapons, A. Costache & K. Niesz, European Biopharmaceutical Review 67: pp70-72, April 2014

9. Any ester or ether of ---
Any salt of ---
Any stereoisomeric form of ---
>>> UK MDA
>>> Schedue II, Part 1, Class A Drugs
Hit
Ether
Ester
Potassium salt
MixtureDimepheptanol
Detects various forms

10. Detects only regulated
structures
Any compound (not being a compound for the time
being specified in sub-paragraph (a) above) structurally
derived from Tryptamine or from a ring-hydroxy
Tryptamine by substitution at the nitrogen atom of a
side-chain with one or more alkyl substituents but no
other substituent;
Any ester or ether of ---
Any salt of ---
Any stereoisomeric form of -
--
>>> UK MDA
>>> Schedule II, Part 1, Class A Drugs
Alkyl
Phosphate ester
and
*Over all description for schedule II

11. Complex controlled substance
definitions
Desomorphine
(krokodil) rule for
the UK MDA
Pethidine (Demerol)
rule for the UK MDA

12. •Poisonous and Deleterious Substances Control Law
•Fire Services Act
Toxic, deleterious and dangerous substances
•Export Trade Control Order
•Law on the Prohibition of Chemical Weapons and the Regulation of Specific Chemicals
•United Nations Recommendations on the Transport of Dangerous Goods
Security
•Industrial Safety and Health Law
•The Rotterdam Convention on the Prior Informed Consent Procedure for Certain Hazardous
Chemicals and Pesticides in International Trade (PIC)
Safety and health
•Act on Confirmation, etc. of Release Amounts of Specific Chemical Substances in the
Environment and Promotion of Improvements to the Management Thereof (PRTR)
•Substances listed of the Montreal Protocol on Substances that Deplete the Ozone Layer
•Agricultural Chemicals Regulation Law
Environment protection
•Unfavorable Substructure
Research Support
Beyond Controlled Substances

13. SOAPWeb Client Windows Client Command Line
Interface for
external systems
(ELN, Inventory,
Registration, etc.)
Batch processing,
Automation,
Pipeline Pilot
KNIME
Quick Check
Batch Check
System administration
Open to everyone
Batch processing
for large SDFs
(library
management)
Compliance Checker Server

14. Compliance Checker
Useful links:
http://www.chemaxon.com/products/compliance-checker/
http://www.pistoiaalliance.org/news_events/in-the-news-24838/489-cscs-vendor-
selection.html
http://www.pistoiaalliance.org/news_events/press-releases/502-cscs-press-release.html
http://edition.pagesuite-professional.co.uk/Launch.aspx?PBID=587773cf-29c4-46f2-9d9d-
2f87bf178b5c