The Devil’s in the Regulations Impact on Product Testing May 18, 2009

1. Richard G. Higby President / Managing Director The Devil’s in the Regulations Impact on Product Testing May 18, 2009

2. Arista Laboratories • An independent, ISO 17025:2005 accredited laboratory (A2LA, UKAS) specializing in the characterization of tobacco and tobacco smoke • Locations: Richmond, VA; Kingston upon Thames • Founded: April 2000 • Ownership: Molins PLC

3. Fast, Good, Cheap Pick any two…

4. Family Smoking Prevention and Tobacco Control Act (S. 982; May 5, 2009) • Annual registration of products • Testing requirements (passage + 24 months) • Data submission (passage + 36 months)

5. Specific [chemistry] Requirements • Ingredients • Tar, nicotine yield • Smoke constituents • Mainstream • Side stream • Tobacco constituents • All brands

6. Definition of “Brand” • “Brand” distinguished by: • Tobacco (blend) • Tar content (yield) • Nicotine content (yield) • Flavor (menthol, non-characterizing flavor) • Size (King, 100, slim, etc.) • Filtration (non-filter, charcoal) Every stick and blend variant manufactured is a “brand”

7. ABC Tobacco Brand-Styles

8. FDA will likely look to other regulatory paradigms • Health Canada • ANVISA – Brazil • WHO –TFI • Framework Convention on Tobacco Control • TobReg • TobLabNet

9. Fast?

10. Smoke Constituents (mainstream) • Ammonia • Aromatic amines (4) • Benzo[a]pyrene • Carbonyls (9) • Eugenol • Hydrogen cyanide • Mercury • Metals (6) • Nitrosamines (4) • NOx • Organics (5) • Phenolics (7) • Semivolatiles (3) • Tar, nicotine, CO • Aromatic amines (2) • Benzo[a]pyrene • Carbonyls (3) • Hydrogen cyanide • Mercury • Metals (6) • Nitrosamines (4) • NOx • Benzene • 1,3-butadiene • Ethylene oxide • Tar, Nicotine/free nicotine, CO Health Canada/ANVISA TobReg

11. Smoke constituents (side stream) • Ammonia • Aromatic amines (4) • Benzo[a]pyrene • Carbon monoxide • Carbonyls (9) • Hydrogen cyanide • Mercury • Metals (6) • Nitrosamines (4) • NOx • Organics (5) • Phenolics (7) • Semivolatiles (3) • Tar and nicotine Health Canada/ANVISA TobReg

12. Tobacco Constituents • Alkaloids (5) • Ammonia • Benzo[a]pyrene • Eugenol • Humectants (3) • Metals (7) • Nitrate • Nitrosamines (4) • pH • Propionate • Sorbic acid • Triacetin Health Canada/ANVISA TobReg

13. Multiple Smoking Regimes • FTC Smoking (35/60/2; 24h conditioning) • ISO Smoking (35/60/2; 48h conditioning) • “Canadian” Intense Smoking (45/30/2; 100% vent blocking) • “Massachusetts” smoking (45/30/2; 50% vent blocking) • Other methods yet to be defined XXX

14. Summary of Constituents • Smoke constituents • Mainstream methods (14) • Mainstream constituents (47) • Side stream methods (14) • Side stream constituents (45) • Tobacco constituents • Methods (12) • Constituents (27) • Smoking regimes (2) Total Methods (40) Total Endpoints (121) • Smoke constituents • Mainstream methods (10) • Mainstream constituents (24) Health Canada/ANVISA TobReg

15. Toxicology • Health Canada • In vitro assays are required to measure: • Cytotoxicity (neutral red uptake assay) • Mutagenicity (Ames Salmonella assay) • Genotoxicity (micronucleus) • Family Smoking Prevention and Tobacco Control Act • Toxicology is mentioned in terms of reduced harm products

16. Good

17. Quality System • ISO 17025:2005 • Laboratories are accredited in accordance with the recognized International Standard ISO/IEC 17025:2005 General Requirements for the Competence of Testing and calibration Laboratories. This accreditation demonstrates technical competence for a defined scope and the operation of a laboratory quality management system (refer to joint ISO-ILAC-IAF Communiqué dated 18 June 2005). • Good Laboratory Practices (GLP) • Good Laboratory Practice (GLP) embodies a set of principles that provides a framework within which laboratory studies are planned, performed, monitored, recorded, reported and archived. These studies are undertaken to generate data by which the hazards and risks to users, consumers and third parties, including the environment, can be assessed for pharmaceuticals (only preclinical studies), agrochemicals, cosmetics, food additives, feed additives and contaminants, novel foods, biocides, detergents etc.... GLP helps assure regulatory authorities that the data submitted are a true reflection of the results obtained during the study and can therefore be relied upon when making risk/safety assessments.

18. …at Arista • ISO 17025:2005 • 22 quality procedures • Good Laboratory Practices • 104 standard operating procedures

19. Cheap?

20. TMA Update • United States Lobbying activity surrounding the bill to grant the US Food and Drug Administration regulatory control over tobacco products, which passed the House in a 298-112 vote on April 2nd and will be taken up by the Senate Health, Education, Labor and Pensions HELP Committee this week, was intense in the first quarter of 2009, with Altria, the lone industry player to support the measure, spending $4.29 million on the FDA bill and a couple of other pieces of tobacco legislation, while rivals Reynolds American and Lorillard paid lobbyists $1.59 million and $850,000, respectively, in that period, according to Federal lobbying records. (Washington Post 05/11)

21. Clinical use trials • E.g. 100 smokers with puff profiling • Toxicology • In vitro assays • Cytotoxicity • Neutral red uptake assay • Clastogenicity • Micronucleus, sister chromatid exchange • Mutagenicity • Ames Salmonella assay • Other assays • Inflammation