1. Development and Justification of Qualification Threshold Ron Wolff IPAC-RS Representative Fellow, Life Sciences Nektar Therapeutics

2. Outline Decision criteria Process for setting qualification threshold (QT) –Comparison to non-carcinogenic reference thresholds in a similar manner to SCT Consideration of irritation, hypersensitivity, age Relation of QT to –Ambient particulate matter –Examples from marketed products

3. Decision Criteria A leachable with a tolerable daily intake (TDI) at or below the qualification threshold – would have a dose so low as to present negligible safety concerns from noncarcinogenic toxic effects –would be considered qualified, so no toxicological assessment would be required –would require a toxicology risk assessment with a structural alert or known class effect for carcinogenicity/genotoxicity, irritation, or hypersensitivity

4. Reference Exposure Levels (RELs) Definition –Daily exposure concentration considered to present negligible risk to human health from non-carcinogenic effects –Usually a no-observed-adverse-effect-level (NOAEL) from animal toxicology studies with the use of an appropriate safety factor (usually  100) Sources –US EPA –Agency for Toxic Substances Disease Registry (ATSDR) –California Environmental Protection Agency (CAL EPA)

5. Inhalation Reference Levels in Various Databases

6. Summary of Inhalation Reference Toxicity Values (µg/day) Respiratory ToxicitySystemic Toxicity median10 th %tilemedian10 th %tile CAL EPA RELs601.250004.0 ATSDR MRLs1891.154265.4 US EPA RfDs900.514004.2 Combined1201.519405.0

7. Most Compounds with Reference Levels < 5  g/day Are Metals, Carcinogens or Identified Irritants Compounds with Respiratory ToxicityCompounds with Systemic Toxicity Compound Ref Value (µg/ day) SourceCompound Ref Value (µg/day) Source chromium vi (chromic acid mists)0.086REL RfD MRLchlorinated dioxins0.0008REL beryllium and compounds0.237RfD RELcadmium0.4REL hexamethylene diisocyanate0.525RfD MRLarsenic0.6REL acrolein0.583REL RfD MRLarsine1.0RfD chloroacetophenone, 2-0.600RfDmanganese1.5REL RfD MRL toluene diisocyanate mixture1.4RfD RELmercury1.9REL RfD MRL glutaraldehyde1.6RELchlordane2.4REL MRL nickel & compounds2.0REL MRLdicyclopentadiene4.0RfD cobalt2.0MRLnitroaniline, 2-4.0RfD titanium tetrachloride2.0MRLdisulfoton4.0MRL nickel oxide2.0REL1,2-dibromoethane4.0RfD antimony trioxide4.0RfD 1,2-dibromo-3- chloropropane 4.0RfD chlorine4.0RfD RELhydrazine4.0REL chlorine dioxide4.0RfD hexachlorocyclopentadiene4.0RfD Note: For compounds with more than 1 source, Ref Value is geometric mean from all available sources. Ref Value = reference value.

8. Irritation Evaluated from the point of view that asthmatics are the most sensitive population Used the RD50 database developed on inhaled irritants in mice as a starting point –Validated, well-accepted, extensive database of commodity chemicals –RD50 is the concentration that produces marked effects in mice by reducing respiratory frequency by 50% Confluence of data suggest that 0.001 X RD50 is a safe concentration for most asthmatics –Corresponds to a concentration that produces no discernible effects on lung tissue, and thus also unlikely to elicit any bronchoconstrictor response, since the two are correlated –RD50 based safe dose = 0.001 X RD50 breathed for 10 minutes

9. Sensitivity of Asthmatics Compared to Normal Population Cockcroft (Ann Allergy, 1985) studied 253 normals and 181 symptomatic asthmatics challenged with aerosolized histamine –25% of normals responded at a concentration of 16 mg/L [effectively, an RD50 concentration] –25% of asthmatics responded at 0.2 mg/L –No observable responses in asthmatics at 0.015 mg/L Illustrates that 1/1000 of RD50 values is likely to pose negligible risk for most asthmatics

10. RD50 Based Safe Dose in Asthmatics is Less than Occupational Short Term Exposure Limits (STELs)

11. RD50 Based Safe Doses are Similar to California RELs Designed to Protect the General Population (Including Sensitive Sub-Populations)

12. Hypersensitivity Data on isocyanates used to provide perspective RD50 of toluene diisocyanate is 0.4 ppm Permissible Exposure Level (PEL) is 0.02 ppm –Level designated to prevent induction of sensitization Lowest concentration eliciting responses in sensitized subjects –0.001 ppm These data and other similar examples suggest that 0.001 X RD50 is also protective of hypersensitivity reactions

13. Acute Irritation and Sensitization Have Similar Dose-Response to Chronic Respiratory Toxicity

14. Most Compounds with RD50 Based Reference Exposure Levels < 5  g/day Can be Identified with Structural Alerts Isocyanates Aldehydes Pesticides Nitriles Styrenes

15. Comparison of 5  g/day QT with Ambient Particulate Exposures Ambient reference concentration - 18  g/m 3 –Data from Portage, Wisconsin Cleanest environment in the “Six cities study” Best air quality and least cardio-respiratory disease Designated as the “control” city against which others were compared – Well below the National Air Quality Standards for PM10 (respirable fraction) 50  g/m 3 annual average 150  g/m 3 twenty-four hr average

16. QT of 5 µg/day Compared to Inhaled Particulate in the Cleanest of the “Six Cities” Age Body Mass (kg) Ventilation Inhaled Environmental Particulates * 5 µg/day Limit as % of Inhaled Environmental Particulates (m³/day)(m³/kg/day)(µg/day)(µg/kg/day) 1 year 11.5 †5.1 †0.4938.0 5.4% 5 years 20.0 †8.7 †0.41577.8 3.2% 10 years 33.7 †15.3 †0.52758.2 1.8% 15 years 55.0 †17.7 †0.33195.8 1.6% Adult 58.0 †17.8 †0.33205.5 1.6% 70.0 ‡20.0 ‡0.33605.1 1.4% * Based on PM 10 inhalable particle concentration of 18  g/m³ in reference city Portage WI, USA, (Dockery et al, 1993). † Estimates based on measurements for different ages of ventilation rate at various activity levels and percentage of daily time spent at those activity levels (Roy, 1992) ‡ Standard estimates used by US EPA for risk assessment

17. Perspective for Exposures to Children 5  g/day QT –Represents a minor additional load compared to daily environmental exposure for any age group, including children Comparisons of toxicokinetics in adults and children are within the toxicokinetic safety factor of 3.16 greater than 90% of the time Comparison of deposition of particles and gases in adults vs children are within the toxicokinetic safety factor of 3.16 Therefore, the standard intraspecies safety factor of 10 (toxicokinetic factor of 3.16 x toxicodynamic factor of 3.16) appears to be adequate to account for possible differences between adults and children, however additional research in this area is warranted

18. Comparison of 5 µg/day QT with ICH Thresholds Product Type Active Ingredient Maximum Dose * (µg/day) ICH Qualification Threshold Drug SubstanceDrug Product basis(µg/day)basis(µg/day) FORADIL DPI formoterol fumarate200.15% 0.03 1%0.2 SEREVENT MDI-DPI salmeterol xinafoate1000.15% 0.15 1%1.0 FLONASE NAS fluticasone propionate2000.15% 0.30 1%2.0 ATROVENT MDI ipratropium bromide2160.15% 0.32 1%2.2 ATROVENT NAS ipratropium bromide2520.15% 0.38 1%2.5 BECONASE AQ NAS beclomethasone dipropionate3360.15% 0.50 1%3.4 QVAR MDI beclomethasone dipropionate5120.15% 0.77 1%5.1 ASTELIN NAS azelastine hydrochloride1,0960.15% 1.6 1%11.0 VANCERIL 84 MDI beclomethasone dipropionate1,2600.15% 1.9 1%12.6 PULMICORT DPI budesonide1,2800.15% 1.9 1%12.8 PROVENTIL HFA MDI albuterol sulfate1,2960.15% 1.9 1%13.0 AZMACORT MDI triamcinolone acetonide1,6000.15% 2.4 1%16.0 FLOVENT MDI-DPI fluticasone propionate2,0000.15% 3.0 1%20.0 AEROBID MDI flunisolide2,0000.15% 3.0 1%20.0 MAXAIR MDI pirbuterol acetate2,4000.15% 3.6 1%24.0 INTAL MDI cromolyn sodium6,4000.15% 9.6 ≤50 µg50.0 TILADE MDI nedocromil sodium14,0000.15% 21 0.50%70.0 RELENZA DPI zanamivir20,0000.15% 30 0.50%100 IMITREX NAS sumatriptan40,0000.15% 60 0.50%200 NICOTROL NS NAS nicotine40,0000.15% 60 0.50%200 Median1,4481.912.9 * Based on dose delivered from mouthpiece or actuator when reported. "Every 4 hours" is assumed to allow up to 6 times daily. Abbreviations: DPI = dry powder inhaler; MDI = metered dose inhaler; NAS = nasal spray

19. OINDP L&E Threshold Perspective Recommended thresholds based on dose inhaled by patients –Rather than a percentage (%) as in ICH Guidelines 5  g/day QT –Recommendations intermediate between API and drug product ranges –Relevance maximized based on considerations of Total daily intake Structural alerts Conservative risk assessment

20. Summary A Qualification Threshold (QT) of 5 µg/day meets the criterion of a dose that is sufficiently low as to present negligible safety concerns for noncarcinogenic toxic effects. Consideration of possible irritancy and hypersensitivity suggest that 5 µg/day will adequately protect sensitive sub-populations The risk assessment must include structural alert information to provide case-by-case assessments for metals, isocyanates, aldehydes, nitriles, and styrenes whose levels are below the QT