Altria Group, Inc. · NYSE:MO

Altria — Tobacco Science Research Conference 2019

27 slides from Altria's conference presentation, September 2019

  1. Slide 1: In Vitro Dissolution Testing of Nicotine Release from Smokeless Tobacco Products

    In Vitro Dissolution Testing of Nicotine Release from Smokeless Tobacco Products John H. Miller, Fadi Aldeek, Tim Danielson, Yezdi B. Pithawalla, Anthony A. Brown and Celeste Wilkinson Tobacco Science Research Conference Sept. 15-18th 2019 J.H. Miller I Regulatory Sciences I Altria Client Services I

  2. Slide 2: Substantial Equivalence (SE) Pathway “905”

    Substantial Equivalence (SE) Pathway “905” Compare Predicate vs. New Product US FDA: Abbreviated HPHC List* Demonstrates if the new product has:  Same characteristics as the predicate  Product does not raise different questions of public health “Reporting Harmful and Potentially Harmful Constituen

  3. Slide 3: Substantial Equivalence (SE) for Smokable Tobacco Products

    Substantial Equivalence (SE) for Smokable Tobacco Products Predicate vs. New Product  Comparison of HPHCs in cigarette filler and in smoke (route of exposure)  Smoking machines allow for a comparison of multiple products  Standardized smoking protocols: ISO, CORESTA & HC  Not meant to replicate

  4. Slide 4: Substantial Equivalence (SE) for Smokeless Tobacco Products

    Substantial Equivalence (SE) for Smokeless Tobacco Products Cigarette Smoking Machine Loose Snus Pouch J.H. Miller I Regulatory Sciences I Altria Client Services I TSRC Sept 15-18th 2019 I FINAL 4

  5. Slide 5: Dissolution Testing

    Dissolution Testing In vitro laboratory test method designed to demonstrate how efficiently an active ingredient is extracted out of a solid oral dosage into solution Applications in Pharmaceutical Industry  Guide product design  Quality control testing  Product to product performance comparison

  6. Slide 6: Dissolution Methodology Considerations

    Dissolution Methodology Considerations  Apparatus  Dissolution Media  Analytical Method Development & Validation J.H. Miller I Regulatory Sciences I Altria Client Services I TSRC Sept 15-18th 2019 I FINAL 6

  7. Slide 7: Dissolution Apparatus

    Dissolution Apparatus Multiple commercial & non-commercial options available for measuring release of constituents from oral dosage forms Example: U.S. Pharmacopeia Apparatus Name Apparatus Type USP-1 Basket USP-2 Paddle USP-3 Reciprocating cylinder USP-4 Flow-through cell USP-5 Paddle over disk USP

  8. Slide 8: ALCS Dissolution Method

    ALCS Dissolution Method SOTAX CE7 Smart Flow-Through Cell Apparatus (USP-4) Seven Cell Holders Pump Fractions Collector Artificial Saliva  Flow rate 4.0 mL/min  Temperature 37oC J.H. Miller I Regulatory Sciences I Altria Client Services I TSRC Sept 15-18th 2019 I FINAL 8

  9. Slide 9: Direction of Artificial Saliva Flow

    ALCS Dissolution Method Flow-Through Cell in USP-4 Apparatus 1 g of Loose Tobacco 1 Pouch (Snus) Direction of Artificial Saliva Flow Filter Chamber 3 mm Beads 3 mm Loose Tobacco Beads 1 mm Beads 1 mm Beads 5 mm Red Ruby Bead J.H. Miller I Regulatory Sciences I Altria Client Services I TSRC Sept 15-1

  10. Slide 10: ALCS Dissolution Method: Artificial Saliva Composition

    ALCS Dissolution Method Artificial Saliva Composition* *German Institute for Standardization (DIN) Recipe is based upon German standard DIN v53160-1, “Determination of the Colour Release of Articles of Daily Use, Part1: Resistance to Artificial Saliva”, section 4.2, October 2002. J.H. Miller I Regul

  11. Slide 11: ALCS Dissolution Method: Fraction Collection Protocol

    ALCS Dissolution Method Fraction Collection Protocol Fraction Number Fraction Collection Fraction Collection Volume Collected Time (min) Duration (min) (mL) 1 4 4 16 2 8 4 16 3 12 4 16 4 16 4 16 5 20 4 16 6 30 10 40 7 40 10 40 8 50 10 40 9 60 10 40  Flow rate 4.0 mL/min  Temperature 37oC J.H. Mill

  12. Slide 12: Analytical Method: Determination of Nicotine in Dissolution Fractions

    Analytical Method: Determination of Nicotine in Dissolution Fractions Sample Preparation in Autosampler Vials 1. 0.1 mL of the dissolution fraction 2. 0.8 mL of artificial saliva 3. 0.1 mL of ISTD (Ethyl Benzoate, 1 mg/mL) 4. Cap, vortex and analyze by UPLC-PDA* ISTD: Internal Standard UPLC-PDA: Ult

  13. Slide 13: Analytical Method: Determination of Nicotine in Dissolution Fractions

    Analytical Method: Determination of Nicotine in Dissolution Fractions Instrument: Waters Acquity I-Class UPLC system coupled to Photodiode Array Detector Column: BEH C18, 2.1 x 100 mm, 1.7 µm, Waters Corporation Guard column: BEH C18 VanGuard, 2.1 x 5 mm, 1.7 µm, Waters Corporation UPLC Parameter Se

  14. Slide 14: UPLC-PDA Chromatograms of Nicotine and Ethyl Benzoate

    Analytical Method: Determination of Nicotine in Dissolution Fractions UPLC-PDA Chromatograms of Nicotine and Ethyl Benzoate (ISTD) Nicotine Ethyl Benzoate Intensity RT = 5.90 min RT = 8.21 min N N Time (min) Time (min) ISTD: Internal Standard UPLC-PDA: Ultra-high Performance Liquide Chromatography P

  15. Slide 15: Analytical Method: Method Validation

    Analytical Method: Determination of Nicotine in Dissolution Fractions Method Validation Parameter Outcome Turn into Table Calibration (0.5-100 µg/mL)  R2 > 0.998 on all days  %RCR < 10% Accuracy - 3 fortification levels in triplicate 96.2% - 102% for each product type Repeatability (Intra-day prec

  16. Slide 16: Analysis of Products for Regulatory Submissions

    Analysis of Products for Regulatory Submissions Predicate vs. New Product 12 replicates per product*  Requires two runs for each product (7 cell holders per unit) 1. 6 Reps + 1 IQCS (CRP 2.1, American style loose moist snuff) 2. 6 Reps + 1 reagent blank  9 fractions collected for each sample repli

  17. Slide 17: Calculations for Cumulative Release Profile

    Calculations for Cumulative Release Profile Averaged Concentrations of Fractions Sum of Fractions 3000 12000 n = 12 n = 12 2500 10000 Averaged Conc. (μg/g) Averaged Conc. (μg/g) 2000 8000 1500 6000 1000 4000 500 2000 0 0 1 2 3 4 5 6 7 8 9 1 1-2 1-3 1-4 1-5 1-6 1-7 1-8 1-9 Fraction number Sum of Frac

  18. Slide 18: CORESTA Smokeless Tobacco Reference Products (CRPs)

    CORESTA Smokeless Tobacco Reference Products (CRPs) CRP 1.1 (Swedish style snus pouch) CRP 2.1 (American style loose moist snuff) CRP 4 (loose-leaf chewing tobacco) CRP 4.1 (chopped loose-leaf chewing tobacco) https://www.coresta.org/coresta-smokeless-tobacco-reference-products J.H. Miller I Regulat

  19. Slide 19: Results: Cumulative Release Profile of Nicotine

    Results CORESTA Smokeless Tobacco Reference Products (CRPs) Cumulative Release Profile of Nicotine 12000 10000 Nicotine Conc. (μg/g) 8000 6000 4000 2000 Snus (CRP 1.1) Loose Snuff (CRP 2.1) Loose Leaf (CRP 4) Chopped Loose Leaf (CRP 4.1) 0 0 10 20 30 40 50 60 70 Time (min) Error Bars ± 1 S.D. J.H. M

  20. Slide 20: Results: Total Release Profile of Nicotine

    Results CORESTA Smokeless Tobacco Reference Products (CRPs) Total Release Profile of Nicotine 120% 100% Percent Release 80% 60% 40% Snus (CRP 1.1) Loose Snuff (CRP 2.1) Loose Leaf (CRP 4) Chopped Loose Leaf (CRP 4.1) 20% 0% 0 10 20 30 40 50 60 70 Time (min) Error Bars ± 1 S.D. J.H. Miller I Regulato

  21. Slide 21: Dissolution Profiles Comparison

    Dissolution Profiles Comparison Approach based on FDA guidance from CDER*  Determine nicotine release profiles for predicate and new product (12 replicates per product)  Use mean dissolution values from both curves at each time point to calculate difference factor (f1) and similarity factor (f2) f

  22. Slide 22: Results: Product to Product Comparison using f1 and f2

    Results Product to Product Comparison using f1 and f2 Compared Products f1 f2 Equivalency CRP 2.1 vs CRP 4.1 11.3 52.7 Yes CRP 2.1 vs CRP 4 27.5 30.0 No CRP 2.1 vs CRP 1.1 39.2 21.9 No CRP 4.1 vs CRP 4 23.1 35.3 No CRP 4.1 vs CRP 1.1 36.1 24.8 No CRP 4 vs CRP 1.1 20.2 42.2 No CRP 1.1 (Swedish style

  23. Slide 23: Results: Commercial Products with Different Flavors

    Results Commercial Products with Different Flavors Total Release Profile of Nicotine 120% 100% Percent Release 80% f1 = 4.2 60% f2 = 73.1 40% 20% Flavor-A Flavor-B 0% 0 10 20 30 40 50 60 70 Time (min) Error Bars ± 1 S.D. J.H. Miller I Regulatory Sciences I Altria Client Services I TSRC Sept 15-18th

  24. Slide 24: Results: Loose vs Pouched Commercial Products

    Results Loose vs Pouched Commercial Products Total Release Profile of Nicotine 120% 100% Percent Release 80% f1 = 29.1 60% f2 = 29.6 40% 20% Loose Pouch 0% 0 10 20 30 40 50 60 70 Time (min) Error Bars ± 1 S.D. J.H. Miller I Regulatory Sciences I Altria Client Services I TSRC Sept 15-18th 2019 I FINA

  25. Slide 25: Summary

    Summary  An efficient method for the dissolution testing and analytical quantitation of nicotine was validated for a variety of smokeless tobacco products using a USP-4 flow-through cell apparatus and UPLC-PDA  Percent of total release profiles, and f1 and f2 calculations were used to evaluate the

  26. Slide 26: Questions?

    Questions? This presentation may be accessed @ www.altria.com/ALCS-Science J.H. Miller I Regulatory Sciences I Altria Client Services I TSRC Sept 15-18th 2019 I FINAL 26

  27. Slide 27: Results: f1 and f2 Calculations

    Results f1 and f2 Calculations 𝑛 𝑛 1 𝑡=1 𝑡=1 2 𝑡=𝑛 𝑡=1 𝑡 𝑡 2 Rt and Tt are the cumulative percentage dissolved at each of the selected n time points of the two products. f1 values up to 15 (0-15) and f2 values of 50 or greater (50-100) ensure similarity or equivalence between two products…

Altria Group — Tobacco Science Research Conference 2019 on 6ix