1. 1 Dose Content Uniformity for Aerosol Products Wallace P. Adams, Ph.D. OPS/IO Advisory Committee for Pharmaceutical Science 13 March 2003 Rockville, MD

2. 2 Two Guidances Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products - CMC Documentation (Draft, October 1998) Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products - CMC Documentation (Final, July 2002)

3. 3 The DCU and SCU Issue DCU (dose content uniformity) SCU (spray content uniformity) Uniformity of metered doses from an MDI, DPI or nasal spray –within a container for multiple dose products –among containers –among batches

4. 4 Present DCU and SCU Tests Nonparametric (with a parametric element) Single dose and multi-dose products At tier 1 –NMT 1 of 10 containers outside of 80 - 120% of label claim (LC) –0 outside 75 - 125% of LC –Mean of 10 not outside 85 - 115% LC

5. 5 Present DCU and SCU Tests: DCU Through Container Life for Multi-dose Products MDIs –DCU measured at B, M and E lifestages –for each of three containers –NMT 1 of 9 determinations outside 80 - 120% of LC –0 outside 75 - 125% of LC –means at each of B, M and E not outside 85 - 115% of LC

6. 6 Present DCU and SCU Tests: DCU Through Container Life for Multi-dose Products DPIs (device-metered) –Same as for MDIs Nasal sprays –Similar to MDIs, except 10 determinations at B and 10 at E

7. 7 A Parametric Tolerance Interval Approach General form of the criterion: Y  kS where: Y = absolute value (LC - sample mean) k = a tolerance interval constant s = sample std dev Per discussion with Dr. Walter Hauck

8. 8 A Parametric Tolerance Interval Intended to control ranges of specified coverage, e.g., –85% of the doses within –75 - 125% of LC at –95% confidence We therefore specify –min proportion of the batch that should fall within the limits (coverage) –acceptable tolerance limits (target interval) –degree of confidence Per discussion with Dr. Walter Hauck

9. 9 Development Of Parametric Tolerance Interval Approaches Official in Japanese Pharmacopoeia (JP, 1996) Pharmacopoeial Discussion Group –European Pharmacopoeia, JP, and USP Statistics Working Group of PhRMA ICH/PDG Task Force

10. 10 Development Of Parametric Tolerance Interval Approaches, cont. Content Uniformity and Dose Uniformity: Current Approaches, Statistical Analyses, and Presentation of an Alternative Approach, with Special Reference to Oral Inhalation and Nasal Drug Products –RL Williams et al, Pharm Res, 2002;19:359-66 A Parametric Tolerance Interval Test for Improved Control of Delivered Dose Uniformity of Orally Inhaled and Nasal Drug Products –IPAC-RS, 15 November 2001

11. 11 OPS Issues Definition of limiting quality –Essential to an acceptable DDU test 85% of doses in the batch within 75 - 125% of label claim? 85% of doses within 80 - 120% of label claim? 90% of doses within 75 - 125% of label claim? 90% of doses within 80 - 120% of label claim? other options?

12. 12 OPS Issues Robustness of the test –for non-normally distributed data e.g., short-tailed distribution –properties of the test when the batch is at or below the IPAC-proposed limiting quality (e.g., 85% coverage)

13. 13 OPS Issues Impact of eliminating the zero tolerance criterion (ZTC) –IPAC-RS claims that ZTC increases producer risk with little improvement in consumer protection –value for skewed data

14. 14 OPS Issues  level (less than or equal to 0.05) –Estimated consumer risk of IPAC-RS proposal exceeds 5% –Approaches to assuring   0.05

15. 15 Question # 1 for ACPS Does ACPS agree that a parametric tolerance interval test is conceptually acceptable as a replacement for the agency’s nonparametric (with certain parametric elements) DCU and DCU through container life tests for OINDPs?

16. 16 Question # 2 for ACPS Does ACPS feel that DCU quality standards should provide assurance that batch failure rates do not exceed some specified level, e.g., 10%?

17. 17 Acknowledgments Ajaz Hussain (FDA) Guirag Poochikian (FDA) Don Schuirmann (FDA Meiyu Shen (FDA) Yi Tsong (FDA) Walter Hauck (Thomas Jefferson University) Roger Williams (USP)