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Dose Content Uniformity for Aerosol Products

Dose Content Uniformity for Aerosol Products. Wallace P. Adams, Ph.D. OPS/IO Advisory Committee for Pharmaceutical Science 13 March 2003 Rockville, MD. Two Guidances. Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products - CMC Documentation (Draft, October 1998)

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Dose Content Uniformity for Aerosol Products

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

  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. 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. 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. Present DCU and SCU Tests:DCU Through Container Lifefor 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. Present DCU and SCU Tests:DCU Through Container Lifefor 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. 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. 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. Development Of ParametricTolerance 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. 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. 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. 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. 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. 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. Question # 1 for ACPS • Does ACPS agree that a parametrictolerance 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. 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. Acknowledgments • Ajaz Hussain (FDA) • Guirag Poochikian (FDA) • Don Schuirmann (FDA • Meiyu Shen (FDA) • Yi Tsong (FDA) • Walter Hauck (Thomas Jefferson University) • Roger Williams (USP)

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