# Presentation: 670507

## 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)
*Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products - CMC Documentation* (Final, July 2002)

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## 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?

## 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)

## 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

## OPS Issues

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

## 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?

## 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%?

## Acknowledgments

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