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PTIT for DCU of OINDP: Approaches to Resolution of Identified Issues. Wallace P. Adams, Ph.D. OPS/IO Advisory Committee for Pharmaceutical Science 21 October 2003 Rockville, MD. Outline. Current DCU and SCU Tests Parametric Tolerance Interval Test (PTIT) Consensus Points OPS Issues

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Ptit for dcu of oindp approaches to resolution of identified issues

PTIT for DCU of OINDP:Approaches to Resolution of Identified Issues

Wallace P. Adams, Ph.D.

OPS/IO

Advisory Committee for Pharmaceutical Science

21 October 2003

Rockville, MD


Outline
Outline

  • Current DCU and SCU Tests

  • Parametric Tolerance Interval Test (PTIT)

  • Consensus Points

  • OPS Issues

  • The “Gap” and the Quality Assurance Constraint

  • Proposed Resolutions


Two guidances
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
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


Current dcu and scu tests
Current DCU and SCU Tests

  • Nonparametric (with a parametric element, the sample mean restriction)

  • Single dose and multi-dose products


Present dcu and scu tests dcu through container life for multi dose products tier 1
Present DCU and SCU Tests:DCU Through Container Lifefor Multi-dose Products (Tier 1)

  • MDIs

    • DCU measured through container life

  • DPIs (device-metered)

    • Same as for MDIs

  • Nasal sprays

    • SCU measured at B and E lifestages

    • for each of 10 containers


FDA DCU and DCU TCL Tests

1 Metered Dose Inhaler and Dry Powder Inhaler CMC Draft Guidance, Oct 1998

2 Nasal Spray, Inhalation Solution, Suspension, and Spray Drug Products CMC Guidance, July 2002

3 Both DCU and TCL tests apply to MDIs and device-metered DPIs


A parametric tolerance interval approach

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

RL Williams et al, Pharm Res, 2002; 19:359-66


A parametric tolerance interval
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 specify1

    • minimum proportion of the batch that should fall within the limits (coverage)

    • acceptable tolerance limits (target interval)

    • degree of confidence

1 RL Williams et al, Pharm Res, 2002; 19:359-66


Consensus point 1
Consensus Point # 1

  • Acceptability of the PTIT statistical approach conceptually

    • Based on a statistical hypothesis test

    • Facilitates risk communication to practitioners and patients/consumers

    • Places constraints on both maximum sample SD and sample mean


Consensus point 2
Consensus Point # 2

  • Elimination of the Zero Tolerance Criterion (ZTC)

    • ZTC:

      • prohibits any dose in the sample from falling outside the stated interval

      • reduces the likelihood that a unit in the batch will deviate substantially from LC

    • ZTC conflicts with the producer’s choice of sample size

    • for normal distributions, PTIT preserves the specified alpha level without the ZTC


Ops issue 1
OPS Issue # 1

  • Robustness to  level

    • Non-normal distributions

      • for certain data distributions,  can substantially exceed 0.05

      • do non-normal distributions exist for some OINDP products and batches?

    • Estimated consumer risk of IPAC-RS proposal exceeds 0.05

      • by a small amount, e.g., 0.051, for normally distributed data

      • at certain deviations in batch mean from LC

    • Approaches to assuring  0.05?

  •   0.05,   0.025?


Maximum type i error is 5 1 occurs for smallest sample size at mean deviation of 9 lc
Maximum Type I Error is 5.1% (occurs for smallest sample size at mean deviation of ±9 %LC)

Sample size

Normal distribution at limiting quality

(85% coverage of 100±25% LC)

B. Olsson, ACPS Meeting, 13 Mar 2003


Non-normal Distribution

IPAC-RS Report, 15 Nov 2001, p. 68


Ops issue 2
OPS Issue # 2

  • Definition of limiting quality

    • 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?

  • The “Gap” widens as the sample size increases

  • The “Gap” tends to widen as the mean deviates increasingly from 100% LC

  • The “Gap” narrows as the coverage increases and the target interval narrows



PTI Test, Multi-Dose Products

IPAC-RS Report, 15 Nov 2001, p. 25


Comparison of Operating Characteristic Curves

21

“Gap”

LQ

FDA test: as in Draft MDI/DPI Guidance

  • Consumer protection (Limiting Quality, LQ) same

  • PTI test’s curve is sharper (narrowed area of uncertainty)

  • Fewer acceptable batches rejected (lower producer risk)

  • “Gap”: Fewer rejections does not mean lower quality of accepted batches (see simulated production illustration below)

B. Olsson, ACPS Meeting, 13 Mar 2003


Ops issue 3
OPS Issue # 3

  • Robustness in the Producer Protection Region

    • does the PTIT become more conservative for non-normal distributions?



The quality assurance constraint an additional limiting quality
The Quality Assurance Constraint:An Additional Limiting Quality

  • The “Gap” exists between the “FDA curve” and the PTIT curves for all limiting qualities

  • At a 90% acceptance probability, the PTIT allows greater batch variability than does the “FDA curve” for three of four limiting qualities

  • OPS desires to limit the magnitude of the “Gap”


Operating characteristic curve
Operating Characteristic Curve

Producer protection region (changes with sample size)

100

90

80

Area of uncertainty

70

60

Probability to Accept (%)

Quality Assurance Region (fixed)

50

40

30

20

10

5%

0

Consumer protection region

Variability

(either standard deviation at a given batch mean

or coverage)

Y. Tsong, ACPS Meeting, 13 Mar 2003. Slide adapted from B. Olsson, 13 Mar 2003


Fda working group to determine over the next six months
FDA Working Group to Determine(Over the Next Six Months)

Limiting Quality Standard

  • Confirm appropriateness of  0.05

  • Establish appropriate “Quality Assurance Constraint” (at 90% acceptance probability)

  • To include FDA clinical recommendations


A Proposed Resolution

  • Adopt the PTIT approach

  • Left side of Operating Characteristic (OC) curve to be approximately superimposable with the FDA OC curve, with emphasis on the 90% acceptance probability region


Acknowledgments

Craig Bertha, Ph.D.

Alan Carlin

Walter Hauck, Ph.D.

Ajaz Hussain, Ph.D.

Guirag Poochikian, Ph.D.

Donald Schuirmann

Meiyu Shen, Ph.D.

Edward Sherwood

Yi Tsong, Ph.D.

Marilyn Welschenbach, Ph.D.

Helen Winkle

Acknowledgments


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