# Presentation: 305857

## Parametric Tolerance Interval (PTI) Test for Improved Control of Delivered Dose Uniformity (DDU) in Orally Inhaled and Nasal Drug Products (OINDP)

- Presented by Bo Olsson (AstraZeneca)
*on behalf of International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS)*
- 13 March 2003Rockville, MD

## Purpose of Delivered Dose Uniformity Test

- DDU, which is one of several quality attributes for OINDP, combines performance of delivery device and formulation
- DDU verifies delivered (emitted) dose in the batch
- dose uniformity between containers
- dose uniformity within multi-dose containers
- closeness of mean dose to target - label claim

- IPAC-RS

- March 2003

## Scope of Products

- Oral inhalation and nasal drug products (OINDP) are either single-dose or multi-dose
- pressurized metered dose inhalers (pMDIs)
- dry powder inhalers (DPIs)
- nasal sprays
- inhalation solutions
- deliver medication to the respiratory tract
- lung
- nasal passages
- in the form of aerosol to treat diseases and conditions
- respiratory (*e.g.,* asthma, COPD, rhinitis)
- systemic (*e.g.,* diabetes, migraine)

- IPAC-RS

- March 2003

## Inhalation Product History

- First pressurized Metered Dose Inhaler (pMDI) introduced in 1955
- Until early 1990 pMDI technology based on chlorofluorocarbons (CFC)
- CFCs linked to ozone depletion and banned by international environmental treaty (Montreal Protocol), phased out in medical use applications
- With phase-out of CFC for medical use, reformulation of pMDIs with hydrofluorocarbons (HFCs) and other new types of OINDP became necessary

- IPAC-RS

- March 2003

## OINDP DDU Test History

- Regulatory requirements for DDU evolved based on FDA experience with CFC products
- DDU testing requirements became more stringent over time
**from** multiple actuations per test **to** minimal clinical dose per test
**from** testing beginning of container only **to** testing beginning, middle, end
**from** USP limits **to** tighter limits
- DDU requirements are more challenging for new technology from CMC perspective
- Formulation flexibility significantly reduced with HFC’s due to their physico-chemical characteristics and compatibility with excipients
- Challenging flow characteristics of powders

- IPAC-RS

- March 2003

## Traditional DDU Tests

- USP: counting test, *e.g.*
- 10 doses from one inhaler (3 beginning +  4 middle + 3 end)
- no more than 1 of 10 doses outside 75-125% of label claim (LC)
- none of 10 doses outside 65-135% LC (zero tolerance)
- under certain conditions 2nd tier allowed with larger sample
- FDA: counting test with tighter limits, *e.g.* (**through-container-life DDU test for multi-dose pMDIs/DPIs):**
- 3 doses from each of 3 inhalers (3 beginning + 3 middle + 3 end)
- no more than 1 of 9 doses outside 80-120% LC
- none of 9 doses outside 75-125% LC (zero tolerance)
- each of 3 means (B, M, E) within 85-115% LC
- under certain conditions 2nd tier allowed with larger sample

- IPAC-RS

- March 2003

## Reason for DDU Replacement

- Parametric Tolerance Interval (PTI) test is proposed as replacement of current FDA DDU tests
-  BECAUSE

- PTI test is more powerful and discriminating than current tests
- simultaneously uses mean and standard deviation to make quality assessment
- The FDA counting test is less efficient in use of data
- unnecessarily rejects good batches
- The FDA counting test penalizes increased testing
*e.g.,* stability testing increases chances to fail not due to product quality change
- OINDP cannot routinely meet expectations in draft Guidances
*e.g., *many products have been approved with exceptions  to DDU test and acceptance criteria in published Guidances

- IPAC-RS

- March 2003

## Origins of PTI Test 

- _Statistical design_ built on previous work
- 1999 AAPS/FDA/USP Workshop presentation by Dr. Walter Hauck
- Williams, Adams, Poochikian and Hauck, Pharm. Res. (2002)
- JP/EP/USP parametric test for dose uniformity in tablets
- Features of FDA Draft Guidance test (*e.g., *target interval and mean criteria)
- _Acceptance criteria_ designed to match or exceed statistical consumer protection implied by published Draft Guidances
*Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products* 1998
*Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products*  Draft: 1999, Final: 2002

- IPAC-RS

- March 2003

## Define Batch Quality With Coverage

**Coverage = Proportion of doses in the batch that are within target interval**
**Batches having same coverage of given target interval  are considered to be of equal quality**

- IPAC-RS

- March 2003

## Hypothesis Testing Framework

- To assure with high confidence that sub-standard batches are rejected, set statistical hypothesis as:
- H0: batch quality is out of specification
- Ha: batch quality is in specification
- Type I error: batch released but is outside specification
- Type II error: batch rejected but is within specification

- IPAC-RS

- March 2003

## Hypothesis Testing Usefulness 

- Quality of batches released to consumer is  of greatest importance
- Need to control risk of releasing substandard batches to consumer (*i.e.,* Type I error)
- Type I error is controlled independently of sample size
- Therefore UNACCEPTABLE (limiting) quality is defined as baseline standard

- IPAC-RS

- March 2003

## Proposed Standard of Batch Quality

- The proposed limiting quality is set at 85% batch coverage of the 75-125% LC target interval
- corresponds to 5% acceptance for FDA multi-dose test
- This means that commercial batches must far exceed 85% coverage with high confidence

- IPAC-RS

- March 2003

## Comparison of Coverage at Limiting Quality between FDA and PTI tests

_**DDU Test Approach**__**	**__**Minimum **__**BATCH**__** Coverage **__**	**__**	**_**(95% confidence)**

**	****85% coverage of ****75-125%LC**

***FDA for multi-dose products *****(Counting Test)**

***IPAC-RS for all OINDP*****(Parametric Tolerance Interval Test)**

**	****85% coverage of ****75-125%LC**

**	****78% coverage of ****75-125%LC**

***FDA for single-dose products *****(Counting Test)**

- IPAC-RS

- March 2003

## PTI Test Mechanics

**CALCULATE: ****	****mean (m), ****standard deviation (s), ****Acceptance Value ****(AV) =********100-m****LS******** + ks **
**COMPARE: ****	****AV ********  25,**
**	****	********100-m****LS********  15, and**
** ****	****	****s ********  25f/k  (Maximum Sample ****Standard Deviation)**
**IF NOT ACCEPTED, GO TO SECOND TIER**

**Emitted Dose**

**Target (100%LC)**

**Mean (m)**

**Standard Deviation (s)**

**k and f pre-defined based on n**
**n determined as appropriate for each product**

- IPAC-RS

- March 2003

## Revised PTI Test Coefficients

- Test plan (sample size) selected as appropriate for each product
- Consumer protection the same for all sample sizes by design
- Producer risk decreases with increasing sample size

- n - sample size in tier 1/ total sample size for tiers 1+ 2
- k1 and k2  - acceptability coefficients in 1st and 2nd tier
- f - factor for maximum sample standard deviation

- Ensure less than 5.1% Type I error for all batch means

- IPAC-RS

- March 2003

## Maximum Type I Error is 5.1% (occurs for smallest sample size at mean deviation of ±9 %LC)

- Normal distribution at limiting quality
- (85% coverage of 100±25% LC)

- Sample size

- IPAC-RS

- March 2003

## Issues Discussed in Previous Meetings with FDA 

**“****Gap” in OC curves **
**Quality Standard**
**“****Zero tolerance”**
**Performance for normal and non-normal distributions**
- Representative sampling from batch
- Differences between product types

- IPAC-RS

- March 2003

## Progress to Date for DDU Replacement

- FDA has stated that conceptually, PTI approach is acceptable
- Need to resolve: acceptance criteria to be used by PTI test

- IPAC-RS

- March 2003

## “Gap”

## Operating Characteristic Curve

- 0

- 10

- 20

- 30

- 40

- 50

- 60

- 70

- 80

- 90

- 100

**Probability to Accept (%)**

**5%**

- Area of uncertainty

- Consumer protection region

- Producer protection region

**Variability **
**(either standard deviation at a given batch mean **
**or coverage)**

- IPAC-RS

- March 2003

## Comparison of Operating Characteristic Curves

- 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)*

- 21

**“****Gap”**

**LQ**

- FDA test: as in Draft MDI/DPI Guidance

- IPAC-RS

- March 2003

## Examples of Effect of Deviations on current FDA OC Curve

- Examples of Effect of Deviations on current FDA OC Curve

- Majority of OINDP products approved by FDA in 1990-2001 have DDU test or acceptance criteria or both that deviate from draft Guidances (IPAC-RS 2001 survey)
- The ”gap” between FDA and PTI OC curves decreases with such deviations, and consumer protection is eroded
- PTIT provides reduction of producer risk without compromising consumer protection

- FDA DCU & TCL test as in Draft MDI/DPI Guidance

- 22

- IPAC-RS

- March 2003

## Simulated Illustration* (see figures in next two slides)

- Unacceptable quality: FDA and PTI tests have comparable performance
- Acceptable quality: PTI test rejects fewer acceptable batches than FDA test
- 	* 	*Used 5000 simulations, normal distributions*
*	**	*

- IPAC-RS

- March 2003

## Unacceptable Quality 

*Batch Mean** ~1**00****14, Batch SD **~** 20****3*

- 1.2%
- Accepted by FDA test
- (median cov= 80.3%)

- 0.3% Accepted by PTI test
- (median cov= 81.2%)

- 98.8%
- Rejected by FDA test
- (median cov= 76.5%)

- 99.7%
- Rejected  by PTI test
- (median cov= 76.6%)

- IPAC-RS

- March 2003

## Acceptable Quality 

- 65%
- Accepted by FDA test
- (median cov= 98.6%)

- 95%
- Accepted by PTI test
- (median cov= 98.1%)

- 35%
- Rejected by FDA test
- (median cov= 96.5%)

- 5%
- Rejected  by PTI test
- (median cov= 91.5%)

- Acceptable Quality
*Batch Mean** ~1**00****9, Batch SD **~**10****3*

- IPAC-RS

- March 2003

## Quality Standard

## Quality Standard

- 	Quality of a batch should be judged against a specific standard. Within presented hypothesis framework that standard is
- Limiting (Unacceptable) Quality
- coverage corresponding to 5% acceptance probability
- consumer protection
- typical batch quality has to be far above the limiting quality to achieve reasonable batch acceptance probability
- 	not
- Typical Batch Quality
- coverage corresponding to *e.g.,* greater than 95% acceptance
- producer risk
- is different for different products

- IPAC-RS

- March 2003

## Proposed Quality Standard

- IPAC-RS 2001 Proposal: Limiting quality set to
- 	85% coverage of 75 -125% LC interval
- same limiting quality as implied by Draft Guidances
- demonstrated for each batch with high confidence
- FDA comment: tighter standard may be needed
- Significantly tighter standard will be problematic
- in setting the standard, both producer risk and consumer protection should be considered
- standard must be compatible with capability of current and pipeline products and analytical methodology
- if standard exceeds capability, it will create difficulties for manufacturing of current products, and development and approval of new products and generic versions

- IPAC-RS

- March 2003

## Non-Normal Distributions and Zero Tolerance Criterion 

## Non-Normal Distributions

- IPAC-RS database demonstrates that assumption of normality is appropriate
- Studied non-normal distributions: symmetric short-tailed (beta) or bimodal, asymmetric short-tailed (beta and gamma) or long-tailed (outliers)
- Revised PTI test assures < 5.1 % Type I error for all normal and most non-normal distributions
- For a few extreme distributions, 5% is exceeded at the limiting quality:
- Notably off-target, relatively symmetric distributions with extremely short tails
- Notably off-target, notably asymmetric distributions with longer tail in the off-target direction
- PTI test is appropriate for real products

- IPAC-RS

- March 2003

## Effect of Zero Tolerance (ZT) Criteria

- A ZT criterion does not protect from having values outside ZT limits in the batch
- A fixed ZT criterion degrades parametric tests;this effect escalates with sample size
- A ZT must scale with sample size in order to avoid degrading parametric test and to have no effect on producer risk
- A scaled ZT has little or no effect on consumer protection even for extreme non-normal distributions
- Any ZT penalizes thorough testing  (stability, validations)
- Conclusion: ZT does not help control product quality

- IPAC-RS

- March 2003

## ZT Criterion Has No or Little Effect on Acceptance rate at 85% coverage

- The addition of ZT criterion does not materially improve consumer protection

- IPAC-RS

- March 2003

## Desired Outcome of DDU Effort for IPAC-RS

- Agree that PTI test is conceptually acceptable as a replacement
- Parametric (no Zero Tolerance)
- Coverage as quality definition
- Allow product-by-product justification of sample size n
- multiple sampling plans, *e.g., *12/36 to 30/90
- Maintain limiting quality standard implied by FDA Guidances
- 85% coverage of 75-125% LC target interval
- 5% acceptance (95% rejection) at limiting quality

- IPAC-RS

- March 2003

## Acknowledgements

- FDA / CDER / OPS
- IPAC-RS Members
- Aradigm
- AstraZeneca
- Aventis
- Boehringer Ingelheim
- Eli Lilly
- GlaxoSmithKline
- Members of IPAC-RS DDU Working Group
- IPAC-RS Secretariat

- IVAX
- Kos Pharmaceuticals
- Nektar Therapeutics
- Novartis
- Pfizer
- Schering-Plough

- IPAC-RS

- March 2003