1. Presented by Bo Olsson (AstraZeneca)
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 2003 Rockville, MD

2. 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
March 2003
IPAC-RS

3. 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)
March 2003
IPAC-RS

4. 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
March 2003
IPAC-RS

5. 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
March 2003
IPAC-RS

6. 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 % of label claim (LC)
none of 10 doses outside % 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 % LC
none of 9 doses outside % LC (zero tolerance)
each of 3 means (B, M, E) within % LC
March 2003
IPAC-RS

7. 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
March 2003
IPAC-RS

8. 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
March 2003
IPAC-RS

9. 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
Emitted Dose
Target Interval
March 2003
IPAC-RS

10. 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
March 2003
IPAC-RS

11. 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
March 2003
IPAC-RS

12. Proposed Standard of Batch Quality
The proposed limiting quality is set at 85% batch coverage of the % 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
March 2003
IPAC-RS

13. Comparison of Coverage at Limiting Quality between FDA and PTI tests
DDU Test Approach Minimum BATCH Coverage (95% confidence)
FDA for single-dose products (Counting Test)
78% coverage of %LC
FDA for multi-dose products (Counting Test)
85% coverage of %LC
IPAC-RS for all OINDP (Parametric Tolerance Interval Test)
85% coverage of %LC
March 2003
IPAC-RS

14. PTI Test Mechanics
SAMPLE: pre-defined number of units (n), from different portions in container (Life Stages - LS), one dose from each unit
CALCULATE: mean (m), standard deviation (s), Acceptance Value (AV) =100-mLS + ks
COMPARE: AV  25,
100-mLS 15, and
s  25f/k (Maximum Sample Standard Deviation)
IF NOT ACCEPTED, GO TO SECOND TIER
Target (100%LC)
Mean (m)
Standard Deviation (s)
Emitted Dose
k and f pre-defined based on n
n determined as appropriate for each product
March 2003
IPAC-RS

15. Revised PTI Test Coefficients
Ensure less than 5.1% Type I error for all batch means
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
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
March 2003
IPAC-RS

16. Normal distribution at limiting quality
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)
March 2003
IPAC-RS

17. 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
March 2003
IPAC-RS

18. 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
March 2003
IPAC-RS

19. “Gap”

20. Operating Characteristic Curve
Producer protection region
100 90 80 70 60
Area of uncertainty
Probability to Accept (%) 50 40 30 20 10 5%
Consumer protection region
Variability
(either standard deviation at a given batch mean
or coverage)
March 2003
IPAC-RS

21. Comparison of Operating Characteristic Curves21
“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)

22. Examples of Effect of Deviations on current FDA OC Curve22
FDA DCU & TCL test as in Draft MDI/DPI Guidance
Majority of OINDP products approved by FDA in 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

23. 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
March 2003
IPAC-RS

24. Batch Mean ~10014, Batch SD ~ 203
Unacceptable Quality
Batch Mean ~10014, Batch SD ~ 203
Batch SD, s (%LC)
1.2%
Accepted by FDA test
(median cov= 80.3%)
98.8%
Rejected by FDA test
(median cov= 76.5%)
0.3% Accepted by PTI test
(median cov= 81.2%)
99.7%
Rejected by PTI test
(median cov= 76.6%)
March 2003
IPAC-RS

25. Batch Mean ~1009, Batch SD ~103
Acceptable Quality
Batch Mean ~1009, Batch SD ~103
65%
Accepted by FDA test
(median cov= 98.6%)
Batch SD, s (%LC)
35%
Rejected by FDA test
(median cov= 96.5%)
95%
Accepted by PTI test
(median cov= 98.1%) 5%
Rejected by PTI test
(median cov= 91.5%)
March 2003
IPAC-RS

26. Quality Standard

27. 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
March 2003
IPAC-RS

28. Proposed Quality Standard
IPAC-RS 2001 Proposal: Limiting quality set to
85% coverage of % 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
March 2003
IPAC-RS

29. Non-Normal Distributions and Zero Tolerance Criterion

30. 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
March 2003
IPAC-RS

31. 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
March 2003
IPAC-RS

32. ZT Criterion Has No or Little Effect on Acceptance rate at 85% coverage
The addition of ZT criterion does not materially improve consumer protection
March 2003
IPAC-RS

33. 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 % LC target interval
5% acceptance (95% rejection) at limiting quality
March 2003
IPAC-RS

34. 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
March 2003
IPAC-RS