Michael Golden On behalf of IPAC-RS Advisory Committee of Pharmaceutical Science October 26, 2005

1. Parametric Tolerance Interval (PTI) Testfor Delivered Dose Uniformity (DDU) for Orally Inhaled and Nasal Drug Products (OINDP) Michael Golden On behalf of IPAC-RS Advisory Committee of Pharmaceutical Science October 26, 2005

2. Overview • Communication is key to resolving the issue • IPAC-RS presentation on 25 October was based on information received at4 October meeting • Revised case studies and OC curves based on 25 October information • Coverage to reflect current OINDP still needs to be agreed • ACPS endorsement of PTI test

3. FDA’s Proposal • A standard PTI Test applied to pooled sample of beginning and end doses • Target interval (’goalposts’) 80-120% LC • Sample sizes n=10/30, 20/60, and 30/90 in the 1st/2nd tier • Coverage of 87.5% is proposed as the standard • Coverages ranging from 82.5 to 90% were also presented by FDA Test coefficients “Standard” test

4. IPAC-RS interpretation of FDA’s test – Tier 1 • For the 20/60 test: • Select 10 units representative of the batch • Test each unit at Beginning and End • Calculate: • Mean beginning (n=10) • Mean end (n=10) • Overall mean (n=20) • Overall standard deviation (n=20) • Acceptance Value as |100-overall mean| + 2.45(k20)*overall SD • Overall mean – 100 + (k*SD) < 20 • Overall mean – 100 – (k*SD) > -20 • Evaluate Mean Beginning and Mean End results for compliance with 85-115 • Evaluate Acceptance Value for compliance with 80-120 goalposts • If any of the acceptance criteria are not met, go to Tier 2 (therefore, no batch failures at Tier 1).

5. IPAC-RS interpretation of FDA’s test – Tier 2 • For the 20/60 test: • Select 20 additional units representative of the batch • Test each unit at Beginning and End • Calculate: • Mean beginning (n=30) • Mean end (n=30) • Overall mean (n=60) • Overall standard deviation (n=60) • Acceptance Value as |100-overall mean| + 1.94(k60)*overall SD • Overall mean – 100 + (k*SD) < 20 • Overall mean – 100 – (k*SD) > -20 • Evaluate Mean Beginning and Mean End results for compliance with 85-115 • Evaluate Acceptance Value for compliance with 80-120 goalposts • If any of the acceptance criteria are not met, the test fails.

6. FDA’s proposal (87.5% coverage) is tighter than the 1998 MDI/DPI draft guidance test Batch mean at 97% LC

7. FDA proposal (87.5% coverage) requires significantly larger sample than 1998 MDI/DPI draft guidance test Batch mean at 97% LC Batch mean at 97% LC

8. Updated IPAC-RS case studies (1) • US commercial solution HFA MDI (preventer) • 23 batches evaluated • Sample means 100-108% LC • Sample SDs 4.3-8.0% LC In this case study, 22 of 23 batches (96%) comply with the FDA proposal of 87.5% coverage Average sample size needed is 25 Results

9. Updated IPAC-RS case studies (2) • US commercial suspension HFA MDI (preventer) • 28 batches evaluated • Sample means 94-109% LC • Sample SDs 5.1-10.0% LC In this case study, 18 of 28 batches (82%) comply with the FDA proposal of 87.5% coverage Average sample size needed is 39 Results

10. Updated IPAC-RS case studies (3) • US commercial suspension HFA MDI (reliever) • 26 batches evaluated • Sample means 94-108% LC • Sample SDs 4.6-12.7% LC In this case study, 20 of 26 batches (77%) comply with the FDA proposal of 87.5% coverage Average sample size needed is 48 Results

11. Conclusions from Updated Case Studies on US Commercial Products • 12 of the 77 batches would have failed the FDA proposed ”87.5%” test and thus would not have been released. However, all 77 batches passed their approved specifications for uniformity and were suitable for their intended use • The lowest coverage presented by FDA on October 4th (82.5%) resulted in a pass rate of 77-96%, which is still unacceptable from both compliance and business perspectives • These case studies illustrate why the FDA proposal is not acceptable to IPAC-RS

12. Updated Comparison of different DDU tests Batch mean at 97% LC The figure indicates (1) that current FDA standard (green) is much more restrictive than other international requirements (brown and purple), (2) that IPAC-RS current positions (blue and yellow) represent a significant tightening compared to the initial proposals (black and pink) and provide a reasonable compromise between different international standards, and (3) that the FDA October 4 proposal is significantly tighter than current US requirements.

13. Comparison of different DDU tests Batch mean at 97% LC Figure shows (1) that OC curve for LR PTI test is a potential compromise between the IPAC-RS proposal and the FDA Draft Guidance, and that (2) neither of the PTI tests proposed by FDA October 25 are close to providing the regulatory relief required. What coverage is required to move OC curve for FDA PTI test to position of LR test OC curve?

14. Match of OC curves for FDA and IPAC-RS test Batch mean at 97% LC Figure shows that if coverage is reduced to 70%, an FDA PTI test which matches the OC curve of LR PTI test for low SDs is obtained. This test (k20=1.77, k60=1.37) provides some regulatory relief and is potentially acceptable to OINDP Industry.

15. Updated OC Curves for US Approved OINDP (Frequent Exceptions From Guidance) Batch mean at 100% LC Red: FDA draft guidance Green: FDA Proposal 20/60 87.5% coverage Yellow: IPAC-RS 20/60 82.5% coverage LR PTI Subset of DDU Specifications Approved by FDA (24 products from 1990-2003)

16. Updated Comments on FDA Proposal • The FDA proposal is tighter than the 1998 MDI/DPI draft guidance test • The design coverage in FDA’s proposal will need to be significantly reduced to have an acceptable quality standard because the coverage required when the mean is off target is higher than the design point • This proposal results in very significant increase in sample size compared to current requirements due to frequent use of tier 2.

17. IPAC-RS Conclusions • Further accelerated dialogue is needed to reach a consensus quality standard for DDU • IPAC-RS is flexible about the methodology of the test as long as the required quality standard is attainable • The majority of modern OINDPs should be able to comply with the agreed quality standard using the ”standard” sample size (20/60)

18. Remaining Issues/Details • Confirmation that IPAC-RS is accurately interpreting and running the FDA’s proposed test • Confirmation that it is not possible to fail the batch at Tier 1 • Appropriate quality standard, i.e., coverage

19. Question to ACPS • Would you support the PTI test for control of DDU for OINDP ANDendorse the WG to continue discussion to agree an quality standard that is appropriate for the majority of modern OINDPs?