1. Parametric Tolerance Interval (PTI) Test for 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. 2 Overview Communication is key to resolving the issue IPAC-RS presentation on 25 October was based on information received at 4 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. 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 1 st /2 nd tier Coverage of 87.5% is proposed as the standard Coverages ranging from 82.5 to 90% were also presented by FDA n=10 n=30n=20 n=60n=30 n=90 CoverageTier ITier IITier ITier IITier ITier II 82.52.821.942.201.742.001.66 85.02.962.042.321.832.111.75 87.53.122.162.451.942.231.86 90.03.312.302.602.072.371.98 Test coefficients “Standard” test

4. 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(k 20 )*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. 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(k 60 )*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6. 6 FDA’s proposal (87.5% coverage) is tighter than the 1998 MDI/DPI draft guidance test Batch mean at 97% LC

7. 7 FDA proposal (87.5% coverage) requires significantly larger sample than 1998 MDI/DPI draft guidance test Batch mean at 97% LC

8. 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 Coverage# pass 1 st tier# pass 2 nd tierTotal # pass 82.521 of 231 of 222 of 23 85.021 of 231 of 222 of 23 87.520 of 232 of 322 of 23 90.020 of 231 of 321 of 23 Results In this case study, 22 of 23 batches (96%) comply with the FDA proposal of 87.5% coverage Average sample size needed is 25

9. 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 Coverage# pass 1 st tier# pass 2 nd tierTotal # pass 82.520 of 286 of 826 of 28 85.018 of 287 of 1025 of 28 87.515 of 288 of 1323 of 28 90.013 of 289 of 1522 of 28 Results In this case study, 18 of 28 batches (82%) comply with the FDA proposal of 87.5% coverage Average sample size needed is 39

10. 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 Coverage# pass 1 st tier# pass 2 nd tierTotal # pass 82.517 of 263 of 920 of 26 85.014 of 266 of 1220 of 26 87.58 of 2612 of 1820 of 26 90.07 of 2611 of 1918 of 26 Results In this case study, 20 of 26 batches (77%) comply with the FDA proposal of 87.5% coverage Average sample size needed is 48

11. 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 4 th (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. 12 Updated Comparison of different DDU tests 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. Batch mean at 97% LC

13. 13 Comparison of different DDU tests 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? Batch mean at 97% LC

14. 14 Match of OC curves for FDA and IPAC-RS test 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 (k 20 =1.77, k 60 =1.37) provides some regulatory relief and is potentially acceptable to OINDP Industry. Batch mean at 97% LC

15. 15 Updated OC Curves for US Approved OINDP (Frequent Exceptions From Guidance) Subset of DDU Specifications Approved by FDA (24 products from 1990-2003) 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

16. 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. 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. 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. 19 Question to ACPS Would you support the PTI test for control of DDU for OINDP AND endorse the WG to continue discussion to agree an quality standard that is appropriate for the majority of modern OINDPs?