Parametric Tolerance Interval (PTI) TestParametric Tolerance Interval (PTI) Testfor Delivered Dose Uniformity (DDU) for for Delivered Dose Uniformity (DDU) for Orally Inhaled and Nasal Drug Products Orally Inhaled and Nasal Drug Products

(OINDP)(OINDP)

Michael GoldenOn behalf of IPAC-RS

Advisory Committee of Pharmaceutical Science

October 26, 2005

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OverviewOverview• 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

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FDA’s ProposalFDA’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

n=10 n=30 n=20 n=60 n=30 n=90

Coverage Tier I Tier II Tier I Tier II Tier I Tier II

82.5 2.82 1.94 2.20 1.74 2.00 1.66

85.0 2.96 2.04 2.32 1.83 2.11 1.75

87.5 3.12 2.16 2.45 1.94 2.23 1.86

90.0 3.31 2.30 2.60 2.07 2.37 1.98

Test coefficients “Standard” test

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IPAC-RS interpretation of FDA’s test – IPAC-RS interpretation of FDA’s test – Tier 1Tier 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).

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IPAC-RS interpretation of FDA’s test – IPAC-RS interpretation of FDA’s test – Tier 2Tier 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.

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FDA’s proposal (87.5% coverage) is tighter FDA’s proposal (87.5% coverage) is tighter than the 1998 MDI/DPI draft guidance testthan the 1998 MDI/DPI draft guidance test

Batch mean at 97% LC

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FDA proposal (87.5% coverage) requires significantly FDA proposal (87.5% coverage) requires significantly larger sample than 1998 MDI/DPI draft guidance testlarger sample than 1998 MDI/DPI draft guidance test

Batch mean at 97% LC

Batch mean at 97% LC

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Updated IPAC-RS case studies (1)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 1st tier # pass 2nd tier Total # pass

82.5 21 of 23 1 of 2 22 of 23

85.0 21 of 23 1 of 2 22 of 23

87.5 20 of 23 2 of 3 22 of 23

90.0 20 of 23 1 of 3 21 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

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Updated IPAC-RS case studies (2)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 1st tier # pass 2nd tier Total # pass

82.5 20 of 28 6 of 8 26 of 28

85.0 18 of 28 7 of 10 25 of 28

87.5 15 of 28 8 of 13 23 of 28

90.0 13 of 28 9 of 15 22 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

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Updated IPAC-RS case studies (3)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 1st tier # pass 2nd tier Total # pass

82.5 17 of 26 3 of 9 20 of 26

85.0 14 of 26 6 of 12 20 of 26

87.5 8 of 26 12 of 18 20 of 26

90.0 7 of 26 11 of 19 18 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

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Conclusions from Updated Case Conclusions from Updated Case Studies on US Commercial ProductsStudies 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

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Updated Comparison of different DDU testsUpdated 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

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Comparison of different DDU testsComparison 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

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Match of OC curves for FDA and IPAC-RS testMatch 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 (k20=1.77, k60=1.37) provides some regulatory relief and is potentially acceptable to OINDP Industry.

Batch mean at 97% LC

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Updated OC Curves for US Approved OINDP Updated OC Curves for US Approved OINDP (Frequent Exceptions From Guidance)(Frequent Exceptions From Guidance)

Subset of DDU Specifications Approved by FDA (24 products from 1990-2003) 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

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Updated Comments on FDA ProposalUpdated 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.

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IPAC-RS ConclusionsIPAC-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)

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Remaining Issues/DetailsRemaining 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

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Question to ACPSQuestion 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?