DEMONSTRATING CAPABILITY TO COMPLY WITH A TEST PROCEDURE: THE CONTENT UNIFORMITY AND DISSOLUTION ACCEPTANCE LIMITS (CUDAL) APPROACH

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1 1 DEMONSTRATING CAPABILITY TO COMPLY WITH A TEST PROCEDURE: THE CONTENT UNIFORMITY AND DISSOLUTION ACCEPTANCE LIMITS (CUDAL) APPROACH Jim Bergum September 12, 2011

2 Key Responses For Batch Release 2 Potency (Average Drug Substance/Dosage Unit) Dissolution (% Drug Substance Released at Specified Time) Content Uniformity USP <905> The degree of uniformity in the amount of the drug substance among dosage units.

3 Harmonized Uniformity of Dosage Unit (UDU) Test 3 All measurements of dosage units and criteria values are in percentage label claim (%LC). At each stage calculate the sample average and the sample standard deviation s. Stage Number tested Pass stage if: X X S 1 10 M s 15.0, where M is defined below. S 2 20 X i) M s 15.0 using all 30 results (S 1 + S 2 ) ii) No dosage unit is outside the maximum allowed range of 0.75*M to 1.25*M. M is defined as follows: (i) If X is less than 98.5%LC, then M = 98.5%LC. X (ii) If X is between 98.5 and 101.5%LC, then M = X. Indifference Zone (iii) If X is greater than 101.5%LC, then M = 101.5%LC.

4 CuDAL Test: Background 4 Methodology Developed in Mid 80 s Application: Process Validation (Show process does what it purports to do) Show Specific Quality Attributes will meet associated Testing Standards (eg: CU) Content Uniformity (units have similar amount of drug) Dissolution (units dissolve at required rate) Request/Mission - Develop limits based on the process validation sample results that provide confidence that the testing standard samples will pass the testing standard.

5 Acceptance Limit Table Example for UDU Test 5 Acceptance Limit Sample Results: Mean = 99.0 RSD (%) = % Confidence Interval, 95% Coverage, n=30 Mean (%LC) RSD(%) Acceptance Limit Meeting Relative Standard Deviation (RSD) Limit assures, with 90% confidence, that a future testing standard sample take from the batch has greater than a 95% chance of passing the UDU test.

6 Justification 6 Provides high assurance that batch meets regulatory standard Assurance increases with increased sample size. Will always need a standard to define Acceptable. Can be used for more than validation or product release (ex: evaluation of NIR methods for CU used in real time release). Tied directly to regulatory requirements Ensures compliance with 21 CFR (d) - Testing and Release for distribution Can be used as a tool to meet the expectations set forth by FDA's Process Validation Guidance

7 Final Statistical Statement 7 If acceptance limit sample passed limits, then with a pre-specified confidence level, the probability that a testing standard sample will pass the testing standard is greater than a pre-specified coverage value. Example: With 90% confidence, a future testing standard sample take from the batch has greater than a 95% chance of passing the testing standard.

8 Strategy Part Select Testing Standard (Ex: UDU) 2. Assume probability distribution for individual observations (ex: Normal with parameters µ (Mu) & σ (Standard Deviation)) 3. Assuming known distribution parameters, mathematically derive* the Lower Bound for each stage (Note: Each stage may have multiple criteria!) This is the hard part! 4. Lower bound for overall test is the maximum of the individual stage lower bounds *Bergum, J.S. and Hua Li, "Acceptance Limits for the New ICH USP 29 Content Uniformity Test," Pharmaceutical Technology, October 2007, pp

9 UDU Test - 95% Lower Bound Contour 9 Batch Standard Deviation Prob(Passing UDU) Mean Std Dev Simulate USP (N=1,000,000) 90, , Batch Mean

10 Two Sample/Criteria Types 10 Acceptance Limit Sample (Results Compared to Acceptance Limit Table Criteria) Sampling Plan 1: One unit per location Sampling Plan 2: n units per location (allows estimation of between/within location variability) UDU Sample (Results Compared to Testing UDU Criteria) Sampling Plan: Defined by the Testing Standard (Usually a random sample from the batch Sampling Plan 1)

11 Strategy Part Select Sampling Plan (1 or 2). 6. Construct confidence interval for the distribution parameters based on user defined confidence level. 7. Determine lower bound probabilities for each point in the confidence interval. 8. Determine maximum probability across all points in confidence interval. 9. Compare maximum probability to user defined coverage (Lower Bound).

12 UDU Test Lower Bound with Simultaneous Confidence Interval 12 Batch Standard Deviation X ( ± Z*ULS/ n, ULS) ( X, S) 95% Lower Bound Confidence Interval Batch Mean ULS = Upper CI for Batch SD

13 Construct Acceptance Limit Table 13 To Generate Table, user selects Confidence Level (Usually 90 or 95%) Coverage Lower Bound - Desired Probability of future Testing Standard Samples passing Testing Standard (usually 95%). Sampling Plan/Sample Size Possible values specific to the Testing Standard (ex: Q for Dissolution, Target for Content Uniformity)

14 14 Acceptance Limit Table (Sampling Plan 1, 90% CI, 95% Coverage, n=30) Mean RSD(%)

15 15 Sample Size Effect on RSD Limit Sampling Plan 1 Sample Mean(%LC) RSD(%) Limit

16 16 Evaluating Acceptance Limit Table - Determining Adequate Sample Size Pick sample size such that the probability of passing the acceptance limit table is: High for a Good Batch (Acceptable Batch Mean and Std Dev) Low for a Bad Batch (Unacceptable Batch Mean and Std Dev) For given sample size, find probability of passing acceptance limit table by integrating over tabled values.

17 Example: Sampling Plan 1 P(Passing Acceptance Limit Table) 17 Batch Mean Batch RSD Sample Size

18 18 Sampling Plan 1 Operating Characteristic Curve (OC) USP Batch Mean = 100%LC Large N CuDAL USP CuDAL N = 10 CuDAL N= 100 CuDAL N= 300

19 19 Sampling Plan 1 Operating Characteristic (OC) Curve Batch Mean = 96%LC USP CuDAL N = 10 CuDAL N= 100 CuDAL N= 300

20 Example: Sampling Plan 2 (15 X 4) 20 Result Summary statistics Location Mean Variance Std Dev

21 21 Example: Sampling Plan 2

22 Example: Sampling Plan 2 22 Descriptive Statistics Mean SE (within-location Std Dev) 1.07 Standard deviation of location means 1.06 Standard Deviation of Location Means SE LL UL LL UL LL UL LL UL

23 23 Sampling Plan 2: Sample Size Evaluation Batch Mean Prob(Passing Acceptance Limit Table) Variance Component (SD) Sampling Plan (Loc x #/Loc) Between Location* Within Location (Example = 0.91) (Example = 1.1) 15x4 15x2 10x * = ((SD Location Means) 2 - SE 2 /n)

24 Current Status 24 General Methodology: ASTM E11 Standard E2709 Original (Done) Lower Bound Confidence Intervals Acceptance Limit Table Revision (In 2 nd Ballot) Add Sampling Plan 2 Content Uniformity: ASTM E55 Standard (3 rd Ballot) Lower Bound Calculations Specific to UDU Test Future Other Tests?