1

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

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.

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 X and the sample standard deviation s. Stage Number tested Pass stage if:

S1

10

|M - X | + 2.4s 15.0, where M is defined below. i) |M - X | + 2.0s 15.0 using all 30 results (S1 + S2) ii) No dosage unit is outside the maximum allowed range of 0.75*M to 1.25*M.

S2

20

M is defined as follows: (i) If X is less than 98.5%LC, then M = 98.5%LC. (ii) If X is between 98.5 and 101.5%LC, then M = X . (iii) If X is greater than 101.5%LC, then M = 101.5%LC.

Indifference Zone

CuDAL Test: Background

4

Methodology Developed in Mid 80s Application: Process Validation (Show process does what it purports to do)

Request/Mission - Develop limits based on the process validation sample results that provide confidence that the testing standard samples will pass the testing standard.

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)

Acceptance Limit Table Example for UDU Test

5

90% Confidence Interval, 95% Coverage, n=30

Mean (%LC)
Acceptance Limit Sample Results: Mean = 99.0 RSD (%) = 3.76

RSD(%) 3.79 4.03 4.26 4.47 4.17 3.87 3.57

Acceptance Limit

97.0 98.0 99.0 100.0 101.0 102.0 103.0

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.

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 211.165(d) - Testing and Release for distribution Can be used as a tool to meet the expectations set forth by FDA's Process Validation Guidance

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.

Strategy Part 1
8

1. 2. 3.

Select Testing Standard (Ex: UDU) Assume probability distribution for individual observations
(ex: Normal with parameters (Mu) & (Standard Deviation))

4.

Assuming known distribution parameters, mathematically derive* the Lower Bound for each stage (Note: Each stage may have multiple criteria!) This is the hard part! 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. 90-100.

UDU Test - 95% Lower Bound Contour

9

Batch Standard Deviation

Mean 90, 110 95, 105 100

Std Dev 2.59 4.57 6.11

Prob(Passing UDU) Simulate USP (N=1,000,000) 95.960 96.022 95.996

Batch Mean

Two Sample/Criteria Types

10

Acceptance Limit Table Criteria)

Sampling

Acceptance Limit Sample (Results Compared to

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)

Strategy Part 2
11

5. 6.

7.

8.

9.

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

UDU Test Lower Bound with Simultaneous Confidence Interval

12

Batch Standard Deviation

( X Z*ULS/n, ULS)

95% Lower Bound Confidence Interval

( X , S)

Batch Mean ULS = Upper CI for Batch SD

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)

Acceptance Limit Table

14

(Sampling Plan 1, 90% CI, 95% Coverage, n=30)

Mean 97.0 98.0 99.0 100.0 101.0 102.0 103.0

RSD(%) 3.79 4.03 4.26 4.47 4.17 3.87 3.57

Sample Size Effect on RSD Limit Sampling Plan 1

15

Sample Mean(%LC) 95.0 98.0 100.0 102.0 105.0

RSD(%) Limit 10 2.35 2.88 3.21 2.77 2.13 30 3.30 4.03 4.47 3.87 2.99 60 3.71 4.53 5.00 4.36 3.36

Evaluating Acceptance Limit Table - Determining Adequate Sample Size

16

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.

Example: Sampling Plan 1 P(Passing Acceptance Limit Table)

17

Sample Size Batch Mean Batch RSD 2 3 2 3 2 3 10 99.0 59.7 96.0 46.2 84.5 26.0 30 100.0 99.9 100.0 98.8 100.0 84.9 60 100.0 100.0 100.0 100.0 100.0 99.7

100.0 98.0 96.0

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

Sampling Plan 1 Operating Characteristic (OC) Curve

Batch Mean = 96%LC USP CuDAL N = 10 CuDAL N= 100 CuDAL N= 300

Example: Sampling Plan 2 (15 X 4)

20

Result
Location
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Summary statistics
3 4
98.37 101.01 98.88 98.94 99.66 99.06 98.65 98.63 97.67 100.26 97.49 97.28 100.48 98.49 100.14 97.5 100.29 97.96 97.78 97.2 98.8 99.98 98.06 98.95 98.74 97.5 98.8 98.62 100.93 99.2

1
97.08 99.72 99.9 98.78 96.32 100.97 97.02 99.39 99.59 97.97 96.09 98.87 101.1 100.8 99.7

2
99.72 100.32 98.27 98.17 96.61 102.17 97.35 98.81 97.8 98.54 98.61 97.81 102.6 100.34 100.09

Mean
98.17 100.34 98.75 98.42 97.45 100.25 98.25 98.72 98.50 98.88 97.42 98.19 100.70 100.14 99.78

Variance
1.36 0.28 0.73 0.29 2.31 2.57 1.83 0.30 0.86 0.96 1.07 0.60 2.71 1.27 0.19

Std Dev
1.17 0.53 0.86 0.54 1.52 1.60 1.35 0.55 0.93 0.98 1.03 0.78 1.65 1.13 0.44

Example: Sampling Plan 2

21

Example: Sampling Plan 2

22

Descriptive Statistics Mean SE (within-location Std Dev) Standard deviation of location means
98.93 1.07 1.06

Standard Deviation of Location Means 0.9 SE 0.9 1.0 1.1 1.2 1.3
LL UL LL

1.0
UL LL

1.1
UL LL

1.2
UL

88.1 88.2 88.4 88.5 88.7

111.9 111.8 111.6 111.5 111.3

88.5 88.6 88.7 88.9 89.0

111.5 111.4 111.3 111.1 111.0

88.9 89.0 89.1 89.2 89.4

111.1 111.0 110.9 110.8 110.6

89.3 89.4 89.5 89.6 89.7

110.7 110.6 110.5 110.4 110.3

23

Sampling Plan 2: Sample Size Evaluation

Prob(Passing Acceptance Limit Table) Variance Component (SD) Batch Mean Between Location* Within Location
(Example = 0.91) (Example = 1.1)

Sampling Plan (Loc x #/Loc) 15x4 100.0 100.0 100.0 99.6 100.0 98.6 100.0 90.4 15x2 100.0 100.0 100.0 98.2 100.0 97.9 99.9 81.9 10x2 100.0 96.6 99.7 81.7 100.0 82.3 94.8 53.3

1 100 2

1 2 1 2

1 97 2

1 2 1 2

* = ((SD Location Means)2 - SE2/n)

Current Status
24

General Methodology: ASTM E11 Standard E2709

Original (Done)

Lower Bound Confidence Intervals Acceptance Limit Table

Revision (In 2nd Ballot)

Add Sampling Plan 2

Content Uniformity: ASTM E55 Standard (3rd Ballot)

Lower Bound Calculations Specific to UDU Test

Future Other Tests?