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Evaluation of Validation Content Uniformity Test Results Using Lower Probability Bound Distribution Charts Pramote Cholayudth
INTRODUCTION One of the widely recognized references on process validation with regard to sampling and testing plans is the US Food and Drug Administration’s Draft Guidance for Industry: Powder Blends and Finished Dosage Units—Stratified In-Process Dosage Unit Sampling and Assessment (1) that is based on the Product Quality Research Institute (PQRI)’s Recommendation Report (2). However, it is a non-binding document (i.e., the industry may use any alternative approaches even after it becomes the official guidance). Another well-known relevant reference is the PDA Technical Report No. 25: Blend Uniformity Analysis: Validation and In-Process Testing (3). The sampling, testing, and corresponding acceptance criteria limits in validation study will follow these two statistics-based documents. The validation test results with respect to critical quality attributes (CQAs) require to be statistically evaluated (e.g., estimating confidence limits as appropriate, demonstrating the high probability of passing the tests, etc.). According to Torbeck (4), “… If statistical procedures were given in the USP, companies would have little incentive to develop better procedures.” His comment is now reconfirmed. The industry may not have
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a good approach like J.S. Bergum’s method if the United States Pharmacopeia (USP) provided some kind of statistical procedures. Bergum is one of the leading professionals who suggested the use of the new statistical procedures. His methods (5, 6) introduced both how to establish the validation acceptance criteria and how to evaluate the validation test results. In protocol development, all the validation practitioners may follow some recognized documents including Bergum’s in establishing the acceptance criteria limits. However some of them may not be confident in using statistical tools for evaluation of the test results, especially for the multiple stage tests (e.g., content uniformity and dissolution). To provide an alternative to such a statistical evaluation, this article introduces an approach to using lower probability bound distribution charts, constructed according to Bergum’s methods, for evaluation of content uniformity test results.
USP TEST ACCEPTANCE CRITERIA The two USP content uniformity tests may be summarized in Tables I and II.
ABOUT THE AUTHOR Pramote Cholayudth is a validation consultant to Biolab in Thailand and executive director of Valitech, a wellestablished GMP and validation service firm to the pharmaceutical industry. He is a guest speaker on process validation to the industry organized by local FDA. He can be contacted by e-mail at [email protected].
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Table I: Current USP uniformity of dosage units: Test acceptance criteria. USP Criteria Stage 1: Assay 10 units. Pass if the following criteria are met.
USP Criteria Stage 2: Assay 20 additional units. Pass if, for all 30 units, the following criteria are met.
1) Relative standard deviation (RSD) is not more than 7.8% 1) Relative standard deviation (RSD) is not more (n = 30) than 6.0% (n = 10) 2) Not more than c unit(s) is outside 85 – 115% label 2) Not more than c unit(s) is outside 85 – 115% label claim (LC) and no unit is outside 75 – 125% LC where c = 1 for claim (LC) and no unit is outside 75 – 125% LC tablet and 3 for capsule where c = 0 for tablet and 1 for capsule
Table II: New USP uniformity of dosage units: Test acceptance criteria. USP Criteria Stage 1: Assay 10 units. Pass if the following criteria are met.
USP Criteria Stage 2: Assay 20 additional units. Pass if, for all 30 units, the following criteria are met.
1.
1. 2. Xmin > 0.75M and Xmax < 1.25M
Where M = reference value, s = standard deviation, 5 content uniformity data mean, Xmin 5 minimum and Xmax 5 maximum (individual values) Acceptance Value (AV) = 1 ks < L1, k = 2.4 (n 5 10) and 2.0 (n = 30), Xmin > (1 2 L2* 0.01)M, Xmax < (1 1 L2*0.01)M If not specified in individual monographs, L1 5 15 and L2 5 25
Table III: New USP uniformity of dosage units: Reference value criteria. Case Target (T) < 101.5 % of label claim (% LC)
Subcase 98.5 <
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< 98.5 > 101.5
101.5
98.5 2
1 ks
2 101.5 1 ks ks
< 98.5
98.5
>T
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98.5
98.5 < Target (T) > 101.5 % LC
M
98.5 2
1 ks
2 T 1 ks
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P R A M O T E C H O L AY U D T H
To help understand the new USP test acceptance criteria, a scenario for calculation of acceptance value (AV) is introduced: In a new USP content uniformity testing, the stage 1 test results (n = 10) are mean = 101.2 % of label claim (LC) and standard deviation (SD) = 4.15 % LC. The manufacturing target is 102.5 % LC. The acceptance value is (101.2-101.2) + 2.4x4.15 = 9.96 (< 15), so the AV limit is met.
PROBABILITY OF PASSING THE CURRENT CONTENT UNIFORMITY TEST According to Bergum’s method described in “Use of the Bergum Method and MS Excel to Determine the Probability of Passing the USP Content Uniformity Test” (7), the probability formulae are illustrated in
Table IV. The formulae in Tables IV, XIV, and XV may be copied to construct the Microsoft Excel file for computing the probability. However, note that the sample is taken in accordance with sampling plan 1 (one unit from each of 30 locations).
PROBABILITY OF PASSING THE NEW CONTENT UNIFORMITY TEST The article “Using Bergum’s New Method and MS Excel to Determine the Probability of Passing the New ICH USP 29 Content Uniformity Test” (8), has the formulae as illustrated in Table V. The readers may copy the formulae in Tables V, VI, and VII to construct the Microsoft Excel file. Also note that the sample is taken in accordance with sampling plan 1.
Table IV: MS Excel formula sheet1: Current USP test. Excel Formula Sheet1 A
B
C
D
E
F
1
Confidence Level (%)
95
Overall Bound Results
2
Sample Size (n)
30
3
Sample Mean (% LC)
98.00
LB Prob
96.50%
LB Prob
99.96%
4
Sample RSD (%)
3.50
Prob1
99.90%
Prob1
100.00%
5
UB: Mean (% LC)
99.93
Prob2
96.50%
Prob2
99.96%
6
LB: Mean (% LC)
96.07
7
UB: SD (% LC)
4.74
Tablet
Capsule
Prob at UB: Mean
8
Part 1/1
89.08%
Part 2/1
100.00%
Prob at LB: Mean
9 10
Part 1/2
84.63%
11
Part 2/2
99.96%
UB: Upper Bound, LB: Lower Bound, UB & LB formulae are as below: B5 =B3+B7*NORMSINV(1-(1-(B1/100)^0.5)/2)/B2^0.5 B6 =B3-B7*NORMSINV(1-(1-(B1/100)^0.5)/2)/B2^0.5 B7 =B4*(B3/100)*((B2-1)/(CHIINV((B1/100)^0.5,B2-1)))^0.5 The cells B1 – B4 are entered with sample data. The numerical results in the other cells, including those in D3 and F3, are generated using the formulae in Tables XIV and XV. The Excel file (as a combination of tables IV, XIV, and XV) can be downloaded from www.pharmtech.com – search “Pramote”.
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Table V: Microsoft Excel formula sheet1: New USP test. Excel Formula Sheet1 C
D
UB: SD
4.74
Formula Examples
A
B
1
UB: Mean
99.93
2
Stage 1 (n = 10)
3
I1
63.19%
I1
91.62%
See formulae below (B3 & D3)
4
I2
12.93%
I2
3.52%
B4 =Sheet2!B36, D4 =Sheet2!D36
5
I3
14.73%
I3
4.86%
B5 =Sheet2!C36, D5 =Sheet2!E36
6
P(S1)
90.85%
P(S2)
99.99%
B6 =SUM(B3:B5), D6 (See below)
7
Probability
8
LB: Mean
9
Stage 1 (n = 10)
10
I1
4.81%
I1
0.24%
B10, D10: Follow formulae for B3 & D3
11
I2
0.01%
I2
0.00%
B11 =Sheet3!B36, D11 =Sheet3!D36
12
I3
64.67%
I3
97.74%
B12 =Sheet3!C36, D12 =Sheet3!E36
13
P(S1)
69.50%
P(S2)
97.90%
B13 =SUM(B10:B12), D13 (See below)
14
Probability
15
Lbound Probability
B1 =C22, D1 =C24
Stage 2 (n = 30)
C7 =MAX(B6,D6)
99.99% 96.07
UB: SD
—
4.74
B8 =C23, D8 =C24
Stage 2 (n = 30)
16
—
97.90%
C14 =MAX(B13,D13)
97.90%
C15 =MIN(C7,C14)
Sample Data
C22 =C20+C24*NORMSINV(1-(10.95^0.5)/2)/C19^0.5
17
Target
100
18
Confidence Level (%)
95
19
Sample Size (n)
30
20
Sample Mean (% LC)
98.00
21
Sample RSD (%)
3.60
C24 =(C20*C21/100)*((C19-1)/(CHIINV(0.95^0.5,C19-1)))^0.5
22
Upper Bound: Mean
99.93
Linked to B1 & Sheet2!B2
23
Lower Bound: Mean
96.07
Linked to B8 & Sheet3!B2
24
Upper Bound: SD
4.74
Linked to D1,D8,Sheet2!C2,&Sheet3!C2
C23 =C20-C24*NORMSINV(1-(10.95^0.5)/2)/C19^0.5
B3 =(NORMSDIST((10^0.5)*(100-B1)/D1)-NORMSDIST((10^0.5)*(98.5-B1)/D1))*(1-CHIDIST((10-1)*(15/(2.4*D1))^2,10-1)) = 63.19% (For B10, replace B1 with B8 and D1 with D8) D3 =(NORMSDIST((30^0.5)*(100-B1)/D1)-NORMSDIST((30^0.5)*(98.5-B1)/D1))*(1-CHIDIST((30-1)*(15/(2*D1))^2,30-1)) = 91.62% (For D10, replace B1 with B8 and D1 with D8) D6 =MAX(SUM(D3:D5)+((NORMSDIST((123.125-B1)/D1)-NORMSDIST((IF(C17<=101.5,101.5,C17)-24.625-B1)/D1))^30)-1,0) D13 =MAX(SUM(D10:D12)+((NORMSDIST((123.125-B8)/D8)-NORMSDIST((IF(C17<=101.5,101.5,C17)-24.625-B8)/D8))^30)-1,0) The cells C17 – C21 are entered with sample data information. The numerical results in the other cells, including the probability and LB results in C7, C14, and C15, are generated by the program.
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Table VI: MS Excel formula sheet2: New USP test. Excel Formula Sheet2 A
B
C
1
Target
UB: Mean
2
100
99.93
3
—
4
—
5
i
I2
I3
I2
I3
6
1
5.85%
0.00%
2.67%
0.00%
7
2
3.58%
0.00%
0.70%
0.00%
8
3
1.95%
0.00%
0.13%
0.00%
9
4
0.94%
0.00%
0.02%
0.00%
5
0.40%
0.00%
0.00%
0.00%
... ➔ ...%
... ➔ ...%
... ➔ ...%
... ➔ ...%
10 11 ➔ 30
6 ➔ 25
D
E
UB: SD
h
4.74
0.5
i 1 ➔ 30
Stage 1
Formula Examples
Stage 2
10
30
31
26
0.00%
0.49%
0.00%
0.00%
32
27
0.00%
1.13%
0.00%
0.03%
33
28
0.00%
2.28%
0.00%
0.21%
34
29
0.00%
4.08%
0.00%
1.02%
35
30
0.00%
6.47%
0.00%
3.59%
36
Sum
12.93%
14.73%
3.52%
4.86%
B6 =(NORMSDIST((B4^0.5)*((101.5+A6*D2)B2)/C2)-NORMSDIST((B4^0.5)*((101.5+(A61)*D2)-B2)/C2))*(1-CHIDIST((B4-1)*(15-(A60.5)*D2)^2/(2.4*C2)^2,B4-1)) = 5.85% B35 =(NORMSDIST((B4^0.5)*((101.5+A35*D2)B2)/C2)-NORMSDIST((B4^0.5)*((101.5+(A351)*D2)-B2)/C2))*(1-CHIDIST((B4-1)*(15-(A350.5)*D2)^2/(2.4*C2)^2,B4-1)) = 0.00% B36 =SUM(B6:B35) = 12.93%
The number of intervals (i) 30 with interval width (h) 0.5 is selected to ensure that the integration result, especially when using the higher sigma values, is valid. The stage 2 formula is similar except for n = 30 (B4 ➔ D4) and k = 2.0 (2.4 ➔ 2). The Target (also Mean and Sigma) value is linked from Sheet1 e.g. A2 =Sheet1!B2. And I2 (B36 & D36) and I3 (C36 & E36) are linked to Sheet1 e.g., B4 (of Sheet1) =Sheet2!B36
When sample data (n = 30) associated with sample mean: 98% LC and sample RSD: 3.6% are plotted, the lower probability bound distributions can be constructed and illustrated in Figures 1 and 2. In these figures, one can imagine how a sample data comprising a mean and relative standard deviation (RSD) values will influence the probability of passing a content uniformity test. Furthermore, the way in which a larger sample size influences the distribution patterns is demonstrated in Figure 3.
JUSTIFICATION OF USING THE PROBABILITY CHARTS Validation content uniformity test results must be evaluated for probability of passing the test. The evaluation employs Bergum’s methods by using statistical programs like SAS or Microsoft Excel. To provide a practical tool as an alternative to such complicated methods, the distribution curves for lower probability bounds constructed in a high precision scale are introduced so that validation practitioners can use them to determine the probability instead of using the programs. However one must realize that the use of Excel for validation work requires validation of the spreadsheet itself (e.g., Tables IV, V, VI, and VII).
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Table VII: MS Excel Formula Sheet3: New USP Test. Excel Formula Sheet3 A
B
C
1
Target
LB: Mean
2
100
96.07
3
—
4
—
5
i
I2
I3
I2
I3
6
1
0.01%
0.00%
0.00%
0.00%
7
2
0.00%
0.00%
0.00%
0.00%
8
3
0.00%
0.00%
0.00%
0.00%
9
4
0.00%
0.00%
0.00%
0.00%
10
E
UB: SD
h
4.74
0.5
i 1 ➔ 30
Stage 1
Formula Examples
Stage 2
10
30
0.00%
0.00%
0.00%
0.00%
6 ➔ 25
... ➔ ...%
... ➔ ...%
... ➔ ...%
... ➔ ...%
31
26
0.00%
9.80%
0.00%
22.13%
32
27
0.00%
9.54%
0.00%
16.74%
33
28
0.00%
8.21%
0.00%
9.13%
34
29
0.00%
6.25%
0.00%
3.59%
35
30
0.00%
4.22%
0.00%
1.02%
36
Sum
0.01%
64.67%
0.00%
97.74%
11 ➔ 30
5
D
B6 =(NORMSDIST((B4^0.5)*((101.5+A6*D2)B2)/C2)-NORMSDIST((B4^0.5)*((101.5+(A61)*D2)-B2)/C2))*(1-CHIDIST((B4-1)*(15-(A60.5)*D2)^2/(2.4*C2)^2,B4-1)) = 0.01% B35 =(NORMSDIST((B4^0.5)*((101.5+A35*D2)B2)/C2)-NORMSDIST((B4^0.5)*((101.5+(A351)*D2)-B2)/C2))*(1-CHIDIST((B4-1)*(15-(A350.5)*D2)^2/(2.4*C2)^2,B4-1)) = 0.00% B36 =SUM(B6:B35) = 0.01%
The Target value (also Mean and Sigma) is linked from Sheet1 e.g., A2 =Sheet1!B2. And I2 (B36 & D36) and I3 (C36 & E36) are linked to Sheet1 e.g., B11 (of Sheet1) =Sheet3!B36
Figure 1: Operating Operating Characteristic (OC) Curves for USP Characteristic (OC) Curves for Content. USP Content uniformity tests (n
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Figure 2: Distribution Curves for Probability of Passing USP Content Uniformity Test (n=30).
Figure 3: Distribution Curves for Probability of Passing USP Content Uniformity Test (n = 70).
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P R A M O T E C H O L AY U D T H
tablet product tested using the current USP content uniformity test with sample mean = 100.15% LC and RSD = 3.9%, is performed by determining on Figure 4 the intersection of the curves for mean = 100.2 (rounded up) and RSD = 3.9. The point will indicate the lower probability bound of approximately 97%. The probability generated using the Excel program is 97.46%. The determined value deviates slightly from the computed one.
To justify the use of probability charts is to justify such deviations, so analysis of the deviation data in Tables VIII, IX, and X is carried out. Each numerical value of mean and RSD is intended to provide the second decimal digits with 4, 5, or 6 (e.g., 97.04, 4.25, 97.06) so that when the numbers are rounded up, the maximized deviation in the probability determination result is challenged. The results are satisfactory since most of the deviations are close to or equal to the calculated results except for those data sets with means greater than the target (> 100% LC) and RSDs with the second decimals with 4, 5, or 6 where the maximum biases (deviation) will occur. In the worst case, the maximum deviation is 5.3% (Table IX) or 4.6% (Table X). Therefore, the use of these types of probability charts should be justified.
Figure 4: Determining Probability Using the Probability Charts (n = 30).
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Table VIII: Comparison of Excel and Determination Results, Current CU Test (n=30). Tablet
Capsule
Mean (% LC)
RSD (%)
97.00
4.20
68.57
69
0.00
96.70
97
0.00
97.04
4.24
67.08
69
1.49
96.26
97
0.44
97.05
4.25
66.70
65
1.92
96.14
95
0.66
97.06
4.26
66.32
65
1.54
96.01
95
0.53
97.10
4.30
64.78
65
0.00
95.48
95
0.00
102.90
4.20
58.04
58
0.00
93.95
94
0.00
102.94
4.24
55.09
58
2.95
92.84
94
1.11
102.95
4.25
54.35
51
3.70
92.54
91
1.62
102.96
4.26
53.61
51
2.96
92.24
91
1.32
103.00
4.30
50.65
51
0.00
90.92
91
0.00
Prob Excel (%) Prob Deter. (%) Deviation (%) Prob Excel (%) Prob Deter. (%) Deviation (%)
Table IX: Comparison of Excel and Determination Results, New CU Test (n = 30). Mean (% LC)
RSD (%)
Prob Prob Deviation Excel (%) Deter. (%) (%)
Mean (% LC)
RSD (%)
Prob Excel (%)
Prob Deter. (%)
Deviation (%)
97.00
3.90
79.19
79
0.00
102.90
3.90
65.12
65
0.00
97.04
3.94
77.32
79
1.87
102.94
3.94
60.98
65
4.14
97.05
3.95
76.85
74
2.45
102.95
3.95
59.94
55
5.31
97.06
3.96
76.36
74
1.96
102.96
3.96
58.88
55
4.25
97.10
4.00
74.40
74
0.00
103.00
4.00
54.63
55
0.00
Prob Deter. (%)
Deviation (%)
Table X: Comparison of Excel and Determination Results, New CU Test (n = 60). Mean (% LC)
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Prob Prob Deviation Excel (%) Deter. (%) (%)
Mean (% LC)
RSD (%)
Prob Excel (%)
97.00
4.60
73.71
74
0.00
102.90
4.60
59.04
59
0.00
97.04
4.64
72.10
74
1.61
102.94
4.64
55.38
59
3.66
97.05
4.65
71.70
70
2.06
102.95
4.65
54.46
50
4.63
97.06
4.66
71.29
70
1.65
102.96
4.66
53.53
50
3.70
97.10
4.70
69.64
70
0.00
103.00
4.70
49.83
50
0.00
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P R A M O T E C H O L AY U D T H
SAMPLING PLAN 1 AND 2 To take a validation sample of the dosage units (e.g., tablets or capsules) for content uniformity testing, stratified sampling plan 1 or 2 is followed. Sampling plan 1 will involve taking one unit from each of L locations (e.g., 30 locations). Sampling plan 2 involves taking two or more units from each of L locations throughout the tablet compression or encapsulation cycle. In multiple stage tests (including content uniformity), it is unavoidable to employ sampling plan 2 since the overall (stages 1 and 2) test number of dosage units per location is more than 1 unit. Examples for sampling plan 2, during compression or encapsulation cycle, are illustrated in Table XI.
RECOMMENDATION FOR USE OF PROBABILITY CHARTS For sampling plan 1 (one unit from each of L locations), the validation practitioners can simply use the probability charts by using the sample mean and RSD. For sampling plan 2 (two or more units from each of L locations), a number of different charts are provided. The data are required to be computed for within-location standard deviation (SE) and between-location standard deviation (SM) prior to determination of the probability on the charts. Examples for computing these statistics (SE and SM) and determining the probability using sampling plan 2 data are demonstrated in Table XII and Figure 5, respectively. Table XII is provided with content uniformity data in cells B3:K5 and related calculation formulae (10).
Table XI: Sampling Plans 1 and 2 with Examples for Plan 2. Location # (of 20 Locations, L = 20) Sampling/Testing Plans
1
2
3
4
5
6 ➔ 19
20
Sampling Plan 1 (One Unit from Each Location) Sampling plan: 1x20
1
1
1
1
1
1➔1
1
Test plan: 1x20
1
1
1
1
1
1➔1
1
Take 1 unit from each of 20 locations. Test each unit in order. Sampling Plan 2 (More than One Unit, e.g., 7 Units, from Each Location) Sampling plan: 7x20
7
7
7
7
7➔7
7
7
Take 7 units from each of 20 locations throughout the operation cycle and keep each location sample in separate container. Stage 1 test plan: 3x20
3
3
3
3
3➔3
3
3
Test 3 units of each location in order, the test results for 3x20 units require to meet stage 1’s acceptance criteria. If failed, proceed to stage 2. Stage 2 test plan: 4x20
4
4
4
4
4➔4
4
4
Test 4 remaining units of each location in order, the overall test results for 7x20 units should meet stage 2’s acceptance criteria. Examples for Stratified Sampling Plan 2: Compression/Encapsulation Cycle * Tests Content Uniformity
Testing Plans (nxL)
Sampling Plans (nxL) 7 units x 20 locations
Stage1: 3 units x 20 locations Stage2: 4 units x 20 locations
Dissolution
5 units x 20 locations
Stage1: 2 units x 20 locations Stage2: 3 units x 20 locations Stage1: 1 unit x 20 locations
Degradents
3 units x 20 locations Stage2: 2 units x 20 locations
* Modified from Reference (9), n: sample size at each location, L: number of locations
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Table XII: Evaluation of Data from Sampling Plan 2 (N = nxL = 3x10). Excel Formula Sheet A 1 2
B
C
D
E
F
G
H
I
J
K
Stratified Sampling Location # (Sampling Plan 2: 3 Units x 10 Locations) Unit # 1
2
3
4
5
6
7
8
9
10
3
1
95.01
93.91
99.37
97.97
94.93
93.83
101.31
98.74
97.87
106.44
4
2
100.93
99.11
103.93
105.8
98.52
105.85
96.48
97.53
103.71
99.18
5
3
102.27
98.96
99.83
97.64
100.27
98.68
97.46
95.83
98.23
96.14
6
SQD
29.85
17.52
12.61
42.67
14.82
73.14
13.04
4.27
21.42
56.01
7
Average (% LC)
99.19*
RSD (%)
3.43
8
Degree of freedom (between-location) (L-1)
9
9
Degree of freedom (within-location) {(n-1)L}
20
10
Total square deviation
335.56
11
Square deviation (within-location)
285.35
12
Square deviation (between-location)
50.21
13
Standard deviation (within-location) (SE)
3.78*
14
Standard deviation (between-location) (SM)
2.36*
15
Note: SQD: Square Deviation
-
N (nxL)
30
C7 =AVERAGE(B3:K5) G7 =STDEV(B3:K5)/C7, K7 =3*10 B6 = DEVSQ(B3:B5) C6,…,K6 – same as B6 F8 =10-1, F9 =(3-1)*10 F10 =DEVSQ(B3:K5), F11 =SUM(B6:K6) F12 =F10-F11, F13 =(F11/F9)^0.5 F14 =(F12/F8)^0.5
16 Probability of Passing the USP CU Test
Calculated**
Determined
17 Probability (Current Tablet CU Test)
91.17%
90%
18 Probability (Current Capsule CU Test)
99.25%
99%
19 Probability (New CU Test)
91.31%
90%
20 *These data are used for determination of the probability in Figure 5 where rounded numbers are used 21 i.e., 99.19 ➔ 99.2 (C7), 3.78 ➔ 3.8 (F13) & 2.36 ➔ 2.4 (F14). 22 **Calculated (in Tables IV & V ) from the upper & lower bounds estimated using ANOVA (11) 23 SE = Square Root of Mean Square Error, SM = Standard Deviation of Location Means
Upon completing a trial using an Excel formula sheet (using worst cases of numerical values), the deviation was found to be about 6% at maximum because of poor processes, i.e., the mean deviated from the target value with high variability (within-location and between-location), resulting in low probability results. Table XIII provides an example of the worst cases and probability results data.
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CONCLUSION The concept of probability charts will help validation practitioners visualize the integrated views of the lower probability bound distributions and understand the effect of sample mean location and variability (e.g., RSD, SE, and SM) on the probability of passing the USP content uniformity test. Acceptability of the probability charts is subject to the chart accuracy. The charts with accuracy better than those provided in Appendix 2 of this article can be developed, but the consequence ivthome.com
P R A M O T E C H O L AY U D T H
Table XIII: Comparison of Excel and Determination Results (n = 30). Comparison of Excel and Determination Results Current CU Test: Tablets
New CU Test
Mean (% LC)
SE
96.54
3.65
2.65
61.44
57
4.44
48.79
43
5.79
97.54
3.75
2.75
72.00
68
4.00
62.70
57
5.70
98.54
3.85
2.85
79.72
77
2.72
74.26
70
4.26
101.55
3.75
2.75
84.07
81
3.07
79.80
75
4.80
102.55
3.65
2.65
76.73
73
3.73
69.38
64
5.38
103.55
3.55
2.55
66.54
62
4.54
56.10
50
6.10*
SM
Prob Exc Prob Det (%) (%)
Dev (%)
Prob Exc (%) Prob Det (%)
Dev (%)
SE = Square Root of Mean Square Error, SM = Standard Deviation of Location Means, * Maximum
Figure 5: Determining Probability Using Sampling Plan 2 Data (n = 30).
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P R A M O T E C H O L AY U D T H
are that a lot of charts will have to be generated, since one chart may be broken down into two or three charts, resulting in complication of their use. Justification of the accuracy (i.e., deviation) on practical basis, as described earlier, should be acceptable. Since the worst case probability results (low results at 50 to 60% with deviation of up to 5 or 6%) will occur only to inadequately controlled and/or developed processes. The adequately developed processes with proper in-process control will not fall into this case (i.e., the deviation will be much less than 5%).
9. Pluta, P., “Keep in Step with Confidence; Keep in Step through Benchmarking” Journal of Validation Technology, Volume 12, No. 1, November 2005. 10. Cholayudth, P., “Application of Probability of Passing Multiple Stage Tests in Benchmarking and Validation of Processes” Journal of Validation Technology, Volume 13, No. 4, August 2007. 11. Chow, S.C. and Liu, Statistical Design and Analysis in Pharmaceutical Science: Validation, Process Controls, Practical and Clinical Applications, 3rd ed. New York: Marcel Dekker, Inc. JVT
REFERENCES
ARTICLE ACRONYM LISTING
1. FDA Center for Drug Evaluation and Research (CDER), Draft Guidance for Industry: Powder Blends and Finished Dosage Units—Stratified In-Process Dosage Unit Sampling and Assessment, Rockville, MD , October 2003. 2. Product Quality Research Institute (PQRI) Blend Uniformity Working Group (BUWG), “The Use of Stratified Sampling of Blend and Dosage Units to Demonstrate Adequacy of Mix for Powder Blends,”Final Report on Blend Uniformity Recommendations, December 20, 2002, www.pqri.org. 3. Parenteral Drug Association, “Blend Uniformity Analysis: Validation and In-Process Testing,” PDA Technical Report No. 25,1997. 4. Torbeck, L. D., “In Defense of USP Singlet Testing,” Pharmaceutical Technology, Volume 29, Number 2, February 2005, www.pharmtech.com. 5. J. S. Bergum, “Constructing Acceptance Limits for Multiple Stage Tests,” Drug Development and Industrial Pharmacy, 16 (14), Marcel Dekker, Inc, 1990, pp. 2153-2166. 6. J. S. Bergum and H. Li, “Acceptance Limits for the New ICH USP 29 Content-Uniformity Test,” Pharmaceutical Technology, October 2007, Vol. 31, No. 10, www.pharmtech.com. 7. Cholayudth, P., “Use of the Bergum Method and MS Excel to Determine the Probability of Passing the USP Content Uniformity Test,” Pharmaceutical Technology, Volume 28, Number 9, September 2004, www.pharmtech.com. 8. Cholayudth, P., “Using Bergum’s New Method and MS Excel to Determine the Probability of Passing the New ICH USP 29 Content Uniformity Test” Journal of Validation Technology, Volume 14, No. 2, February 2008.
AV CQAs FDA ICH LB LC MS OC PDA PQRI RSD SD SE Sigma SM UB USP
Acceptance Value Critical Quality Attributes Food and Drug Administration International Conference on Harmonization Lower Bound Label Claim Microsoft Operating Characteristic Parenteral Drug Association Product Quality Research Institute Relative Standard Deviation Standard Deviation (for a Sample) Square Root of Mean Square Error Population Standard Deviation Standard Deviation of Location Means Upper Bound United States Pharmacopeia
ACKNOWLEDGMENT This paper is intended to support James Bergum’s methods with regard to probability of passing the current and new USP Content Uniformity tests. Although the Microsoft Excel programs were developed from his SAS programs by the author (7, 8), a more practical approach to use the distribution curves for lower probability bounds in place of the Excel programs is introduced. Finally, the author is very grateful to the reviewers of this paper for their helpful comments especially regarding the OC curves.
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APPENDIX 1 EXCEL FORMULAE
Table XIV: Tablet formulae: Current USP test. Tablet formulae are as below: D3 =MIN(D4,D5) D4 =MAX((FDIST(10/((0.06^2)*(1+10*(B5/B7)^2)),(1+10*(B5/B7)^2)^2/(1+2*10*(B5/B7)^2),10-1))+ ((NORMSDIST((115-B5)/B7)-NORMSDIST((85-B5)/B7))^10)1,(FDIST(30/((0.078^2)*(1+30*(B5/B7)^2)),(1+30*(B5/B7)^2)^2/(1+2*30*(B5/B7)^2),30-1))+((NORMSDIST((115-B5)/B7)NORMSDIST((85-B5)/B7))^30+COMBIN(30,1)*((NORMSDIST((115-B5)/B7)-NORMSDIST((85-B5)/B7))^29)*(((NORMSDIST((85-B5)/B7)-NORMSDIST((75-B5)/B7))+(NORMSDIST((125-B5)/B7)-NORMSDIST((115-B5)/B7)))^1))-1,0) D5 =MAX((FDIST(10/((0.06^2)*(1+10*(B6/B7)^2)),(1+10*(B6/B7)^2)^2/(1+2*10*(B6/B7)^2),10-1))+((NORMSDIST((115B6)/B7)-NORMSDIST((85-B6)/B7))^10)1,(FDIST(30/((0.078^2)*(1+30*(B6/B7)^2)),(1+30*(B6/B7)^2)^2/(1+2*30*(B6/B7)^2),30-1))+((NORMSDIST((115-B6)/B7)NORMSDIST((85-B6)/B7))^30+COMBIN(30,1)*((NORMSDIST((115-B6)/B7)-NORMSDIST((85-B6)/B7))^29)*(((NORMSDI ST((85-B6)/B7)-NORMSDIST((75-B6)/B7))+(NORMSDIST((125-B6)/B7)-NORMSDIST((115-B6)/B7)))^1))-1,0)
Table XV: Capsule formulae: Current USP test. Capsule formulae are as below: F3 =MIN(F4,F5), F4 =MAX(F7,F8,0), F5 =MAX(F10,F11,0) F7 =(FDIST(10/((0.06^2)*(1+10*(B5/B7)^2)),(1+10*(B5/B7)^2)^2/(1+2*10*(B5/B7)^2),10-1))+((NORMSDIST((115B5)/B7)-NORMSDIST((85-B5)/B7))^10+COMBIN(10,1)*((NORMSDIST((115-B5)/B7)-NORMSDIST((85B5)/B7))^9)*(((NORMSDIST((B5-75)/B7)-NORMSDIST((B5-85)/B7))+(NORMSDIST((125-B5)/B7)-NORMSDIST((115B5)/B7)))^1))-1 F8 =(FDIST(30/((0.078^2)*(1+30*(B5/B7)^2)),(1+30*(B5/B7)^2)^2/(1+2*30*(B5/B7)^2),30-1))+((NORMSDIST((115B5)/B7)-NORMSDIST((85-B5)/B7))^30+COMBIN(30,1)*((NORMSDIST((115-B5)/B7)-NORMSDIST((85B5)/B7))^29)*(((NORMSDIST((85-B5)/B7)-NORMSDIST((75-B5)/B7))+(NORMSDIST((125-B5)/B7)-NORMSDIST((115B5)/B7)))^1)+COMBIN(30,2)*((NORMSDIST((115-B5)/B7)-NORMSDIST((85-B5)/B7))^28)*(((NORMSDIST((85-B5)/B7)-N ORMSDIST((75-B5)/B7))+(NORMSDIST((125-B5)/B7)-NORMSDIST((115-B5)/B7)))^2)+COMBIN(30,3)*((NORMSDIST((115-B5)/B7)-NORMSDIST((85-B5)/B7))^27)*(((NORMSDIST((85-B5)/B7)-NORMSDIST((75-B5)/B7))+(NORMSDIST((125-B5)/B7)-NORMSDIST((115-B5)/B7)))^3))-1 F10 =(FDIST(10/((0.06^2)*(1+10*(B6/B7)^2)),(1+10*(B6/B7)^2)^2/(1+2*10*(B6/B7)^2),10-1))+((NORMSDIST((115B6)/B7)-NORMSDIST((85-B6)/B7))^10+COMBIN(10,1)*((NORMSDIST((115-B6)/B7)-NORMSDIST((85B6)/B7))^9)*(((NORMSDIST((B6-75)/B7)-NORMSDIST((B6-85)/B7))+(NORMSDIST((125-B6)/B7)-NORMSDIST((115B6)/B7)))^1))-1 F11 =(FDIST(30/((0.078^2)*(1+30*(B6/B7)^2)),(1+30*(B6/B7)^2)^2/(1+2*30*(B6/B7)^2),30-1))+((NORMSDIST((115B6)/B7)-NORMSDIST((85-B6)/B7))^30+COMBIN(30,1)*((NORMSDIST((115-B6)/B7)-NORMSDIST((85B6)/B7))^29)*(((NORMSDIST((85-B6)/B7)-NORMSDIST((75-B6)/B7))+(NORMSDIST((125-B6)/B7)-NORMSDIST((115B6)/B7)))^1)+COMBIN(30,2)*((NORMSDIST((115-B6)/B7)-NORMSDIST((85-B6)/B7))^28)*(((NORMSDIST((85-B6)/B7)-N ORMSDIST((75-B6)/B7))+(NORMSDIST((125-B6)/B7)-NORMSDIST((115-B6)/B7)))^2)+COMBIN(30,3)*((NORMSDIST((115-B6)/B7)-NORMSDIST((85-B6)/B7))^27)*(((NORMSDIST((85-B6)/B7)-NORMSDIST((75-B6)/B7))+(NORMSDIST((125-B6)/B7)-NORMSDIST((115-B6)/B7)))^3))-1
APPENDIX 2 PROBABILITY CHARTS Appendix 2 is available for download at http://www.ivthome.com/jvtspring. Probability charts provided in Appendix 2 are presented in order of sampling plan types and overall sample sizes. The charts for 1 unit x 60 locations are also available although it is not practical to do the sampling. The author only wants the readers to have the integrated views on this sampling plan 1. 80
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Journal of Validation Technology MAY 2008 ISSUE ARTICLE: Evaluation of Validation Content Uniformity Test Results Using Probability Distribution Charts By: Pramote Cholayudth
APPENDIX 2: PROBABILITY CHARTS Probability charts provided in the following pages are presented in order of product types, sampling plan types and overall sample sizes. All the charts are constructed on 95% joint confidence level. The charts for 1 unit x 60 locations are also available although it is not practical to do the sampling. The author only wants the readers to have the integrated views on this sampling plan 1. In the new USP test, the probability charts provided are applicable to the processes with target of not more than 101.5% label claim (LC). For processes with target > 101.5% LC, please contact [email protected].
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TABLE OF CONTENTS (CURRENT USP TEST: TABLETS)
Sampling Plan 1 (1 x 30): Current USP Test (RSD: 2.1 – 4.8%) Sampling Plan 1 (1 x 60): Current USP Test (RSD: 2.7 – 5.4%) Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.0 – 4.7, SM: 0.3 – 0.7) Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.9 – 4.6, SM: 0.8 – 1.2) Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.9 – 4.6, SM: 1.3 – 1.7) Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.8 – 4.5, SM: 1.8 – 2.2) Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.7 – 4.4, SM: 2.3 – 2.6) Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.6 – 4.3, SM: 2.7 – 2.9) Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.6 – 4.3, SM: 3.0 – 3.2) Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.4 – 4.1, SM: 3.3 – 3.5) Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.0 – 3.7, SM: 3.6 – 3.8) Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.6 – 5.3, SM: 0.3 – 0.7) Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.6 – 5.3, SM: 0.8 – 1.2) Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.5 – 5.2, SM: 1.3 – 1.7) Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.5 – 5.2, SM: 1.8 – 2.2) Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.5 – 5.2, SM: 2.3 – 2.6) Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.5 – 5.2, SM: 2.7 – 2.9) Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.4 – 5.1, SM: 3.0 – 3.2) Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.4 – 5.1, SM: 3.3 – 3.5) Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.4 – 5.1, SM: 3.6 – 3.8)
4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58 61
TABLE OF CONTENTS (CURRENT USP TEST: CAPSULES)
Sampling Plan 1 (1 x 30): Current USP Test (RSD: 2.5 – 5.2%) Sampling Plan 1 (1 x 60): Current USP Test (RSD: 3.0 – 5.7%) Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.3 – 5.0, SM: 0.3 – 0.7) Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.3 – 5.0, SM: 0.8 – 1.2) Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.3 – 5.0, SM: 1.3 – 1.7) Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.2 – 4.9, SM: 1.8 – 2.2) Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.2 – 4.9, SM: 2.3 – 2.6) Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.1 – 4.8, SM: 2.7 – 2.9) Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.1 – 4.8, SM: 3.0 – 3.2) Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.1 – 4.8, SM: 3.3 – 3.5) All Rights Reserved. Advanstar Communications Inc. 2008 • www.ivthome.com
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Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.9 – 4.6, SM: 3.6 – 3.8) Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.1 – 5.8, SM: 0.3 – 0.7) Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 0.8 – 1.2) Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 1.3 – 1.7) Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 1.8 – 2.2) Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 2.3 – 2.6) Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 2.7 – 2.9) Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 3.0 – 3.2) Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.9 – 5.6, SM: 3.3 – 3.5) Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.9 – 5.6, SM: 3.6 – 3.8)
35 38 41 44 47 50 53 56 59 62
TABLE OF CONTENTS (NEW USP TEST: TABLETS/CAPSULES) • • • • • • • • • • • • • • • • • • • •
Sampling Plan 1 (1 x 30): New USP Test (RSD: 2.0 – 4.7%) Sampling Plan 1 (1 x 60): New USP Test (RSD: 2.7 – 5.4%) Sampling Plan 2 (3 x 10): New USP Test (SE: 2.0 – 4.7, SM: 0.3 – 0.7) Sampling Plan 2 (3 x 10): New USP Test (SE: 1.9 – 4.6, SM: 0.8 – 1.2) Sampling Plan 2 (3 x 10): New USP Test (SE: 1.9 – 4.6, SM: 1.3 – 1.7) Sampling Plan 2 (3 x 10): New USP Test (SE: 1.7 – 4.4, SM: 1.8 – 2.2) Sampling Plan 2 (3 x 10): New USP Test (SE: 1.6 – 4.3, SM: 2.3 – 2.6) Sampling Plan 2 (3 x 10): New USP Test (SE: 1.4 – 4.1, SM: 2.7 – 2.9) Sampling Plan 2 (3 x 10): New USP Test (SE: 1.4 – 4.1, SM: 3.0 – 3.2) Sampling Plan 2 (3 x 10): New USP Test (SE: 1.0 – 3.7, SM: 3.3 – 3.5) Sampling Plan 2 (3 x 10): New USP Test (SE: 0.7 – 3.4, SM: 3.6 – 3.8) Sampling Plan 2 (3 x 20): New USP Test (SE: 2.7 – 5.4, SM: 0.3 – 0.7) Sampling Plan 2 (3 x 20): New USP Test (SE: 2.7 – 5.4, SM: 0.8 – 1.2) Sampling Plan 2 (3 x 20): New USP Test (SE: 2.6 – 5.3, SM: 1.3 – 1.7) Sampling Plan 2 (3 x 20): New USP Test (SE: 2.5 – 5.2, SM: 1.8 – 2.2) Sampling Plan 2 (3 x 20): New USP Test (SE: 2.5 – 5.2, SM: 2.3 – 2.6) Sampling Plan 2 (3 x 20): New USP Test (SE: 2.4 – 5.1, SM: 2.7 – 2.9) Sampling Plan 2 (3 x 20): New USP Test (SE: 2.4 – 5.1, SM: 3.0 – 3.2) Sampling Plan 2 (3 x 20): New USP Test (SE: 2.3 – 5.0, SM: 3.3 – 3.5) Sampling Plan 2 (3 x 20): New USP Test (SE: 2.3 – 5.0, SM: 3.6 – 3.8)
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Sampling Plan 1 (1 x 30): Current USP Test (RSD: 2.1 – 4.8%) Probability of Passing Current USP Tablet Content Uniformity Test (N = 1x30 = 30, RSD = 2.1-4.7%)
100% 95% 2.1%
90%
2.3% 2.5% 2.7%
Probability (%)
85%
2.9%
80%
3.1% 3.3%
75%
3.5%
70%
3.7% 3.9% 4.1%
65%
4.3% 4.5%
60%
4.7%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 1x30 = 30, RSD = 2.2-4.8%)
100% 95% 2.2%
90%
2.4% 2.6% 2.8% 3%
80%
3.2% 3.4%
75%
3.6%
70%
3.8% 4% 4.2%
65%
4.4% 4.6%
60%
4.8%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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Sampling Plan 1 (1 x 30): Current USP Test (RSD: 2.5 – 5.2%) Probability of Passing Current USP Capsule Content Uniformity Test (N = 1x30 = 30, RSD = 2.5-5.1%)
100% 95% 2.5%
90%
2.7% 2.9% 3.1%
Probability (%)
85%
3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 1x30 = 30, RSD = 2.6-5.2%)
100% 95% 2.6%
90%
2.8% 3% 3.2% 3.4%
80%
3.6% 3.8%
75%
4%
70%
4.2% 4.4% 4.6%
65%
4.8% 5%
60%
5.2%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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Sampling Plan 1 (1 x 30): New USP Test (RSD: 2.0 – 4.7%) Probability of Passing New USP 29 Content Uniformity Test (N = 1x30 = 30, RSD = 2.0-4.6%)
100% 95% 2%
90%
2.2% 2.4% 2.6%
Probability (%)
85%
2.8%
80%
3% 3.2%
75%
3.4%
70%
3.6% 3.8% 4%
65%
4.2% 4.4%
60%
4.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 1x30 = 30, RSD = 2.1-4.7%)
100% 95% 2.1%
90%
2.3% 2.5% 2.7% 2.9%
80%
3.1% 3.3%
75%
3.5%
70%
3.7% 3.9% 4.1%
65%
4.3% 4.5%
60%
4.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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6/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 1 (1 x 60): Current USP Test (RSD: 2.7 – 5.4%) Probability of Passing Current USP Tablet Content Uniformity Test (N = 1x60 = 60, RSD = 2.7-5.3%)
100% 95% 2.7%
90%
2.9% 3.1% 3.3%
Probability (%)
85%
3.5%
80%
3.7% 3.9%
75%
4.1%
70%
4.3% 4.5% 4.7%
65%
4.9% 5.1%
60%
5.3%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 1x60 = 60, RSD = 2.8-5.4%)
100% 95% 2.8%
90%
3% 3.2% 3.4% 3.6%
80%
3.8% 4%
75%
4.2%
70%
4.4% 4.6% 4.8%
65%
5% 5.2%
60%
5.4%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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7/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 1 (1 x 60): Current USP Test (RSD: 3.0 – 5.7%) Probability of Passing Current USP Capsule Content Uniformity Test (N = 1x60 = 60, RSD = 3.0-5.6%)
100% 95% 3%
90%
3.2% 3.4% 3.6%
Probability (%)
85%
3.8%
80%
4% 4.2%
75%
4.4%
70%
4.6% 4.8% 5%
65%
5.2% 5.4%
60%
5.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 1x60 = 60, RSD = 3.1-5.7%)
100% 95% 3.1%
90%
3.3% 3.5% 3.7% 3.9%
80%
4.1% 4.3%
75%
4.5%
70%
4.7% 4.9% 5.1%
65%
5.3% 5.5%
60%
5.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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8/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 1 (1 x 60): New USP Test (RSD: 2.7 – 5.4%) Probability of Passing New USP 29 Content Uniformity Test (N = 1x60 = 60, RSD = 2.7-5.3%)
100% 95% 2.7%
90%
2.9% 3.1% 3.3%
Probability (%)
85%
3.5%
80%
3.7% 3.9%
75%
4.1%
70%
4.3% 4.5% 4.7%
65%
4.9% 5.1%
60%
5.3%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 1x60 = 60, RSD = 2.8-5.4%)
100% 95% 2.8%
90%
3% 3.2% 3.4% 3.6%
80%
3.8% 4%
75%
4.2%
70%
4.4% 4.6% 4.8%
65%
5% 5.2%
60%
5.4%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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9/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.0 – 4.7, SM: 0.3 – 0.7) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 2.0-4.6, SM = 0.5)
100% 95% 2%
90%
2.2% 2.4% 2.6%
Probability (%)
85%
2.8%
80%
3% 3.2%
75%
3.4%
70%
3.6% 3.8% 4%
65%
4.2% 4.4%
60%
4.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 2.1-4.7, SM = 0.5)
100% 95% 2.1%
90%
2.3% 2.5% 2.7% 2.9%
80%
3.1% 3.3%
75%
3.5%
70%
3.7% 3.9% 4.1%
65%
4.3% 4.5%
60%
4.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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10/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.3 – 5.0, SM: 0.3 – 0.7) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.3-4.9, SM = 0.5)
100% 95% 2.3%
90%
2.5% 2.7% 2.9%
Probability (%)
85%
3.1%
80%
3.3% 3.5%
75%
3.7%
70%
3.9% 4.1% 4.3%
65%
4.5% 4.7%
60%
4.9%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.4-5.0, SM = 0.5)
100% 95% 2.4%
90%
2.6% 2.8% 3% 3.2%
80%
3.4% 3.6%
75%
3.8%
70%
4% 4.2% 4.4%
65%
4.6% 4.8%
60%
5%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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11/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): New USP Test (SE: 2.0 – 4.7, SM: 0.3 – 0.7) Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 2.0-4.6, SM = 0.5)
100% 95% 2%
90%
2.2% 2.4% 2.6%
Probability (%)
85%
2.8%
80%
3% 3.2%
75%
3.4%
70%
3.6% 3.8% 4%
65%
4.2% 4.4%
60%
4.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 2.1-4.7, SM = 0.5)
100% 95% 2.1%
90%
2.3% 2.5% 2.7% 2.9%
80%
3.1% 3.3%
75%
3.5%
70%
3.7% 3.9% 4.1%
65%
4.3% 4.5%
60%
4.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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12/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.9 – 4.6, SM: 0.8 – 1.2) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.9-4.5, SM = 1.0)
100% 95% 1.9%
90%
2.1% 2.3% 2.5%
Probability (%)
85%
2.7%
80%
2.9% 3.1%
75%
3.3%
70%
3.5% 3.7% 3.9%
65%
4.1% 4.3%
60%
4.5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 2.0-4.6, SM = 1.0)
100% 95% 2%
90%
2.2% 2.4% 2.6% 2.8%
80%
3% 3.2%
75%
3.4%
70%
3.6% 3.8% 4%
65%
4.2% 4.4%
60%
4.6%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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13/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.3 – 5.0, SM: 0.8 – 1.2) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.3-4.9, SM = 1.0)
100% 95% 2.3%
90%
2.5% 2.7% 2.9%
Probability (%)
85%
3.1%
80%
3.3% 3.5%
75%
3.7%
70%
3.9% 4.1% 4.3%
65%
4.5% 4.7%
60%
4.9%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.4-5.0, SM = 1.0)
100% 95% 2.4%
90%
2.6% 2.8% 3% 3.2%
80%
3.4% 3.6%
75%
3.8%
70%
4% 4.2% 4.4%
65%
4.6% 4.8%
60%
5%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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14/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): New USP Test (SE: 1.9 – 4.6, SM: 0.8 – 1.2) Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.9-4.5, SM = 1.0)
100% 95% 1.9%
90%
2.1% 2.3% 2.5%
Probability (%)
85%
2.7%
80%
2.9% 3.1%
75%
3.3%
70%
3.5% 3.7% 3.9%
65%
4.1% 4.3%
60%
4.5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 2.0-4.6, SM = 1.0)
100% 95% 2%
90%
2.2% 2.4% 2.6% 2.8%
80%
3% 3.2%
75%
3.4%
70%
3.6% 3.8% 4%
65%
4.2% 4.4%
60%
4.6%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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15/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.9 – 4.6, SM: 1.3 – 1.7) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.9-4.5, SM = 1.5)
100% 95% 1.9%
90%
2.1% 2.3% 2.5%
Probability (%)
85%
2.7%
80%
2.9% 3.1%
75%
3.3%
70%
3.5% 3.7% 3.9%
65%
4.1% 4.3%
60%
4.5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 2.0-4.6, SM = 1.5)
100% 95% 2%
90%
2.2% 2.4% 2.6% 2.8%
80%
3% 3.2%
75%
3.4%
70%
3.6% 3.8% 4%
65%
4.2% 4.4%
60%
4.6%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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16/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.3 – 5.0, SM: 1.3 – 1.7) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.3-4.9, SM = 1.5)
100% 95% 2.3%
90%
2.5% 2.7% 2.9%
Probability (%)
85%
3.1%
80%
3.3% 3.5%
75%
3.7%
70%
3.9% 4.1% 4.3%
65%
4.5% 4.7%
60%
4.9%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.4-5.0, SM = 1.5)
100% 95% 2.4%
90%
2.6% 2.8% 3% 3.2%
80%
3.4% 3.6%
75%
3.8%
70%
4% 4.2% 4.4%
65%
4.6% 4.8%
60%
5%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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17/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): New USP Test (SE: 1.9 – 4.6, SM: 1.3 – 1.7) Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.9-4.5, SM = 1.5)
100% 95% 1.9%
90%
2.1% 2.3% 2.5%
Probability (%)
85%
2.7%
80%
2.9% 3.1%
75%
3.3%
70%
3.5% 3.7% 3.9%
65%
4.1% 4.3%
60%
4.5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 2.0-4.6, SM = 1.5)
100% 95% 2%
90%
2.2% 2.4% 2.6% 2.8%
80%
3% 3.2%
75%
3.4%
70%
3.6% 3.8% 4%
65%
4.2% 4.4%
60%
4.6%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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18/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.8 – 4.5, SM: 1.8 – 2.2) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.8-4.4, SM = 2.0)
100% 95% 1.8%
90%
2% 2.2% 2.4%
Probability (%)
85%
2.6%
80%
2.8% 3%
75%
3.2%
70%
3.4% 3.6% 3.8%
65%
4% 4.2%
60%
4.4%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.9-4.5, SM = 2.0)
100% 95% 1.9%
90%
2.1% 2.3% 2.5% 2.7%
80%
2.9% 3.1%
75%
3.3%
70%
3.5% 3.7% 3.9%
65%
4.1% 4.3%
60%
4.5%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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19/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.2 – 4.9, SM: 1.8 – 2.2) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.2-4.8, SM = 2.0)
100% 95% 2.2%
90%
2.4% 2.6% 2.8%
Probability (%)
85%
3%
80%
3.2% 3.4%
75%
3.6%
70%
3.8% 4% 4.2%
65%
4.4% 4.6%
60%
4.8%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.3-4.9, SM = 2.0)
100% 95% 2.3%
90%
2.5% 2.7% 2.9% 3.1%
80%
3.3% 3.5%
75%
3.7%
70%
3.9% 4.1% 4.3%
65%
4.5% 4.7%
60%
4.9%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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20/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): New USP Test (SE: 1.7 – 4.4, SM: 1.8 – 2.2) Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.7-4.3, SM = 2.0)
100% 95% 1.7%
90%
1.9% 2.1% 2.3%
Probability (%)
85%
2.5%
80%
2.7% 2.9%
75%
3.1%
70%
3.3% 3.5% 3.7%
65%
3.9% 4.1%
60%
4.3%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.8-4.4, SM = 2.0)
100% 95% 1.8%
90%
2% 2.2% 2.4% 2.6%
80%
2.8% 3%
75%
3.2%
70%
3.4% 3.6% 3.8%
65%
4% 4.2%
60%
4.4%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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21/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.7 – 4.4, SM: 2.3 – 2.6) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.7-4.3, SM = 2.5)
100% 95% 1.7%
90%
1.9% 2.1% 2.3%
Probability (%)
85%
2.5%
80%
2.7% 2.9%
75%
3.1%
70%
3.3% 3.5% 3.7%
65%
3.9% 4.1%
60%
4.3%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.8-4.4, SM = 2.5)
100% 95% 1.8%
90%
2% 2.2% 2.4% 2.6%
80%
2.8% 3%
75%
3.2%
70%
3.4% 3.6% 3.8%
65%
4% 4.2%
60%
4.4%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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22/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.2 – 4.9, SM: 2.3 – 2.6) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.2-4.8, SM = 2.5)
100% 95% 2.2%
90%
2.4% 2.6% 2.8%
Probability (%)
85%
3%
80%
3.2% 3.4%
75%
3.6%
70%
3.8% 4% 4.2%
65%
4.4% 4.6%
60%
4.8%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.3-4.9, SM = 2.5)
100% 95% 2.3%
90%
2.5% 2.7% 2.9% 3.1%
80%
3.3% 3.5%
75%
3.7%
70%
3.9% 4.1% 4.3%
65%
4.5% 4.7%
60%
4.9%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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23/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): New USP Test (SE: 1.6 – 4.3, SM: 2.3 – 2.6) Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.6-4.2, SM = 2.5)
100% 95% 1.6%
90%
1.8% 2% 2.2%
Probability (%)
85%
2.4%
80%
2.6% 2.8%
75%
3%
70%
3.2% 3.4% 3.6%
65%
3.8% 4%
60%
4.2%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.7-4.3, SM = 2.5)
100% 95% 1.7%
90%
1.9% 2.1% 2.3% 2.5%
80%
2.7% 2.9%
75%
3.1%
70%
3.3% 3.5% 3.7%
65%
3.9% 4.1%
60%
4.3%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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24/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.6 – 4.3, SM: 2.7 – 2.9) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.6-4.2, SM = 2.8)
100% 95% 1.6%
90%
1.8% 2% 2.2%
Probability (%)
85%
2.4%
80%
2.6% 2.8%
75%
3%
70%
3.2% 3.4% 3.6%
65%
3.8% 4%
60%
4.2%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.7-4.3, SM = 2.8)
100% 95% 1.7%
90%
1.9% 2.1% 2.3% 2.5%
80%
2.7% 2.9%
75%
3.1%
70%
3.3% 3.5% 3.7%
65%
3.9% 4.1%
60%
4.3%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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25/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.1 – 4.8, SM: 2.7 – 2.9) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.1-4.7, SM = 2.8)
100% 95% 2.1%
90%
2.3% 2.5% 2.7%
Probability (%)
85%
2.9%
80%
3.1% 3.3%
75%
3.5%
70%
3.7% 3.9% 4.1%
65%
4.3% 4.5%
60%
4.7%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.2-4.8, SM = 2.8)
100% 95% 2.2%
90%
2.4% 2.6% 2.8% 3%
80%
3.2% 3.4%
75%
3.6%
70%
3.8% 4% 4.2%
65%
4.4% 4.6%
60%
4.8%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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26/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): New USP Test (SE: 1.4 – 4.1, SM: 2.7 – 2.9) Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.4-4.0, SM = 2.8)
100% 95% 1.4%
90%
1.6% 1.8% 2%
Probability (%)
85%
2.2%
80%
2.4% 2.6%
75%
2.8%
70%
3% 3.2% 3.4%
65%
3.6% 3.8%
60%
4%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.5-4.1, SM = 2.8)
100% 95% 1.5%
90%
1.7% 1.9% 2.1% 2.3%
80%
2.5% 2.7%
75%
2.9%
70%
3.1% 3.3% 3.5%
65%
3.7% 3.9%
60%
4.1%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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27/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.6 – 4.3, SM: 3.0 – 3.2) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.6-4.2, SM = 3.1)
100% 95% 1.6%
90%
1.8% 2% 2.2%
Probability (%)
85%
2.4%
80%
2.6% 2.8%
75%
3%
70%
3.2% 3.4% 3.6%
65%
3.8% 4%
60%
4.2%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.7-4.3, SM = 3.1)
100% 95% 1.7%
90%
1.9% 2.1% 2.3% 2.5%
80%
2.7% 2.9%
75%
3.1%
70%
3.3% 3.5% 3.7%
65%
3.9% 4.1%
60%
4.3%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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28/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.1 – 4.8, SM: 3.0 – 3.2) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.1-4.7, SM = 3.1)
100% 95% 2.1%
90%
2.3% 2.5% 2.7%
Probability (%)
85%
2.9%
80%
3.1% 3.3%
75%
3.5%
70%
3.7% 3.9% 4.1%
65%
4.3% 4.5%
60%
4.7%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.2-4.8, SM = 3.1)
100% 95% 2.2%
90%
2.4% 2.6% 2.8% 3%
80%
3.2% 3.4%
75%
3.6%
70%
3.8% 4% 4.2%
65%
4.4% 4.6%
60%
4.8%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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29/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): New USP Test (SE: 1.4 – 4.1, SM: 3.0 – 3.2) Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.4-4.0, SM = 3.1)
100% 95% 1.4%
90%
1.6% 1.8% 2%
Probability (%)
85%
2.2%
80%
2.4% 2.6%
75%
2.8%
70%
3% 3.2% 3.4%
65%
3.6% 3.8%
60%
4%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.5-4.1, SM = 3.1)
100% 95% 1.5%
90%
1.7% 1.9% 2.1% 2.3%
80%
2.5% 2.7%
75%
2.9%
70%
3.1% 3.3% 3.5%
65%
3.7% 3.9%
60%
4.1%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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30/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.4 – 4.1, SM: 3.3 – 3.5) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.4-4.0, SM = 3.4)
100% 95% 1.4%
90%
1.6% 1.8% 2%
Probability (%)
85%
2.2%
80%
2.4% 2.6%
75%
2.8%
70%
3% 3.2% 3.4%
65%
3.6% 3.8%
60%
4%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.5-4.1, SM = 3.4)
100% 95% 1.5%
90%
1.7% 1.9% 2.1% 2.3%
80%
2.5% 2.7%
75%
2.9%
70%
3.1% 3.3% 3.5%
65%
3.7% 3.9%
60%
4.1%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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31/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.1 – 4.8, SM: 3.3 – 3.5) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.1-4.7, SM = 3.4)
100% 95% 2.1%
90%
2.3% 2.5% 2.7%
Probability (%)
85%
2.9%
80%
3.1% 3.3%
75%
3.5%
70%
3.7% 3.9% 4.1%
65%
4.3% 4.5%
60%
4.7%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.2-4.8, SM = 3.4)
100% 95% 2.2%
90%
2.4% 2.6% 2.8% 3%
80%
3.2% 3.4%
75%
3.6%
70%
3.8% 4% 4.2%
65%
4.4% 4.6%
60%
4.8%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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32/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): New USP Test (SE: 1.0 – 3.7, SM: 3.3 – 3.5) Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.0-3.6, SM = 3.4)
100% 95% 1%
90%
1.2% 1.4% 1.6%
Probability (%)
85%
1.8%
80%
2% 2.2%
75%
2.4%
70%
2.6% 2.8% 3%
65%
3.2% 3.4%
60%
3.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.1-3.7, SM = 3.4)
100% 95% 1.1%
90%
1.3% 1.5% 1.7% 1.9%
80%
2.1% 2.3%
75%
2.5%
70%
2.7% 2.9% 3.1%
65%
3.3% 3.5%
60%
3.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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33/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.0 – 3.7, SM: 3.6 – 3.8) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.0-3.6, SM = 3.7)
100% 95% 1%
90%
1.2% 1.4% 1.6%
Probability (%)
85%
1.8%
80%
2% 2.2%
75%
2.4%
70%
2.6% 2.8% 3%
65%
3.2% 3.4%
60%
3.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.1-3.7, SM = 3.7)
100% 95% 1.1%
90%
1.3% 1.5% 1.7% 1.9%
80%
2.1% 2.3%
75%
2.5%
70%
2.7% 2.9% 3.1%
65%
3.3% 3.5%
60%
3.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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34/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.9 – 4.6, SM: 3.6 – 3.8) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 1.9-4.5, SM = 3.7)
100% 95% 1.9%
90%
2.1% 2.3% 2.5%
Probability (%)
85%
2.7%
80%
2.9% 3.1%
75%
3.3%
70%
3.5% 3.7% 3.9%
65%
4.1% 4.3%
60%
4.5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.0-4.6, SM = 3.7)
100% 95% 2%
90%
2.2% 2.4% 2.6% 2.8%
80%
3% 3.2%
75%
3.4%
70%
3.6% 3.8% 4%
65%
4.2% 4.4%
60%
4.6%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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35/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): New USP Test (SE: 0.7 – 3.4, SM: 3.6 – 3.8) Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 0.7-3.3, SM = 3.7)
100% 95% 0.7%
90%
0.9% 1.1% 1.3%
Probability (%)
85%
1.5%
80%
1.7% 1.9%
75%
2.1%
70%
2.3% 2.5% 2.7%
65%
2.9% 3.1%
60%
3.3%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 0.8-3.4, SM = 3.7)
100% 95% 0.8%
90%
1% 1.2% 1.4% 1.6%
80%
1.8% 2%
75%
2.2%
70%
2.4% 2.6% 2.8%
65%
3% 3.2%
60%
3.4%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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36/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.6 – 5.3, SM: 0.3 – 0.7) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.6-5.2, SM = 0.5)
100% 95% 2.6%
90%
2.8% 3% 3.2%
Probability (%)
85%
3.4%
80%
3.6% 3.8%
75%
4%
70%
4.2% 4.4% 4.6%
65%
4.8% 5%
60%
5.2%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.7-5.3, SM = 0.5)
100% 95% 2.7%
90%
2.9% 3.1% 3.3% 3.5%
80%
3.7% 3.9%
75%
4.1%
70%
4.3% 4.5% 4.7%
65%
4.9% 5.1%
60%
5.3%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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37/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.1 – 5.8, SM: 0.3 – 0.7) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.1-5.7, SM = 0.5)
100% 95% 3.1%
90%
3.3% 3.5% 3.7%
Probability (%)
85%
3.9%
80%
4.1% 4.3%
75%
4.5%
70%
4.7% 4.9% 5.1%
65%
5.3% 5.5%
60%
5.7%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.2-5.8, SM = 0.5)
100% 95% 3.2%
90%
3.4% 3.6% 3.8% 4%
80%
4.2% 4.4%
75%
4.6%
70%
4.8% 5% 5.2%
65%
5.4% 5.6%
60%
5.8%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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38/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): New USP Test (SE: 2.7 – 5.4, SM: 0.3 – 0.7) Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.7-5.3, SM = 0.5)
100% 95% 2.7%
90%
2.9% 3.1% 3.3%
Probability (%)
85%
3.5%
80%
3.7% 3.9%
75%
4.1%
70%
4.3% 4.5% 4.7%
65%
4.9% 5.1%
60%
5.3%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.8-5.4, SM = 0.5)
100% 95% 2.8%
90%
3% 3.2% 3.4% 3.6%
80%
3.8% 4%
75%
4.2%
70%
4.4% 4.6% 4.8%
65%
5% 5.2%
60%
5.4%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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39/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.6 – 5.3, SM: 0.8 – 1.2) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.6-5.2, SM = 1.0)
100% 95% 2.6%
90%
2.8% 3% 3.2%
Probability (%)
85%
3.4%
80%
3.6% 3.8%
75%
4%
70%
4.2% 4.4% 4.6%
65%
4.8% 5%
60%
5.2%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.7-5.3, SM = 1.0)
100% 95% 2.7%
90%
2.9% 3.1% 3.3% 3.5%
80%
3.7% 3.9%
75%
4.1%
70%
4.3% 4.5% 4.7%
65%
4.9% 5.1%
60%
5.3%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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40/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 0.8 – 1.2) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.0-5.6, SM = 1.0)
100% 95% 3%
90%
3.2% 3.4% 3.6%
Probability (%)
85%
3.8%
80%
4% 4.2%
75%
4.4%
70%
4.6% 4.8% 5%
65%
5.2% 5.4%
60%
5.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.1-5.7, SM = 1.0)
100% 95% 3.1%
90%
3.3% 3.5% 3.7% 3.9%
80%
4.1% 4.3%
75%
4.5%
70%
4.7% 4.9% 5.1%
65%
5.3% 5.5%
60%
5.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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41/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): New USP Test (SE: 2.7 – 5.4, SM: 0.8 – 1.2) Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.7-5.3, SM = 1.0)
100% 95% 2.7%
90%
2.9% 3.1% 3.3%
Probability (%)
85%
3.5%
80%
3.7% 3.9%
75%
4.1%
70%
4.3% 4.5% 4.7%
65%
4.9% 5.1%
60%
5.3%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.8-5.4, SM = 1.0)
100% 95% 2.8%
90%
3% 3.2% 3.4% 3.6%
80%
3.8% 4%
75%
4.2%
70%
4.4% 4.6% 4.8%
65%
5% 5.2%
60%
5.4%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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42/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.5 – 5.2, SM: 1.3 – 1.7) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.5-5.1, SM = 1.5)
100% 95% 2.5%
90%
2.7% 2.9% 3.1%
Probability (%)
85%
3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.6-5.2, SM = 1.5)
100% 95% 2.6%
90%
2.8% 3% 3.2% 3.4%
80%
3.6% 3.8%
75%
4%
70%
4.2% 4.4% 4.6%
65%
4.8% 5%
60%
5.2%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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43/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 1.3 – 1.7) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.0-5.6, SM = 1.5)
100% 95% 3%
90%
3.2% 3.4% 3.6%
Probability (%)
85%
3.8%
80%
4% 4.2%
75%
4.4%
70%
4.6% 4.8% 5%
65%
5.2% 5.4%
60%
5.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.1-5.7, SM = 1.5)
100% 95% 3.1%
90%
3.3% 3.5% 3.7% 3.9%
80%
4.1% 4.3%
75%
4.5%
70%
4.7% 4.9% 5.1%
65%
5.3% 5.5%
60%
5.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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44/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): New USP Test (SE: 2.6 – 5.3, SM: 1.3 – 1.7) Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.6-5.2, SM = 1.5)
100% 95% 2.6%
90%
2.8% 3% 3.2%
Probability (%)
85%
3.4%
80%
3.6% 3.8%
75%
4%
70%
4.2% 4.4% 4.6%
65%
4.8% 5%
60%
5.2%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.7-5.3, SM = 1.5)
100% 95% 2.7%
90%
2.9% 3.1% 3.3% 3.5%
80%
3.7% 3.9%
75%
4.1%
70%
4.3% 4.5% 4.7%
65%
4.9% 5.1%
60%
5.3%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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45/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.5 – 5.2, SM: 1.8 – 2.2) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.5-5.1, SM = 2.0)
100% 95% 2.5%
90%
2.7% 2.9% 3.1%
Probability (%)
85%
3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.6-5.2, SM = 2.0)
100% 95% 2.6%
90%
2.8% 3% 3.2% 3.4%
80%
3.6% 3.8%
75%
4%
70%
4.2% 4.4% 4.6%
65%
4.8% 5%
60%
5.2%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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46/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 1.8 – 2.2) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.0-5.6, SM = 2.0)
100% 95% 3%
90%
3.2% 3.4% 3.6%
Probability (%)
85%
3.8%
80%
4% 4.2%
75%
4.4%
70%
4.6% 4.8% 5%
65%
5.2% 5.4%
60%
5.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.1-5.7, SM = 2.0)
100% 95% 3.1%
90%
3.3% 3.5% 3.7% 3.9%
80%
4.1% 4.3%
75%
4.5%
70%
4.7% 4.9% 5.1%
65%
5.3% 5.5%
60%
5.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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47/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): New USP Test (SE: 2.5 – 5.2, SM: 1.8 – 2.2) Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.5-5.1, SM = 2.0)
100% 95% 2.5%
90%
2.7% 2.9% 3.1%
Probability (%)
85%
3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.6-5.2, SM = 2.0)
100% 95% 2.6%
90%
2.8% 3% 3.2% 3.4%
80%
3.6% 3.8%
75%
4%
70%
4.2% 4.4% 4.6%
65%
4.8% 5%
60%
5.2%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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48/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.5 – 5.2, SM: 2.3 – 2.6) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.5-5.1, SM = 2.5)
100% 95% 2.5%
90%
2.7% 2.9% 3.1%
Probability (%)
85%
3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC): n = 30
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.6-5.2, SM = 2.5)
100% 95% 2.6%
90%
2.8% 3% 3.2% 3.4%
80%
3.6% 3.8%
75%
4%
70%
4.2% 4.4% 4.6%
65%
4.8% 5%
60%
5.2%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC): n = 30
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49/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 2.3 – 2.6) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.0-5.6, SM = 2.5)
100% 95% 3%
90%
3.2% 3.4% 3.6%
Probability (%)
85%
3.8%
80%
4% 4.2%
75%
4.4%
70%
4.6% 4.8% 5%
65%
5.2% 5.4%
60%
5.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC): n = 30
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.1-5.7, SM = 2.5)
100% 95% 3.1%
90%
3.3% 3.5% 3.7% 3.9%
80%
4.1% 4.3%
75%
4.5%
70%
4.7% 4.9% 5.1%
65%
5.3% 5.5%
60%
5.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC): n = 30
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50/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): New USP Test (SE: 2.5 – 5.2, SM: 2.3 – 2.6) Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.5-5.1, SM = 2.5)
100% 95% 2.5%
90%
2.7% 2.9% 3.1%
Probability (%)
85%
3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC): n = 30
Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.6-5.2, SM = 2.5)
100% 95% 2.6%
90%
2.8% 3% 3.2% 3.4%
80%
3.6% 3.8%
75%
4%
70%
4.2% 4.4% 4.6%
65%
4.8% 5%
60%
5.2%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC): n = 30
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51/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.5 – 5.2, SM: 2.7 – 2.9) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.5-5.1, SM = 2.8)
100% 95% 2.5%
90%
2.7% 2.9% 3.1%
Probability (%)
85%
3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.6-5.2, SM = 2.8)
100% 95% 2.6%
90%
2.8% 3% 3.2% 3.4%
80%
3.6% 3.8%
75%
4%
70%
4.2% 4.4% 4.6%
65%
4.8% 5%
60%
5.2%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 2.7 – 2.9) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.0-5.6, SM = 2.8)
100% 95% 3%
90%
3.2% 3.4% 3.6%
Probability (%)
85%
3.8%
80%
4% 4.2%
75%
4.4%
70%
4.6% 4.8% 5%
65%
5.2% 5.4%
60%
5.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.1-5.7, SM = 2.8)
100% 95% 3.1%
90%
3.3% 3.5% 3.7% 3.9%
80%
4.1% 4.3%
75%
4.5%
70%
4.7% 4.9% 5.1%
65%
5.3% 5.5%
60%
5.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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53/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): New USP Test (SE: 2.4 – 5.1, SM: 2.7 – 2.9) Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.4-5.0, SM = 2.8)
100% 95% 2.4%
90%
2.6% 2.8% 3%
Probability (%)
85%
3.2%
80%
3.4% 3.6%
75%
3.8%
70%
4% 4.2% 4.4%
65%
4.6% 4.8%
60%
5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.5-5.1, SM = 2.8)
100% 95% 2.5%
90%
2.7% 2.9% 3.1% 3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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54/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.4 – 5.1, SM: 3.0 – 3.2) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.4-5.0, SM = 3.1)
100% 95% 2.4%
90%
2.6% 2.8% 3%
Probability (%)
85%
3.2%
80%
3.4% 3.6%
75%
3.8%
70%
4% 4.2% 4.4%
65%
4.6% 4.8%
60%
5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.5-5.1, SM = 3.1)
100% 95% 2.5%
90%
2.7% 2.9% 3.1% 3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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55/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 3.0 – 3.2) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.0-5.6, SM = 3.1)
100% 95% 3%
90%
3.2% 3.4% 3.6%
Probability (%)
85%
3.8%
80%
4% 4.2%
75%
4.4%
70%
4.6% 4.8% 5%
65%
5.2% 5.4%
60%
5.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.1-5.7, SM = 3.1)
100% 95% 3.1%
90%
3.3% 3.5% 3.7% 3.9%
80%
4.1% 4.3%
75%
4.5%
70%
4.7% 4.9% 5.1%
65%
5.3% 5.5%
60%
5.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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56/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): New USP Test (SE: 2.4 – 5.1, SM: 3.0 – 3.2) Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.4-5.0, SM = 3.1)
100% 95% 2.4%
90%
2.6% 2.8% 3%
Probability (%)
85%
3.2%
80%
3.4% 3.6%
75%
3.8%
70%
4% 4.2% 4.4%
65%
4.6% 4.8%
60%
5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.5-5.1, SM = 3.1)
100% 95% 2.5%
90%
2.7% 2.9% 3.1% 3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.4 – 5.1, SM: 3.3 – 3.5) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.4-5.0, SM = 3.4)
100% 95% 2.4%
90%
2.6% 2.8% 3%
Probability (%)
85%
3.2%
80%
3.4% 3.6%
75%
3.8%
70%
4% 4.2% 4.4%
65%
4.6% 4.8%
60%
5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.5-5.1, SM = 3.4)
100% 95% 2.5%
90%
2.7% 2.9% 3.1% 3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.9 – 5.6, SM: 3.3 – 3.5) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 2.9-5.5, SM = 3.4)
100% 95% 2.9%
90%
3.1% 3.3% 3.5%
Probability (%)
85%
3.7%
80%
3.9% 4.1%
75%
4.3%
70%
4.5% 4.7% 4.9%
65%
5.1% 5.3%
60%
5.5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.0-5.6, SM = 3.4)
100% 95% 3%
90%
3.2% 3.4% 3.6% 3.8%
80%
4% 4.2%
75%
4.4%
70%
4.6% 4.8% 5%
65%
5.2% 5.4%
60%
5.6%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): New USP Test (SE: 2.3 – 5.0, SM: 3.3 – 3.5) Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.3-4.9, SM = 3.4)
100% 95% 2.3%
90%
2.5% 2.7% 2.9%
Probability (%)
85%
3.1%
80%
3.3% 3.5%
75%
3.7%
70%
3.9% 4.1% 4.3%
65%
4.5% 4.7%
60%
4.9%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.4-5.0, SM = 3.4)
100% 95% 2.4%
90%
2.6% 2.8% 3% 3.2%
80%
3.4% 3.6%
75%
3.8%
70%
4% 4.2% 4.4%
65%
4.6% 4.8%
60%
5%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.4 – 5.1, SM: 3.6 – 3.8) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.4-5.0, SM = 3.7)
100% 95% 2.4%
90%
2.6% 2.8% 3%
Probability (%)
85%
3.2%
80%
3.4% 3.6%
75%
3.8%
70%
4% 4.2% 4.4%
65%
4.6% 4.8%
60%
5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.5-5.1, SM = 3.7)
100% 95% 2.5%
90%
2.7% 2.9% 3.1% 3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.9 – 5.6, SM: 3.6 – 3.8) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 2.9-5.5, SM = 3.7)
100% 95% 2.9%
90%
3.1% 3.3% 3.5%
Probability (%)
85%
3.7%
80%
3.9% 4.1%
75%
4.3%
70%
4.5% 4.7% 4.9%
65%
5.1% 5.3%
60%
5.5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.0-5.6, SM = 3.7)
100% 95% 3%
90%
3.2% 3.4% 3.6% 3.8%
80%
4% 4.2%
75%
4.4%
70%
4.6% 4.8% 5%
65%
5.2% 5.4%
60%
5.6%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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62/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): New USP Test (SE: 2.3 – 5.0, SM: 3.6 – 3.8) Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.3-4.9, SM = 3.7)
100% 95% 2.3%
90%
2.5% 2.7% 2.9%
Probability (%)
85%
3.1%
80%
3.3% 3.5%
75%
3.7%
70%
3.9% 4.1% 4.3%
65%
4.5% 4.7%
60%
4.9%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.4-5.0, SM = 3.7)
100% 95% 2.4%
90%
2.6% 2.8% 3% 3.2%
80%
3.4% 3.6%
75%
3.8%
70%
4% 4.2% 4.4%
65%
4.6% 4.8%
60%
5%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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Evaluation of Validation Content Uniformity Test Results Using Lower Probability Bound Distribution Charts Pramote Cholayudth
INTRODUCTION One of the widely recognized references on process validation with regard to sampling and testing plans is the US Food and Drug Administration’s Draft Guidance for Industry: Powder Blends and Finished Dosage Units—Stratified In-Process Dosage Unit Sampling and Assessment (1) that is based on the Product Quality Research Institute (PQRI)’s Recommendation Report (2). However, it is a non-binding document (i.e., the industry may use any alternative approaches even after it becomes the official guidance). Another well-known relevant reference is the PDA Technical Report No. 25: Blend Uniformity Analysis: Validation and In-Process Testing (3). The sampling, testing, and corresponding acceptance criteria limits in validation study will follow these two statistics-based documents. The validation test results with respect to critical quality attributes (CQAs) require to be statistically evaluated (e.g., estimating confidence limits as appropriate, demonstrating the high probability of passing the tests, etc.). According to Torbeck (4), “… If statistical procedures were given in the USP, companies would have little incentive to develop better procedures.” His comment is now reconfirmed. The industry may not have
[
For more Author
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a good approach like J.S. Bergum’s method if the United States Pharmacopeia (USP) provided some kind of statistical procedures. Bergum is one of the leading professionals who suggested the use of the new statistical procedures. His methods (5, 6) introduced both how to establish the validation acceptance criteria and how to evaluate the validation test results. In protocol development, all the validation practitioners may follow some recognized documents including Bergum’s in establishing the acceptance criteria limits. However some of them may not be confident in using statistical tools for evaluation of the test results, especially for the multiple stage tests (e.g., content uniformity and dissolution). To provide an alternative to such a statistical evaluation, this article introduces an approach to using lower probability bound distribution charts, constructed according to Bergum’s methods, for evaluation of content uniformity test results.
USP TEST ACCEPTANCE CRITERIA The two USP content uniformity tests may be summarized in Tables I and II.
ABOUT THE AUTHOR Pramote Cholayudth is a validation consultant to Biolab in Thailand and executive director of Valitech, a wellestablished GMP and validation service firm to the pharmaceutical industry. He is a guest speaker on process validation to the industry organized by local FDA. He can be contacted by e-mail at [email protected].
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Table I: Current USP uniformity of dosage units: Test acceptance criteria. USP Criteria Stage 1: Assay 10 units. Pass if the following criteria are met.
USP Criteria Stage 2: Assay 20 additional units. Pass if, for all 30 units, the following criteria are met.
1) Relative standard deviation (RSD) is not more than 7.8% 1) Relative standard deviation (RSD) is not more (n = 30) than 6.0% (n = 10) 2) Not more than c unit(s) is outside 85 – 115% label 2) Not more than c unit(s) is outside 85 – 115% label claim (LC) and no unit is outside 75 – 125% LC where c = 1 for claim (LC) and no unit is outside 75 – 125% LC tablet and 3 for capsule where c = 0 for tablet and 1 for capsule
Table II: New USP uniformity of dosage units: Test acceptance criteria. USP Criteria Stage 1: Assay 10 units. Pass if the following criteria are met.
USP Criteria Stage 2: Assay 20 additional units. Pass if, for all 30 units, the following criteria are met.
1.
1. 2. Xmin > 0.75M and Xmax < 1.25M
Where M = reference value, s = standard deviation, 5 content uniformity data mean, Xmin 5 minimum and Xmax 5 maximum (individual values) Acceptance Value (AV) = 1 ks < L1, k = 2.4 (n 5 10) and 2.0 (n = 30), Xmin > (1 2 L2* 0.01)M, Xmax < (1 1 L2*0.01)M If not specified in individual monographs, L1 5 15 and L2 5 25
Table III: New USP uniformity of dosage units: Reference value criteria. Case Target (T) < 101.5 % of label claim (% LC)
Subcase 98.5 <
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< 98.5 > 101.5
101.5
98.5 2
1 ks
2 101.5 1 ks ks
< 98.5
98.5
>T
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98.5
98.5 < Target (T) > 101.5 % LC
M
98.5 2
1 ks
2 T 1 ks
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To help understand the new USP test acceptance criteria, a scenario for calculation of acceptance value (AV) is introduced: In a new USP content uniformity testing, the stage 1 test results (n = 10) are mean = 101.2 % of label claim (LC) and standard deviation (SD) = 4.15 % LC. The manufacturing target is 102.5 % LC. The acceptance value is (101.2-101.2) + 2.4x4.15 = 9.96 (< 15), so the AV limit is met.
PROBABILITY OF PASSING THE CURRENT CONTENT UNIFORMITY TEST According to Bergum’s method described in “Use of the Bergum Method and MS Excel to Determine the Probability of Passing the USP Content Uniformity Test” (7), the probability formulae are illustrated in
Table IV. The formulae in Tables IV, XIV, and XV may be copied to construct the Microsoft Excel file for computing the probability. However, note that the sample is taken in accordance with sampling plan 1 (one unit from each of 30 locations).
PROBABILITY OF PASSING THE NEW CONTENT UNIFORMITY TEST The article “Using Bergum’s New Method and MS Excel to Determine the Probability of Passing the New ICH USP 29 Content Uniformity Test” (8), has the formulae as illustrated in Table V. The readers may copy the formulae in Tables V, VI, and VII to construct the Microsoft Excel file. Also note that the sample is taken in accordance with sampling plan 1.
Table IV: MS Excel formula sheet1: Current USP test. Excel Formula Sheet1 A
B
C
D
E
F
1
Confidence Level (%)
95
Overall Bound Results
2
Sample Size (n)
30
3
Sample Mean (% LC)
98.00
LB Prob
96.50%
LB Prob
99.96%
4
Sample RSD (%)
3.50
Prob1
99.90%
Prob1
100.00%
5
UB: Mean (% LC)
99.93
Prob2
96.50%
Prob2
99.96%
6
LB: Mean (% LC)
96.07
7
UB: SD (% LC)
4.74
Tablet
Capsule
Prob at UB: Mean
8
Part 1/1
89.08%
Part 2/1
100.00%
Prob at LB: Mean
9 10
Part 1/2
84.63%
11
Part 2/2
99.96%
UB: Upper Bound, LB: Lower Bound, UB & LB formulae are as below: B5 =B3+B7*NORMSINV(1-(1-(B1/100)^0.5)/2)/B2^0.5 B6 =B3-B7*NORMSINV(1-(1-(B1/100)^0.5)/2)/B2^0.5 B7 =B4*(B3/100)*((B2-1)/(CHIINV((B1/100)^0.5,B2-1)))^0.5 The cells B1 – B4 are entered with sample data. The numerical results in the other cells, including those in D3 and F3, are generated using the formulae in Tables XIV and XV. The Excel file (as a combination of tables IV, XIV, and XV) can be downloaded from www.pharmtech.com – search “Pramote”.
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Table V: Microsoft Excel formula sheet1: New USP test. Excel Formula Sheet1 C
D
UB: SD
4.74
Formula Examples
A
B
1
UB: Mean
99.93
2
Stage 1 (n = 10)
3
I1
63.19%
I1
91.62%
See formulae below (B3 & D3)
4
I2
12.93%
I2
3.52%
B4 =Sheet2!B36, D4 =Sheet2!D36
5
I3
14.73%
I3
4.86%
B5 =Sheet2!C36, D5 =Sheet2!E36
6
P(S1)
90.85%
P(S2)
99.99%
B6 =SUM(B3:B5), D6 (See below)
7
Probability
8
LB: Mean
9
Stage 1 (n = 10)
10
I1
4.81%
I1
0.24%
B10, D10: Follow formulae for B3 & D3
11
I2
0.01%
I2
0.00%
B11 =Sheet3!B36, D11 =Sheet3!D36
12
I3
64.67%
I3
97.74%
B12 =Sheet3!C36, D12 =Sheet3!E36
13
P(S1)
69.50%
P(S2)
97.90%
B13 =SUM(B10:B12), D13 (See below)
14
Probability
15
Lbound Probability
B1 =C22, D1 =C24
Stage 2 (n = 30)
C7 =MAX(B6,D6)
99.99% 96.07
UB: SD
—
4.74
B8 =C23, D8 =C24
Stage 2 (n = 30)
16
—
97.90%
C14 =MAX(B13,D13)
97.90%
C15 =MIN(C7,C14)
Sample Data
C22 =C20+C24*NORMSINV(1-(10.95^0.5)/2)/C19^0.5
17
Target
100
18
Confidence Level (%)
95
19
Sample Size (n)
30
20
Sample Mean (% LC)
98.00
21
Sample RSD (%)
3.60
C24 =(C20*C21/100)*((C19-1)/(CHIINV(0.95^0.5,C19-1)))^0.5
22
Upper Bound: Mean
99.93
Linked to B1 & Sheet2!B2
23
Lower Bound: Mean
96.07
Linked to B8 & Sheet3!B2
24
Upper Bound: SD
4.74
Linked to D1,D8,Sheet2!C2,&Sheet3!C2
C23 =C20-C24*NORMSINV(1-(10.95^0.5)/2)/C19^0.5
B3 =(NORMSDIST((10^0.5)*(100-B1)/D1)-NORMSDIST((10^0.5)*(98.5-B1)/D1))*(1-CHIDIST((10-1)*(15/(2.4*D1))^2,10-1)) = 63.19% (For B10, replace B1 with B8 and D1 with D8) D3 =(NORMSDIST((30^0.5)*(100-B1)/D1)-NORMSDIST((30^0.5)*(98.5-B1)/D1))*(1-CHIDIST((30-1)*(15/(2*D1))^2,30-1)) = 91.62% (For D10, replace B1 with B8 and D1 with D8) D6 =MAX(SUM(D3:D5)+((NORMSDIST((123.125-B1)/D1)-NORMSDIST((IF(C17<=101.5,101.5,C17)-24.625-B1)/D1))^30)-1,0) D13 =MAX(SUM(D10:D12)+((NORMSDIST((123.125-B8)/D8)-NORMSDIST((IF(C17<=101.5,101.5,C17)-24.625-B8)/D8))^30)-1,0) The cells C17 – C21 are entered with sample data information. The numerical results in the other cells, including the probability and LB results in C7, C14, and C15, are generated by the program.
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Table VI: MS Excel formula sheet2: New USP test. Excel Formula Sheet2 A
B
C
1
Target
UB: Mean
2
100
99.93
3
—
4
—
5
i
I2
I3
I2
I3
6
1
5.85%
0.00%
2.67%
0.00%
7
2
3.58%
0.00%
0.70%
0.00%
8
3
1.95%
0.00%
0.13%
0.00%
9
4
0.94%
0.00%
0.02%
0.00%
5
0.40%
0.00%
0.00%
0.00%
... ➔ ...%
... ➔ ...%
... ➔ ...%
... ➔ ...%
10 11 ➔ 30
6 ➔ 25
D
E
UB: SD
h
4.74
0.5
i 1 ➔ 30
Stage 1
Formula Examples
Stage 2
10
30
31
26
0.00%
0.49%
0.00%
0.00%
32
27
0.00%
1.13%
0.00%
0.03%
33
28
0.00%
2.28%
0.00%
0.21%
34
29
0.00%
4.08%
0.00%
1.02%
35
30
0.00%
6.47%
0.00%
3.59%
36
Sum
12.93%
14.73%
3.52%
4.86%
B6 =(NORMSDIST((B4^0.5)*((101.5+A6*D2)B2)/C2)-NORMSDIST((B4^0.5)*((101.5+(A61)*D2)-B2)/C2))*(1-CHIDIST((B4-1)*(15-(A60.5)*D2)^2/(2.4*C2)^2,B4-1)) = 5.85% B35 =(NORMSDIST((B4^0.5)*((101.5+A35*D2)B2)/C2)-NORMSDIST((B4^0.5)*((101.5+(A351)*D2)-B2)/C2))*(1-CHIDIST((B4-1)*(15-(A350.5)*D2)^2/(2.4*C2)^2,B4-1)) = 0.00% B36 =SUM(B6:B35) = 12.93%
The number of intervals (i) 30 with interval width (h) 0.5 is selected to ensure that the integration result, especially when using the higher sigma values, is valid. The stage 2 formula is similar except for n = 30 (B4 ➔ D4) and k = 2.0 (2.4 ➔ 2). The Target (also Mean and Sigma) value is linked from Sheet1 e.g. A2 =Sheet1!B2. And I2 (B36 & D36) and I3 (C36 & E36) are linked to Sheet1 e.g., B4 (of Sheet1) =Sheet2!B36
When sample data (n = 30) associated with sample mean: 98% LC and sample RSD: 3.6% are plotted, the lower probability bound distributions can be constructed and illustrated in Figures 1 and 2. In these figures, one can imagine how a sample data comprising a mean and relative standard deviation (RSD) values will influence the probability of passing a content uniformity test. Furthermore, the way in which a larger sample size influences the distribution patterns is demonstrated in Figure 3.
JUSTIFICATION OF USING THE PROBABILITY CHARTS Validation content uniformity test results must be evaluated for probability of passing the test. The evaluation employs Bergum’s methods by using statistical programs like SAS or Microsoft Excel. To provide a practical tool as an alternative to such complicated methods, the distribution curves for lower probability bounds constructed in a high precision scale are introduced so that validation practitioners can use them to determine the probability instead of using the programs. However one must realize that the use of Excel for validation work requires validation of the spreadsheet itself (e.g., Tables IV, V, VI, and VII).
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Table VII: MS Excel Formula Sheet3: New USP Test. Excel Formula Sheet3 A
B
C
1
Target
LB: Mean
2
100
96.07
3
—
4
—
5
i
I2
I3
I2
I3
6
1
0.01%
0.00%
0.00%
0.00%
7
2
0.00%
0.00%
0.00%
0.00%
8
3
0.00%
0.00%
0.00%
0.00%
9
4
0.00%
0.00%
0.00%
0.00%
10
E
UB: SD
h
4.74
0.5
i 1 ➔ 30
Stage 1
Formula Examples
Stage 2
10
30
0.00%
0.00%
0.00%
0.00%
6 ➔ 25
... ➔ ...%
... ➔ ...%
... ➔ ...%
... ➔ ...%
31
26
0.00%
9.80%
0.00%
22.13%
32
27
0.00%
9.54%
0.00%
16.74%
33
28
0.00%
8.21%
0.00%
9.13%
34
29
0.00%
6.25%
0.00%
3.59%
35
30
0.00%
4.22%
0.00%
1.02%
36
Sum
0.01%
64.67%
0.00%
97.74%
11 ➔ 30
5
D
B6 =(NORMSDIST((B4^0.5)*((101.5+A6*D2)B2)/C2)-NORMSDIST((B4^0.5)*((101.5+(A61)*D2)-B2)/C2))*(1-CHIDIST((B4-1)*(15-(A60.5)*D2)^2/(2.4*C2)^2,B4-1)) = 0.01% B35 =(NORMSDIST((B4^0.5)*((101.5+A35*D2)B2)/C2)-NORMSDIST((B4^0.5)*((101.5+(A351)*D2)-B2)/C2))*(1-CHIDIST((B4-1)*(15-(A350.5)*D2)^2/(2.4*C2)^2,B4-1)) = 0.00% B36 =SUM(B6:B35) = 0.01%
The Target value (also Mean and Sigma) is linked from Sheet1 e.g., A2 =Sheet1!B2. And I2 (B36 & D36) and I3 (C36 & E36) are linked to Sheet1 e.g., B11 (of Sheet1) =Sheet3!B36
Figure 1: Operating Operating Characteristic (OC) Curves for USP Characteristic (OC) Curves for Content. USP Content uniformity tests (n
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Figure 2: Distribution Curves for Probability of Passing USP Content Uniformity Test (n=30).
Figure 3: Distribution Curves for Probability of Passing USP Content Uniformity Test (n = 70).
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tablet product tested using the current USP content uniformity test with sample mean = 100.15% LC and RSD = 3.9%, is performed by determining on Figure 4 the intersection of the curves for mean = 100.2 (rounded up) and RSD = 3.9. The point will indicate the lower probability bound of approximately 97%. The probability generated using the Excel program is 97.46%. The determined value deviates slightly from the computed one.
To justify the use of probability charts is to justify such deviations, so analysis of the deviation data in Tables VIII, IX, and X is carried out. Each numerical value of mean and RSD is intended to provide the second decimal digits with 4, 5, or 6 (e.g., 97.04, 4.25, 97.06) so that when the numbers are rounded up, the maximized deviation in the probability determination result is challenged. The results are satisfactory since most of the deviations are close to or equal to the calculated results except for those data sets with means greater than the target (> 100% LC) and RSDs with the second decimals with 4, 5, or 6 where the maximum biases (deviation) will occur. In the worst case, the maximum deviation is 5.3% (Table IX) or 4.6% (Table X). Therefore, the use of these types of probability charts should be justified.
Figure 4: Determining Probability Using the Probability Charts (n = 30).
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Table VIII: Comparison of Excel and Determination Results, Current CU Test (n=30). Tablet
Capsule
Mean (% LC)
RSD (%)
97.00
4.20
68.57
69
0.00
96.70
97
0.00
97.04
4.24
67.08
69
1.49
96.26
97
0.44
97.05
4.25
66.70
65
1.92
96.14
95
0.66
97.06
4.26
66.32
65
1.54
96.01
95
0.53
97.10
4.30
64.78
65
0.00
95.48
95
0.00
102.90
4.20
58.04
58
0.00
93.95
94
0.00
102.94
4.24
55.09
58
2.95
92.84
94
1.11
102.95
4.25
54.35
51
3.70
92.54
91
1.62
102.96
4.26
53.61
51
2.96
92.24
91
1.32
103.00
4.30
50.65
51
0.00
90.92
91
0.00
Prob Excel (%) Prob Deter. (%) Deviation (%) Prob Excel (%) Prob Deter. (%) Deviation (%)
Table IX: Comparison of Excel and Determination Results, New CU Test (n = 30). Mean (% LC)
RSD (%)
Prob Prob Deviation Excel (%) Deter. (%) (%)
Mean (% LC)
RSD (%)
Prob Excel (%)
Prob Deter. (%)
Deviation (%)
97.00
3.90
79.19
79
0.00
102.90
3.90
65.12
65
0.00
97.04
3.94
77.32
79
1.87
102.94
3.94
60.98
65
4.14
97.05
3.95
76.85
74
2.45
102.95
3.95
59.94
55
5.31
97.06
3.96
76.36
74
1.96
102.96
3.96
58.88
55
4.25
97.10
4.00
74.40
74
0.00
103.00
4.00
54.63
55
0.00
Prob Deter. (%)
Deviation (%)
Table X: Comparison of Excel and Determination Results, New CU Test (n = 60). Mean (% LC)
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Prob Prob Deviation Excel (%) Deter. (%) (%)
Mean (% LC)
RSD (%)
Prob Excel (%)
97.00
4.60
73.71
74
0.00
102.90
4.60
59.04
59
0.00
97.04
4.64
72.10
74
1.61
102.94
4.64
55.38
59
3.66
97.05
4.65
71.70
70
2.06
102.95
4.65
54.46
50
4.63
97.06
4.66
71.29
70
1.65
102.96
4.66
53.53
50
3.70
97.10
4.70
69.64
70
0.00
103.00
4.70
49.83
50
0.00
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SAMPLING PLAN 1 AND 2 To take a validation sample of the dosage units (e.g., tablets or capsules) for content uniformity testing, stratified sampling plan 1 or 2 is followed. Sampling plan 1 will involve taking one unit from each of L locations (e.g., 30 locations). Sampling plan 2 involves taking two or more units from each of L locations throughout the tablet compression or encapsulation cycle. In multiple stage tests (including content uniformity), it is unavoidable to employ sampling plan 2 since the overall (stages 1 and 2) test number of dosage units per location is more than 1 unit. Examples for sampling plan 2, during compression or encapsulation cycle, are illustrated in Table XI.
RECOMMENDATION FOR USE OF PROBABILITY CHARTS For sampling plan 1 (one unit from each of L locations), the validation practitioners can simply use the probability charts by using the sample mean and RSD. For sampling plan 2 (two or more units from each of L locations), a number of different charts are provided. The data are required to be computed for within-location standard deviation (SE) and between-location standard deviation (SM) prior to determination of the probability on the charts. Examples for computing these statistics (SE and SM) and determining the probability using sampling plan 2 data are demonstrated in Table XII and Figure 5, respectively. Table XII is provided with content uniformity data in cells B3:K5 and related calculation formulae (10).
Table XI: Sampling Plans 1 and 2 with Examples for Plan 2. Location # (of 20 Locations, L = 20) Sampling/Testing Plans
1
2
3
4
5
6 ➔ 19
20
Sampling Plan 1 (One Unit from Each Location) Sampling plan: 1x20
1
1
1
1
1
1➔1
1
Test plan: 1x20
1
1
1
1
1
1➔1
1
Take 1 unit from each of 20 locations. Test each unit in order. Sampling Plan 2 (More than One Unit, e.g., 7 Units, from Each Location) Sampling plan: 7x20
7
7
7
7
7➔7
7
7
Take 7 units from each of 20 locations throughout the operation cycle and keep each location sample in separate container. Stage 1 test plan: 3x20
3
3
3
3
3➔3
3
3
Test 3 units of each location in order, the test results for 3x20 units require to meet stage 1’s acceptance criteria. If failed, proceed to stage 2. Stage 2 test plan: 4x20
4
4
4
4
4➔4
4
4
Test 4 remaining units of each location in order, the overall test results for 7x20 units should meet stage 2’s acceptance criteria. Examples for Stratified Sampling Plan 2: Compression/Encapsulation Cycle * Tests Content Uniformity
Testing Plans (nxL)
Sampling Plans (nxL) 7 units x 20 locations
Stage1: 3 units x 20 locations Stage2: 4 units x 20 locations
Dissolution
5 units x 20 locations
Stage1: 2 units x 20 locations Stage2: 3 units x 20 locations Stage1: 1 unit x 20 locations
Degradents
3 units x 20 locations Stage2: 2 units x 20 locations
* Modified from Reference (9), n: sample size at each location, L: number of locations
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Table XII: Evaluation of Data from Sampling Plan 2 (N = nxL = 3x10). Excel Formula Sheet A 1 2
B
C
D
E
F
G
H
I
J
K
Stratified Sampling Location # (Sampling Plan 2: 3 Units x 10 Locations) Unit # 1
2
3
4
5
6
7
8
9
10
3
1
95.01
93.91
99.37
97.97
94.93
93.83
101.31
98.74
97.87
106.44
4
2
100.93
99.11
103.93
105.8
98.52
105.85
96.48
97.53
103.71
99.18
5
3
102.27
98.96
99.83
97.64
100.27
98.68
97.46
95.83
98.23
96.14
6
SQD
29.85
17.52
12.61
42.67
14.82
73.14
13.04
4.27
21.42
56.01
7
Average (% LC)
99.19*
RSD (%)
3.43
8
Degree of freedom (between-location) (L-1)
9
9
Degree of freedom (within-location) {(n-1)L}
20
10
Total square deviation
335.56
11
Square deviation (within-location)
285.35
12
Square deviation (between-location)
50.21
13
Standard deviation (within-location) (SE)
3.78*
14
Standard deviation (between-location) (SM)
2.36*
15
Note: SQD: Square Deviation
-
N (nxL)
30
C7 =AVERAGE(B3:K5) G7 =STDEV(B3:K5)/C7, K7 =3*10 B6 = DEVSQ(B3:B5) C6,…,K6 – same as B6 F8 =10-1, F9 =(3-1)*10 F10 =DEVSQ(B3:K5), F11 =SUM(B6:K6) F12 =F10-F11, F13 =(F11/F9)^0.5 F14 =(F12/F8)^0.5
16 Probability of Passing the USP CU Test
Calculated**
Determined
17 Probability (Current Tablet CU Test)
91.17%
90%
18 Probability (Current Capsule CU Test)
99.25%
99%
19 Probability (New CU Test)
91.31%
90%
20 *These data are used for determination of the probability in Figure 5 where rounded numbers are used 21 i.e., 99.19 ➔ 99.2 (C7), 3.78 ➔ 3.8 (F13) & 2.36 ➔ 2.4 (F14). 22 **Calculated (in Tables IV & V ) from the upper & lower bounds estimated using ANOVA (11) 23 SE = Square Root of Mean Square Error, SM = Standard Deviation of Location Means
Upon completing a trial using an Excel formula sheet (using worst cases of numerical values), the deviation was found to be about 6% at maximum because of poor processes, i.e., the mean deviated from the target value with high variability (within-location and between-location), resulting in low probability results. Table XIII provides an example of the worst cases and probability results data.
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CONCLUSION The concept of probability charts will help validation practitioners visualize the integrated views of the lower probability bound distributions and understand the effect of sample mean location and variability (e.g., RSD, SE, and SM) on the probability of passing the USP content uniformity test. Acceptability of the probability charts is subject to the chart accuracy. The charts with accuracy better than those provided in Appendix 2 of this article can be developed, but the consequence ivthome.com
P R A M O T E C H O L AY U D T H
Table XIII: Comparison of Excel and Determination Results (n = 30). Comparison of Excel and Determination Results Current CU Test: Tablets
New CU Test
Mean (% LC)
SE
96.54
3.65
2.65
61.44
57
4.44
48.79
43
5.79
97.54
3.75
2.75
72.00
68
4.00
62.70
57
5.70
98.54
3.85
2.85
79.72
77
2.72
74.26
70
4.26
101.55
3.75
2.75
84.07
81
3.07
79.80
75
4.80
102.55
3.65
2.65
76.73
73
3.73
69.38
64
5.38
103.55
3.55
2.55
66.54
62
4.54
56.10
50
6.10*
SM
Prob Exc Prob Det (%) (%)
Dev (%)
Prob Exc (%) Prob Det (%)
Dev (%)
SE = Square Root of Mean Square Error, SM = Standard Deviation of Location Means, * Maximum
Figure 5: Determining Probability Using Sampling Plan 2 Data (n = 30).
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P R A M O T E C H O L AY U D T H
are that a lot of charts will have to be generated, since one chart may be broken down into two or three charts, resulting in complication of their use. Justification of the accuracy (i.e., deviation) on practical basis, as described earlier, should be acceptable. Since the worst case probability results (low results at 50 to 60% with deviation of up to 5 or 6%) will occur only to inadequately controlled and/or developed processes. The adequately developed processes with proper in-process control will not fall into this case (i.e., the deviation will be much less than 5%).
9. Pluta, P., “Keep in Step with Confidence; Keep in Step through Benchmarking” Journal of Validation Technology, Volume 12, No. 1, November 2005. 10. Cholayudth, P., “Application of Probability of Passing Multiple Stage Tests in Benchmarking and Validation of Processes” Journal of Validation Technology, Volume 13, No. 4, August 2007. 11. Chow, S.C. and Liu, Statistical Design and Analysis in Pharmaceutical Science: Validation, Process Controls, Practical and Clinical Applications, 3rd ed. New York: Marcel Dekker, Inc. JVT
REFERENCES
ARTICLE ACRONYM LISTING
1. FDA Center for Drug Evaluation and Research (CDER), Draft Guidance for Industry: Powder Blends and Finished Dosage Units—Stratified In-Process Dosage Unit Sampling and Assessment, Rockville, MD , October 2003. 2. Product Quality Research Institute (PQRI) Blend Uniformity Working Group (BUWG), “The Use of Stratified Sampling of Blend and Dosage Units to Demonstrate Adequacy of Mix for Powder Blends,”Final Report on Blend Uniformity Recommendations, December 20, 2002, www.pqri.org. 3. Parenteral Drug Association, “Blend Uniformity Analysis: Validation and In-Process Testing,” PDA Technical Report No. 25,1997. 4. Torbeck, L. D., “In Defense of USP Singlet Testing,” Pharmaceutical Technology, Volume 29, Number 2, February 2005, www.pharmtech.com. 5. J. S. Bergum, “Constructing Acceptance Limits for Multiple Stage Tests,” Drug Development and Industrial Pharmacy, 16 (14), Marcel Dekker, Inc, 1990, pp. 2153-2166. 6. J. S. Bergum and H. Li, “Acceptance Limits for the New ICH USP 29 Content-Uniformity Test,” Pharmaceutical Technology, October 2007, Vol. 31, No. 10, www.pharmtech.com. 7. Cholayudth, P., “Use of the Bergum Method and MS Excel to Determine the Probability of Passing the USP Content Uniformity Test,” Pharmaceutical Technology, Volume 28, Number 9, September 2004, www.pharmtech.com. 8. Cholayudth, P., “Using Bergum’s New Method and MS Excel to Determine the Probability of Passing the New ICH USP 29 Content Uniformity Test” Journal of Validation Technology, Volume 14, No. 2, February 2008.
AV CQAs FDA ICH LB LC MS OC PDA PQRI RSD SD SE Sigma SM UB USP
Acceptance Value Critical Quality Attributes Food and Drug Administration International Conference on Harmonization Lower Bound Label Claim Microsoft Operating Characteristic Parenteral Drug Association Product Quality Research Institute Relative Standard Deviation Standard Deviation (for a Sample) Square Root of Mean Square Error Population Standard Deviation Standard Deviation of Location Means Upper Bound United States Pharmacopeia
ACKNOWLEDGMENT This paper is intended to support James Bergum’s methods with regard to probability of passing the current and new USP Content Uniformity tests. Although the Microsoft Excel programs were developed from his SAS programs by the author (7, 8), a more practical approach to use the distribution curves for lower probability bounds in place of the Excel programs is introduced. Finally, the author is very grateful to the reviewers of this paper for their helpful comments especially regarding the OC curves.
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APPENDIX 1 EXCEL FORMULAE
Table XIV: Tablet formulae: Current USP test. Tablet formulae are as below: D3 =MIN(D4,D5) D4 =MAX((FDIST(10/((0.06^2)*(1+10*(B5/B7)^2)),(1+10*(B5/B7)^2)^2/(1+2*10*(B5/B7)^2),10-1))+ ((NORMSDIST((115-B5)/B7)-NORMSDIST((85-B5)/B7))^10)1,(FDIST(30/((0.078^2)*(1+30*(B5/B7)^2)),(1+30*(B5/B7)^2)^2/(1+2*30*(B5/B7)^2),30-1))+((NORMSDIST((115-B5)/B7)NORMSDIST((85-B5)/B7))^30+COMBIN(30,1)*((NORMSDIST((115-B5)/B7)-NORMSDIST((85-B5)/B7))^29)*(((NORMSDIST((85-B5)/B7)-NORMSDIST((75-B5)/B7))+(NORMSDIST((125-B5)/B7)-NORMSDIST((115-B5)/B7)))^1))-1,0) D5 =MAX((FDIST(10/((0.06^2)*(1+10*(B6/B7)^2)),(1+10*(B6/B7)^2)^2/(1+2*10*(B6/B7)^2),10-1))+((NORMSDIST((115B6)/B7)-NORMSDIST((85-B6)/B7))^10)1,(FDIST(30/((0.078^2)*(1+30*(B6/B7)^2)),(1+30*(B6/B7)^2)^2/(1+2*30*(B6/B7)^2),30-1))+((NORMSDIST((115-B6)/B7)NORMSDIST((85-B6)/B7))^30+COMBIN(30,1)*((NORMSDIST((115-B6)/B7)-NORMSDIST((85-B6)/B7))^29)*(((NORMSDI ST((85-B6)/B7)-NORMSDIST((75-B6)/B7))+(NORMSDIST((125-B6)/B7)-NORMSDIST((115-B6)/B7)))^1))-1,0)
Table XV: Capsule formulae: Current USP test. Capsule formulae are as below: F3 =MIN(F4,F5), F4 =MAX(F7,F8,0), F5 =MAX(F10,F11,0) F7 =(FDIST(10/((0.06^2)*(1+10*(B5/B7)^2)),(1+10*(B5/B7)^2)^2/(1+2*10*(B5/B7)^2),10-1))+((NORMSDIST((115B5)/B7)-NORMSDIST((85-B5)/B7))^10+COMBIN(10,1)*((NORMSDIST((115-B5)/B7)-NORMSDIST((85B5)/B7))^9)*(((NORMSDIST((B5-75)/B7)-NORMSDIST((B5-85)/B7))+(NORMSDIST((125-B5)/B7)-NORMSDIST((115B5)/B7)))^1))-1 F8 =(FDIST(30/((0.078^2)*(1+30*(B5/B7)^2)),(1+30*(B5/B7)^2)^2/(1+2*30*(B5/B7)^2),30-1))+((NORMSDIST((115B5)/B7)-NORMSDIST((85-B5)/B7))^30+COMBIN(30,1)*((NORMSDIST((115-B5)/B7)-NORMSDIST((85B5)/B7))^29)*(((NORMSDIST((85-B5)/B7)-NORMSDIST((75-B5)/B7))+(NORMSDIST((125-B5)/B7)-NORMSDIST((115B5)/B7)))^1)+COMBIN(30,2)*((NORMSDIST((115-B5)/B7)-NORMSDIST((85-B5)/B7))^28)*(((NORMSDIST((85-B5)/B7)-N ORMSDIST((75-B5)/B7))+(NORMSDIST((125-B5)/B7)-NORMSDIST((115-B5)/B7)))^2)+COMBIN(30,3)*((NORMSDIST((115-B5)/B7)-NORMSDIST((85-B5)/B7))^27)*(((NORMSDIST((85-B5)/B7)-NORMSDIST((75-B5)/B7))+(NORMSDIST((125-B5)/B7)-NORMSDIST((115-B5)/B7)))^3))-1 F10 =(FDIST(10/((0.06^2)*(1+10*(B6/B7)^2)),(1+10*(B6/B7)^2)^2/(1+2*10*(B6/B7)^2),10-1))+((NORMSDIST((115B6)/B7)-NORMSDIST((85-B6)/B7))^10+COMBIN(10,1)*((NORMSDIST((115-B6)/B7)-NORMSDIST((85B6)/B7))^9)*(((NORMSDIST((B6-75)/B7)-NORMSDIST((B6-85)/B7))+(NORMSDIST((125-B6)/B7)-NORMSDIST((115B6)/B7)))^1))-1 F11 =(FDIST(30/((0.078^2)*(1+30*(B6/B7)^2)),(1+30*(B6/B7)^2)^2/(1+2*30*(B6/B7)^2),30-1))+((NORMSDIST((115B6)/B7)-NORMSDIST((85-B6)/B7))^30+COMBIN(30,1)*((NORMSDIST((115-B6)/B7)-NORMSDIST((85B6)/B7))^29)*(((NORMSDIST((85-B6)/B7)-NORMSDIST((75-B6)/B7))+(NORMSDIST((125-B6)/B7)-NORMSDIST((115B6)/B7)))^1)+COMBIN(30,2)*((NORMSDIST((115-B6)/B7)-NORMSDIST((85-B6)/B7))^28)*(((NORMSDIST((85-B6)/B7)-N ORMSDIST((75-B6)/B7))+(NORMSDIST((125-B6)/B7)-NORMSDIST((115-B6)/B7)))^2)+COMBIN(30,3)*((NORMSDIST((115-B6)/B7)-NORMSDIST((85-B6)/B7))^27)*(((NORMSDIST((85-B6)/B7)-NORMSDIST((75-B6)/B7))+(NORMSDIST((125-B6)/B7)-NORMSDIST((115-B6)/B7)))^3))-1
APPENDIX 2 PROBABILITY CHARTS Appendix 2 is available for download at http://www.ivthome.com/jvtspring. Probability charts provided in Appendix 2 are presented in order of sampling plan types and overall sample sizes. The charts for 1 unit x 60 locations are also available although it is not practical to do the sampling. The author only wants the readers to have the integrated views on this sampling plan 1. 80
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Journal of Validation Technology MAY 2008 ISSUE ARTICLE: Evaluation of Validation Content Uniformity Test Results Using Probability Distribution Charts By: Pramote Cholayudth
APPENDIX 2: PROBABILITY CHARTS Probability charts provided in the following pages are presented in order of product types, sampling plan types and overall sample sizes. All the charts are constructed on 95% joint confidence level. The charts for 1 unit x 60 locations are also available although it is not practical to do the sampling. The author only wants the readers to have the integrated views on this sampling plan 1. In the new USP test, the probability charts provided are applicable to the processes with target of not more than 101.5% label claim (LC). For processes with target > 101.5% LC, please contact [email protected].
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TABLE OF CONTENTS (CURRENT USP TEST: TABLETS)
Sampling Plan 1 (1 x 30): Current USP Test (RSD: 2.1 – 4.8%) Sampling Plan 1 (1 x 60): Current USP Test (RSD: 2.7 – 5.4%) Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.0 – 4.7, SM: 0.3 – 0.7) Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.9 – 4.6, SM: 0.8 – 1.2) Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.9 – 4.6, SM: 1.3 – 1.7) Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.8 – 4.5, SM: 1.8 – 2.2) Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.7 – 4.4, SM: 2.3 – 2.6) Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.6 – 4.3, SM: 2.7 – 2.9) Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.6 – 4.3, SM: 3.0 – 3.2) Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.4 – 4.1, SM: 3.3 – 3.5) Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.0 – 3.7, SM: 3.6 – 3.8) Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.6 – 5.3, SM: 0.3 – 0.7) Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.6 – 5.3, SM: 0.8 – 1.2) Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.5 – 5.2, SM: 1.3 – 1.7) Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.5 – 5.2, SM: 1.8 – 2.2) Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.5 – 5.2, SM: 2.3 – 2.6) Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.5 – 5.2, SM: 2.7 – 2.9) Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.4 – 5.1, SM: 3.0 – 3.2) Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.4 – 5.1, SM: 3.3 – 3.5) Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.4 – 5.1, SM: 3.6 – 3.8)
4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58 61
TABLE OF CONTENTS (CURRENT USP TEST: CAPSULES)
Sampling Plan 1 (1 x 30): Current USP Test (RSD: 2.5 – 5.2%) Sampling Plan 1 (1 x 60): Current USP Test (RSD: 3.0 – 5.7%) Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.3 – 5.0, SM: 0.3 – 0.7) Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.3 – 5.0, SM: 0.8 – 1.2) Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.3 – 5.0, SM: 1.3 – 1.7) Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.2 – 4.9, SM: 1.8 – 2.2) Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.2 – 4.9, SM: 2.3 – 2.6) Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.1 – 4.8, SM: 2.7 – 2.9) Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.1 – 4.8, SM: 3.0 – 3.2) Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.1 – 4.8, SM: 3.3 – 3.5) All Rights Reserved. Advanstar Communications Inc. 2008 • www.ivthome.com
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Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.9 – 4.6, SM: 3.6 – 3.8) Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.1 – 5.8, SM: 0.3 – 0.7) Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 0.8 – 1.2) Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 1.3 – 1.7) Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 1.8 – 2.2) Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 2.3 – 2.6) Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 2.7 – 2.9) Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 3.0 – 3.2) Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.9 – 5.6, SM: 3.3 – 3.5) Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.9 – 5.6, SM: 3.6 – 3.8)
35 38 41 44 47 50 53 56 59 62
TABLE OF CONTENTS (NEW USP TEST: TABLETS/CAPSULES) • • • • • • • • • • • • • • • • • • • •
Sampling Plan 1 (1 x 30): New USP Test (RSD: 2.0 – 4.7%) Sampling Plan 1 (1 x 60): New USP Test (RSD: 2.7 – 5.4%) Sampling Plan 2 (3 x 10): New USP Test (SE: 2.0 – 4.7, SM: 0.3 – 0.7) Sampling Plan 2 (3 x 10): New USP Test (SE: 1.9 – 4.6, SM: 0.8 – 1.2) Sampling Plan 2 (3 x 10): New USP Test (SE: 1.9 – 4.6, SM: 1.3 – 1.7) Sampling Plan 2 (3 x 10): New USP Test (SE: 1.7 – 4.4, SM: 1.8 – 2.2) Sampling Plan 2 (3 x 10): New USP Test (SE: 1.6 – 4.3, SM: 2.3 – 2.6) Sampling Plan 2 (3 x 10): New USP Test (SE: 1.4 – 4.1, SM: 2.7 – 2.9) Sampling Plan 2 (3 x 10): New USP Test (SE: 1.4 – 4.1, SM: 3.0 – 3.2) Sampling Plan 2 (3 x 10): New USP Test (SE: 1.0 – 3.7, SM: 3.3 – 3.5) Sampling Plan 2 (3 x 10): New USP Test (SE: 0.7 – 3.4, SM: 3.6 – 3.8) Sampling Plan 2 (3 x 20): New USP Test (SE: 2.7 – 5.4, SM: 0.3 – 0.7) Sampling Plan 2 (3 x 20): New USP Test (SE: 2.7 – 5.4, SM: 0.8 – 1.2) Sampling Plan 2 (3 x 20): New USP Test (SE: 2.6 – 5.3, SM: 1.3 – 1.7) Sampling Plan 2 (3 x 20): New USP Test (SE: 2.5 – 5.2, SM: 1.8 – 2.2) Sampling Plan 2 (3 x 20): New USP Test (SE: 2.5 – 5.2, SM: 2.3 – 2.6) Sampling Plan 2 (3 x 20): New USP Test (SE: 2.4 – 5.1, SM: 2.7 – 2.9) Sampling Plan 2 (3 x 20): New USP Test (SE: 2.4 – 5.1, SM: 3.0 – 3.2) Sampling Plan 2 (3 x 20): New USP Test (SE: 2.3 – 5.0, SM: 3.3 – 3.5) Sampling Plan 2 (3 x 20): New USP Test (SE: 2.3 – 5.0, SM: 3.6 – 3.8)
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Sampling Plan 1 (1 x 30): Current USP Test (RSD: 2.1 – 4.8%) Probability of Passing Current USP Tablet Content Uniformity Test (N = 1x30 = 30, RSD = 2.1-4.7%)
100% 95% 2.1%
90%
2.3% 2.5% 2.7%
Probability (%)
85%
2.9%
80%
3.1% 3.3%
75%
3.5%
70%
3.7% 3.9% 4.1%
65%
4.3% 4.5%
60%
4.7%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 1x30 = 30, RSD = 2.2-4.8%)
100% 95% 2.2%
90%
2.4% 2.6% 2.8% 3%
80%
3.2% 3.4%
75%
3.6%
70%
3.8% 4% 4.2%
65%
4.4% 4.6%
60%
4.8%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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Sampling Plan 1 (1 x 30): Current USP Test (RSD: 2.5 – 5.2%) Probability of Passing Current USP Capsule Content Uniformity Test (N = 1x30 = 30, RSD = 2.5-5.1%)
100% 95% 2.5%
90%
2.7% 2.9% 3.1%
Probability (%)
85%
3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 1x30 = 30, RSD = 2.6-5.2%)
100% 95% 2.6%
90%
2.8% 3% 3.2% 3.4%
80%
3.6% 3.8%
75%
4%
70%
4.2% 4.4% 4.6%
65%
4.8% 5%
60%
5.2%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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Sampling Plan 1 (1 x 30): New USP Test (RSD: 2.0 – 4.7%) Probability of Passing New USP 29 Content Uniformity Test (N = 1x30 = 30, RSD = 2.0-4.6%)
100% 95% 2%
90%
2.2% 2.4% 2.6%
Probability (%)
85%
2.8%
80%
3% 3.2%
75%
3.4%
70%
3.6% 3.8% 4%
65%
4.2% 4.4%
60%
4.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 1x30 = 30, RSD = 2.1-4.7%)
100% 95% 2.1%
90%
2.3% 2.5% 2.7% 2.9%
80%
3.1% 3.3%
75%
3.5%
70%
3.7% 3.9% 4.1%
65%
4.3% 4.5%
60%
4.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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6/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 1 (1 x 60): Current USP Test (RSD: 2.7 – 5.4%) Probability of Passing Current USP Tablet Content Uniformity Test (N = 1x60 = 60, RSD = 2.7-5.3%)
100% 95% 2.7%
90%
2.9% 3.1% 3.3%
Probability (%)
85%
3.5%
80%
3.7% 3.9%
75%
4.1%
70%
4.3% 4.5% 4.7%
65%
4.9% 5.1%
60%
5.3%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 1x60 = 60, RSD = 2.8-5.4%)
100% 95% 2.8%
90%
3% 3.2% 3.4% 3.6%
80%
3.8% 4%
75%
4.2%
70%
4.4% 4.6% 4.8%
65%
5% 5.2%
60%
5.4%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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7/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 1 (1 x 60): Current USP Test (RSD: 3.0 – 5.7%) Probability of Passing Current USP Capsule Content Uniformity Test (N = 1x60 = 60, RSD = 3.0-5.6%)
100% 95% 3%
90%
3.2% 3.4% 3.6%
Probability (%)
85%
3.8%
80%
4% 4.2%
75%
4.4%
70%
4.6% 4.8% 5%
65%
5.2% 5.4%
60%
5.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 1x60 = 60, RSD = 3.1-5.7%)
100% 95% 3.1%
90%
3.3% 3.5% 3.7% 3.9%
80%
4.1% 4.3%
75%
4.5%
70%
4.7% 4.9% 5.1%
65%
5.3% 5.5%
60%
5.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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8/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 1 (1 x 60): New USP Test (RSD: 2.7 – 5.4%) Probability of Passing New USP 29 Content Uniformity Test (N = 1x60 = 60, RSD = 2.7-5.3%)
100% 95% 2.7%
90%
2.9% 3.1% 3.3%
Probability (%)
85%
3.5%
80%
3.7% 3.9%
75%
4.1%
70%
4.3% 4.5% 4.7%
65%
4.9% 5.1%
60%
5.3%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 1x60 = 60, RSD = 2.8-5.4%)
100% 95% 2.8%
90%
3% 3.2% 3.4% 3.6%
80%
3.8% 4%
75%
4.2%
70%
4.4% 4.6% 4.8%
65%
5% 5.2%
60%
5.4%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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9/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.0 – 4.7, SM: 0.3 – 0.7) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 2.0-4.6, SM = 0.5)
100% 95% 2%
90%
2.2% 2.4% 2.6%
Probability (%)
85%
2.8%
80%
3% 3.2%
75%
3.4%
70%
3.6% 3.8% 4%
65%
4.2% 4.4%
60%
4.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 2.1-4.7, SM = 0.5)
100% 95% 2.1%
90%
2.3% 2.5% 2.7% 2.9%
80%
3.1% 3.3%
75%
3.5%
70%
3.7% 3.9% 4.1%
65%
4.3% 4.5%
60%
4.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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10/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.3 – 5.0, SM: 0.3 – 0.7) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.3-4.9, SM = 0.5)
100% 95% 2.3%
90%
2.5% 2.7% 2.9%
Probability (%)
85%
3.1%
80%
3.3% 3.5%
75%
3.7%
70%
3.9% 4.1% 4.3%
65%
4.5% 4.7%
60%
4.9%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.4-5.0, SM = 0.5)
100% 95% 2.4%
90%
2.6% 2.8% 3% 3.2%
80%
3.4% 3.6%
75%
3.8%
70%
4% 4.2% 4.4%
65%
4.6% 4.8%
60%
5%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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11/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): New USP Test (SE: 2.0 – 4.7, SM: 0.3 – 0.7) Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 2.0-4.6, SM = 0.5)
100% 95% 2%
90%
2.2% 2.4% 2.6%
Probability (%)
85%
2.8%
80%
3% 3.2%
75%
3.4%
70%
3.6% 3.8% 4%
65%
4.2% 4.4%
60%
4.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 2.1-4.7, SM = 0.5)
100% 95% 2.1%
90%
2.3% 2.5% 2.7% 2.9%
80%
3.1% 3.3%
75%
3.5%
70%
3.7% 3.9% 4.1%
65%
4.3% 4.5%
60%
4.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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12/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.9 – 4.6, SM: 0.8 – 1.2) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.9-4.5, SM = 1.0)
100% 95% 1.9%
90%
2.1% 2.3% 2.5%
Probability (%)
85%
2.7%
80%
2.9% 3.1%
75%
3.3%
70%
3.5% 3.7% 3.9%
65%
4.1% 4.3%
60%
4.5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 2.0-4.6, SM = 1.0)
100% 95% 2%
90%
2.2% 2.4% 2.6% 2.8%
80%
3% 3.2%
75%
3.4%
70%
3.6% 3.8% 4%
65%
4.2% 4.4%
60%
4.6%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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13/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.3 – 5.0, SM: 0.8 – 1.2) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.3-4.9, SM = 1.0)
100% 95% 2.3%
90%
2.5% 2.7% 2.9%
Probability (%)
85%
3.1%
80%
3.3% 3.5%
75%
3.7%
70%
3.9% 4.1% 4.3%
65%
4.5% 4.7%
60%
4.9%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.4-5.0, SM = 1.0)
100% 95% 2.4%
90%
2.6% 2.8% 3% 3.2%
80%
3.4% 3.6%
75%
3.8%
70%
4% 4.2% 4.4%
65%
4.6% 4.8%
60%
5%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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14/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): New USP Test (SE: 1.9 – 4.6, SM: 0.8 – 1.2) Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.9-4.5, SM = 1.0)
100% 95% 1.9%
90%
2.1% 2.3% 2.5%
Probability (%)
85%
2.7%
80%
2.9% 3.1%
75%
3.3%
70%
3.5% 3.7% 3.9%
65%
4.1% 4.3%
60%
4.5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 2.0-4.6, SM = 1.0)
100% 95% 2%
90%
2.2% 2.4% 2.6% 2.8%
80%
3% 3.2%
75%
3.4%
70%
3.6% 3.8% 4%
65%
4.2% 4.4%
60%
4.6%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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15/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.9 – 4.6, SM: 1.3 – 1.7) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.9-4.5, SM = 1.5)
100% 95% 1.9%
90%
2.1% 2.3% 2.5%
Probability (%)
85%
2.7%
80%
2.9% 3.1%
75%
3.3%
70%
3.5% 3.7% 3.9%
65%
4.1% 4.3%
60%
4.5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 2.0-4.6, SM = 1.5)
100% 95% 2%
90%
2.2% 2.4% 2.6% 2.8%
80%
3% 3.2%
75%
3.4%
70%
3.6% 3.8% 4%
65%
4.2% 4.4%
60%
4.6%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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16/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.3 – 5.0, SM: 1.3 – 1.7) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.3-4.9, SM = 1.5)
100% 95% 2.3%
90%
2.5% 2.7% 2.9%
Probability (%)
85%
3.1%
80%
3.3% 3.5%
75%
3.7%
70%
3.9% 4.1% 4.3%
65%
4.5% 4.7%
60%
4.9%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.4-5.0, SM = 1.5)
100% 95% 2.4%
90%
2.6% 2.8% 3% 3.2%
80%
3.4% 3.6%
75%
3.8%
70%
4% 4.2% 4.4%
65%
4.6% 4.8%
60%
5%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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17/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): New USP Test (SE: 1.9 – 4.6, SM: 1.3 – 1.7) Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.9-4.5, SM = 1.5)
100% 95% 1.9%
90%
2.1% 2.3% 2.5%
Probability (%)
85%
2.7%
80%
2.9% 3.1%
75%
3.3%
70%
3.5% 3.7% 3.9%
65%
4.1% 4.3%
60%
4.5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 2.0-4.6, SM = 1.5)
100% 95% 2%
90%
2.2% 2.4% 2.6% 2.8%
80%
3% 3.2%
75%
3.4%
70%
3.6% 3.8% 4%
65%
4.2% 4.4%
60%
4.6%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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18/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.8 – 4.5, SM: 1.8 – 2.2) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.8-4.4, SM = 2.0)
100% 95% 1.8%
90%
2% 2.2% 2.4%
Probability (%)
85%
2.6%
80%
2.8% 3%
75%
3.2%
70%
3.4% 3.6% 3.8%
65%
4% 4.2%
60%
4.4%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.9-4.5, SM = 2.0)
100% 95% 1.9%
90%
2.1% 2.3% 2.5% 2.7%
80%
2.9% 3.1%
75%
3.3%
70%
3.5% 3.7% 3.9%
65%
4.1% 4.3%
60%
4.5%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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19/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.2 – 4.9, SM: 1.8 – 2.2) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.2-4.8, SM = 2.0)
100% 95% 2.2%
90%
2.4% 2.6% 2.8%
Probability (%)
85%
3%
80%
3.2% 3.4%
75%
3.6%
70%
3.8% 4% 4.2%
65%
4.4% 4.6%
60%
4.8%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.3-4.9, SM = 2.0)
100% 95% 2.3%
90%
2.5% 2.7% 2.9% 3.1%
80%
3.3% 3.5%
75%
3.7%
70%
3.9% 4.1% 4.3%
65%
4.5% 4.7%
60%
4.9%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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20/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): New USP Test (SE: 1.7 – 4.4, SM: 1.8 – 2.2) Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.7-4.3, SM = 2.0)
100% 95% 1.7%
90%
1.9% 2.1% 2.3%
Probability (%)
85%
2.5%
80%
2.7% 2.9%
75%
3.1%
70%
3.3% 3.5% 3.7%
65%
3.9% 4.1%
60%
4.3%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.8-4.4, SM = 2.0)
100% 95% 1.8%
90%
2% 2.2% 2.4% 2.6%
80%
2.8% 3%
75%
3.2%
70%
3.4% 3.6% 3.8%
65%
4% 4.2%
60%
4.4%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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21/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.7 – 4.4, SM: 2.3 – 2.6) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.7-4.3, SM = 2.5)
100% 95% 1.7%
90%
1.9% 2.1% 2.3%
Probability (%)
85%
2.5%
80%
2.7% 2.9%
75%
3.1%
70%
3.3% 3.5% 3.7%
65%
3.9% 4.1%
60%
4.3%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.8-4.4, SM = 2.5)
100% 95% 1.8%
90%
2% 2.2% 2.4% 2.6%
80%
2.8% 3%
75%
3.2%
70%
3.4% 3.6% 3.8%
65%
4% 4.2%
60%
4.4%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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22/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.2 – 4.9, SM: 2.3 – 2.6) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.2-4.8, SM = 2.5)
100% 95% 2.2%
90%
2.4% 2.6% 2.8%
Probability (%)
85%
3%
80%
3.2% 3.4%
75%
3.6%
70%
3.8% 4% 4.2%
65%
4.4% 4.6%
60%
4.8%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.3-4.9, SM = 2.5)
100% 95% 2.3%
90%
2.5% 2.7% 2.9% 3.1%
80%
3.3% 3.5%
75%
3.7%
70%
3.9% 4.1% 4.3%
65%
4.5% 4.7%
60%
4.9%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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23/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): New USP Test (SE: 1.6 – 4.3, SM: 2.3 – 2.6) Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.6-4.2, SM = 2.5)
100% 95% 1.6%
90%
1.8% 2% 2.2%
Probability (%)
85%
2.4%
80%
2.6% 2.8%
75%
3%
70%
3.2% 3.4% 3.6%
65%
3.8% 4%
60%
4.2%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.7-4.3, SM = 2.5)
100% 95% 1.7%
90%
1.9% 2.1% 2.3% 2.5%
80%
2.7% 2.9%
75%
3.1%
70%
3.3% 3.5% 3.7%
65%
3.9% 4.1%
60%
4.3%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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24/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.6 – 4.3, SM: 2.7 – 2.9) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.6-4.2, SM = 2.8)
100% 95% 1.6%
90%
1.8% 2% 2.2%
Probability (%)
85%
2.4%
80%
2.6% 2.8%
75%
3%
70%
3.2% 3.4% 3.6%
65%
3.8% 4%
60%
4.2%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.7-4.3, SM = 2.8)
100% 95% 1.7%
90%
1.9% 2.1% 2.3% 2.5%
80%
2.7% 2.9%
75%
3.1%
70%
3.3% 3.5% 3.7%
65%
3.9% 4.1%
60%
4.3%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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25/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.1 – 4.8, SM: 2.7 – 2.9) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.1-4.7, SM = 2.8)
100% 95% 2.1%
90%
2.3% 2.5% 2.7%
Probability (%)
85%
2.9%
80%
3.1% 3.3%
75%
3.5%
70%
3.7% 3.9% 4.1%
65%
4.3% 4.5%
60%
4.7%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.2-4.8, SM = 2.8)
100% 95% 2.2%
90%
2.4% 2.6% 2.8% 3%
80%
3.2% 3.4%
75%
3.6%
70%
3.8% 4% 4.2%
65%
4.4% 4.6%
60%
4.8%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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26/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): New USP Test (SE: 1.4 – 4.1, SM: 2.7 – 2.9) Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.4-4.0, SM = 2.8)
100% 95% 1.4%
90%
1.6% 1.8% 2%
Probability (%)
85%
2.2%
80%
2.4% 2.6%
75%
2.8%
70%
3% 3.2% 3.4%
65%
3.6% 3.8%
60%
4%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.5-4.1, SM = 2.8)
100% 95% 1.5%
90%
1.7% 1.9% 2.1% 2.3%
80%
2.5% 2.7%
75%
2.9%
70%
3.1% 3.3% 3.5%
65%
3.7% 3.9%
60%
4.1%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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27/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.6 – 4.3, SM: 3.0 – 3.2) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.6-4.2, SM = 3.1)
100% 95% 1.6%
90%
1.8% 2% 2.2%
Probability (%)
85%
2.4%
80%
2.6% 2.8%
75%
3%
70%
3.2% 3.4% 3.6%
65%
3.8% 4%
60%
4.2%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.7-4.3, SM = 3.1)
100% 95% 1.7%
90%
1.9% 2.1% 2.3% 2.5%
80%
2.7% 2.9%
75%
3.1%
70%
3.3% 3.5% 3.7%
65%
3.9% 4.1%
60%
4.3%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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28/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.1 – 4.8, SM: 3.0 – 3.2) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.1-4.7, SM = 3.1)
100% 95% 2.1%
90%
2.3% 2.5% 2.7%
Probability (%)
85%
2.9%
80%
3.1% 3.3%
75%
3.5%
70%
3.7% 3.9% 4.1%
65%
4.3% 4.5%
60%
4.7%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.2-4.8, SM = 3.1)
100% 95% 2.2%
90%
2.4% 2.6% 2.8% 3%
80%
3.2% 3.4%
75%
3.6%
70%
3.8% 4% 4.2%
65%
4.4% 4.6%
60%
4.8%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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29/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): New USP Test (SE: 1.4 – 4.1, SM: 3.0 – 3.2) Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.4-4.0, SM = 3.1)
100% 95% 1.4%
90%
1.6% 1.8% 2%
Probability (%)
85%
2.2%
80%
2.4% 2.6%
75%
2.8%
70%
3% 3.2% 3.4%
65%
3.6% 3.8%
60%
4%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.5-4.1, SM = 3.1)
100% 95% 1.5%
90%
1.7% 1.9% 2.1% 2.3%
80%
2.5% 2.7%
75%
2.9%
70%
3.1% 3.3% 3.5%
65%
3.7% 3.9%
60%
4.1%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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30/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.4 – 4.1, SM: 3.3 – 3.5) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.4-4.0, SM = 3.4)
100% 95% 1.4%
90%
1.6% 1.8% 2%
Probability (%)
85%
2.2%
80%
2.4% 2.6%
75%
2.8%
70%
3% 3.2% 3.4%
65%
3.6% 3.8%
60%
4%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.5-4.1, SM = 3.4)
100% 95% 1.5%
90%
1.7% 1.9% 2.1% 2.3%
80%
2.5% 2.7%
75%
2.9%
70%
3.1% 3.3% 3.5%
65%
3.7% 3.9%
60%
4.1%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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31/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 2.1 – 4.8, SM: 3.3 – 3.5) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.1-4.7, SM = 3.4)
100% 95% 2.1%
90%
2.3% 2.5% 2.7%
Probability (%)
85%
2.9%
80%
3.1% 3.3%
75%
3.5%
70%
3.7% 3.9% 4.1%
65%
4.3% 4.5%
60%
4.7%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.2-4.8, SM = 3.4)
100% 95% 2.2%
90%
2.4% 2.6% 2.8% 3%
80%
3.2% 3.4%
75%
3.6%
70%
3.8% 4% 4.2%
65%
4.4% 4.6%
60%
4.8%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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32/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): New USP Test (SE: 1.0 – 3.7, SM: 3.3 – 3.5) Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.0-3.6, SM = 3.4)
100% 95% 1%
90%
1.2% 1.4% 1.6%
Probability (%)
85%
1.8%
80%
2% 2.2%
75%
2.4%
70%
2.6% 2.8% 3%
65%
3.2% 3.4%
60%
3.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 1.1-3.7, SM = 3.4)
100% 95% 1.1%
90%
1.3% 1.5% 1.7% 1.9%
80%
2.1% 2.3%
75%
2.5%
70%
2.7% 2.9% 3.1%
65%
3.3% 3.5%
60%
3.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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33/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.0 – 3.7, SM: 3.6 – 3.8) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.0-3.6, SM = 3.7)
100% 95% 1%
90%
1.2% 1.4% 1.6%
Probability (%)
85%
1.8%
80%
2% 2.2%
75%
2.4%
70%
2.6% 2.8% 3%
65%
3.2% 3.4%
60%
3.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x10 = 30, SE = 1.1-3.7, SM = 3.7)
100% 95% 1.1%
90%
1.3% 1.5% 1.7% 1.9%
80%
2.1% 2.3%
75%
2.5%
70%
2.7% 2.9% 3.1%
65%
3.3% 3.5%
60%
3.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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34/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): Current USP Test (SE: 1.9 – 4.6, SM: 3.6 – 3.8) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 1.9-4.5, SM = 3.7)
100% 95% 1.9%
90%
2.1% 2.3% 2.5%
Probability (%)
85%
2.7%
80%
2.9% 3.1%
75%
3.3%
70%
3.5% 3.7% 3.9%
65%
4.1% 4.3%
60%
4.5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x10 = 30, SE = 2.0-4.6, SM = 3.7)
100% 95% 2%
90%
2.2% 2.4% 2.6% 2.8%
80%
3% 3.2%
75%
3.4%
70%
3.6% 3.8% 4%
65%
4.2% 4.4%
60%
4.6%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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35/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 10): New USP Test (SE: 0.7 – 3.4, SM: 3.6 – 3.8) Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 0.7-3.3, SM = 3.7)
100% 95% 0.7%
90%
0.9% 1.1% 1.3%
Probability (%)
85%
1.5%
80%
1.7% 1.9%
75%
2.1%
70%
2.3% 2.5% 2.7%
65%
2.9% 3.1%
60%
3.3%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x10 = 30, SE = 0.8-3.4, SM = 3.7)
100% 95% 0.8%
90%
1% 1.2% 1.4% 1.6%
80%
1.8% 2%
75%
2.2%
70%
2.4% 2.6% 2.8%
65%
3% 3.2%
60%
3.4%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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36/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.6 – 5.3, SM: 0.3 – 0.7) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.6-5.2, SM = 0.5)
100% 95% 2.6%
90%
2.8% 3% 3.2%
Probability (%)
85%
3.4%
80%
3.6% 3.8%
75%
4%
70%
4.2% 4.4% 4.6%
65%
4.8% 5%
60%
5.2%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.7-5.3, SM = 0.5)
100% 95% 2.7%
90%
2.9% 3.1% 3.3% 3.5%
80%
3.7% 3.9%
75%
4.1%
70%
4.3% 4.5% 4.7%
65%
4.9% 5.1%
60%
5.3%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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37/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.1 – 5.8, SM: 0.3 – 0.7) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.1-5.7, SM = 0.5)
100% 95% 3.1%
90%
3.3% 3.5% 3.7%
Probability (%)
85%
3.9%
80%
4.1% 4.3%
75%
4.5%
70%
4.7% 4.9% 5.1%
65%
5.3% 5.5%
60%
5.7%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.2-5.8, SM = 0.5)
100% 95% 3.2%
90%
3.4% 3.6% 3.8% 4%
80%
4.2% 4.4%
75%
4.6%
70%
4.8% 5% 5.2%
65%
5.4% 5.6%
60%
5.8%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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38/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): New USP Test (SE: 2.7 – 5.4, SM: 0.3 – 0.7) Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.7-5.3, SM = 0.5)
100% 95% 2.7%
90%
2.9% 3.1% 3.3%
Probability (%)
85%
3.5%
80%
3.7% 3.9%
75%
4.1%
70%
4.3% 4.5% 4.7%
65%
4.9% 5.1%
60%
5.3%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.8-5.4, SM = 0.5)
100% 95% 2.8%
90%
3% 3.2% 3.4% 3.6%
80%
3.8% 4%
75%
4.2%
70%
4.4% 4.6% 4.8%
65%
5% 5.2%
60%
5.4%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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39/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.6 – 5.3, SM: 0.8 – 1.2) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.6-5.2, SM = 1.0)
100% 95% 2.6%
90%
2.8% 3% 3.2%
Probability (%)
85%
3.4%
80%
3.6% 3.8%
75%
4%
70%
4.2% 4.4% 4.6%
65%
4.8% 5%
60%
5.2%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.7-5.3, SM = 1.0)
100% 95% 2.7%
90%
2.9% 3.1% 3.3% 3.5%
80%
3.7% 3.9%
75%
4.1%
70%
4.3% 4.5% 4.7%
65%
4.9% 5.1%
60%
5.3%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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40/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 0.8 – 1.2) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.0-5.6, SM = 1.0)
100% 95% 3%
90%
3.2% 3.4% 3.6%
Probability (%)
85%
3.8%
80%
4% 4.2%
75%
4.4%
70%
4.6% 4.8% 5%
65%
5.2% 5.4%
60%
5.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.1-5.7, SM = 1.0)
100% 95% 3.1%
90%
3.3% 3.5% 3.7% 3.9%
80%
4.1% 4.3%
75%
4.5%
70%
4.7% 4.9% 5.1%
65%
5.3% 5.5%
60%
5.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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41/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): New USP Test (SE: 2.7 – 5.4, SM: 0.8 – 1.2) Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.7-5.3, SM = 1.0)
100% 95% 2.7%
90%
2.9% 3.1% 3.3%
Probability (%)
85%
3.5%
80%
3.7% 3.9%
75%
4.1%
70%
4.3% 4.5% 4.7%
65%
4.9% 5.1%
60%
5.3%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.8-5.4, SM = 1.0)
100% 95% 2.8%
90%
3% 3.2% 3.4% 3.6%
80%
3.8% 4%
75%
4.2%
70%
4.4% 4.6% 4.8%
65%
5% 5.2%
60%
5.4%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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42/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.5 – 5.2, SM: 1.3 – 1.7) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.5-5.1, SM = 1.5)
100% 95% 2.5%
90%
2.7% 2.9% 3.1%
Probability (%)
85%
3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.6-5.2, SM = 1.5)
100% 95% 2.6%
90%
2.8% 3% 3.2% 3.4%
80%
3.6% 3.8%
75%
4%
70%
4.2% 4.4% 4.6%
65%
4.8% 5%
60%
5.2%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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43/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 1.3 – 1.7) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.0-5.6, SM = 1.5)
100% 95% 3%
90%
3.2% 3.4% 3.6%
Probability (%)
85%
3.8%
80%
4% 4.2%
75%
4.4%
70%
4.6% 4.8% 5%
65%
5.2% 5.4%
60%
5.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.1-5.7, SM = 1.5)
100% 95% 3.1%
90%
3.3% 3.5% 3.7% 3.9%
80%
4.1% 4.3%
75%
4.5%
70%
4.7% 4.9% 5.1%
65%
5.3% 5.5%
60%
5.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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44/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): New USP Test (SE: 2.6 – 5.3, SM: 1.3 – 1.7) Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.6-5.2, SM = 1.5)
100% 95% 2.6%
90%
2.8% 3% 3.2%
Probability (%)
85%
3.4%
80%
3.6% 3.8%
75%
4%
70%
4.2% 4.4% 4.6%
65%
4.8% 5%
60%
5.2%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.7-5.3, SM = 1.5)
100% 95% 2.7%
90%
2.9% 3.1% 3.3% 3.5%
80%
3.7% 3.9%
75%
4.1%
70%
4.3% 4.5% 4.7%
65%
4.9% 5.1%
60%
5.3%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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45/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.5 – 5.2, SM: 1.8 – 2.2) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.5-5.1, SM = 2.0)
100% 95% 2.5%
90%
2.7% 2.9% 3.1%
Probability (%)
85%
3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.6-5.2, SM = 2.0)
100% 95% 2.6%
90%
2.8% 3% 3.2% 3.4%
80%
3.6% 3.8%
75%
4%
70%
4.2% 4.4% 4.6%
65%
4.8% 5%
60%
5.2%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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46/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 1.8 – 2.2) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.0-5.6, SM = 2.0)
100% 95% 3%
90%
3.2% 3.4% 3.6%
Probability (%)
85%
3.8%
80%
4% 4.2%
75%
4.4%
70%
4.6% 4.8% 5%
65%
5.2% 5.4%
60%
5.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.1-5.7, SM = 2.0)
100% 95% 3.1%
90%
3.3% 3.5% 3.7% 3.9%
80%
4.1% 4.3%
75%
4.5%
70%
4.7% 4.9% 5.1%
65%
5.3% 5.5%
60%
5.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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47/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): New USP Test (SE: 2.5 – 5.2, SM: 1.8 – 2.2) Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.5-5.1, SM = 2.0)
100% 95% 2.5%
90%
2.7% 2.9% 3.1%
Probability (%)
85%
3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.6-5.2, SM = 2.0)
100% 95% 2.6%
90%
2.8% 3% 3.2% 3.4%
80%
3.6% 3.8%
75%
4%
70%
4.2% 4.4% 4.6%
65%
4.8% 5%
60%
5.2%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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48/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.5 – 5.2, SM: 2.3 – 2.6) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.5-5.1, SM = 2.5)
100% 95% 2.5%
90%
2.7% 2.9% 3.1%
Probability (%)
85%
3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC): n = 30
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.6-5.2, SM = 2.5)
100% 95% 2.6%
90%
2.8% 3% 3.2% 3.4%
80%
3.6% 3.8%
75%
4%
70%
4.2% 4.4% 4.6%
65%
4.8% 5%
60%
5.2%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC): n = 30
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49/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 2.3 – 2.6) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.0-5.6, SM = 2.5)
100% 95% 3%
90%
3.2% 3.4% 3.6%
Probability (%)
85%
3.8%
80%
4% 4.2%
75%
4.4%
70%
4.6% 4.8% 5%
65%
5.2% 5.4%
60%
5.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC): n = 30
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.1-5.7, SM = 2.5)
100% 95% 3.1%
90%
3.3% 3.5% 3.7% 3.9%
80%
4.1% 4.3%
75%
4.5%
70%
4.7% 4.9% 5.1%
65%
5.3% 5.5%
60%
5.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC): n = 30
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50/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): New USP Test (SE: 2.5 – 5.2, SM: 2.3 – 2.6) Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.5-5.1, SM = 2.5)
100% 95% 2.5%
90%
2.7% 2.9% 3.1%
Probability (%)
85%
3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC): n = 30
Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.6-5.2, SM = 2.5)
100% 95% 2.6%
90%
2.8% 3% 3.2% 3.4%
80%
3.6% 3.8%
75%
4%
70%
4.2% 4.4% 4.6%
65%
4.8% 5%
60%
5.2%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC): n = 30
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51/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.5 – 5.2, SM: 2.7 – 2.9) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.5-5.1, SM = 2.8)
100% 95% 2.5%
90%
2.7% 2.9% 3.1%
Probability (%)
85%
3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.6-5.2, SM = 2.8)
100% 95% 2.6%
90%
2.8% 3% 3.2% 3.4%
80%
3.6% 3.8%
75%
4%
70%
4.2% 4.4% 4.6%
65%
4.8% 5%
60%
5.2%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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52/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 2.7 – 2.9) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.0-5.6, SM = 2.8)
100% 95% 3%
90%
3.2% 3.4% 3.6%
Probability (%)
85%
3.8%
80%
4% 4.2%
75%
4.4%
70%
4.6% 4.8% 5%
65%
5.2% 5.4%
60%
5.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.1-5.7, SM = 2.8)
100% 95% 3.1%
90%
3.3% 3.5% 3.7% 3.9%
80%
4.1% 4.3%
75%
4.5%
70%
4.7% 4.9% 5.1%
65%
5.3% 5.5%
60%
5.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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53/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): New USP Test (SE: 2.4 – 5.1, SM: 2.7 – 2.9) Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.4-5.0, SM = 2.8)
100% 95% 2.4%
90%
2.6% 2.8% 3%
Probability (%)
85%
3.2%
80%
3.4% 3.6%
75%
3.8%
70%
4% 4.2% 4.4%
65%
4.6% 4.8%
60%
5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.5-5.1, SM = 2.8)
100% 95% 2.5%
90%
2.7% 2.9% 3.1% 3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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54/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.4 – 5.1, SM: 3.0 – 3.2) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.4-5.0, SM = 3.1)
100% 95% 2.4%
90%
2.6% 2.8% 3%
Probability (%)
85%
3.2%
80%
3.4% 3.6%
75%
3.8%
70%
4% 4.2% 4.4%
65%
4.6% 4.8%
60%
5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.5-5.1, SM = 3.1)
100% 95% 2.5%
90%
2.7% 2.9% 3.1% 3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 3.0 – 5.7, SM: 3.0 – 3.2) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.0-5.6, SM = 3.1)
100% 95% 3%
90%
3.2% 3.4% 3.6%
Probability (%)
85%
3.8%
80%
4% 4.2%
75%
4.4%
70%
4.6% 4.8% 5%
65%
5.2% 5.4%
60%
5.6%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.1-5.7, SM = 3.1)
100% 95% 3.1%
90%
3.3% 3.5% 3.7% 3.9%
80%
4.1% 4.3%
75%
4.5%
70%
4.7% 4.9% 5.1%
65%
5.3% 5.5%
60%
5.7%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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56/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): New USP Test (SE: 2.4 – 5.1, SM: 3.0 – 3.2) Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.4-5.0, SM = 3.1)
100% 95% 2.4%
90%
2.6% 2.8% 3%
Probability (%)
85%
3.2%
80%
3.4% 3.6%
75%
3.8%
70%
4% 4.2% 4.4%
65%
4.6% 4.8%
60%
5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.5-5.1, SM = 3.1)
100% 95% 2.5%
90%
2.7% 2.9% 3.1% 3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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57/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.4 – 5.1, SM: 3.3 – 3.5) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.4-5.0, SM = 3.4)
100% 95% 2.4%
90%
2.6% 2.8% 3%
Probability (%)
85%
3.2%
80%
3.4% 3.6%
75%
3.8%
70%
4% 4.2% 4.4%
65%
4.6% 4.8%
60%
5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.5-5.1, SM = 3.4)
100% 95% 2.5%
90%
2.7% 2.9% 3.1% 3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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58/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.9 – 5.6, SM: 3.3 – 3.5) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 2.9-5.5, SM = 3.4)
100% 95% 2.9%
90%
3.1% 3.3% 3.5%
Probability (%)
85%
3.7%
80%
3.9% 4.1%
75%
4.3%
70%
4.5% 4.7% 4.9%
65%
5.1% 5.3%
60%
5.5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.0-5.6, SM = 3.4)
100% 95% 3%
90%
3.2% 3.4% 3.6% 3.8%
80%
4% 4.2%
75%
4.4%
70%
4.6% 4.8% 5%
65%
5.2% 5.4%
60%
5.6%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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59/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): New USP Test (SE: 2.3 – 5.0, SM: 3.3 – 3.5) Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.3-4.9, SM = 3.4)
100% 95% 2.3%
90%
2.5% 2.7% 2.9%
Probability (%)
85%
3.1%
80%
3.3% 3.5%
75%
3.7%
70%
3.9% 4.1% 4.3%
65%
4.5% 4.7%
60%
4.9%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.4-5.0, SM = 3.4)
100% 95% 2.4%
90%
2.6% 2.8% 3% 3.2%
80%
3.4% 3.6%
75%
3.8%
70%
4% 4.2% 4.4%
65%
4.6% 4.8%
60%
5%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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60/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.4 – 5.1, SM: 3.6 – 3.8) Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.4-5.0, SM = 3.7)
100% 95% 2.4%
90%
2.6% 2.8% 3%
Probability (%)
85%
3.2%
80%
3.4% 3.6%
75%
3.8%
70%
4% 4.2% 4.4%
65%
4.6% 4.8%
60%
5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Tablet Content Uniformity Test (N = 3x20 = 60, SE = 2.5-5.1, SM = 3.7)
100% 95% 2.5%
90%
2.7% 2.9% 3.1% 3.3%
80%
3.5% 3.7%
75%
3.9%
70%
4.1% 4.3% 4.5%
65%
4.7% 4.9%
60%
5.1%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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61/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): Current USP Test (SE: 2.9 – 5.6, SM: 3.6 – 3.8) Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 2.9-5.5, SM = 3.7)
100% 95% 2.9%
90%
3.1% 3.3% 3.5%
Probability (%)
85%
3.7%
80%
3.9% 4.1%
75%
4.3%
70%
4.5% 4.7% 4.9%
65%
5.1% 5.3%
60%
5.5%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing Current USP Capsule Content Uniformity Test (N = 3x20 = 60, SE = 3.0-5.6, SM = 3.7)
100% 95% 3%
90%
3.2% 3.4% 3.6% 3.8%
80%
4% 4.2%
75%
4.4%
70%
4.6% 4.8% 5%
65%
5.2% 5.4%
60%
5.6%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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62/63
INSTITUTE OF VALIDATION TECHNOLOGY
Sampling Plan 2 (3 x 20): New USP Test (SE: 2.3 – 5.0, SM: 3.6 – 3.8) Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.3-4.9, SM = 3.7)
100% 95% 2.3%
90%
2.5% 2.7% 2.9%
Probability (%)
85%
3.1%
80%
3.3% 3.5%
75%
3.7%
70%
3.9% 4.1% 4.3%
65%
4.5% 4.7%
60%
4.9%
55%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
50%
CU Sample Mean (% LC)
Probability of Passing New USP 29 Content Uniformity Test (N = 3x20 = 60, SE = 2.4-5.0, SM = 3.7)
100% 95% 2.4%
90%
2.6% 2.8% 3% 3.2%
80%
3.4% 3.6%
75%
3.8%
70%
4% 4.2% 4.4%
65%
4.6% 4.8%
60%
5%
55% 50%
95.0 95.2 95.4 95.6 95.8 96.0 96.2 96.4 96.6 96.8 97.0 97.2 97.4 97.6 97.8 98.0 98.2 98.4 98.6 98.8 99.0 99.2 99.4 99.6 99.8 100.0 100.2 100.4 100.6 100.8 101.0 101.2 101.4 101.6 101.8 102.0 102.2 102.4 102.6 102.8 103.0 103.2 103.4 103.6 103.8 104.0 104.2 104.4 104.6 104.8 105.0
Probability (%)
85%
CU Sample Mean (% LC)
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63/63
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