2.9.47. Uniformity of dosage units using large sample sizes EUROPEAN PHARMACOPOEIA 8.0 04/2013:20947 Unless otherwise speciﬁed, L1 is 15.0 and L2 is 25.0. Table 2.9.47.-1. is to be interpreted as follows : 2.9.47. DEMONSTRATION OF UNIFORMITY OF DOSAGE UNITS USING LARGE SAMPLE SIZES The procedure is intended for, but not limited to, the evaluation of medicinal products that are manufactured using process analytical technology (PAT) methodology. Compliance with general chapter 2.9.40. Uniformity of dosage units can be demonstrated by the following procedure, when large samples (sample size n ≥ 100) are evaluated. Application of this chapter does not constitute a mandatory requirement. It presents 2 alternative tests (Alternative I and Alternative II). Fulﬁlling the requirements of either of the 2 alternatives is considered as evidence that the medicinal product tested complies with general chapter 2.9.40. The 2 alternatives are considered equivalent in their demonstration of compliance with general chapter 2.9.40. ALTERNATIVE 1 (PARAMETRIC) Select not fewer than 100 units according to a predeﬁned sampling plan. The consistency of dosage units is evaluated by content uniformity or mass variation as prescribed in Table 2.9.40.-1. Calculate the acceptance value (AV) using the following expression : – for a sample size of n = 400, enter the table at n ≥ 385 : k = 2.23 and c2 = 3 ; – for a sample size of n = 450, enter the table at n ≥ 407 : k = 2.24 and c2 = 3 ; – for a sample size of n = 500, enter the table at n ≥ 490 : k = 2.24 and c2 = 4. ALTERNATIVE 2 (NON-PARAMETRIC) Select not fewer than 100 units according to a predeﬁned sampling plan. The consistency of dosage units is evaluated by content uniformity or mass variation as prescribed in Table 2.9.40.-1. Assay individually or weigh the units and calculate individual contents as prescribed in general chapter 2.9.40. Count the number of individual dosage units with a content outside (1 ± L1 × 0.01)M and the number of individual dosage units with a content outside (1 ± L2 × 0.01)M. Evaluate if the values are within the limits deﬁned in Table 2.9.47.-2. CRITERIA Apply the following criteria, unless otherwise speciﬁed. The requirements for dosage form uniformity are met if : 1. the number of individual dosage units outside (1 ± L1 × 0.01)M is less than or equal to c1 ; and 2. the number of individual dosage units outside (1 ± L2 × 0.01)M is less than or equal to c2. for which the terms are deﬁned in Table 2.9.40.-2, but using the sample size-dependent value for k deﬁned in Table 2.9.47.-1. c1 and c2 for a given sample size n are deﬁned in Table 2.9.47.-2. CRITERIA Unless otherwise speciﬁed, L1 is 15.0 and L2 is 25.0. Apply the following criteria, unless otherwise speciﬁed. Table 2.9.47.-2 is to be interpreted as follows : The requirements for dosage form uniformity are met if : 1. the acceptance value (AV) is less than or equal to L1 ; and – for a sample size of n = 400, enter the table at n ≥ 394 : c1 = 11 and c2 = 3 ; 2. in the calculation of acceptance value (AV) under content – for a sample size of n = 450, enter the table at n ≥ 434 : uniformity or under mass variation, the number of c1 = 12 and c2 = 3 ; individual dosage units outside (1 ± L2 × 0.01)M is less than or equal to c2 as deﬁned for a given sample size n in – for a sample size of n = 500, enter the table at n ≥ 490 : Table 2.9.47.-1. c1 = 13 and c2 = 4. 368 See the information section on general monographs (cover pages) 2.9.47. Uniformity of dosage units using large sample sizes EUROPEAN PHARMACOPOEIA 8.0 Table 2.9.47.-1. – Acceptability constant (k) and acceptable number of dosage units with a content outside (1 ± L2 × 0.01)M (= c2) for a given sample size n n (≥) k 100 2.15 c2 n (≥) k 804 2.26 c2 n (≥) k c2 n (≥) k c2 n (≥) k c2 n (≥) k c2 2480 2.29 23 4366 2.30 41 6252 2.31 59 8243 2.31 78 2585 2.29 24 4471 2.30 42 6357 2.31 60 8347 2.31 79 8452 2.31 80 8557 2.31 81 8662 2.31 82 8767 2.31 83 8871 2.31 84 7 105 2.16 120 2.17 139 2.18 161 176 189 0 2.19 2.19 1 2.21 270 2.22 280 2.22 2 328 2.23 385 2.23 3 407 2.24 490 2.24 516 2.25 594 2.25 672 2.26 699 2.26 2.27 908 2.27 8 2690 2.29 25 4576 2.30 43 6462 2.31 61 1013 2.27 9 2794 2.29 26 4680 2.30 44 6566 2.31 62 1118 2.27 10 2899 2.29 27 4785 2.30 45 6671 2.31 63 1223 2.27 3004 2.29 28 4890 2.30 46 6776 2.31 64 1276 2.28 3109 2.29 4995 2.30 47 6881 2.31 65 1328 2.28 12 3171 2.30 5099 2.30 48 6985 2.31 66 1432 2.28 13 3213 2.30 30 5204 2.30 49 7090 2.31 67 8976 2.31 85 1537 2.28 14 3318 2.30 31 5309 2.30 50 7195 2.31 68 9081 2.31 86 1642 2.28 15 3423 2.30 32 5414 2.30 51 7300 2.31 69 9186 2.31 87 1747 2.28 16 3528 2.30 33 5519 2.30 52 7404 2.31 70 9290 2.31 88 1851 2.28 3633 2.30 34 5623 2.30 53 7509 2.31 71 9395 2.31 89 3737 2.30 35 5728 2.30 54 7614 2.31 72 9500 2.31 90 9605 2.31 91 9710 2.31 92 11 2.20 224 905 4 5 6 29 17 1918 2.29 1956 2.29 18 3842 2.30 36 5833 2.30 55 7719 2.31 73 2061 2.29 19 3947 2.30 37 5938 2.30 56 7824 2.31 74 2166 2.29 20 4052 2.30 38 6042 2.30 7928 2.31 75 2270 2.29 21 4156 2.30 39 6136 2.31 8033 2.31 76 9814 2.31 93 2375 2.29 22 4261 2.30 40 6147 2.31 8138 2.31 77 9919 2.31 94 57 General Notices (1) apply to all monographs and other texts 58 369 2.9.47. Uniformity of dosage units using large sample sizes EUROPEAN PHARMACOPOEIA 8.0 Table 2.9.47.-2. – Acceptable number of individual dosage units with a content outside (1 ± L1 × 0.01)M (= c1) and (1 ± L2 × 0.01)M (= c2) respectively, for a given sample size n n (≥) c1 100 c2 n (≥) c1 3 1432 35 123 4 1476 36 159 5 1521 37 176 5 1537 37 196 6 1566 38 234 7 1611 273 8 280 8 313 9 353 10 385 10 394 434 11 12 476 13 490 13 517 14 559 15 594 15 601 16 644 17 686 0 1 2 3 c1 2899 67 2935 68 4377 99 2981 69 4424 100 3004 69 4471 101 3027 70 4518 102 39 3073 71 4565 1642 39 3109 71 1656 40 3120 72 3166 73 3212 74 3213 74 3259 75 3305 76 3318 76 3351 77 3398 78 3423 78 3444 79 3491 80 3528 80 3537 81 3584 82 3630 83 3633 83 3677 84 3723 85 3737 85 3770 86 3817 87 3842 87 3863 88 3910 89 3947 89 3956 90 1701 41 1746 42 1747 42 1791 43 1836 44 1851 44 1882 45 46 1956 46 1972 47 2018 48 2061 48 2063 49 18 2109 50 699 18 2154 51 729 19 2166 51 772 20 2200 52 804 20 2246 53 815 21 2270 53 858 22 2291 54 902 23 2337 55 908 23 2375 55 945 24 989 25 1013 25 1033 26 1077 27 1118 27 1121 28 1165 29 1209 30 1223 30 1253 31 1298 5 6 7 8 9 10 15 16 17 18 19 20 21 56 57 2475 58 2480 58 2520 59 2566 60 4003 91 2585 60 4050 92 2612 61 2658 62 22 23 24 4052 4097 27 28 29 30 31 32 33 34 35 36 37 92 93 38 n (≥) c1 4366 98 c2 c1 7300 160 7304 161 7351 162 132 7399 163 5938 132 7404 163 103 5977 133 7447 164 4576 103 6024 134 7494 165 4612 104 6042 134 7509 165 4658 105 6072 135 7542 166 4680 105 6119 136 7589 167 4705 106 6147 136 7614 167 6166 137 7637 168 6214 138 7684 169 6252 138 7719 169 6261 139 7732 170 6308 140 7779 171 6355 141 7824 171 6357 141 7827 172 6403 142 7875 173 6450 143 7922 174 6462 143 7928 174 6498 144 7970 175 6545 145 8017 176 6566 145 8033 176 6592 146 8065 177 6640 147 8113 6671 147 6687 148 6734 6776 4752 42 43 44 107 4785 107 4799 108 4846 109 4890 109 4893 110 4940 111 4987 112 4995 112 5034 113 5081 114 5099 114 5128 115 5175 116 5204 116 5222 117 5269 118 5309 118 5317 119 5364 120 5411 121 5414 121 45 46 47 48 49 50 51 c1 5833 129 5835 130 5883 131 5930 c2 n (≥) 41 n (≥) c1 8767 191 8780 192 8828 193 8871 193 8875 194 8923 195 8971 196 8976 196 9019 197 9066 198 9081 198 9114 199 9162 200 9186 200 9210 201 9257 202 9290 202 9305 203 9353 204 9395 204 9401 205 9449 206 178 9496 207 8138 178 9500 207 8160 179 9544 208 149 8208 180 9592 209 149 8243 180 9605 209 6782 150 8256 181 6829 151 8303 182 9640 210 6877 152 8347 182 9688 211 6881 152 8351 183 9710 211 6924 153 8399 184 9735 212 6972 154 8446 185 9783 213 6985 154 8452 185 9814 213 8494 186 9831 214 9879 215 9919 215 9927 216 9975 217 10023 218 10070 219 55 56 57 58 59 60 61 62 63 64 5458 122 5505 123 5519 123 5552 124 7019 155 125 7067 156 8542 187 7090 156 8557 187 7114 157 8589 188 52 65 66 4143 94 4156 94 5623 125 64 4190 95 5647 126 2794 64 4237 96 5694 127 7161 158 8637 189 2796 65 4261 96 5728 127 7195 158 8662 189 2843 66 4284 97 5741 128 7209 159 8685 190 2889 67 4330 98 5788 129 7256 160 8732 191 63 2750 32 1328 32 1342 33 1387 34 25 26 39 40 53 54 c2 n (≥) 5599 2704 370 14 2429 62 12 13 2383 2690 11 c2 n (≥) 1927 4 c2 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 c2 83 84 85 86 87 88 89 90 91 92 93 94 See the information section on general monographs (cover pages)