Design Verification Turbidos Contents 1 adjustment... 2 2 Target value determination... 2 3 Stability... 2 3.1 Accelerated stress data... 2 3.2 Open vial stability... 3 3.3 Real Time Stability... 4 4 Result documentation... 9 5 Traceability... 9 Form: 4.2-01.06-04 1/9 valid of 22.04.2010
1 adjustment The liquid raw material is tested by the quality control for the content of each individual parameter. If necessary, respective parameters are spiked or stripped to meet the specification for normal, elevated or pathological range. Imprecision 2 Target value determination The target value determination of HUMAN s control sera Turbidos is performed by own QC laboratories. The assigned target values for each parameter reflect the consensus value, obtained by statistical evaluation of the results of all participating laboratories. 3 Stability The shelf life of Turbidos has been confirmed by the results of real-time studies. Each lot of control serum is checked by temperature stress studies at the time of production. Retained samples of each batch are further tested at suitable intervals in order to monitor real-time stability during the assigned shelf life. Turbidos has an assigned shelf life of 2 years from the date of production. Data have been established during the design development and are secured by stress tests on each production batch. In parallel, each lot will be retested at the end of the expiration date to verify the stability. 3.1 Accelerated stress data Pilot batches have been subjected to accelerated stress studies. A typical data set is provided below. Turbidos Level 1 Level 2 fresh 5 d @ 41 C Dev. % fresh 5 d @ 41 C Dev. % Unit Albumin 2007 1880 6 5008 4838 3 mg/dl Alpa-1-acid glycoprotein 48.2 47.9 1 141 140 1 mg/dl antitrypsin 89.6 85.6 4 294 299-2 mg/dl Alpha-2-macroglobulin 94.7 93.0 2 320 330-3 mg/dl Antistreptolysin (ASO) 85.9 91.0-6 362 359 1 IU/l Apolipoprotein A1 104 1-8 286 259 9 mg/dl Apolipoprotein B 60.0 56.0 7 134 133 1 mg/dl Beta-2-microglobulin 0.97 0.94 3 3.20 3.00 6 mg/l C3 Complement 114 114 0 314 313 0 mg/dl C4 Complement 21.9 20.7 5 74.1 73.8 0 mg/dl Ceruloplasmin 17.8 16.8 6 62.1 57.8 7 mg/dl (CRP) 1.06 1.01 5 6.80 7.00-3 mg/dl Haptoglobulin 70.9 72.2-2 229 237-3 mg/dl IgA 1 0 1 407 416-2 mg/dl IgE 186 183 2 501 515-3 IU/ml IgG 528 519 2 1783 1840-3 mg/dl IgM 57.7 57.1 1 208 218-5 mg/dl Kappa Light Chain 464 456 2 1552 1597-3 mg/dl Lambda Light Chain 219 215 2 686 667 3 mg/dl Prealbumin 16.1 16.0 1 48.1 48.4-1 mg/dl Rheumatoid Factors (RF) 22.0 21.4 3 105 97 8 IU/ml Total Protein 3984 4083-2 11768 199-4 mg/dl Transferrin 136 138-1 429 433-1 mg/dl Predicted product stability: From the above results of accelerated stress testing no degradation could be observed. Assuming an activation energy of 25,000 calories per mol, from the Arrhennius equation at least months stability at 2...8 C can be predicted. Design Verification and Product Data for TURBIDOS 2/9
3.2 Open vial stability The stability after opening has been checked at storage conditions 2...8 C. The data are summarised below (units and parameters follow the above scheme). Turbidos Level 1 Level 2 fresh 30 d @ 2...8 C Dev. % fresh 30 d @ 2...8 C Dev. % Unit Albumin 2287 2273 1 56 5630 0 mg/dl Alpa-1-acid glycoprotein 48.5 49.3-2 142 154-8 mg/dl antitrypsin 89.8 94.0-5 297 310-4 mg/dl Alpha-2-macroglobulin 91.3 94.0-3 323 332-3 mg/dl Antistreptolysin (ASO) 84.5 84.5 0 368 371-1 IU/l Antithrombin III 16.6 17.4-5 57.2 59.0-3 mg/dl Apolipoprotein A1 94.0 98.0-4 281 303-8 mg/dl Apolipoprotein B 65.0 62.0 5 172 178-3 mg/dl Beta-2-microglobulin 0.96 0.90 6 3.30 3.20 3 mg/l C3 Complement 115 115 0 321 337-5 mg/dl C4 Complement 22.2 21.5 3 73.6 75.7-3 mg/dl Ceruloplasmin 17.9 18.0-1 63.5 65.6-3 mg/dl (CRP) 1.00 0.98 2 7.10 7.30-3 mg/dl Haptoglobulin 71.4 72-1 233 343-47 mg/dl IgA 1 4-2 4 429-4 mg/dl IgE 187 184 2 504 496 2 IU/ml IgG 529 523 1 1830 1880-3 mg/dl IgM 58.8 57.4 2 211 221-5 mg/dl Kappa Light Chain 465 474-2 1598 1683-5 mg/dl Lambda Light Chain 223 227-2 685 694-1 mg/dl Prealbumin 16.5 16.4 1 48.7 50.3-3 mg/dl Rheumatoid Factor (RF) 22.0 20.0 9 105 109-4 IU/ml Total Protein 4134 4384-6 656 382 2 mg/dl Transferrin 135 136-1 437 456-4 mg/dl Conclusion: The claimed stability of 30 days after opening, stored at 2...8 C, is confirmed Design Verification and Product Data for TURBIDOS 3/9
3.3 Real Time Stability The real time stability was confirmed with three independent lots. Lot IM0704 Level 1 Level 2 after after Acidglycoprotein mg/dl 46.0 47.0 48.0 4.30 88.0 87.0 87.0-1.10 Antitrypsin mg/dl 74.0 83.0 81.0 9.50 150 148 148 1.40 Alph-2-Macroglobulin mg/dl 88.0 91.0 78.0-11.4 162 160 158 2.50 (ASO) IU/ml 90.0 89.0 86.0-4.40 188 174 180 4.40 Antithrombin III (AT3) mg/dl 10.1 10.9 10.7 5.90 19.8 19.8 18.3 8.20 Beta-2-Microglobulin mg/l 2.65 2.71 2.36-10.9 7.60 6.41 5.19 46.4 Ceruloplasmin (CER) mg/dl 13.7 15.2 15.1 10.2 26.8 27.6 27.6-2.90 Complement C3 (C3) mg/dl 69.0 67.0 64.0-7.20 142 133 134 6.00 Complement C4 (C4) mg/dl 17.1 16.6 16.2-5.30 33.6 32.3 32.0 5.00 mg/dl 1.59 1.51 1.46-8.20 3.25 3.71 3.03 7.30 (hscrp) mg/dl 1.86 1.87 1.57-15.6 4.00 3.80 3.21.6 Haptoglobin (HPT) mg/dl 58.0 59.0 54.0-6.90 0 113 114 5.30 IgA mg/dl 116 115 1-3.40 230 216 211 9.00 IgG mg/dl 9 886 604-34.6 2030 1850 1675 21.2 IgM mg/dl 56 62.0 55.0-1.80 105 1 100 5.00 Kappa Light Chain mg/dl 880 793 857-2.60 1960 1675 1715 14.3 Lambda Light Chain mg/dl 375 479 348-7.20 844 928 728 15.9 Prealbumin mg/dl 15.0 14.7 14.1-6.00 29.8 27.6 26.4.9 Properdin Factor B (PFB) mg/dl 13.3 13.3 <.0 Xxx 25.7 25.0 23.7 8.40 Rhematoid Factor (RF) IU/ml 41.8 34.0 36.0-13.9 106.0 85.0 80.0 32.5 Transferrin (TRF) mg/dl 147 138 133-9.50 277 256 259 6.90 IgE IU/ml 100 157 166 66.0 214 331 326-34.4 Albumin g/dl 2.10 2.30 2.20 4.80 3.90 3.95 3.90 0.00 Total Protein g/dl 4.50 4.60 4.40-2.20 7.90 7.90 7.70 2.60 Design Verification and Product Data for TURBIDOS 4/9
Lot IM0704 Level 3 after Acidglycoprotein mg/dl 119 6 1 1.70 Antitrypsin mg/dl 180 186 202.2 Alph-2-Macroglobulin mg/dl 398 365 381-4.30 (ASO) IU/ml 287 213 233-18.8 Antithrombin III (AT3) mg/dl.4 23.0 26.6 9.00 Beta-2-Microglobulin mg/l 8.40 8.03 7.26-13.7 Complement C3 (C3) mg/dl 262 237 251-4.20 Complement C4 (C4) mg/dl 67 54.0 54.7-18.4 Ceruloplasmin (CER) mg/dl 66.5 56.5 49.6-25.4 mg/dl 4.45 4.41 4.33-2.70 (hscrp) mg/dl 4.08 5.17 4. 1.00 Ferritin ng/ml 391 376 393 0.50 Haptoglobin (HPT) mg/dl 183 190.0 179.0-2.20 IgA mg/dl 431 428 379 -.1 IgG mg/dl 3160 3465 3160 0.00 IgM mg/dl 251 203 192-23.5 Kappa Light Chain mg/dl 2950 2940 2810-4.70 Lambda Light Chain mg/dl 1165 30 1310.4 Prealbumin mg/dl 47.5 41.4 42.7-10.1 Properdin Factor B (PFB) mg/dl 59.8 54.0 46.4-22.4 Rhematoid Factor (RF) IU/ml 152 135 3-19.1 Transferrin (TRF) mg/dl 428 447 444 3.70 IgE IU/ml 359 338 385 7.20 Albumin g/dl 5.50 5.60 5.50 0.00 Total Protein g/dl.2 11.9 11.7-4.10 Design Verification and Product Data for TURBIDOS 5/9
Lot IM0910 Level 1 Level 2 after after Acidglycoprotein mg/dl 50.4 46.1 46.8-7.1 81.9 80.5 81.6-0.40 Antitrypsin mg/dl 78.7 86.2 67.9-13.7 117 110 143-18.2 Alph-2-Macroglobulin mg/dl 2 115 1-8.2 252 235 2.5 (ASO) IU/ml 85.2 77.5 76.7-10.0 165 143 144 14.6 Antithrombin III (AT3) mg/dl 14.1 14.1 14.3 1.4 20.4 19.1 21.5-5.10 Beta-2-Microglobulin mg/l 2.20 2.22 1.97-10.5 5.44 5. 4.85.2 Complement C3 (C3) mg/dl 82.0 84.6 84.9 3.5 168 162 170-1.20 Complement C4 (C4) mg/dl 18.4 16.6 18.9 2.7 39.7 34.0 35.1 13.1 Ceruloplasmin (CER) mg/dl 18.2 19.3 17.3-4.9 38.8 37.2 31.2.4 mg/dl 1.36 1.37 1.43 5.1 2.75 2.60 2.69 2.20 (hscrp) mg/dl 1.42 1.83 1.58 11.3 2.80 3.53 2.85-1.80 Ferritin ng/ml 52.9 59.7 82.6 56.1 225 213 3-7.40 Haptoglobin (HPT) mg/dl 64.1 66.7 69.2 8.0 3 8 1 1.70 IgA mg/dl 152 145 137-9.9 293 281 262 11.8 IgG mg/dl 833 964 858 3.0 1965 2100 1945 1.00 IgM mg/dl 82.0 70.0 88.2 7.6 158 137 131 20.6 Kappa Light Chain mg/dl 805 830 885 9.9 1775 1900 1895-6.30 Lambda Light Chain mg/dl 378 371 442 16.9 793 786 889-10.8 Prealbumin mg/dl 15.0 15.3 14.7-2.0 30.9 28.1 28.9 6.90 Properdin Factor B (PFB) mg/dl 18.7 17.6 17.0-9.1 37.9 34.9 31.0 22.3 Rhematoid Factor (RF) IU/ml 39.7 33.8 31.1-21.7 88.0 74.0 68.0 29.4 Transferrin (TRF) mg/dl 154 166 168 9.1 295 309 289 2.10 IgE IU/ml 140 141 135-3.6 5 253 267-8.20 Albumin g/dl 2.40 2.40 2.40 0.0 3.90 4.00 3.90 0.00 Total Protein g/dl 5.30 5.20 5.20-1.9 8.80 8.50 8.40 4.80 Design Verification and Product Data for TURBIDOS 6/9
Lot IM0910 Level 3 after Acidglycoprotein mg/dl 119 6 1 1.70 Antitrypsin mg/dl 180 186 202.2 Alph-2-Macroglobulin mg/dl 398 365 381-4.30 (ASO) IU/ml 287 213 233-18.8 Antithrombin III (AT3) mg/dl.4 23.0 26.6 9.00 Beta-2-Microglobulin mg/l 8.40 8.03 7.26-13.7 Complement C3 (C3) mg/dl 262 237 251-4.20 Complement C4 (C4) mg/dl 67.0 54.0 54.7-18.4 Ceruloplasmin (CER) mg/dl 66.5 56.5 49.6-25.4 mg/dl 4.45 4.41 4.33-2.70 (hscrp) mg/dl 4.08 5.17 4. 1.00 Ferritin ng/ml 391 376 393 0.50 Haptoglobin (HPT) mg/dl 183 190 179-2.20 IgA mg/dl 431 428 379 -.1 IgG mg/dl 3160 3465 3160 0.00 IgM mg/dl 251 203 192-23.5 Kappa Light Chain mg/dl 2950 2940 2810-4.70 Lambda Light Chain mg/dl 1165 30 1310.4 Prealbumin mg/dl 47.5 41.4 42.7-10.1 Properdin Factor B (PFB) mg/dl 59.8 54.0 46.4-22.4 Rhematoid Factor (RF) IU/ml 152 135 3-19.1 Transferrin (TRF) mg/dl 428 447 444 3.70 IgE IU/ml 359 338 385 7.20 Albumin g/dl 5.50 5.60 5.50 0.00 Total Protein g/dl.2 11.9 11.7-4.10 Design Verification and Product Data for TURBIDOS 7/9
Lot IM0904 Level 1 Level 2 after after Acidglycoprotein mg/dl 67.7 63.5 64.0-5.50 155 141 139-10.3 Antitrypsin mg/dl 39.4 37.4 43.1 9.40 77.8 70.0 75.0-3.60 Alph-2-Macroglobulin mg/dl 64.9 89.9 86.0 32.5 140 133 8-8.60 (ASO) IU/ml 88.9 76.8 83.0-6.60 173 149 144-16.8 Antithrombin III (AT3) mg/dl 10.4 9.70 10.3-1.00 19.5 19.3 20.0 2.60 Beta-2-Microglobulin mg/l 2.67 2.72 2.65-0.70 6.30 6.20 5. -18.7 Ceruloplasmin (CER) mg/dl 14.1.8 14.0-0.70 31.3 25.9 26.9-14.1 Complement C3 (C3) mg/dl 52.2 56.7 53.0 1.50 3 6 119-3.30 Complement C4 (C4) mg/dl 17.2 15.3 15.1 -.2 35.7 31.2 29.7-16.8 mg/dl 1.42 1.33 1.38-2.80 2.98 3.05 2.96-0.70 (hscrp) mg/dl 1.32 1.42 1.26-4.50 2.99 3.16 2.88-3.70 Ferritin ng/ml 46.7 54.0 58.0.2 230 251 271 17.8 Haptoglobin (HPT) mg/dl 60.1 57.5 64.0 6.50 0 113 1 0.80 IgA mg/dl 110 109 113 2.70 202 207 206 2.00 IgG mg/dl 1070 1085 15 5.10 1935 2200 2215 14.5 IgM mg/dl 46.3 47.3 40.0-13.6 98.0 100 84.0-14.3 Kappa Light Chain mg/dl 1025 1085 1085 5.90 1945 1935 2050 5.40 Lambda Light Chain mg/dl 433 446 472 9.00 808 802 898 11.1 Prealbumin mg/dl 11.4 11.2.3 7.90.2 23.8 23.8-1.70 Properdin Factor B (PFB) mg/dl 19.3 17.8 17.7-8.30 34.3 32.2 31.8-7.30 Rhematoid Factor (RF) IU/ml 42.4 29.0 33.0-22.2 113 86.5 89.3-21.0 Transferrin (TRF) mg/dl 107 118 111 3.70 216 228 227 5.10 IgE IU/ml 142 135 139-2.10 282 252 258-8.50 Albumin g/dl 1.70 1.80 1.80 5.90 3.30 3.40 3.50 6.10 Total Protein g/dl 4.20 4.50 4.40 4.80 7.50 7.60 7.70 2.70 Design Verification and Product Data for TURBIDOS 8/9
Lot IM0904 Level 3 after Acidglycoprotein mg/dl 234 227 229-2.10 Antitrypsin mg/dl 113 104 107-5.30 Alph-2-Macroglobulin mg/dl 196 182 196 0.00 (ASO) IU/ml 273 235 239 -.5 Antithrombin III (AT3) mg/dl 28.2 28.7 32.4 14.9 Beta-2-Microglobulin mg/l 9.50 8.96 8.79-7.40 Ceruloplasmin (CER) mg/dl 48.2 41.4 42.0 -.9 Complement C3 (C3) mg/dl 200 210 194-3.00 Complement C4 (C4) mg/dl 59.4 47.6 51.5-13.3 mg/dl 6.36 5.21 4.92-22.6 (hscrp) mg/dl 4.83 4.72 4.38-9.30 Ferritin ng/ml 389 442 439.9 Haptoglobin (HPT) mg/dl 175 165 173-1.10 IgA mg/dl 314 304 3-0.60 IgG mg/dl 3180 3265 3465 9.00 IgM mg/dl 151 152 132 -.6 Kappa Light Chain mg/dl 2860 3030 3140 9.80 Lambda Light Chain mg/dl 30 50 1340 8.90 Prealbumin mg/dl 36.1 36.6 36.0-0.30 Properdin Factor B (PFB) mg/dl 47.0 48.1 47.8 1.70 Rhematoid Factor (RF) IU/ml 164 132 138-15.9 Transferrin (TRF) mg/dl 338 358 343 1.50 IgE IU/ml 387 328 400 3.40 Albumin g/dl 4.90 5.00 5.10 4.10 Total Protein g/dl 10.6 11.0 11.0 3.80 Any value outside of above target ranges is acceptable provided it is within the linearity of the specified method and differs by more than 30% from the other levels. Conclusion: The data confirm a 2 year stability of Turbidos 4 Result documentation For each batch of Turbidos quality control sera a leaflet is created which contains information on handling, stability, target values and permitted ranges for all specified parameters. 5 Traceability The assigned target values of Turbidos quality control sera are traceable to reference methods (i.e. IFCC) or reference materials (i.e. NIST), if applicable. Design Verification and Product Data for TURBIDOS 9/9