CA2874077C - Method for determining a concentration of a polysorbate species in a mixture - Google Patents
Method for determining a concentration of a polysorbate species in a mixture Download PDFInfo
- Publication number
- CA2874077C CA2874077C CA2874077A CA2874077A CA2874077C CA 2874077 C CA2874077 C CA 2874077C CA 2874077 A CA2874077 A CA 2874077A CA 2874077 A CA2874077 A CA 2874077A CA 2874077 C CA2874077 C CA 2874077C
- Authority
- CA
- Canada
- Prior art keywords
- polysorbate
- proteins
- atr
- sample
- test sample
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 229920000136 polysorbate Polymers 0.000 title claims abstract description 100
- 238000000034 method Methods 0.000 title claims abstract description 97
- 229950008882 polysorbate Drugs 0.000 title claims abstract description 86
- 239000000203 mixture Substances 0.000 title claims abstract description 50
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims abstract description 78
- 229920000053 polysorbate 80 Polymers 0.000 claims abstract description 78
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims abstract description 70
- 229940068968 polysorbate 80 Drugs 0.000 claims abstract description 70
- 238000005102 attenuated total reflection Methods 0.000 claims abstract description 51
- 238000001228 spectrum Methods 0.000 claims abstract description 48
- 238000012360 testing method Methods 0.000 claims abstract description 46
- 238000004483 ATR-FTIR spectroscopy Methods 0.000 claims abstract description 43
- 150000001540 azides Chemical class 0.000 claims abstract description 20
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims abstract description 17
- 229920001213 Polysorbate 20 Polymers 0.000 claims abstract description 16
- 238000011088 calibration curve Methods 0.000 claims abstract description 16
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims abstract description 15
- 229940068977 polysorbate 20 Drugs 0.000 claims abstract description 13
- 229920001219 Polysorbate 40 Polymers 0.000 claims abstract description 10
- 229920001214 Polysorbate 60 Polymers 0.000 claims abstract description 10
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 claims abstract description 9
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 claims abstract description 9
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 claims abstract description 9
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 claims abstract description 9
- 229940101027 polysorbate 40 Drugs 0.000 claims abstract description 9
- 229940113124 polysorbate 60 Drugs 0.000 claims abstract description 9
- 108090000623 proteins and genes Proteins 0.000 claims description 46
- 102000004169 proteins and genes Human genes 0.000 claims description 44
- 108091007433 antigens Proteins 0.000 claims description 28
- 102000036639 antigens Human genes 0.000 claims description 28
- 229960005486 vaccine Drugs 0.000 claims description 28
- 239000000427 antigen Substances 0.000 claims description 24
- 206010022000 influenza Diseases 0.000 claims description 21
- 150000004676 glycans Chemical class 0.000 claims description 19
- 239000007788 liquid Substances 0.000 claims description 19
- 229920001282 polysaccharide Polymers 0.000 claims description 19
- 239000005017 polysaccharide Substances 0.000 claims description 19
- 241000894007 species Species 0.000 claims description 19
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 15
- 241000701806 Human papillomavirus Species 0.000 claims description 8
- 241000700605 Viruses Species 0.000 claims description 8
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- 241000606768 Haemophilus influenzae Species 0.000 claims description 5
- 229910003460 diamond Inorganic materials 0.000 claims description 5
- 239000010432 diamond Substances 0.000 claims description 5
- 229940124856 vaccine component Drugs 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 241000186216 Corynebacterium Species 0.000 claims description 4
- 241000701022 Cytomegalovirus Species 0.000 claims description 4
- 241000991587 Enterovirus C Species 0.000 claims description 4
- 101710154606 Hemagglutinin Proteins 0.000 claims description 4
- 241000712079 Measles morbillivirus Species 0.000 claims description 4
- 102000005348 Neuraminidase Human genes 0.000 claims description 4
- 108010006232 Neuraminidase Proteins 0.000 claims description 4
- 101710093908 Outer capsid protein VP4 Proteins 0.000 claims description 4
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- 101710176177 Protein A56 Proteins 0.000 claims description 4
- 241000725643 Respiratory syncytial virus Species 0.000 claims description 4
- 229940047650 haemophilus influenzae Drugs 0.000 claims description 4
- 239000000185 hemagglutinin Substances 0.000 claims description 4
- 241000193449 Clostridium tetani Species 0.000 claims description 3
- IELOKBJPULMYRW-NJQVLOCASA-N D-alpha-Tocopheryl Acid Succinate Chemical compound OC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C IELOKBJPULMYRW-NJQVLOCASA-N 0.000 claims description 3
- 241000193998 Streptococcus pneumoniae Species 0.000 claims description 3
- 241000700647 Variola virus Species 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000011018 current good manufacturing practice Methods 0.000 claims description 3
- 229940099418 d- alpha-tocopherol succinate Drugs 0.000 claims description 3
- 239000003599 detergent Substances 0.000 claims description 3
- 241001529453 unidentified herpesvirus Species 0.000 claims description 3
- ODWNBAWYDSWOAF-UHFFFAOYSA-N 2,4,4-trimethylpentan-2-yloxybenzene Chemical compound CC(C)(C)CC(C)(C)OC1=CC=CC=C1 ODWNBAWYDSWOAF-UHFFFAOYSA-N 0.000 claims description 2
- 241000588807 Bordetella Species 0.000 claims description 2
- 241000588832 Bordetella pertussis Species 0.000 claims description 2
- 201000006082 Chickenpox Diseases 0.000 claims description 2
- 241000193403 Clostridium Species 0.000 claims description 2
- 241000725619 Dengue virus Species 0.000 claims description 2
- 201000009906 Meningitis Diseases 0.000 claims description 2
- 241000711386 Mumps virus Species 0.000 claims description 2
- 241000588653 Neisseria Species 0.000 claims description 2
- 241000710799 Rubella virus Species 0.000 claims description 2
- 241000607142 Salmonella Species 0.000 claims description 2
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 claims description 2
- 241000194017 Streptococcus Species 0.000 claims description 2
- 206010046980 Varicella Diseases 0.000 claims description 2
- 206010013023 diphtheria Diseases 0.000 claims description 2
- 108700010900 influenza virus proteins Proteins 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 229920002114 octoxynol-9 Polymers 0.000 claims description 2
- 241000700721 Hepatitis B virus Species 0.000 claims 1
- 241000709721 Hepatovirus A Species 0.000 claims 1
- 201000005010 Streptococcus pneumonia Diseases 0.000 claims 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 claims 1
- 108700010850 rotavirus proteins Proteins 0.000 claims 1
- 238000000985 reflectance spectrum Methods 0.000 abstract description 3
- 239000000523 sample Substances 0.000 description 101
- 108090000765 processed proteins & peptides Proteins 0.000 description 20
- 230000005855 radiation Effects 0.000 description 19
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 18
- 239000013078 crystal Substances 0.000 description 18
- 238000011002 quantification Methods 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 102000004196 processed proteins & peptides Human genes 0.000 description 17
- 238000001514 detection method Methods 0.000 description 15
- 229920001184 polypeptide Polymers 0.000 description 15
- 238000002329 infrared spectrum Methods 0.000 description 14
- 229940068965 polysorbates Drugs 0.000 description 14
- -1 sorbitan laurate ester Chemical class 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- 238000009472 formulation Methods 0.000 description 12
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 10
- 238000004949 mass spectrometry Methods 0.000 description 10
- 238000004817 gas chromatography Methods 0.000 description 9
- 239000011159 matrix material Substances 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 238000002835 absorbance Methods 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 8
- 238000005259 measurement Methods 0.000 description 7
- 239000002736 nonionic surfactant Substances 0.000 description 7
- 238000004007 reversed phase HPLC Methods 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000012669 liquid formulation Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 241000712461 unidentified influenza virus Species 0.000 description 6
- 238000005452 bending Methods 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 230000035515 penetration Effects 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 230000003595 spectral effect Effects 0.000 description 5
- 239000004094 surface-active agent Substances 0.000 description 5
- 238000000108 ultra-filtration Methods 0.000 description 5
- 102000003886 Glycoproteins Human genes 0.000 description 4
- 108090000288 Glycoproteins Proteins 0.000 description 4
- 238000004566 IR spectroscopy Methods 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 229960000074 biopharmaceutical Drugs 0.000 description 4
- 238000001212 derivatisation Methods 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 239000012875 nonionic emulsifier Substances 0.000 description 4
- 244000052769 pathogen Species 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 238000012552 review Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000001179 sorption measurement Methods 0.000 description 4
- 238000005199 ultracentrifugation Methods 0.000 description 4
- 241000710842 Japanese encephalitis virus Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 239000000084 colloidal system Substances 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 208000006454 hepatitis Diseases 0.000 description 3
- 231100000283 hepatitis Toxicity 0.000 description 3
- 230000002779 inactivation Effects 0.000 description 3
- 229960003971 influenza vaccine Drugs 0.000 description 3
- YAQXGBBDJYBXKL-UHFFFAOYSA-N iron(2+);1,10-phenanthroline;dicyanide Chemical compound [Fe+2].N#[C-].N#[C-].C1=CN=C2C3=NC=CC=C3C=CC2=C1.C1=CN=C2C3=NC=CC=C3C=CC2=C1 YAQXGBBDJYBXKL-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 3
- 230000001717 pathogenic effect Effects 0.000 description 3
- 238000011182 polysorbate quantification Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000002098 selective ion monitoring Methods 0.000 description 3
- 238000004611 spectroscopical analysis Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- IQQRAVYLUAZUGX-UHFFFAOYSA-N 1-butyl-3-methylimidazolium Chemical compound CCCCN1C=C[N+](C)=C1 IQQRAVYLUAZUGX-UHFFFAOYSA-N 0.000 description 2
- 241000287828 Gallus gallus Species 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- 201000005702 Pertussis Diseases 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 241000702670 Rotavirus Species 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 230000003373 anti-fouling effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000012062 aqueous buffer Substances 0.000 description 2
- 230000002238 attenuated effect Effects 0.000 description 2
- 235000013405 beer Nutrition 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000012062 charged aerosol detection Methods 0.000 description 2
- INDBQWVYFLTCFF-UHFFFAOYSA-L cobalt(2+);dithiocyanate Chemical compound [Co+2].[S-]C#N.[S-]C#N INDBQWVYFLTCFF-UHFFFAOYSA-L 0.000 description 2
- 238000004737 colorimetric analysis Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 235000013601 eggs Nutrition 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000000105 evaporative light scattering detection Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000012417 linear regression Methods 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000004530 micro-emulsion Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229940031348 multivalent vaccine Drugs 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000010355 oscillation Effects 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 238000002203 pretreatment Methods 0.000 description 2
- 238000000513 principal component analysis Methods 0.000 description 2
- 229940021993 prophylactic vaccine Drugs 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 229950004959 sorbitan oleate Drugs 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 230000009897 systematic effect Effects 0.000 description 2
- 229940021747 therapeutic vaccine Drugs 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- JJRVRELEASDUMY-JXMROGBWSA-N (5e)-5-[[4-(dimethylamino)phenyl]methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one Chemical compound C1=CC(N(C)C)=CC=C1\C=C\1C(=O)NC(=S)S/1 JJRVRELEASDUMY-JXMROGBWSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- PFNQVRZLDWYSCW-UHFFFAOYSA-N (fluoren-9-ylideneamino) n-naphthalen-1-ylcarbamate Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1=NOC(=O)NC1=CC=CC2=CC=CC=C12 PFNQVRZLDWYSCW-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- HMFKFHLTUCJZJO-UHFFFAOYSA-N 2-{2-[3,4-bis(2-hydroxyethoxy)oxolan-2-yl]-2-(2-hydroxyethoxy)ethoxy}ethyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCCOCC(OCCO)C1OCC(OCCO)C1OCCO HMFKFHLTUCJZJO-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 241000272525 Anas platyrhynchos Species 0.000 description 1
- 101100167667 Arabidopsis thaliana CML24 gene Proteins 0.000 description 1
- 238000012935 Averaging Methods 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 241000282552 Chlorocebus aethiops Species 0.000 description 1
- 241000186227 Corynebacterium diphtheriae Species 0.000 description 1
- 206010014596 Encephalitis Japanese B Diseases 0.000 description 1
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 238000004971 IR microspectroscopy Methods 0.000 description 1
- 201000005807 Japanese encephalitis Diseases 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- QYDYPVFESGNLHU-ZHACJKMWSA-N Methyl (9E)-9-octadecenoate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OC QYDYPVFESGNLHU-ZHACJKMWSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 208000035109 Pneumococcal Infections Diseases 0.000 description 1
- 229920002730 Poly(butyl cyanoacrylate) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- 206010043376 Tetanus Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000012382 advanced drug delivery Methods 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000003225 biodiesel Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229940126587 biotherapeutics Drugs 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229940022399 cancer vaccine Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000010961 commercial manufacture process Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- QYDYPVFESGNLHU-UHFFFAOYSA-N elaidic acid methyl ester Natural products CCCCCCCCC=CCCCCCCCC(=O)OC QYDYPVFESGNLHU-UHFFFAOYSA-N 0.000 description 1
- 210000001671 embryonic stem cell Anatomy 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000012921 fluorescence analysis Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000005350 fused silica glass Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910052732 germanium Inorganic materials 0.000 description 1
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000001985 kidney epithelial cell Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 238000001471 micro-filtration Methods 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 238000004476 mid-IR spectroscopy Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229940031346 monovalent vaccine Drugs 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 238000001320 near-infrared absorption spectroscopy Methods 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000006353 oxyethylene group Chemical group 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 229960000380 propiolactone Drugs 0.000 description 1
- 230000004845 protein aggregation Effects 0.000 description 1
- 239000012460 protein solution Substances 0.000 description 1
- 231100000654 protein toxin Toxicity 0.000 description 1
- 230000006432 protein unfolding Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012723 sample buffer Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000002047 solid lipid nanoparticle Substances 0.000 description 1
- 229950006451 sorbitan laurate Drugs 0.000 description 1
- 235000011067 sorbitan monolaureate Nutrition 0.000 description 1
- 238000012306 spectroscopic technique Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 238000000411 transmission spectrum Methods 0.000 description 1
- 238000012384 transportation and delivery Methods 0.000 description 1
- STCOOQWBFONSKY-UHFFFAOYSA-N tributyl phosphate Chemical compound CCCCOP(=O)(OCCCC)OCCCC STCOOQWBFONSKY-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 238000002460 vibrational spectroscopy Methods 0.000 description 1
- 229960004854 viral vaccine Drugs 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
- G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
- G01N21/3577—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light for analysing liquids, e.g. polluted water
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/55—Specular reflectivity
- G01N21/552—Attenuated total reflection
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/55—Specular reflectivity
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
- G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
- G01J3/28—Investigating the spectrum
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
- G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
- G01N2021/3595—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light using FTIR
Landscapes
- Physics & Mathematics (AREA)
- Biochemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Investigating Or Analysing Materials By Optical Means (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261650735P | 2012-05-23 | 2012-05-23 | |
| US61/650,735 | 2012-05-23 | ||
| PCT/IB2013/001590 WO2013175312A1 (en) | 2012-05-23 | 2013-05-21 | Method for determining a concentration of a polysorbate species in a mixture |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2874077A1 CA2874077A1 (en) | 2013-11-28 |
| CA2874077C true CA2874077C (en) | 2020-07-07 |
Family
ID=48916129
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2874077A Active CA2874077C (en) | 2012-05-23 | 2013-05-21 | Method for determining a concentration of a polysorbate species in a mixture |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US9134228B2 (enExample) |
| EP (1) | EP2852828B1 (enExample) |
| JP (1) | JP6129302B2 (enExample) |
| CN (1) | CN104487823B (enExample) |
| BR (1) | BR112014029107B1 (enExample) |
| CA (1) | CA2874077C (enExample) |
| ES (1) | ES2574614T3 (enExample) |
| IN (1) | IN2014KN02807A (enExample) |
| WO (1) | WO2013175312A1 (enExample) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2504928A (en) * | 2012-08-06 | 2014-02-19 | Perkinelmer Uk Ltd | Diamond attenuated total reflectance spectrum artefact correction |
| CN103940773B (zh) * | 2014-04-09 | 2016-01-06 | 清华大学 | 一种快速测定血必净注射液中吐温-80含量的方法 |
| JP6859707B2 (ja) * | 2015-01-13 | 2021-04-14 | 東洋紡株式会社 | 被処理水の水質評価方法、定量方法および水処理方法 |
| CN105424636B (zh) * | 2015-12-29 | 2018-04-27 | 南京财经大学 | 一种粮食真菌污染情况的快速检测方法及其应用 |
| PL3497440T3 (pl) * | 2016-08-15 | 2025-08-04 | F. Hoffmann-La Roche Ag | Sposób chromatograficzny oznaczania ilościowego niejonowego środka powierzchniowo czynnego w kompozycji zawierającej niejonowy środek powierzchniowo czynny i polipeptyd |
| ES2985321T3 (es) * | 2017-06-27 | 2024-11-05 | Coriolis Pharma Res Gmbh | Ensayo de cuantificación de polisorbatos |
| EP3813651B1 (en) * | 2018-06-28 | 2023-09-06 | Becton, Dickinson and Company | Systems and methods for normalizing signals in blood culture measurement systems |
| WO2020002342A1 (en) * | 2018-06-29 | 2020-01-02 | F. Hoffmann-La Roche Ag | Fully implantable sensor element and method for detecting at least one analyte in a body fluid |
| TWI870390B (zh) * | 2019-02-27 | 2025-01-21 | 法商賽諾菲公司 | 以具內標之lc-ms於樣品中進行聚山梨醇酯定量之方法 |
| US10845248B1 (en) * | 2019-05-01 | 2020-11-24 | Trustees Of Boston University | Systems and methods for bond-selective transient phase imaging |
| GB202000670D0 (en) | 2020-01-16 | 2020-03-04 | Clinspec Diagnostics Ltd | Cell culture analysis |
| EP4121756A1 (en) * | 2020-03-20 | 2023-01-25 | GlaxoSmithKline Intellectual Property Development Limited | Method for detecting polysorbates |
| CN113049727B (zh) * | 2021-03-08 | 2024-04-26 | 哈尔滨瀚邦医疗科技有限公司 | 一种聚山梨酯80含量的检测方法 |
| CN115078557A (zh) * | 2021-03-12 | 2022-09-20 | 深圳赛保尔生物药业有限公司 | 一种蛋白制剂中吐温80含量的检测方法 |
| WO2022201862A1 (ja) * | 2021-03-26 | 2022-09-29 | 浜松ホトニクス株式会社 | 全反射減衰分光装置及び全反射減衰分光方法 |
| EP4202413B1 (en) * | 2021-12-21 | 2024-01-31 | Bruker Optics GmbH & Co. KG | Computer-implemented method for predicting sample properties based on spectral measurements and computer system therefor |
| CN116297915B (zh) * | 2023-02-10 | 2023-12-01 | 中国食品药品检定研究院 | 聚山梨酯类辅料的分析鉴定方法 |
| CN116448709A (zh) * | 2023-04-07 | 2023-07-18 | 上海佑尼化学有限公司 | 一种检测清洗剂工作液中非离子乳化剂的方法及其应用 |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6040191A (en) * | 1996-06-13 | 2000-03-21 | Grow; Ann E. | Raman spectroscopic method for determining the ligand binding capacity of biologicals |
| US5866430A (en) * | 1996-06-13 | 1999-02-02 | Grow; Ann E. | Raman optrode processes and devices for detection of chemicals and microorganisms |
| US7531358B2 (en) * | 2001-04-17 | 2009-05-12 | Chugai Seiyaku Kabushiki Kaisha | Method of quantifying surfactant |
| US7255835B2 (en) | 2001-09-04 | 2007-08-14 | North Carolina State University | Single pass attenuated total reflection fourier transform infrared microscopy apparatus and method for identifying protein secondary structure, surface charge and binding affinity |
| JP2003232727A (ja) * | 2001-12-04 | 2003-08-22 | Japan Organo Co Ltd | 水溶液中のスルホン酸基含有有機化合物の定量分析法 |
| US7435600B2 (en) * | 2004-06-23 | 2008-10-14 | Johns Manville | Infrared methods of measuring the extent of cure of a binder in fibrous products |
| JP2007117221A (ja) * | 2005-10-25 | 2007-05-17 | Hirato Koji | Ｆｔｉｒを用いた非侵襲血液検査「光人間ドックシステム」 |
| US20100304406A1 (en) * | 2008-09-17 | 2010-12-02 | Cell Signaling Technology, Inc. | Protein Phosphorylation by Serine/Threonine Kinases in Insulin Signaling Pathways |
| CN101943684B (zh) * | 2009-07-10 | 2012-12-05 | 华北制药集团制剂有限公司 | 一种聚山梨酯80有关物质的检测方法 |
-
2013
- 2013-05-21 EP EP13745180.3A patent/EP2852828B1/en active Active
- 2013-05-21 BR BR112014029107-1A patent/BR112014029107B1/pt active IP Right Grant
- 2013-05-21 CA CA2874077A patent/CA2874077C/en active Active
- 2013-05-21 ES ES13745180.3T patent/ES2574614T3/es active Active
- 2013-05-21 US US14/402,849 patent/US9134228B2/en active Active
- 2013-05-21 CN CN201380026314.2A patent/CN104487823B/zh active Active
- 2013-05-21 IN IN2807KON2014 patent/IN2014KN02807A/en unknown
- 2013-05-21 JP JP2015513294A patent/JP6129302B2/ja active Active
- 2013-05-21 WO PCT/IB2013/001590 patent/WO2013175312A1/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| EP2852828B1 (en) | 2016-04-06 |
| US9134228B2 (en) | 2015-09-15 |
| BR112014029107A8 (pt) | 2020-09-24 |
| CN104487823B (zh) | 2017-02-22 |
| BR112014029107A2 (pt) | 2017-06-27 |
| EP2852828A1 (en) | 2015-04-01 |
| JP6129302B2 (ja) | 2017-05-17 |
| US20150129766A1 (en) | 2015-05-14 |
| IN2014KN02807A (enExample) | 2015-05-08 |
| CA2874077A1 (en) | 2013-11-28 |
| ES2574614T3 (es) | 2016-06-21 |
| JP2015523556A (ja) | 2015-08-13 |
| BR112014029107B1 (pt) | 2021-07-13 |
| WO2013175312A1 (en) | 2013-11-28 |
| CN104487823A (zh) | 2015-04-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2874077C (en) | Method for determining a concentration of a polysorbate species in a mixture | |
| Pisupati et al. | A multidimensional analytical comparison of Remicade and the biosimilar Remsima | |
| Chatonnet et al. | Monitoring toasting intensity of barrels by chromatographic analysis of volatile compounds from toasted oak wood | |
| JP2016128822A (ja) | バイオプロセス操作用のラマン分光法 | |
| de Castro et al. | Direct determination of sorbitol and sodium glutamate by attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) in the thermostabilizer employed in the production of yellow-fever vaccine | |
| JP2015523556A5 (enExample) | ||
| Zhang et al. | Rapid, quantitative determination of aggregation and particle formation for antibody drug conjugate therapeutics with label-free Raman spectroscopy | |
| CN102046815A (zh) | 用于病毒检测的方法 | |
| Manceur et al. | Critical review of current and emerging quantification methods for the development of influenza vaccine candidates | |
| US20160305877A1 (en) | Early detection of cell activation by atr-ftir spectroscopy | |
| Yang et al. | Characterization and stabilization in process development and product formulation for super large proteinaceous particles | |
| US11598757B2 (en) | Methods and systems for efficient separation of polarized UV light | |
| CN116087363A (zh) | 一种吸附型疫苗中羧甲基葡聚糖含量的检测方法 | |
| CN102608058A (zh) | 一种虫草菌粉苏氨酸含量快速检测方法 | |
| Cotte et al. | Determination of molecular size parameters and quantification of polyacrylic acid by high performance size-exclusion chromatography with triple detection | |
| Jordan et al. | Characterizing Monoclonal Antibody Aggregation Using Charge Detection Mass Spectrometry and Industry Standard Methods | |
| Heigl et al. | Near infrared spectroscopy, cluster and multivariate analysis hyphenated to thin layer chromatography for the analysis of amino acids | |
| CN120188039A (zh) | 通过中红外光谱法监测和控制生物生产过程的系统和方法 | |
| CN204924937U (zh) | 果蔬农药残留测量系统 | |
| Chubchenko et al. | Features of determining the isotope composition of carbon in gaseous, liquid, and solid media | |
| WO2019117750A1 (ru) | Способ измерения количества полисорбата-80 с применением щелочного гидролиза образца с последующей вэжх | |
| Qian et al. | The CombE-IDMS Assay as an Alternate Potency Method for Adjuvanted Quadrivalent Influenza Vaccines | |
| CN112219117B (zh) | 使用内源荧光测定佐剂化蛋白质浓度和吸附百分比的方法 | |
| Liu et al. | Separation‐Based analytical methods for measuring protein aggregation | |
| Mukhopadhyay et al. | Development and validation of an UV-spectrophotometric method for the estimation of fluoxetine in pure and tablet dosage forms |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request |
Effective date: 20180509 |