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Ростовский Государственный Медицинский Университет
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Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_101_библиотеки_им_акад_М_И_Перельмана

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298
Formulation of Biopharmaceuticals
effective in intranasal distribution of biopharmaceuticals and peptides, facilitating direct nose- to­brain drug delivery via nanoparticles.
Liposomes are efcient carriers for delivering therapeutics into the skin due to their identical components to skin lipids. They are rapidly absorbed by the epidermis, reaching deep skin layers. Additionally, hydration layers enhance absorption by molecular mixing of the liposome bilayer with intracellular lipids in the stratum corneum.
A non- invasive macromolecule transdermal delivery system has been developed by encapsulating proteins in liposomes. Advanced liposomes have increased macromolecule permeation through the stratum corneum, overcoming limitations in drug delivery through the skin. To enhance macro­molecule delivery into the skin, liposomal formulations are integrated into dissolving microneedle arrays.
Liposomes stand out as highly effective pulmonary carriers for protein drugs due to their enhanced and sustained drug release, biocompatibility, biodegradability, and non- immunogenicity. Altering a drug’s physicochemical properties (increasing hydrophobicity) and reducing mucociliary clearance with liposomes may enhance drug permeation through the alveolar epithelium due to increased sur­face viscosity. This has led to the development of liposomal formulations for protein drug delivery to the lungs.
Apart from liposomes, solid lipid nanoparticles (SLN) have been investigated as carriers for delivering biopharmaceuticals through the lung epithelium. For instance, spray- dried powders containing SLNs have addressed the issue of low inertia, preventing nanoparticles from settling in the lungs.
12.6 SUMMARY
Drug delivery necessitates a dosage form delivering the active molecule at a predetermined rate and concentration to the site of action. Biopharmaceutical products, being large and inherently unstable molecules in various administration environments, often rely on the parenteral route. The safety and efcacy of biopharmaceuticals signicantly depend on the applied formulation and manufac­turing technology, unlike chemical products. Research exploring novel administration routes aims to expand biopharmaceutical applications. This chapter outlines model formulations for various classes of biopharmaceuticals.
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APPENDIX: PHYSICOCHEMICAL PROPERTIES OF PROTEINS AND PEPTIDES APPROVED BY THE FOOD AND DRUG ADMINISTRATION
Name MOA MW Formula IEP Hydrophobicity MP Half- Life
Abarelix IIIc 1416 C72H95ClN14O14 NA NA NA 13.2 ± 3.2 d Abatacept IIa 92300 C3498H5458N922O1090S32 NA NA NA 12– 23 d Abciximab IIa 145651 C6462H9964N1690O2049S48 6.16 −0.424 71 0.5 hrs Adalimumab Ic 144190 C6428H9912N1694O1987S46 8.25 −0.441 NA 240– 480 hrs Aibercept Ib 115000 C4318H6788N1164O1304S32 NA NA NA 7.13 d Agalsidase beta Ia 45352 C2029H3080N544O587S27 5.17 −0.307 NA 45– 102 min Albiglutide Ib 72970 C3232H5032N864O979S41 NA NA NA 4– 7 d Aldesleukin Ib 15315 C690H1115N177O202S6 7.31 −0.192 NA 0.22– 1.42 hrs Alefacept IIa 51801 C2306H3594N610O694S26 7.86 −0.432 NA 270 hrs Alemtuzumab IIa 145454 C6468H10066N1732O2005S40 8.76 −0.431 288 hrs Alglucerase Ia 55597 C2532H3854N672O711S16 7.41 −0.168 NA 3.6– 10.4 min Alglucosidase alfa Ic 105271 C4435H6739N1175O1279S32 NA NA NA 2.3 ± 0.4 hrs Alirocumab Ic 146000 C6472H9996N1736O2032S42 NA NA NA 17– 20 d Aliskiren IIa 552 C30H53N3O6 NA NA NA 24 hrs Alpha- 1- proteinase inhibitor IIa 44325 C2001H3130N514O601S10 5.37 −0.302 59 NA Alteplase Ib 59042 C2569H3928N746O781S40 7.61 −0.516 60 NA Anakinra IIa 17258 C759H1186N208O232S10 5.46 −0.412 NA 4– 6 hrs Ancestim Ib 18500 NA NA NA NA NA Anistreplase Ic 59042 C2569H3928N746O781S40 7.61 −0.516 60 NA Anthrax immune globulin human IIa NA NA NA NA NA 24.3 d Anti- inhibitor coagulant complex Ia NA NA NA NA NA 4– 7 hrs Anti- thymocyte Globulin (Equine) IIIb NA NA NA NA NA 1.5– 13 d Anti- thymocyte Globulin (Rabbit) IIIb NA NA NA NA 61 2– 3 d Antihemophilic Factor Ia 264726 C11794H18314N3220O3553S83 6.97 −0.533 NA 8.4– 19.3 hrs Antithrombin Alfa Ia 57215 C2191H3457N583O656S18 NA NA NA 11.6– 17.7 hrs Antithrombin III human Ia 58000 NA NA NA NA 2.5– 4.8 d Antithymocyte globulin IIa NA NA NA NA 61 2– 3 d Aprotinin IIa 6511 C284H432N84O79S7 NA NA >100 10 hrs Arcitumomab IIb 144483 C6398H9900N1714O1995S54 8.26 −0.423 61 1 hr Asfotase Alfa Ia 180000 C7108H11008N1968O2206S56 NA NA NA 5 d
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Formulation of Biopharmaceuticals
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Name MOA MW Formula IEP Hydrophobicity MP Half- Life
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Asparaginase Ic 31732 C1377H2208N382O442S17 4.67 0.059 NA 8– 30 hrs Asparaginase erwinia chrysanthemi Ic 140000 C1546H2510N432O476S9 NA NA NA 16 hrs Atezolizumab IIa 145000 NA NA NA NA 27 d Autologous cultured chondrocytes Ia NA NA NA NA NA NA Basiliximab IIa 143801 C6378H9844N1698O1997S48 8.68 −0.473 61 7.2 ± 3.2 Becaplermin Ib 12294 C532H892N162O153S9 9.38 −0.16 NA NA Belatacept IIa 92300 C3508H5440N922O1096S32 NA NA NA 9.8 d Belimumab IIa 147000 C 6358 H 9904 N 1728 O 2010 S 44 NA NA NA 19.4 d Beractant Ia NA NA NA NA NA 20– 30 hrs Bevacizumab IIa 149000 C6538H10034N1716O2033S44 NA NA 61 NA Bivalirudin Ia 2180 C98H138N24O33 3.91 −0.985 NA 0.42 hrs Blinatumomab IIIc 54100 C2367H3577N649O772S19 NA NA NA 2.11 hrs Botulinum Toxin Type A Ic 149323 C6760H10447N1743O2010S32 6.06 - 0.368 NA NA Botulinum Toxin Type B Ic 150804 C690H1115N177O202S6 NA NA NA NA Brentuximab vedotin IIb 149200– 151800 C6476H9930N1690O2030S40 NA NA NA 4– 6 d Brodalumab IIa 144000 C6372H9840N1712O1988S52 NA NA NA NA Buserelin IIIc NA C62H90N16O15 NA NA NA 50– 80 min C1 Esterase Inhibitor (Human) Ia 105000 NA NA NA NA 56 hrs C1 Esterase Inhibitor (Recombinant) IIa 67000 NA NA NA NA 2.4– 2.7 hrs Canakinumab IIIb 145200
C6452H9958N1722O2010S42 NA NA NA 26 d
(deglycosylated) Canakinumab IIa 145200 C6452H9958N1722O2010S42 NA NA NA 26 d Capromab IV NA NA NA NA NA NA Certolizumab pegol IIb 91000 C2115H3252N556O673S16 NA NA NA 14 d Cetuximab IIIc 145782 C6484H10042N1732O2023S36 8.48 −0.413 71 114 hrs Choriogonadotropin alfa Ib 25720 C1105H1770N318O336S26 8.61 −0.258 55 29 ± 6 hrs Chorionic Gonadotropin (Human) Ia 25719 C1105H1770N318O336S26 NA NA NA NA Chorionic Gonadotropin
Ia 25720 C1105H1770N318O336S26 8.61 −0.258 55°C 4.5 ± hrs
(Recombinant) Coagulation factor ix Ia 46548 C2041H3136N558O641S25 5.2 −0.431 54 19.4 4 hrs Coagulation factor VIIa Ib 45079 C1972H3076N560O597S28 6.09 −0.311 58 NA Coagulation factor X human Ib NA NA NA NA NA NA Coagulation Factor XIII A- Subunit
Ia NA NA NA NA NA 5.1 d
(Recombinant)
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Collagenase Ic 112023 C5028H7666N1300O1564S21 5.58 −0.714 NA NA
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Conestat alfa Ia NA NA NA NA NA 2.4– 2.7 hrs Corticotropin IV 4541 C207H308N56O58S NA NA NA 15 min Cosyntropin IV 2933 C136H210N40O31S NA NA NA 15 min Daclizumab Iia 142612 C6332H9808N1678O1989S42 8.46 −0.437 61 11– 38 d Daptomycin IIa 1621 C72H101N17O26 NA NA NA 7 d Daratumumab IIIc 148000 NA NA NA NA 18 d Darbepoetin alfa Ib 18396 C815H1317N233O241S5 8.75 −0.188 53 NA Debrotide NA NA NA NA NA NA a few hrs Denileukin diftitox IIb 57647 C2560H4042N678O799S17 5.45 −0.301 NA 1.16– 1.3 hrs Denosumab IIIc 144700 C6404H9912N1724O2004S50 NA NA NA 25.4 d Desirudin Ib 6964 C287H440N80O110 S6 NA NA NA 2– 3 hrs Digoxin Immune Fab (Ovine) IIa 47302 C2085H3223N553O672S16 8.01 −0.343 15– 20 hrs Dinutuximab IIIc 145000 C6422H9982N1722O2008S48 NA NA NA 10 d Dornase alfa Ib 29254 C1321H1999N339O396S9 4.58 −0.083 67 NA Drotrecogin alfa Ib 55000 C1786H2779N509O519S29 6.78 −0.291 NA 5.5 hrs Dulaglutide Ib 59670 C2646H4044N704O836S18 NA NA NA 5 d Eculizumab Ia 148000 NA NA NA NA 272 hrs Efalizumab IIa 150000 NA NA NA 5 d Efmoroctocog alfa Ib NA NA NA NA NA NA Elosulfase alfa Ia 110800 C5020H7588N1364O1418S34 NA NA NA 7.52– 35.9 min Elotuzumab IIIc 148100 C6476H9982N1714O2016S42 NA NA NA NA Enfuvirtide IIa 4492 C204H301N51O64 4.3 −0.875 NA 3.8 hrs Epoetin alfa Ib 18396 C815H1317N233O241S5 8.75 NA 53 NA Epoetin zeta Ib 18200 C809H1301N229O240S5 NA NA NA 7.37 hrs Eptibatide NA 832 C35H49N11O9S2 NA −2.3 NA 29 ± 6 hrs Etanercept IIa 51235 C2224H3475N621O698S36 7.89 −0.529 71 102 ± 30 hrs Evolocumab Iia 141800 C6242H9648N1668O1996S56 NA NA NA NA Exenatide Ib 4187 C184H282N50O60S NA NA NA 2.4 hrs Factor IX complex (human) Ib NA NA NA NA NA 11– 28 Fibrinogen concentrate (human) Ia 340000 NA NA NA NA 78.7 ± 18.13 hrs Fibrinolysin aka plasmin Ic 88400 C3848H5912N1096O1185S60 NA NA NA 24 hrs Filgrastim 1b 18800 C845H1343N223O243S9 5.65 0.209 60 3.5 hrs Filgrastim- sndz IIIc NA NA NA NA NA 3.5 hrs
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Formulation of Biopharmaceuticals
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Name MOA MW Formula IEP Hydrophobicity MP Half- Life
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Follitropin alpha Ib NA NA NA NA NA 24– 53 hrs in
females Follitropin beta Ib 22673 C975H1513N267O304S26 7.5 −0.33 55 35– 40 hrs Galsulfase Ia 56013 C2534H3851N691O719S16 NA NA NA 6– 40 min Gastric intrinsic factor Ib NA NA NA NA NA NA Gemtuzumab ozogamicin IIb 151000– 153000 NA NA NA 61 NA Glatiramer acetate IIa 5000– 9000 C254H422N70O72 NA NA NA NA Glucagon recombinant IV 3767 C165H249N49O51S1 9.52 −1.197 NA NA Glucarpidase Ic 44017 C1950H3157N543O599S7 NA NA NA 5.6 hrs Golimumab IIb 146943 C6530H10068N1752O2026S44 NA NA NA 2 weeks Gramicidin D IIa 1882 C99H140N20O17 NA NA 229 NA Hepatitis A vaccine IIIa NA NA NA NA NA Hepatitis B immune globulin IIIa NA NA NA NA NA 22– 25 d Human calcitonin Ib NA NA NA NA NA NA Human clostridium tetani toxoid
IIIb NA NA NA NA NA NA
immune globulin Human rabies virus immune globulin IIIa NA NA NA NA NA NA Human Rho(D) immune globulin IIIb NA NA NA NA NA 24– 30.9 d Human serum albumin Ia 66472 C2936H4624N786O889S41 5.67 −0.395 62 NA Human Varicella- Zoster Immune
IIIa NA NA NA NA NA 26.2 d
Globulin Hyaluronidase Ic 53871 C2455H3775N617O704S21 5.73 −0.117 NA NA Hyaluronidase (Human
Ib 61000 NA NA NA NA NA
Recombinant) Ibritumomab IIb 143376 C6382H9830N1672O1979S54 7.91 −0.359 0.8 hrs Ibritumomab tiuxetan IIIc 143376 C6382H9830N1672O1979S54 7.91 −0.359 61°C 0.8 hrs Idarucizumab Ib 47766 C2131H3299N555O671S11 NA NA NA 4.5– 10.8 hrs Idursulfase Ia 76000 C2654H4000N688O774S14 NA NA NA 44 ± 19 min Imiglucerase Ia 55597 C2532H3854N672O711S16 7.41 −0.168 NA 0.06– 0.173 hrs Immune globulin human IIIb 142682 C6332H9826N1692O1980S42 NA NA NA >20 hrs Iniximab IIa 144190 C6428H9912N1694O1987S46 8.25 - 0.441 9.5 d Insulin aspart Ia 582580 C256H381N65O79S6 NA NA NA 81 mins Insulin beef Ia 5734 C254H377N65O75S6 NA NA NA NA Insulin Degludec Ia 6104 C274H411N65O81S6 NA NA NA 25 hrs Insulin detemir Ia 5917 C267H402N64O76S6 NA NA NA 425 ± 78 min
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Insulin Glargine Ia 6063 C267H404N72O78S6 6.88 0.098 81 30 hrs
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Insulin glulisine Ib 5823 C258H384N64O78S6 NA NA NA 42 min Insulin Lispro Ia 5808 C257H387N65O76S6 5.39 0.218 81 1 hr Insulin Pork Ia 5796 C257H387N65O76S6 5.39 0.218 NA NA Insulin regular Ia 5808 C257H383N65O77S6 5.39 0.218 81 NA Insulin, porcine Ia 5796 C257H387N65O76S6 5.39 0.298 NA NA Insulin,isophane Ia 5808 C257H383N65O77S6 9 NA NA NA Interferon alfa- 2a, recombinant Ib 19241 C860H1353N227O255S9 5.99 −0.336 NA 6– 8 hrs Interferon alfa- 2b Ib 19271 C860H1353N229O255S9 5.99 −0.339 61 2– 3 hrs Interferon alfa- n1 Ib 19241 C860H1353N227O255S9 5.99 −0.336 61 1.2 hrs Interferon alfa- n3 Ib NA NA 5.99 NA 61 NA Interferon alfacon- 1 Ib 19271 C860H1353N229O255S9 5.99 0.339 61 2– 3 hrs Interferon beta- 1a Ib 20027 C908H1408N246O252S7 8.93 −0.427 NA 10 hrs Interferon beta- 1b Ib 20011 C908H1408N246O253S6 9.02 −0.447 NA 10– 20 min Interferon gamma- 1b Ib 17146 C761H1206N214O225S6 9.54 −0.823 61 NA Intravenous Immunoglobulin Ia 142682 C6332H9826N1692O1980S42 8.13 −0.331 61 20 hrs Ipilimumab IIIc 148000 C6572H10126N1734O2080S40 NA NA NA 14.7– 15.4 d Ixekizumab Ic 146158 NA NA NA NA 13 d Laronidase Ia 69899 C3160H4848N898O881S12 9.09 −0.3 NA 1.5– 3.6 hrs Lenograstim Ib 18668 C840- H1330- N222- O242- S8 NA NA NA 2.3– 3.3 hrs Lepirudin Ia 6963 C287H440N80O110S6 4.04 −0.777 65 1.3 hrs Leuprolide IIa 1209 C59H84N16O12 NA 0.1 NA 3 hrs Liraglutide Ib 3751 C172H265N43O51 NA NA NA 13 hrs Lucinactant Ib 2470 C126H238N26O22 NA NA NA NA Lutropin alfa Ib 30000 C1014H1609N287O294S27 8.44 −0.063 55 4.4 hrs Mecasermin Ib 7649 C331H518N94O101S7 NA NA NA 2 hrs Menotropins Ib 23390 C1014H1609N287O294S27 8.44 −0.063 55 NA Mepolizumab Ib 149000 NA NA NA 16– 22 d Methoxy polyethylene glycol-
Ib 60000 NA NA NA NA 134 ± 65 hrs
epoetin beta Metreleptin Ib 16155 C714H1167N191O221S6 NA NA NA 3.8– 4.7 hrs Muromonab IIa 146190 C6460H9946N1720O2043S56 8.31 −0.513 61 0.8 hrs Natalizumab IIa NA NA NA NA 61 11 ± 4 d
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Formulation of Biopharmaceuticals
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Name MOA MW Formula IEP Hydrophobicity MP Half- Life
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Natural alpha interferon OR
IIa 19300– 22100 NA NA NA NA NA
multiferon Necitumumab IIIc 144800 NA NA NA NA 14 d Nesiritide Ib 3464 NA NA NA NA 18 mins Nivolumab IIIc 143597 C6362H9862N1712O1995S42 NA NA NA 26.7 d Obiltoxaximab IIIa 148000 NA NA NA NA NA Obinutuzumab IIb 146100 C6512H10060N1712O2020S44 NA NA NA 28.4 d Ocriplasmin Ic 272500 C1214H1890N338O348S14 NA NA NA NA Ofatumumab IIIc 146100 C6480H10022N1742O2020S44 NA NA NA 2.3– 61.5 d Omalizumab IIa 145058 C6450H9916N1714O2023S38 7.03 −0.432 61 624 hrs Oprelvekin Ib 19047 C854H1411N253O235S2 11.16 −0.07 NA 6.9 hrs OspA lipoprotein IIIa 27743 C1198H2012N322O422S2 6.72 −0.652 NA 1.2 Hrs Oxytocin Ib 1007 C43H66N12O12S2 5.51 −2.7 NA 1– 6 min Palifermin Ib 16193 C721H1142N202O204S9 9.47 −0.65 NA NA Palivizumab IIIa NA NA NA NA 61 18– 20 d Pancrelipase Ia 131126 C5850H8902N1606O1739S49 6.44 NA 48– 50 NA Panitumumab IIa NA NA NA NA NA 7.5 d Pegademase bovine Ia 40788 C1821H2834N484O552S14 5.33 −0.428 NA NA Pegaptanib IIa NA NA NA NA NA 10 ± 4 d Pegaspargase Ic 31732 C1377H2208N382O442S17 4.67 0.059 NA NA Peglgrastim Ib 18803 C845H1343N223O243S9 5.65 0.209 60 15– 80 hrs Peginterferon alfa- 2a Ib 60000 NA 5.99 NA 61 80 hrs Peginterferon alfa- 2b Ib 31000 C130H219N43O42 5.99 NA 61 40 hrs Peginterferon beta- 1a Ia 20000 NA NA NA NA 78 hrs Pegloticase Ib 34193 C1549H2430N408O448S8 NA NA NA 14 d Pegvisomant IIa 22129 C990H1532N262O300S7 5.27 −0.411 76 6 d Pembrolizumab IIIc 146286 C6504H10004N1716O2036S46 NA NA NA 28 d Pertuzumab IIIc 148000 NA NA NA NA 18 d Poractant alfa Ia NA NA NA NA NA NA Pramlintide Ia 3949 C171H267N51O53S2 NA NA NA 48 min Preotact Ib 9420 C408H674N126O126S2 NA NA NA 1.5 hrs Protamine sulfate Ib NA NA NA NA NA 4.5 min Protein S human Ib 69000 NA 5.05.5 NA NA NA Prothrombin complex concentrate Ia NA NA NA NA NA 48– 60 hrs Ragweed Pollen Extract IIIa NA NA NA NA NA NA
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Ramucirumab IIIc 143600 C6374H9864N1692O1996S46 NA NA NA 15 d
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Ranibizumab IIa 48350 C2158H3282N562O681S12 NA NA NA 9 d Rasburicase Ic 34110 C1521H2381N417O461S7 7.16 −0.465 NA 18 hrs Raxibacumab IIa 142845 C6320H9794N1702O1998S42 NA NA NA 16– 19 d Reteplase Ib 39590 C1736H2671N499O522S22 6.86 −0.435 60 NA Rilonacept IIa 251000 C9030H13932N2400O2670S74 NA NA NA 8.6 d Rituximab IIa 143860 C6416H9874N1688O1987S44 8.68 −0.414 61 0.8 hrs Romiplostim Ib 59000 C2634H4086N722O790S18 NA NA NA 3.5 d Sacrosidase Ia 100000 NA NA NA NA NA Salmon Calcitonin Ib 3432 C145H240N44O48S2 8.86 −0.537 NA 0.83– 1.33 hrs Sargramostim Ib 14435 C639H1006N168O196S8 5.05 NA NA NA Satumomab Pendetide IV 141479 C6268H9708N1666O1971S48 7.02 −0.427 61 0.80 hrs Sebelipase alfa Ia 55000 C1968H2945N507O551S15 NA NA NA 5.4– 6.6 min Secretin IV 3056 C130H219N43O42 9.45 −0.463 NA NA Secukinumab IIa 147940 C6584H10134N1754O2042S44 NA NA NA NA Sermorelin Ia 3358 C149H246N44O42S 9.99 −0.33 NA 11– 12 min Serum albumin IV 66472 C2936H4624N786O889S41 5.67 −0.395 62 NA Serum albumin iodonated IV 66472 C2936H4624N786O889S41 5.67 −0.395 62 NA Siltuximab Iia 145000 C6450H9932N1688O2016S50 NA NA NA 20.6 d Simoctocog Alfa Ia 170000 NA NA NA NA 14.7 hrs Sipuleucel- T IIIc NA NA NA NA NA NA Somatotropin Recombinant Ib 22129 C990H1532N262O300S7 5.27 −0.411 76 at pH 3.5 NA Somatropin recombinant Ib 22129 C990H1532N262O300S7 5.27 −0.411 76 NA Streptokinase Ic 47287 C2100H3278N566O669S4 5.12 −0.728 NA NA Sulodexide IIIc 5000– 8000 NA NA NA NA 11.7 ± 2.0 hrs Susoctocog alfa Ib NA NA NA NA NA ~17 h Taliglucerase alfa Ia 56638 C2580H3918N680O727S17 10.54 NA NA NA Teduglutide Ia 3752 C164H252N44O55S NA NA NA 2 hrs Teicoplanin IIa 1880 C88H97Cl2N9O33 NA NA NA 70– 100 hrs Tenecteplase Ib 58951 C2561H3919N747O781S40 7.61 −0.528 60 1.9 hrs Teriparatide Ib 4118 C181H291N55O51S2 NA NA NA NA Tesamorelin Ib 5136 C221H366N72O67S NA NA NA 38 min Thrombomodulin Alfa Ib 52124 C2230- H3357- N633- O718- S50 NA NA NA 2– 3 d Thymalfasin Ib 3108 C129H215N33O55 NA NA NA 2 hrs
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Name MOA MW Formula IEP Hydrophobicity MP Half- Life
Thyroglobulin Ib 660 NA 65 hrs Thyrotropin Alfa IV 22673 C975H1513N267O304S26 7.5 −0.33 55 5 ± 10 hrs Tocilizumab IIa 148000 C6428H9976N1720O2018S42 NA NA NA 11 d Tositumomab IIb 143860 C6416H9874N1688O1987S44 8.68 −0.4144 0.8 hrs Trastuzumab IIa 145532 C6470H10012N1726O2013S42 8.45 −0.415 61 28.5 d Tuberculin Puried Protein
IV NA NA NA NA NA NA
Derivative Turoctocog alfa Ia NA NA NA NA NA NA Urofollitropin Ib 980 C42H65N11O12S2 7.5 −0.33 55 35– 40 hrs Urokinase Ib 31127 C1376H2145N383O406S18 8.66 −0.466 76 12 min Ustekinumab IIIb 14690 NA NA NA NA NA Vasopressin Ib 1050 C43H67N15O12S2 NA −4.9 NA 10– 20 min Vedolizumab IIa 146837 C6528H10072N1732O2042S42 7.6 NA NA 336– 362 hrs Velaglucerase alfa Ia 63000 C2532H3850N672O711S16 NA NA NA 11– 12 min
Notes: MOA (Mode of Action) Group Ia– Replacing a protein that is decient or abnormal; Group Ib– Augmenting an existing pathway; Group Ic– Providing a novel function or activity;
Group IIa– Interfering with a molecule or organism; Group IIb– Delivering other compounds or proteins; Group IIIa– Protecting against a deleterious foreign agent; Group IIIb– Treating any harmful disease; Group IIIc– Treating cancer; Group IV– Protein diagnostics.
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Quality and Compliance
13
Systems
13.1 COMPLIANCE
A detailed survey of common QA missteps found in audits is presented.
The core principles articulated in cGMP regulations forming a contemporary quality system
include
• Every product must exhibit distinct identity, strength, purity, and other quality attributes ensuring safety and effectiveness standards.
• Quality- by- design involves creating and developing manufacturing processes during product creation to consistently maintain predened quality at the manufacturing phase’s end.
• A robust quality system facilitates the ow of process information from production to com­mercial manufacturing and post- development improvements.
• The quality control unit (QCU) responsibilities, according to cGMP regulations, generally encompass quality control (QC) and quality assurance (QA) functions.
• QC involves evaluating in- process materials and nished goods to assess manufacturing pro­cess efciency and compliance with requirements.
• QA primarily encompasses reviewing and authorizing manufacturing, maintenance, associated records and procedures, and conducting audits and trend analysis.
13.1.1 cuRRent good ManufactuRing PRactice coMPliance
For a biopharmaceutical product to enter the market, it must receive approval (authorization in the EU and licensure in the US), necessitating a successful inspection by regulatory authorities. Understanding deciencies recorded by regulatory authorities is crucial in establishing a contem­porary quality system.
13.1.1.1 Food and Drug Administration
A comprehensive analysis of FDA observations over the past two decades reveals the most common issues companies overlook. The top- ten frequently cited observations by FDA inspections from 2006 to 2017 are outlined.
1. QC (quality control): Procedures not available in writing or followed.
2. QC: Controls of identity, strength, quality, and purity lacking due to missing specication, standards, sampling plans, or test procedures.
3. QA (quality assurance): CAPA not in place or practiced.
4. MFG (manufacturing): Written methods inadequate.
DOI: 10.1201/9781003392026-13
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