COPYRIGHTED MATERIALINDEX AAT-deficient patients, 233, 237. See also Alpha-1 antitrypsin (AAT)...
Transcript of COPYRIGHTED MATERIALINDEX AAT-deficient patients, 233, 237. See also Alpha-1 antitrypsin (AAT)...
INDEX
AAT-deficient patients, 233, 237.
See also Alpha-1 antitrypsin (AAT)
deficiency
ABCAI-mediated efflux, 292, 293.
See also ATP-binding cassette
transporter AI (ABCAI)
ATP binding cassette transporter G1
(ABCGI), 292, 293
Accreditation Council for Continuing
Medical Education (ACCME), 418
Acid-citrate-dextrose (ACD) blood
collection solution, 4
Acid-stabilized plasmin, 268
as a direct-acting thrombolytic, 259–271
Acquired angioedema (AAE), 249
Acquired ATIII deficiency, 152
Acquired Factor X deficiency, 107, 108
Acquired human TSE infections, 369
Acquired immunodeficiency syndrome
(AIDS), convalescent plasma
treatment of, 209. See also HIV
entries; Human immunodeficiency
virus (HIV); National AIDS Control
Organization (NACO)
Acquired inhibitors, 57
Activated clotting factors, 66
Activated Factor VII (FVIIa), 51, 69, 75
Activated Factor IX (aFIX, FIXa), 75,
81–83
Activated Factor X (FXa), 81. See also
Activated purified Factor X
Activated Factor XI (FXIa), 94
Activated Factor XII (FXIIa), 242
in Factor XI activation, 94
Activated Factor XIII (aFXIII, FXIIIa),
102, 139, 140
Activated factors, in PCC products, 72
Activated Hageman factor (HFa),
193
Activated partial thromboplastin time
(aPTT), 95
Activated partial thromboplastin time
(APTT) assay, 49, 50
Activated partial thromboplastin time
(APTT) test, 111, 112, 118
Activated PCC, 76. See also Activated
prothrombin complex concentrates
(APCCs); Prothrombin complex
concentrates (PCCs)
Activated Protein C (APC), 67, 148
Activated prothrombin complex
concentrate (FEIBA1), 37
composition of, 53
Activated prothrombin complex
concentrates (APCCs), 49, 50
clinical trials with, 52
mechanism of action of, 51–57
Activated purified Factor X, 112.
See also Activated Factor X (FXa)
Active coagulation enzymes, 51
Active lipids, 74
Acute coronary syndrome (ACS), 274,
288, 289
Acute hemorrhages, 57
Acute ischemic stroke, 268
Acute ITP, 220. See also Immune
thrombocytopenic purpura (ITP)
Acute lung injury (ALI), 352
Acute respiratory distress syndrome
(ARDS), 161, 341
ADAMTS-13 metalloprotease, 42
Adhesion molecules, expression of, 276
Adjunctive cancer therapy, ceruloplasmin
in, 341
Adsorption processes, for virus
removal, 364
Adsorption techniques, in plasma
fractionation, 441
Advanced glycation end products
(AGEs), 192
Advate1, 36
Adverse effects/events (AEs), 57, 58, 74
albumin-related, 176, 177
in ITP treatment, 220, 221
related to IVIG preparations, 198, 199
Adverse reactions
blood-cell-induced, 351
related to IVIG preparations, 198, 199
Aerosol alpha1-PI, 237, 238. See also
Alpha1-proteinase inhibitor
(Alpha1-PI)
Affinity chromatography, 33–35, 44,
84–86, 97, 105, 439, 440. See also
Double affinity chromatography
in albumin manufacture, 165
in FVIII manufacturing, 150
of FEIBA1 components, 51
of haptoglobin, 328
on heparin gels, 149
in plasma fractionation, 441
plasminogen purification by, 314, 315
in vWF purification, 45
Production of Plasma Proteins for Therapeutic Use, First Edition. Edited by Joseph Bertolini, Neil Goss, and John Curling.� 2013 John Wiley & Sons, Inc. Published 2013 by John Wiley & Sons, Inc.
471
COPYRIG
HTED M
ATERIAL
Affinity ligand chromatography, 349, 350
Affinity purification method, for
alpha1-PI, 231
Aggregate formation, in IVIG prepara-
tions, 195. See also Aggregation
Aggregation
preventing, 340
of viruses, 191
Albondin, 163, 164
Albumin, 437. See also Human albumin
entries; Human serum albumin
(HSA)
accompanying IVIG preparations, 197
aluminum limits for, 169, 170
anticoagulant activity of, 164
appropriate and inappropriate use
of, 174, 175
binding properties of, 175
biochemistry of, 160, 161
burn patient benefits of, 174, 175
as carrier for nitric oxide, 164
centrifugation of, 167, 168
characteristics and specifications
of, 168–171
citrate concentrations in, 171
clinical issues related to, 171–176
color of, 169
demand for, 21, 464
demand in China for, 453
drug binding to, 163
effects of, 172, 173
esterase activity of, 164
fatty acids in, 162, 163
fluid balance and, 161
free thiol in, 171
future trends for, 177, 178
glycation of, 164
guidelines for therapeutic use of, 171
guidelines for use of, 159
haptoglobin precipitation and, 328
immunomodulatory properties of, 164
ionic properties of, 232
ligands binding to, 162–164
as a low-risk product, 176
manufacturing of, 164–171
manufacturing process development
for, 166, 167
mechanism of action of, 161–164
molecular size distribution for, 171
pasteurization of, 165, 166
physiology and function of, 160
PKA activity in, 171
in plasma buffering, 164
preparation of, 159
prognostic value of, 174
properties of, 178
redox properties of, 164
role in critical illness, 160
roles of, 159, 171
as a safe plasma protein, 177
sepsis and, 176
transport and ligand binding of,
161–164
in treating liver disease, 175
Albumin concentration, 175
Albumin dialysis system, 175
Albumin fusion proteins, 178
Albumin microspheres, 178
Albumin preparations, purity of, 169, 170
Albumin production, 12
global, 159
Alkjaersig purification method, 313
Allergic PCC reactions, 75
Allergic reactions, 351–353
Alloantibodies, 37
inhibitory, 57
Alpha-1 antitrypsin (AAT)
deficiency, 227–229. See also AAT-
deficient patients
Alpha1-PI, 227, 228. See also Alpha1-
proteinase inhibitor (Alpha1-PI)
Augmentation therapy with, 229
elastase inhibition by, 229
future of, 237, 238
isolating, 230–232
new indications for, Inc., 238
structure of, 228, 229
trypsin-inhibitory activity of, 232
Alpha1-PI inactivation, 232
Alpha1-PI isoforms, 228
Alpha1-PI production methods,
comparison of, 236
Alpha1-PI purification methods
at industrial scale, 231–237
at laboratory scale, 229–231
Alpha1-proteinase inhibitor (Alpha1-PI),
227–240
Alphanate, 45
Alphanine1, 88
replacement therapy recommendations
for, 89
Alpha Therapeutics, 466
Aluminum limits, for albumin, 169, 170
Alzheimer’s disease, 195, 197, 200
American Association of Blood Banks
(AABB), 8, 423, 425
American market, 464
American Red Cross (ARC), 5, 7, 8, 10
in blood collection, 8
fractionation capability of, 9
Analytical comparability, strategies for
demonstrating, 408, 409
Analytical programs, successful, 410
Anamnestic responses, 58
Anaphylactic PCC reactions, 75
Anaphylactic reactions, 351, 352
Anaphylactoid reaction rate, for Octaplas
(LG), 352
Anastomosis, 3, 4
Angioedema
acquired, 249
hereditary, 241, 242, 248, 249
Angiogenic compounds, 152
Anhaptoglobinemia, 322
Animal bioassay, 375
Animal disease models, transferrin in,
306
Animal models
of blood loss and replacement, 326
in investigating hemophilia
therapies, 55
relevance of, 55–57
TSE-related, 371, 372
Animal parvoviruses, 328
Animal studies, haptoglobin in, 331
Animal thrombolysis studies, 265, 266
Anion(ic) exchange chromatography
(AEC), 44 , 187, 189
Anion exchange chromatography
procedure, 213
Anion exchangers, for PCC capture, 84
Anion exchange technology, 9
Annual Product Review, 399
Anthrax, as biological weapon, 210
Anthrax immune globulin (AIG), 212
Antibodies, 207
immobilized, 33
inhibitory, 37, 73, 74
inhibitory and noninhibitory, 57
monoclonal and polyclonal, 200
neutralizing, 191
reducing, 351
Antibody–antigen binding, 208
Antibody-based immunotherapy, 210
Antibody-based therapies, 207
Antibody concentrates, 7
Antibody degradation, 33
Antibody-dependent cellular cytotoxicity
(ADCC), 208
Antibody therapy, 208
Antibody titers, in IVIG
preparations, 195–197
Anticoagulant activity, of albumin, 164
Anticoagulant effect, reversal of, 73
Anticoagulants, 3
development of, 4
Anticoagulant solution, for source plasma
collection, 426
Anticoagulant system, 69
Anticomplementary active
aggregates, 198
Anticomplementary activity (ACA), 191,
193
of IVIG preparations, 192, 193
472 INDEX
Anti-D immune globulin, 9
Anti-D Mab, 222. See alsoMonoclonal
antibodies (Mabs)
Anti-D products, manufacturing process
of, 221
Antifibrinolytic agents, 249
Antifibrinolytic drugs, 96
Antihemophilic Factor B, 65
Antihemophilic globulin, in hemophilia
treatment, 33
Anti-HLA/HNA antibodies, 351, 352
Anti-inflammatory activity, of C1-
inhibitor, 249
Anti-inflammatory action, of
ceruloplasmin, 339
Antioxidant activity, of
ceruloplasmin, 338, 342
Antioxidant properties, of albumin, 164
Antiplasmin, 317
Anti-RBC antibodies, 220
Anti-Rh antibody, 218
Anti-Rh immunoglobulin, antenatal
administration of, 218
Antithrombin, 66, 67, 69, 70
in PCCs, 75
Antithrombin activity, 147, 148
Anti-thrombin–heparin complex, 52
Antithrombin III (ATIII). See also ATIII
entries
gene structure and function of,
147–149
manufacturing methods for, 149, 150
pasteurization of, 150
production and clinical use of, 147–157
protein structure and function of,
147–149
purification of, 149, 150
Antithrombin III deficiency, 151, 152
Antithrombin III therapy, 152
Antitoxins, virus neutralization and, 208
Antiviral products, 467
APCC composition, 53. See also
Activated prothrombin complex
concentrates (APCCs)
APCC potency, 53
Apheresis, plasma collected by,
423–425
Aplastic anemia, ceruloplasmin treatment
of, 340–342
ApoA-1, 273–276. See also
Apolipoprotein AI entries
Apolipoprotein AI (ApoAI), 283
Apolipoprotein AIMilano (ApoAIMilano)
first characterization of, 286, 287
as a fusion protein, 290
low plasma levels of, 287
manufacture by seed-based expression
in plants, 289–295
plant-derived manufacturing of,
283–300
purification of, 291
safflower-derived, 290–292
Apolipoprotein AIMilano HDL
therapy, 289
Apolipoprotein AIMilano production, cost
estimates of, 289
Apotransferrin, 304, 306
Apple domains, 93–95
Applicant plasma, 431
Aprotinin, 141, 142
Aralast NP production method, 236,
238
Aralast purification process, 233, 234,
236, 237
Argentine hemorrhagic fever,
convalescent plasma treatment
of, 209
Armour & Company, 8
Armour Pharmaceutical, 21
Army Blood Transfusion Service, 5
Arterial plaque, control of, 283
Arterial/venous thrombosis models, 265
Arteriovenous anastomosis, 3, 4
Artificial aggregation, of viruses, 191
Artificial HDL particles, 273, 274
Ascites, 175
Asher, David M., xi, 369
Asia
fibrin glues in, 137
plasma collection in, 21
Assays, to detect TSE infectivity, 375
ATIII concentrates, treatment with, 152.
See also Antithrombin III (ATIII)
ATIII deficiency, 147
ATIII–HSPG interaction, 148
ATIII inherited deficiencies, 151, 152
classification of, 151
ATIII isoforms, 147
ATIII-protease complexes, 149
ATIII protease inhibition, regulators
of, 148, 149
Atheroma volume, 288
Atherosclerosis, 273
ERASE study of, 278
role of inflammation in, 275
Atherosclerotic lesions, 284
Atherosclerotic models, 294
ATP-binding cassette transporter AI
(ABCAI), 284–286. See also
ABCAI-mediated efflux
Attenuated androgens, 249
Audit execution, 398, 399
Audit management, 397–399
risk-based, 398
Auditor qualification, 398, 399
Audit reports, 397, 399
Audits
from external bodies, 398
frequency and scope of, 398
Audit schedule, 397
Audits/inspections, 398
Augmentation therapy, with alpha1-PI,
229
Australia, plasma fractionation in, 16, 17
Australian Red Cross, 17
Autodegradation, 260–262
Auto-FIX concentrates, 49
Autoplex, 49, 50
Aventis Behring, 15, 466
“Axial flow” type columns, in plasma
fractionation, 441, 442
B19 NAT, 349. See also Nucleic acid-
based testing (NAT); Parvovirus B19
(B19V)
Bacterial endotoxin test (BET), 194
“Bad cholesterol,” 274
Bags, peeling of plasma into, 439
Barga, 345
Batch adsorption, in plasma protein
collection, 439, 440
Batch mode manufacturing, solvent/
detergent plasma and, 345
Baxter Bioscience, 8, 9, 21, 451, 461
growth of, 16
manufacturing strategy of, 15
Baxter Healthcare, 233, 236, 247
Bayer AG, 15
B-domain deleted FVIII product, 36, 37
Bebulin VH, 71
Bees, William, xi, 217
Behringwerke AG, 10
Benesis, 18
Berinert1, 247
Beriplex P/N, 71
Berkovsky, Aron, xi, 337
Bertolini, Joseph, x, xi, 3, 423
b-amyloids, antibodies to, 197
b-glucans, in IVIG preparations, 194
b-glucocerebrosidase, 11
Beta-hydroxylation modifications, 108
b-thalassemia, 307
Biesert, Lothar, xi, 345
Bilateral membranous conjunctivitis, 317
Bilirubin, albumin binding to, 163
Binding affinities, haptide, 120, 121
Bioactive lipids, 351, 352
Biochemical IVIG parameters, 194–198.
See also
Biogenic amines, regulation of, 339
Biolex, 290
Biological IVIG parameters, 194–198.
See also Intravenous
immunoglobulin (IVIG)
INDEX 473
Biological products, pathogen safety
of, 72, 73
Biological products commercialization,
licensure requirements for, 405, 406
Biological variance, 193
Biological weapons, hyperimmunes as
defense against, 210–212
Biologic(al)(s) License Application
(BLA), 143, 405, 406
solvent/detergent plasma and, 346
Biomarkers, of haptoglobin efficacy, 331
Biomedical devices, fibrinogen in, 125
Biopharmaceutical industry, contribution
of, 468
Biopharmaceutical products,
development/commercialization
of, 403
Biopharmaceuticals, 283
Bio Products Laboratory (BPL), 327, 328
manufacturing process used by, 329
Bio Products Laboratory concentrate, 96
Bio Products Laboratory Factor X
properties of, 111
Biotest AG, 10, 461
Bleeding
FXI deficiency and, 94, 95
PCCs to stop massive, 73
termination of, 66
Bleeding control agents, 57
Bleeding disorders, treatment of, 73
Bleeding episodes, 58. See alsoMassive
bleeding
in hemophiliacs, 37
regulation of, 105
spontaneous, 58
Bleeding events, PCC dosage for, 74
Blood. See also Hemo- entries; Plasma
entries; Serum entries
infectious agents in, 361
for medical use, 4
storing, 4
TSE infectivity in, 371–373
Blood banking, early history of, 3–5
Blood banks
first, 5
in India, 19
Blood Betterment Association, 5
Blood-borne lipid-enveloped viruses
(LEVs), 72, 73
Blood-borne viruses, 366
Blood-cell-induced adverse reactions,
351
Blood cell separators, 4
Blood clotting, FX zymogen and, 52
Blood coagulation, 66–68. See also
Coagulation entries
Blood coagulation cascade, 122, 123.
See also Clotting cascade;
Coagulation cascade
Blood collecting agencies, 425
Blood collection unit, sterile vacuum-
type, 9
Blood components
TSE infectivity reduction studies
for, 374
use of, 4
Blood contaminants, inactivating, 35
Blood Derivatives Production Centers
Act, 12
Blood donation/transfusion centers, 11
Blood donor deferral policies, 374
Blood donor organizations, 10
Blood donor recruitment, 4, 5
Blood donors, paid, 12. See also
Nonremunerated plasma
Blood donor screening, 376
“Blood establishment” (BE), 384, 397,
398
Blood field depots, 4
Blood groups, discovery of, 3, 4
Blood plasma, use of, 4. See also Plasma
entries
Blood Plasma Corp. of Japan, 17
Blood processing industry, 5
Blood procurement, expanding, 5
Blood products, viral safety of, 189, 190
Blood Products Laboratory (BPL), 11
Blood-related viruses, removal of, 190
Blood safety programs, 20
Blood substitutes, 5
Blood testing, 427, 428
Blood transfusion, early history of, 3–5
Blood-typing globulins, 7
“Blue” proteins, 337
Blundell, James, 3
Bogdanov, Alexander, 4
Boothe, Joseph, xi, 283
Bottles, peeling of plasma in, 439
Botulism antitoxin (eBAT), 212
Botulism antitoxin product, 213
Bourgeois, Louise, 217
Bovine plasma, 6
Bovine spongiform encephalitis/
encephalopathy (BSE), 370–372
albumin and, 177
atypical forms of, 376, 377
Bovine thrombin solution, 137
Bowl-type centrifuges, 440
Boyd, W. C., 7
Bradykinin, 242, 248, 249
Brain-derived infectivity, 375
Brazil
contract fractionation arrangements
in, 458
plasma fractionation plant in, 13
BRIC (Brazil, Russia, India, China)
countries, new plant investments
among, 454
Buchacher, Andrea, xi, 185
Bulmer, Mark, xi, 159
Burn patients, benefits of albumin use
in, 174, 175
Burn treatment, ceruloplasmin and,
341, 342
Bypassing agents, 57, 74
PCCs as, 75, 76
C1-inhibitor, 241–258
biochemistry of, 241
clinical issues related to, 248, 249
in fibrolytic treatment, 250
future trends of, 250, 251
large-scale production of, 244
mechanism of action of, 243
physiology of, 242, 243
potential clinical application
of, 251
potential clinical indications for,
249, 250
in prophylactic regimens, 250
published purification methods
for, 245, 246
roles of, 242, 243
C1-inhibitor capture, 247
C1-inhibitor manufacturing 243–247
virus reduction steps in, 244
C1-inhibitor measurement, international
standards for, 247, 248
C1-inhibitor molecule, 248
C1-inhibitor mutations, 241
hereditary angioedema and, 248
C1-inhibitor products, characterization
of, 247, 248
C1-inhibitor purification, 244–247
C1-inhibitor purified concentrate, 249
Cadaver blood, 8
Call centers, 417, 418
Canada, fractionation facilities of, 9
Canadian Red Cross, 9, 10
Cancer therapy, ceruloplasmin in, 341
Cangene, 10
Canine coronary occlusion model, 261
Canine hemophilia model, 55
Capillary electrophoresis, 263
Capillary leak syndrome (CLS),
C1-inhibitor and, 250
Caprylate (octanoate) fractionation, 187
Caprylate (octanoate) treatment, 190
Caprylic (octanoic) acid treatment, 365
CarboPlatinum (CarboPt), 119, 120
Carboxylate reaction, 81
Cardiovascular disease models, 287, 288.
See also Heart entries
Cardiovascular diseases, 277, 283
Cascade plasma fractionation
processes, 38
Catheter-assisted thrombolysis, 264
474 INDEX
Catheter-assisted thrombolysis therapy,
261
Catheter-delivered plasmin, 265
Cation binding, 119
Cation(ic) exchange chromatography
(CEC), 142, 189
Cation exchange chromatography
procedure, 213, 214
Cations, albumin binding to, 163
Cattle-derived products, regulations
for, 374
CD163 macrophage receptor, 326, 327,
330
Celestial Biologics, 20
Cell-based assays, 375
of haptoglobin, 330
Cell culture
fibrinogen-based products for, 125, 126
recombinant FVIII production in,
36, 37
Cell-free hemoglobin (CFH), 321,
324–327, 330, 331
pathological consequences of, 325, 326
toxicity of, 325, 326, 331, 332
Cell membrane removal, 351
Cellular blood components, vCJD
transfusion transmission risk and,
373
Cellular cholesterol, 286
Centeon company, 15
Center for Biologics Evaluation and
Research (CBER), 404
Central Drugs Standard Control
Organization (CDSCO), 20
Central Laboratory of the Netherlands
Red Cross (CLB), 14
Central regulatory systems, role of,
67, 68
Centre National de Transfusion Sanguine
(CNTS), 11
Centre R�egional de Transfusion Sanguine(CRTS), 247
Centres of Excellence, 15
Centrifugation
in albumin manufacture, 167, 168
continuous-flow, 4
in ethanol fractionation, 440
intermittent flow, 4
Ceruloplasmin (CP), 337–344. See also
CP entries
as an acute inflammatory phase
protein, 339
as an adjunctive cancer therapy, 341
administration of, 340
anti-inflammatory action of, 339
antioxidant activity of, 338, 342
in aplastic anemia treatment, 340–342
biogenic amine regulation by, 339
biological functions of, 337–339
clinical effectiveness of, 342
clinical uses of, 340–342
as copper carrier and copper cycle
regulator, 338
in emergency medicine, 341, 342
ferroxidase action of, 338
manufacture of, 339, 340
pharmaceutical indications for, 340
structure and function of, 337, 338
Ceruloplasmin deficiency, 337
Cetor1, 244
CFH removal, 332. See also Cell-free
hemoglobin (CFH)
cGMP compliant equipment, in plasma
fractionation, 441. See also Current
good manufacturing practice
(cGMP) guidelines
Chain-cleavage reactions, 123
Change, actions to execute, 397
Change control philosophy, 392
Change control process, 396, 397
Change control reports, 393
Change control system, 396, 397
objective of, 397
Change strategy, 396
Chart construction, 390, 391
Chart interpretation, 391
Chemical virus inactivation, 364, 365
Chemo-Sera Therapeutic Research
Institute, 18
China
demand for albumin in, 453
plasma fractionation in, 18, 19
China National Blood Products
Corporation, 18
Cholate-based method, 292
Cholesterol efflux, 292, 293
Cholesterol ester (CE), 284
Cholesterol ester transfer protein
(CETP), 284, 286
Cholesterol homeostasis, 283, 284
Cholesterol levels, safflower-derived
apolipoprotein AIMilano:POPC
and, 292, 293
Cholesterol metabolism, 275
Cholesterol transport, 274, 275, 283
Cholesteryl ester transfer protein
(CETP), 273, 274
Christmas factor, 65
Chromatographic fractionation, 188, 189
Chromatographic manufacturing, 9, 10
Chromatographic matrices, 84
Chromatographic procedures, 213, 214
for plasma fractionation, 437, 438
for virus removal, 364
Chromatographic processes, 17
albumin-related, 165
Chromatographic purification methods/
techniques, 105, 124
Chromatographic resins, in plasma
fractionation, 441
Chromatographic separation process, 221
Chromatographic technology, 11, 13
Chromatography
in human serum albumin manufacture,
166
in plasma fractionation, 441
Chromatography-based purification
method, for alpha1-PI, 230
Chromatography methods, for isolating
proteins, 38
Chromatography polishing, 188
Chronic intoxication, ceruloplasmin
and, 341
Chronic ITP, 219, 220. See also Immune
thrombocytopenic purpura (ITP)
Chtourou, Sami, xi, 31, 41, 93
CIP fluids, 168. See also Clean in place
(CIP) centrifuge design
Circulatory volume, albumin and, 175
Cirrhotic ascites, 175
Citrate concentrations, in albumin, 171
Cleaning procedures, validation of, 394
Clean in place (CIP) centrifuge
design, 167. See also CIP fluids
Cleavage loop (CL), in plasminogen, 311
Clinical coagulation tests, 118
Clinical efficacy, of products, 406
Clinical-grade plasmin, manufacturing
of, 261–264
Clinical safety, of plasma-derived
products, 406
Clot formation, 139, 140. See also
Coagulation entries; Thromb- entries
Clot parameters, 119
Clotting cascade, FVIII during, 32.
See also Blood coagulation cascade;
Coagulation cascade
Clotting Factor VIII, 31–40. See also
Factor VIII (FVIII)
gene structure and function/regulation
of, 31, 32
immune tolerance to, 37, 38
nanofiltering, 36
production methods for, 33–35
Clotting factors, activated, 66
Clotting pathways, 82
Clotting-related proteins, 7
Clotting time (CT), simulating, 118,
119
Coagulant factor therapy, 35. See also
Clot- entries
Coagulation cascade, 94, 122, 123.
See also Clotting cascade
activators in, 59
INDEX 475
Coagulation disorders, replacement
therapy for, 46
Coagulation FVIII interaction, vWF
protein and, 42, 43
Coagulation Factor IX, 88. See also
Factor IX (IX)
Coagulation factor concentrates, 106
Coagulation factors, 59, 81
deficiencies of, 67, 68
elevated levels of, 68
mutations in, 75
of prothrombin complex, 65
Coagulation factor treatment, access
to, 37
Coagulation mechanisms, alternative,
123
Coagulation pathway physiology, 66–68
Coagulation products, safety of, 38
Coagulative system, C1-inhibitor role
in, 243
Coagulopathy, 152
Coan, Michael, 232
Cochrane Injuries Group Albumin
Reviewers Meta-analysis, 172, 173,
176
Code of Federal Regulations (CFR), 385,
423
Cofact, 71
Cohn, Edwin J., 4, 5–7, 423, 437
plasma fractionation industry and, 7, 8
Cohn I precipitate, 141. See also Cohn
Fraction I precipitate
Cohn IV-1 precipitation conditions, 232.
See also Cohn Fraction IVentries
steps in, 150
Cohn-Chromatography process, 17
Cohn Fraction I precipitate, 102. See also
Cohn I precipitate
Cohn Fraction IV, transferrin from, 303
Cohn Fraction IV-1, in ceruloplasmin
manufacture, 339
Cohn Fraction IV-1, 4 pastes, 230,
231–233, 235–237
Cohn fractionation method/process, 33,
43, 164, 186, 187, 437. See also
Cohn’s Method
transferrin from, 303
Kistler–Nitschmann fractionation
method vs., 165
Cohn/Oncley fractionation process, 191,
213, 262, 407
Cohn’s Method, 11, 221. See also Cohn
fractionation method/process
modifications to, 12
purification of hyperimmune
immunoglobulin and, 212
Cold ethanol fractionation, 363
Cold ethanol fractionation processes, 262
albumin-related, 164, 165
transferrin from, 303
Collagen binding assay (vWF:CB), 43
Collection centers, in United States, 21
Colloid osmotic pressure (COP)
of plasma, 161
Colloids, 172
Color, of albumin, 169
Column adsorption, in plasma protein
collection, 439, 440
Columns, membranes vs., 445, 446
Commercial blood banks, in Japan, 17
Commercial fractionators
developments of, 16
processing capacity of, 14, 15
Commercial plasma fractionation
facilities, total number of, 15
Commercial product strategy, Medical
Affairs and, 416, 417
Commercial sector, 461
Commonwealth Serum Laboratories
(CSL), in Australia, 16, 17. See also
CSL entries
Communication centers, 417
Communication channels, cross-
functional, 421
Community-based Donor standard, 427
Company–government
relationships, 466, 467
Comparability concept, 407–410
Comparability Master Plan, 407, 408
Comparability program, successful, 409,
410
Comparability strategy, 409
Comparability study, 409
Comparability testing, 408, 409
Complement activation, 208
Complement activation pathways,
regulation of, 242, 243
Complement control protein (CCP)
domain, in haptoglobin, 323
Complement system, C1-inhibitor role
in, 243
Compliance
with GMP and GLP, 388
with key regulatory standards, 416
“Compliance Program Guidance for
Pharmaceutical
Manufacturers,” 414
Component plasma, 431
Comprehensive change strategy, 396
Concanavalin A chromatography step, in
alpha1-PI purification, 230
Concentrates
differences among, 70
formation of, 69, 70
Concurrent plasma, 431
Conestat alpha, 250
Confidence interval (CI), 58
Congenital emphysema, 229
Connaught Laboratories, 9
Contact centers, 417
Contact system, C1-inhibitor role in, 243
Contaminant removal, 214
Contaminated plasma, solvent/detergent
plasma and, 345
Continuous centrifuges, 440
Continuous-flow centrifugation, 4
Continuous process verification, 393
Continuous small volume mixing
(CSVM) process, 11
Contract fractionation, 90, 458
Contract manufacturing, 465, 466
Control chart, 390, 391
Convalescent plasma, 209
passive immunotherapy with, 209, 210
Convalescent serum (sera), 210
for infectious diseases, 209
Copley, A., 117
Copper, 337, 338
Copper binding areas, of
ceruloplasmin, 337
Copper deficiency, 338
Core Summary of Product Characteristics
(cSmPC), 173, 174
CorifactTM, 105
Coronary atherosclerosis, ERASE study
of, 278
Coronary heart disease, ApoAI and, 284
Corporate restructuring, 413
Corrective Action/Preventive Action
(CAPA) principle, 387, 389, 395,
396
Corrective actions, 395, 396
Corticosteroids, 316
Corticoteroid treatment, 219
Courtland Laboratories, 9
Covalent complex, 244
CP isoforms, 337. See also
Ceruloplasmin (CP)
CP-mediated copper excretion
cycle, 338
CP properties, role in disease
treatment, 342
CP proteolysis, 340
CP synthesis, 337
Creutzfeldt-Jakob disease. See Sporadic
CJD (sCJD); Variant Creutzfeldt-
Jakob disease entries
Critical process parameters (CPP), 389
Critical quality attributes (CQA), 389
Critical therapeutics, control and
oversight of, 446
Cross-contamination, 429
“Cross flow” filtration, in plasma
fractionation, 443
476 INDEX
Cross-functional communication
channels, 421
Cryo-poor plasma, 431, 432, 439
Cryoprecipitate(s), 44, 102, 141, 375
fibrinogen from, 123, 124
in hemophilia treatment, 33
Cryoprecipitation, in plasma protein
collection, 438, 439
Cryo-rich plasma, 432, 439
Cryosupernatant, 456
Crystalloids, 172
CSL-112 formulation, 278. See also
Commonwealth Serum Laboratories
(CSL)
CSL Behring, 15, 234, 236, 237, 451,
461, 466
CSL Ltd., 17, 21
growth of, 16
CSL process, 234
“Cup and saucer” architecture, 94
Curling, John, x, xi, 3, 451
Current good manufacturing practice
(cGMP) guidelines, 429, 444, 445.
See also cGMP compliant equipment
Cutter, Robert, 5, 8
Cutter Laboratories, 8
Cutter purification process, 232, 233
Cyclic adenosine monophosphate
(cAMP), 293
Cyclic Fenton reaction, 123
Cysteine residues, in haptoglobin, 323
Cysteine
in albumin, 161
in FXI molecular structure, 93
Cysteine residues, in vWF protein
structure, 42
Cystic fibrosis, 238
Dalton, Joan, xi, 321
“Dead-end” filtration, in plasma
fractionation, 443
DEAE-Cellulose, 84, 244
DEAE-Sephadex1, 83, 84, 108, 213,
244, 247, 313, 439, 445
DEAE-Sepharose1 FF, 70, 83, 84
in albumin manufacture, 165
Dempster, F. J., 16
Denatured FVIII, 37. See also Factor VIII
(FVIII)
Denmark State Serum Institute, 14
De novo donors, 221
Depth filters, 440
des-1,2-ApoAIMilano, 291, 292. See also
Apolipoprotein AIMilano
(ApoAIMilano)
Desiccated plasma, 5
Design of experiments (DoE), 389, 390,
407
Design qualification (DQ), 391
Design space, 389, 390
Desmopressin (DDAVP), 43, 96
Deutsches Rotes Kreuz (DRK)
Blutspendedienst Nordrhein-
Westfalen, 345. See also German
Red Cross (DRK)
Developing countries/nations
blood collection improvements
within, 454
dependency on plasma products, 458
providing plasma products to, 453,
454
Developing country needs,
addressing, 465, 466
Developing markets, growth potential
of, 468
Deviations
dealing with, 393–396
process flow for handling, 395
Dextran sulfate affinity resins, 85
Diabetes, therapeutics for, 283. See also
Type 1 diabetes
Diafiltration
in alpha1-PI purification, 230, 231
in plasma fractionation, 442
Diatomaceous earths, filter aids based
on, 168
Dichtelm€uller, Herbert, xi, 361
Diphtheria, antibodies to, 195, 196
Direct-acting thrombolytics, acid-
stabilized plasmin as, 259–271
Direct transfusion, 3, 4
Diseases. See also Alzheimer’s disease;
Atherosclerosis; Cardiovascular
diseases; Diabetes; Emphysema;
Graft-versus-host disease (GVHD);
Hemolytic disease of the fetus and
newborn (HDFN); Hemolytic
disease of the new born (HDN);
Hepatitis entries; Infectious diseases;
Infectious inflammatory diseases;
Ischemic heart disease; Ligneous
conjunctivitis; Liver disease;
Pancreatitis; Polio; Prion diseases;
Pseudomembraneous disease; TSE
diseases; Variant Creutzfeldt-Jakob
disease (vCJD); Viral diseases;
Wilson–Konovalov disease
as biological weapons, 210–212
pulmonary, 228
rare, 101, 462, 463
reconstituted HDL replacement therapy
for, 277
transmission of, 151
Disease state plasma, 212
Disposables, 445
Disruptive processes, 445
Disseminated intravascular coagulation
(DIC), 152
Disulfide bonds, in haptoglobin, 323
Disulfide bridges, in alpha1-PI, 230, 231
Divalent cations, albumin binding to, 163
Domains. See also Apple domains; Factor
IX catalytic domain; Kringle
domains; Serpin C1-inhibitor
domain
albumin, 160
for coagulation factors, 82
fibrinogen, 138, 139
in haptoglobin, 323
plasminogen, 312
thrombin, 139
in vWF protein structure, 42
Domain structure, of fibrinogen, 117, 118
Donation centers, 426
Donations, testing of, 427, 428
Donor deferral, 374, 428
Donor Education Standard, 427
Donor history questionnaire, 426, 427
Donor screening, 426, 427
Donor selection, 361, 366
“Donor stim” program, 213
Dosage optimization, for PCCs, 74
Dose-efficacy relationship, 89
Double affinity chromatography, 85, 86
Drew, Charles, 5, 10
Dried human plasma, 6
Drugs
albumin binding to, 163
binding and transport of, 163
binding to fibrinogen, 119, 120
HDL-increasing, 273
Dry fibrin glue formulations, 143
Dry heat treatment, 35, 87
DTT treatment, 234
Duran-Jord�a, F., 10Dysplasminogenemia, 315
Early generation PCCs, thrombotic events
with, 66
ECH-Lysine Sepharose resin, 314
Economic growth, 18
Economics, of plasma
fractionation, 451–460
Edsall, John T., 7
Educational grants, 418
Efficacy, preclinical evidence of,
264–267
Efficacy studies, 264–266
Egyptian Organization for Biological and
Vaccine Production (Vacsera), 20
Ehrlich, Hartmut, xi, 413
Ehrlich, Paul, 5
VIIISelect affinity matrix, 38
Elastase, alpha1-PI inhibition of, 229
INDEX 477
Elastase, 227, 228
Electrophoresis, of haptoglobin, 330
Electrospun fibrinogen fibers, 125
Electrostatic interactions, haptoglobin
quaternary structure and, 323
Elsinger, Fritz, 50, 51
EMABling1, 221, 222
EMA regulatory documents, 385
Emergency medicine, ceruloplasmin
in, 341, 342
Emerging markets, 464, 465
Emphysema, 227–229
Enders, J. F., 7
Endogenous blood infectivity, reduction
studies with, 375
Endothelial glycocalyx layer (EGL), 161
Endotoxemia, C1-inhibitor and, 249,
250
Endotoxins, in IVIG preparations,
193, 194
Enveloped viruses, inactivating, 190
Epidemiological data, 384
Epidermal growth factor (EGF)-like
domains, 82
Epitope masking, 218
Epitopes, fibrinogen, 120–122
Equine IgG, 213, 214
Equine serum, 6
Equipment, 444
ERASE study, 278
Erythroblastosis fetalis, 217
Esterase activity, of albumin, 164
Etablissement FranScais du SangAquitaine-Limousin, 345
ETC216 (1-palmitoyl-2-oleoyl
phosphatidylcholine), 288, 289, 292
Ethanol-based precipitation methods, 7
Ethanol fractionation, 186, 187, 440.
See also Cold ethanol fractionation
entries
in human serum albumin
manufacture, 166
Ethicon, 20
EU GMP regulations, 386. See also
European Union (EU)
Europe
AAT deficiency in, 228
fibrin glues in, 137
for-profit fractionation in, 12, 13
legal plasma-regulatory documents
in, 385
multinational fractionation industry
in, 14–16
not-for-profit fractionation in, 11–13
not-for-profit sector consolidation
in, 14
plasma collection in, 21
plasma fractionation in, 13
plasma manufacture in, 384, 385
European Directorate for the Quality of
Medicines and HealthCare (EDQM),
429
European fractionation industry, 10–13
European governments, Red Cross
and, 11–13
European guidelines, for plasma
collection, 424
European market, 463, 464
European Medicines Agency
(EMA), 318, 362, 384, 467
European Medicines Agency Committee
for Medicinal Products for Human
Use (EMEA/CHMP), 66
European Pharmacopoeia (EP), IVIG
parameters defined by, 191–194
European Pharmacopoeia Monograph
1223, 87, 88
European Union (EU). See also EU GMP
regulations
plasma standards in, 425
rare disorders in, 101
Exogenous infectivity, reduction studies
with, 375, 376
Exosites, 139
Expanded bed chromatography, 446
External audits, 399
Extracellular matrix (ECM), 119
Extrinsic clotting pathway, 82
Eye drop plasminogen concentrate, 311
in case study, 317, 318
FI-C precipitate, 102–104. See also
Fibrinogen (Factor I)
FII-FXa complexes, 56. See also
Factor II (FII, prothrombin); Factor
Xa (FXa); Prothrombin entries
FV-deficient plasma, 54. See also Factor
V (FV)
FVIIa concentration, 72. See also Factor
VII (FVII, proconvertin)
FVII activation, 59
FVIII antibodies, 73, 74. See also Factor
VIII (FVIII); Plasma-derived FVIII
FVIII coagulant activity, 51
FVIII concentrates, 37
FVIII-deficient hemophilic dog, 55
FVIII gene, 31
FVIII immunogenicity, 37
FVIII-inactivating inhibitors, rescue
therapy for patients with, 37, 38
FVIII infusions, 37
FVIII inhibitor plasma, 53, 54
FVIII inhibitors, therapeutic approaches
for, 57
FVIII molecule, improving expression
levels of, 36, 37
FVIII mutations, 31
FVIII products, improvement of, 44
FVIII protein, structure and function
of, 31, 32
FVIII protein synthesis, 31
FVIII replacement, 33
FVIII variants, 38
FVIII/vWF–heparin interaction, 45
FVIII/vWF-rich plasma fraction, 43
FIX activation, 85. See also Factor IX
(FIX, antihemophilic Factor B,
Christmas factor)
FIX concentrates, 52, 73
clinical efficacy of, 89
FIX deficiency, 49, 73
FIX dosing, 88
FIX manufacture, processes used in, 87
FIX product yield, 87
FIX units, 74
FX activation, 32. See also Factor X (FX,
Stuart–Prower factor)
FX separation, 85
FXIa inhibition, 243. See also Factor XI
(FXI)
FXIa procoagulant activity, 199
FXI binding, 59
FXI cleavage, 94
FXI coagulation activity, 95, 96
FXI concentrates, 97
FXI zymogen crystal structure, 94
FXIII-A subunit, 102. See also Factor
XIII (FXIII, fibrin stabilizing factor)
deficiency of, 105
FXIII-B subunit, 102
FXIII concentration, 142
Facility design, 443, 444
Facnyne, 71
Factane1, principal steps in
manufacturing, 36
Factor I. See Fibrinogen (Factor I)
Factor II (FII, prothrombin), 65, 69. See
also FII–FXa complexes
biochemical characteristics of, 68
Factor II concentration, 66
Factor V (FV), 55. See also FV-deficient
plasma
Factor VII (FVII, proconvertin), 65, 69.
See also FVII entries
biochemical characteristics of, 68
reduction of, 52
Factor VIIa (FVIIa), 37. See also Plasma-
derived FVIIa
Factor VII concentration, 66
Factor VIII (FVIII), 439. See also
Clotting Factor VIII; FVIII entries;
Human plasma coagulant
Factor VIII; Plasma-derived FVIII;
Plasma-derived FVIII; Purified
FVIII; Recombinant Factor VIII
(rFVIII)
inhibitors and, 57
478 INDEX
prophylactic therapy with, 58
risk of contamination of, 375
sales of, 452
Factor VIII inhibitor bypassing activity
(FEIBA1), 49–63, 65
active principle of, 51–57
clinical use/experience with, 57, 58
in FVIII-deficient plasma with
inhibitors, 59
inhibitor bypassing potency of, 52, 53
as multicomponent therapeutic agent,
59, 60
pharmacokinetic properties of, 57
Factor VIII products, 34, 467
Factor IX (FIX, antihemophilic Factor B,
Christmas factor), 65, 69, 81–92.
See also FIX entries
biochemical characteristics of, 68
biochemistry and physiology of, 81–83
clinical aspects of, 88, 89
posttranslational modifications of, 83
prophylactic therapy with, 58
sales of, 452
Factor IXa-a, 82
Factor IX catalytic domain, 82
Factor IX concentrates
developing high-purity, 87
flow diagram for, 85
highly purified plasma-derived, 86
production processes for, 83–87
Factor IX concentration, 66
Factor IX gene, 81
Factor IX isolation, techniques used
for, 84
Factor IX products, 82, 83, 467
process comparison for, 86
purification methods of, 85
Factor IX purification, 84
Factor X (FX, Stuart–Prower factor), 65,
101, 107–111. See also FX entries
biochemical characteristics of, 68
biochemistry of, 108
clinical issues related to, 110, 111
future trends for, 111, 112
indications for, 112
in prothrombin complex
concentrates, 108
manufacturing of, 108–110
physiology of, 107, 108
Factor Xa (FXa), 51, 53, 69. See also
FII-FXa complexes
prothrombin protection by, 59
role of, 53–55
Factor X activation, 107
Factor Xa inactivation, 107
Factor X concentrate
functionality of, 111
safety profile of, 111
therapeutic, 108
toxicity of, 111
Factor X concentration, 66, 110
Factor X deficiency, 107
bleeding patterns of, 107
substitution therapy for, 110
Factor X gene, 107
Factor X manufacturing process,
characteristics of, 111
Factor X potency, 110
Factor X products, development of, 108
Factor X safety concerns, 110, 111
Factor X-specific activity, 108, 110
Factor X zymogen, 52
Factor XI (FXI), 93–99. See also FXI
entries
biochemistry of, 93, 94
fibrinolysis and, 95
mechanism of action of, 94, 95
pathophysiology of, 95
Factor XI activation, 94
Factor XI concentrates, 96
Factor XI deficiency
management of, 95, 96
understanding, 97
Factor XI dimerization, 93
Factor XI gene structure, 95
Factor XI inhibition, by plasma
inhibitors, 95
Factor XI mutations, 95
Factor XII (FXII), in Factor XI
activation, 94
Factor XII activation, 242
Factor XIII (FXIII, fibrin stabilizing
factor), 101–107, 139. See also
FXIII entries
binding sites for, 138, 139
biochemistry of, 102
clinical issues related to, 105, 106
freeze-dried, 104
future trends for, 111, 112
manufacturing of, 102–105
physiological roles of, 102
physiology of, 101, 102
Factor XIII activity, 107
functional assays for, 107
Factor XIII concentrate pasteurization,
virus inactivation by, 106
Factor XIII concentrates
characterization of, 106, 107
indications for, 112
manufacture of therapeutic, 103
Factor XIII deficiency, 102
Factor XIII process, characteristics
of, 105
Factor XIII product, properties of, 105
Factor XIII purification procedures,
modification of, 104, 105
Factor XIII purity, 107
Factor XIII replacement therapy, efficacy
of, 106
Factor XIII subunits, 101, 102
Falksveden fractionation scheme,
187, 188
False Claims Act, 414
Fantus, Bernard, 5
Farhood, Ramin, xi, 413
Fatty acid binding, to fibrinogen, 124
Fatty acids, in albumin, 162, 163
Favism, haptoglobin in treating, 330
Fc function, in IVIG preparations, 195
Fc section, 207, 213
FDA Blood Products Advisory
Committee, 424. See also Food and
Drug Administration (FDA)
FDA meeting, recommendations for,
404, 405
Feasibility Study, for SAPG, 21
Feed bans, 374
FEIBA1 components, affinity
chromatography of, 51. See also
Factor VIII inhibitor bypassing
activity (FEIBA1)
FEIBA1 NF, manufacture of, 50
FEIBA1 NF prophylactic treatment, 58
FEIBA1/NovoSeven1 Comparison
(FENOC) study, 58
FEIBA1 products, efficacy and safety
of, 57, 58
FEIBA1 unit, 49, 50
FEIBA1 VH, 58
Feldman, Peter, xi, 101
Fenton reactions, 123
Fibrin, 312, 313
classic blood coagulation cascade
leading to, 122, 123
interaction with plasminogen, 140
interaction with tissues, 140
Fibrin associations, haptide contribution
to, 121, 122
Fibrin bandages, 143
Fibrin clot, 81
as hydrogel, 137
Fibrin clot dissolution, plasmin in, 259,
260
Fibrin clot formation, 66, 81, 139, 140
Fibrin degradation, 139
Fibrin degradation products, 140
Fibrin glue producers, 137, 138
Fibrin glues, 137–145
biochemistry of, 137, 138
clinical use of, 144
downstream steps in
manufacturing, 141
fibrinogen component of, 137, 141, 142
future perspective on, 144
INDEX 479
Fibrin glues (Continued)
history of, 137, 138
manufacture of, 137
physiology of, 138
production of, 141–143
recombinant, 144
safety of, 144
thrombin component of, 137, 142, 143
Fibringluraas1, 137
Fibrin microbeads (FMBs), 125
Fibrinogen (Factor I), 102, 117–135, 138,
139. See also FI-C precipitate
binding of molecules to, 119, 120
cell attachment activity of, 120
exposure to free radicals, 123
fatty acid binding to, 124
haptide epitopes in, 120
heat stability of, 117–119
hydrophobicity of, 120, 124
hygroscopic nature of, 118
intracellular biosynthesis of, 117
metabolites and drugs that bind to, 119
minimal concentration of, 118
new forms and composites of, 125
production of, 123, 124
spray-dried, 143
structure and composition of, 117
variants of, 117
Fibrinogen associations, haptide
contribution to, 121, 122
Fibrinogen-based products
for cell culture, 125, 126
future prospects for, 126
Fibrinogen binding, 119
Fibrinogen component, 137
production of, 141, 142
Fibrinogen concentrates, 142
Fibrinogen concentration, clotting time
and, 118, 119
Fibrinogen domains, 117, 118, 138, 139
Fibrinogen epitopes, 120–122
Fibrinogen molecule, 117, 138, 139
Fibrinogen packaging/applicators, 126
Fibrinogen polymerization
induced by thrombin activation,
118, 119
turbidity and phase change during, 118
Fibrinogen preparations, 124
viral inactivation in, 124
Fibrinogen removal, 104
Fibrinogen stabilization, 141
Fibrinogen standard, 124
Fibrinolysis, 140
Factor XI and, 95
role of plasminogen in, 312
Fibrinolysis inhibitors, 141, 142
Fibrinolytic system
C1-inhibitor role in, 243
main purpose of, 260
regulation of, 242
Fibrinopeptide A (FPA), 139
Fibrinopeptide B (FPB), 139
Fibrin polymerization reactions, 122
Fibrin protofibrils, 119
Fibrin stabilizing factor, 139. See also
Factor XIII (FXIII, fibrin stabilizing
factor)
Fibrin tubes/stents, 125
Fibrogammin1, 105
Fibrolytic treatment, C1-inhibitor in, 250
Filling process, in plasma fractionation,
443
Filter aids, based on diatomaceous earths,
168
Filter presses, 440
Filtration, 354
in ethanol fractionation, 440
in the plasma fractionation industry, 168
for virus removal, 363, 364
Filtration technology, 440
Finnish Red Cross Blood Transfusion
Service, 11
Finnish Red Cross fractionation plant, 14
Firazyr1, 251
Five Layer Safety Net, 426, 429
Flebogamma 5% DIF preparation, 187,
189
“Fl�ebula,” 10
Flexbumin, 169
Flood Review, 17
Fluorescence intensity, 53
Food and Drug Administration (FDA),
404, 414, 423, 467
guidance on comparability from, 408
qualification/validation guidelines
by, 391, 392
TSE clearance studies and, 375, 376
Food-borne vCJD cases, 370, 371
Formalin-stabilized human serum, 11
Formulation process, in plasma
fractionation, 443
For-profit fractionation, in Europe, 12, 13
Foster, P. R., 11
Fractionated placental serum, 11
Fractionation. See also Caprylate
fractionation; Cascade plasma
fractionation processes;
Chromatographic fractionation;
Cohn fractionation process; Cohn/
Oncley fractionation process; Cold
ethanol fractionation processes;
Commercial plasma fractionation
facilities; Contract fractionation;
Ethanol fractionation; European
fractionation industry; Falksveden
fractionation scheme; Finnish Red
Cross fractionation plant; For-profit
fractionation; Ion exchange
chromatographic fractionation
technology; Kistler–Nitschmann
fractionation method; Multinational
fractionation industry; Not-for-profit
fractionation; Octanoic acid
fractionation; Plasma fractionation
entries; Plasma protein fractionation
entries; Regional fractionation
centers; Small-scale fractionation;
Subfractionation methods; Toll
fractionation
in North Africa, 20, 21
in the Middle East, 20, 21
not-for-profit, 11–13
plasma for, 423–436
Fractionation centers
difficulties in maintaining, 14
in Japan, 17
Fractionation economics, 452
Fractionation facilities, in China, 18
Fractionation industry, 101
companies dominating, 21
Fractionation intermediates,
exchanging, 408
Fractionation processes, 50
Fractionation products, clinical use of, 7
Fractionators
in China, 19
commercial, 7, 8
Fraction facilities, decrease in, 14
Fraction I paste, 123
Free cholesterol (FC), 284
Free radicals, 164
fibrinogen exposure to, 123
Free thiol, in albumin, 171
Freeze-dried Factor XIII, 104
Freeze-dried PCCs, 70
Freeze-dried plasma, 5, 9, 11
Freeze-drying technology, 10
Frenzel, Wolfgang, xi, 345
Fresh frozen plasma (FFP), 4, 96, 110,
350–353, 430
European guidelines for
collecting, 424
Frozen plasma, 438, 439
Fusion protein, 290, 291
Fusion protein therapeutics, albumin in,
178
Gamma-carboxylated factors, 68
Gammagard liquid process steps, 189
Gamunex process steps, 187
Gelatin plasma expander, 10
Gel filtration
in plasma fractionation, 441
in vWF purification, 44, 45
480 INDEX
Gel filtration chromatography, 33
Gelmont, David, xi, 413
Genereux, Maurice, xi, 207, 217
Gene therapy, 97
Genetic ATIII deficiency, 147. See also
Antithrombin III (ATIII)
German Red Cross (DRK), 14. See also
Deutsches Rotes Kreuz (DRK)
Blutspendedienst Nordrhein-
Westfalen
German Red Cross centers, 12
Glaser purification method, 230, 231
GlassiaTM purification process,
235–237
Global fractionation capacity, 21
Global hemostatic function, assessment
of, 111
Global Medical Affairs departments
emerging roles of, 413–422
internal communication and, 420, 421
outsourcing by, 417, 418
publication strategy and, 417
Global Medical Affairs function, 415
Global plasma industry, 466
Global regulatory environment, 403
b-Glucans, in IVIG preparations, 194
b-Glucocerebrosidase, 11
Glucose 6 phosphate dehydrogenase
deficiency (G6PD), haptoglobin in
treating, 330
Glutamic acid (GLA) domain, 81
Glutamic acid (Gla) residues, 108
Glycation, of albumin, 164
O-Glycosylation, 151
N-Glycosylation sites, 93
Glycosylation variants, 303
GMP compliance, 437. See also Good
manufacturing practices (GMP)
state of, 397
GMP guidelines, 429
GMP information, 387
Golgi apparatus, proteolytic processing
in, 41
“Good cholesterol,” 274
Good development practice (GDP), 386
Good laboratory practice (GLP),
386–389
Good manufacturing practices (GMP),
386–389, 399, 423
in plasma collection/manufacture, 383
solvent/detergent plasma and, 345
Goss, Neil, xi, 3, 451
Government–company
relationships, 466, 467
Graft-versus-host disease (GVHD), 307
Grancha, Salvador, xi, 81
Green Cross Corporation, 17, 18, 327
manufacturing process used by, 329
Gregori, Luisa, xi, 369
Grifols Bioscience, 451, 461, 466.
See also Laboratorios Grifols
Grifols Lucas, J. A., 10
Grifols plasmin production process,
262, 263
Grifols Roig, J. A., 10
Grifols SA, 233
Guidance documents, 404
“Guidance on Qualification of Existing
Equipment,” 393
Guideline of Plasma-derived Medicinal
Products, 444, 445
Gulle, Heinz, xi, 137
H5N1 influenza, convalescent plasma
treatment of, 210
Haemate P, 44
Hagen, P. J., 12
Haptide aggregation, 120, 121
Haptide epitopes
in fibrinogen and other proteins, 120
in protein chains, 122
Haptide–haptide (Hap–Hap)
interactions, 121, 122
Haptides
contribution to fibrin(ogen)
associations, 121, 122
hydrophobicity of, 120
Haptoglobin (Hp), 169, 321–336. See
also Hp entries
active sites of, 323, 324
as an acute phase protein, 325
administration of, 331
in animal studies, 331
biological properties of, 327
characterization of, 328–330
clinical issues related to, 330, 331
future trends in, 331, 332
genetics and biochemistry of, 321–324
hemoglobin binding by, 326
manufacture of, 327, 328
multiple infusions of, 331
physiology of, 324–327
potency of, 330
primary function of, 325
primary structure of, 322, 323
prophylactic, 330
quantitation of, 329, 330
quaternary structure of, 323
secondary structure of, 323
as a sequestrator of free
hemoglobin, 325, 326
tertiary structure of, 323
toxicity of, 331
usage of, 330–332
Haptoglobin efficacy, 331
biomarkers of, 331
Haptoglobin–hemoglobin (Hp–Hb)
complex, 321, 324, 326, 327
Haptoglobin multimers, identification and
characterization of, 329
Haptoglobin precursor, 322
HAS products, 169. See also Human
albumin solutions (HAS)
HAVantibody levels, 197. See also
Hepatitis A virus (HAV)
Hayes, Timothy, xi, 423
HDL-cholesterol, secretion of, 287, 288.
See also High-density lipoprotein
(HDL)
HDL-increasing therapies, 273, 279
HDL manufacturing process, 276
HDL metabolism, 284–286
HDL particle size, 291, 292
HDL therapy, 286–289
in cardiovascular disease risk
reduction, 287
efficacy of, 287, 288
HDN Mab candidates, 222. See also
Hemolytic disease of the newborn
(HDN); Monoclonal antibodies
(Mabs)
Health Canada, 9
Healthcare, evolving landscape of, 415
Healthcare environment, transparency
in, 413
Health economics outcomes research
(HEOR), 419, 421
Heart damage, iron depositions and, 301.
See also Cardiovascular disease
entries; Myocardial infarction
Heat treatment, of IVIG solutions, 190
Hedrich, Hans Christian, xi, 137
Heger, Andrea, xi, 345
Hemagglutinins, IVIG preparations
and, 193
Hemasure, 14
Hemin, 326
Hemodialysis catheter occlusions
(HCOs), 267, 268. See also Blood
entries; Plasma entries
Hemoglobin (Hb)
haptoglobin and, 321
oxidation of, 326
Hemoglobin-based oxygen carriers
(HBOCs), 325, 326
Hemoglobin clearance mechanism,
326, 327
HEMOLEVEN1, 96, 97
Hemolysis, 3, 4, 331, 332
Hemolytic disease of the fetus and
newborn (HDFN), 9, 217
treatment of, 217, 218
Hemolytic disease of the newborn (HDN),
351. See also HDN Mab candidates
INDEX 481
Hemophilia, 31
temporary, 55
transformation of, 38
Hemophilia A, 31
inhibitor development in, 57
replacement therapy for, 57
Hemophilia A treatment, 33
complications of, 37, 38
Hemophilia B, 49, 73, 88
Hemophilia B treatment, 89, 90
Hemophilia C, 93
Hemophiliacs, bleeding episodes in, 37
Hemophilia therapies, animal models in
investigating, 55
Hemophilia treatment
milestones in, 32
morbidity and mortality in, 37
Hemorrhages, intracranial, 219
Hemorrhagic events, therapeutic
approaches for, 57
Hemostasis
pathophysiology of, 59
regulation of, 66–68
thrombin solutions for, 142, 143
vWF protein role in, 42
Hemostasis evaluations, 351
Hemostasis regulators, 65
Hemostatic balance, 68, 75
Hemostatic products, need for, 143
Hemostatic regulatory proteins, 69
in PCC products, 70
Hemostatic safety studies, 266
Hemostatic system, 74
Hemovigilance, 384, 385
Heparin, 52, 69, 70
in PCCs, 75
thrombin inhibition and, 139
Heparin-based resins, 85
Heparin binding site, of antithrombin III,
148
Heparin gels, 149
Heparin induced thrombocytopenia
(HIT), 75
Heparin Sepharose-FF1, 85
Heparin-Sepharose1 (HS), 96
Heparin sulfate proteoglycans (HSPGs),
148
Heparin therapy, 152
Hepatitis A virus (HAV), 72, 73, 349.
See also Liver disease
antibodies to, 196, 197
in virus validation studies, 362
Hepatitis B immune globulin/
immunoglobulin (HBIG), 20, 209
Hepatitis B infection, 12
Hepatitis B surface antigen (anti-HBs),
209
Hepatitis B vaccine, plasma-derived, 9
Hepatitis B virus (HBV)
antibodies to, 196
transmission risk for, 348
Hepatitis C infections, 12
Hepatitis C virus (HCV), 35
transmission risk for, 348
Hepatology, albumin in, 175
Hereditary angioedema (HAE), 241, 242,
248, 249
diagnosis of, 249
products for treating, 250, 251
Herring, Steven, xi, 81
Hetzl, Ernst, xi, 437
Hexyl-Sepharose1, 244
High barrier-to-entry/investment
cost, 461, 462
High-density lipoprotein (HDL). See also
HDL entries; Reconstituted HDL
(rHDL)
antiatherogenic activities of, 275
antiatherogenic function of, 286
apolipoprotein components in, 275
biogenesis of, 274
heterogeneity of, 286
physiological function of, 284
physiology, biochemistry, and
mechanism of action of, 274–276
pleiotropic effects of, 275, 276
reconstituted, plasma-derived, 273–282
High development countries, 465
Highly purified Factor X, 108–110.
See also High-purity entries
Highly purified plasma-derived FIX
concentrates, 86
High molecular weight kininogen
(HMWK), 242
High molecular weight kininogen
binding, 93, 94
High performance liquid chromatography
(HPLC), 263
High purity alpha1-PI, 235
High-purity FIX, 83
High-purity Factor IX, self-sufficiency
and, 89, 90
High-purity Factor IX pharmacological
monographs, 87, 88
High-purity IgG preparations, 188. See
also Immunoglobulin G (IgG)
High-purity products, 33, 408, 409
High-purity vWF concentrate, 44–46
High quality plasma, availability of, 454
High specificity, of antibody-based
therapies, 207, 208
HIV infections, 12. See also Acquired
immunodeficiency syndrome
(AIDS); Human immunodeficiency
virus (HIV)
ITP secondary to, 219
HO-1 expression, 327
Hoechst AG, 15
Holotransferrin, 304, 306
Homosolvex Factor IX, 71
Hoppe, Hans, 221
Hp genes, 321, 322. See also
Haptoglobin (Hp)
Hp phenotypes, 321, 322
differences among, 327
monomer units for, 324
Hp precipitation, 328
Hp synthesis, 321, 324
impact of hemolysis on, 324, 325
Hp turnover, 324, 325
in animals, 325
HSA infusion, 175. See also Human
serum albumin (HSA)
HSA products, 169
HT DEFIX, 71
Human albumin, 6, 7
Human albumin solutions (HAS)
specifications for, 169–171
tests and limits for, 169, 170
in therapeutic plasma exchange,
175, 176
Human blood transfusion, early history
of, 3
Human development index (HDI), 465
Human Factor X (FX) zymogen, 52
Human immune serum globulin, 7
Human immunodeficiency virus
(HIV), 35, 72. See also HIV
infections
transmission risk for, 348
in virus validation studies, 362
Human plasma
dried, 6
fractionation of, 6
intravenous immunoglobulin G
from, 185–205
Human plasma-based hyperimmune
products, 210–212
Human plasma coagulant Factor VIII,
production and clinical profile
of, 31–40
Human plasma-derived products, outlook
for, 468
Human plasma-derived von Willebrand
Factor, production and clinical
profile of, 41–48
Human plasma fibrinogen, 138
Human plasma proteins, recombinant
plasma proteins vs., 467, 468
Human plasma substitute, 6
Human plasminogen gene, 311
Human sCJD, 373. See also Sporadic
CJD (sCJD); Variant Creutzfeldt-
Jakob disease entries
482 INDEX
Human serum, formalin-stabilized, 11
Human serum albumin (HSA), 159–183
characteristics and specifications
of, 168–171
clinical issues related to, 171–176
future trends for, 177, 178
guidance for use of, 174
ligands binding to, 162
managing critically ill with, 172
manufacturing processes for, 166
molecular structure of, 160, 161
as a NO carrier, 177
physiology and function of, 160
safety of, 176–178
in therapeutic plasma exchange,
175, 176
Human serum albumin (HSA)–fatty acid
complexes, 162, 163
Human transferrin, characterization
of, 305
Human vCJD, 372, 373. See also
Sporadic CJD (sCJD); Variant
Creutzfeldt-Jakob disease entries
Hustin, Albert, 4
HVAC units, 444
Hydrophobic interaction chromatography
(HIC), 234, 263, 328
in plasma fractionation, 441
Hydrophobicity, of fibrinogen, 120, 124
Hydrops fetalis, 217
Hydroxyethyl starch (HES), 172
Hydroxylation modifications, 108
Hyland Laboratories, 9, 49, 50
Hyperfibrinolysis, 351
Hyperimmune globulins, 209
Hyperimmune immunoglobulin G,
207–216
complement activation and, 208
Hyperimmune immunoglobulin
products, 211
development of, 209
worldwide market in, 215
Hyperimmune immunoglobulins, 210–212
production of, 212, 213
Hyperimmune initiatives, past, 214
Hyperimmune passive
immunotherapy, 209, 210
Hyperimmune plasma, 433
Hyperimmune products, 10, 22
human plasma-based, 210–212
production of, 9
Hyperimmunes, 214
as defense against biological
weapons, 210–212
Hyperimmune therapy, 210
Hyperoncotic albumin, 172
Hypoplasminogenemia, 315
Hypotransferrinemia, 306
Iatrogenic CJD, 369. See also Variant
Creutzfeldt-Jakob disease entries
ICH 09, 396, 398. See also International
Conference on Harmonization of
Technical Requirements for
Registration of Pharmaceuticals for
Human Use (ICH) project
ICH Guidances, 392
ICH Q5E, 410
ICH Q7A, 388
ICH Q10, 387, 388
Icterus gravis, 217
Identification, of IVIG preparations, 192
IgG–Fc receptor interactions, 208. See
also Immunoglobulin G (IgG)
IgG fragments, accompanying IVIG
preparations, 197, 198
IgG production process, 199, 200
IgG purification process, 187
Immobilized antibodies, 33
Immune neutralizing antibodies, solvent
detergent treatment and, 348, 349
Immune response, 57, 106
“Immune sera,” 207
Immune serum globulin, 16, 214
Immune suppressive action,
ceruloplasmin and, 341
Immune thrombocytopenic purpura
(ITP), 218–221. See also
Thrombotic thrombocytopenic
purpura (TTP)
Immune tolerance, to FVIII, 37, 38
Immunization, passive, 7
Immunoaffinity chromatography, 33, 34,
85
Immuno AG, 13, 49, 50, 247
Immunoassays, 375
Immunodeficiencies, secondary, 185
Immunogenicity, 89, 251, 406
Immunogenic potential, 111
Immunoglobulin(s)
Hepatitis B, 20
inactivation of, 365
intravenous, 17, 20
in ITP treatment, 219, 220
purification of, 7
structure and function of, 207, 208
Immunoglobulin A (IgA), IVIG
preparations and, 193
Immunoglobulin G (IgG). See also IgG
entries
characteristics of, 207
demand for, 462
hyperimmune, 207–216
recovery of, 7
Immunoglobulin G loss, 1868
Immunoglobulin molecule
integrity of, 191
structure of, 20
Immunoglobulin preparations, 7
procoagulant activity in, 199
Immunoglobulin production, 12, 21, 22
Immunoglobulin products, 199
treatment of, 364
Immunoglobulin protein removal, 187
Immunohistochemical techniques, 316
Immunological incompatibility, 6
Immunomodulatory properties, of
albumin, 164
Immunoprotection, ceruloplasmin
and, 341
Immunotherapy
passive, 207, 209, 210
Imported plasma products, 18
Impurities
accompanying IVIG preparations, 194,
197, 198
control of, 409
Independent medical education
(IME), 418
India, plasma fractionation in, 19, 20
Industrialized countries, as strategic
partners, 465
Industrial-scale alpha1-PI
purification, 231–237
Industry consolidation, overview
of, 466
Industry standards, 385
Infection, caused by inflammation, 325
Infectious agents, in blood, 361
Infectious diseases, convalescent serum
for, 209
Infectious inflammatory diseases,
ceruloplasmin and, 342
Inflammation
atherosclerosis and, 275
infection caused by, 325
Inflammatory cascade, 330. See also
Clotting cascade
Infusion solutions, 8
Inhalable alpha1-PI, 238
Inhibitor development, 89
in hemophilia A, 57
Inhibitor dogs, 55
Inhibitor patients, controlled bleeding
in, 52
Inhibitor plasma, clotting time of, 53
Inhibitor rabbits, 55, 56
Inhibitors
FVIII-inactivating, 37, 38
in previously treated proteins, 37
in previously untreated patients, 37
Inhibitory alloantibodies, 57
Inhibitory antibodies, 37, 57, 73, 74
Inhibitory factors, 66
Innovation, industry success and, 468
INDEX 483
Innovative plant biotechnology, future
of, 295
Innovative products, development of, 462
Installation qualification (IQ), 391
Institut M�erieux, 11
Integrated medical action plan (IMAP),
420
Interleukin 6 (IL-6), 326
Intermittent flow centrifugation, 4
Internal audits, 399
Internal communication/
coordination, 420, 421
International Conference on
Harmonization of Technical
Requirements for Registration of
Pharmaceuticals for Human Use
(ICH) project, 385, 429. See also
ICH entries
International normalized ratio (INR), 74
introduction of, 66
International Organization for
Standardization (ISO), 386
International Plasma Fractionation
Association (IPFA), 467
International Quality Plasma Program
(IQPP), 424, 427
International Society for Pharmaceutical
Engineering (ISPE), 392, 393
International suppliers, 398
Intoxication, ceruloplasmin and, 341
Intracellular Factor XIII (cFXIII), 102.
See also Factor XIII (FXIII)
Intracranial hemorrhages, 219
Intratect manufacturing process, 187, 188
Intrauterine exchange transfusion, 217,
218
Intravenous hyperimmune products, 207
Intravenous immunoglobulin (IVIG), 17,
20, 185, 219–221. See also IVIG
entries
global sales of, 462
safety of, 220, 221
Intravenous immunoglobulin G (IgG),
from human plasma, 185–205
Intravenous immunoglobulin products,
sales of, 451–453
Intravenous lys-plasminogen, 316, 317
Intrinsic clotting pathway, 82
Inventory Hold standard, 427, 428
Investigations, actions related to, 395
Investigator-initiated trials (IITs),
418, 419
In vitro cholesterol efflux, 294
In vitro efficacy studies, 264, 265
In vitro studies, 53–55
In vivo efficacy studies, 265, 266
In vivo recovery (ivr) concept, 88, 89
In vivo studies, 55–57
Ion exchange chromatographic
fractionation technology, 11
Ion exchange chromatographic steps, 188
Ion exchange chromatography (IEC), 33,
34, 213, 214
in albumin manufacture, 165
in plasma fractionation, 441
in vWF purification, 44, 45
Ion exchange/gel filtration combination,
in vWF purification, 45
Iranian Blood Transfusion
Organization, 21, 458
Iron-binding proteins, 301, 306
Iron depositions, heart damage and, 301
Iron metabolism, regulation of, 306, 307
Irradiation, for virus inactivation, 364
Ischemia, C1-inhibitor and, 250
Ischemic heart disease, 273
Israel, plasma fractionation facilities
in, 20
Israeli Red Cross, 20
Italian Medicines Agency (AIFA), 314,
317
Italian plasma, fractionating, 12
Italian Voluntary Blood Association
(AVIS), 12
ITP phases, 219. See also Immune
thrombocytopenic purpura (ITP)
ITP treatment
immunoglobulin in, 219, 220
Rh (D) immunoglobulin in, 220
IVIG concentrates, quality criteria
for, 185, 186. See also Intravenous
immunoglobulin (IVIG)
IVIG preparations
aggregate formation in, 195
antibody titers in, 195–197
anticomplementary activity of,
192, 193
Fc function in, 195
formulation of, 198
hemagglutinins and, 193
identification of, 192
immunoglobulin A and, 193
molecular size distribution of, 192
osmolality of, 192
pH of, 192
plasma proteins accompanying,
197, 198
prekallikrein activator in, 193
process-related impurities in, 194
protein composition of, 192
purification schemes for, 199
pyrogens and endotoxins in, 193, 194
safety and adverse events related
to, 198, 199
sterility of, 193
subclass distribution in, 194, 195
total proteins of, 192
visual appearance of, 191, 192
IVIG products, differences among, 199
IVIG quality parameters, 191–195
IVIG-related thrombotic events, 199
IVIG solutions, heat treatment of, 190
IV pastes. See Cohn Fraction IV-1, 4
pastes
Janeway, Charles, 6
Japan
blood transfusion in, 17
haptoglobin studies in, 331
plasma fractionation in, 17, 18
Japanese monograph, 87, 88
Japanese Red Cross (JRC), 14, 17
Jesse, Jens, xi, 383
Joint bleeding, 58
Jorquera, Juan Ignacio, xi, 81
JTT-705, 273
Kaar, Waltraud, xii, 185
Kabi, 11
Kaketsuken, 18
Kalbitor, 251
Kallikrein, 242
hereditary angioedema and, 248
Kamada Ltd., 20, 238
Kamada Ltd GlassiaTM purification
process, 235–237
KASKADIL, 71
Kedrion, 15, 461
Kedrion clinical development
program, 317, 318
Kedrion evaluation of plasminogen
product, 318
Kedrion plasminogen case study, 317
Kedrion plasminogen manufacturing
process, 311, 314, 315
Kendrick, D. B., 6
Kernicterus, 217
Key opinion leaders (KOLs),
relationships with, 418
Key regulatory standards, compliance
with, 416
Kininogen binding, 93, 94
KIOVIG process steps, 189
Kirschbaum, Nancy, xii, 403
Kistler, P., 12
Kistler–Nitschmann fractionation
method, 12, 186, 213, 327
Cohn fractionation process vs., 165
Kitasate, Shibasaburo, 207
Kline purification method, 313
Koenderman, Anky, xii, 241, 301
Kogenate1, 36
Korean Red Cross (KRC), 18, 19
Kramer, Christine, xii, 241
484 INDEX
Kringle domains, 259
in plasminogen, 311, 312
Labeling, for source plasma, 426
Laboratoire FranScaise du Fractionnement
et des Biotechnologies (LFB)
concentrate, 96
Laboratorios Grifols, 10, 21. See also
Grifols entries
growth of, 16
internationalization of, 15
Laboratory deviations, 396
Laboratory-scale alpha1-PI
purification, 229–231
Laboratory-scale purification
methods, 229–231
Landsteiner, Karl, 3
Large buffer volumes, in plasma
fractionation, 442
Large-scale manufacturing, of
transferrin, 303, 304
“Last liter economics,” 452
Law on Securing a Stable Supply of Safe
Blood Products and the Revised
Pharmaceutical Affairs Law (Blood
Law) of 2003, 18
Lebing, Wytold, xii, 227
Lecithin-cholesterol acyltransferase
(LCAT), 273, 274, 284, 286
Lee, Timothy, xii, 403
Lerch, Peter, xii, 273
Less than 6 h plasma, 432
Less than 24 h plasma, 432
Leukoreduction filters, 374
Licensure requirements, 405, 406
Ligneous conjunctivitis
early treatment methods for, 316, 317
etiology of, 315, 316
inheritance of, 315, 316
surgery for, 316
Ligneous conjunctivitis therapy,
plasminogen in, 311–320
Limulus polyphemus Amoebocyte Lysate-
test (LAL test), 194
Lipid-enveloped viruses (LEVs), 72, 73
Lipid peroxidation (LPO), 338
Lipids
active, 74
bioactive, 351, 352
Lipoprotein lipase (LPL), 284
Lister Institute, 11
Liver, ceruloplasmin synthesis in, 337,
338
Liver disease, albumin treatment
for, 175. See also Cirrhotic ascites;
Hepatitis entries
Logistical operations, efficient, 462
Long chain fatty acid (LCFA)
binding, 162, 163
Low-density lipoprotein (LDL), 273,
274, 284
oxidized, 326
Low pH, immunoglobulin preparation
treatment at, 191
Low pH plasmin formulation, 261, 262
Low plasma albumin, 171, 172
Low-purity products, 409
LPO level, effects of, 338
Lucas, Victor Grifols, 5
Lyophilization steps, in alpha1-PI
purification, 230
Lyophilized CP, 340
Lyophilized plasma, 5, 11
Lyophilized products, 364
Lyophilized reconstituted HDL, 276.
See also High-density lipoprotein
(HDL)
Lyophilizing fibrinogen solutions, 118
LYOplasLG, 346, 353
Lys-Glu polymorphism, in
haptoglobin, 322, 323
Lys-plasminogen, 261
Lys-plasminogen application, 315
Lys-plasminogen intravenous infusions,
316, 317
Lys-plasminogen preparations, 314
Lys-plasmin structure, 312
Macrophages, 324
Maillard reaction, 192
Major inflammatory events, 152
“Make-or-buy” decisions, 458
Management leadership, 429
Mannan binding lectin-associated
protease (MASP), 243. See also
MASP-2
Manufacturing failures, 446
Manufacturing processes
for apolipoprotein AIMilano, 283–300
optimization of, 66
Manufacturing technologies, new, 445, 446
Marcucci, Paolo, xii, 461
Marcucci Group, 15
Marketing departments, independence
from Medical Affairs, 413
Market performance, 462–464
Marx, Gerard, xii, 117
MASP-2, inactivation mechanism
of, 244. See alsoMannan binding
lectin-associated protease (MASP)
Massachusetts Biologic Laboratories
(MBL), 9
Massive bleeding, PCCs to stop, 73
Master Batch Record, 444
Matrix-assisted laser-desorption
ionization (MALDI) analysis, 263
Mature markets, 463, 464
Measles, antibodies to, 195, 196
Medical Affairs departments, 413, 414
diverse functions of, 415–420
emerging role of, 413–415
globalization of, 414
goals of, 415
IIT issues and, 419
independence from Marketing, 413
independent medical education
and, 418
key bridging function of, 419
partnership with R&D and
Marketing, 414
Phase 4 studies and, 420
strategic planning and, 417
“Medical Affairs: Effective Global
Resource Allocation,: 415, 416
Medical Affairs partnership, 416
Medical Affairs personnel, 421
Medical Affairs policy, 418
Medical Affairs reporting structure,
changes in, 415
Medical and Scientific Advisory Council
(MASAC), 58
Medical information centers, 417, 418
effectively managed, 418
Medical science liaisons (MSLs), role
of, 418
Meeting briefing document, 405
Meeting questions, 405
Membrane attack complex (MAC), 243
Membrane chromatography, 445, 446
Membranes, columns vs., 445, 446
Mercaptoalbumin (MA), 171
Messenger RNA (mRNA) splicing, 95
Metal-chelating chromatography, 85
Michaelis complex, 244
Microbiological purity, 194
Microfiltration, in plasma
fractionation, 442
Microfluidic devices, 119
Microgen, CP manufacture by, 339, 340
Middle East, fractionation in, 20, 21
Mimetic ligand affinity, 97
Minimal concentration of fibrinogen, 118
Minimum Requirements for Biological
Products 2006, 87, 88
Minipool testing, 428
“Missense” mutation, 95
“Mixed mode” resins, in plasma
fractionation, 441
Model viruses, 362, 363
Molecular adsorbent recirculating system
(MARS), 175
Molecular integrity, 107
Molecular size distribution
for albumin, 171
of IVIG preparations, 192
Molecules, binding to fibrinogen,
119, 120
INDEX 485
Moloney, Maurice, xii, 283
Monoclonal antibodies (Mabs), 200, 214,
215, 221, 467
More, John, xii, 159
Morelli, Andrea, xii, 147
More than 24 h plasma, 432
“Mousetrap” effect, 243
Multichamber centrifuges, in albumin
manufacture, 167
Multimeric protein structure, 43
Multimerization, 41
Multinational fractionation industry,
14–16
Murine models, of Hp expression, 324
Murray, Elizabeth, xii, 283
Mutations, of Factor XI, 95
Myocardial infarction, 261
Nanofiltration, 35, 36, 70, 87, 142,
190, 191, 247, 264
in plasma fractionation, 443
terminal, 87
for virus removal, 363, 364
Nanofiltration techniques, 73
Nardini, Claudia, xii, 311
Natal Bioproducts Institute, 345
Natal Blood Transfusion Service (NBTS),
13, 14
National AIDS Control Organization
(NACO), 20. See also Acquired
immunodeficiency syndrome
(AIDS)
National Bioproducts Institute (NBI), 14
National Blood Authority (NBA), 17
National Blood Center (NBC), 20
National Donor Deferral Registry
(NDDR), 427
National Hemophilia Foundation, 58
National Organization for Rare Disorders
(NORD), 101
National Plasma Fractionation Center,
19, 20
National policies, 13, 14
National transfusion infrastructures, 4, 5
NAT testing, 427, 428, 453. See also
Nucleic acid-based testing (NAT)
Negative column chromatography, 188
Negatively charged platelet micro-
particles, removal of, 351, 352
Neisser-Svae, Andrea, xii, 345
neoFib, 123
Netherlands Red Cross, 14
Neurodegenerative illnesses, 369
Neutralizing antibodies, 191
Neutrophil elastase, 228
New manufacturing technologies,
445, 446
New York Blood Center (NYBC), 9
New York Blood Transfusion Betterment
Association, 10
Nexin 2, 95
N-glycosylation sites, 93
Niche products, 214
Nitric oxide (NO), albumin as carrier
for, 164. See also NO signaling
Nitschmann, H., 12
Nomenclature, plasma-related, 424
Noncholate-based methods, 292
Nonclinical pharmacology/toxicology,
406
Nonenveloped viruses (NEVs), 72, 73,
190, 191
solvent detergent treatment and, 348
Nongovernmental organizations (NGOs),
454
Noninhibitory antibodies, 57
Nonreducing SDS-PAGE, 329
Nonremunerated plasma, 384
“Nonsense” mutation, 95
No observed adverse effect level
(NOAEL), 266
“Norfolk Incident,” 6
Normalized water permeability (NWP),
168
North Africa, fractionation in, 20, 21
North America
immunoglobulin consumption in, 186
plasma collection in, 21
plasma fractionation industry in,
7–10
North American market, 463, 464
NO signaling, 326. See also Nitric oxide
(NO)
Not-for-profit fractionation, in Europe,
11–13
Not-for-profit fractionators, processing
capacity of, 14
Not-for-profit manufacturers, 21
Not-for-profit sector, 461
consolidation in, 14
Novel viruses, 65
Novokhatny, Valery, xii, 259
Nucleic acid-based testing (NAT), 72,
361–363, 384. See also NAT
testing
Nykiforuk, Cory, xii, 283
Octagam batches, 197
Octagam process steps, 190
Octanoic (caprylic) acid fractionation, 187
Octanoic (caprylic) acid treatment, 190
Octapharma AG, 13–15, 190, 451, 453,
461
growth of, 16
as solvent/detergent plasma producer,
345, 346, 348
Octaplas1, 345, 346
biochemical characterization of, 351
Octaplas(LG), 347, 351, 352, 354
anaphylactoid reaction rate for, 352
biochemical profile of, 350
clinical efficacy of, 353
indications for, 353
manufacturing of, 346
single-donor FFP vs., 352, 353
virus neutralization and prior removal
from, 349
Octaplex1, 70, 71
Octaplex1 manufacturing process, 72
Oilbody (OB) biogenesis, 290
Okemefuna, Azubuike, xii, 321
Oliver, Percy, 4
Omni Bio Pharmaceuticals, Inc., 238
On-demand treatment, 58
Oniplas, 353
OOS handling system, main requirements
for, 395. See also Out of
specification (OOS) occurrences
OOS results, 396
Operational costs, of a developing-nation
plasma fractionation facility,
456, 457
Operation qualification (OQ), 391
Operations, in the production
process, 444, 445
Opsonization, 208
Orphan drugs, 238, 468
Orphan drug system, 101
Osmolality, of IVIG preparations, 192
Outcomes research, 419
Out of specification (OOS) occurrences,
393–395. See also OOS entries
Over, Jan, xii, 301
Oxidation, of hemoglobin, 326
Oxidation damage, 326
Oxidative process reduction,
ceruloplasmin and, 341
Oxidative stress, albumin and, 164
Oxidized LDL, 326. See also Low-
density lipoprotein (LDL)
P�aez, Antonio, xii, 81Paid blood donors, 12
in India, 19
Pancreatitis, C1-inhibitor and, 250
Parasites, pathogen transmission via, 347
Parkkinen, Jaakko, xii, 301
Partial prothrombinase complex, 57
Partial thromboplastin time (PTT) test,
118
Parvovirus B19 (B19V), 72, 191.
See also B19 NAT
Parvoviruses, 328
Passive antibody administration, 210
486 INDEX
Passive immunization, 7
protective factor of, 349
Passive immunotherapy, 207
with convalescent plasma, 209, 210
hyperimmune, 209, 210
Pasteurization, 35, 104, 190, 247
of albumin, 165, 166
of ATIII, 150
enhanced, 176, 177
in plasma fractionation, 442, 443
for virus inactivation, 364
Past hyperimmune initiatives, 214
Pathogen inactivation/removal proce-
dures, product safety via, 150, 151
Pathogen reduction, 65
Pathogen removal, 354
Pathogen safety, ix, 65, 72, 73, 233, 251,
263, 264
in plasma fractionation industry, 231
solvent/detergent plasma and, 346, 347
Pathogen safety-related measures, 86, 87
Pathogen transmission, risk of, 106
Patients, with FVIII-inactivating
inhibitors, 37, 38
PCC capture, 83, 84. See also
Prothrombin complex concentrates
(PCCs)
PCC dosage optimization, 74
PCC factor deficiencies, 73
PCC factor domain structures, 68
PCC factor function, 67
PCC factors, 74
PCC manufacturing procedures, 71
PCC manufacturing process, state-of-the-
art, 70, 72PCC packaging, 72
PCC product characteristics, 66
PCC production processes, state-of-the-
art, 73PCC reactions, 75
PCC starting material, 83
PCC starting material isolation, facility
requirements for, 87
Peeling. See Plasma peeling process
Peer-to-peer scientific exchange, with
physicians, 415
Performance qualification (PQ), 391
Peripheral arterial occlusion (PAO), 268
Peripheral vascular disease, 277
Perry, David, xii, 413
Persistent ITP, 219. See also Immune
thrombocytopenic purpura (ITP)
Petteway, Stephen, Jr., xii, 259
pFXIII tetramer, 102. See also Factor
XIII (FXIII)pH
immunoglobulin preparation treatment
at low, 191
of IVIG preparations, 192
Phagocytes, 208
Pharmaceutical industry
nanofiltration in, 190, 191
quality by design in, 389
Pharmaceutical Inspection Convention
(PIC/S) Code, 388
Pharmaceutical manufacturing
environment, 437, 448
Pharmaceutical products
commercially successful, 417
implementation of GMP for, 388
Pharmaceutical sector, quality systems
in, 387
Pharmacodynamic studies, 406
Pharmacological monographs, high-
purity Factor IX, 87, 88
Pharmacological Research and
Manufacturers of America (PhRMA)
Code, 414
Pharmacology
nonclinical, 406
safety and plasmin-related, 266,
267
Pharmacovigilance studies, 176
Phase 4 clinical trials, 419, 420
Phospholipid micelles, 59
Phospholipids (PLs), 284
Phospholipid transfer protein (PLTP),
284, 286
Physical virus inactivation procedures,
364Physicians, peer-to-peer scientific
exchange with, 415
Placenta, plasma derivatives from, 11
Placental extracts, 8
Placental serum, fractionated, 11
Plaminogen, 260
Plant-based production platform, 295
Plant biotechnology, future of, 295
Plant capacity increase, plasma to
feed, 453
Plant construction costs, in the developing
world, 456
Plant-derived manufacturing, of
apolipoprotein AIMilano, 283–300
Plant design, for the developing world,
455Plant location, in the developing
world, 455
Plant production, 283
Plants
seed-based expression in, 289–295
transgenic, 283, 295
Plaque lipids, reduction of, 293
Plasma
as a source of C1-inhibitor, 249Plasma
bovine, 6
colloid osmotic pressure of, 161
convalescent, 209
desiccated, 5
donation of, 361
for fractionation, 423–436
freeze-dried, 5, 9, 11
fresh frozen, 110
frozen, 438, 439
intravenous immunoglobulin G from,
185–205
lyophilized, 5, 11
main fractions of, 8
manufacture of, 384, 385
quality and safety of, 408
recovered, 423, 424
regulations governing the control
of, 385
as a source of therapeutic
proteins, 1013
sourcing of, 212, 213, 384
thrombolytic efficacy of, 265
for transfusion and further
manufacture, 423–425
from U.S.-based collection
facilities, 42
Plasma antithrombin III (ATIII),
production and clinical use of,
147–157. See also Antithrombin III
(ATIII)
Plasma bags, peeling of plasma in,
439
Plasma-borne pathogens, 35
Plasma bottles, peeling of plasma in,
439Plasma buffering, albumin in, 164
Plasma clarification processes, 194
Plasma collection, 8, 383, 425, 426
in Asia, 21
assessment of, 397, 398
in China, 18
in Europe, 21
increased scrutiny of, 429
methods for, 423, 424
in North America, 21
Plasma collection centers, 424
Plasma component, vCJD transfusion
transmission risk and, 373, 374
Plasma component solubility, 187
Plasma concentration, increase in,
88, 89Plasma derivatives, 8, 410
characterization of, 408
in emerging market countries,
464, 465
regulation of, 404
viruses of concern for, 362
Plasma derivatives business, importance
of, 467Plasma derivatives industry, 461
goals of, 468
INDEX 487
Plasma-derived (pd) FII-FXa
complex, 56. See also Factor II (FII,
prothrombin); Factor Xa (FXa);
Prothrombin entries
Plasma-derived coagulation products,
viral contamination of, 36
Plasma-derived FVIIa, 56. See also
Factor VIIa (FVIIa)
Plasma-derived FVIII, 55. See also
Factor VIII (FVIII)
purification of, 33–35
Plasma-derived FVIII concentrates, 37
Plasma-derived FIX concentrate, 89.
See also Factor IX (FIX)
Plasma-derived Factor IX products,
82, 83
Plasma-derived Factor XIII
concentrate, 105, 106. See also
Factor XIII (FXIII)
manufacturing processes for, 102
Plasma-derived fibrin glues, safety
of, 144
Plasma-derived HDL, 273–282
Plasma-derived hepatitis B vaccine, 9
Plasma-derived hyperimmune products,
future trends in, 214, 215
Plasma-derived Medicinal Products
guideline, 444, 445
Plasma-derived pharmaceuticals, per
capita consumption of, 464
Plasma-derived plasmin, as a direct-
acting thrombolytic agent, 268
Plasma-derived products, 251
availability of, 465
demand and supply of, 468
in vivo recovery of, 89
manufacture of, 429
regulatory environment of, 383–385
safety of, 35
Plasma-derived proteins, 55
producing, 7
Plasma-derived therapeutic products, ix,
461
Plasma-derived vWF concentrates, 43,
45
Plasma donations, screening, 361, 362
Plasma donors, screening, 264. See also
Blood donor entries
Plasma enzymes, accompanying IVIG
preparations, 197
Plasma Factor XIII (pFXIII)
activity, 102. See also Factor XIII
(FXIII)
Plasma for fractionation, 434
“Plasma for Great Britain Project,” 10
Plasma for stable products, 432
Plasma fractionation, 9, 11, 237
in Australia, 16, 17
in China and South-East Asia, 18, 19
commercial environment and
economics of, x
current technologies used in, 437–443
development of, 5–7
economics of, 451–460
in Europe, 13
first practical process for, 437
history of, 5–7
in India, 19, 20
in Japan, 17, 18
key validation activities for, 394
quality system specific to, 386
steps in, 438
Plasma fractionation companies,
worldwide, 466
Plasma fractionation facilities
in China, 18
construction cost of, 454–456
in developing nations, 453, 454
in Israel, 20
operating costs of, 456, 457
Plasma fractionation industry, 461
changes in, 111, 112
in Europe, 10–13
future of, 22
in North America, 7–10
multinational, 14–16
pathogen safety in, 231
process technology development
in, 167, 168
strengths of, 451
in 2010, 2011, 21, 22
2010 economic environment of,
451–454
Plasma fractionation industry screening
systems, 237
Plasma fractionation plants, in Brazil, 13
Plasma fractionation process,
specifications for, 389
Plasma fractionators, worldwide, 13
Plasma frozen within 24 h after
phlebotomy, 434
Plasma FXIII, 139. See also Factor XIII
(FXIII)
Plasma half-lives, 75
Plasma HDL increase, therapeutic
approaches for, 274. See also
High-density lipoprotein (HDL)
Plasma Hp, turnover of, 324, 325.
See also Haptoglobin (Hp)
Plasma human serum albumin (pHSA),
development of, 177, 178
Plasma imports, independence from, 18
Plasma inhibitors, Factor XI inhibition
by, 95
Plasma investigation, 429
Plasma kallikrein, 242
Plasma manufacturing processes, 385
Plasma Master File (PMF), 362, 384. See
also PMF concept
Plasma peeling process,438, 439
Plasmapheresis, 4, 8, 10
Plasmapheresis centers, 362
Plasmapheresis donors, repetitive
donation pattern of, 427
Plasma pooling, 428, 437
Plasma pools, 366, 374
Plasma processing, 8
for the developing world, 455, 456
Plasma processing industry, 12
Plasma product classes, international
sales of, 452
Plasma production market, future trends
in, 461–470
Plasma product life cycle, 392
Plasma product manufacture, quality
assurance requirements in, 383–401
Plasma product manufacturing industry,
governance of, 383, 384
Plasma product revenues, 457, 458
Plasma products, 22
global demand for, 453
global market for, 429
global sales of, 451
manufacture of, 446
providing to developing
countries, 453, 454
safety and quality of, 399
supply and demand for, 14
TSE infectivity reduction studies
for, 374–376
TSEs and, 369–380
viral transmission risk from, 176, 177
virus safety of, 361–368
Plasma product safety issues, 106
Plasma products market, barriers to entry
into, 461, 462
Plasma products sector, trading conditions
in, 464
Plasma product substitutes, preparing
for, 467, 468
Plasma protein fractionation, history and
evolution of, ix
Plasma protein fractionation industry, ix
history and development of, 3–28
Plasma protein fractions (PPFs), 159, 186
Plasma protein products, qualification and
validation aspects for, 393
Plasma Protein Purification System
(PPPS), 165, 167
Plasma proteins
accompanying IVIG preparations, 197,
198
biology of, ix
deficiencies in, 101
488 INDEX
manufacture of, 437
production of, ix
purification of, 376
recombinant, 36
Plasma protein therapeutics, future
of, 410
Plasma Protein Therapeutics Association
(PPTA), 385, 398, 424, 426, 457,
467. See also PPTAvoluntary
standards
Plasma protein therapeutics production/
commercialization, regulatory
activities associated with, 403–411
Plasma purification, 440, 441
Plasma quarantine, 428
Plasma safety, 426–429
Plasma safety net, 426
Plasma serine protease inhibitors, 95
Plasma sources, voluntary, 12
Plasma specifications, 424
Plasma standards, U.S. and European,
425
Plasma storage, 9, 426
Plasma suppliers, monitoring, 400
Plasma supply problems, 8
Plasma transfusion, 73
Plasma transfusion therapy, 43
Plasma types/specifications, 430–434
Plasmin
acid-stabilized, 268
catheter-delivered, 265
clinical experience with, 267, 268
clinical-grade, 261–264
as a direct-acting thrombolytic,
259–271
general properties of, 259
historical perspective on, 260, 261
main physiological function of,
259, 260
manufacturing of clinical-grade,
261–264
purification of, 262
structure and physiological function
of, 259, 260
thrombolytic efficacy of, 267, 268
toxicology/safety pharmacology
summary, 266, 267
Plasmin development, as a direct-acting
thrombolytic agent, 260, 261
Plasmin efficacy, relationship to safety,
268, density
Plasmin formulation, low pH, 261, 262
Plasmin inhibitors, 141
activity of, 350
Plasmin manufacturing process, 262, 263
Plasminogen, 139, 140, 262
activation of, 259
clinical issues related to, 315–318
mechanism of action of, 312, 313
mutant form of, 314
purification of, 262
purification of, 313–315
role in ligneous conjunctivitis
therapy, 311–320
structure and function of, 311, 312
Plasminogen activation, 263, 313
by tPA, 259, 260
Plasminogen activators (PAs), 261
failure of, 261
Plasminogen concentrate, 311, 317
Plasminogen concentrate preparation, key
development in, 313, 314
Plasminogen deficiencies, 311, 315,
316
Plasminogen eye drops case studies, 317
Plasminogen–plasmin system, 260
Plasminogen process, 263
Plasminogen products
future of, 318
Kedrion evaluation of, 318
Plasminogen purification, by affinity
chromatography, 314, 315
Plasminogen reduction, 141
Plasminogen synthesis, 311, 312
Plasmin process, 263
Plasmin products, characterization
of, 263
Plasmin Revascularization for the
Ischemic lOwer extRemITY
(PRIORITY) trial, 268
Plasmin storage, 260
Plasmin structures, 260
Plasmin therapeutic index, 269
Plasmin tolerance, 266
PLAS þ SD (S/D-treated plasma), 9
Plastic bag blood collection system, 4
Plate filter designs, 168
Platelet adhesion, vWF protein and, 42
Platelet agglutination, 43
Platelet counts, 220
Platelet Factor XI, 94, 95. See also
Factor XI (FXI)
Platelet poor plasma, 431
Platelet rich plasma (PRP), 431
PMF concept, 397, 398. See also Plasma
Master File (PMF)
Pneumonic anthrax infection, as
biological weapon, 210
Pock, Katharina, xii, 65
Polio, antibodies to, 195, 196
Polyacrylamide gel electrophoresis
(PAGE), 306, 321, 322
Polyclonal antibodies, recombinant, 467
Polyclonal antibody preparations, 200
Polyether sulfone (PES) membranes, in
albumin manufacture, 168
Polyethylene glycol (PEG)
precipitation, 149, 187, 188
Polymerase chain reaction (PCA),
427, 428
Polyvinyl chloride (PVC) bags, 346
Pooled plasma, 433. See also Plasma
pool entries
Porcine FVIII, 55, 57. See also Factor
VIII (FVIII)
Portfolio management, 404
Postmarketing surveillance study, 58
Postoperative complications,
ceruloplasmin and, 341
Posttranslational modifications, of
Factor IX, 83
Poulle, Michel, xii, 41, 93
PPSB-human SD/Nano 300/600, 71
PPTAvoluntary standards, 427. See also
Plasma Protein Therapeutics
Association (PPTA)
Preactivation peptide, 139
Precipitate A, 186
Precipitate separation, by centrifugation
and filtration, 440
Precipitation
in ethanol fractionation, 440
sequential, 437
virus removal via, 191, 363
Precipitation agents, 141
Precipitation processes, 214
Precipitation purification procedure, for
alpha1-PI, 230
Precipitation techniques, in plasma
fractionation, 441
Precision Pharma, 15
Prekallikrein, 94, 242
Prekallikrein activator (PKA)
activity, 104
in albumin, 171
in IVIG preparations, 193
Premarket regulatory processes, 403
Preventive actions, 395, 396
Previously treated proteins (PTPs),
inhibitors in, 37
Previously untreated patients (PUPs),
inhibitors in, 37
Price, Hugh, xii, 207
Primary ITP, 219. See also Immune
thrombocytopenic purpura (ITP)
Principal component analysis (PCA), 389
Prins-de Nijs, Ingrid, xii, 301
Prion (PrPsc) affinity ligands, 36
Prion-based disease, 65
Prion diseases, 369
Prion disease transmission, 354
Prion protein (PrP), 151. See also PrPc
protein; PrPTSE protein
Prion protein removal, 264
INDEX 489
Prion removal, 349, 350
Prions, inactivation of, 73
Privigen manufacturing process, 187, 188
PRNP gene, 376
PRNP genotypes, 373
ProApoAI proprotein, 285
Procedures, in the production process,
444, 445
Process analytical technology (PAT),
387, 390
Process charting, 390, 391
Process comparability strategy, 409
Processes, control of, 406, 407
Process-induced aggregation, 195
Process quality, 386
Process-related impurities, in IVIG
preparations, 194
Process technology development, in the
plasma fractionation industry,
167, 168
Procoagulant activity, in immunoglobulin
preparations, 199
Procoagulant process, maintaining, 60
Procoagulants, 59
Proconvertin, 65
Product characterization, 408
Product development, 112
Production facilities, design of, 443, 444
Production management, 444, 445
Production methods, for purified FVIII,
33–35
Production processes, for Factor IX
concentrates, 83–87
Product life cycle management, quality by
design in, 407, 408
Product quality, 408
Product Quality Review, 399
Product range, for the developing
world, 455
Products, control of, 406, 407
Product safety, 398, 399
ensuring, 35, 36
ensuring by pathogen inactivation/
removal, 150, 151
Product testing, 263
PRO-FEIBA1 study, 58
Profilnine SD, 71
Project management, 404
Prolastin1, 227, 233
Prolastin-C purification process, 234, 235,
236, 237
Prolastin purification process, 232, 233,
236
Prophylactic regimens, C1-inhibitor
in, 250
Prophylactic therapy, with FVIII and
FIX, 58
Proplex-T, 71
Protalix, 290
Protease inhibition, 148
Protein augmentation therapy, with
alpha1-PI, 229
Protein C, 70, 75, 148
biochemical characteristics of, 68
HDL and, 275
Protein chains, haptide epitopes in, 122
Protein composition, of IVIG
preparations, 192
Protein C pathway, 67
Protein formulation, 328
Protein Fractionation Center, 11
Protein misfolding cyclic amplification
(PMCA), 376
Protein multimerization, 41
“Protein only” hypothesis, 370
Protein S, 69, 70, 75
biochemical characteristics of, 68
HDL and, 275
reduced levels of, 351
Proteins
chromatography methods for
isolating, 38
clotting-related, 7
hemostasis regulators among, 65
plasma as a source of therapeutic, 101
types of, ix
vitamin K-dependent, 68
Protein stabilization, 261
Protein therapeutics, 399, 400. See also
Plasma protein therapeutics
production/commercialization
Protein Z, 69, 70, 75
biochemical characteristics of, 68
Protein Z-dependent protease inhibitor,
107
Proteolytic processing, in Golgi
apparatus, 41
ProthoRAAS, 71
Prothrombin, 65, 139. See also Factor II
(FII, prothrombin)
FXa and, 59
role of, 53–55
Prothrombinase complex, 59
Prothrombin complex (PCC), 65–79,
142, 439
characteristics of, 70–72
Prothrombin complex concentrates
(PCCs), 49, 51–53, 65, 110, 353,
439
as bypassing agents, 75, 76
for bypassing therapy, 52
clinical issues related to, 73–75
clinical trials with, 52
clinical use of, 66
effectiveness of, 52
Factor X in, 108
freeze-dried, 70
heparin and antithrombin in, 75
history of, 65, 66
importance of, 66
in intensive care medicine, 75)
manufacturing of, 69, 70
quality of, 66
safety considerations related to, 74, 75
to stop massive bleeding, 73
therapeutic indications for, 66
thrombotic events with early
generation, 66
Prothrombin complex zymogens, roles
of, 51–53. See also Prothrombin
zymogen
Prothrombinex-VF, 71
Prothrombin–FXa complex, 54, 58, 59
pharmacokinetic properties of, 57
potency of, 55, 56
results obtained with, 57
Prothrombin time (PT), 74
Prothrombin time (PT) test, 111, 112, 118
Prothrombin zymogen, role of, 59
Prothrombotic reactions, 74, 75
Prothromplex-T, 71
PrPc protein, 269, 370. See also Prion
protein (PrP)
PrPTSE protein, 369, 370, 371, 372, 373,
375, 376
Pseudomembraneous disease, 315
Pseudomembranes, recurrence of, 317
Publication planning/execution, 417
Public health, regulatory authority
and, 410
Public/private collection systems, 467
Pulmonary diseases, 228
Pure rFXa, 54
Purification, in plasma fractionation, 440,
441
Purification concepts, 186–189
Purification methods
for alpha1-PI, 229–231
in development, 38
Purification principles, 185
Purification schemes/techniques, 142
for IVIG preparations, 199
Purification technologies, 33–35
development of, 46
Purified FVIII, production methods
for, 33–35. See also Factor VIII
(FVIII)
Purified Factor IX, European and
Japanese requirements for, 87, 88
Purified plasma-derived porcine
FVIII, 37
Purified prothrombin, 53
Pyrogens, in IVIG preparations, 193, 194
Pyrogen testing, 194
490 INDEX
QAE-Sephadex1, 70
QA system, 397. See also Quality
assurance system
QC laboratories, 388, 389. See also
Quality control (QC)
“Quaking-induced conversion”
(QuIC), 376
Qualification, 391–393
Qualified donors, 361
Qualified Donor standard, 427
Quality Agreement, 399
Quality assurance (QA), 383, 395, 397
Quality assurance requirements, in
plasma product manufacture,
383–401
Quality assurance system, 386, 387.
See also QA system; Quality systems
responsibilities of, 386
Quality by design (QbD), 387, 389, 407,
410
applying to product life cycle
management, 407, 408
Quality control (QC), 386, 387. See also
QC laboratories
Quality maintenance, 444, 445
Quality management reviews, 387
Quality Risk Management guideline, 398
Quality Standards of Excellence,
Assurance and Leadership (QSEA),
424
Quality systems, 429. See also Quality
assurance system
interfaces to, 399
Quality Systems Regulation, 403
Quarantine, of plasma, 428
Quarantine plasma, 433
Quarantine residual plasma, 433
Quick, J., 74
Quick value, 74
Rabbit stroke model, 265, 266
Rabies immunoglobulin products, 20
“Radial flow” type columns, in plasma
fractionation, 442
Rare diseases, 101, 462, 463
Ravdin, Isador, 6, 7
Reactive nitrogen species (RNS), 164
Reactive oxygen species (ROS),
164, 326
Rebbeor, James, xii, 259
Recombinant activated Factor VII
(rFVIIa), 96
Recombinant ApoA-1 preparations, 274
Recombinant apolipoprotein AIMilano,
manufacturing large quantities
of, 289
Recombinant DNA products, 17
Recombinant-DNA technology, 250, 451
Recombinant (r) FII-FXa complex, 56.
See also Factor II (FII, prothrombin);
Factor Xa (FXa); Recombinant
prothrombin–FXa complex
Recombinant FVIIa (rFVIIa), 65
Recombinant FVIIa (rFVIIa) treatment,
57
response to, 56
Recombinant FVIII, 55. See also
Recombinant Factor VIII entries
Recombinant FVIII preparations, von
Willebrand factor in, 37
Recombinant FVIII production, in
transgenic animals, 38
Recombinant FIX concentrate, 89. See
also Recombinant Factor IX entries
Recombinant FXa (rFXa), 53
pure, 54
Recombinant Factor VIII (rFVIII), 22.
See also Recombinant FVIII entries
production in cell culture, 36, 37
Recombinant Factor VIII products, 36, 37
Recombinant Factor IX (rFIX), 83. See
also Recombinant FIX concentrate
Recombinant Factor IX products, 82, 83
Recombinant Factor XIII-A (rFXIII-A),
105, 106
Recombinant fibrin glues, 144
Recombinant hepatitis B vaccine, 209
Recombinant human alpha1-PI, 237
Recombinant human antithrombin III
(rhATIII), 151
Recombinant human serum albumin
(rHSA), development of, 177, 178
Recombinant plasma proteins, 36
human plasma proteins vs., 467, 468
Recombinant polyclonal antibodies, 467
Recombinant products, 251, 467
Recombinant protein therapeutics,
transgenically produced, 38
Recombinant prothrombin–FXa
complex, 54. See also Recombinant
(r) FII-FXa complex
Recombinant techniques, 112
Recombinant technology, 467
Recombinant transferrin products,
304, 305
Recombinant vWF, plasma- and albumin-
free, 46
Recombinate1, 36
Reconstituted HDL (rHDL), 273–282. See
alsoHigh-density lipoprotein (HDL)
beneficial effects of, 278
clinical experienced related to, 277, 278
efficacy of, 277, 278
future trends in, 278, 279
manufacture and characterization
of, 276, 277
Reconstituted HDL disks, 277
Reconstituted HDL infusions, effects
of, 278
Reconstituted HDL preparations, 274
tolerability of, 277
Reconstituted HDL therapies, 295
Recovered plasma, 423, 424, 430
Recovered-plasma products, 195, 196
Red blood cells (RBCs), 120, 326
vCJD transfusion transmission risk
and, 373
Red Cross, European governments
and, 11–13. See also American Red
Cross (ARC); Australian Red Cross;
Canadian Red Cross; Central
Laboratory of the Netherlands Red
Cross (CLB); Deutsches Rotes
Kreuz (DRK) Blutspendedienst
Nordrhein-Westfalen; Finnish Red
Cross entries; German Red Cross
entries; Israeli Red Cross; Japanese
Red Cross (JRC); Korean Red Cross
(KRC); Netherlands Red Cross;
Swiss Red Cross
Red Cross transfusion services, 11, 12
Redox properties, of albumin, 164
Reduced vitamin K, 81
Reducing SDS-PAGE, 329
Reduction studies
with endogenous blood infectivity, 375
with exogenous infectivity, 375, 376
ReFacto1, 37
ReFactoR1, 36
Regional fractionation centers, 11
Regulations
plasma-related, 385
standardized, 414
Regulatory affairs (RA) departments, role
of, 403, 404
Regulatory affairs (RA)
professionals, 403, 404
Regulatory agencies, role in
biopharmaceutical development/
commercialization, 404, 405
Regulatory application, preparation
of, 407
Regulatory authorities
interaction with, 404
public health and, 410
Regulatory compliance, 112
Regulatory environment
changes in, 413
of plasma-derived products, 383–385
Regulatory processes, differences
among, 403
Regulatory standards, compliance
with, 416
“Reischauer Affair,” 17
INDEX 491
Reliseal1, 137
REMS programs, 420. See also Risk
evaluation and mitigation strategies
(REMS)
Renal adverse reaction, related to IVIG
preparations, 199
Renal failure, during ITP treatment,
220, 221
Reperfusion injury, C1-inhibitor
and, 250
Replacement therapy, 89, 316. See also
vWF replacement therapy
for coagulation disorders, 46
for hemophilia A, 57
for hemophilia B, 88
Reprecipitation, 104
Rescue therapy, for patients with FVIII-
inactivating inhibitors, 37, 38
Research and development (R&D), 413.
See also Scientific/medical
knowledge
Resin density, 446
Resource management, 404
RETAIN trial, 238
Reverse cholesterol transport (RCT),
273–275, 283, 284, 291, 292
Rh-antigen, 217
Rh blood group system, 217
Rh (D) antibodies, 218
inhibition of, 218
Rh (D) immunoglobulin, 17, 217–225
advantages of, 220
in ITP treatment, 220
safety of, 220, 221
Rh (D) immunoglobulin doses, 220
Rh (D) immunoglobulin products, 20
Rh (D) isoimmunization, 218
Rh Institute, 9, 10
Rh-isoimmunization, prevention of, 218
Rhone-Poulenc Rorer, 15
Rh Pharmaceuticals Inc., 10
Risk assessment, in virus inactivation,
365, 366
Risk-based auditing schedules, 398
Risk-based audit management, 398
Risk evaluation and mitigation strategies
(REMS), 419–421, 414
Ristol, Pere, xii, 81
Robertson, Oswald, 4
R€omisch, J€urgen, xii, 65
Rotating horizontal leaf filter, 168
Rouleaux formation, 120
Rous-Turner solution, 4
Rozrolimupab, 221
Ruconest, 250, 251
Russia
blood donors in, 12
CP manufacture in, 339, 340, 342
Safety. See also Blood safety programs;
Pathogen safety entries; Product
safety; Virus safety; Virus safety
system
of blood products, 189, 190
of coagulation products, 38
ensuring by pathogen inactivation/
removal, 150, 151
Factor X-related, 110, 111
of FEIBA1 products, 57, 58
of human albumin, 176–178
of IVIG preparations, 198, 199
of PCCs, 74, 75
of plasma, 408
of plasma-derived fibrin glues, 144
of plasma-derived products, 35, 406
of plasma products, 106
plasmin efficacy relationship to, 268,
269
preclinical evidence of, 264–267
of Rh (D) immunoglobulin and IVIG,
220, 221
of solvent/detergent plasma, 351–353
viral, 86, 96
Safety assessments, 267
Safety pharmacology studies, plasmin-
related, 266, 267
Safflower-derived apolipoprotein
AIMilano, 290–292
biological activity of, 292–295
preclinical efficacy of, 294
Saline versus Albumin Fluid Evaluation
(SAFE) study, 172, 173
Salvaged plasma, 433
Sanquin-CAF-DCF organization, 14
Sanquin Plasma Products, 304
SARS-Corona virus, 363. See also Severe
acute respiratory syndrome (SARS)
Saturated ammonium sulfate (SAS), 244
Saudi Arabia (KSA), fractionation facility
in, 20, 21
Saudi Arabian Plasma Group (SAPG), 21
Saudi Pharmaceutical and Appliances
Corporation (SPIMACO), 20, 21
Schultze–Heimburger purification
method, 230
Schwarz, Hans Peter, xii, 49
Scientific/medical knowledge,
disseminating, 421. See also
Research and development (R&D)
Scope of a project, 454
Scott, Dorothy, xii, 369
Scottish National Blood Transfusion
Service (SNBTS), 11, 20
Scrapie, atypical forms of, 376
Scuderi, Philip, xii, 259
S/D plasma, 433. See also Solvent
detergent (S/D) plasma
S/D plasma production methods, 346
S/D plasma products, coagulation factors
and inhibitors in, 350
S/D reagents, 348
Secondary immunodeficiencies, 185
Secondary ITP, 219. See also Immune
thrombocytopenic purpura (ITP)
Seed-based expression, in plants, 289–295
Seed overexpression, 290
Self-sufficiency, high-purity Factor IX
and, 89, 90
Self-sufficiency plan, 21
Self-sufficiency policies, 13, 14, 16, 17,
18
SemBioSys Genetics Inc., 290, 295
SemBioSys production platform, 290
Separation resins, 33
Sepharose1 beads (SBs), 120, 122, 125.
See also DEAE-Sepharose1 FF;
ECH-Lysine Sepharose resin;
Heparin-Sepharose1 entries;
Hexyl-Sepharose1
Sepsis
albumin and, 176
C1-inhibitor and, 249, 250
Sequential ethanol precipitation, 440
Sequential precipitation, 437
Serine protease inhibitors
(“serpins”), 227, 228, 241. See also
Serpin entries
Serious adverse events (SAEs), 268
Serpin C1-inhibitor, 244
Serpin C1-inhibitor domain, 3D models
of, 241, 242
SERPING1 gene, 241
Serum, 3. See also Blood entries; Plasma
entries
equine, 6
Serum albumin, clinical issues related
to, 171–176
Serum Institute of India, 19
Serum levels, albumin and, 171, 172
Serum therapy, 207, 214
Severe acute respiratory syndrome
(SARS), convalescent plasma
treatment of, 209, 210. See also
SARS-Corona virus
Severe ITP, 219. See also Immune
thrombocytopenic purpura (ITP)
Shearer process, 232
Shen, Yin, xii, 283
Short consensus report (SCR) domain, in
haptoglobin, 323
Short Supply Agreement, 406
Sinclair, Christopher, xii, 207, 217
Single-donor FFP, Octaplas(LG) vs., 352,
353. See also Fresh frozen plasma
(FFP)
492 INDEX
Single donor plasma, 433
6–12 h plasma, 432
Six Sigma concept, 387
Size exclusion chromatography
(SEC), 33, 34, 192, 263
in vWF purification, 44
Small-scale fractionation, 13
Smith, Jodi, xii, 217
Sodium dodecyl sulfate (SDS)
electrophoresis, 43
Sodium dodecyl sulfate polyacrylamide
gel electrophoresis (SDS-PAGE)
analysis, 241, 263, 329
Soluble fibrinogen, transformation into a
clot, 118, 119
Solvent detergent (S/D) method/
treatment, 33, 35, 190, 328
in FIX manufacture, 87
in plasma fractionation, 443
superiority of, 347
for virus inactivation, 365
in vWF purification, 44, 45
Solvent/detergent (S/D) plasma, 345–357.
See also S/D entries
biochemical profile of, 350, 351
clinical efficacy of, 353
clinical safety and tolerability of,
351–353
producers of, 345, 346
Solvent/detergent (S/D) technology, 9
Sorbitol concentration, 104
Source material, control of, 406
Source plasma, 21, 424, 430
control of, 406
donation of, 361
labeling for, 426
Source plasma centers, 427
Source plasma collection, anticoagulant
solution for, 426
Source plasma regulations, 424
South African Blood Transfusion Service
(SABTS), 13, 14
South American market, 463
South-East Asia, plasma fractionation
in, 18, 19
Spanish flu H1N1 pandemic, 209
Specific activity (SA), 83, 84
Spiked infectivity, reducing, 375, 376
Spiked viruses, inactivation of, 364
Spiking preparations, 375
Splenectomy, 219
Spongiform encephalitis/
encephalopathy, 35
Spontaneous bleeding episodes, 58
Sporadic CJD (sCJD), 369, 371. See also
Human sCJD; Variant Creutzfeldt-
Jakob disease entries
Spray-dried fibrinogen/thrombin, 143
SRBI receptor, 292, 293
“Standardized” filtered blood, 10
Standardized regulations, 414
Standard operating procedures (SOPs),
388, 389, 399, 429, 444
Standard procedures, violation of,
393–395
Standard purification principles, 185
Standards, in donor screening, 426, 427
Starling’s Law, 161
Starting material plasma, composition
of, 200
State-of-the-art PCC manufacturing
process, 70, 72. See also
Prothrombin complex concentrates
(PCCs)
State-of-the-art PCC production
processes, 73
Statin therapy, 273
Statistical data/charts, 396
Steam in place (SIP) centrifuge
design, 167
Stem cell harvesting, 125
Sterile filtration, solvent/detergent plasma
and, 347
Sterile vacuum-type blood collection
unit, 9
Sterility, of IVIG preparations, 193
Steroid hormones, albumin binding
to, 163
S-TIM4 vapor heat treatment, 49
Stokes, Joseph, 7
Strategic National Stockpile (SNS),
210–212
Strategic planning, Medical Affairs
departments and, 417
Streptokinase, 260
Stroke, 268
Stuart–Prower factor, 65
Subclass distribution, in IVIG
preparations, 194, 195
Subfractionation methods, 7
Substitution therapy, 306
for Factor X deficiency, 110
Substrate concentrations, increasing, 59
Sudlow sites, 161
Suicide inhibitor, 243
Summary of product characteristics
(SPC), 66
Superoxide dismutases (SODs), 338
Supplier audit program, 399
Supplier audits/inspections, 398
Suppliers, audits/inspections of, 398.
See also Plasma suppliers
Surgical glues, 137
Sustainability, 16, 17
Svae, Tor-Einar, xii, 345
Svedberg, Theodore, 6
Swine flu, convalescent plasma treatment
of, 210
Swiss Red Cross, 20
SympressTM expression system, 221
Synthetic colloids, 172
Synthetic plasma expanders, 172
Talecris Biotherapeutics, Inc., 15, 21,
234, 235, 236, 262, 451, 461, 466
growth of, 16
Target antigen binding, 208
Task Force on Clinical Use of FIX
Concentrates, 52
Technology types, for the developing
world, 455
Temporary hemophilia, 55
Tenascins, 122
“Tenase” complex, 81, 82
ter Hart, Hennie, xii, 301
Terminal incubation, in albumin
manufacture, 166
Terminal nanofiltration, 87
TF/Factor VIIa complex, 81
b-Thalassemia, 307
Thawing process, in plasma protein
collection, 438, 439
Therapeutic C1-inhibitor products,
247, 248
Therapeutic exchange plasma (TEP),
433
Therapeutic FVIII production,
development strategies for, 38.
See also Factor VIII (FVIII)
Therapeutic Factor X concentrate, 108
manufacture of, 108–110
Therapeutic Factor XIII concentrate,
manufacture of, 103
Therapeutic plasma exchange (tPEx),
175, 176
Therapeutic plasma proteins, availability
of, 465
Therapeutic products, plasma-derived,
461
Therapeutic proteins
extraction and purification of, 290
plasma as a source of, 101
from transgenic plants, 295
Therapeutics, control and oversight of
critical, 446
Thiol, in albumin, 171
Thrombin, 139
FXI activation by, 94
spray-dried, 143
Thrombin activatable fibrinolysis
inhibitor (TAFI), 95
Thrombin activation, 42, 43
fibrinogen polymerization induced
by, 118, 119
INDEX 493
Thrombin component, 137
production of, 142, 143
Thrombin concentration, 81
Thrombin generation, 57, 59
Thrombin generation assay, 53
Thrombin generation curves, 53, 54
Thrombin inhibition, heparin and, 139
Thrombin inhibitors, 141
Thrombin polypeptide chains, 139
Thrombin regulation, 147
Thrombin solutions, for hemostasis,
142, 143
Thrombocytopenias, 218, 219
Thromboembolic events, 74, 199
Thromboembolic risk factors, 75
Thromboembolism, risk of, 176
Thrombogenicity, 84, 106
Thrombogenicity risks, 89
Thrombogenicity tests, 111
Thrombogenic material, separating, 110
Thrombolysis therapy, 261
Thrombolysis treatment testing, 266
Thrombolytic agents
limitations of, 261
plasma-derived plasmin as, 268
Thrombolytic conditions, human plasmin
for, 266
Thrombolytics, acid-stabilized plasmin
as, 259–271
Thrombosis, 73, 221, 351
Thrombosis model system, 264, 265
Thrombotic events, 58, 96
with early generation PCCs, 66
Thrombotic stroke, 277
Thrombotic thrombocytopenic purpura
(TTP), 42, 353. See also Immune
thrombocytopenic purpura (ITP)
Tiselius, Arne, 6
Tissue factor (TF), 81
Tissue factor pathway inhibitor (TFPI),
148
Tissue plasmin activator (tPA), 259, 260,
261, 265
Tissue-type plasminogen activator (tPA),
312
Titmuss, Richard, 12
Toll arrangement, 458
Toll fractionation, 17
Toll manufacturing, 458
Topical plasminogen drops, 317
Torcetrapib, 273
Total proteins, of IVIG preparations,
192
Toxicity
of cell-free hemoglobin, 325, 326
of early plasmin preparations, 260
of Factor X concentrate, 111
of haptoglobin, 331
Toxicological studies, plasmin-related, 266
Toxicology
nonclinical, 406
plasmin-related, 266, 267
Toxin neutralization, 208
Tranexamic acid, 142
Transferrin, 301–310
accompanying IVIG preparations,
197
binding capacity of, 303
biochemistry of, 302, 303
characterization of, 305, 306
clinical applications for, 306
clinical development of, 306, 307
future trends in, 306, 307
iron-binding capacity of, 301, 306
manufacture of, 303–305
mechanism of action of, 301, 302
physiology of, 301
as a targeting molecule, 307
Transferrin-dependent iron uptake, 302
Transferrin formulations, 304
Transferrin preparations, 304, 306
Transferrin purification, 304, 305
Transferrin-receptor complex, 302
Transferrin receptors, 302
Transferrin substitution therapy, 306
Transferrin synthesis, 301
Transfusion
early history of, 3–5
plasma collected for, 423–425
Transfusion complications, 353
Transfusion Medicine Epidemiological
Review (TMER), 372, 373
Transfusion related acute lung injury
(TRALI), 221, 351, 352
risk of, 352, 353
Transfusion Sanguine d’Urgence (TSU),
11
Transfusion substitutes, developing, 5–7
Transfusion-transmitted (TT) sCJD
(TTsCJD) infections, 373
Transfusion-transmitted (TT) vCJD
(TTvCJD) infections, 372, 373
Transgenic animals, recombinant FVIII
production in, 38
Transgenic plants, 283
therapeutic proteins from, 295
Transgenic rhATIIIs, 151
Transmembrane pressure (TMP), 442
Transmissible spongiform encephalitis/
encephalopathies (TSEs), 35.
See also TSE entries
albumin and, 177
future issues related to, 376, 377
histopathological changes of, 369, 370
new developments concerning, 376,
377
plasma products and, 369–380
Transplacental blood transfer, 218
Treatment-emergent adverse events
(TEAEs), 268
Triacylglycerol (TAG), 284
Triglycerides, 284
Trinuclear cluster, of ceruloplasmin, 337
Trypsin-inhibitory activity, of alpha1-
PI, 232
Trypsone1, 233
TSE clearance studies, 375, 376. See
also Transmissible spongiform
encephalitis/encephalopathies (TSEs)
TSE diseases, classification of human, 370
TSE infections, transmissibility of, 369
TSE infectivity, in blood, 371–373
TSE infectivity reduction studies
for blood components, 374
for plasma products, 374–376
TSE infectivity removal, 375
TSE removal methods, 36, 151
TSE screening tests, 376
Tubular-bowl centrifuge designs, 167
Tubular bowl centrifuges, 167
Tubular centrifuges, 440
Tumor necrosis factor (TNF), 321
Turbidity monitoring, in centrifuge
design, 167
Turecek, Peter L., xii, 49
12–24 h plasma, 432
Type 1 diabetes, 238. See also Diabetes
Tzanck, Arnault, 11
Ultrafiltration, 234, 328
in albumin manufacture, 168
in plasma fractionation, 442
Ultrafiltration membranes, 442
Ultrasound, in HDFN treatment, 217, 218
Ultraviolet light inactivation, 36. See also
UV-irradiation
UMAN Complex D.I., 71
Uniplas, 346
UniProt, 322
United States. See also American entries;
Code of Federal Regulations (CFR);
Food and Drug Administration
(FDA); Government–company
relationships; National entries; U.S.
entries
AAT deficiency in, 228
fibrin glues in, 137
immune globulin product sales in, 185
legal plasma-regulatory documents
in, 385
licensure requirements in, 405, 406
plasma collection/recovery in, 21, 423,
424
plasma manufacture in, 384
plasma standards in, 425
quality control systems in, 387
rare disorders in, 101
494 INDEX
United States Pharmacopoeia (USP)
Factor IX complex monograph, 87
Urokinase-type plasminogen activator
(uPA), 312
U.S.-based collection facilities, plasma
from, 423
U.S. collection centers, 21
US Food and Drug Administration
Amendments Act of 2007, 414
Utilities, 444
UV-irradiation, for virus
inactivation, 364. See also
Ultraviolet light inactivation
V.I. Technologies, Inc. (VITEX), 9,
345, 346
Vaccines, development of, 209
Vaccinia immune globulin (VIG), 212
Vaccinia virus (VACV), 347, 348
Vacuum-type blood collection unit, 9
Validation, 391–393, 429
of cleaning procedures, 394
Validation Master Plan (VMP),
392, 393
items included in, 393
Vapor heat treatment, 247, 443
Variant Creutzfeldt-Jakob disease (vCJD),
35, 65, 73, 347. See also vCJD
entries
albumin and, 177
epidemiology of, 369, 370, 371
precautionary measures against, 374
risk for developing, 372
Variant Creutzfeldt-Jakob disease
outbreak, 11
Vaschenko, Vladimir, xii, 337
Vascular cell adhesion molecule-1
(VCAM-1), 275, 278
Vasoactive mediators, 249
vCJD blood test, 376. See also Variant
Creutzfeldt-Jakob disease (vCJD)
vCJD exposure, reducing, 374
vCJD-infected blood components, risk of
transfusion transmission from, 373,
374
vCJD infectivity removal, 374
vCJD risks, 373, 374
reduction of, 374–376
vCJD spreading, controlling, 374
vCJD transmission, 349, 350
Vendor assessment, 399
Vendor contracts, 399
Venous/arterial thrombosis models, 265
Venous thromboembolism, risk of, 176
Venous thrombosis, 199
Very low-density lipoproteins (VLDLs),
284, 286
VIIISelect affinity matrix, 38
Viral clearance, in plasma fractionation,
440, 441
Viral “clearance” studies, 375
Viral contamination, of plasma-derived
coagulation products, 36
Viral diseases, transmission of, 151
Viral (virus) filtration, 35, 36, 328
for ATIII, 150
Viral inactivation/removal processes, 37
solvent/detergent plasma and, 345
Viral (virus) inactivation/removal, 104,
142, 150, 187, 190, 214, 232, 235,
237, 247, 305, 362
by Factor XIII concentrate
pasteurization, 106
in fibrinogen preparations, 124
in Octaplas(LG) treatment
method, 347, 348, 349
in plasma fractionation, 442, 443
via precipitation, 191, 363
Virus removal procedures, 363, 364
Viral (virus) inactivation/removal
methods/procedures, 33–36, 65, 86,
141, 142, 364, 365
Viral inactivation/removal
technologies, 35, 36
Viral marker testing, 385
Viral safety, 86, 96
of blood products, 189, 190
Viral segregation, 444
Viral zones, 444
Viremic donations, excluding, 349
Viruses
artificial aggregation of, 191
blood-borne, 366
identification of, 65
nonenveloped, 190
novel, 65
Virus-inactivated ATIII concentrates, 152
Virus inactivation/removal
combination, 365
Virus inactivation reagents, in IVIG
preparations, 194
Virus marker testing, 176
Virus neutralization, 208
Virus reduction, 72, 361–366
Virus reduction methods, 189, 190
Virus reduction steps, in C1-inhibitor
manufacturing, 244
Virus reduction studies, 264
Virus removal steps, 363
Virus-safe plasma derivatives, production
of, 366
Virus safety, of plasma products, 361–368
Virus safety system, 363
Virus transmission, risk from, 176, 177
Virus validation studies, 362, 363
examples from, 364
Visual appearance, of IVIG preparations,
191, 192
Vitamin K, reduced, 81
Vitamin K antagonists (VKAs), 66, 73
INR and, 74
Vitamin K-dependent factors
function of, 68, 69
structure of, 68
Vitamin K-dependent proteins,
biochemical characteristics of, 68
Vitamin K system, 68
Volume expansion, 172
Voluntary blood donation, 12
Voluntary plasma sources, 12
Voluntary viral marker standard, 426
von Behring, Emil, 207. See also
Behringwerke AG; CSL Behring
von Bonsdorff, Leni, xii, 301
von Willebrand, Erik, 41
von Willebrand antigen II, 41
von Willebrand disease (VWD), 41.
See also VWD entries
von Willebrand factor (VWF), 31, 32,
439. See also VWF entries
production and clinical profile of
human plasma-derived, 41–48
in recombinant FVIII preparations, 37
structure, synthesis, and function
of, 41–43
von Willebrand Factor deficiency, 41
VWD categories, 41. See also von
Willebrand disease (VWD)
VWD therapy, 43
VWD treatment products, 44
VWD types, 43
VWF concentrates. See also von
Willebrand factor (VWF)
high-purity, 44–46
plasma-derived, 43, 45
production of, 43–45
VWF deficiency (VWD), 43
VWF/FVIII complex, 42. See also
Factor VIII (FVIII)
VWF:FVIIIB binding, 43
VWF gene mutations, 41
VWF protein
characterization of, 43
coagulation FVIII interaction and,
42, 43
in hemostasis, 42
initial glycosylation of, 42
platelet adhesion and, 42
VWF purification
ion exchange chromatography in, 44, 45
size exclusion chromatography/gel
filtration in, 44
VWF replacement therapy, 41
VWF synthesis, 41
INDEX 495
Ward, Gordon R., 4
Warfarin reversal, 68
Water
albumin and, 161
fibrinogen and, 118
Watt, J. G., 11
Weibel–Palade bodies, 42
Welfide Corporation, 17, 18
West Nile virus (WNV), 363
White blood cells (WBC), depletion of,
374
WHO guidance document, 386. See also
World Health Organization (WHO)
Whole blood-derived plasma, 423, 424
Whole-blood transfusion, risks associated
with, 4
Wilate, 45
Wilfactin1, 45
Willfact1, 45
Wilson–Konovalov disease, 337, 338
Winnipeg process, 221
World Health Organization (WHO), 467.
See alsoWHO guidance document
Worldwide plasma market, 462
Wound healing, fibrinogen and, 117
Wouters, Diana, xii, 241
Zeerleder, Sacha, xii, 241
Zemaira1, 227, 231, 234
Zemaira purification process, 234,
236
Zentrallaboratorium, Blutspendedienst
SRK (ZLB), 11, 12
Zymogen Factor X activation, 107
Zymogens, 51–53, 59
496 INDEX