Subject Index. chromatography step, 125-

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1 A Alert limits, description, 70 Aluminum hydroxide based vaccine manufacture, start up and validation of sterile formulation and filling processes, Anion-exchange chromatography step for clinical-grade ciliary neurotrophic factor purification, reuse validation, B BebeFDC, production, 55 Biologies License Application, description, 171 Biologies regulations assay development and validation, case study of assay costs and times, change to approved application, 176 costs, 171 development, establishment license application elimination, lot release elimination, 177 methodology, process development, product comparability demonstration, use of pilot facilities, Biopharmaceutical agents, development process, 80 Biopharmaceutical manufacturing process validation concurrent validation, 5 current trends coordination of validation program and start up, 7 importance of communication, 8 prospective validation, 6-7 scope, 7-8,9t Subject Index 185 definitions, 2 Food and Drug Administration guidelines, 3 future trends, 8,10 history, 3-4 incentive, 1-2 requirements, 5 retrospective validation, 5 Biotechnology, process validation history, 1 C Cell culture process validation for monoclonal antibody production, See Continuously perfused cell culture process validation for monoclonal antibody production Center for Biologies Evaluation and Research, function, 4 Center for Drug Evaluation and Research, function, 4 Chinese hamster ovary cell line production of BebeFDC, 55 proven acceptable process control ranges for monoclonal antibody production, Chromatographic purification step used in recombinant factor DC manufacture, robustness testing, Chromatography, virus removal and inactivation validation, , Ciliary neurotrophic factor purification, reuse validation of anion-exchange chromatography step, Clean-in-place/steam-in-place technology, advances, 167 Clinical-grade ciliary neurotrophic factor purification, reuse validation of anionexchange chromatography step, Coagulation factor DC purification process, recombinant, See Recombinant coagulation factor DC

2 186 purification process validation for host cell DNA removal Concurrent validation description, 5 Container closure integrity, advances, 167 Continuously perfused cell culture process validation for monoclonal antibody production bioreactor validation, cell bank stability, 32, 33/, 40 definition, 41 experimental materials, antibody concentration, 31 immunoreactivity, 31 structure, cell banking, 31 clonality, 30 continuous perfusion process, 31 stability, 30 generation accumulation, 32, 34f process, requirements, 41 stability during production, 34, Coomassie-stained sodium dodecyl sulfate-polyacrylamide gel electrophoresis, role in proven acceptable process control ranges for monoclonal antibody production by recombinant Chinese hamster ovary cell cultures, Critical process parameters, Critical quality attributes, Development, role of biologies regulations on manufacturing processes for well-characterized products, DNA removal, recombinant coagulation factor DC purification process validation, Doubling times, calculation, 30 Drugs, process characterization for validation of recombinant protein fermentation, 1 F Factor DC manufacture, recombinant, robustness testing of chromatographic purification step, Factor IX purification process for host cell DNA removal, validation, Factorial approach, description, 70,72 Fermentation, recombinant protein, validation via process characterization, Filling process, See Sterile formulation and filling process start up and validation for parenteral aluminum hydroxide based vaccine manufacture predemonstration validation studies Filtration, virus removal and inactivation validation, , Food and Drug Administration, regulations of biologies, Fractional factorial designs, robustness testing of chromatographic purification step used in recombinant factor IX manufacture, G Guide to Inspection of Bulk Pharmaceutical Chemicals, description, 4 Guideline for the Inspection of Biotechnology Manufacturing Facilities, description, 4 Guideline on General Principles of Process Validation, description, 4 Guideline on Sterile Drug Products Produced by Aspectic Processing, description, 4

3 187 H Host cell DNA removal, recombinant coagulation factor DC purification process validation, N Neurotrophic factor purification, reuse validation of anion-exchange chromatography step, Inactivation, virus, Isoelectric focusing gel analysis, role in proven acceptable process control ranges for monoclonal antibody production by recombinant Chinese hamster ovary cell cultures, L Locally controlled environments, advances, 167 M Manufacturing of drugs and medical devices, process validation, 1 Manufacturing processes for wellcharacterized products, role of biologies regulations on development and validation, Maximum operating range, description, 70 Medical devices, process characterization for validation of recombinant protein fermentation, 1 Monoclonal antibody production continuously perfused cell culture process validation, proven acceptable process control ranges by recombinant Chinese hamster ovary cell cultures, Monoclonal antibody purification process, establishment of operating ranges, Monoclonal antibody validation, worstcase approach, O Operating range(s) in monoclonal antibody purification process establishment of ranges for critical input variables DNA content and clearance, 91 host cell protein content, protein A content, purity, results, 86, 87-90/ yield, purification process, 81 small-scale model development identification input variables, 82 output variables, 83 procedure, 82 quantification, use to establish operating ranges experimental design, 84 selection of ranges for input variables, Operating range validation goal, 69 worst-case approach, Parenteral aluminum hydroxide based vaccine manufacture, start up and validation of sterile formulation and filling processes, Parenteral formulations, importance of final sterile step, 144 Performance measures, role in proven acceptable process control ranges for monoclonal antibody production by recombinant Chinese hamster ovary cell cultures, 47,49, 50/

4 188 Process characterization for validation of recombinant protein fermentation bridging between small and large scales, critical process parameters and quality attributes, 19,23,4 experimental materials, 13 analytical methods, 14 culture conditions, fermentation kinetics, 14,16/ fermentation process, 14,15/ galactose feed rate and amount, 19,22/ glucose feed rate and amount, 17, 19, 20-21/ inoculum transfer criteria, 17,18/ window for harvest, 14, 17 Process validation components, 80 importance, 1 product quality acceptability, 44 standardization, 1 Product(s), role of biologies regulations on development and validation of manufacturing processes, Product titer, role in proven acceptable process control ranges for monoclonal antibody production by recombinant Chinese hamster ovary cell cultures, 47,48/ Production-level purification influencing factors, objective, 125 validation, Prospective validation description, 6-7 formal process validation, 6-7 performance qualification, 6 process characterization and optimization, 6 sterile processes, Protein(s), production problems, 114 Protein fermentation, validation via process characterization, Proven acceptable process control ranges for monoclonal antibody production by recombinant Chinese hamster ovary cell cultures Coomassie-stained sodium dodecyl sulfate-polyacrylamide gel electrophoresis, experimental materials, 45 measures of process performance and product quality, process variables and variable ranges, 45 study design, isoelectric focusing gel analysis, performance measure effects, 47,49, 50/ product titer effects, 47,48/ silver-stained sodium dodecyl sulfatepolyacrylamide gel electrophoresis, 51,52/ Purification establishment of operating ranges for monoclonal antibodies, reuse validation of anion-exchange chromatography for clinical grade ciliary neurotrophic factor, R Recombinant Chinese hamster ovary cell cultures, proven acceptable process control ranges for monoclonal antibody production, Recombinant coagulation factor DC purification process validation for host cell DNA removal concurrent validation of DNA evaluation ceramic HA peak pool, Q Sepharose load samples, Q Sepharose peak pool, 59 development, 56 laboratory-scale validation

5 189 radiolabeled DNA spike preparation, 60, 61/ results, 60-62, 63/ purification procedure, 57 robustness of DNA removal description, 62 drug substance DNA levels, immobilized metal affinity chromatography column robustness, 64-65, 66/ Q Sepharose column robustness, Recombinant factor IX manufacture, robustness testing of chromatographic purification step, Recombinant protein fermentation, validation via process characterization, Regeneron's recombinant human ciliary neurotrophic factor manufacturing process, reuse validation, Reinventing Government Initiative of 1995, description, 171 Removal, virus, Residual cellular DNA assaying problems, 56 role in process consistency and product purity, 56 Retrospective validation description, 5 Reuse validation of anion-exchange chromatography step for clinical-grade ciliary neurotrophic factor purification anthrone reactive material release, 140, 142/ column requirements, 125 consistency of pool material, 133,137, 138/ DNA clearance, 137, elution volume, 133, 136/ endotoxin clearance, 137, analytical methods DNA quantitation, 133 endotoxin quantitation, 133 protein determination, 132 sodium dodecyl sulfatepolyacrylamide gel electrophoresis, 132 bench-scale column system, 128 diethylaminoethyl-sepharose chromatography conditions elution, 131 final equilibration, 129 initial equilibration, 129 loading, 131 production run, 129, 130/ resin regeneration/sanitization, 131 wash step, 131 diethylaminoethyl-sepharose smallscale reuse study column specifications, 131,132r procedure, production process, 129 manufacturing process, percent yield, 133, 136/ reproducibility, 133, 135/ resin leachable release, 140,141/ retention volume, 133, 136/ small-scale profile vs. manufacturingscale profile, 133, 134/ 137r Robust process step, description, Robustness definition, 93, 36 establishment for complex unit operation, 94 Robustness testing of chromatographic purification step used in recombinant factor DC manufacture example choice of variables and ranges load conductivity and ph, 97-98, 111 load flow rate, 97 recombinant factor DC load mass, 97 untested variables, 99 data analysis, 100

6 190 fractional factorial design and execution, 100, 101* outputs, 99 process goals, 97 purification process, analytical methods, 96 chromatography, 96 variable manipulation, 96 future work, 111 principles of study design analysis of experimental results, 95 choice of variables, 95 definition of output, 94 experimental design, 95 identification of process goals, 94 selection of variable ranges, 95 results impurity levels, product composition, 109, 111 product recovery, Scaled-down model, Silver-stained sodium dodecyl sulfatepolyacrylamide gel electrophoresis, role in proven acceptable process control ranges for monoclonal antibody production by recombinant Chinese hamster ovary cell cultures, 51,52/ Start up, sterile formulation and filling process for parenteral aluminum hydroxide based vaccine manufacture, Sterile formulation and filling process start up and validation for parenteral aluminum hydroxide based vaccine manufacture approach steps, 152 variables affecting performance, ,155* background, current analyses, 146, 147* current trends, 164,167 demonstration phase, 162,164, / dilution and filling steps characterization phase, 158,162, 163/,* predemonstration validation studies, 158,162,163/,* formal validation phase, 162,164, / formulation step characterization phase, 153 demonstration phase, , / future trends, predemonstration validation studies aluminum and antigen concentration effect, 157 ph effect, procedure, 154 sterility, 157 processes automated ph titration system, 146, 149/ dilution, 146, 150 filling filling system, 152 mixing, formulation via aluminum hydroxide coprecipitation, 146,148/ Sterile products, process validation, 144 Sterile welding, advances, 167 Vaccine manufacture, parenteral aluminum hydroxide based, start up and validation of sterile formulation and filling processes, Validation continuously perfused cell culture process for monoclonal antibody production, definition, 12,80 process characterization of recombinant protein fermentation, 12-27

7 191 recombinant coagulation factor DC purification process for host cell DNA removal, requirements, reuse validation of anion-exchange chromatography step for clinicalgrade ciliary neurotrophic factor purification, role of biologies regulations on manufacturing processes for wellcharacterized products, sterile formulation and filling process for parenteral aluminum hydroxide based vaccine manufacture, virus removal and inactivation, worst-case approach to operating ranges, Viral contaminants, importance of removal, 114 Virus removal and inactivation validation chromatography procedure, 117 results, , design requirements, 116 equipment, 111 filtration procedure, 119 results, , goal, 114 inactivation procedure, 121 results, model viruses, unit operations, 117 W Well-characterized biologies designation, 10 role of biologies regulations on development and validation of manufacturing processes, Worst case, Worst-case approach to operating range validation advantages and disadvantages, 70 concept of operating ranges, definition, 70 experimental materials, 72, factorial approach, 70,72 isoelectric focusing gel quantitation, 74,78/ worst case and standard condition, 74, 77/ performance of cell culture process, 73-74,75/ protein A levels in purification process intermediates, 74,76/ purity of purification process intermediates, 74,76/ typical process flow for monoclonal antibody production, 70,71/ yield of purification process, 74,75/