FILTRATION IN THE PHARMACEUTICAL INDUSTRY

Transcription

1 FILTRATION IN THE PHARMACEUTICAL INDUSTRY Theodore H. Meltzer Capitola Consulting Co. Arlington, Virginia and Senior Consultant Brunswick Technetics (Filterite Corp.) Timonium, Maryland with contributions by Eric W. Blakie, F. Raymond Gabler, Harwood Green, Hyman B. Katz, Julius Z. Knapp, Alvin Lieberman, David S. Linton, Rosalie M. Mandaro MARCEL DEKKER, INC. NEW YORK BASEL

2 Series I introduction Foreword Preface Contributors v vii ix xix Part I FILTERS 1 1 Depth Filters, Particles, and Filter Ratings Filtration Depth-Type Filters Filter-Medium Migration Differential Pressure Effects on the Filtration Process 37» 1.5 Depth Filter/Membrane Comparisons Prefilter Action Nominal and Absolute Ratings Particles Filter Permeability Filter Capacity Particle Deformability 58 References 58 2 Membrane Porosity: Its Origins and Modifications Overview of Membrane Porosity Track-Etch Membranes Porous Polytetrafluoroethylene Genesis of Porosity in Solution-Cast Films Phase-Inversion Membranes Pore Collapse Clearing of Membrane Orientation Effects 80 xi

3 2.9 Influences on Tensile and Elongation Properties Membrane Variability in Manufacture 85 References 85 3 Filter Porosity Characteristics Numerical Pore Dimensions Pore-Size Distribution Pore Shapes Implication of the Largest Pore Implications of Breadth of Pore-Size Distributions Anisotropic Pore Structures Effect of Pore Length on Flow and Retention 138 References Filter/Fluid Interactions Scope of Considered Interactions Extractables Structural Compatibilities Adsorptive Removal of Preparational Components by Filters 174 References Charge-Modified Depth Filters: Cationic-Charge- Modified Nylon Membranes 183 Rosalie M. Mandaro 5.1 Overview Depth Filter Materials Typical and Atypical Properties of Depth Filters Asbestos The First CMD Filter Development of Nonasbestos Depth Filters Use of CMD Filters in Blood Fractionation Measurement of Surface.Charge Density on CMD Filters CMD Filter Use in Pharmaceutical Processing Conclusions: Charge-Modified Depth Filters Cationic Charge-Modified Nylon Membranes Conclusions: Cation Charge-Modified Nylon Membranes 205 References Quality Assurance of Filters for Fluid Clarification 209 Hyman B. Katz 6.1 Introduction Product Development Manufacturing Contamination Control Cleanliness Levels Performance Testing Technical Support 218 References 218

4 xiii 7 The Integrity Tests Introduction Bubble Point and Organism Retention Causes of Bubble-Point Deviations Bubble-Point Protocol Measurement at Robust Air Flows Bubble-Point Testing at Fixed Air Pressure Levels Polymer Contribution to Bubble-Point Values Significance of the Williams Structure The Knee Region of the Curve Diffusive Air Flow as Integrity Indicator Effects of Membrane Anisotropy Single-Point Integrity Test Measurement Sensitivity of Diffusive Air Flows Pressure-Hold Test Sensitivity of Integrity Tests Water Intrusion Test Initial Integrity Test Automated Integrity Testing Devices Flow Ratio Test Conclusions 292 References 2 93 Part II FILTRATION Filtrative Particle Removal from Liquids Particle Trapping Mechanisms Adsorptive Sequestration The Modeling of Filter Blocking Practical Implications of Adsorptive Sequestration Reliability of Adsorptive Sequestrations Summary of Trapping Forces and \ Their Loci The Sterilizing Filter Retention of Latex Spheres " 350 References Filtrative Particle Removal from Cases Introduction Fermentation Air Filters Vent Filters Service Air Filtration Mechanisms Operative in Gas Filtrations Hydrophobicity Steam Sterilizability Integrity Testing Multiple Steamings Criteria for Air Filters Sizing of Vent Filters Validation of Air Filters Summary of Gas Filtration 400

5 xiv Contents 9.14 Steam 401 References Flow and Pressure, Filter Sizing, and Filter System Design 409 Harwood Green and Theodore H. Meltzer 10.1 Influences on Flow Pressure Considerations Constant-Pressure Filtrations Consumption of Filter Capacity Constant-Flow Filtrations Manufacturers' Catalog Information The Utilization of Flow Decay Measurements Sizing Prefilter/Final Filter Combinations Design Considerations 450 References Principles of Tangential Flow Filtration: Applications to Biological Processing 453 F. Raymond Gabler 11.1 Introduction Filter Types Used in Tangential Flow Microporous Membranes and Secondary Layer Formation Definition of Terms Theory of Tangential Flow Filtration Practical Aspects of Tangential Flow Filtration Concentration Polarization Determining Optimum Operating Parameters Via Total Recycle Membrane Fouling Particulate Loading Tangential Flow Applications Tangential Flow Equipment Summary 488 References 488 Part III PARTICLES Viable/Nonviable Particle and Pyrogen Retention Parenteral Requirements Sterilization by Filtration Sterilizing Filter Evaluation Other-Than Sterilizing Grade Filters Sterility Testing Determination of Bioburden Depyrogenation Particulate Material Filter Validation Grow-Through 537 References 541

6 xv 13 Detection and Measurement of Particles in Bulk Pharmaceutical Liquids 545 Alvin Lieberman 13.1 Definition of Scope Sample Handling Problems Particle Measurement Methods for Pharmaceutical Liquids Electronic Operation Liquid Feeders and Flow Controls Operating Parameters for Optical Particle Counters Liquid Flow Rate Effects Calibration Bases Dilution Effects Measurement Procedures Calculation of Results Conclusions ' 584 References Detection and Measurement of Particles in Sealed Containers 587 Julius I. Knapp 14.1 Introduction Analytical and Visual Pharmaceutical Particulate Standards Visible Particulate Sources Vial Stoppers: A Major Particulate Source Physiological Effect of Participates in Parenteral Products The Probabilistic Inspection A Probabilistic Evaluation of the Visual Inspection for Particulates Effect of Container Clarity on Visual Particulate Inspection Rejection Rate Analysis by Histogram Showing Distribution of Visual Particulate Rejects Visual Inspection Reject Rate Unmasked as a Mortality Table Effect Relationships of Rejection Probability and Rejects in a Normal Parenteral Production Batch Effect of Second or Cull Inspection of Final Reject Distribution in a Normal Parenteral Production Batch Transformation of Rule-of-Thumb Quality Categories into Probabilistically Defined Regions Inspection Security Evaluated with the Rejection Zone Efficiency (RZE) Parameter Accept/Reject Discrimination Evaluated with the Reject Rate in the Accept and Gray Zone (RAG) Parameter 615

7 xvi Contents The Science of Visual Inspection Effect on the 50% Detectability Response of a Target When Contrast and Background Luminance Are Varied in Time-Limited Trials Review of Biophysics Vision Experiments Supporting and Extending Particulate Inspection Experiments Results IES Lighting Recommendations for Various Visual Tasks Inspector Selection and Validation Bootstrap Inspector Selection under Actual Inspection Conditions Using RZE and RAG Durability of RZE and RAG Determinations for a Validated Inspector Group Durability of Individual and Group RZE and RAG Parameters The Core Validation Problem for Visual and Optical Inspection Comparison of Different Probabilistic Inspection Techniques Two-Dimensional Rejection Probability Distribution Application of the Manual Inspection Performance Yardstick Objective Standards Hologrammic Evaluation of Automated and Visual Inspection Performance Visibility Region Boundaries for Actual Particulates in Parenteral Products Accuracy Limitations Imposed by Sampling Inspection Procedures Uhlir's Model of Particulate Inspection A Practical Cost-Effective Inspection Validation Procedure Inspection Systems: Practical Considerations Objective Physical Criteria Validations Commercial Systems 705 References Pump Types and Their Selection 709 David S. Linton 15.1 Introduction Definition of Terms Pump Parameters Materials of Compositon Sterilization of Pumps Types of Pumps Summary 725 Reference Filter and Filter Holder/Housing Design General Filter Holder/Housing Design Disk versus Cartridge Configuration 770

8 xvii 16.3 Filter Cartridges Sterilization of Filter and Holder Disposable Filter Devices 784 References 787 Part V PRACTICAL FILTRATION APPLICATIONS Water Purification Grades of Water Various Water Purification Treatments Overview of Water Purification Deionization by Ion-Exchange Reactions Reverse Osmosis Ultrafiltration Membranes Ultraviolet Irradiation of Water Electrodialysis Distillation of Water Use of Filters in Water Purification Water Storage and Distribution Water for Injection Installations 897 References Pyrogens, and the Depyrogenation of Solutions with Ultrafiltration Membranes 919 F. Raymond Gabler 18.1 Biochemistry of Bacterial Pyrogens Classical Methods of Removing Pyrogens Removing Pyrogens with Ultrafiltration Membrane Filters Scaling Up a UF System from Laboratory to Production Summary! 938 References Theory and Practice of Compressed Air Filtration and Sterilization in the Production of Antibiotics 941 Eric W. Blakie 19.1 Introduction Compressed Air Contamination Prefiltration The Compressed Air Sterilization Filter Filtration Theory The Modern Air Sterilization Cartridge Filter Housings Performance Comparison Filter Selection and Sizing Installation Steam Sterilization In Situ Steam Sterilization Procedure Problem Areas Filter Cartridge Life Integrity Testing 970

9 xviii, Contents Microbial Testing Conclusion 977 References Filtration in the Pharmaceutical Processing Practices Regulatory Functions Cleanliness of People and Facilities Sterilization of Filters Repeated Advice Concerning Filtration Large-Volume Parenterals Small-Volume Parenterals Ophthalmic Preparations Antibiotics Specific Elaborations Blood, Plasma, and Serum Tissue Culture Medium Filtration Filtration in Vaccines Preparation 1045 References 1051 Postscript 1055 Present Status 1055 Future Developments 1055 Basis for Prediction 1057 Author Index 1059 Subject Index 1069