anatomy of a pharmaceutical filtration · assembled over many years of practice in filter sizing,...

CONTENTS

Preface xiiiDedication xvAcknowledgements xviiForeword xix

Part One Microporous Membranes

1 Membrane Formation 3The Casting Dope 3The Phase Inversion 6Matrix Formation 6Viscosity and Solvent Removal Rate 7Temperature and Relaxation Time 8

Crystallinity 10

2 Filter Properties 11Narrow Pore Size Distribution 11Stresses: Casting-induced/Heat-released 13Multi-steamings 14Pertinence of Disposable Filters 16

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Anatomy of a Pharmaceutical Filtration: Differential Pressures, Flow Rates, Filter Areas,

Throughputs and Filter Sizing

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Anisotropic Membranes 17Accept higher particle loads 19Enhanced flow rates 19

3 Types of Membranes 21Reverse Osmosis Membranes 22

RO mechanism, hydration based 22RO membrane structure 23Tangential flow filtration 24

Percent Recovery of ROWater 26Integrity tests for RO membranes 27

Red dye test for RO membranes 28Comparisons of chloride and sulfate rejections 28

Ultrafilters 28Molecular weight cutoffs 29Ultrafilter integrity testing 30

Nanofilters or Dalton Filters 31Use in viral clearance 32

Charge-modified Membranes 32Expanded PTFE Membranes 33

Hydrophobicity 34PTFE: Non-shedding of fibers 37

Track Etched Membranes 37

4 The Final (or only) Filter 41Filter Expectations 41Filtration Criteria 42General Properties 43Polymeric Filter Types 45Extractables and Leachables 45

Objectionable particles 48Physiological Effects of Particles 49Particles: Permitted Levels 50

Fiber release 51Particle Shedding by Membranes 51

Possible sources of particles 52Shedding vs. retention 53Flushing of filters 54Particle counting 55

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PartTwo Particle Retention Mechanisms

5 The Mechanisms 59Sieve Retention or Size Exclusion 59

Shearing effects 60Adsorptive Sequestration 61Surface Free Energy 65

Validation of Adsorption 66Filter Cake Formation 66

Filter Cake Density 67Adhesive EPS Retention 69

Removal of exo-polymeric substances 70Impactions 70

6 Impactions and Consequences 71Informational Sources on Impactions 71The Genesis of Impactions 72Gravitational Forces 72Inertial Impaction 72Brownian Motion 74Electrostatic Charges 75

Electrostatics: origins and adsorptivity 75Effect of fluid’s dielectric constant 77Third body collisions 78

The Mean Free Path 79The Most Penetrating Particle 79

Penetration: particle size vs. velocity 81

PartThree Microbiological Considerations

7 The Organisms andTheir Assays 85Brevundimonas Diminuta: Shape and Size 85Bioburden Analysis 87Procedural Considerations 89

Sampling and frequency 90Storage of samples 91Culturing 91

The CFU AssayValues 92Microbiological Assaying 93

Methods 94Recovery method 94

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Using 0.45 vs. 0.2/0.22 membranes 95Direct transfer method 97

Organisms’ life cycles 97

8 Biofilms 99Organism/Surface Attachments 99

Biofilm sanitizations 101Planktonic enumeration 102

9 Organism Penetrations 103Matching Pores and Particles 103CFU: Sterility Implications 104

Part FourThe Atomic and Molecular Structures

10 Electronics Arrangements 109The States of Matter 109

Partial-charge bonding 111The dipole structure 112

11 Atomic and Molecular Motion 115Rotational,Translational, andVibrational 115First and Second Order Transitions 117The Glass Transition Point 117The Glassy State 119Molecular Density 120Particle Suspensions 121

Part FiveThe AirVent Filter

12 Function and Design 125Its Purpose 125Steam Sanitizations 126Implosion Resistance 127Vent-Filter Requirements 128

Organism retentivity 128Hydrophobicity 128Integrity testable 129

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Repeatability of in situ steaming 130Non-fiber releasing 130Materials of construction 130

13 Concerning Retentions 133Fiber Diameter and Particle Retention 133

PTFE fibrils’ thin diameters 134Bonding forces 135

Flow Rates and Adsorption 135Determining filter retentivity 137Filter efficiency 141

Part Six The Filter Pore Structure

14 The pore ratings 145Absence of Pore Size Standards 145Pore Ratings and Flow Rates 148Pore Morphology 150The Polyhedral Pore Shape 151The Pore Passageways 155

Surface Pores 156

Part Seven Depth Filters and Membranes

15 Depth Filters 159Fibrous Constructions 159

Melt-blown technique 162Polypropylene: Heat Labile 162

Other thermal concerns 164Surface vs. depth blockage 165

Mathematical models 167

16 Membrane Filters 169Selection of the (Final) Filter 169The Sterilizing Membrane 170

Organism shrinkage and grow-through 172Restatement of pore structure 173

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Part EightThe Parameters of Filter Performance

17 Parameter Interdependence 177The Pressure Parameter 178Applied Differential Pressure 179

Pressure gauge locations 181Pressure and Flow Rate 181

Diminishing returns 183Filter consumption 183

18 EFA and Flow 185Plus and Minus of Larger Flow Rates 185Influences on Flow Rates 186Filter/Housings: Flow Rate Limitations 187Filter Porosity and Flow Rates 190Viscosity/Temperature Effects 191

Viscosity “drag” effect 192High Flow Rate Limits 193

Recommended flow rates 194

19 Throughput 197Throughput or Filter Capacity 197

Increasing the EFA 198Elevated delta pressure 198Prefiltration 199Remaining filter capacity 199

Part Nine Effective Filtration Area

20 Available Filtration Area 203Effective Filtration Area 203Hold-upVolume of Filters 204

Methods for increasing EFA 205

21 Pleated Filter Cartridge 207The Pleated Cartridge 207The Pleat Pack 208

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Center Core Diameter 209Pleated Filter Characteristics 210

Pleat heights 211Parallel filter arrangements 212

Dextrose solution filtration 214Example of parallel flow system 215

PartTen Prefiltration and Prefilters

22 Serial and Prefiltration 219Serial Filtration 219

Prefilter(s)/final-filter combinations 219Prefilters and final filter efficiencies 222

The Utility of Prefiltrations 222Number of prefilters 223Prefilter vs. final filter: consumption 225

Depth and Membrane Prefilters 225

Part Eleven Multi-filter Arrangements

23 Multifilters 231Double Layered Filters 231The Heterogeous Prefilter 231Heterogenous and Homogeneous Filters 232Redundant Filters 234

Economics of redundant filtrations 235Integrity Testing of Single and Multi-Round Housings 236Regulators’ Views of Redundant Filters 236

24 Filter Separation Effects 239Redundant and Congruent Filters 239Redundant and Separated Filters 240

25 Ingredient Adsorption 243Effect Upon Drug Formulae 243Effect Upon Integrity Testing 244

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PartTwelveThe Organism Challenge

Chapter 26The Challenge Level 247FDAView 247EMEAView 248Higher Challenges and Penetrations 249Actual ChallengeValues 251The “Ultimate” Challenge 251

Dilute suspensions: effects: on retentions 252Experimental findings 252

27 Implications to Retentions 257Mean Flow-Pore 257Mean Flow-Pore Effect 263

PartThirteen PreludeToThe Flow Decline Method

28 Prior to Measurements 267Factors Influencing Flow Decline 267Information: for Test Purposes 268Test Conditions: Delta Pressure an Flow Rate 270Choosing Inlet Pressure 271

By system robustness 271By filter efficiency 272By pressure and blockage 272

29 Performance Conditions 273Constant Pressure 273Constant Volume (Flow) Filtration 274Changing Pressure toVolume 276Termination of Test 276Lower vs. Higher Differential Pressure 277

Part Fourteen Selecting Differential Pressures and Flow Rates

30 ChoosingThe Delta Pressure 283Differential Pressure Level 283The Inlet Pressure Level 284Recommended Inlet Pressure 284

Example of Application 285

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Flow Decline Approaches 286Applied Delta Pressure Limit 288Rates of Flow and Differential Pressure 288

31 Test Rationale, Equipment, Limits 291Limitations of 47 mm Disc Filters 291Use of Pleated Model Filters 292Verification and Assurance Trials 293

Part Fifteen Components of Flow DeclineTesting

32 Features, Examples, Calculations 297The Equipment and Filter Sequencing 298TheWhat andWhy of Flow Decline Measurements 301

Step 1. Determine the maximum available differential pressure 302Step 2. Determine initial clean differential pressure 303Step 3. Determine the flow rate per unit EFA at the

clean differential pressure 303Step 4. Correct the flow rate for fluid viscosity 303Step 5. Determine the numer of filtration units 304Step 6. Recalculate the actual clean differential pressure 305Step 7. Determine percentage of filter blockage and portion

still available 305The Filter Unit 305Identifying the Multiplier Factor 306Using the 47 mm Flat Disc Filter 307Using pre-assembled 47 mm flat disc filters 308Filter Trial Design 308Disposable Filters 309

33 Selecting Final Filter and Prefilter 311Outline of Operational Procedure 311

Operational pointers 311Prefilter Selection: Total Throughput 313Manual Throughput Study 316Conversion Factors 317Manual Extrapolation to EFA Needs 317Convert EFA to Cartridges 318Cartridge Numbers and Lengths 319

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34 Examples of Applications 321Conversion Factors 321Examples 322

Liquid system — manual throughput study 322Plotting flow vs. pressure 324Prefilter/final filter combination 328Compressed air 331Derivation of formula 333Sizing chamber vents 334Ethylene oxide (EtO) sterilizer vent 334Carboy vent 335

35 AutomatedTesting and Modeling 337Automated Throughput Measurement 337Possibility of 47 mm Filter Inhomogeneity 340Overdesign 341EFA Size of Model Filter 342

36 Ancillary Matters 347Manufacturers’ Catalogue Data 347Pragmatic Findings 348Membrane Filtration: Present Status 349

Bibliography 351

Index 365

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PREFACE

This volume is the eighth book on the subject of Pharmaceutical Filtration writtenby the coauthors in addition to books on given aspects of the subject composedindividually by each of them. This extraordinarily productive collegiality hasproduced three Filtration Handbooks dedicated separately to Integrity Testing,Liquid Filtration, and Air and Gas Filtration. Two edited works, Filtration in theBiopharmaceutical Industry (1998), and Filtration and Purification in theBiopharmaceutical Industry (2008) consist of collected chapters authored byexperts in many aspects of the pharmaceutical filtration field. PharmaceuticalFiltration: The Management of Organism Removal, their last offering, continuedthe authors’ broader search for topics that are independent and distinct in theirtechnical approaches, but that, nevertheless, share a commonality with thediscipline of pharmaceutical filtration.

Considerations of background material such as the welding and passivationof Austenitic steels, the physicochemical genesis of the capillary rise effect, thenature of the van der Waals forces, and the subject of surface free energy arediscussed in conjunction with more immediate filtration concerns such as themechanisms of particle capture, the nature of the filter pore, and the validationrequirements of pharmaceutical filtration systems.

The authors seek to establish the science of pharmaceutical filtration withinthe wider reaches of the physical and biological disciplines so that its connection

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with other technical operations will gain wider understanding. Ordinarily, suchtechnical pursuits are seen as being apart from the filtration activity because theyare not immediately involved in its problem solving operations.

The current book continues the tradition. It is an extension of topics lesscommonly dealt with, and an elaboration of subjects previously broached.Consider, for example, that subject to the modifications caused by suspendedsolids, the throughputs of filter systems can be speeded by the use of largereffective filtration areas, or by the impress of higher differential pressures. Whichroute to take under what particular conditions is a topic that lends itself to riskassessments. Likewise, polymeric membranes may become stressed whenmanufactured by the casting process. Nevertheless, the properly dimensionedfinished filter may not be disadvantaged by these induced stresses. However, therelease of the stresses, as by steam sanitization, may deform the filter’s dimensionscausing functional interferences. Discussed are the implications regarding at whichstage of the process, if any, there is need for filter integrity testing.

The format planned is the investigation and discussion of a select number ofindividual topics whose compilation will form the book. These will, in turn, bedivided into chapters devoted to different aspects of the subject. The chapters willbe of lengths appropriate to the intended discussions.

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DEDICATION

With love and respect

We dedicate this work to those who inspire and support us

With an enduring love, Xavier, wife and companion,for making my life worthwhile.

And to Kathryne Anne Robinson for her steadfast caritas.

To Alta Dorette Jornitz, my wife and treasure, and Lisa Kara Jornitz,My daughter and joy, for making my life perfect

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ACKNOWLEDGEMENTS

Pharmaceutical sterilizing membrane filtration has been practiced for possiblyclose to 80 years, and a multitude of different filtration systems have beendesigned during this period. The design criteria during the past decades likelyconverged on the filtration of an entire batch without interruption. This oftenresulted in a more generous sizing allowance for the effective filtration area (EFA).

With the advent of biopharmaceutical aseptic processing applications, thesizing of filtration systems has necessitated a focus on multiple performanceparameters. Now, for example, the rates of flow, the total throughputs, unspecificadsorptions, and the filters’ hold-up volumes all require being addressed, althoughtheir fulfillment is not mutual. This book will describe the fine balancing amongsuch factors that is now needed to determine the correct sizing of a filtration system.

As always in their writings , the authors could not have accomplished theirventure without the reliable information and guidance that resulted from theexperimental endeavors of the experts who pursued this balancing act on a dailybasis. It is the experimentally obtained technical information that is precious inscientific terms. Assembled over many years of practice in filter sizing, thistechnique, learned from failures and successes, was generously made available bythe experimentalists in support to the common weal.

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We, the authors, express our deepest gratitude for the information imparted tous by the aforementioned specialists. Our efforts derive solely from theexperiences they acquired. The expertise and knowledge they contributed to thisbook were invaluable for us. Our comprehension is the product of their elucidation.

Their efforts also benefitted practitioners of pharmaceutical andbiopharmaceutical operations in general. The public shares the priceless generosityof this knowledge. It contributes to cost savings in the processes optimized, and thedrugs produced, directed especially to those of a high value price-tag variety.

We take pleasure in identifying by name a few among the many of ourcolleagues who contributed to filter sizing by the flow decline method. By theirwork they elevated the topic to a higher and more useful standard. We gratefullyacknowledge their much appreciated contributions to our efforts: James P.Agalloco, James A. Akers, S. Anderson, C. Thomas Badenhop, D.L. Beals, Daniel.J. Brose, Steven Cates, M.E. Clarke, Jack C. Cole, Mandar Dixit, Wayne E,Garafola, Harwood W. Green, J. Hermia, David H. Hussong, Fred H. Hutchison,Peter R. Johnston, Russell E. Madsen, Peter Makowenskyj, Marc W. Mittelman,Bala Raghunath, Anurag S. Rathore, J. Royce, Larry A. Scheer, Amit Sharma,R.H. Shumsky, and Joseph Zahka.

Additionally, we recognize and appreciate the indispensible assistance of Ms.Amy Davis of DHI, our publisher, for her inexhaustible patience in support of ourefforts. We value the helpful endeavors of the many PDA staff members whoassisted us over so long a time. In particular we thank Wanda Neal-Ballard, JannyChua, Nahid Kiani, and Iris Rice among those who furthered our endeavors. Ourthanks extends to Patricia Stancotti and A. Mark Trotter of Sartorius StedimBiopharm Inc. for their helpful participation in our venture. We especially thankKieren J. Schrader for significant assistance in computer operations. We aregreatly indebted to Kathryn A. Robinson for her timely typewriting assistance.

In particular we acknowledge with gratitude the permission given us byInforma Healthcare, successors to Marcel Dekker, and by Sandra Beberman of thatorganization, to utilize the writings of Green and Meltzer (1987), Green andScheer (1998), and other of our writings in the books we have published with them.

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FOREWORD

There is the belief that mankind was endowed with the “gift of understanding”.That would explain our never ending efforts to acquire a practical appreciation oftechnical operations whose results are often the sums of complex primaryinfluences and more obscure subsidiary interactions. Pharmaceutical filtration isone such activity. Its mastery requires a scientific comprehension of its stepwise,logical procedures assembled from different disciplines.

FILTRATION OBJECTIVES

An adequacy of objectionable-particle (organism) removal to a stipulated level isthe principal goal in most pharmaceutical filtrations. Given the attainment of thissine qua non, the throughput volume achieved is perhaps the most practicalconsideration. It represents an important economic aspect of the drug manufacturingeffort. The rate of filtration should lead expeditiously to the timely completion of thefiltration by way of an adequacy of filter area, EFA, in combination with a suitablelevel of differential pressure. The volume of the drug preparation and its degree ofloading are the determinants of the rates of flow through the available filter area asmotivated by the applied differential pressures. Its modification is subject, however,to the nature and amount of particulate matter whose retention by the filter under thegiven filtration conditions determines the filter’s service life.

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As said, the two particular objectives sought in the filtrative processing ofpharmaceutical drug suspensions are the completeness of objectionable-particleremoval by the filter, and the maximum throughput quantity achieved before poreblockage terminates the filtration. Each is a function of the combined influencesof the effective filtration area, (EFA), the differential pressure motivating the fluidflow, and the total solids suspended (TSS),in the fluid preparation. The batch sizevolume of the drug preparation, and its degree of particulate loading are givens.

Presumably, the applied differential pressure and the effective filtration areavailable as choices, except that selecting the one necessarily circumscribes theother. If so, once the filtration is underway, the prospect of changing the EFAbecomes highly impractical as compared with altering the differential pressure.This means that in practice one is required to know in advance the EFA that oughtto be selected, the volume to be filtered, its load, being fixed, and the delta pressurebeing subject to control. Time is also a variable, except that its limitations areusually avoided by a correct selection of the EFA and the delta pressure.

Flow decline is the most cost-effective method for determining the extent ofEFA required for a filtration, and/or for selecting filter types, pore sizes, andprefilters, particularly for a new system. Flow decays can be performed quicklyand easily in a matter of hours using small filters as models or in pilot roles.Foregoing this option may require experimentation with process filters for days orweeks. A reliable prognosis of the filtration area needed for batch processing canbe ascertained by application of the flow decline or flow decay method.

Achieving a filtration sterilization, theoretically a complete absence ofspecified organisms from drug preparations, is a most demanding operation. Suchis not always necessary or sought, but in its requiring a flawless performance, itssuccessful application serves as a verification of the filtration technique. It isagainst the background of sterile effluent production that the adequacy of design ofa filtration system is judged. In a broader sense, the worth of the design is revealedby the congruency of its requirements and fulfillments in filtration sterilizations.

Anatomical approach

The anatomical approach to the understanding and consequent management of aprocess is to identify its individual components, whether molecular or mechanicalin structure, and to appraise each for its contribution to the integrated performanceof the whole. The practical goals of pharmaceutical filtrations are seen as beingthe removal of objectionable particulates, organisms included, to a specifieddegree with a concern for the rate at which the filtration takes place, and the extentto which it proceeds before the retained particles block the filter’s pores

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sufficiently to render further filtration so slow as to be impractical. What is soughtare the maximization of throughputs, and the accommodation of time constraints,wanted are the avoidance of product losses, whether through adventitiouscontamination, or by adsorption to the filters. It is understood that asepticconditions are mandatory for filtration sterilizations.

Filtrations are constructs of the filter’s area size; its porosity in terms of thepore size ratings and distribution of its complement of pores; the sizes anddistribution of the particles whose passage they are meant to restrain; and thefiltration conditions selected for the operation. Chief among the latter are theselected applied differential pressure, and time constraints, if any. What ismeasured are the progressively decreasing flow rates engendered, and thethroughput produced over the time period leading to the filtration’s cessation byits increasing retention of particles. If the ratio of particle density to the extent ofavailable filter area is large enough to limit the throughput, the latter can beincreased by employing larger filter areas or higher applied differential pressures.The purpose of filter sizing is to calculate in advance the effective filter area, EFA,that will be required to process a batch sized undertaking. It is based on the flowdecline or flow decay method that is a subject of this writing.

The flow decline method, simple to perform, is used to determine theeffective filtration area required to process an entire batch volume within anacceptable time frame under a given delta pressure. It is managed by a simplearithmetic proportioning. A small filter of known effective area is used to disclosethe volume of the drug preparation that can be processed at that delta P, given therate of flow and the throughput it produces. The ratio of the filtration area to thesample’s volume is extrapolated to the filter area required for batch processing.The simplicity of the test assures its easy mastery; its performance demands onlya modest technical background.

Because of its practical utility, those interested will learn how to perform theassay and interpret its measurements. However, comprehending the scientificunderpinnings of filter sizing will prove appreciably more demanding.Consequently, acquiring the somewhat complicated but, nevertheless, relevanttechnical background may be considered an unnecessary option by some. Theauthors believe it to be a most useful undertaking. Learning to perform the sizingoperation may be the goal, but understanding its governance optimizes thepossibilities of its being attained, and of its application being expanded. Therefore,as a prelude to investigating filter sizing by the flow decline method, the authorswill refer to the method’s scientific basis and to fundamental elements thatunderlie all filtrations.

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• Filters: their mode of manufacture and their resulting properties.Structure, stresses: release by steam, consequences.

• Filter types: microporous membranes, depth-types, prefilters, final filters.

• Filter Variety: applicability, e.g., reverse osmosis, nanofilters, ultrafiltrations.Casting process, anisotropic, track etched, stretched.The consequences of different polymeric compositions.The “sterilizing grade” membrane, the vent filter.

• Filter dispositions: flatstock, cartridges, their dimensions, constructions,polar and non-polar substituents, hydrophylic/hydrophobic, heterogenous,homogeneic, double filters, redundant, parallel, series, prefilter, final filter.

• Bonding: valence, covalent, ionic, partial charge, van der Waals, dipoles, H-bonds.

• Pores: pore architecture; the pore passageway, pore size and distribution, poresize ratings.Size alterations during filtrations.

• Microbiology: organisms: sizes, shapes, numbers, dimensional changes.Brevundimonas diminuta as model organism.Challenge levels: FDA, EMEA standard, dilute.

• Assaying: Sampling frequency, storing, culturing, interpreting CFU counts,biofilm, biooburden.

• Atomic and molecular: movements: rotational, translational, vibrational,molecular densities.

• Organism retention: mechanisms:(a) Sieving, or size exclusion

(b) Adsorptive sequestration: electrical effects: opposite-sign attractions,dipoles.

(c) Filter cakes: partial charges, H-bonding, van der Waals forces,compactions.

(d) Impactions: gravity, inertia, Brownian Motion, electrostatics.

(e) Exo-polymeric substance: adhesive-like.

(f) Retention capabilities: nominal, absolute.

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Regulatory agencies

The guiding presence and activities of regulatory bodies, usually governmental orof other provenance, dedicated to the supervision and responsibility for overseeingthe correct implementations of actions necessary for the safe and effectiveprocessing of drug preparations is known well enough to merit only a reminder. Inthe U.S.A., the governmental regulating body is the Food and DrugAdministration, (FDA). Also involved is the United States PharmacopeialConvention (USP). This is a private not-for-profit organization that among otherfunctions sets standards for drugs, focusing on safety and efficiency. There is asymbiotic relationship between the USP and FDA. The established USPcompendium has legal standing. The USP sets standards but cannot enforce them.The FDA in recognizing the USP-set standards is empowered to enforce them.

The FDA promulgates current good manufacturing practices, (cGMP), withthe intention of identifying and controlling key steps in pharmaceuticalprocessing. By means of the GMPs it becomes possible to validate that equipmentcomponents and their assemblages do indeed function as they are intended to. Theresult is a reliance on building quality into the product, rather than a totaldependence on final product testing alone. Validation, as described by the FDA,is, “The attaining and documenting of sufficient evidence to give reasonableassurance, given the current state of science and the art of drug manufacturing,that the process under consideration does or will do what it purports to do or isexpected to do.” Validation requires substantiation of the operation by documentedexperimentally obtained data.

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anatomy of a pharmaceutical filtration · assembled over many years of practice in filter sizing,...

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