Daftar Isi Aulton,m

24.Powders and granules Malcolm Summers CHAPTER CONTENTS Powdered and granulated products as dosage forms 360 Advantages and disadvantages of powdered and granulated products 361 Dispensed preparations 361 Bulk powders 361 Divided powders 361 Bulk granules 362 Divided granules 362 Dusting powders 362 Insufflations 362 Dry-powder inhalers 362 Preparations requiring further treatment at time of dispensing 363 Oral antibiotic syrups 363 Powders for injection 363 Bibliography 363 25.Granulation Malcolm Summers, Michael Aulton CHAPTER CONTENTS Introduction to granulation 365 Reasons for granulation 365 To prevent segregation of the constituents of the powder mix 365 To improve the flow properties of the mix 366 To improve the compaction characteristics of the mix 366 Other reasons 366 Methods of granulation 366 Dry granulation 366 Wet granulation (involving wet massing) 366 Effect of granulation method on granule structure 367 Granulation mechanisms 367 Particle-bonding mechanisms 367 Adhesion and cohesion forces in immobile films 367 tnterfacial forces in mobile liquid films 367 Solid bridges 368 Partial melting 368 Hardening binders 368 Crystallization of dissolved substances 368 Attractive forces between solid particles 368 Mechanisms of granule formation 369 Nucleation 369 Transition 369 Ball growth 369 Coalescence 369 Breakage 369 Abrasion transfer 369 Layering 369

Pharmaceutical granulation equipment 369 Wet granulators 369 Shear granulators 370 High-speed mtxer/granulators 371 Fluidized-bed granulators 372 Advantages of fluidized-bed granulation 372 Disadvantages of fluidized-bed granulation 373 Spray-driers 374 Spheronizers/pelletizers 374 Extrusion/spheronization 374 Applications of extrusion/spheronization 374 Controlled drug release 374 Processing 374 Desirable properties of pellets 375 The process 375 Dry mixing of ingredients 375 Wet massing 375 Extrusion 375 Spheronization 375 Drying 376 Screening 376 Formulation variables 376 Summary 376 Rotor granulation 376 Dry granuiators 378 Sluggers 378 Roller compactors 378 Bibliography 378 26.Drying Michael Aulton CHAPTER CONTENTS Introduction 380 The drying of wet solids 380 Moisture content of wet solids 380 Total moisture content 380 Unbound water 380 Equilibrium moisture content 380 Bound water 380 Relative humidity (RH) of air 381 Wet-bulb and dry-bulb temperature 381 Moisture content of air 381 Relationship between equilibrium moisture content and relative humidity 382 Loss of water from wet solids 382 Types of drying method 382 383 Convective drying of wet solids 383 Fixed (or static) bed convective drying Tray drier 383 Rate of drying in fixed beds 383 Constant-rate period 383 First falling-rate period 384 Second falling-rate period 384 Dynamic convective driers 384 Fluidized-bed drier 384 Advantages of fluidized-bed drying 385

Disadvantages of fluidized-bed drying 385 Conductive drying of wet solids Vacuum oven 386 Vacuum tumbling drier 386 386 Radiation drying of wet solids 386 Radiant heat transmission 386 Use of infrared radiation 386 The use of microwave radiation 387 Generation and action of microwaves 387 A microwave drier for granulates 387 Advantages of microwave drying 387 Disadvantages of microwave drying 388 Driers for dilute solutions and suspensions Drum drier 388 Advantages of the drum drier 389 388 Spray drier 389 Advantages of the spray drying process 390 Disadvantages of the spray drying process 390 Uses of the spray drying process 390 Freeze drying 390 The phase diagram for water 391 Application of the phase diagram of water to freeze drying 391 Stages of the freeze drying process 392 Freezing stage 392 Shell freezing 392 Centrifugal evaporative freezing 392 Vacuum application stage 392 Sublimation stage 392 Primary drying 392 Heat transfer 392 Vapour removal 392 Rate of drying 392 Secondary drying 393 Packaging 393 Freeze-drying in practice 393 Advantages 393 Disadvantages 393 Uses of freeze drying 393 Solute migration during drying 393 Intergranular migration 394 Intragranular migration 394 Consequences of solute migration 394 Loss of active drug 394 Mottling of coloured tablets 394 Migration of soluble binders 394 The influence of formulation factors on solute migration 395 Nature of substrate 395 Viscosity of granulating fluid 395 The influence of process factors on solute migration 395 Drying method 395 Initial moisture content 395 Some practical means of minimizing solute migration 395 References 395 Bibliography 396

27.Tablets and compaction Goran Alderborn CHAPTER CONTENTS Introduction 398 Quality attributes of tablets 398 Tablet manufacturing 399 Stages in tablet formation 399 Die filling 399 Tablet formation 399 Tablet ejection 399 Tablet presses 399 Single-punch press (eccentric press) 399 Rotary press 400 Computerized hydraulic press 400 Instrumentation of tablet presses 400 Technical problems during tabletting 402 Tablet production via granulation 403 Rationale for granulating powders prior to tabletting 403 Granulation by convective mixing 403 Alternative granulation procedures 404 Tablet production by direct compaction 404 Tablet excipients 404 Filler (or diluent) 404 Disintegrant 406 Binder 407 Glidant 408 Lubricant 408 Antiadherent 410 Sorbent 410 Flavour 410 Colourant 410 Tablet types 410 Classification of tablets 410 Disintegrating tablets 411 Chewable tablets 412 Effervescent tablets 412 Lozenges 413 Sublingual and buccal tablets 413 Extended-release tablets 413 Classification of extended-release tablets 413 Diffusion-controlled release systems 414 Reservoir systems 414 Matrix systems 415 Dissolution-controlled release systems 415 Erosion-controlled release systems 416 Osmosis-controlled release systems 417 Tablet testing 417 Uniformity of content of active ingredient 417 Disintegration 418 Dissolution 419 Stirred-vessel methods 419 Continuous-flow methods 419 Mechanical strength 420 Attrition-resistance methods 422 Fracture-resistance methods 422 Fundamental aspects of the compression of

powders 423 Mechanisms of compression of particles 423 Evaluation of compression behaviour 424 Procedures 424 Inspection of tablets 425 Pore structure and specific surface area of tablets 425 Force-displacement profiles 426 Tablet volume-applied pressure profiles 427 Heckel equation 427 Strain-rate sensitivity 428 Kawakita equation 428 Evaluation of die-wall friction during compression 428 Fundamental aspects of the compaction of powders 430 Bonding in tablets 430 The compactability of powders and the strength of tablets 431 Post-compaction tablet strength changes 433 Relationships between material properties and tablet strength 435 Factors of importance for powder compactability 435 The compaction of solid particles 435 The compaction of granules 437 The compaction of binary mixtures 438 References 439 Bibliography 439 28.Coating of tablets and multiparticulates John Hogan CHAPTER CONTENTS DEFINITION Definition 441 Types of tablet coating 441 Reasons for coating tablets 441 Film coating 442 Process description 442 Coating suspension formulation 442 Ideal characteristics of a film coating polymer 442 Solubility 442 Viscosity 443 Permeability 443 Mechanical properties 443 Types of polymer available 443 Cellulose derivatives 443 Methacrylate amino ester copolymers 443 Aqueous polymer dispersions 443 Plasticizers 444 Colourants 444 Solvents 444 Process details 444 Basic process requirements for film coating 444 Ideal characteristics of film-coated tablets 445 Coating faults 445 Sugar coating 445 Stages involved in the production of sugar-coated tablets 445

Process details 446 Ideal characteristics of sugar-coated tablets 446 Coating faults 446 Press coating 446 Functional coatings 447 Controlled-release coatings 447 Types of multiparticulate 447 Extruded/spheronized granulates 447 Non-pareils 447 Mechanisms of drug release from multiparticulates 447 Diffusion 447 Erosion 447 Osmosis 447 Enteric coating 448 Enteric film coating 448 Enteric sugar coating 448 Standards for coated tablets 448 References 448 Bibliography 448 29.Hard gelatin capsules Brian Jones CHAPTER CONTENTS Introduction 449 Raw materials 449 Gelatin 449 Colourants 450 Process aids 450 Manufacture 451 Empty capsule properties 452 Capsule filling 452 Capsule sizes 452 Capsule shell filling 453 Capsule-filling machines 453 Filling of powder formulations 453 Bench-scale filling 453 Industrial-scale filling 454 Dependent dosing systems 454 The auger 454 Independent dosing systems 454 Dosators 454 Tamping finger and dosing disc 455 Instrumented capsule-filling machines and simulators 455 Pellet filling 455 Tablet filling 456 Sernisolid and liquid filling 456 Formulation 456 Powder formulation 456 Formulation for filling properties 457 Formulation for release of active ingredients 457 Formulation optimization 459 Formulation for position of release 459 References 460 30.Soft gelatin capsules Keith Hutchison, Josephine Ferdinando CHAPTER CONTENTS Introduction 461 Description of the soft gelatin capsule dosage

form (softgels) 461 Rationale for the selection of softgels as a dosage form 463 Improved drug absorption 463 Increased rate of absorption 463 Increased bioavailability 464 Decreased plasma variability 464 Patient compliance and consumer preference 464 Safety for potent and cytotoxic drugs 465 Oils and low melting-point drugs 465 Dose uniformity of low-dose drugs 465 Product stability 465 Manufacture of softgels 465 Formulation of softgels 467 Gelatin shell formulation 467 Gelatin 467 Plasticizers 467 Water 468 Colourants/opacifiers 468 Properties of soft gelatin shells 468 Oxygen permeability 468 Residual water content 468 Formulation of softgel fill materials 469 Types of softgel fill matrices 469 Lipophilic liquids/oils 469 Hydrophilic liquids 469 Self-emulsifying oils 469 Microemulsion and nanoemulsion systems 469 Suspensions 470 Lipolysis systems 470 Formulation using lipolysis systems 470 Product quality considerations 471 Ingredient specifications 471 In-process testing 472 Finished product testing 472 References 472 31.Pulmonary drug delivery Kevin Taylor CHAPTER CONTENTS Inhaled drug delivery 473 Lung anatomy 473 Inhalation aerosols and the importance of size distribution 474 The influence of environmental humidity on particle size 474 Particle deposition in the airways 475 Gravitational sedimentation 475 Inertial impaction 475 Brownian diffusion 475 Other methods of deposition 475 Breathing patterns 476 Clearance of inhaled particles and drug absorption 476 Formulating and delivering therapeutic inhalation aerosols 476 Metered-dose inhalers 476 Containers 476 Propellents 476

Metering valve 478 Formulating metered-dose inhalers 478 Filling metered-dose inhaler canisters 479 Advantages and disadvantages of metered-dose inhalers 479 Spacers and breath-actuated metered-dose inhalers 479 Dry powder inhalers 480 Formulating dry powder inhalers 480 Unit-dose devices with drug in hard gelatin capsules 480 Multidose devices with drug in foil blisters 481 Multidose devices with drug preloaded in inhaler 481 Non-breath actuated devices 482 Nebulizers 482 Jet nebulizers 483 Ultrasonic nebulizers 483 Formulating nebulizer fluids 484 Physicochemicat properties of nebulizer fluids 484 Temperature effects during nebulization 484 Duration of nebulization and 'dead volume' 484 Variability between nebulizers 485 Methods of aerosol size analysis 485 Cascade impactors and impingers 485 References 487 Bibliography 487 32.Nasal drug delivery Peter Taylor CHAPTER CONTENTS Introduction 489 The anatomy and physiology of the nose 489 Nasal mucosa and mucoctliary clearance 491 Nasal metabolism 491 Physicochemical factors influencing drug absorption in the nasal cavity 492 Molecular size and weight 492 The effect of pH and the partition coefficient 492 Other physicochemical factors affecting nasal absorption 493 Physicochemical properties and mechanisms of absorption - a summary 493 Strategies for improving drug availability in nasal administration 493 Increasing nasal residence time 494 Enhancing nasal absorption 494 Modifying drug structure 496 INTRODUCTION Nasal delivery systems and their formulation General formulation issues 496 Types of nasal dosage form and delivery system 496 Deposition mechanisms 496 Impaction 496 Sedimentation 497 Diffusion 497 Nasal dosage forms 497

Liquid formulation 497 Squeezed bottles 497 Metered-dose pump systems 497 Concluding remarks 497 References 498 33.Transdermal drug delivery Brian Barry CHAPTER CONTENTS Structure, function and topical treatment of human skin 500 Anatomy and physiology 501 The epidermis 502 The dermis 502 The subcutaneous tissue 502 The skin appendages 502 Functions of the skin 502 Mechanical function 502 Protective function 503 Microbiological barrier 503 Chemical barrier 503 Radiation barrier 503 Heat barrier and temperature regulation 503 Electrical barrier 503 Mechanical shock 503 Rational approach to drug delivery to and via the skin 503 Surface treatment 503 Stratum corneurn treatment 504 Skin appendage treatment 505 Viable epidermis and dermis treatment 505 Transcutaneous immunization 505 Systemic treatment via transdermal absorption 505 Drug transport through the skin 505 Basic principles of diffusion through membranes 505 The diffusion process 506 Complex diffusional barriers 506 Barriers in series 506 Barriers in parallel 50? Skin transport 507 Routes of penetration 507 Sebum and surface material 507 Skin appendages 507 Epidermal route 508 Conclusions 508 Properties that influence transdermal delivery 508 Biological factors 509 Skin condition 509 Skin age 510 Blood flow 510 Regional skin sites 510 Skin metabolism 510 Species differences 510 Physicochemical factors 511 Skin hydration 511 Temperature and pH 511 Diffusion coefficient 512

Drug concentration 512 Partition coefficient 512 Molecular size and shape 513 Ideal molecular properties for drug penetration 513 Drug permeation through skin 513 Stratum corneum rate controlling 513 Stratum corneum not rate controlling 514 Absorption from solution: skin a perfect sink 514 Absorption from suspensions: skin a perfect sink 515 Methods for studying transdermal drug delivery 516 In vitro methods 516 Excised skin 516 Artificial membranes 518 Release methods without a rate-limiting membrane 518 In vivo methods 518 Histology 519 Surface loss 519 Microdialysis 520 Analysis of body tissues or fluids 520 Observation of a pharmacological or physiological response 520 Physical properties of the skin 520 Bioassays 520 Maximizing the bioavailability of drugs applied to skin 521 Drug or prodrug selection 521 Chemical potential adjustment 521 Hydration 521 Ultrasound (phonophoresis) 521 Iontophoresis 521 34.Rectal and vaginal drug delivery Josef Tukker CHAPTER CONTENTS Rectal drug delivery 534 Introduction 534 Anatomy and physiology of the rectum 535 Absorption of drugs from the rectum 535 Formulation of suppositories 537 The vehicle (suppository base) 537 Requirements of the vehicle 537 Fatty vehicles 537 Water-soluble vehicles 538 Choice of vehicle 538 The drug 538 Drug solubility in vehicle 538 Surface properties 539 Particle size 539 Amount of drug 539 Other additives 540 The finished product 540 Manufacture 540 Quality control 540 Drug release from suppositories 541 Rectal formulations other than suppositories 542 Vaginal drug delivery 542

Vaginal administration of drugs 542 Formulation of vaginal dosage forms 543 Bibliography 543 35.Delivery of pharmaceutical proteins Daan Crommelin, Ewoud van Winden, Albert Mekking CHAPTER CONTENTS Introduction 544 Protein structures 544 Sources of pharmaceutical proteins Specific challenges 545 Formulation of pharmaceutical proteins for parenteral administration 545 Stability issues 545 Physical instability 545 Chemical instability 547 Excipients used 547 Microbiological requirements 548 Analytical techniques to characterize proteins 549 Administration of pharmaceutical proteins 550 Routes of administration 550 Release control 552 Concluding remarks 553 Bibliography 553 36.Packs and packaging Dixie Dean CHAPTER CONTENTS The role of the pack 555 The pack as a protection 555 Mechanical hazards 556 Shock or impact damage 556 Compression 556 Vibration 556 Abrasion 556 Puncture or piercing 556 Climatic or environmental hazards 556 Moisture 556 Temperature 556 Pressure 556 Light 557 Atmospheric gases 557 Solid airborne contamination (particulates) 557 Biological hazards 557 Microbiological 557 Other forms of infestation 557 Pilferage and adulteration risks 557 Chemical hazards 557 Stages in the development of a pack-product combination 558 Development stages 558 Preformulation 558 Product formulation 558 Consideration of container materials 559 Pack feasibility tests 559 Formal stability tests 559 Ongoing stability 559 Complaints 559 Pack selection 559

Factors influencing choice of pack 559 The product 560 The market 560 The distribution System 560 Manufacturing facilities 560 Packaging materials 560 Glass and glass containers 560 Metal and metal containers 561 Plastics and plastic containers 561 Types and uses 561 Disadvantages 562 Additives 562 Fabrication of plastics 563 Paper and board 563 Films, foils and laminates 563 Rubber-based compounds 564 Closures 564 Functions of a closure 564 Determination of closure efficiency 565 Heat seals 566 Other sealing methods 566 Filling 566 Packaging lines 566 Organization of packaging lines 566 Packaging of certain products 567 Aerosols 567 Parenterats 567 Glass 567 Rubber 567 Plastics 568 Sterilization 568 Labelling 568 Quality Control of Packaging 568 Concluding comment 569 Bibliography 570 37.Pharmaceutical plant design Michael Aulton, Andrew Twitchell CHAPTER CONTENTS Manufacturing facilities for pharmaceutical products 572 Manufacturing site selection 572 Considerations when selecting a new site 572 Design and utilization of manufacturing facilities 572 Aims of manufacturing facility design 572 Achievement of manufacturing aims 573 Environmental conditions 573 Architectural considerations 573 Validation of manufacturing facilities 574 Validation and why it Is required 574 The scope of validation 574 Types of validation 574 Prospective validation 574 Retrospective validation 574 Concurrent validation 574 Revalidation 574 Costs/benefits of validation 574 Cleaning as an example of a validation process 574

Materials of fabrication 575 Desirable properties and selection 575 Chemical factors 575 Physical factors 575 Strength 575 Weight 575 Wearing qualities 575 Ease of fabrication 575 Thermal expansion 575 Thermal conductivity 575 Cleaning 575 Sterilization 576 Transparency 576 Economic factors 576 Materials used in fabrication 576 Metals 576 Ferrous metals - steels 576 Mild steel 576 Cast Iron 576 Stainless steels 576 Non-ferrous metals 577 Copper 577 Copper alloys 577 Aluminium 577 Lead 578 Tin 578 Non-metals 578 Inorganics 578 Glass 578 Fused silica 578 Glass linings and coatings 578 Organics 578 Plastics 578 Rubber 579 Corrosion 579 General introduction and theory 579 Importance of corrosion 579 Safety 579 Financial losses 579 Contamination of the product 580 Appearance of plant 580 Corrosion mechanisms 580 Single-metal corrosion 580 Corrosion between metals 581 Cathodic protection 581 Passivity 581 Types of corrosion 582 Uniform attack 582 Galvanic corrosion 582 Control of galvanic corrosion 582 Concentration-cell corrosion 583 Metal-ion cells 583 Oxygen cells 583 Control of concentration-cell corrosion 583 Pitting 583 Control of pitting 583 Intergranular corrosion 583 Control of intergranular corrosion 583 Parting (or dezincification) 584 Control of parting 584

Stress corrosion 584 Stress-accelerated corrosion 584 Stress corrosion cracking 584 Erosion corrosion 585 Bibliography 585 38.Heat transfer and the properties and use of steam Andrew Twitchell CHAPTER CONTENTS Heat and heat transfer 586 introduction 586 Methods of heat transfer 587 Conduction 587 Convection 587 Radiation 587 Heat transfer by conduction and practical heat transfer 587 Illustrative calculation 589 Heat transfer through multiple layers 589 Film heat-transfer coefficient 590 Overall heat-transfer coefficient 590 Steam as a heating medium 590 Heat content of steam 591 Effect of pressure on steam properties 592 Steam tables 592 Adverse effects of air in steam 592 Steam generation and use 593 Manufacturing Installations for liquid and semisolld products 593 Steam traps 594 Example calculations involving the use of steam 595 References 596 Part five PHARMACEUTICAL MICROBIOLOGY 597 39.Fundamentals of microbiology Geoff Hanlon CHAPTER CONTENTS Introduction 600 Viruses 600 Reproduction of viruses 601 Adsorption to host cell 601 Penetration 602 Uncoating 602 Nucleic acid and protein synthesis 602 Assembly of new virions 602 Release of virus progeny 602 Latent infections 602 Oneogenic viruses 602 Bactertophages 602 Archaeobacteria 602 Eubacteria 603 Atypical bacteria 603 Rlckettsiae 603 Chlamydiae 603 Mycoplasmas 603 Actinomycetes 603

Typical bacteria 604 Shape, size and aggregation 604 Anatomy 604 Capsule 604 Cell wall 605 Cytoplasmic membrane 606 Nuclear material 607 Mesosomes 607 Ribosomes 607 Inclusion granules 607 Flagella 607 Pili (fimbriae) 607 Endospores 607 Microscopy and staining of bacteria 609 Differential stains 609 Fluorescence microscopy 609 Dark-ground microscopy 610 Phase-contrast microscopy 610 Differential-interference contrast microscopy 610 Electron microscopy 610 Growth and reproduction of bacteria 610 Genetic exchange 611 Bacterial nutrition 611 Oxygen requirements 612 Influence of environmental factors on the growth of bacteria 612 Handling and storage of microorganisms 612 Inoculation of agar surfaces by streaking 613 Inoculation of slopes 614 Transference, of liquids 614 Release of infectious aerosols 614 Cultivation of anaerobes 614 Counting bacteria 615 Total counts 615 Viable counts 616 Pour plates 616 Isolation of pure bacterial cultures 617 Classification and identification 617 Nomenclature 617 Identification 617 Fungi 619 Fungal morphology 620 Yeasts 620 Yeast-like fungi 620 Dimorphic fungi 620 Filamentous fungi 620 Mushrooms and toadstools 620 Reproduction of fungi 620 Asexual reproduction 621 Sexual reproduction 622 Fungal classification 622 Zygomycetes 622 Ascomycetes 622 Deuteromycetes 622 Basidiomycetes 622 Bibliography 622 40.Pharmaceutical applications of microbiological techniques

Norman Hodges CHAPTER CONTENTS Measurement of antimicrobial activity 624 Factors to be controlled in the measurement of antimicrobial activity 624 Origin of the test organism 624 Composition and pH of the culture medium 624 Exposure and incubation conditions 625 Inoculum concentration and physiological state 625 Antibiotic assays 626 Agar diffusion assays 627 Practical aspects of the conduct of agar diffusion assays 628 Turbidimetric assays 629 Practical aspects of the conduct of turbidimetric assays 629 Minimum inhibitory concentration determinations (MICs) 629 MIC test methods 630 Preservative efficacy tests (challenge tests) 630 Choice of test organisms and inoculum concentration 631 Inactivation of preservative 631 Interpretation of results 632 Disinfectant evaluation 632 Microbiological quality of pharmaceutical materials 634 Non-sterile products 634 Environmental monitoring 634 Counting of microorganisms in pharmaceutical products 635 Very low concentrations of microorganisms in aqueous solutions 636 Insoluble solids 636 Oils and hydrophobic Of ntments 636 Creams and lotions 637 Detection of specific hazardous organisms 637 Microbiological assays of B-group vitamins 637 Sterile products 638 Sterilization monitoring 639 Tests for sterility 639 Endotoxin and pyrogen testing 641 References 641 Bibliography 642 41.The action of physical and chemical agents on microorganisms Geoff Hanlon, Norman Hodges CHAPTER CONTENTS The kinetics of cell inactivation 643 D value, or decimal reduction time 644 Z values 644 Alternative survivor plots 645 Antimicrobial effects of moist and dry heat 646 Resistance of microorganisms to moist and dry heat 646 Factors affecting heat resistance and its measurement 647 Species and strain differences 648

Cell form 648 Cultural conditions 648 pH and composition of heating menstruum 648 Recovery of heat treated cells 649 Ionizing radiations 649 Paniculate radiation 649 Electromagnetic radiation 649 Units of radioactivity 650 Effect of ionizing radiations on materials 650 Factors affecting the radiation resistance of microorganisms 651 Ultraviolet radiation 651 Factors affecting resistance to UV light 651 Gases 651 Ethylene oxide 652 Factors affecting the activity of ethylene oxide 652 Formaldehyde 652 0-propiolactone 653 Propylene oxide 653 Methyl bromide 653 Gas plasmas 653 Antimicrobial effects of chemical agents 653 Principal factors affecting activity 654 The range of chemical agents 654 Phenolics 654 Alcohols, aldehydes, acids and esters 655 Quaternary ammonium compounds 656 Biguanides and amidines 656 The halogens and their compounds 656 Metals 657 The acridines 657 References 657 Bibliography 657 42.Microbiological contamination and preservation of pharmaceutical products Malcolm Parker (updated by Norman Hodges) CHAPTER CONTENTS Sources and Incidence of Contamination 658 Growth and Multiplication of Microorganisms in Pharmaceutical Products 660 Consequences of Contamination 660 Screening for Contamination 661 Air sampling 661 Free fall or settling 661 Forced air flow 661 Filtration 662 Sampling of surfaces and equipment 662 Measuring contamination levels in raw materials and final preparations 662 Control of Microbial Contamination 662 Premises and equipment 662 Raw materials 664 Personnel 664 The Preservation of Pharmaceutical Preparations 664 Factors in preservative efficacy 664 Oil/water partition 665 Emulsions 665

Interaction with other formulation components 665 Effects of containers 666 Influence of pH 666 Preservatives in combination 666 Microbial Standards for Pharmaceutical Preparations 667 Challenge testing 667 Conclusion 667 References 667