Practical Pharmaceutics: An International Guideline for the Preparation, Care and Use of Medicinal Products

Description

Practical Pharmaceutics contains essential knowledge on the preparation, quality control, logistics, dispensing and use of medicines. It features chapters written by experienced pharmacists and scientists working in hospitals, academia and industry throughout Europe, including practical examples as well as information on current GMP and GMP-based guidelines and EU-legislation. In this second edition all chapters have been updated with numerous new as well as didactically revised illustrations and tables. A completely new chapter about therapeutic proteins and Advanced Therapy Medicinal Products was added. From prescription to production, from usage instructions to procurement and the impact of medicines on the environment, the book provides step-by-step coverage that will help a wide range of readers, students as well as professionals. It offers product knowledge for all pharmacists working directly with patients and it will enable them to make the required medicine available, to store medicines properly, to adapt medicines if necessary and to dispense medicines with the appropriate information for patients as well as caregivers about product care and how to maintain the quality of the product. The basic knowledge presented in the book will also be valuable for industrial pharmacists to remind and focus them on the application of the medicines manufactured. The basic and practical knowledge on the design, preparation and quality management of medicines can directly be applied by the pharmacists whose main duty is production in community and hospital pharmacies and in industry. Undergraduate as well as graduate pharmacy students will find knowledge presented in a coherent way and fully supported with relevant examples. Practical Pharmaceutics has become a reliable and recognised source for the acquisition of pharmaceutical-technological knowledge. The book is used in the curriculum of a number of international universities and schools of Pharmacy. Preface Contents About the Editors 1: Introduction 1.1 Structure of the Book 1.2 Definitions 1.2.1 Types of Pharmacy Preparations 1.2.2 Aseptic Preparation, Aseptic Handling and Reconstitution 1.3 Terminology 1.4 Spelling and Notation 1.5 Formulations 1.6 Examples, Guidelines, Legislation, Ph. Eur. 1.7 References 2: Prescription Assessment 2.1 Pharmacy Preparation: Way Out or Unjustified 2.2 Prescription Assessment 2.2.1 Alternative Treatment Options 2.2.2 Considerations Upon Receiving a Request 2.2.3 Structured Assessments 2.2.3.1 Leeds Approach 2.2.3.2 German Reason Check 2.2.3.3 Risk-Benefit Form [4] 2.3 The Prescription 2.3.1 Legal Requirements 2.3.2 Consultations with the Prescriber and the Patient 2.3.2.1 Consultation About a Prescription 2.3.3 Dose 2.3.3.1 Dosage Expression 2.3.3.2 Paediatric Population 2.3.3.3 Cutaneous (Dermal) Medicines Used in Children 2.3.3.4 Elderly Population 2.3.4 Contra Indications, Interactions and Intolerances 2.3.5 Narcotic and Psychotropic Substances 2.3.6 Standard Amounts 2.4 Special Categories of Prescriptions 2.4.1 Herbal Medicines 2.4.2 Agents Used for Assisted Suicide 2.4.3 Homoeopathic and Anthroposophic Medicines 2.4.4 Veterinary Medicines 2.4.5 Medical Devices 2.5 Essentials References 3: Availability of Medicines 3.1 Accessibility and Availability 3.2 The Pharmacist’s Mandate to Provide Medicines 3.2.1 Mandate 3.2.2 Medicines Shortages (Also Referred to as Drug Shortages) 3.2.2.1 Deterioration of Medicines Shortages Situations 3.2.2.1.1 Medicines Shortages Situation in the USA 3.2.2.1.2 Medicines Shortages Situation in the EU 3.2.2.1.3 General Worldwide Supply Chain Disruptions 3.2.2.2 Causations of Medicines Shortages Situations 3.2.2.3 Approaches to Prevent and Manage Medicines Shortages Situations 3.2.2.3.1 Approaches to Exploit Alternative Medicinal Products Sources 3.2.2.3.2 Approaches to Mitigate Medicines Shortages 3.2.2.3.3 Systems Dynamics’ Contributions to Forecast Supply Chain Threats 3.2.3 Bioequivalence Considerations for Coping with Shortages 3.3 Availability of Medicines with a Market Authorisation 3.3.1 Market Authorisation (Formerly “Registration”) 3.3.2 Reimbursement 3.4 Availability of Investigational Medicinal Products 3.5 Availability of Unlicensed Medicines 3.6 Availability of Orphan Medicines 3.6.1 Orphan Medicines 3.6.2 Neglected Patients 3.6.3 Improving Accessibility in Low- and Middle-Income Countries 3.7 Medicines Import 3.8 Preparation of the Remaining Necessary Medicines 3.9 Organisation of Pharmacy Preparation 3.10 Importance of Pharmaceutical Production in Hospitals 3.11 Legislation of Pharmacy Preparation 3.12 Preparations’ Categories 3.13 Feasibility of Pharmacy Preparation References 4: Product Design 4.1 Orientation and Scope 4.2 Patients’ Needs 4.3 Quality by Design 4.4 Biopharmaceutics 4.4.1 Physicochemical Properties and Route of Administration 4.4.2 Target Population and Pharmacokinetics 4.5 Formulation 4.6 Preparation Process 4.6.1 Process Design 4.6.2 Control Strategy: Critical Quality Attributes, Process Parameters and Sources of Variability 4.6.3 Product/Process Validation 4.7 Shelf-Life 4.8 Documentation 4.9 Product Life Cycle Management & Future Trends 4.9.1 Product Life Cycle Management 4.9.2 Future Trends References 5: Biopharmaceutics 5.1 From Medicinal Product to Effect and Beyond 5.1.1 Design of a Medicinal Product 5.1.2 Pharmaceutical Availability and Bioavailability 5.1.3 Pharmacokinetics, Pharmacodynamics and Toxicology 5.1.4 Solubility, Dissolution and Partition Coefficient 5.1.5 Absorption and Bioavailability 5.1.5.1 Absorption 5.1.5.2 Bioavailability 5.1.5.3 Dose Number and Biopharmaceutical Classification System 5.1.6 Excipient and Food Interactions 5.1.7 Stability of the Active Substance in the Physiological Environment 5.1.8 First-Pass Effect 5.1.8.1 First-Pass Metabolism and Controlled Release Products 5.1.9 Charge and the pH Partition Theory 5.1.10 Distribution 5.1.11 Clearance 5.1.12 P-Glycoproteins 5.1.13 Drug Metabolising Enzymes 5.1.14 Slow Release and Flip-Flop Pharmacokinetics 5.2 Dosage Forms and Routes of Administration 5.2.1 Parenteral Administration 5.2.2 Oromucosal Administration 5.2.3 Oral Administration 5.2.4 Rectal Administration 5.2.5 Dermal and Transdermal Administration 5.2.6 Nasal Administration 5.2.7 Pulmonary Administration 5.2.8 Ocular Administration 5.3 New Developments and Advanced Drug Delivery Systems References 6: Physical Chemistry 6.1 Solubility 6.1.1 Solubility and pH 6.1.2 Solubility and Salt Formation 6.1.3 Solubility in Non-aqueous Solvents 6.1.4 Solubility and Complex Formation 6.1.5 Solubility of Derivatives 6.1.6 Solubility and Supersaturation 6.2 Rheology 6.2.1 Rheograms 6.2.2 Measurement Methods 6.3 Phase Behaviour 6.3.1 Gibbs’ Phase Rule 6.3.2 Application of the Gibbs’ Phase Rule to One Component Systems 6.3.3 Application of the Gibbs’ Phase Rule to Two Component Systems 6.4 Interfaces and Surface Active Agents 6.4.1 Surface and Interfacial Tension 6.4.2 Wetting 6.4.3 Micelle Formation and Solubilisation 6.5 Disperse Systems 6.5.1 Colloidal Systems 6.5.1.1 Lyophilic and Lyophobic Systems 6.5.1.2 Stabilisation of Colloidal Systems 6.5.1.3 Destabilisation of Colloidal Systems 6.5.1.4 Protein Solutions as an Example of Colloidal Systems 6.5.1.5 Stabilisation of Proteins by Freeze Drying Them Together with Sugars 6.5.2 Suspensions 6.5.2.1 Sedimentation Behaviour 6.5.2.2 Influencing Sedimentation Behaviour 6.5.2.3 Particle Size Stability 6.5.2.4 Polymorphism, Pseudo-Polymorphism, Glassy State 6.5.3 Emulsions 6.6 Osmosis 6.6.1 Osmotic Pressure 6.6.2 Iso-osmotic and Isotonic 6.6.3 Non-ideal Solutions 6.6.4 Calculation of Osmotic Value 6.6.5 Importance of Osmotic Value in Dosage Forms References 7: Raw Materials 7.1 Herbal drugs and Traditional Chinese Medicine Label, Identity and Quality 7.1.1 Pharmacopoeial Designation 7.1.2 Sources 7.1.3 Registration of Active Substances 7.1.3.1 Certificate of Suitability (CEP) 7.1.4 Other Designations 7.1.5 Water Content 7.1.6 Salt-and Ester Forms 7.1.6.1 Corticosteroids 7.1.6.2 Excipients 7.1.6.3 Label Claims 7.1.7 International Units 7.1.8 Microbiological Purity 7.1.8.1 Micro-organisms 7.1.8.2 Bacterial Endotoxins and Pyrogens 7.1.8.3 Prions 7.1.9 Physico-chemical and Functionality-Related Characteristics 7.1.9.1 Particle Size 7.1.9.2 Viscosity 7.1.10 Mix-Up of Names 7.2 Quality, Stability and Shelf Life 7.2.1 Impurities 7.2.1.1 Nitrosamine Impurities 7.2.1.2 Elemental Impurities 7.2.1.3 Residual Solvents 7.3 Solvents 7.3.1 Water 7.3.1.1 Potable Water 7.3.1.2 Purified Water 7.3.1.3 Water for Injections 7.3.2 Ethanol 7.3.2.1 Denaturated Ethanol 7.3.3 Glycols and Glycerol 7.3.4 Macrogols 7.3.5 Fatty Oils, Fat, Waxes and Paraffin Waxes 7.3.6 Acetem 7.4 Filling and Disintegration Agents 7.4.1 Starch and Microcrystalline Cellulose 7.4.2 Polyols 7.4.3 Calcium Hydrogen Phosphate Dihydrate 7.4.4 Sugars 7.4.4.1 Syrups 7.5 Lubricants 7.6 Surfactants 7.6.1 Anionic-Active Substances 7.6.1.1 Examples with Anionic-Active Substances 7.6.2 Cationic-Active Substances 7.6.3 Amphoteric Substances 7.6.4 Non-ionic Substances 7.7 Viscosity Enhancing Substances 7.7.1 Overview 7.7.2 Gel Preparation Methods 7.7.2.1 Disperse by Hand in Hot Water 7.7.2.2 Disperse by Hand in Viscous Fluid 7.7.2.3 pH Change 7.7.2.4 Dispersing Mechanically 7.7.2.5 Classic Hydrogel Formers 7.7.2.6 Specific Emulsifying Method 7.7.3 Details of Viscosity Enhancers 7.7.3.1 Natural Gel Formers 7.7.3.2 Cellulose Derivatives 7.7.3.3 Xanthan Gum 7.7.3.4 Povidone 7.7.3.5 Carbomers 7.7.3.6 Mineral Viscosity Enhancers 7.8 Preservatives 7.8.1 Hypersensitivity and Toxicity 7.8.1.1 Hypersensitivity 7.8.1.2 Toxicity 7.8.2 Activity, Concentration and Applicability 7.8.3 Quaternary Ammonium Compounds 7.8.4 Mercury Compounds 7.8.5 Hydroxybenzoic Acid Esters 7.8.6 Sorbic Acid and Benzoic Acid 7.8.7 Chlorhexidine 7.8.8 Phenols 7.8.9 Alcohols, Di- and Trioles 7.8.10 Silver 7.9 Antioxidants 7.10 Complexing Agents 7.11 Colouring Agents 7.12 Herbal Raw Materials 7.12.1 Herbal Drugs and Granules of Traditional Chinese Medicine 7.13 Medical Gases References 8: Containers 8.1 Orientation 8.1.1 Purpose of Packaging, Requirements 8.1.2 Protection of the Product 8.1.2.1 Protection Against Moisture 8.1.2.2 Protection Against Oxygen 8.1.2.3 Protection Against Light 8.1.2.4 Protection Against Micro-organisms and Particulates 8.1.2.5 Protection Against Deformation/Fracture 8.1.2.6 No Interaction with the Container 8.1.2.7 No Transmittance of Liquid, Vapour or Gas 8.1.3 Transport, Handling, and Information 8.2 Container Materials 8.2.1 Glass 8.2.1.1 Contents and Characteristics 8.2.1.2 Glass: Erosion 8.2.1.3 Glass: Hydrolytic Resistance and Quality Control 8.2.2 Aluminium 8.2.3 Plastics 8.2.3.1 Polyethylene (PE) 8.2.3.2 Cyclic Olefin Copolymer (COC) 8.2.3.3 Polyethylene Terephthalate (PET) 8.2.3.4 Polypropylene (PP) 8.2.3.5 Polystyrene (PS) 8.2.3.6 Polyurethane (PUR) 8.2.3.7 Polyvinylchloride (PVC) 8.2.4 Rubber 8.2.4.1 Vulcanisation Methods 8.2.4.2 Additives 8.2.4.3 Natural Rubber 8.2.4.4 Butyl Rubber, Bromobutyl Rubber and Chlorobutyl Rubber 8.2.4.5 Silicone Rubber 8.2.4.6 Ethylene Propylene Rubber 8.2.5 Paper and Cardboard 8.2.6 Labels 8.3 Closures 8.3.1 Closure Systems and Functions 8.3.2 Container Closure Testing 8.4 Packaging Forms 8.4.1 Bottles 8.4.1.1 Requirements 8.4.1.2 Materials 8.4.1.3 Pouring Ring 8.4.2 Containers for Eye Drops 8.4.2.1 Requirements 8.4.2.2 Eye Drop Bottles for Multiple Use 8.4.2.3 Gemo Bottle 8.4.2.4 Eye Drop Bottle with Polypropylene Dropper 8.4.2.5 Eye Drop Bottle with Zentrop® Upper Part 8.4.2.6 Single Use Eye Drop Containers 8.4.3 Eye Lotion Bottles 8.4.4 Enema Containers 8.4.4.1 Microenema Bottle 8.4.4.2 Enema Bottle 100 mL 8.4.5 Infusion Bottle and Injection Vials with Closure 8.4.6 Containers for Bladder Irrigations 8.4.7 Jar 8.4.7.1 Special Jars 8.4.8 Tube 8.4.8.1 Material 8.4.8.2 Tube Cap 8.4.8.3 Inside and Outside Lacquer Control 8.4.8.4 Tubes as Stock Container 8.4.8.5 Membrane Tube 8.4.9 Eye Ointment Tube 8.4.9.1 Material 8.4.9.2 Sterilisation 8.4.9.3 Metal Particles 8.4.10 Suppository Strip 8.4.10.1 Material 8.4.10.2 Identification 8.4.10.3 Taping Up 8.4.10.4 Pharmacy Suppository Strips 8.4.11 Blister Pack 8.4.12 Powder Paper 8.4.13 Bag 8.4.13.1 Irrigation Bag 8.4.13.2 Enema Bag 8.4.13.3 Infusion Bag 8.4.13.4 Bag as Container for Oral Dry Dosage Forms 8.4.14 Single-Dose Containers (Miscellaneous) 8.4.14.1 Ampoule 8.4.14.2 Unit-Dose Cup 8.4.15 Syringes 8.4.15.1 Material 8.4.16 Oral and Rectal Dosing Syringe 8.4.17 Syringe for Parenteral Administration 8.4.18 Stock Container 8.4.19 Dosage Delivery Devices 8.4.19.1 Delivery Devices for Dermal Preparations 8.4.19.2 Delivery Devices for Oral Preparations 8.4.19.3 Measuring Spoons and Cups 8.4.19.4 Dropper and Pipette 8.4.19.5 Screw Caps with Dropping or Measuring Pipette 8.4.19.6 Dropper Insert 8.4.19.7 Spout Cap 8.4.19.8 Supporting Devices for the Administration of Eye Drops and Eye Lotions 8.4.19.9 Devices for the Administration of Nose Drops and Nasal Sprays 8.4.19.10 Devices for the Administration of Ear Drops 8.4.19.11 Devices for the Administration of Vaginal Preparations 8.4.19.12 Devices to Administer Rectal Preparations 8.4.20 Child-Resistant Closure 8.4.21 Containers for Arthritic Patients 8.4.21.1 Tablets and Capsules 8.4.21.2 Tubes 8.4.21.3 Suppositories 8.4.22 Elastomeric Infusion Devices 8.5 Quality Control of Packaging Materials 8.5.1 Quality Assessment 8.5.2 Defining Quality Requirements 8.5.3 Incoming Container Material Control 8.5.4 AQL-System 8.6 Quality Control of Primary Containers 8.6.1 Quality Control of Syringes 8.6.2 Extractables and Leachables 8.6.3 Overview Primary Containers References 9: Microbiology 9.1 Microbial Contaminants 9.1.1 Bacteria 9.1.2 Fungi (Yeasts and Moulds) 9.1.3 Viruses 9.1.4 Prions 9.2 Factors Affecting Microbial Survival and Proliferation in Pharmaceutical Preparations 9.2.1 Temperature 9.2.2 Water Activity 9.2.3 Availability of Nutrients 9.2.4 pH 9.2.5 Redox Potential 9.2.6 Presence of Substances with Antimicrobial Properties 9.2.7 Combination of Factors Affecting Microbial Growth in Pharmaceutical Preparations 9.3 Origin of Microbial Contamination 9.4 Microbial Controls 9.4.1 Basic Hygiene 9.4.2 Controlled Environments 9.4.3 Gowned and Qualified Personnel 9.4.4 Defined Cleaning and Disinfection Programmes of Facility/Equipment 9.4.5 Controlled Clean Utilities 9.4.6 Controlled Raw Materials 9.4.7 Sterilisation 9.4.8 Manufacturing Process Steps Reducing or Limiting the Microbial Contamination 9.4.9 Including Microbial Preservatives in the Product Formulation 9.4.10 Container Closure Integrity 9.4.11 Microbiological Stability Testing of Pharmaceutical Products 9.5 Microbiological Monitoring/Testing 9.5.1 Environmental Monitoring 9.5.2 Monitoring of Utilities 9.5.3 Testing of Product Components and Final Formulated Product 9.5.3.1 Sterility Test 9.5.3.2 Requirements for Non-sterile Products and Raw Materials 9.5.4 Other Compendial Test Methods 9.5.5 Alternative Methods 9.5.6 Microbiological Identification References 10: Impact on Environment 10.1 Environmental Hazards and Risks 10.2 Regulatory Framework 10.2.1 Environmental Legislation 10.2.1.1 IED (The New Industrial Emissions Directive: 2010/75/EU) [6] 10.2.1.2 REACH – EC 1907/2006 [7] 10.2.1.3 Packaging and Packaging Waste Directive: 94/62/EC [8] 10.2.1.4 WFD (Water Framework Directive [9]) 10.2.2 Pharmaceutical Legislation 10.2.2.1 Unused Medicines 10.2.2.2 Environmental Risk Assessments (ERA), Directive 2001/83/EC—Community Code Relating to Medicinal Products for Human Use and Guideline on the ERA of Medicinal Products for Human Use (EMEA/CHMP/SWP/4447/00) 10.3 Manufacturing of Medicines 10.4 Pharmacy Operations 10.4.1 Preparation of Medicines in Pharmacies 10.4.2 Preparation from Raw Materials 10.4.3 Generation of Waste Such as Overalls and Gloves 10.4.4 Packaging Material 10.4.4.1 Effect of the COVID-19 Pandemic on the Use of Plastic 10.4.5 Laboratory 10.4.6 Waste Disposal 10.4.7 Energy Use 10.5 The Use of Medicines 10.5.1 Patient Excretion 10.5.2 Unused Medicines 10.5.3 Potential Mitigating Measures 10.6 Essentials References 11: Information Sources 11.1 Introduction 11.2 Essential References 11.2.1 Fiedler Encyclopedia of Excipients 11.2.2 Handbook of Pharmaceutical Excipients 11.2.3 Martindale, the Complete Drug Reference 11.2.4 PubMed/MEDLINE 11.2.5 Stabilis 11.3 Textbooks 11.3.1 Aultons Pharmaceutics – The Design and Manufacture of Medicines 11.3.2 Martin’s Physical Pharmacy and Pharmaceutical Sciences 11.4 Specific References 11.4.1 British Pharmacopoeia 11.4.2 Deutscher Arzneimittel-Codex/Neues Rezeptur-Formularium 11.4.3 EU Legislation/GMP 11.4.4 European Pharmacopoeia 11.4.5 Formularium der Nederlandse Apothekers 11.4.6 Handbook of Extemporaneous Preparation 11.4.7 Hugo and Russell’s Pharmaceutical Microbiology 11.4.8 Kommentar zum Europäischen Arzneibuch & Kommentar zum Deutschen Arzneibuch 11.4.9 Fundamentals of Pharmacognosy and Phytotherapy 11.4.10 Profiles of Drug Substances, Excipients and Related Methodology 11.4.11 Quality Assurance of Aseptic Preparation Services: Standards Handbook 11.4.12 Sampson’s Textbook on Radiopharmacy 11.4.13 Stabilitätsprüfung in der Pharmazie – Theorie und Praxis 11.4.14 Trissel’s Stability of Compounded Formulations 11.4.15 United States Pharmacopeia and the National Formulary 11.5 Further Studying 11.5.1 Arbeitsgemeinschaft für Pharmazeutische Verfahrenstechnik 11.5.2 European Journal of Hospital Pharmacy 11.5.3 International Journal of Pharmaceutics 11.5.4 International Journal on Pharmaceutical Compounding 11.5.5 International Pharmaceutical Abstracts 11.5.6 International Society of Pharmaceutical Engineering 11.5.7 PDA Journal of Pharmaceutical Science and Technology and Technical Reports 11.5.8 Pharmaceutical Technology in Hospital Pharmacy 12: Oral Solids 12.1 Orientation 12.2 Definitions 12.3 Biopharmaceutics 12.4 Product Formulation 12.4.1 The Need for Excipients 12.4.2 Active Substance 12.4.3 Dilution and Flowability of the Powder Mixture 12.4.3.1 Diluents 12.4.3.2 Glidants 12.4.3.3 Binding Agents 12.4.4 Disintegration 12.4.5 Incompatibilities 12.4.6 Colouring and Flavouring 12.5 Method of Preparation 12.5.1 Homogeneous Powder Mixtures 12.5.1.1 Particle Size 12.5.1.2 Starting from Tablets or Capsules 12.5.1.3 The Mixing Process 12.5.1.4 Solvent Method 12.5.2 Colouring of Powder Mixtures 12.6 Capsules 12.6.1 Capsule Shells 12.6.2 Different Methods for Preparing the Powder Mass 12.6.2.1 High Dose Method 12.6.2.2 Low Dose Method 12.6.2.3 Solvent Method 12.6.2.4 Preparation from Tablets 12.6.2.5 Preparation from Other Capsules 12.6.2.6 Supplementing to Volume 12.6.3 Filling of Capsule Shells 12.6.3.1 In Process Controls 12.6.4 Preparation of Coated Capsules 12.6.5 Release Control and Quality Requirements 12.6.5.1 Appearance 12.6.5.2 Average Weight 12.6.5.3 Uniformity of Mass 12.6.5.4 Homogeneity 12.7 Powders 12.7.1 Single-Dose Powders 12.7.1.1 Product Formulation and Method of Preparation 12.7.1.2 Release Control and Quality Requirements 12.7.2 Multidose Powders 12.8 Cachets 12.8.1 Filling of Cachets 12.8.2 Patient Instruction 12.8.3 Stability 12.9 Tablets 12.9.1 Orientation and Definitions 12.9.2 Formulation 12.9.2.1 Diluents 12.9.2.2 Disintegrants 12.9.2.3 Binders 12.9.2.4 Glidants 12.9.2.5 Lubricants 12.9.2.6 Mechanical Strength 12.9.2.7 Disintegration and Dissolution Rate 12.9.3 Method of Preparation 12.9.3.1 Flow 12.9.3.2 Mixing 12.9.4 Release Control and Quality Requirements 12.10 Modified-Release Tablets and Capsules 12.10.1 Pharmacokinetics 12.10.2 Physicochemical Mechanisms on Active Substance Release 12.10.3 Desired Release Rate 12.10.4 Dosage Form 12.10.5 Matrix Systems 12.10.6 Reservoir Systems 12.10.7 Adapting Modified-Release Preparations 12.11 Orodispersible Films 12.11.1 Formulation 12.11.1.1 Polymers 12.11.1.2 Plasticizers 12.11.1.3 Surfactants 12.11.1.4 Expectorants 12.11.1.5 Flavouring Agents 12.11.2 Film Production Methods 12.11.2.1 Solvent Casting 12.11.2.2 Hot-Melt Extrusion 12.11.2.3 Electrospinning 12.11.2.4 3D Printing 12.11.3 Release Control and Quality Requirements 12.12 3D Printing of Oral Solids 12.13 Complementary Information 12.13.1 Containers and Labelling 12.13.2 Storage and Stability 12.13.3 Advice on Use 12.13.4 Swallowing Problems References 13: Oral Liquids 13.1 Orientation 13.2 Definitions 13.3 Biopharmaceutics 13.4 Product Formulation 13.4.1 Assessment of the Prescription 13.4.1.1 Request Because of Swallowing Problems with Oral Solids 13.4.1.2 Request for Paediatric Patients 13.4.2 Choice of the Oral Liquid Dosage Form 13.4.3 Additional Formulation Demands When the Patient Is on Enteral Feeding 13.4.3.1 No Blocking the Tubes 13.4.3.2 Incompatibility with Tubes 13.4.3.3 Microbiological Quality 13.4.4 Active Substance Solubility 13.4.4.1 Sufficient Solubility 13.4.4.2 pH 13.4.4.3 Co-solvents 13.4.4.4 Better Soluble Salt or Ester 13.4.4.5 Low Solubility: Suspension 13.4.5 Vehicles 13.4.5.1 Water 13.4.5.2 Ethanol 13.4.5.3 Propylene Glycol 13.4.5.4 Glycerol 85% 13.4.5.5 Lipophilic Solvents 13.4.6 Suspending Agents 13.4.6.1 Wetting Agents (Hydrophilic Excipients) 13.4.6.2 Wetting Agents (Surfactants) 13.4.6.3 Thickening Agents 13.4.6.4 Flocculating Agents 13.4.7 Agents for Emulsifying and Solubilising 13.4.8 pH 13.4.9 Preservation 13.4.9.1 Methyl and Propyl Parahydroxybenzoate 13.4.9.2 Benzoic Acid and Sorbic Acid 13.4.9.3 Other Preservatives 13.4.10 Flavour 13.4.10.1 Flavouring Agents 13.4.10.2 Shielding the Taste Buds 13.4.10.3 Adjusting the Taste of Active Substances 13.4.11 Colouring Agents 13.4.12 Excipients and Children 13.4.13 Incompatibilities 13.4.14 Chemical Stability 13.4.15 Physical Stability 13.4.16 Containers and Labelling 13.4.17 Dosage Delivery Devices 13.4.18 Storage 13.5 Method of Preparation 13.5.1 Pre-treatment of the Active Substance or Licensed Medicines 13.5.1.1 Use and Pre-treatment of the Raw Material 13.5.1.2 Use of a Solution Licensed for a Different Route 13.5.1.3 Adapting Oral Solid Dosage Forms 13.5.1.3.1 Crushing and Pulverising Solid Dosage Forms 13.5.1.3.2 Dispersing in Water 13.5.2 Dissolving 13.5.3 Mixing 13.5.4 Dispersing 13.5.4.1 Dispersing Raw Material or Pre-treated Solid Dosage Forms in Ready-Made (Commercial) Bases 13.5.5 Emulsifying 13.5.6 Solubilising 13.5.7 In-Process Controls 13.5.8 Release Control and Quality Requirements 13.5.8.1 Solutions 13.5.8.2 Suspensions 13.5.8.3 Emulsions 13.5.8.4 Solubilisates References 14: Pulmonary 14.1 General Introduction 14.1.1 Aerosol Characterisation 14.1.2 Particle Deposition Mechanisms and Efficiency 14.2 Metered Dose Inhalers 14.2.1 General Introduction 14.2.2 MDI Design Variations 14.2.3 Special MDI Designs, Add-On Devices for MDIs and Developments 14.2.4 Practical Notes on the Use of MDIs 14.3 Dry Powder Inhalers 14.3.1 General Introduction 14.3.2 Basic DPI Concept and Working Principle 14.3.2.1 The Powder Formulation 14.3.2.2 The Dose (Metering) Compartment 14.3.2.3 The Powder Dispersion Principle 14.3.2.4 The Inhaler Housing with Control and Feedback Functions 14.4 Nebulizers 14.4.1 Ultrasonic Nebulizers 14.4.2 Jet Nebulizers 14.4.3 Vibrating Mesh Nebulizers 14.4.4 Soft Mist Inhaler Respimat 14.4.5 New Developments and Add-On Devices 14.4.6 Drug Solutions, Suspensions and Excipients for Nebulization 14.4.7 Maintenance and Cleaning of Nebulizers 14.5 New Developments and Some Future Expectations 14.6 Inhaler Performance, Choice, Instruction and Error Use 14.6.1 General Introduction 14.6.2 Inhaler Performance 14.6.3 Inhaler Choice 14.6.4 Inhaler and Inhalation Errors and Instruction References 15: Oropharynx 15.1 Orientation 15.2 Definitions 15.3 Biopharmaceutics and Side Effects 15.4 Product Formulation 15.4.1 Liquid Preparations (Mouthwashes, Gingival Solutions and Gargles) 15.4.1.1 Physico-chemical Properties of the Active Substance 15.4.1.2 Vehicle 15.4.1.3 pH 15.4.1.4 Osmotic Value 15.4.1.5 Viscosity 15.4.1.6 Microbiological Stability (Preservation) 15.4.1.7 Preservatives 15.4.1.8 Taste, Smell and Colour 15.4.2 Semisolid Preparations 15.4.2.1 Active Substance 15.4.2.2 Ointment Base 15.4.2.3 Hydrogel Base 15.4.2.4 Microbiological Stability (Preservation) 15.4.2.5 Scent and Colour 15.4.3 Solid Preparations 15.5 Method of Preparation 15.5.1 Liquid Preparations 15.5.2 Semisolid Preparations 15.5.3 Solid Preparations 15.6 Container, Label, Dosage Delivery Devices 15.7 Release Control and Quality Requirements 15.8 Storage and Stability References 16: Nose 16.1 Orientation 16.1.1 Local Action 16.1.2 Systemic Action 16.1.3 Central Nervous System (CNS) Action 16.1.4 Advantages and Disadvantages of Nasal Preparations 16.2 Definitions 16.3 Biopharmaceutics 16.3.1 Anatomy and Function of the Nose 16.3.1.1 Mucociliary Clearance 16.3.2 Biopharmaceutical Aspects of Nasal Preparations 16.3.2.1 Intranasal Absorption (Systemic Delivery) 16.3.2.2 Intranasal Absorption (Nose-to-Brain Delivery) 16.3.2.3 Local Effect 16.4 Adverse Effects and Toxicity of Nasal Drops and Sprays 16.5 Product Formulation 16.5.1 Liquid Preparations (Nasal Drops and Nasal Sprays) 16.5.1.1 Physico-Chemical Properties of the Active Substance 16.5.1.2 Vehicle 16.5.1.3 pH and Buffer Capacity 16.5.1.4 Osmotic Value 16.5.1.5 Viscosity 16.5.1.6 Preservation 16.5.1.7 Appearance, Smell and Taste 16.5.1.8 Method of Preparation (Nasal Drops and Liquid Nasal Sprays) 16.5.2 Semisolid Preparations (Nasal Ointments and Gels) 16.5.2.1 Active Substance 16.5.2.2 Ointment Base 16.5.2.3 Hydrogel Base 16.5.2.4 pH 16.5.2.5 Preservation 16.5.2.6 Method of Preparation (Nasal Ointments and Nasal Gels) 16.5.3 Nasal Powders 16.5.4 Nasal In Situ Gelling Systems 16.5.5 Nasal Vaccines 16.6 Containers and Labeling 16.6.1 Packaging of Nasal Drops 16.6.2 Packaging of Nasal Sprays 16.6.3 Packaging of Nasal Ointments and Gels 16.6.4 Packaging of Nasal Powders 16.6.5 Labelling and Patient Counselling 16.7 Release Control and Quality Requirements 16.8 Storage and Stability References 17: Ear 17.1 Orientation 17.2 Definitions 17.3 Biopharmaceutics 17.3.1 Anatomy of the Ear 17.3.2 Passing the Eardrum 17.4 Ototoxicity 17.5 Product Formulation 17.5.1 Active Substance 17.5.2 Chemical Stability 17.5.3 Solvents 17.5.4 pH 17.5.5 Osmotic Value 17.5.6 Viscosity 17.5.7 Preservation 17.5.8 Preservatives 17.5.9 Method of Sterilisation 17.6 Method of Preparation 17.6.1 Non-sterile Ear Drops 17.6.2 Sterile Ear Drops 17.7 Containers and Labelling 17.7.1 Containers 17.7.2 Labelling 17.8 Release Control and Quality Requirements 17.9 Storage and Stability 17.9.1 Non-sterile Ear Drops 17.9.2 Sterile Ear Drops 17.10 Administration and Dosage Delivery Devices 17.11 Off Label Use References 18: Eye 18.1 Orientation 18.2 Definitions 18.3 Anatomy and Physiology 18.3.1 Structure of the Eye 18.3.2 Tear Film and Lachrymal Secretion 18.3.2.1 Tear Film Stability 18.4 Biopharmaceutics 18.4.1 Lipophilicity and Ionisation of Active Substance 18.4.2 Active Substance Concentration, Drop Size, Surface Tension 18.4.3 Dilution and Drainage 18.4.4 Viscosity of the Tear Film 18.4.5 pH Value and Buffer Capacity of the Solution 18.4.6 Osmotic Value of the Preparation 18.5 Adverse Effects and Toxicity 18.6 Product Formulation 18.6.1 Eye Drops 18.6.1.1 Active Substance 18.6.1.2 Vehicle 18.6.1.3 pH and Buffer Capacity 18.6.1.4 Viscosity 18.6.1.5 Viscosity Enhancing Polymers 18.6.1.6 Preservatives 18.6.1.7 Sterility 18.6.1.8 Osmotic Value 18.6.1.9 Container and Labeling 18.6.1.10 Storage and Stability 18.6.2 Eye Lotions 18.6.2.1 Osmotic Value 18.6.2.2 Packaging and Labeling 18.6.3 Eye Ointments and Eye Creams 18.6.3.1 Choice of the Dosage Form 18.6.3.2 Vehicle 18.6.3.3 Preservatives 18.6.3.4 Packaging and Labeling 18.7 Method of Preparation 18.7.1 Eye Drops 18.7.1.1 Dissolution of the Ingredients 18.7.1.2 Filtration 18.7.1.3 Sterilisation 18.7.1.4 Aseptic Preparation 18.7.1.5 Handling Containers 18.7.2 Eye Lotions 18.7.3 Eye Ointments and Eye Creams 18.7.3.1 Solution-Type Preparations 18.7.3.2 Suspension-Type Preparations 18.8 Release Control and Quality Requirements 18.9 Administration of Ophthalmic Preparations References 19: Rectal and Vaginal 19.1 Orientation 19.2 Definitions 19.3 Biopharmaceutics 19.4 Product Formulation, Suppositories 19.4.1 Particle Size of Active Substance 19.4.2 Solubility of Active Substance 19.4.3 Types of Suppository Base 19.4.4 Hard Fat (Adeps Solidus) 19.4.4.1 Hydroxyl Value 19.4.4.2 Acid Value 19.4.4.3 Iodine Value 19.4.4.4 Peroxide Value 19.4.4.5 Saponification Value 19.4.4.6 Solidification Point or Solidification Range 19.4.4.7 Compatibility 19.4.5 Macrogol 19.4.5.1 Advantages and Disadvantages 19.4.6 Less Common Suppository Bases 19.4.6.1 Cocoa Butter 19.4.6.2 Glycerinated Gelatin 19.4.7 Other Excipients 19.4.7.1 Lactose 19.4.7.2 Colloidal Anhydrous Silica 19.4.7.3 Lecithin 19.4.7.4 Antioxidants 19.4.8 Shape and Size of Suppository Molds 19.4.9 Stability 19.4.9.1 Chemical Stability 19.4.9.2 Physical Stability 19.4.10 Packaging 19.4.11 Storage 19.4.12 Labelling 19.5 Methods of Preparation, Fat-Based Suspension-Suppositories 19.5.1 Calculation of the Required Base 19.5.2 Excess of Suppository Mass 19.5.3 Dispersing Methods 19.5.3.1 Dispersing with Mortar and Pestle 19.5.3.2 Dispersing with Rotor-Stator Disperser 19.5.3.3 Dispersing with an Unguator 19.5.4 Mixing, Pouring and Filling 19.5.5 Choice of Preparation Method 19.5.6 Choice of Pouring Temperature 19.5.7 Cooling and Finishing 19.6 Methods of Preparation, Fat-Based Solution-Suppositories 19.7 Method of Preparation, Hydrophilic-Based Suppositories 19.8 Release Control and Quality Requirements 19.8.1 In-Process Controls 19.8.2 Appearance 19.8.3 Average Weight and Theoretical Weight 19.8.4 Uniformity of Mass 19.8.5 Uniformity of Content 19.9 Product Formulation, Enemas 19.9.1 Particle Size and Solubility of Active Substance 19.9.2 Vehicle 19.9.3 Volume 19.9.4 Choice of pH and Buffering 19.9.5 Excipients 19.9.5.1 Osmotic Pressure 19.9.5.2 Viscosity 19.9.5.3 Wetting 19.9.6 Stability 19.9.7 Containers 19.9.8 Storage 19.9.9 Labelling 19.10 Preparation, Release Control and Quality Requirements 19.11 Product Formulation, Pessaries 19.11.1 Active Substance 19.11.2 Base 19.11.3 Shape and Size 19.11.4 Packaging and Labelling 19.12 Product Formulation, Vaginal Solutions 19.12.1 Vehicle 19.12.2 Volume 19.12.3 Choice of pH and Buffer Capacity 19.12.4 Osmotic Pressure 19.12.5 Sterility 19.12.6 Stability 19.12.7 Containers 19.12.8 Storage 19.12.9 Labeling 19.13 Preparation, Release Control and Quality Requirements of Vaginal Solutions 19.14 Semi-solid Dosage Forms, Rectal or Vaginal 19.14.1 Active Substance 19.14.2 Base 19.14.3 Additives with a Spermicidal Effect 19.14.4 Dosage Delivery Devices 19.15 Research Trends and Future Perspectives References 20: Dermal 20.1 Prescription Assessment 20.1.1 Need for Cutaneous Pharmacy Preparations 20.1.2 Adapting Licensed Products 20.1.3 Recommendations 20.2 Definitions 20.2.1 Classification of the European Pharmacopoeia 20.2.2 Classification in Practice 20.3 Biopharmaceutics 20.3.1 Anatomy of the Skin 20.3.2 Release and Penetration 20.3.3 Choice of the Base 20.3.4 Base and Different Skin Disorders 20.3.4.1 Acute Skin Disorders 20.3.4.2 Normal Skin 20.3.4.3 Strong Keratotic Disorders 20.3.4.4 Greasy (Oily) Skin 20.3.4.5 Itching Skin Disorders 20.3.4.6 Scalp 20.3.4.7 Haemorrhoids 20.3.4.8 Open Wounds 20.3.5 Method of Application and Dosing 20.3.5.1 Method of Application 20.3.5.2 Quantity to be applied 20.3.5.3 Application Frequency 20.3.5.4 Duration of Therapy 20.3.6 Occlusive and Transdermal Preparations 20.3.6.1 Medicated Plasters 20.3.6.2 Patches 20.4 Adverse Effects 20.5 Product Formulation 20.5.1 Properties and Function of Excipients 20.5.1.1 Solid Substances 20.5.1.2 Lipophilic Substances 20.5.1.3 Aqueous Phase 20.5.1.4 Preservatives 20.5.1.5 Co-solvents 20.5.1.6 Humectants 20.5.1.7 Viscosity Enhancers 20.5.1.8 Emulsifiers 20.5.1.9 Dyes and fragrances 20.5.2 Stability 20.5.2.1 Incompatibilities 20.5.2.2 Physical Stability 20.5.2.3 Chemical Stability 20.5.2.4 Microbiological Stability 20.5.3 Containers 20.5.4 Dosage Delivery Devices 20.5.5 Labeling 20.5.6 Storage 20.6 Method of Preparation 20.6.1 Preparation Method of the Base 20.6.1.1 Solid Phase 20.6.1.2 Lipophilic Phase 20.6.1.3 Aqueous Phase 20.6.1.4 Aqueous and Lipophilic Phase 20.6.2 Incorporation of Active Substances 20.6.2.1 Processing the Active Substance with the Base 20.6.3 Large Batches 20.6.3.1 Processing of Sorbic Acid 20.6.3.2 Processing of Low-Dosed Substances 20.6.3.3 Air Inclusion and Lumps 20.6.4 In-process Controls 20.6.5 Release Control and Quality Requirements 20.6.5.1 Quality Requirements 20.7 Specific Formulations and Preparation Methods 20.7.1 Powders for Cutaneous Application 20.7.1.1 Formulation 20.7.1.2 Preparation Method 20.7.2 Solutions 20.7.2.1 Formulation 20.7.2.2 Preparation Method 20.7.3 Suspensions 20.7.3.1 Formulation 20.7.3.2 Preparation Method 20.7.4 Emulsions 20.7.4.1 Formulation and Preparation Method 20.7.5 Hydrophobic Ointments 20.7.5.1 Formulation 20.7.5.2 Preparation Method 20.7.6 W/o Emulsifying Ointments 20.7.6.1 Formulation 20.7.6.2 Preparation Method 20.7.7 O/w Emulsifying Ointments 20.7.7.1 Formulation 20.7.7.2 Preparation Method 20.7.8 Hydrophilic Ointments 20.7.8.1 Formulation 20.7.8.2 Preparation Method 20.7.9 Lipophilic Creams 20.7.9.1 Formulation 20.7.9.2 Preparation Method 20.7.10 Hydrophilic Creams 20.7.10.1 Formulation 20.7.10.2 Preparation Method 20.7.11 Hydrogels 20.7.11.1 Formulation 20.7.11.2 Preparation Method of Carbomer Gels 20.7.11.3 Preparation Method of Gels with Cellulose Derivatives 20.7.12 Oleogels 20.7.12.1 Formulation and Preparation Method 20.7.13 Pastes 20.7.13.1 Stiff Pastes 20.7.13.2 Weak Pastes 20.7.13.3 Aqueous Pastes 20.7.14 Collodia 20.7.14.1 Formulation 20.7.14.2 Preparation Method 20.7.15 Shampoos 20.7.15.1 Formulation 20.7.15.2 Preparation Method 20.7.16 Sticks 20.7.16.1 Formulation 20.7.16.2 Preparation Method 20.7.17 Sterile Cutaneous Preparations 20.7.17.1 Sterile Cutaneous Powders 20.7.17.2 Irrigations for Wounds 20.7.17.3 Sterile Hydrophobic Ointments 20.7.17.4 Sterile Creams 20.7.17.5 Sterile (Wound) Gels References 21: Parenteral 21.1 Orientation 21.1.1 Advantages and Disadvantages of the Parenteral Route 21.1.2 Type of Parenteral Administration 21.1.3 Availability of Parenteral Administration Forms 21.2 Definitions 21.2.1 Definitions of the European Pharmacopoeia (Ph. Eur) 21.2.2 Colloidal Forms 21.2.3 Routes of Administration 21.2.4 Specific Routes of Administration 21.3 Biopharmaceutics 21.3.1 Rapid Action 21.3.2 Prolonged Action 21.3.2.1 Route of Administration 21.3.2.2 Formulation 21.4 Side Effects and Toxicity 21.4.1 Protein Hypersensitivity 21.4.2 (Thrombo)phlebitis 21.4.3 Pain 21.4.4 Extravasation 21.4.5 Damage by Foreign Particles 21.5 Product Formulation of Injections 21.5.1 Active Substance 21.5.2 Solubility of the Active Substance 21.5.2.1 Buffers and pH Adjustment 21.5.2.2 Salt Formation 21.5.2.3 Complexation 21.5.3 Vehicle 21.5.3.1 Co-solvents in Mixed Aqueous/Organic Solutions 21.5.3.2 Lipophilic Solvents 21.5.3.3 Microspheres and Liposomes 21.5.3.4 Surfactants 21.5.4 pH and Buffer Capacity 21.5.5 Osmotic Value 21.5.6 Viscosity 21.5.7 Antioxidants 21.5.8 Preservatives 21.5.9 Excipients Used in Freeze-Drying 21.5.10 Packaging and Labelling 21.5.11 Stability 21.5.12 Storage Temperature and Shelf Life 21.5.13 Quality Requirements 21.5.14 Special Parenteral Preparations 21.5.14.1 Suspensions 21.5.14.2 Gels 21.5.14.3 Implants 21.5.14.4 Derivatives 21.6 Product Formulation of Infusions 21.6.1 Types of Infusions 21.6.2 Buffer Capacity 21.6.3 Osmolarity 21.6.4 Stability 21.6.5 Container and Labelling 21.6.6 Quality Requirements 21.7 Method of Preparation 21.7.1 Starting Material 21.7.2 Premises and Equipment 21.7.3 Preparation of the Bulk Solution 21.7.4 Control of Bioburden 21.7.5 Purging with Inert Gas 21.7.6 Filling and Closing 21.7.7 Sterilisation 21.7.8 Visual Inspection 21.7.9 Labelling 21.7.10 In-process Controls 21.7.11 Release Control 21.8 Reconstitution 21.8.1 Definition 21.8.2 Product Formulation 21.8.2.1 Solvent and Diluting 21.8.2.2 pH and Osmotic Value 21.8.2.3 Packaging 21.8.2.4 Storage and Shelf Life 21.8.2.5 Compatibilities and Incompatibilities 21.8.3 Method of Preparation 21.8.4 Control and Quality Requirements 21.9 Parenteral Nutrition 21.9.1 Orientation 21.9.2 Product Formulation 21.9.2.1 Components 21.9.2.2 pH 21.9.2.3 Osmotic Value and Fluid Supplement 21.9.2.4 Compatibility 21.9.2.5 Excipients 21.9.2.6 Stability 21.9.2.7 Packaging 21.9.2.8 Shelf Life 21.9.3 Method of Preparation 21.9.3.1 Prescribing 21.9.3.2 Preparation 21.9.3.3 Automated Compounding Devices 21.9.4 Release Control and Quality Requirements 21.9.5 Administration of Parenteral Nutrition Admixtures 21.10 Administration 21.10.1 Terminology 21.10.2 Injections 21.10.3 Infusions 21.10.3.1 Peripheral Access Devices 21.10.3.2 Midline and Peripherally Inserted Central Catheters 21.10.3.3 Central Access Devices: Central Venous Catheters 21.10.3.4 Central Access Devices: Port Systems 21.10.4 Infusion- and Administration Systems 21.10.4.1 Infusion by Gravity 21.10.4.2 Syringe Pump 21.10.4.3 Infusion Pump 21.10.4.4 Portable Pumps 21.10.5 Filters 21.10.6 Management of Parenteral Administration References 22: Irrigations and Dialysis Solutions 22.1 Orientation 22.1.1 Irrigations 22.1.2 Dialysis Solutions 22.2 Definitions 22.3 Biopharmaceutics 22.4 Product Formulation 22.4.1 Irrigations 22.4.1.1 Bacterial Endotoxins 22.4.1.2 Osmotic Value 22.4.1.3 pH 22.4.1.4 Viscosity 22.4.1.5 Stability 22.4.1.6 Sterilisation Method 22.4.2 Dialysis Solutions 22.4.2.1 Formulation 22.4.2.2 Bacterial Endotoxins 22.4.2.3 Water Quality 22.4.2.4 Stability of Added Active Substances 22.5 Method of Preparation 22.6 Containers and Labelling 22.6.1 Containers 22.6.2 Labelling 22.7 Release Control and Quality Requirements 22.8 Storage and Stability 22.9 Administration and Dosage Delivery Devices References 23: Radiopharmaceuticals 23.1 Introduction 23.2 Definitions 23.3 Radionuclides 23.4 Radiopharmaceuticals 23.4.1 Use of Radiopharmaceuticals 23.4.2 Biopharmaceutics 23.4.3 Parenteral Radiopharmaceuticals 23.4.3.1 Radiopharmaceuticals for Planar Scintigraphy or SPECT 23.4.3.2 PET Tracers 23.4.3.3 Radiolabelled Blood Cells 23.4.4 Oral Radiopharmaceuticals 23.4.5 Radiopharmaceuticals for Inhalation 23.4.6 Other Routes of Administration 23.5 Legislation 23.5.1 Sources of Legislation 23.5.2 Radiopharmaceuticals with a Marketing Authorisation 23.5.3 Radiopharmaceuticals to Be Used in Clinical Trials 23.5.4 Good Manufacturing Practice (GMP) 23.5.5 Product Quality 23.5.6 Legislation on Radiation Protection 23.5.7 Interpretation of Legislation for Extemporaneously Prepared Radiopharmaceuticals 23.6 Preparation and Dispensing 23.6.1 Location of Preparation 23.6.2 Prescription and Dose 23.6.3 Layout of the Radiopharmacy Department 23.6.4 Equipment in the Radiopharmacy 23.6.5 Radionuclide Generators 23.6.5.1 Molybdenum-99/Technetium-99m Generator 23.6.5.2 Germanium-68/Gallium-68 Generator 23.6.5.3 Strontium-82/Rubidium-82 Generator 23.6.5.4 Rubidium-81/Krypton-81m Generator 23.6.6 Preparation and Handling 23.6.6.1 Radioactive Stock and Waste Management 23.6.7 Packaging and Labelling 23.6.8 Quality Control and Release 23.6.8.1 Radionuclidic Purity 23.6.8.2 Radiochemical Purity 23.6.8.3 Non-radioactive Impurities 23.6.8.4 Sterility 23.6.8.5 Endotoxins 23.6.8.6 Quality Control of Purchased Ready to Use Radiopharmaceuticals 23.7 New Developments References 24: Therapeutic Proteins and Advanced Therapy Medicinal Products 24.1 Orientation 24.2 Production of Therapeutic Proteins 24.2.1 Introduction 24.2.2 Upstream Processing 24.2.2.1 Cell Line Development 24.2.2.2 Cell Culture Media 24.2.2.3 Fermentation 24.2.2.3.1 Preculture and Seed Train 24.2.2.3.2 Bioreactor 24.2.2.3.3 Harvesting 24.2.2.4 USP from Lab Scale to Pilot Scale 24.2.3 Downstream Processing 24.2.3.1 Filtration 24.2.3.2 Chromatographic Separations 24.2.3.3 DSP from Lab Scale to Pilot Scale 24.2.4 Manufacturing of a Therapeutic Protein Medicinal Product 24.3 Formulating a Therapeutic Protein 24.3.1 Introduction 24.3.2 Protein Structure and Protein Stability 24.3.3 Physical and Chemical Stability 24.3.3.1 Chemical Stability 24.3.3.2 Physical Stability 24.3.4 Analytical Toolbox 24.3.5 Primary Packaging 24.3.5.1 The Needle Diameter 24.3.5.2 Glass or Polymer? 24.3.5.3 Leachables 24.3.6 Formulation Development 24.3.6.1 Buffer Selection 24.3.6.2 Salts 24.3.6.3 Sugars/Polyols 24.3.6.4 Surfactants 24.3.6.5 Amino Acids 24.3.6.6 Anti-oxidants 24.3.6.7 Preservatives 24.3.6.8 Freeze-Drying 24.4 Biopharmaceutics and Use of Therapeutic Proteins 24.4.1 Introduction 24.4.2 Pharmacokinetics 24.4.3 Therapeutic Use 24.4.3.1 Immunogenicity 24.4.4 Administration 24.4.5 Logistics 24.5 Advanced Therapy Medicinal Products 24.5.1 Definitions and Legislation 24.5.1.1 The “ATMP Regulation” 24.5.1.2 Contained Use of Genetically Modified Micro-organisms 24.5.1.3 Cell and Tissue Directive 24.5.1.4 Regulation in Different Member States 24.5.2 Different Classes of ATMPs and Their Manufacture 24.5.2.1 Gene Therapy 24.5.2.1.1 In-Vivo Gene Therapy 24.5.2.1.2 Ex-Vivo Gene Therapy 24.5.2.2 Somatic Cell Therapy 24.5.2.3 Tissue Engineered Products 24.5.2.4 Manufacturing Challenges 24.5.3 Product Handling 24.5.3.1 Specialist Handling and Storage Requirements Within the Clinical Setting 24.5.3.1.1 Cryopreserved Products 24.5.3.1.2 ‘Fresh’ Cells and Tissues 24.5.3.1.3 Ultra Low Freeze Products 24.5.3.2 Good Preparation Practice 24.5.3.3 Administration of ATMPs 24.5.4 Considerations for Pharmacy 24.5.4.1 Medicines Governance Role 24.5.4.2 Operational and Clinical Role 24.5.5 Considerations for Pharmacy Implementation References 25: Human Resources 25.1 Introduction 25.2 Range of Human Resources 25.3 Competences 25.3.1 Functions of Pharmacists 25.3.2 Pharmacists in Patient Care and Product Care 25.3.3 Pharmacy Technicians and Assistants in Healthcare 25.3.4 Qualified Person 25.3.4.1 Functions 25.3.4.2 Qualified Person for Pharmacovigilance (QPPV) 25.3.4.3 QP/QPPV – Like Functions in Pharmacy 25.4 Education 25.4.1 Basic Academic Education for Pharmacists 25.4.2 Education of QPs and Pharmacists in Pharmaceutical Industry 25.4.3 Education Related to Preparation in Community and Hospital Pharmacies 25.4.4 Academic Professionals from Other Disciplines in Pharmaceutical Industry 25.4.5 Education Courses for Pharmacy Technicians and Assistants 25.5 Structure and Responsibilities Within the Organisation 25.5.1 Training and Continuous Education 25.5.2 Assessment of Employees 25.6 Human Resources Management in Pharmaceutical Areas as Part of Pharmaceutical Quality System References 26: Occupational Safety and Health 26.1 Legal Framework 26.1.1 European Occupational Safety and Health Legislation 26.1.2 European Chemicals Legislation 26.2 Evaluation of Hazardous Properties of Active Pharmaceutical Ingredients and Finished Products 26.3 Hazard Types 26.3.1 Carcinogenic, Mutagenic and Reprotoxic Hazards (CMR) 26.3.2 Sensitisation of the Skin and the Respiratory System 26.4 Exposure Assessment 26.4.1 Types of Exposure 26.4.2 Tasks with (Potential) Substance Exposure in the Pharmacy 26.5 Controlling Occupational Exposure 26.5.1 General Principles 26.5.2 Elimination or Substitution 26.5.3 Engineering Control Measures 26.5.4 Administrative Control Measures 26.5.5 Personal Protective Equipment 26.5.6 Combination of Measures 26.5.7 Protective Clothing 26.5.8 Gloves 26.5.9 Mask 26.5.10 Procedure for Calamities References 27: Premises 27.1 Processes as a Starting Point for the Design of Areas and Installations 27.2 User Requirements Specification 27.3 Functional Specifications 27.3.1 Contents 27.3.2 Classification of Premises 27.3.3 Routing and Gowning 27.3.4 Interlock Systems for Air Locks 27.3.5 Communication and Interior Design 27.4 Design 27.4.1 Main Layout Considerations 27.4.2 Non-sterile Extemporaneous Preparations 27.4.3 Non-sterile Stock Production 27.4.4 Sterile Stock Preparations 27.4.5 Aseptic Extemporaneous Preparations 27.4.6 Aseptic Stock Preparations 27.5 Built-in Installations 27.5.1 Installations for Heating, Ventilation and Air Conditioning (HVAC) 27.5.1.1 Preliminary Treatment Installation 27.5.1.2 Recirculation- and Control Installation 27.5.1.3 Distribution Net and Fine Tuning 27.5.2 Installations for Storage and Distribution of Pharmaceutical Water 27.5.3 Provisions for Pressurised Air, Vacuum and Various Gasses 27.5.3.1 Gasses and Pressurised Air 27.5.3.2 Vacuum 27.5.4 Electrical and ICT Provisions 27.5.5 Building Control Systems 27.6 Detail Specification and Building 27.6.1 Inner and Outer Walls 27.6.1.1 Inner Walls 27.6.2 Doors 27.6.3 Floors 27.6.4 Ceilings 27.6.5 Heating 27.6.6 Furniture 27.7 The Implementation Phase of Building or Rebuilding References 28: Equipment 28.1 Orientation 28.2 General Requirements and Qualification of Equipment 28.2.1 Design 28.3 Local Air Filtration and Exhaust Units 28.3.1 Functionalities 28.3.1.1 Protection of the Operator and Environment 28.3.1.2 Protection of the Product 28.3.1.3 Types of Equipment 28.3.2 Fume Cupboard 28.3.2.1 Description 28.3.2.2 Maintenance and Inspections 28.3.2.3 Operation 28.3.3 Moveable Exhaust Equipment 28.3.3.1 Applications 28.3.3.2 Description 28.3.4 Powder Exhaust Units 28.3.4.1 Application 28.3.4.2 Description 28.3.4.3 Operating Instructions 28.3.4.4 Replacement of the Pre-filters 28.3.5 Class I Safety Cabinets (Laminar Airflow Units) 28.3.5.1 Application 28.3.5.2 Description 28.3.5.3 Operating Instructions 28.3.5.4 Qualification of a Class I Safety Cabinet (LAF Unit) 28.3.6 Class II Safety Cabinets 28.3.6.1 Application 28.3.6.2 Description 28.3.6.3 Specifications and Classification 28.3.6.4 Operating Instructions 28.3.6.5 Qualification 28.3.7 Class III Safety Cabinets (Isolators) 28.3.7.1 Description 28.3.7.2 Using an Isolator 28.4 Apparatus for the Production and Storage of Pharmaceutical Water 28.4.1 Water Softeners 28.4.1.1 Application 28.4.1.2 Description 28.4.1.3 Operating Procedure 28.4.2 Demineralisation Apparatus Based on Ion Exchange 28.4.2.1 Application 28.4.2.2 Description 28.4.2.3 Operating Procedure 28.4.3 Apparatus for Reverse Osmosis 28.4.3.1 Application 28.4.3.2 Description 28.4.3.3 Operating Procedure 28.4.4 Apparatus for Electro-Deionisation 28.4.4.1 Application 28.4.4.2 Description 28.4.4.3 Operating Procedure 28.4.5 Distillation 28.4.5.1 Application 28.4.5.2 Description 28.4.5.3 Operating Procedure 28.4.6 Equipment (Installations) for Storage and Distribution of Pharmaceutical Water 28.4.6.1 Equipment (Systems) for the Storage of Pharmaceutical Water 28.4.6.2 Distribution of Pharmaceutical Water 28.4.6.3 Maintenance and Disinfecting Water Storage and Distribution Systems 28.5 Ultrasonic Baths and Heaters 28.5.1 Orientation 28.5.2 Ultrasonic Baths 28.5.2.1 Application 28.5.2.2 Description 28.5.2.3 Procedure 28.5.3 Gas Stove and Gas Burner 28.5.3.1 Application 28.5.3.2 Description 28.5.4 Electric Heating Plate, Immersion Heater and Heating Mantle 28.5.4.1 Application 28.5.4.2 Description 28.5.5 Water Bath 28.5.5.1 Application 28.5.5.2 Description 28.5.5.3 Procedure 28.5.6 Heating Lamp 28.5.6.1 Application 28.5.6.2 Description 28.5.7 Microwave 28.5.7.1 Application 28.5.7.2 Description 28.5.7.3 Procedure 28.6 Grinding, Mixing and Dispersing Apparatus 28.6.1 Mortar with Pestle 28.6.1.1 Application 28.6.1.2 Description 28.6.1.3 Operating Procedure 28.6.2 Stephan Mixer 28.6.2.1 Application 28.6.2.2 Description 28.6.2.3 Operating Procedure 28.6.3 Rotor-Stator Mixer 28.6.3.1 Application 28.6.3.2 Description 28.6.3.3 Operating Procedure 28.6.3.4 Cleaning 28.6.4 Planetary Mixer 28.6.4.1 Application 28.6.4.2 Description 28.6.4.3 Operating Procedure 28.6.5 Beaker Mixer/Blender 28.6.5.1 Description 28.6.5.2 Operating Procedure 28.6.6 Three Roll Mill 28.6.6.1 Application 28.6.6.2 Description 28.6.6.3 Operating Procedure 28.6.6.4 Cleaning 28.6.7 Topitec and Unguator 28.6.7.1 Application 28.6.7.2 Description 28.6.7.3 Topitec 28.6.7.4 Unguator 28.6.7.5 Preparation Method 28.6.7.6 Testing and Validation 28.6.7.7 Packaging and Shelf Life 28.6.8 Grinders 28.6.8.1 Application 28.6.8.2 Description 28.6.8.3 Operating Procedure 28.6.8.4 Cleaning 28.6.9 Three-Dimensional Mixer 28.6.9.1 Application 28.6.9.2 Description 28.6.9.3 Operating Procedure 28.6.9.4 Cleaning 28.7 Filling and Apportioning Apparatus 28.7.1 Small Scale Filling Apparatus for Fluids 28.7.1.1 Application 28.7.1.2 Description 28.7.1.3 Dispenser 28.7.1.4 Peristaltic Pumps 28.7.1.5 Pump Tubing 28.7.1.6 Automatic Liquid Filling Machine 28.7.1.6.1 Oral Liquids Filling Machine 28.7.1.6.2 Injectables Filling Machines 28.7.2 Suppository Molding Apparatus 28.7.2.1 Application 28.7.2.2 Description 28.7.2.3 Operating Procedure 28.7.3 Hard Capsule Filling and Closing Apparatus 28.7.3.1 Application 28.7.3.2 Description 28.7.3.3 Operating Procedure 28.7.3.4 Cleaning 28.7.4 Tube Filling Apparatus 28.7.4.1 Polypropylene Film or Weighing Paper 28.7.4.2 Piston-Cylinder Apparatus, Simple 28.7.4.3 Piston-Cylinder Apparatus with Hand Wheel 28.7.5 Unit Dose Packaging 28.7.5.1 Application 28.7.5.2 Description 28.7.5.3 Operating Procedure 28.7.5.4 Cleaning 28.8 Cleaning Apparatus 28.8.1 Application 28.8.2 Description 28.8.3 Operating Procedure 28.9 Apparatus for Cooled Storage 28.9.1 Application 28.9.2 Description 28.9.3 Operating Procedure 28.9.3.1 Installation 28.9.3.2 Use 28.9.3.3 Cleaning 28.9.3.4 Thawing (for Non Automatic Fridges) 28.9.3.5 Monitoring 28.10 3D Printing 28.10.1 Introduction 28.10.2 Material Extrusion 28.10.3 Vat Photopolymerization 28.10.4 Binder Jetting 28.10.5 Powder Bed Fusion 28.10.6 Material Jetting References 29: Basic Operations 29.1 Weighing and Volume Measuring 29.1.1 Required Accuracy and Precision 29.1.1.1 Concepts of Accuracy and Precision 29.1.1.2 Required Accuracy and Precision 29.1.2 Weighing Versus Volume Measuring 29.1.3 Physical Principles of Weighing 29.1.3.1 Electronic Balance 29.1.3.2 Mechanical Beam (Equal Arm) Balance 29.1.3.3 Weighing Uncertainty at Preparation 29.1.4 Selection of an Electronic Balance 29.1.4.1 General Selection Criteria 29.1.4.2 Metrological Approval 29.1.5 Installation and Minimum Weight 29.1.5.1 Installation 29.1.5.2 Concept of Minimum Weight 29.1.6 Operation and Maintenance 29.1.6.1 Operation of a Balance for Pharmacy Preparation 29.1.6.2 Utensils for Weighing 29.1.6.3 Maintenance 29.1.7 Volume Measurement 29.1.7.1 Accuracy and Precision 29.1.7.2 Graduated Pipettes 29.1.7.3 Syringes 29.1.7.4 Measuring Cylinders 29.1.7.5 Preparation Vessels 29.1.8 Non-directly Weighable Quantities 29.1.8.1 Triturations and Dilutions 29.1.8.2 Starting from Pharmaceutical Preparations 29.2 Particle Size Reduction 29.2.1 The Purpose of Particle Size Reduction 29.2.2 Grinding 29.2.3 Physico-chemical Particle Size Reduction 29.2.3.1 Solvent Deposition Method 29.2.3.2 Precipitation Method 29.3 Dispersing Agglomerates 29.3.1 Orientation and Definitions 29.3.2 Selection of the Medium 29.3.3 Dispersion Methods 29.4 Mixing of Solid Substances 29.4.1 Orientation 29.4.2 Random Mixing 29.4.3 Ordered Mixing 29.4.4 Mixing Methods 29.4.4.1 Geometrical Mixing and Wrapping Method 29.4.4.2 Demixing 29.5 Dissolving Solid Substances 29.6 Mixing of Liquids, Semisolid Substances and Molten Solid Substances 29.7 Dispersing in Liquids and Semisolids 29.7.1 Dispersing a Solid into a Liquid 29.7.2 Dispersion of a Solid into a Semi Solid Substance 29.7.3 Dispersion of a Liquid into a Non-miscible Liquid References 30: Sterilisation Methods 30.1 Introduction 30.2 The Death of Microorganisms 30.3 Sterilisation Time 30.4 Initial Contamination 30.5 Terminal Sterilisation Methods 30.5.1 Steam (and Hot Water) Sterilisation 30.5.1.1 Steam Autoclave or Steam Steriliser 30.5.1.2 Process Description of Steam Sterilisation for Medical Devices 30.5.1.3 Packaging Medical Devices 30.5.1.4 Process Description of Steam Sterilisation of Aqueous Pharmaceutical Products 30.5.1.5 Hot Water Sterilisation 30.5.1.6 Validation of Steam and Hot Water Sterilisers 30.5.1.7 Monitoring of Steam and Hot Water Sterilisation Processes 30.5.2 Dry Heat Sterilisation 30.5.3 Ionising Radiation Sterilisation 30.5.3.1 Process Description of Radiation Sterilisation 30.5.4 Gas Sterilisation 30.5.4.1 Ethylene Oxide 30.5.4.2 Process Description Ethylene Oxide Sterilisation 30.5.4.3 Hydrogen Peroxide Gas (Plasma) Sterilisation 30.5.4.4 Process Description Hydrogen Peroxide Gas (Plasma) Sterilisation 30.6 Filtration 30.6.1 Sterilisation by Membrane Filtration 30.6.2 Theory of Membrane Filtration 30.6.3 Retention Capacity 30.6.4 Application of Membrane Filters 30.6.4.1 Filter Size and Filtration Rate 30.6.4.2 Membrane Filter Types 30.6.5 Integrity Testing of Membrane Filters 30.6.5.1 Bubble Point Test 30.6.5.2 Gas Diffusion Filter Testing 30.6.5.3 Water Intrusion Test (for Hydrophobic Filters) 30.7 Sterilisation of Heat Sensitive Formulations 30.8 Biological Indicators 30.9 Choosing the Best Sterilisation Method for Medicinal Products 30.10 Sterility Testing and Parametric Release References 31: Aseptic Handling 31.1 Definitions 31.2 Aseptic Processing 31.3 Aseptic Handling 31.3.1 Guidelines for Aseptic Handling 31.3.2 Sources of Risk of Non-sterility 31.3.3 Complexity 31.3.4 Batchwise Filling of Syringes 31.3.5 Aseptic Handling of Antineoplastics 31.3.6 Storage Periods 31.4 Cleaning and Disinfection 31.4.1 Cleaning and Disinfection of the Background Area 31.4.2 Cleaning and Disinfection of LAF Cabinets, Safety Cabinets and Isolators 31.4.3 Disinfection of Materials with a Non-sterile Surface (Ampoules, Vials and Bottles) 31.5 Microbiological Controls 31.5.1 Microbiological Monitoring 31.5.1.1 Monitoring Techniques 31.5.1.2 Environmental Sampling Plan 31.5.1.2.1 Sampling Inside a LAF/SC/I 31.5.1.2.2 Sampling in the Background Area 31.5.1.3 Media and Incubation Time 31.5.1.4 Limits 31.5.1.5 Assessing MM Results 31.5.2 Microbiological Validation of the Process 31.5.3 Assessing the Aseptic Techniques of an Operator 31.6 Audit of the Operators References 32: Product Quality, Quality Control and Validation 32.1 Introduction 32.2 Quality of Production 32.3 Prevention of Contamination and Cross-Contamination 32.3.1 Technical Measures 32.3.2 Organisational Measures 32.3.2.1 Supervision 32.4 Material Handling 32.5 Batch Documentation 32.6 In-Process Controls 32.7 Label and Yield Reconciliation 32.8 Quarantine Management 32.9 Quality Control and Release 32.9.1 Batch Documentation Review 32.9.2 Quality Control 32.9.3 Release Policy 32.9.4 Parametric Release and Real Time Release Testing 32.10 Validation: General Principles and Terminology 32.10.1 Validation and Qualification 32.10.2 Prospective and Concurrent Validation 32.10.3 Revalidation and Requalification 32.10.4 Organisation 32.11 Validation Master Plan 32.12 Validation Documentation 32.13 Validation Team 32.14 Process Validation 32.14.1 General Aspects 32.14.2 Process Validation in Practice 32.14.3 Extemporaneous Preparations 32.15 Qualification of Premises, Installations, Equipment and Automated Systems 32.16 Cleaning 32.16.1 Good Cleaning Practice and Cleaning Validation 32.16.2 Premises, Workbenches and Worktops 32.16.3 Equipment 32.16.4 Utensils and Clothing References 33: Quality Requirements and Analysis 33.1 Quality Requirements and Regulations 33.2 The European Pharmacopoeia 33.3 Identity 33.4 Average Content of Active Substance 33.4.1 Content of the Raw Material and Factorisation 33.4.2 Preparation Process 33.4.3 Stability 33.4.4 Sample Size 33.4.5 Analytical Error 33.4.6 Interpretation of the Result 33.5 Chemical Purity 33.6 Average Mass, Volume and Content 33.6.1 Average Mass and Theoretical Mass of Single Dose Preparations 33.6.2 Volume and Content 33.7 Uniformity of Mass and Content of Single Dose Preparations 33.7.1 Uniformity of Mass 33.7.2 Uniformity of Content 33.7.2.1 Content Variation 33.7.2.2 Content Uniformity According to Ph. Eur. 2.9.6 33.7.2.3 Content Uniformity and Mass Variation According to Ph. Eur. 2.9.40 Uniformity of Dosage Units 33.7.2.4 Content Uniformity of Liquid Dispersions 33.7.2.5 Content Uniformity of Semisolid Dispersions 33.8 Microbiological Purity, Sterility, Pyrogens and Bacterial Endotoxins 33.9 Disintegration 33.10 Dissolution 33.11 Particle Size 33.12 Particulate Contamination 33.13 Physical Tests 33.14 Herbals 33.15 Quality Requirements, Overview 33.16 Analytical Validation 33.16.1 Purpose of Analytical Validation (AV) 33.16.2 Guidance from EDQM and European Pharmacopeia 33.16.3 Performance Properties of an Analytical Method 33.16.3.1 Specificity 33.16.3.2 Linearity and Range 33.16.3.3 Accuracy 33.16.3.4 Precision/Reproducibility 33.16.3.5 Detection Limit and Sensitivity 33.16.3.6 Quantitation Limit 33.16.3.7 Robustness 33.16.3.8 Ruggedness 33.16.3.9 System Suitability Test 33.16.4 European Regulations and Impurities in Active Substances 33.16.5 Selection of Test Samples 33.16.6 Reference Standards 33.16.6.1 Physical Quantities 33.16.6.2 Chemical Quantities 33.16.6.3 Validation of Reference Standards 33.16.7 Technology Transfer 33.16.8 Different Applications Require Different Validation Approaches References 34: Stability 34.1 Physical Degradation 34.2 Chemical Degradation 34.2.1 Hydrolysis 34.2.2 Oxidation and Reduction 34.2.2.1 Limiting the Availability of Oxygen 34.2.2.2 Antioxidants 34.2.3 Isomerisation 34.2.4 Photolysis 34.2.5 Degradation of the Protein Structure 34.3 Microbiological Degradation 34.3.1 Growth Promoting Qualities 34.3.1.1 Water 34.3.1.2 pH 34.3.1.3 Antimicrobial Activity of Active Substances or Excipients 34.3.1.4 Viability of Micro-organisms in Ready-to-Administer Parenterals 34.3.2 Hygienic Handling 34.3.3 Packaging Material 34.3.4 Storage Temperature and Humidity 34.4 Content Limits During Storage 34.4.1 Limits for Decline of Content 34.4.2 Limits to the Amount of Toxic Degradation Products 34.5 Stability Studies 34.5.1 Method of Analysis 34.5.2 Stability Parameters and Number of Samples 34.5.3 Accelerated Stability Testing 34.5.4 Long-Term Stability Testing 34.5.5 In-Use Stability Testing 34.5.6 Ongoing Stability Testing 34.5.7 Reaction Kinetics 34.5.7.1 Reaction Rate 34.5.7.2 Temperature Influence 34.5.8 Searching Information about Physico-chemical Stability and Compatibility for Practice 34.6 Definitions and Labelling 34.7 General Instructions for Storage Conditions and Storage Times 34.7.1 Storage Temperature 34.7.2 Shelf Life and Usage Period 34.7.3 Assignation System for Pharmacy Preparations 34.7.4 Starting Points and Flow Chart 34.7.4.1 Storage of Semi-Finished Products 34.8 Stability Data in a Pharmacist’s Daily Practice 34.8.1 Storage at a Different Temperature 34.8.1.1 Patient Going on Holiday 34.8.1.2 Doctor’s Bag 34.8.2 Shelf Life When Packaging Has Been Changed 34.8.3 Extension of the Shelf Life of Aseptic Prepared Ready-to-Administer Products 34.8.3.1 Patient Comfort at the EPOCH Regimen 34.8.3.2 Facilitating Administration on the Ward 34.8.4 Preventing Wastage and Saving Money by an Extended Shelf Life of Stock Solution 34.9 What Should a Patient Know? References 35: Pharmaceutical Quality System 35.1 Pharmaceutical Quality System Concepts 35.1.1 PQS Model 35.1.2 PQS Commensurate to Size and Complexity 35.1.3 PQS Scope of Activities 35.1.3.1 Pharmaceutical Development 35.1.3.2 Technology Transfer 35.1.3.3 Production and Distribution 35.1.3.4 Discontinuation 35.2 PQS Enablers 35.2.1 Quality Risk Management 35.2.2 Knowledge Management 35.3 Pharmaceutical Legislation and External Compliance 35.3.1 European Legal Framework 35.3.2 Licensed Medicines 35.3.2.1 Product Marketing Authorization 35.3.2.2 Manufacturing 35.3.2.3 EU Good Manufacturing Practices 35.3.2.4 Other GMP Regulations 35.3.3 Unlicensed Medicines 35.3.3.1 Product Marketing Authorisation 35.3.3.2 Manufacturing 35.3.3.3 Specials Regulations 35.3.3.4 Good Manufacturing Practice Guidelines for Pharmacies 35.3.3.5 USP Compounding Standards 35.3.3.6 PIC/S Good Preparation Practices Guide 35.3.4 Investigational Medicines 35.3.5 Pharmacopoeial Requirements 35.3.6 Quality System Regulations 35.3.6.1 ICH Guidelines 35.3.7 Regulatory Compliance and Inspection 35.3.7.1 Pharmacy-Compounded Unlicensed Products 35.3.7.2 Licensed Products 35.3.7.3 Site Master File 35.4 Documentation Management System 35.4.1 Documentation Hierarchy 35.4.2 Quality System Procedures 35.4.2.1 Change Control 35.4.2.2 Product Quality Review 35.4.2.3 Self-Inspection 35.4.2.4 Non-conformity and CAPA 35.4.2.5 Recalls 35.5 Operational Aspects & Internal Compliance 35.5.1 Quality Culture and Leadership 35.5.2 Product Realisation 35.5.3 State of Control 35.5.3.1 Quality Metrics 35.5.3.2 Quality Management Review 35.5.3.3 Continual Improvement 35.6 Quality Management System Standards – A Broader Perspective 35.6.1 Pharmaceutical Quality – Historical Development 35.6.2 ISO 9001 QMS 35.6.3 Seven Pillars QMS 35.6.3.1 Description of the Model 35.6.3.2 Wider Pharmaceutical Use of the Model References 36: Risk Management in Pharmacy Production 36.1 Introduction 36.2 Risk Management General Principles 36.3 Risk Management Process 36.3.1 Initiation of Quality Risk Management Process 36.3.2 Risk Assessment 36.3.2.1 Risk Identification 36.3.2.2 Risk Analysis 36.3.2.3 Risk Evaluation 36.3.3 Risk Control 36.3.3.1 Risk Reduction 36.3.3.2 Risk Acceptance 36.3.4 Risk Communication 36.3.5 Risk Review 36.4 Responsibilities 36.5 Methods-Tools 36.5.1 Categories for Methods Used in Risk Management 36.5.2 Explanation and Application of Methods 36.5.2.1 Brain Storming, Delphi-Technique, World Café 36.5.2.2 Scenario Techniques: Ishikawa (or Fishbone Diagram), Fault Tree Analysis FTA, Event Tree Analysis 36.5.2.3 Analysis of Indicators: Critical Incident Reporting System (CIRS) 36.5.2.4 Functional Analysis: Failure Mode Effects Analysis FMEA (IEC 60812), HAZOP (IEC 61882), HACCP (WHO Technical Report Series No 908, 2003 Annex 7) 36.5.2.5 Statistical Methods: Standard Deviation, Confidence Interval 36.6 Risk Management Application in the Pharmacy 36.6.1 Risk Landscape 36.6.2 FMEA – Equipment – Washing Machine References 37: Documentation 37.1 Orientation 37.2 Documentation Types for Preparation 37.2.1 Documentation and Quality System 37.2.2 Terminology 37.2.3 Documentation of the Preparation 37.3 Standard Operating Procedures (SOPs) 37.4 Batch Preparation Instructions and Records 37.4.1 Definition and Use 37.4.2 Drafting a Batch Preparation Instruction 37.5 Extemporaneous Preparation Instructions and Records 37.6 Analytical Instructions 37.7 Logbooks 37.8 The Product File 37.8.1 Contents 37.8.2 Prescription Assessment 37.8.3 User Information 37.8.3.1 Composition 37.8.3.2 Information for the Prescriber 37.8.3.3 Information for the Patient 37.8.3.4 Information Needed for Medication Reviews 37.8.4 Pharmacotherapy 37.8.5 Pharmacovigilance 37.8.6 Formulation and Method of Preparation 37.8.6.1 Formulation, Packaging and Labelling 37.8.6.2 Method of Preparation 37.8.6.3 Stability and Storage Conditions 37.8.6.4 Specifications 37.8.6.5 Methods of Analysis 37.8.7 Process Validation 37.8.8 Shelf Life Investigation 37.8.9 History 37.8.10 Product Quality Review 37.9 Other Documents 37.9.1 Service Level Agreements 37.9.2 Technical Agreements 37.9.3 Permits to Work 37.9.4 Validation Procedures and Reports 37.9.5 Deviation/ Error/Out of Specification Reports 37.9.6 Training Records 37.10 Documentation and Automation 37.11 Management of Documents References 38: Statistics 38.1 Basic Statistical Concepts 38.1.1 Population and Sample 38.1.1.1 Population 38.1.1.2 Sample 38.1.2 Central Value and Measures of Variation 38.1.3 Random and Systematic Errors 38.2 Confidence Intervals 38.2.1 Probability and Confidence Intervals 38.2.2 Confidence Interval of μ If the Standard Deviation of the Population Is Known 38.2.3 Confidence Interval of μ If the Standard Deviation of the Population Is Not Known 38.2.4 Confidence Interval of the Variance σ2, and the Standard Deviation σ 38.2.5 Outliers 38.3 Acceptance Sampling 38.3.1 Introduction 38.3.2 Operating Characteristic (OC) Curves 38.3.3 Acceptance Plans 38.3.4 Acceptance by Variables 38.3.5 Acceptance by Attributes 38.3.6 Content Uniformity of Dosage Forms 38.4 Statistical Calculations and Numerical Operations 38.4.1 Effect of More than One Deviation in a Process 38.4.2 The Outcome Is the Sum or Difference of Measurements 38.4.3 The Outcome Is Obtained by Multiplying or Dividing Measurements 38.4.4 Rounding 38.5 Statistic in Process 38.5.1 Measurement Control Chart: and s Chart 38.5.2 Attribute Control Chart: Example p Chart References 39: Logistics 39.1 Scope 39.2 Quality Requirements 39.2.1 General 39.2.2 Competent Authority and Inspectorate 39.2.3 Traceability 39.2.4 Good Distribution Practice (GDP) 39.3 Stock Control 39.3.1 Overview 39.3.2 Shortages 39.3.3 Stock Turn 39.3.3.1 Emergency Medicines 39.3.3.2 Essential Medicines 39.3.3.3 Seasonal Medicines 39.3.3.4 Raw Materials for Preparations 39.4 Procurement 39.4.1 Procurement Process 39.4.2 Tendering 39.4.3 Types of Contracts 39.4.4 Suppliers 39.4.4.1 Manufacturers 39.4.4.2 Marketing Authorisation Holders (MAH) 39.4.4.3 Wholesalers 39.4.4.4 Central Stores (Centralised Pharmacies) 39.4.4.5 Homecare 39.4.4.6 Importation 39.4.4.7 Suppliers for Products Other Than Medicinal Products 39.5 Medical Gasses 39.6 Purchasing Organisations 39.7 Goods Receipt 39.8 Returned Medicines 39.9 Controlled Substances 39.10 Storage 39.10.1 Pharmacy 39.10.1.1 Spilled Substances 39.10.2 Wards 39.10.3 Other Areas 39.10.4 Temperature and Humidity 39.10.5 Waste 39.10.6 Automation 39.10.7 Closed Loop Medication Management 39.11 Distribution 39.11.1 Overview 39.11.2 For Goods Received into the Pharmacy 39.11.3 For the Delivery to the Patient’s Home of Fridge and Freezer Products 39.12 Recalls 39.12.1 Overview 39.12.2 Recall (as a Manufacturer/Preparer) 39.12.3 Recall (as a Receiver) 39.13 Education, Experience, Training 39.14 Falsified Medicines References 40: Product Care & Daily Practise 40.1 The Patient 40.1.1 The Right Medicine 40.1.2 An Explanation of the Vocabulary Used When Describing a Prescriber-Patient Relationship 40.1.3 Adherence in Medication 40.1.4 Mistakes in Practice (What Happens When Something Goes Wrong)? 40.2 The Pharmacist as a Professional 40.2.1 Professionalism 40.2.2 Standards for Pharmacy Professionals GPhC 40.3 The Product 40.3.1 Introduction 40.3.2 General Definitions 40.3.3 Product Portfolio 40.3.4 Marketing Authorization, Off-Label and Unauthorized Medicines Use 40.3.5 Product Classification 40.3.6 Product Information 40.3.7 Product Development 40.4 The Patient Product Interface 40.4.1 Introduction 40.4.2 Patient Acceptability 40.4.3 Tablet Breaking, Splitting, Subdivision and Grinding 40.4.4 Dosage Form and Formulation 40.4.5 Packaging & Medical Devices 40.4.6 Shelf-Life and Storage Condition 40.5 Labelling 40.5.1 General Information 40.5.2 Labelling and Package Leaflet in More Detail 40.5.3 Expiry Date and Beyond-Use Date 40.5.4 Where to Attach the Patient Label References Index