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

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