Practical Pharmaceutics: An International Guideline for the Preparation, Care and Use of Medicinal Products [2 ed.] 303120297X, 9783031202971

Table of contents :
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

Citation preview

Paul Le Brun · Sylvie Crauste-Manciet Irene Krämer · Julian Smith Herman Woerdenbag Editors

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

Practical Pharmaceutics

Paul Le Brun  •  Sylvie Crauste-Manciet Irene Krämer  •  Julian Smith Herman Woerdenbag Editors

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

Editors Paul Le Brun Clinical Pharmacy and Toxicology Leiden University Medical Center Leiden, The Netherlands Irene Krämer Apotheke der Universitätsmedizin Mainz, Rheinland-Pfalz, Germany Herman Woerdenbag Department of Pharmaceutical Technology and Biopharmacy University of Groningen Groningen, The Netherlands

Sylvie Crauste-Manciet Pharmacy Department, MINT URM Inserm 1066 CNRS 6021 University of Angers, CHU Angers Angers, France Julian Smith JCS Pharma Consulting Ltd. Newport, Gwent, UK

ISBN 978-3-031-20297-1    ISBN 978-3-031-20298-8 (eBook) https://doi.org/10.1007/978-3-031-20298-8 1st edition: © KNMP and Springer International Publishing Switzerland 2015 2nd edition: © Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

In 2015, the first edition of Practical Pharmaceutics was published. This was a pan-European textbook on medicine preparation in pharmacies. New developments and new insights create a need for a new edition of the book. In this new edition, chapters have been updated, paragraphs modified, figures and tables refined. Some chapters have been completely rewritten, for example the chapter ‘Pharmaceutical Quality Systems’. The chapter ‘Instruction for Use of Medicines’ is now presented as ‘Product Care & Daily Practice.’ A completely new chapter, ‘ Therapeutic Proteins and Advanced Therapy Medicinal Products’, has been added. The core role of a pharmacist is and always has been to supply the patient with the most appropriate medicines according to their needs, but patients have differing needs. Not all patients fit the ‘normal profile’ where efficiencies of scale enable the pharmaceutical industry to mass produce standard medicines. A significant proportion of patients require medicines to be specifically tailored to suit their special needs. A smaller proportion of pharmacists are involved in medicine preparation. This has resulted in less attention for this specialism in the university curriculum and during the training of hospital pharmacists. However, knowledge of preparation should not be lost as it is a unique activity reserved for the pharmacist. It is not necessary to go back to the past where all pharmacists were preparing medicines and have comprehensive pharmaceutical knowledge. It is not necessary to be up to date with all the Good Manufacturing Practice regulations. However, all pharmacists must retain a basic knowledge of pharmaceutical production. This is to enable the right choices to be made when purchasing medicines, to be able to recognise counterfeits, and above all to ensure that medicines are prepared properly when they are required but not available on the market. This includes scenarios such as the adaptation of a preparation for paediatric administration, or for patients who have difficulty swallowing. This is not just about adjusting the dose, but about knowledge of the formulation in relation to the special needs of the patient. Take, for example, acetem containing oral solutions: insufficiently developed fat digestion in neonates can lead to absorption problems. Without this specific knowledge, optimal treatment is not possible. Furthermore, personalised medicine is becoming more normal in healthcare, and a thorough product knowledge is therefore needed. Many clinical problems cannot be solved without an appropriate knowledge of the technical properties and performance of a medicinal product. In addition, there are more factors that require a prominent role for preparations in (hospital) pharmacies: • (Temporary) shortage of medicines: in many cases, shortages can be solved by preparation of stock in pharmacies. This was clearly shown during the recent Covid pandemic when (hospital) pharmacies all over Europe were involved in making essential medicines available by procurement and more especially by preparation. • Patient safety: reconstitution of medicines is a high-risk process; there are many examples of medication errors due to incorrect reconstitution (a ten-fold dose of phenytoin, a contaminated bottle of propofol used as multi-dose, etc.). Therefore, there is an increasing need for safe, ready-to-use medicines. Some are available on the market, but most need to be prepared in (hospital) pharmacies. v

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• Personalised medicines: there are recent developments where the involvement of pharmacy preparations is required, such as advanced drug therapies (ATMPs), tumour imaging with patient-specific peptides, vaccine therapy, and in the near future 3D printing of personalised medicines. • Orphan medicines are not always available or the costs are sometimes irresponsibly high. The pharmacy preparation might offer a cheaper and effective solution. In short, the pharmaceutical science of preparing medicines should be seen in the social context of guaranteeing the availability of necessary medicines to patients. The Council of Europe Resolution on pharmacy preparation1 considered the preparation of medicinal products in pharmacies as indispensable for accommodating the special needs of individual patients in Europe. The aim of the book Practical Pharmaceutics is to offer: • Basic knowledge for undergraduate and graduate pharmacy students. • Practical knowledge on the design and preparation of medicines for the pharmacists responsible for preparations in community and hospital pharmacies. • Basic knowledge for all pharmacists involved in quality assurance. • Product knowledge for all pharmacists working directly with patients, to enable them to make appropriate medicines available, to store medicines properly, to responsibly adapt medicines if necessary, to dispense medicines with the appropriate information, and to inform patients and caregivers about product care and how to maintain their quality. This basic knowledge will also be of help to industrial pharmacists to remind them on the application of the manufactured medicines. Practical Pharmaceutics has emanated from an already-existing Dutch textbook titled Recepteerkunde. Practical Pharmaceutics covers such a vast area that the production of the book would have taken many more years to complete if the Dutch starting reference work had not been there as a basis. Its first edition, edited by Harry Cox, Gerad Bolhuis, and Jan Zuidema, was published in 1992 as a gift by the Dutch Pharmacists’ Association KNMP to its members on the occasion of its 150th anniversary. It has been used since at the three universities in the Netherlands offering the pharmacy curriculum. The fifth edition from 2009 forms the basis of the first edition of Practical Pharmaceutics, edited by Yvonne Bouwman-Boer, V’Iain Fenton-­ May, and Paul Le Brun and issued in 2015. Since Yvonne Bouwman-Boer and V’Iain Fenton-May are retired, a new editorial board was formed to take care of the second edition. The new board consists of hospital pharmacists and pharmaceutical scientists, chosen from all quarters of Europe. The book is generally written in UK English, but liberties have been taken where it has been considered that an adaptation would make the sense easier to understand across Europe. Some of those changes are explained in the Introduction. We owe a debt of thanks to the authors, most of whom are practising pharmacists with full-­ time and often stressful jobs, especially during the pandemic. The financing of such an enterprise is never easy, and we thank both the Dutch Pharmacists’ Association KNMP and the Dutch Hospital Pharmacists’ Association NVZA for the foresight to invest in this edition. Without this funding, this book would not have been produced. Comments for improvement could be forwarded to Paul Le Brun, chief editor ­([email protected])

Resolution CM/Res(2016)1 on quality and safety assurance requirements for medicinal products prepared in pharmacies for the special needs of patients Available from: https://search.coe.int/cm/Pages/result_details. aspx?ObjectID=090000168065c132 1 

Preface

Preface

vii

Paul Le Brun, Sylvie Crauste-Manciet, Irene Krämer, Julian Smith and Herman Woerdenbag (editors) Leiden, The Netherlands Angers, France Mainz, Rheinland-Pfalz, Germany Newport, Gwent, UK Groningen, The Netherlands

Paul Le Brun Sylvie Crauste-Manciet Irene Krämer Julian Smith Herman Woerdenbag

Contents

1 Introduction���������������������������������������������������������������������������������������������������������������    1 Paul Le Brun, Sylvie Crauste-Manciet, Irene Krämer, Julian Smith, and Herman Woerdenbag 2 Prescription Assessment�������������������������������������������������������������������������������������������    7 Andrew Lowey and Stefanie Melhorn 3 Availability of Medicines �����������������������������������������������������������������������������������������   23 Helena Jenzer, Stefan Groesser, and Nenad Miljković 4 Product Design ���������������������������������������������������������������������������������������������������������   57 Christien Oussoren and Hans de Waard 5 Biopharmaceutics�����������������������������������������������������������������������������������������������������   67 Henderik Frijlink, Frederic Lagarce, Daan Touw, and Herman Woerdenbag 6 Physical Chemistry���������������������������������������������������������������������������������������������������   93 Wouter Hinrichs and Renske van Gestel 7 Raw Materials�����������������������������������������������������������������������������������������������������������  127 Richard Lantink and Michael Hörnig 8 Containers�����������������������������������������������������������������������������������������������������������������  169 Julian Smith and Karin Larmené-Beld 9 Microbiology�������������������������������������������������������������������������������������������������������������  207 David Roesti and Alexandra Staerk 10 Impact on Environment�������������������������������������������������������������������������������������������  227 Bengt Mattson and Tessa Brandsema 11 Information Sources�������������������������������������������������������������������������������������������������  237 Sin Ying Chuah and Paul Le Brun 12 Oral Solids�����������������������������������������������������������������������������������������������������������������  247 Boy van Basten 13 Oral Liquids �������������������������������������������������������������������������������������������������������������  277 Antje Lein and Shi Wai Ng 14 Pulmonary�����������������������������������������������������������������������������������������������������������������  299 Anne de Boer, Paul Hagedoorn, and Floris Grasmeijer 15 Oropharynx���������������������������������������������������������������������������������������������������������������  337 Craig Russell and Stefanie Melhorn 16 Nose ���������������������������������������������������������������������������������������������������������������������������  345 Anita Hafner and Piroska Szabó-Révész

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17 Ear �����������������������������������������������������������������������������������������������������������������������������  367 Monja Gantumur and Craig Russell 18 E  ye �����������������������������������������������������������������������������������������������������������������������������  377 Jens Boventer, Irene Krämer, and Julia Reichhold 19 Rectal and Vaginal ���������������������������������������������������������������������������������������������������  405 Herman Woerdenbag, J. Carolina Visser, Tina Kauss, and Małgorzata Sznitowska 20 Dermal�����������������������������������������������������������������������������������������������������������������������  439 Antje Lein and Shi Wai Ng 21 Parenteral �����������������������������������������������������������������������������������������������������������������  473 Marija Tubic-Grozdanis and Irene Krämer 22 Irrigations  and Dialysis Solutions���������������������������������������������������������������������������  521 Daan Touw, Alain Ragon, and Olga Mučicová 23 Radiopharmaceuticals ���������������������������������������������������������������������������������������������  531 Rogier Lange, Nanno Schreuder, and Harry Hendrikse 24 Therapeutic  Proteins and Advanced Therapy Medicinal Products���������������������  551 Michel Eppink, Martijn Wapenaar, Daan Crommelin, Andrea Hawe, Thijs Giezen, Anne Black, and Alice Tam 25 Human Resources�����������������������������������������������������������������������������������������������������  591 Elfriede Nusser-Rothermundt and Frederic Lagarce 26 Occupational  Safety and Health �����������������������������������������������������������������������������  605 Johannes Gerding, Shi Wai Ng, and Sylvie Crauste-Manciet 27 Premises���������������������������������������������������������������������������������������������������������������������  623 Farshid Sadeghipour and Sylvie Crauste-Manciet 28 Equipment�����������������������������������������������������������������������������������������������������������������  641 Derk Allersma, Pascal Odou, and Bahez Gareb 29 Basic Operations�������������������������������������������������������������������������������������������������������  705 Herman Woerdenbag, Małgorzata Sznitowska, and Oscar Smeets 30 Sterilisation Methods �����������������������������������������������������������������������������������������������  731 Craig Russell, Tove Hansen, and Mattias Paulsson 31 Aseptic Handling�������������������������������������������������������������������������������������������������������  749 Frits Boom and Alison Beaney 32 Product  Quality, Quality Control and Validation �������������������������������������������������  767 Rogier Lange and Trine Schnor 33 Quality Requirements and Analysis �����������������������������������������������������������������������  785 Mark Santillo and Frederic Lagarce 34 Stability ���������������������������������������������������������������������������������������������������������������������  809 Daan Touw, Judith Thiesen, and Jean Vigneron 35 Pharmaceutical Quality System�������������������������������������������������������������������������������  839 Reinout Schellekens and Julian Smith 36 Risk  Management in Pharmacy Production ���������������������������������������������������������  859 Elfriede Nusser-Rothermundt

Contents

Contents

xi

37 Documentation ���������������������������������������������������������������������������������������������������������  875 Rik Wagenaar and Mark Santillo 38 Statistics���������������������������������������������������������������������������������������������������������������������  897 Pascal Odou and Craig Russell 39 Logistics���������������������������������������������������������������������������������������������������������������������  917 Martin Hug and V’Iain Fenton-May 40 Product  Care & Daily Practise �������������������������������������������������������������������������������  931 Diana van Riet-Nales and Anthony Sinclair Index�����������������������������������������������������������������������������������������������������������������������������������  957

About the Editors

Paul  Le Brun, PharmD, PhD, is hospital pharmacist and clinical pharmacologist of the Department of Clinical Pharmacy and Toxicology of Leiden University Medical Center, The Netherlands since 2017. He also teaches pharmacy students in quality, preparation and innovative medicines as associate professor at the university of Leiden. Paul obtained his degree in pharmacy from the Groningen University in 1982. He started his career at the Dutch Laboratory of Pharmacists (LNA), department of the Royal Dutch Association of Pharmacists (KNMP). From 1985 until 1988 he was trained and worked as a hospital pharmacist in the Central Hospital Pharmacy of The Hague. He joined Merck Sharp & Dohme as production pharmacist from 1989 to 1992. From 1992 until 2017 he was director of production of the Central Hospital Pharmacy in The Hague combined with clinical tasks in Haga teaching hospital. In 2001 he obtained his PhD: “Optimization of antibiotic inhalation therapy in Cystic Fibrosis”. Studies on nebulized tobramycin. Development of a colistin dry powder inhaler system. The research was valued in 2000 with the KNMP Innovation Award. To date, his main research themes are Aseptic preparation and Medicinal product development. Paul published numerous scientific papers and was author/editor of the first edition of Practical Pharmaceutics.  

Sylvie  Crauste-Manciet obtained her degree in Pharmacy (PharmD) in 1993, her PhD in 1997 and accreditation to supervise research (HDR) in 2013 from the University of Paris Descartes, France. Until 1999, she combines hospital pharmacy and academic activities as specialist in pharmaceutical technologies for preparation of sterile and not sterile drugs for hospitalized patients e.g. cytotoxic drugs, parenteral nutrition, paediatric capsules in Paris, Bordeaux and she recently moved to Angers. As professor of pharmaceutical technologies, she developed specific research in nanosytems design and characterization firstly at UPCGI Laboratory, UMR 8151 CNRS- U1022 INSERM at Paris Descartes University then at ARNA, ChemBioPharm team, INSERM U1212 UMR 5320 CNRS at Bordeaux University and since September 2022 at MINT laboratory UMR INSERM 1066 /CNRS 6021 at Angers University. She created in 2016 a master’s program dedicated for research on hospital pharmaceutical technology. Since 1998, she is the president of the European society of Hospital Pharmaceutical Technology (GERPAC) which is an association of European hospital pharmacists involved in the research and development of hospital preparations.  

Irene  Krämer, PharmD, PhD, is Director of the Pharmacy Department of the University Medical Center at the Johannes Gutenberg-University Mainz (Germany) and Professor of Clinical Pharmacy at the faculty of pharmacy at the same university. She obtained her doctorate in pharmaceutical chemistry and continued her postgraduate education at the Pharmacy Department of the Johannes Gutenberg-University and went on to complete her postdoctoral thesis in Pharmaceutical Technology, entitled Development, Quality Assurance, and Optimization of Ready-to-Use Parenteral Solutions in the Integrated Cancer Care Concept.  

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About the Editors

The research projects of Prof. Kraemer focus on experimental studies of the physicochemical and microbiological stability of ready-to-administer parenteral preparations mainly used in oncology and intensive care patients. Other research projects deal with the development and evaluation of clinical pharmacy services and the improvement of medication safety by digitalization and automation of the medication process. She also performed numerous studies regarding medication adherence of special patient groups. Prof. Krämer published numerous scientific papers and is author/editor of several clinical pharmacy and pharmaceutical technology textbooks. She received the German Federal Cross of Merit for her dedication to hospital pharmacy and patient care. Julian Smith is a registered pharmacist, and a Qualified Person (QP) responsible for assuring the quality of medicines. He has been a hospital pharmacist for much of his professional career. His time in hospital was spent in “technical services”, mainly in Quality Assurance, where he was involved in the manufacture of Pharmaceutical “Specials” in licensed Production Units. His final role in the NHS was as the All-Wales Quality Assurance Pharmacist. During his career he has taken brief detours into both community pharmacy and academia. He was a lecturer in Pharmaceutics at Aston University in the UK. His PhD is in transdermal drug delivery, and this was where he developed a passion for formulation development which has driven his career. He became a director at Viridian Pharma where he was involved in developing and applying for licensed pharmaceutical products. He is now a Director of JCS Pharma Consulting where he provides advice on product development, lectures in Quality Assurance, and acts as a contract Qualified Person.  

Herman Woerdenbag Dr. H.J. (Herman) Woerdenbag is associate professor of pharmaceutical product care at the University of Groningen, Department of Pharmaceutical Technology and Biopharmacy. He is responsible for teaching activities (theory and practical) in pharmaceutical compounding and dispensing (small and medium scale, including quality management) and product care in the Pharmacy curriculum (BSc and MSc). He is teacher, coordinator and innovator of various compulsory and elective courses. He contributes to quality assurance in pharmacy education and curriculum renewal. Current research is mainly practice-oriented, in collaboration with (hospital) pharmacists in the Netherlands, and often linked with pharmacy education in galenics and compounding. His scientific and societal work covers publications on medicinal plants and herbal medicine, pharmaceutics and pharmaceutical product care.  

1

Introduction Paul Le Brun, Sylvie Crauste-Manciet, Irene Krämer, Julian Smith, and Herman Woerdenbag

Contents 1.1

Structure of the Book

1

1.2

Definitions 1.2.1 Types of Pharmacy Preparations 1.2.2 Aseptic Preparation, Aseptic Handling and Reconstitution

2 2

1.3

Terminology

3

1.4

Spelling and Notation

4

1.5

Formulations

5

1.6

Examples, Guidelines, Legislation, Ph. Eur.

5

1.7

References

5

3

Abstract

This chapter explains some of the principles that have been followed during the production of this and the previous edition of the textbook ‘Practical Pharmaceutics’. P. Le Brun (*) Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, the Netherlands e-mail: [email protected] S. Crauste-Manciet Pharmacy Department, MINT URM Inserm 1066 CNRS 6021, University of Angers, CHU Angers, Angers, France e-mail: [email protected] I. Krämer Apotheke der Universitätsmedizin, Mainz, Rheinland-Pfalz, Germany e-mail: [email protected] J. Smith JCS Pharma Consulting Ltd., Newport, Gwent, UK e-mail: [email protected] H. Woerdenbag Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands e-mail: [email protected]

The basic principle is that the structure follows the patient’s need. Concepts such as preparation, manufacturing, reconstitution, aseptic handling, hazardous substances are defined and explained to avoid ambiguity. Specific terminology on technological operations is also explained. Where applicable, spelling and notations used in de European Pharmacopoeia have been followed.

1.1

Structure of the Book

Practical Pharmaceutics explores the preparation and quality assurance of medicines. The book comprises of chapters brought together in the clusters called; patient needs, product design and pre-formulation, product design and formulation, production and organisation, pharmaceutical quality systems and product quality, and dispensing. These vital elements are structured along patient centricity (see Fig. 1.1). The comprehensive text has a broad scope and content. The chapter structure layout of the first edition, published in 2015, is applied relevant to the second edition, with minor modifications in sequence. In this new edition all chapters have been updated, some with minor revisions and others with substantial amendments. One completely new chapter has been added to reflect the latest developments in innovative medicines focusing on biologicals and advances therapy medicinal products (ATMP’s). In most countries, should a patient require medical treatment, he will require a prescription from a competent practitioner, usually a physician. The prescriber becomes responsible for the pharmacotherapeutic treatment of the patient. A registered pharmacist is responsible for the supply of the prescribed medication. Professional responsibility of the pharmacist includes the procurement, design, preparation, storage and dispensing of medicines. A pharmacist needs to assess the prescription for the best available pharmacotherapy, for product availability and in case of extemporaneous pharmacy preparations for the prod-

© Springer Nature Switzerland AG 2023 P. Le Brun et al. (eds.), Practical Pharmaceutics, https://doi.org/10.1007/978-3-031-20298-8_1

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P. Le Brun et al. Patient needs

2. Prescription assessment 3. Availability of medicines

Dispensing

39.Logistics 40.Product care and daily practice

Product (design and) pre-formulation 4.Product design 5.Biopharmaceutics 6.Physical chemistry 7.Raw materials 8.Containers 9.Microbiology 10.Impact on environment 11.Information sources

Product (design and) formulation

Pharmaceutical Quality systems and product quality 33.Quality requirements and analysis 34.Stability 35.Pharmaceutical quality system 36.Risk management in pharmacy production 37.Documentation 38. Statistics

Production and organisation

25.Human resources 26.Occupational safety and health 27.Premises 28.Equipment 29.Basic operations 30.Sterilisation methods 31.Aseptic handling 32.Product quality, quality control and validation

12. Oral solids 13. Oral liquids 14. Pulmonary 15. Oropharynx 16. Nose 17. Ear 18. Eye 19. Rectal and vaginal 20. Dermal 21. Parenteral 22. Irrigation and dialysis 23. Radiopharmaceuticals 24. Therapeutic proteins and ATMP’s

Fig. 1.1  The structure of the second edition of Practical Pharmaceutics

uct’s safety and quality (Chaps. 1, 2, and 3). In several countries the pharmacist is now allowed to prescribe certain medicines. The administration route and dosage form dictate the design of a medicine and its method of preparation. The design and pre-formulation of medicines is discussed in the Chaps. 4, 5, 6, 7, 8, 9, 10, and 11. Awareness on the impact medicines have on the environment is growing, but it is not yet fully integrated into the professional field. This issue is dealt with in Chap. 10. Chapters 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24 are based on the route of administration of medicines and provide many examples of pharmacy preparations within the cluster product design and formulation. The production of medicines is a highly regulated sector. This topic is reflected in the Chaps. 25, 26, 27, 28, 29, 30, 31, and 32, a cluster about the different aspects of medicines production and organisation. The following chapters (33, 34, 35, 36, 37, and 38) focus on quality aspects and pharmaceutical quality management systems. The approach to writing the chapters on production and quality management systems has focused on techniques of practice and logic rather than regulation. Before a patient can take a medicine, the product has to be stored, procured, and distributed. At the time of dispensing,

the patient should receive written and oral instructions, not only for therapeutic reasons but also for storing and using the medicine correctly (Chaps. 39 and 40). Although many, specific, references are listed at the end of each chapter, the book also describes a list of general references, such as textbooks and suggestions for further reading. These references can be used for deepening and broadening knowledge as well as for postgraduate education (Chap. 11).

1.2 Definitions 1.2.1 Types of Pharmacy Preparations Early editions of Practical Pharmaceutics and its predecessor focused solely on pharmacy preparations. The new edition still concentrates on hospital and community pharmacy but also provides information that is of benefit to the pharmaceutical industry. There is a need for the provision of medicines to patients with specials needs which is not fulfilled by the pharmaceutical industry. For this purpose, a terminology for the non-industrial preparation of medicines is required, as described in Fig. 1.2.

1 Introduction

3

Starting Material

Process

Legal status No extra acvity

Reconstuon Licensed medicinal products

Licensed medicinal product

Repackaging or replenishing Dispensing or administraon to the paent

Reconstuon in excess of SPC instrucons

Licensed medicinal products Or Raw materials

Preparaon by adapng the dosage form of an exisng medicinal product

Unlicensed Pharmaceucal Preparaons

Preparaon from raw materials

Fig. 1.2  Terminology for the non-industrial preparation of medicines

The terminology and definition of the activities is as follows: Reconstitution: manipulation to enable the use or application of a medicinal product with a marketing authorisation in accordance with the instructions given in the summary of product characteristics or in the patient information leaflet (according to Ph. Eur.: Pharmaceutical Preparations). In practice, it regularly occurs that reconstitution is needed beyond such ‘official’ instructions. For instance, when a longer shelf life is assigned or when a different dilution with an infusion solution takes place. Such action is legally considered as a preparation. When speaking about the actual work process, the handlings that are applied, it appears to be unreasonable to distinguish this from the processes. Therefore, this book uses the term ‘reconstitution’ for reconstitution in the strict sense as well as for reconstitution beyond the summary of product characteristics or the patient information leaflet. If reconstitution concerns parenteral medicines, which is often the case, the term ‘aseptic handling’ is used in order to distinguish it from aseptic preparation or processing. Preparation by adapting an existing product: reformulating a licensed product into a different dosage form suitable for the intended use, presented in a suitable and appropriately labelled container (according to Ph. Eur.: Pharmaceutical Preparations). Preparation from raw materials: formulating active substances and excipients into a dosage form suitable for the

intended use, presented in a suitable and appropriately labelled container (according to Ph. Eur.: Pharmaceutical Preparations).

1.2.2 Aseptic Preparation, Aseptic Handling and Reconstitution The reconstitution of parenteral medicines in the strict sense as well in the extended sense (see Sect. 1.2.1) is very frequently performed in hospital pharmacies. The correct ­performance of this process requires extensive precautions on procedures, premises, validation and control. However, these differ considerably from the generally accepted precautions for aseptic processing from raw materials, due to working with closed systems. The use of the term ‘aseptic handling’ therefore was felt justified.

1.3 Terminology The editors have agreed on the following descriptive terms and spelling. Drug The term ‘drug’ is not used. The reason is its wider connotation in the area of abuse and because it does not discriminate between the active substance and the medicine (the product). Instead of ‘drug’ either the term ‘medicine’ is used or – when

4

appropriate  – ‘active substance’. European legislation is thereby followed as well as international harmonisation. Only in biopharmaceutical terminology terms as ‘drug release’ or ‘drug distribution’ the word ‘drug’ is used. The terms ‘orphan drug’ and ‘drug shortage’ are generally changed into orphan medicine and medicines’ shortage (which is sometimes caused by shortage of an active substance).

P. Le Brun et al. Table 1.1  Overview of the terminology used in relation to particle size reduction, mixing and de-agglomeration Topic Particles

Particle size reduction

Preparation The Ph. Eur. defines preparation (of an unlicensed pharmaceutical product) as: the ‘manufacture’ of unlicensed pharmaceutical preparations by or at the request of pharmacies or other healthcare establishments. (The term ‘preparation’ is used instead of ‘manufacture’ in order to clearly distinguish it from the industrial manufacture of licensed pharmaceutical preparations.) As many situations in daily practice will apply to the production of medicines in (hospital) pharmacies, the term ‘preparation’ is used most frequently in the book. In some cases it will be obvious that it concerns indus- Mixing and de-agglomeration trial manufacturing. ‘Compounding’, as a term for small-­ scale preparation often used in the US, is not used in this book. Hazardous Substances The definition of ‘hazardous’ in combination with ‘substances’ follows the European Occupational Safety and Health legislation, i.e. applies to each substance that has been assigned a so-called H(azard)-statement. Carcinogenicity, Mutagenicity or Reprotoxicity (CMR) are reflected in specific H-statements, but various other types of toxicity exist. This approach should diminish the possible confusion that arises when ‘hazardous’ is considered synonym with CMR or, in other situations, even with CMR plus some specific types of toxicity. Terms Terminology for dosage forms, administration routes and containers usually follow the Ph. Eur. or is named according to the EDQM (European Directorate of Quality of Medicines) lists of standard terms. In other areas terms of the International Committee on Harmonisation (ICH), GMP and ISO are used where appropriate. If the difference between industrial scale production and preparation in pharmacies require the use of other terms, they are defined the first time used. Dispersion A main challenge of processing an active substance into a suitable vehicle, if it is not dissolved, is the dispersion of particles. This counts for many dosage forms such as oral suspensions, cutaneous preparations and suspension-type suppositories. It appeared that this process may be performed

Term Primary particles Secondary particles Milling Grinding Wet grinding

Pulverising Comminuting Dispersing

Geometrically dilution (triturating) Mixing (= blending) Rubbing

Triturating

Description Particles are a single crystal Particles are agglomerates Particle size reduction by (different) forces Milling a substance by hand Grinding with an amount of liquid as small as possible for reasons of: preventing agglomeration, augmenting milling efficiency (grease effect) or for occupational safety and health reasons (to prevent the creation of dust particles) Smashing a material into a powder Reducing to powder (US) Distributing primary particles into a medium; may bring about the breaking up of agglomerates (de-agglomeration) Mixing using the ratio 1:1 repeatedly Combining substances to obtain a homogeneous distribution Intensely mixing (triturated) powders with a semi-solid or liquid on a surface to obtain a smooth mixture; making into a (thick) paste; levigating (US) Mixing a solid with a solid, semi-solid or liquid substance in such a ratio and intensity so that agglomerates are dispersed (de-agglomeration); de-agglomeration may take place if the right medium is chosen

in different ways on a small scale, yielding variable results. It was felt justified to use different terms for these different ways of handling. Table 1.1 gives an overview.

1.4 Spelling and Notation Active Substances In the European Union, the quality of specified active substances and excipients has to meet the European Pharmacopoeia criteria and are named according to the

1 Introduction

5

English monograph titles. If not included in the Ph. Eur, another reference pharmacopoeia is given (BP, USP, JP).

1.6 Examples, Guidelines, Legislation, Ph. Eur.

Spelling As in European legislation the UK English spelling is used throughout the book. Commas are used to separate thousands in numbers instead of a space as in the European Pharmacopoeia or the stop sign that is common in many European countries. In some cases English words have been created, such as hydrophilise as a verb (instead of the more descriptive ‘making hydrophilic’), considering that most readers will immediately and unambiguously understand what is means.

Greek Letters Greek letters are indispensable part of specific formulas or equations. But in running text they have to be changed into Latin letters. So: ‘α’ becomes ‘alpha’. The reason behind is that with moving and copying texts between different word processing programmes, as happens during editing and when using electronic books, symbols easily get lost or disfigured. The only exception in the book is the chapter Statistics that definitely needs Greek letters as symbols equations.

The majority of information in this book is universally applicable in the field of preparation and manufacturing of medicines. Focus on specific topics has been prompted by European legislation and guidelines, and by country-specific examples suggested by the authors and members of the editorial advisory group. Most countries in Europe have produced guidelines, publications and textbooks covering aspects of pharmacy that are of particular interest to their unique practice. The emphasis in each country differs, often as a result of some historic incident, focusing efforts in a particular direction. This undeniably means that one single textbook for all will cover topics and practices, being new to some, but old to others. The main legislative starting point for Practical Pharmaceutics is the Ph. Eur., especially the monograph Pharmaceutical Preparations. Other basic legislation used are the EC legislation on medicines, the EU-GMP (Good Manufacturing Practice) and guidelines of ICH (International Conference on Harmonisation). If the Ph. Eur. is referred to it is always the current edition at time of closing the manuscript. Comments on the interpretation of regulation is always offered as a snapshot in time and is only valid as long as the wording of the legal texts is unchanged compared to the cited reference.

1.5 Formulations

1.7 References

The book is not intended to be a formulary, but for many preparations formulas are included to illustrate and explain principles described in the text. Some readers may wish to use such formulas in practice, but more information may be necessary, such as a detailed method of preparation, stability data, appropriate containers, scientific background information and justification. The original source formulary, e.g. FNA or NRF (see Chap. 11) should be consulted to meet that demand. The formula-tables are presented with virtual amounts, that is: they are not meant as to be weighed but refer to the composition. They are used to illustrate the percentages of all substances.

It was noted that scientific publications in the field of pharmacy preparations are sometimes scarce whereas practical experience, guidelines as well as procedures may be widespread. Therefore, some literature quotes in the original Dutch book (Recepteerkunde, 5th edition, 2010) have been retained (but translated into English) to make them available to all. In cases where scientific literature lacks as a base, we first rely on sound thinking and explaining, then on best practices and finally on regulations. The aim is to provide our colleagues with systematic knowledge that gives them the tools to act professionally in the area of pharmaceutical product care in whatever situation they will find themselves.

Neutrality Any reference, in the text, to the word ‘he’ should be taken to be neutral and comprises all individual human beings.

2

Prescription Assessment Andrew Lowey and Stefanie Melhorn

Contents 2.1

Pharmacy Preparation: Way Out or Unjustified

8

2.2

Prescription Assessment 2.2.1 Alternative Treatment Options 2.2.2 Considerations Upon Receiving a Request 2.2.3 Structured Assessments

8 8 9 9

2.3

The Prescription 2.3.1 Legal Requirements 2.3.2 Consultations with the Prescriber and the Patient 2.3.3 Dose 2.3.4 Contra Indications, Interactions and Intolerances 2.3.5 Narcotic and Psychotropic Substances 2.3.6 Standard Amounts

2.4

2.5

13 13 15 16 19 19 19

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

20 20 21

Essentials

21

References

19 19 20

22

Abstract

Upon receipt of a request from a prescriber for a pharmacy preparation, the pharmacist must decide whether the request is appropriate and reasonable, and judge

the level of risk associated with proceeding with the request. The pharmacist must also consider the risks of not supplying a medicine which may lead to the patient not receiving treatment. Further discussion with the medical team may be needed. This chapter approaches the risk assessment of the prescription in a structured way, referring to procedures and forms from different countries. The assessment also includes the feasibility of producing a preparation of appropriate pharmaceutical quality and with all necessary clinical information. Pharmacy legislation defines the framework in which pharmacists can prepare medicines, however there are other legislative and quality frameworks that they must be aware of if other categories of products are requested, such as medical devices, placebo’s, or agents used for euthanasia. Veterinary and homeopathic medicines are also dealt with. What Is New? This chapter was based on the chapter Prescription assessment by Andrew Lowy and Stefanie Melhorn. The chapter was updated and shortened. Learning Objectives • After reading this chapter the reader will: • Know why assessment of a prescription is necessary • Know the legal background of prescription assessment • How a prescription assessment can be performed • Be able to assess the risks of (not) preparing

A. Lowey (*) Leeds Teaching Hospitals NHS Trust, Leeds, West Yorkshire, UK e-mail: [email protected] S. Melhorn Deutscher Arzneimittel-Codex/Neues Rezeptur-Formularium, Avoxa – Mediengruppe Deutscher Apotheker GmbH, Eschborn, Germany e-mail: [email protected] © Springer Nature Switzerland AG 2023 P. Le Brun et al. (eds.), Practical Pharmaceutics, https://doi.org/10.1007/978-3-031-20298-8_2

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A. Lowey and S. Melhorn

2.1 Pharmacy Preparation: Way Out or Unjustified Case Suppositories with Hydrocortisone

Prescription states: Hydrocortisone suppositories 240 mg, 6 units Dosage – Use 1 suppository when required as directed The parents of a 2 month old girl Maria come to the pharmacy with this prescription. The suppositories have been recommended by an endocrinologist at the hospital. Upon inquiry it appears that Maria suffers from a condition known as Prader Willi syndrome, a hereditary disorder which affects hypothalamic function; the adrenal cortex produces insufficient corticosteroid at times of stress. An intramuscular injection with a licensed pharmaceutical preparation that contains hydrocortisone sodium succinate would appear to be a major treatment option. However, the child’s parents do not want to give an injection to their child. Maria is very reluctant to drink, as is common in babies with the Prader Willi syndrome. Therefore, her parents don’t consider administration the contents of a capsule or of crushed tablets as a reliable option; instead, the doctor has suggested a rectal preparation. This case is typical of requests for pharmacy preparations; in order to give tailor-made care, the doctor has prescribed an individual preparation instead of a licensed pharmaceutical preparation. Even when the oral route would have been an option, the licensed oral solid medicines would have had to be adapted due to the low dose required. Before the pharmacist starts preparing the suppositories, he needs to perform a risk assessment to establish the likely safety, quality and efficacy of the product (in comparison with alternative treatment options).

Pharmacy preparation allows the doctor and pharmacist to provide individualised pharmaceutical care. The preparation of a medicine in the pharmacy fulfils a need when the licensed pharmaceutical preparation is not available (see also Chap. 3) or when a licensed pharmaceutical preparation does not satisfy a specific situation. However, pharmacy prepared products are not subject to the same levels of scrutiny with respect to quality assurance and efficacy as licensed medicines; therefore, prescribers and pharmacists cannot make the same assumptions of quality, safety and efficacy about these products as they do for licensed medicines.

This is due to the wide range of elevated risks associated with pharmacy preparation, including calculation and manipulation errors, formulation failures leading to overdose or underdose, possible toxicity from raw materials and microbiological contamination. The relative lack of pharmacovigilance or monitoring systems for pharmacy prepared products also means that the likelihood of detection for any errors that lead to side effects is generally low. Despite the relative lack of information about side effects related to pharmacy prepared products, there have been reports of catastrophic errors associated with them, including an error in the US that led to a 1000-fold overdose of clonidine in a 5  year old child [1]. A high profile error also occurred in 1998 in the UK, when a baby died following a calculation error in preparing peppermint water in a community pharmacy [2]. Therefore, upon receipt of a request from the doctor, the pharmacist must examine the situation and decide whether the request is appropriate and judge the level of risk associated with proceeding with the request. Before proceeding, the pharmacist should review all other potential treatment options. The use of a licensed product in line with its approved indication should be strongly advocated unless there is a specific reason not to use such a medicine. However, the pharmacist must also consider the risks of not supplying a medicine, which may lead to the patient not receiving treatment. In this context, it should be recognised that some patients do have special clinical needs which cannot be met by other viable options. The pharmacist must make every effort to ensure that the medicine produced is of appropriate pharmaceutical quality and is fit for the intended purpose; an approved or authorised formula should be used wherever possible. Where such formulae are not available, steps should be taken to minimize risk where possible e.g. restricted shelf life, fridge storage (if applicable), use of licensed starting materials etc. The same principles apply for reviewing prescriptions for pharmacy preparations as for licensed medicinal products.

2.2 Prescription Assessment 2.2.1 Alternative Treatment Options Depending on the legislative situation in the country and the relation between pharmacists and physicians, alternative treatment options may include: • Use of a (licensed) medicine which can be administered by an alternative route or method e.g. use of a soluble or dispersible product or indeed rectal product in patients who have difficulty swallowing whole tablets.

2  Prescription Assessment

• Use of an appropriate licensed formulation of an alternative medicine from the same therapeutic class (e.g. using a licensed liquid formulation of lisinopril rather than preparing a captopril oral suspension). • Manipulation of a licensed medicine prior to each dose e.g. dispersing a tablet in a small volume of water or halving tablets (Note: the practice of dispersing a tablet in water and then using an aliquot of the liquid is associated with a high risk of inaccurate doses and is generally not recommended except in extraordinary circumstances). • Use of a product intended for a different route e.g. oral administration of an injection. • Use of an imported product which bears a product licence in its country of origin (a check should be made to ensure that the absence of a local license is not due to a revocation of a previous licence). • Purchase of a batch-manufactured unlicensed product from an alternative supplier (e.g. ‘Specials Manufacturers’ in the UK). Note that this practice is not allowed or highly restricted in most European countries.

9

• Are personnel trained and validated for the applicable process • Has a health & safety risk assessment been carried out to establish the risks to staff members? • Are there systems in place to monitor the efficacy and safety of the product? Is the patient being monitored closely (if appropriate)?

2.2.3 Structured Assessments Some pharmacists have suggested a structure approach to the decision-making process: e.g. Leeds approach, German reason check, Risk-benefit Form.

2.2.3.1 Leeds Approach At Leeds Teaching Hospitals NHS Trust in England, the Pharmacy department has a ‘catalogue’ of authorised pharmacy preparations, which is periodically reviewed to ensure that other more suitable options are not available. Each of the approved preparations on the catalogue have been reviewed by a group of senior pharmacy technicians and pharmacists to ensure that they have a sound evidence base and are backed by an authorised preparation instruction and agreed label. 2.2.2 Considerations Upon Receiving This means that the clinical pharmacist has some assurance a Request of the likely quality of the end product. They must, however, When faced with a request for an individualised pharmacy still judge if the individual formulae is appropriate for the preparation, a pharmacist may find it helpful to consider the intended patient. This is the difference between a product of high quality and one that is appropriate or ‘fit for purpose’. following questions in order to reduce or avoid risks: If a ‘non-catalogue’ (non-standard) preparation is requested, • Has a risk assessment been carried out that has established pharmacy preparation as the most appropriate the requesting pharmacist must complete a form (see Fig. 2.1) to acknowledge that other options have been considered, along choice for this patient? • Are there other more suitable alternatives, is a licensed with the possible risks associated with the preparation. High product available, could a licensed product be adapted for risk products may still be authorised if the benefits outweigh each dose, are there other batch-manufactured products the potential risks; however the authorisation must come from available, could you use an imported product that has a one of the senior management team in the department. This process creates an appropriate barrier to pharmacists licence in a mutually-recognised country? In the case of a solid oral dosage form, could the patient be taught how to who might otherwise decide to authorise ad hoc or unusual swallow medicines to avoid the need for a liquid formulations without considering the associated risks. The group of senior pharmacists and technicians then meet every medicine? few months to review the requests for non-catalogue prepara• What is the risk of not treating the patient? • Does the active substance have a narrow therapeutic tions, and review whether other options should be pursued e.g. purchase of a licensed product from a foreign country, use of a index? • Can a peer-reviewed and evidence-based formula be batch-manufactured product rather than an extemporaneously-­ used? If not, have the physico-chemical properties of the prepared product for an individual etc. active substance been considered, and have steps been As a guide to help the risk assessment, the department taken to minimise risk and complexity (e.g. reduce shelf-­ provides a risk assessment matrix to highlight potential problife, store in fridge, prepare a solution instead of a suspen- lems to the clinical pharmacist, see Fig. 2.2. sion, use commercially available suspending agents which have been tested with the active substance in ques- 2.2.3.2 German Reason Check In Germany, pharmacists must perform ‘reason checks’ tion and pharmaceutical-grade raw materials)? • Are the facilities and equipment appropriate and (Plausibilitätsprüfung) to establish the likely safety, calibrated? quality, and efficacy of the product they want to prepare.

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A. Lowey and S. Melhorn

Fig. 2.1  Request form for a non-catalogue extemporaneous product

The Pharmacy Practice Order (Apothekenbetriebsordnung, ApBetrO) specifies parameters of the preparation formula that must be checked, whether it is a doctor’s prescription or self-medication on patient’s request. Beyond that, the guideline recommends that the pharmacist considers the overall rationale for treatment. A form has been developed (Fig. 2.3) for the performance and documentation of the reason check. Some parts will be dealt with. Regarding “Qualitative and quantitative composition”: Substances used as active substance or as an excipient in pharmaceutical preparations have to be described in an individual monograph of the European Pharmacopoeia or comply with the requirements of the relevant general monographs. Cosmetics and medicinal products may only be used if the required quality is documented. In Germany it is not permitted to change or add any active substances without permission of the prescriber. This does not apply to excipients that have no pharmacological effect. Regarding “Compatibility”: if components of a prescribed preparation are not compatible (or there is a lack of evidence), it does not automatically mean that it should not be prepared. The preparation needs to show sufficient compatibility up to the in use expiry date; it may be possible to produce a preparation with a shortened but useful shelf life.

Interactions between the active substances and excipients can however make it impossible to produce a preparation of sufficient quality. These incompatibilities can be visible or invisible during preparation. The attending pharmacist has to verify if incompatibilities are apparent. More information about incompatibilities is to be found in references such as Fiedler, Handbook of Pharmaceutical Excipients, Martindale, Handbook of Extemporaneous Preparation, Kommentar zum Arzneibuch and Trissel’s Stability of Compounded Formulations (see Chap. 11). Regarding “Stability and shelf life”: These items are amply discussed in Chap. 34 Stability. Stability is influenced by the solubility of all substances in the preparation, pH of the base, pH at which the active substances are stable, and the influence of oxygen and light.

2.2.3.3 Risk-Benefit Form [4] A risk-benefit form has been elaborated for extemporaneous and for stock preparation (Figs. 2.4 and 2.5). They enable the pharmacist to list and balance the benefits and risks of the clinical and pharmaceutical qualities of the required pharmacy preparations. The form follows the process for handling requests for preparation, and defines decisive steps, levels of evidence of decisions, individuals concerned and responsibilities.

2  Prescription Assessment

11

Fig. 2.2  Extemporaneous product risk assessment matrix

Possible benefits include: • Unique therapeutic value if there is no comparable authorised medicine available • Improved patient friendliness and therefore a better compliance with therapy • Improved safety of health care processes (using preparations that don’t need any reconstitution steps on the wards or in nursing homes) • Improved occupational safety and health (OSH) of health care personnel (by diminishing exposure from hazardous active substances) • (Lower price; see box) Possible risks include: • Lack of assurance in relation to therapeutic safety and efficacy • Design failure causing quality defects, such as poor bioavailability or poor content uniformity • Preparation risk: if the actual pharmaceutical quality system cannot guarantee that the preparation will fully meet specifications

• Discouraging the marketing of authorised of medicines The forms for extemporaneous and stock preparation use the same benefits and risks. For extemporaneous preparations, the balance refers to an individual patient. In relation to stock preparations, the balance results in the definition of the group of (anonymous) patients for whom, or care situation in which, the benefits may outweigh the risks. Clinical benefits and risks are assessed on the front of the form by the attending pharmacist, who decides if the request adds enough value to be considered further. On the back of the form, the pharmacist assesses the risks of design and preparation. He also checks the feasibility e.g. availability of starting materials or sufficient control of the health and safety risk of the pharmacy personnel. Overall, it is the preparatory pharmacist who decides: In case of an extemporaneous preparation if he accepts the request(or not) In the case of a stock preparation, the conditions under which he will make this preparation available.

12 Fig. 2.3  Form for German reason check ([3] translated). Further explanation about items 3, 4 and 5 is given in Sect. 2.2.3.2

A. Lowey and S. Melhorn Actions Notes

Checklist for Reason Check 1. Sufficiency and readability of the prescription Is the prescription complete?

yes

no

Is everything readable?

yes

no

Are there any perceivable mistakes?

yes

no

Are there questionable ingredients?

yes

no

Is the treatment concept obvious?

yes

no

Is the dosage sensible?

yes

no

Are the dosage instructions sensible?

yes

no

Is the concentration of the active substances higher than the indicative concentration?

yes

no

Is the concentration of the active substances within the normal dosage range?

yes

no

Are all ingredients available in the required pharmaceutical quality?

yes

no

Does the prescription conform to a standard formulation?

yes

no

yes

no

yes

no

Is there a need for an added buffer?

yes

no

Is the microbiological stability sufficient for the targeted shelf life?

yes

no

Is the prescribed preparation stable enough for the targeted shelf life?

yes

no

2. Safety and treatment concept, dosage and dosage instructions

3. Qualitative and quantitative composition

If so, please specify the source: Are there any similar standard formulations? If so, please specify the source: 4. Compatibility Are the ingredients compatible? If no, please specify the incompatibilities: 5. Stability and shelf life

Additional assessments

Date, Signature Responsible Pharmacist/Delegate

2  Prescription Assessment

13

Fig. 2.4  Form for balancing risks and benefits of an extemporaneous preparation; front and back side (see Sect. 2.2.3.3)

Balancing benefits and risks (see Fig. 2.6) is not a matter of mathematics but of professionalism, responsibility and transparency. The forms therefore are transparent about the decisions and show who made them. Social Impact

In some European countries, cost may also play a role in the decision to prepare a medicine in a pharmacy. Although a pharmacy preparation is not preferable when a licensed product is available, in some situations the preparation might be encouraged. This might be the case with e.g. orphan medicines. There are examples of long time existing pharmaceutical substances that are repurposed as orphan medicines. From a therapeutic point of view this is of course recommended but when an unreasonable price is set into the market, a pharmacy preparation might be an alternative to mitigate the social impact. In The Netherlands, a pharmacy preparation is encouraged in this kind of situations. However, GMP and the monograph Pharmaceutical preparations from Ph Eur are applicable and paramount.

2.3 The Prescription 2.3.1 Legal Requirements A prescription is a request from a prescriber (usually a doctor) to a pharmacist to dispense a medicine in the stated amount, strength and method of use. Each country has its own medicines law which will define the exact requirements of a prescription. However, there is a standard data set used with the European Economic Area (European Union plus Lichtenstein, Norway and Switzerland) as given in Table 2.1. In some countries, the list of prescribers may include ‘non-medical prescribers’ such as nurses, pharmacists, dieticians or chiropodists. These other prescribers may have limited formularies in some countries. However, the law varies between different countries; the validating pharmacist must take steps to assure themselves that the prescriber is appropriately registered to prescribe. The pharmacist should consult the prescriber if it is possible or more appropriate to use a different medicine. A licensed medicinal product should be used in preference to a pharmacy preparation, if an appropriate product is available.

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Fig. 2.5  Form for balancing risks and benefits of a stock preparation; front and back side. (See Sect. 2.2.3.3)

Fig. 2.6  Balancing benefits and risks of specific pharmacy preparations. (See Sect. 2.2.3.3)

A. Lowey and S. Melhorn

2  Prescription Assessment Table 2.1  Non-exhaustive list of elements to be included in medical prescriptions in the EEA [5] Identification of the patient

Authentication of the prescription Identification of the prescribing health professional

Identification of the prescribed product, where applicable

Surname(s) First name(s) (written out in full, i.e. no initials) Date of birth Issue date Surname(s) First name(s) (written out in full, i.e. no initials) Professional qualification Details for direct contact (email and telephone or fax, the latter both with international prefix) Work address (including the name of the relevant member state) Signature (written or digital, depending on the medium chosen for issuing the prescription) ‘Common name’ as defined by Article 1 of Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use The brand name if: (a) the prescribed product is a biological medicinal product, as defined in point 3.2.1.1. (b) of Annex I (Part I) to Directive 2001/83; or (b) the prescribing health professional deems it medically necessary; in that case the prescription shall shortly state the reasons justifying the use of the brand name Pharmaceutical formulation (tablet, solution, etc.) Quantity Strength, as defined in Article 1 of Directive 2001/83/EC Dosage regimen

When a pharmacist considers that the delivery of a medicine carries an unacceptable level of risk, he can refuse to dispense the medicine to the patient, as pharmacists have a duty of care to the patient. In this situation, they must contact the prescriber to discuss possible alternatives.

2.3.2 Consultations with the Prescriber and the Patient 2.3.2.1 Consultation About a Prescription When there are doubts about the pharmaceutical options, consultation between the pharmacist and the prescriber takes place. The pharmacist can advise on the options for treatment following consideration of the diagnosis and pathophysiology by the doctor.

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A discussion between the pharmacist and the patient (or caregiver) may also be needed in order to make the most appropriate treatment decision. This is often the case in paediatrics, and the parent or caregiver may require some assurances about the need for medication, especially if the treatment is long term. Adherence to treatment regimens is influenced by a number of other factors, including the formulation (e.g. solid or liquid), administration route (e.g. rectal or oral), dosage size and frequency, and the organoleptic qualities of the medicine chosen (e.g. smell, appearance, flavour). By choosing a formulation that is easy to administer and by giving good information and instruction, the patient is more likely to comply with their treatment regimen.

Case – Vitamin ADEK Mixture

Pim is 14  years old and suffers from cystic fibrosis. Due to his illness, he cannot absorb fat-soluble vitamins very well. The paediatrician recommends that Pim needs treatment with vitamin A, D, E and K in various oral preparations. The licensed pharmaceutical preparation consisting of 400 IU vitamin D is no longer available, meaning Pim potentially has to take even more tablets than previously. The parents express concern to the paediatrician that Pim is unlikely to comply with his treatment. Therefore, the paediatrician requests a pharmacy preparation in which all vitamins are combined. The pharmacist designs an oral liquid based on a standard formulation for an oral vitamin D solution. The mixture contains, per milliliter, 750 IU vitamin A, 250 IU vitamin D, 50 mg vitamin E and 0.25 mg vitamin K. The pharmacist chooses an aqueous solution, because of the better availability of fat-soluble vitamins in patients with absorption disorders, such as cystic fibrosis patients. Due to a lack of data about the shelf life of the mixture and the absence of a stability-­ indicating analytical assay, a shelf life of 1 month in the refrigerator is assigned. Pim now only has to use daily 4  mL of the oral solution that the pharmacy prepares for him every month.

Various national formularies exist and may be useful to consult during discussions with the relevant doctor e.g. the Dutch national child formulary (www.kinderformularium. nl) [6] contains various pharmacy preparations, which are included in the Dutch pharmacists Formulary (FNA, see Chap. 11).

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Such national formularies are good starting points for formulations as they may have been tested or supported by published or validated formulae. A second example is the German Formulary (Neues Rezeptur-Formularium, see Chap. 11). In the UK, the Handbook of Extemporaneous Preparation (see Chap. 11) also lists a selection of 50 commonly used formulae, and the British Pharmacopoeia has a small but growing number of formulations detailed. The existence of validated formulae then allows for the potential for batch manufacture and suitable quality control testing. Another advantage of using a national formulary is that it is kept up to date, with obsolete formulations removed or replaced regularly. This may be due to a change in recommendations (e.g. an excipient is no longer considered appropriate) or when a suitable licensed formulation becomes available. An European-wide collection of paediatric formulations is the pan-European Paediatric Formulary (PaedForm) [7]. The Paedform project was initiated in 2013 with the aim of establishing a freely accessible platform for pharmaceutical formulations specifically for children throughout Europe. The focus is on preparations whose active ingredient is not available in a formulation approved for children of all age groups. The authors and operators of the database are the European Committee on Pharmaceuticals and Pharmaceutical Care and the European Pharmacopoeia Commission.

2.3.3 Dose The doctor writes the dose on the prescription and the pharmacist checks or ‘validates’ this dose. The validation process may take place with the help of a pharmacy computer system or electronic prescribing system. The usual support offered by pharmacy computer systems is limited if local formulae are used, and the pharmacist may need to consult a range of reference sources when considering the appropriate indications, doses, likely side effects and contra-indications. Extra care is required with some patient populations, such as children and the elderly.

2.3.3.1 Dosage Expression The way in which the prescriber writes the dose is dependent on the administration form. Capsules and suppositories are given in an amount (usually milligrams) per dose unit followed by the number of units and the daily or weekly dose. For example: R/Folinic acid capsules 10 mg x 10 1 capsule once a week In the case of oral liquids, the doctor will write the strength in milligrams per millilitre followed by the amount and dose.

A. Lowey and S. Melhorn

In the case of electrolytes the strength is often written in millimol per millilitre because the dosages of electrolyte are based on blood concentrations. For example: R/ Magnesium gluconate oral solution 0.1 mmol/mL 300 mL 1 mmol 3 times a day For the preparation and the dose check, it may be necessary to convert the strength to milligrams per millilitre. In the case of the oral solution in this prescription, magnesium gluconate dihydrate is used. Therefore, the equivalent strength is 45 mg/mL. The above prescription can then be read as: R/ Magnesium gluconate oral solution 45  mg/mL (Magnesium 2.43 mg/mL) 300 mL 10 mL 3 times a day In the case of medicines for cutaneous use (e.g. dermatology medicines), the concentration of the active substance is usually written as a percentage. The prescriber writes the amount and the frequency with which the dermatologic medicine has to be applied. The doctor usually writes the part of the body on which the patient should apply the preparation. In this way the pharmacist can check whether the prescribed amount is sufficient. Furthermore, it is also important to know whether the cutaneous medicine has to be applied thickly (liberally) or thinly. A practical device for dosing a cutaneous preparation is the fingertip unit (FTU), see Chap. 20. In Germany, the Neues Rezeptur-Formularium for doctors [8] contains a useful outline figure for the prescriber to mark the area of application (Fig. 2.7). The pharmacist must look carefully at the chemical form in which the active substance (see Chap. 7) of the preparation is prescribed (or meant to be prescribed), because the active substance may be available in various forms such as a base, ester or salt. Furthermore, the amount of water of crystallisation in the raw material may vary. E.g. folinic acid is dosed as the calcium salt. The doctor may use a brand name in the prescription, in this case Leucovorine®. This contains 15 mg folinic acid in the form of calcium folinate.

2.3.3.2 Paediatric Population Children regularly get prescribed medicines that are licensed only for adults or are licensed for use in other indications in children. This is called ‘off-label’ use and in this case the medicine is used in an ‘unlicensed’ manner. Unlicensed medicines used in children are usually prepared by using raw materials or by adapting a dosage form that was designed for an adult population. Often there is limited data available about the dose and side effects in children. This means that consultation between the prescriber and pharmacist may be necessary.

2  Prescription Assessment

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Fig. 2.7  Form for the instructions for use of dermatological medicines, © Avoxa – Mediengruppe Deutscher Apotheker GmbH

In 2007, the Nederlands Kenniscentrum Farmacotherapie bij Kinderen (NKFK) was founded. It was established to help improve information available about medicines use in children. One of the activities of the NKFK is the compilation and publication of the national children formulary in the Netherlands) [6]. In the UK, the Medicines for Children Research Network [9] has been established to investigate formulation quality and the practice of manipulation of dos-

age forms before administration e.g. cutting tablets, opening capsules etcetera. The idea of the European wide PaedForm is to collect, review and then select the most appropriate formulations currently used in Europe which meet today’s requirements [7]. It is preferable to use an active substance that has been used previously in a pediatric population, as information about the dose, pharmacological effect and side effects will already be available. Doses for babies and chil-

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dren are commonly expressed in mg per kg body weight. For medicines with a large therapeutic window, this approach is satisfactory. However, it must be recognised that during the growth and development of a child, the pharmacokinetic parameters change continuously. Children are not small adults and neonates are not small children. When considering active substances with a narrow therapeutic window, a dose in m2 body surface may therefore be a more accurate

(

)

basis for dose calculation and adjustment. This is because some physiological parameters, which are directly related to the elimination of medicines, are better correlated to body surface e.g. hepatic and renal function. Various formulae for calculating body surface area can be found in literature [10]. For example, the Dutch kinderformularium [6] uses the Mosteller formula as below:

Body surface in m 2 =  length ( in cm ) × weight ( in kg ) / 3,600  Tables with length, weight and body surface of children of different ages with normal proportions [6] are convenient when one does not have the length and weight of the child. The British National Formulary (BNF) for Children in the UK also has tables for guidance, using the Boyd equation [11]. Finally the result has to be rounded to a practical strength for the product to be prepared.

Case Hydrocortisone Suppositories 240 mg

X6 1 suppository when required The pharmacist consults reference sources which suggest a rectal dose of 100 mg/m2 body surface for stress situations in children with adrenal cortex disorder. Maria is 2 months old and a girl of that age has an estimated body surface of 0.27 m2. This means that the prescribed dose is too high. Discussions with the prescribing endocrinologist confirm that a prescribing error has been made. Hydrocortisone suppositories of 24 mg should have been prescribed.

In some cases, it may be necessary to estimate or derive a paediatric dose from a proportion of the adult dose, using a comparison of relevant body surface areas. However, this is a very approximate calculation, and further discussion with the prescriber will be needed to agree on a final dose. Commonly, the frequency of administration is similar to that of adults. However, this does sometimes require amendment. E.g. fluconazole dosing frequency varies with age, due to the changes in elimination.

2.3.3.3 Cutaneous (Dermal) Medicines Used in Children Children, and particularly babies, have a large relative body surface area. Premature babies also have a thinner skin than

0.5

(2.1)

adults, and lack the outer skin layer known as the horny layer or stratum corneum. In a young child with eczema, the skin may also be more damaged than in an adult with eczema. Therefore, the skin functions less well as a barrier. Furthermore, application of any creams or ointments under a nappy or diaper prevents trans-epidermal water loss and leads to an increased absorption of the active substance. Due to the larger risk of adverse effects and toxicity, certain medicines are not administered on the skin of young children. e.g. Salicylic acid is preferably not used on children younger than 2 years old and certainly not on large surfaces. Less potent corticosteroids are preferred as they are associated with a smaller risk of systemic adverse effects. Other options include a decreased dosing frequency to limit adverse effects e.g. application every other day rather than every day.

2.3.3.4 Elderly Population Body composition, homeostasis, body tissues and organs change as people age. Therefore, this has consequences for the pharmacokinetic and pharmacodynamic processes associated with the active substance. E.g. due to a larger percentage of fat tissue, the volume of distribution of lipophilic substances such as diazepam increases in elderly patients. The decrease of blood flow through the liver also has an effect with substances that have a high level of hepatic elimination e.g. morphine. Furthermore, two thirds of the elderly population have some degree of renal impairment. This has consequences for the dose of medicines with mainly renal elimination and a small therapeutic window e.g. digoxin, lithium. Skin also tends to become somewhat thinner with advancing age. The pharmacokinetic and pharmacodynamic changes usually become clinically more relevant over the 75th year of life. There are however large intra- and inter-individual differences in aging of organ functions. Therefore, it is difficult to predict the exact pharmacological response of a given elderly patient. As with licensed medicines, it may be necessary to adjust doses of pharmacy prepared medicines carefully and cautiously in elderly patients.

2  Prescription Assessment

Elderly patients are more sensitive to certain medicines and often use more medicines at the same time (sometimes called polypharmacy). This means that elderly patients are more vulnerable to adverse effects [12]. To avoid overdose and subsequent adverse effects, a lower starting dose may be used. However, lower strengths are not available for every medicine and not every licensed pharmaceutical preparation is available as a tablet that can be divided e.g. coated tablets. In this situation, it might be necessary to produce a lower strength oral liquid that could be used for careful dose titration.

2.3.4 Contra Indications, Interactions and Intolerances In addition to the validation of the dose itself, each preparation has to be reviewed in terms of possible contraindications, interactions and intolerances or allergies.

2.3.5 Narcotic and Psychotropic Substances Based on United Nations conventions [13] most European countries have extra requirements or controls which are applied to medicines with narcotic and psychotropic substances. Requirements vary between countries but may include: • Name, initials, full address and phone number of the prescriber • Date of prescribing • Name of the medicine and amount, written completely in letters • Name, initials and full address of the patient or of the owner of the animal • Clear description of the use, among what the maximal total drug use per 24 h, “use known” or “if necessary” is not correct • If necessary: the amount of repeat doses A prescription on which one or more raw materials fall under these regulations has to comply with these requirements. In Germany the use of narcotic or psychotropic substances is not appropriate if the intended purpose can be achieved in other ways, e. g. with medicines with other active substances. Some active substances falling under these regulations are exempted from the requirements associated with administration and prescribing, such as for preparations with codeine. However, for the raw material codeine, the administrative obligations mentioned in the law do apply in Germany.

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2.3.6 Standard Amounts The amount of a pharmacy preparation requested can vary widely, depending on the indication and area for use. The pharmacist should assess whether the amount is right for the use (see Fig. 2.7), the length of the treatment and the shelf life. In some countries, there are systems for standardising amounts used in order to improve consistency of products and maximise efficiency in the pharmacy setting. In addition, in some countries the amounts are limited by the health insurance.

2.4 Special Categories of Prescriptions Not every request for a pharmacy preparation is by definition a medicine. Examples include biocides, medical devices, starting materials and chemicals. It is important to make this distinction, because with that it becomes clear under which regulation the pharmacy preparation falls. The legal requirements vary with the category. The relevant national regulations should be consulted before any such items are prepared. Depending upon the item in question, the pharmacist may be obliged to ensure that the product is suitable for use in humans, for instance does not contain any material of animal origin that may transmit any known diseases e.g. Transmissible Spongiform Encephalopathies (Creutzfeldt-­ Jacobs Disease).

2.4.1 Herbal Medicines The regulation of herbal medicinal products is complicated and differs between countries.1 Roughly speaking, herbal products can be considered as medicinal products with medicinal claims, but also as food or dietary supplements without medicinal claims. The status will generally depend on the level of scientific evidence supporting their use. A detailed overview of the regulations concerning herbal medicinal products worldwide can be found in Herbal Medicines [14]. Herbal medicinal products are not explicitly mentioned in the Ph. Eur. but herbal raw materials are included. The reason is that any pharmacist should be able to judge the safety of herbal medicines but not the efficacy of the products. According to EC legislation [15], “a herbal medicinal product is any medicinal product, exclusively containing as active ingredients one or more herbal substances or one or more herbal preparations, or one or more such herbal substances in combination with one or more such herbal preparations.” Contribution by Herman J. Woerdenbag, Groningen, The Netherlands.

1 

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Herbal medicinal products are also referred to in the international literature as herbal medicines, herbal remedies, herbal products, phytomedicines, phytotherapeutic agents or phytopharmaceuticals. The use of herbal medicinal products for the treatment and prevention of disease is called phytotherapy [14]. Few herbal medicinal products are on the market as authorised medicines in the EU, fulfilling the same stringent requirements that count for conventional medicinal products. This is largely due to the limited availability of randomised controlled trials to support the quality, safety and efficacy of herbal medicinal products. More often, they are licensed as traditional herbal medicinal products, following an adapted and simplified registration wherein efficacy is made plausible based on available scientific data (well-established use) or long-term historic use in the EU (traditional use). Sufficient data to underpin the safety should be available in all cases and the quality of the herbal medicinal product must always be demonstrated. A vast majority of herbal products however, are unlicensed (not medicinal products) despite the fact that they are frequently intended for health improving purposes [14, 16].

2.4.2 Agents Used for Assisted Suicide In countries with legislation that allows for assisted suicide, pharmacists will be involved in preparing and dispensing the products. These pharmacists are then faced with ethical, moral, and practical questions. Is a pharmacist obliged to dispense these agents or is he allowed or even obliged to refuse in specific situations, and if so, based on which moral and ethical principles? How is professional information about pharmacologically effective agents and preparations distributed among pharmacists? These and similar questions have to be discussed in a social and legal context with the purpose of improving the difficult situation of patients and caregivers. In the Netherlands a “Guidance for the management of euthanasia and assisted suicide” was developed by doctors and pharmacists; it covers the path from the patient’s request onto the arrival of the autopsist. The use of this Guidance is closely monitored [17]. This Guidance demands that any decision on dispensing the agents can only be made after oral consultation between the doctor and the pharmacist. The pharmacist must be ethically and morally independent in his decisions, like the doctor, which may eventually lead to the pharmacist refusing to dispense. The pharmacist has to be informed about all relevant backgrounds, in order to be able to make his decision and to be able to give the doctor or the patient relevant pharmacologic and practical information. The relevant products are prepared by the pharmacist and he will dispense them personally to the doctor, accompanied by

A. Lowey and S. Melhorn

oral or written information about their practical and technical administration. The standard advises pharmacists and doctors making general arrangements before an actual patient’s request will occur.

2.4.3 Homoeopathic and Anthroposophic Medicines The law regarding the supply of homoeopathic and anthroposophic medicines varies between countries. In some countries, a pharmacist can refuse to dispense such an item and refer the patient to an alternative pharmacy. In Europe, the German Homeopathic Pharmacopoeia is available for the regulation of the quality of these medicines. If prescribed it usually is a licensed medicine but occasionally – mainly in cases of non-availability – a pharmacy preparation may be requested. A general pharmacist will not be able to assess the efficacy of a homeopathic or anthroposophic prescription but he will be able to judge the safety, for instance following these recommendations: • The pharmacist should only fulfill a request for a pharmacy preparation when the prescription comes from a homeopathic or anthroposophic doctor and relates to a single medicine of a non-animal or non-microbiological source and with dilution ≥1:10,000, for oral or external use. • When the medicine does not belong to these groups then the preparation is outside the competence of the regularly educated pharmacist. If that is the case, it is recommended to contact a pharmacy that specialises in preparing homoeopathic or anthroposophic medicines. At all times, pharmacists should only practice within their sphere of competence.

2.4.4 Veterinary Medicines In relation to the administration of medicines for animals, the pharmacological differences and local laws have to be observed. The pharmacokinetics of every active substance is different in each species. For animals, especially cats, the toxic concentration of many human medicines is lower than the therapeutic dose in humans due to differences in metabolism of medicines. For example, in cats, the administration of acetaminophen (paracetamol) very quickly leads to intoxication with methemoglobin formation, anemia, hemoglobinuria and liver damage, as they may metabolise the medicine poorly. The European Commission (EC) has acknowledged that insufficient authorised veterinary medicinal products are available for the treatment of every clinical case in every species. Therefore, Regulation (EU) 2019/6 allows, under

2  Prescription Assessment

Articles 112, 113 and 114, veterinary surgeons to prescribe products that are not authorised for the relevant clinical case or for the relevant species, this provision is known as the Cascade. This is a derogation from the main requirement in the EU legislation to use authorised veterinary medicines. Therefore the Cascade increases the range of medicines that a veterinary surgeon can use [18]. The Cascade allows the veterinary surgeon to use medicines designed for other species, only if there is no licensed medicine for the species and the indication and the animal is critically ill. The use of medicines as part of the Cascade system has to be carried out in the order specified: • Licensed Animal medicine, which is licensed for a different species or which has a different indication • Licensed human medicine • Extemporaneous preparation There are further regulations for animals and aquatic species bred for human food and for animals in the UK [19].

2.4.5 Medical Devices As for the regulations which apply to medicines, the regulations for medical devices include consideration of the following issues: diagnosis, prevention, surveillance, treatment or relief of illnesses. However, the set-up of the regulations for medical devices differs essentially from the one for medicines. In the case of medicines licensing, the government is responsible for managing medicines regulation. However, in the case of medical devices, the company itself is responsible for risk assessing the product before it enters the market [20]. Medical devices are classified in four different risk classes [20]. The manufacturer has to decide in which risk class the device falls: I, IIa, IIb or III; the higher the class, the more risks are associated with the use. Therefore, devices in class IIb or III have to be assessed in advance by a competent authority; a so-called Notified Body. This is an independent organisation, designated by the national government. When the device belongs to class I or IIa, the producer only has to inform that authority of the device. How does one handle the request of a hospital ward for the preparation of sodium citrate solution 30% in ampoules? Concentrated sodium citrate solutions are used as catheter locks on dialysis wards of hospitals. By filling the lumen of the catheter with such a solution the formation of blood clots is prevented and the flow is maintained. Sodium citrate solution is an alternative for a concentrated heparin solution and should be preferred because of the anti-microbiological effect [21]. Citra-Lock® is available as a medical device. This product contains 46.7% sodium citrate and is CE registered

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class IIb. Are there justifiable reasons to prepare the solution? This could be, for example, when the marketed product is associated with more side effects due to the higher concentration, or is delivered in a container that is hard to use in practice. If these of other justifiable reasons are absent, then the marketed product is to be preferred. Information about medical devices is generally not as accessible as information about licensed medicines. If a pharmacist has to decide about a medical device being used in a way that is not included in the instructions for use, he therefore often has to contact the manufacturer. The new regulation (EU) 2017/745 came into force in 2017. This means that all medical devices will have to undergo thorough, independent assessment of safety and performance before they can be sold on the European market. Also new rules on traceability are proposed and public information on products available on the EU market [22].

2.5 Essentials Pharmacy preparation allows the doctor and pharmacist to provide individualised and tailor-made pharmaceutical care. The preparation of a medicine in the pharmacy fills a need when the licensed pharmaceutical preparation is not available or when a licensed pharmaceutical preparation does not satisfy a specific situation. Upon receipt of a request from the doctor, the pharmacist must examine the situation and decide whether the request is appropriate and judge the level of risk associated with proceeding with the request. However, the pharmacist must also consider the risks of not supplying a medicine which may lead to the patient not receiving treatment. Further discussion with the medical team may be needed. The pharmacist must make every effort to ensure that the medicine produced is of appropriate pharmaceutical quality and is fit for the intended purpose. An approved or authorised formula should be used wherever possible. Where such formulae are not available, steps should be taken to minimise risk where possible e.g. restricted shelflife, fridge storage (if applicable), use of licensed starting materials etc. The usual support offered by pharmacy computer systems is limited if local formulae are used, and the pharmacist may need to consult a range of reference sources when considering the appropriate indications, doses, likely side effects and contra-indications. Whether the request is for a medicine or other type of preparation, the pharmacist is responsible for ensuring that the final product supplied is of acceptable quality and backed by the best possible evidence base.

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11. BNF for Children. BMJ Group. http://www.bnf.org. Accessed 20 May 2022 12. Alldred DP, Barber N, Buckle P, Carpenter J, Dickinson R, Franklin BD (2009) Care home use of medicines study (CHUMS). Medication errors in nursing and residential care homes–prevalence, consequences, causes and solutions. Report to the Patient Safety Research Portfolio, Dept of Health 13. Single Convention on Narcotic Drugs, 1961, as amended by the protocol amending the single convention on narcotic drugs, 1961; United Nations Convention against Illicit Traffic in Narcotic Drugs References and Psychotropic Substances 1988. https://www.unodc.org/pdf/ convention_1961_en.pdf. Accessed 20 June 2022 1. Roman MJ, Dinh A (2001) A 1,000-fold overdose of clonidine 14. Veitch NC, Smith M, Barnes J, Anderson LA, Phillipson JD (2013) Herbal medicines, 4th edn. Pharmaceutical Press, London caused by a compounding error in a 5-year-old child with attention-­ 15. Directive 2004/24/EC of the European Parliament and of the deficit/hyperactivity disorder. Pediatrics 108(2):471–472 Council of 31 March 2004 amending, as regards traditional herbal 2. Anon (1998) Baby dies after peppermint water prescription for medicinal products, Directive 2001/83/EC on the Community colic. Pharm J 260:768 code relating to medicinal products for human use. https://eur-­ 3. Plausibilitätsprüfung für Rezepturarzneimittel, Beispiel. Tabellen lex.europa.eu/legal-­content/de/TXT/?uri=CELEX:32004L0024. für die Rezeptur. Fassung (2022) Deutscher Arzneimittel-Codex/ Accessed 20 June 2022 Neues Rezeptur-Formularium (NRF). In: Govi (Imprint) in der Avoxa– Mediengruppe Deutscher Apotheker GmbH Eschborn. 16. European Medicines Agency. Human regulatory. Herbal products. http://www.ema.europa.eu. Accessed 20 June 2022 Deutscher Apotheker Verlag, Stuttgart 4. Bouwman Y (2013) Risk assessment forms for pharmacy prepa- 17. Lau HS, Riezebos J, Abas V, Porsius AJ, De Boer A (2000) A nation-wide study on the practice of euthanasia and physician-­ ration. Eur J Hosp Pharm 20:A58. https://doi.org/10.1136/ assisted suicide in community and hospital pharmacies in the ejhpharm-­2013-­000276.161 Netherlands. Pharm World Sci 22(1):3–9 5. Commission Implementing Directive 2012/52/EU of 20 December 2012 laying down measures to facilitate the recognition 18. Regulation (EU) 2019/6 of the European Parliament and of the Council of 11 December 2018 on veterinary medicinal products of medical prescriptions issued in another Member State. Official and repealing Directive 2001/82/EC. https://eur-­lex.europa.eu/eli/ Journal of the European Union. 22.12.2012. L 356/68, and Annex reg/2019/6/oj/eng. Accessed 20 June 2022 L 356/70. http://eur-­lex.europa.eu/LexUriServ/LexUriServ.do?u 19. Veterinary Medicines Guidance. The cascade: prescribing unauri=OJ:L:2012:356:0068:0070:EN:PDF. Accessed 20 June 2022 thorised medicines. https://www.gov.uk/guidance/the-­cascade-­ 6. Kinderformularium. Nederlands Kenniscentrum Farmacotherapie prescribing-­unauthorised-­medicines. Accessed 20 June 2022 bij kinderen. http://www.kinderformularium.nl. Accessed 20 20. Regulation (EU) 2017/745 of the European parliament and of the June 2022 council of 5 April 2017 on medical devices, amending Directive 7. European Paediatric Formulary (PaedForm) European Directorate 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) for the Quality of medicines & Healthcare. https://paedform.edqm. No 1223/2009 and repealing Council Directives 90/385/EEC and eu/home. Accessed 20 June 2022 8. Pharmazeutischen Laboratorium des Neuen Rezeptur-­ 93/42/EEC. https://eur-­lex.europa.eu/eli/reg/2017/745/oj. Accessed 20 June 2022 Formulariums. Formelsammlung für Ärzte. 11te Auflage 2022. Govi (Imprint) in der Avoxa– Mediengruppe Deutscher Apotheker 21. Uhlenbrock S, Bichsel G (2006) Trinatriumcitratlösung zur Blockade von Hämodialyse-Kathetern. Krankenhauspharmazie GmbH, Eschborn 27:144–154 9. Medicines for Children Research Network U.K. http://www.medi22. European Commission, DG health and consumers, public health, cinesforchildren.org.uk medical devices. https://ec.europa.eu/health/medical-­devices-­ 10. van der Sijs H, Guchelaar HJ (2002) Formulas for calculating body sector_en. Accessed 20 June 2022 surface area. Ann Pharmacother 36:345–346

Questions 1. Describe the considerations when you assess a prescription 2. Prepare a structured approach to assess a prescription 3. Mention reasons not to prepare a product

3

Availability of Medicines Helena Jenzer, Stefan Groesser, and Nenad Miljković

Contents

3.11 Legislation of Pharmacy Preparation

47

3.1

Accessibility and Availability

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3.12 Preparations’ Categories

48

3.2

The Pharmacist’s Mandate to Provide Medicines 3.2.1 Mandate 3.2.2 Medicines Shortages (Also Referred to as Drug Shortages) 3.2.3 Bioequivalence Considerations for Coping with Shortages

24 24

3.13 Feasibility of Pharmacy Preparation

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References

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28 35

Abstract

Availability of Medicines with a Market Authorisation 3.3.1 Market Authorisation (Formerly “Registration”) 3.3.2 Reimbursement

36 36

3.4

Availability of Investigational Medicinal Products

38

3.5

Availability of Unlicensed Medicines

39

3.6

Availability of Orphan Medicines 3.6.1 Orphan Medicines 3.6.2 Neglected Patients 3.6.3 Improving Accessibility in Lowand Middle-Income Countries

41 41 42 43

3.7

Medicines Import

43

3.8

Preparation of the Remaining Necessary Medicines

44

Organisation of Pharmacy Preparation

45

3.3

3.9

3.10 Importance of Pharmaceutical Production in Hospitals

H. Jenzer (*) Bern University of Applied Sciences BFH, Bern, Switzerland Hospital of Psychiatry, University of Zurich, Zurich, Switzerland e-mail: [email protected] S. Groesser School of Engineering, Bern University of Applied Sciences, Biel-Bienne, Switzerland e-mail: [email protected] N. Miljković Institute of Orthopaedics Banjica, Belgrade, Serbia European Association of Hospital Pharmacists (EAHP), Brussels, Belgium e-mail: [email protected]

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Fundamental changes and new challenges have been emerging in the last decades as a result of the globalisation of markets and of production, new economic doctrines, tight budgets, development of information technology, as well as the Covid-19 pandemic. This has caused a down-shift in the security of supply. Hospital pharmacists now have to cope with medicines shortages and struggle to ensure availability of the medicinal products for the patients. Medicines are made available as authorised medicines, pharmacy preparations, or investigational medicinal products. For many diseases active substances are available, and yet groups of ‘neglected’ patients or special patient groups will not receive the medicines they need. If a patient needs a medicine, which is not on the national market, it may be imported from abroad or prepared in a pharmacy. Complicated rules for reimbursement (in some countries), which are nationally determined, and long procedures render import a laborious way to make medicines available for the patient. To be reimbursed some countries require that medicines are to be shown whether they are efficacious, appropriate and economic. Medicinal products are produced as unlicensed medicines according to GMP and PIC/S guidelines to cover such shortages. The European Association of Hospital Pharmacists (EAHP) has dedicated a big effort to animate and harmonise pharmacy production. The need for flexibility in preparation and manufacturing processes and the added value of a broad range of pharmacy production have been clearly underlined by the Council of Europe’s resolution CM/ResAP (2011)1 on quality and safety assurance requirements for medicinal products prepared in pharmacies for the special needs of patients(1). Council

© Springer Nature Switzerland AG 2023 P. Le Brun et al. (eds.), Practical Pharmaceutics, https://doi.org/10.1007/978-3-031-20298-8_3

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of Europe – Committee of Ministers. Resolution CM/ ResAP (2011)1 on quality and safety assurance requirements for medicinal products prepared in pharmacies for the special needs of patients. (Adopted by the Committee of Ministers on 19 January 2011 at the 1103rd meeting of the Ministers’ Deputies. https://wcd.coe.int/ViewDoc. jsp?id=1734101. Accessed 20 Oct 2021). What Is New This chapter was based on the chapter “Availability of medicines” in the 2015 edition of Practical Pharmaceutics by Helena Jenzer and V’Iain Fenton May. New in this chapter are the outcomes of both COST Action CA15105 (Medicines shortages) and the Swiss national COST / SNF project (political report). The reimbursement chapter is extended by the aspect of passing on parts of discount attributed by providers. The lessons learnt from disturbances and disruptions of the pharmaceutical supply chain during SARS-CoV-2 pandemic are added. The subsidiary power of intervention of a national economic supply office is explained in case of failure of the private sector. Furthermore, the introduction in the art of foresight in complex economic systems, simulation as applied in business engineering is added. And last, a number of approaches to prevent and manage medicines shortages situations are added. Learning Objectives The reader should be able • To distinguish inaccessibility and unavailability • To identify root causes of medicines shortages • To derive approaches to prevent and manage shortages situations by elimination of the root causes • To recognise the importance of wise stock keeping of licensed medicines and starting materials for hospital pharmacy preparation

3.1 Accessibility and Availability Once a new chemical entity is detected and approved for treatment of a disease, it has to become accessible as well as available. Normally, in a first step, active substances are made available to manufacturers and hospital pharmacies as active pharmaceutical ingredients which are used to manufacture or prepare licenced medicinal products or unlicenced hospital pharmacy preparations. In a second step, medicines are then made available for patients as authorised medicines or as pharmacy preparations (unlicensed medicines). Medicinal products are available and disposable to patients and consumers in the country where they are licenced and approved for market-access. Preparations are available for in- and out-patients of a hospital. The European Association

of Hospital Pharmacists (EAHP) has dedicated a big effort to animate and harmonise pharmacy production. The need for flexibility in preparation and manufacturing processes and the added value of a broad range of pharmacy production have been clearly underlined by the Council of Europe’s resolution CM/ResAP (20161)1 on quality and safety assurance requirements for medicinal products prepared in pharmacies for the special needs of patients  (1).  Accessibility however describes whether a patient or a group of patients may have the opportunity to be provided with the active substance or the medicinal product. In a number of low- and middle-income countries, many of such therapeutic agents are not accessible. Market logic thrives that only medicines with sufficient return on investment will be marketed. However, health care logic requires pharmacists to provide their patients with necessary medicines. Regulations on therapeutic agents cover medicines for clinical research, marketing authorisation, import, and traffic between European countries (parallel imports). If medicines are not available as authorised medicines, various options such as compassionate use or parallel trial programme can be considered. The authorisation of medicines for orphan diseases is promoted by the orphan drug regulations. Reimbursement, situated at the interface of both public health and social insurances, is another driver for availability or non-availability of medicines.

3.2 The Pharmacist’s Mandate to Provide Medicines 3.2.1 Mandate Based on favourable cost-benefit and risk-benefit assessments for both public and individual health, a pharmacist is mandated for the legal provision of medicines used to treat his patients. This scope is defined by Acts, Ordinances or Decrees, national or regional health care needs. In hospitals, provision is formalised in the formulary, currently defined by a therapeutic agents’ committee. This formulary includes medicines, controlled medicines, devices, chemicals, disinfectants, and ethanol in various concentrations and presentations. The performance of a hospital pharmacy has to be available any time without any disruption. Each pharmacy should be responsible for ensuring that a locally agreed list of products should be available to satisfy health care needs of the population even in times of accidents, catastrophes, or pandemics (Table  3.1). Stockpiled medicinal products included in such a list must be agreed by the emergency department and ICU, anaesthesia, and hospital pharmacy. The selection can be established by adapting international or national lists of essential medicines, common electrolyte

3  Availability of Medicines

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Table 3.1  Preparations recommended to be kept minimally on stock for provision in case of accidents and catastrophes Product Acetaminophen/paracetamol 16 Tbl. 500 mg Acetaminophen/paracetamol infusion solution 1 g 100 ml Amoxicillin/clavulanic acid 1 g Ad 20 Tbl Amoxicillin/clavulanic acid infusion solution 1.2 g 5 Ad Amp Amoxicillin/clavulanic acid infusion solution 2.2 g 5 Ad Amp Atracurium besylate injection solution 5 Amp 2.5 ml Bupivacaine injection solution 0.5% 5 Amp 20 ml Ceftazidime vial 2 g Ceftriaxone 2 g vial Cefuroxim injection solution 1.5 g i.v. vials Ciprofloxacin infusion solution 0.2 g 100 ml Clarithromycin injection solution 500 mg i.v. Amp Clindamycin injection solution 600 mg 3 Amp Desflurane 6 bottles 240 ml Dihydralazine mesylate 25 mg 5 Amp Diphtheria tetanus toxoid combination pre-filled syringe Dobutamine concentrate infusion solution 250 mg Epinephrine/adrenalin injection solution 1 mg/ml 10 Amp 10 ml Etomidate injection solution 10 ml 10 Amp Fentanyl injection solution 0.05 mg/ml 5 Amp 10 ml Flucloxacillin injection solution 1 g 10 vials Glucose 5% NaCl 0.9% 2:1 PP 1000 ml Glucose 5% PP 1000 ml Glucose infusion solution 5% PP 100 ml Haloperidol injection solution 5 mg i.m./i.v. 5 Amp 1 ml Hydroxyethyl starch 6% infusion solution 500 ml Imipenem/cilastatin 500 mg 10 Amp 20 ml Isoflurane inhalation solution 250 ml iv Line set Ketamine injection solution 50 mg/ml 5 vials 10 ml Lactated Ringer’s solution infusion solution 1000 ml Lactated Ringer’s solution infusion solution w/o air 1 L Lidocaine CO2 injection solution 2% 10 Amp 20 ml Lidocaine injection solution 1% 10 Amp 5 ml Lidocaine injection solution 2% 5 ml w/o cons 10 Amp Lorazepam 20 Tbl 1 mg Lorazepam injection solution 4 mg/ml i.v. 10 Amp Mefenamic acid 500 mg 100 Tbl Mepivacaine HCl 20 mg/ml 50 ml Metamizole sodium injection solution 50% i.m./i.v. 10 Amp 2 ml Metronidazole infusion solution 500 mg 100 ml

Minimal amount stored 400 9600 180 750 350 100 30 250 800 2800 400 150 100 8 25 300 180 20 40 600 150 1800 350 100 100 2000 60 80 15,000 15 500 1800 30 400 120 400 75 50 100 500 1400 (continued)

Table 3.1 (continued) Product Midazolam injection solution 5 mg/ml i.m./i.v. 10 Amp Midazolam injection solution 50 mg/10 ml i.m./i.v. 5 Amp Morphine HCl 10 mg/ml 10 Amp 1 ml NaCl 0.9% irrigation 1000 ml NaCl 0.9% infusion solution 1 L NaCl 0.9% infusion solution w/o air 1 L Norepinephrine/noradrenaline injection solution 0.1% 10 Amp 10 ml Pancuronium bromide injection solution 2 mg/ml 50 Amp 2 ml Pentothal sodium 2.5 g 12 vials Piperacillin/tazobactam 2.25 g vial Propofol injection solution 1% 5 vials 20 ml Propofol injection solution. 2% vial 50 ml PVP iodine 10 Gauze pads 7,5 × 22.5 cm PVP iodine alcoholic solution 5 × 1000 ml PVP iodine solution standardised 500 ml PVP iodine solution standardised 120 ml Ringer’s solution irrigation 1000 ml Rocuronium bromide injection solution 50 mg 12 vials Ropivacaine injection solution 0.2% 5 Bag 200 ml Ropivacaine injection solution 0.75% 5 Amp 20 ml Sevoflurane liquid 250 ml Silver sulfadiazine cream 50 g Succinolated Gelatine infusion solution 500 ml Sulfamethoxazole/trimethoprim forte 10 Tbl. Sulfamethoxazole/trimethoprim injection solution i.v. 10 Amp 5 ml Suxamethonium 100 mg 2 Amp 2 ml Tetanus hyper gamma globulin 250 units syringe 1 ml (or corresponding amount of gamma globulin)

Minimal amount stored 100 50 500 600 1800 600 10 50 8 120 300 1500 20 75 150 250 1600 15 25 25 60 100 80 150 80 80 15

This table is an example for minimum amounts stored for a 500,000 people region, extracted from a hospital’s internal list. It may vary depending on further regional resources and supply time

infusions or highly specific therapeutic agents such as anti-­ infectives, which in combination with resuscitation procedures and technical resources can be life-saving. The capacity of a stock of medicines needed to cover the needs in catastrophes or accidents should be calculated from the number of inhabitants living in the catchment area where the hospital is situated [2]. For comparison with the list of essential medicines see the WHO model list [3]. The WHO Model List provides an evidence-based model upon which countries can base their own national essential medicines list, e.g. the list of essential medicinal products required to be notified as defined by the Swiss Federal Office for National Economic Supply and by the platform of the Swiss acts and ordinances (Table 3.2) [4, 5].

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Table 3.2  Extract of the list of essential medicines as defined by the Swiss Registration Office for life saving medicines and as applied by the Swiss Federal Office for National Economic Supply Anatomical Therapeutic Chemical (ATC) Code A07A A12CC02 B02BD B02AA02 C01CA24 C07AB02 H01BA02 H01BB02 J01 J02 J04A J05AB06 J05AB14 J05AH02 J06BA02 J06BB01 J06BB02 J06BB03 J06BB04 J06BB05 J07 L01BA01 L01BC05 L01DB01 L01DB03 L01XA01 L01XA02 L01XX19 L04AA04 M03AB01 M03AC09 M03CA01 N01AB07 N01AF03 N01AH N01AX03 N01AX10 N01BB02 N01BB03 N02AA01 N02AA03 N02AA05 N02AA55 N02AB02 N02AB03 N05BA01 N05BA06

Denomination Intestinal Antiinfectives Magnesium sulfats (parenteral formulation) Blood coagulation factors Tranexamic acid (parenteral formulation) Epinephrine (Adrenaline) Metoprolol (parenteral formulation) Desmopressin (parenteral formulation) Oxytocin (parenteral formulation) Antibacterials for systemic use Antimycotics for systemic use Medicines for treatment of tuberculosis Ganciclovir Valganciclovir Oseltamivir Immunoglobulins, normal human (for intravascular administration) Anti-D (rh) immunoglobulin Tetanus immunoglobulin Varicella/zoster immunoglobulin Hepatitis B immunoglobulin Rabies immunoglobulin Vaccines Methotrexate Gemcitabine Doxorubicin Epirubicin Cisplatin Carboplatin Irinotecan Antithymocyte immunoglobulin (rabbit) Suxamethonium Rocuronium bromide Dantrolene Desflurane Thiopental Opioid anesthetics (parenteral formulations) Ketamine Propofol Lidocaine (parenteral formulation) Mepivacaine Morphine Hydromorphone Oxycodone Oxycodon und Naloxone Pethidine Fentanyl Diazepam (parenteral and oral liquid formulations) Lorazepam (parenteral galenic form) (continued)

Table 3.2 (continued) Anatomical Therapeutic Chemical (ATC) Code N07BC02 R03CC02 S01AD03 S01JA01 V03AB14 V03AF03 V08AA V08AB V08BA V08CA V08DA

Denomination Methadone Salbutamol (parenteral formulation) Aciclovir (ophthalmic formulation) Fluorescein (ophthalmic formulation) Protamine Calcium folinate (expressed as Folinic acid) Watersoluble, nephrotrophic, high osmolar X-ray contrast media Watersoluble, nephrotrophic, low osmolar X-ray contrast media Barium sulfate (with and without suspending agents) Paramagnetic contrast media Ultrasound contrast media

Imminent or manifest shortages of medicinal products figuring on this list must be notified to the Office

Furthermore, a short-list of essential medicines for defined patient groups should be considered. Such a list could become crucial in major shortages situations, e.g. pandemics. The European COVID-19 drugs calculation tool was developed by a team of Italian hospital pharmacists for this reason, as an aid for the estimation of the medicines needed during the SARS-CoV 2 pandemic [6]. A psychiatric hospital [7] may be able to work in austerity and shortages situations with basic therapeutic agents such as: • Tranquillisers –– Oxazepam –– Lorazepam • Antipsychotics –– Aripiprazole –– Haloperidol –– Olanzapine –– Paliperidone –– Quetiapine –– Zuclopenthixol • Antidepressants –– Amitritptyline –– Duloxetine –– Escitalopram –– Ketamine –– Lithium –– Trazodon • Antiepileptics –– Valproic acid • Opioid analgetics –– Methadone • Stimulants –– Methylphenidate

3  Availability of Medicines

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Table 3.3  Weighting over time of hospital pharmacists’ contributions to shared responsibility and improved outcomes Clinical pharmacy Production, quality control, quality assurance Provision and supply chain Special tasks according to individual skills

1960 + +++ ++ +

As a rule, medicines used in bigger amounts in hospitals are commercially supplied by industry, smaller amounts and ad hoc orders by wholesalers, see Chap. 39. Some tasks delegated to the hospital pharmacist may be fulfilled by centralised services for allied partners due to economic or effectiveness reasons. The frame for this duty has to be flexible enough to attain a fast-track distribution within the institution and a fast dispensing of medicines to the patient. Thus, not only medicine supply, but also the medication process and consequently the prevention of medications errors, are multidisciplinary tasks within patient care and integral elements of the mandate [8]. Direct-to-pharmacy and direct-to-­ hospital provision are considered as being more resilient to disruptions (due to a more efficient and diversified buffer capacity of the supply chain) and faster than full-line- or short-line-wholesalers, reduced-wholesale arrangements, or single-channel systems [9] (see Sect. 3.2.2). The core of the mandate shows some shifts throughout decades (Table 3.2). The traditional role of the hospital pharmacist still covers production, analysis and assessment of the quality and safety of medicines. It includes the whole supply chain from purchase to pharmacotherapy, and even to disposal of wastes of unused or expired medicines. The complex environment of public health is particularly evident in hospitals. Supply, reconstitution, preparation from raw materials or from adapted products, and correct use are a matter of multidisciplinary contributions of many professionals to the benefit of the patient. They require a specialisation as well as life-long learning to remain in a strong and competent position within a care team. Graduate pharmacists have to pass a postgraduate specialisation to get ready to cope with challenges and tasks inherent to the hospital domain. Fundamental changes and new challenges have been emerging for pharmacists in the last three decades as a result of the globalisation of markets and of production, of new economic doctrines as well as of the development of information technology. This has brought with it a shift in the security of supply and in the hospital pharmacist’s requested and mandatory tasks (Table 3.3). These tasks have become more challenging as new pharmacokinetic and pharmacodynamic knowledge was published and as biopharmaceutic relevant characteristics of highly active ingredients and products can be better anticipated (interactions, drug monitoring, adverse drug events). Therefore, in addition to pure logistics, the hospital pharmacist focusses more and more on rational and economic medicine use in pharmacotherapy and phar-

1980 ++ ++ + ++

2000 +++ ++ ++ +(+)

2020 +++ +++ +++ ++

macovigilance. Today, hospital pharmacists, due to their status as being a medical profession, are established in multidisciplinary clinical care teams together with physicians, medical technicians, social therapists, nurses, physiotherapists, clinical nutritionists, language and speech therapists, and midwives. In the timeline of a hospital stay, clinical pharmaceutical services begin with medicines reconciliation at admission and go to medication review as well as clinical nutrition support and many more along the hospital stay. Mainly in hospitals, medicines use is assessed more and more critically and differentiated. Finally, the mandate is enlarged, where suitable, according to special skills of the pharmacist. In the past 20  years, investments in hospital pharmacy equipment have often been called off, whereas outsourcing has been favoured to keep fixed costs small and to optimise balances. From the 1990s, financial interests dominated more and more the patient-centred outcome objectives defended by physicians, pharmacists, other health care professionals and the patient himself. The freedom of action for the hospital pharmacist had been redefined and became more restricted. Whereas the finished product was analytically and statistically controlled until the seventies, systematic GMP-­ regulated quality management was applied and inspected thereafter according to international pharmaceutical cooperation inspection schemes (PIC/s) to warrant a constant batch quality as predefined by specifications.

Quality, GMP and risk prevention are tightly linked together. Risk management is an enabler of quality management. Anticipating risks well warrants a high quality level. Instead of former error cultures aiming to punish failures, which were focussing on individual so-called active errors, today’s culture aims to prevent errors before they occur. Individual active errors such as slips (i.e. errors of schematic behaviour, e.g. fatigue, stress, lapses in concentration, competing distraction (“multitasking”)) and manifest mistakes (i.e. errors of attentional behaviour, e.g. lack of experience, insufficient training, negligence) are hardly preventable on its own. Coping with errors therefore considers more and more the root causes of errors in the system. Risks arising from system errors (so-called latent errors) comprise inconsistencies and pitfalls of institutions or design (e.g. those represented in the organigram, in the (continued)

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establishment’s management, or in tough requiring regulatory pressure), insufficient technical resources (e.g. staffing, equipment, design of men-machine interfaces), or insufficient human resources (recruitments of insufficiently qualified personal, missing training opportunities, work overload, fear of punishment). Total quality management systems consider more and more human  – machine interfaces such as many computer-aided hardware, software applications, and/or decision support systems, be it in manufacturing or in the pharmaceutical supply chain. [10]. See also Chaps. 35 and 36.

The (hospital) pharmacist is still mandated to control the supply chain due to legal requirements and due to the object medicinal product which needs more than pure logistic procedures. However, this might sometimes be challenging to convince and instruct those supply chain operators who consider medicines to be no different from any other commodity. Procurement nowadays takes place in an environment that is faced more and more by budget restraints and external paralysing constraints, induced by unwanted dependencies of third-party suppliers and sometimes even medicine shortages. In case of outsourcing hospital-internal pharmaceutical provision to third-parties’ suppliers, no guarantee to supply the right medicine in time to patients is warranted. Important financial resources would be needed to reactivate lost know-­ how and requalify neglected technical equipment in case of return to formerly smoothly operating workflows. However, neither time nor unbudgeted finances are readily available in situations such as medicines shortages. Consequently, re-­ adaption may cost more than ever could have been saved.

responsibility. US President Obama signed the Executive Order 13,588 instructing the FDA to require from manufacturers adequately advanced notices of discontinuation of certain prescription medicines and to review more quickly modifications of the production processes of these medicines [17]. These requirements comprised an obligation to notify and inform on medicines shortages, but do not include a disclosure of the reasons nor of the decisions which lead to a withdrawal of products from the market. An adequate announcement is requested in cases where only one provider for a medically necessary active ingredient is available. The FDA has created a task force for a strategic planning [18] and the EMA reflected particularly on shortages caused by GMP compliance problems [19]. As a result, 38 shortages could be prevented in 2010, 195  in 2011, and 150  in 2012 (up to November), but more has to be done to obtain a sustainable troubleshooting [20–24]. The same trend followed in 2018. According to the University of Utah’s Drug Information Service (UUDIS), a miminum of 150 shortages per year is occurring in the USA [25, 26]. Anti-infectives were most frequently in shortages from 2001 to 2016, particularly in intensive care units and emergency care facilities, with cefalosporines as the most affected among the antibiotics between 2001 and 2013, according to the University of Utah Drug Information Service (UUDIS) [21, 27, 28].

3.2.2.1.2 Medicines Shortages Situation in the EU In Europe not only isolated cases are in the focus, but examples representing all therapeutic groups. In Belgium, some 30 medicines are regularly in short supply [29]. In the Netherlands, they are monitored and published on a website. From 2004 to 2011, more than 1400 products were published. The number increased from 91 in 2004 to 242 in 2011. The duration of a shortage increased from 139 to 242 days in the 3.2.2 Medicines Shortages (Also Referred same period. Substitution (62%), alternatives (25%) and to as Drug Shortages) pharmacy preparation (2%) have been the method of choice to cope with such situations [30]. Classic alkylating, anti3.2.2.1 Deterioration of Medicines Shortages metabolic or topoisomerase-inhibiting antineoplastics with a Situations long time market presence and vaccines are the products for Medicines shortages (also referred to as drug shortages) have which there is the most concern on the steadily growing list. become a global phenomenon that has grown steadily and Pharmaceutical expertise succeeded in finding a suitable become a crisis in terms of delivering patient care. solution in 90% of all cases [31, 32]. To bridge a gap arising from a case of medicines shortage will take 1–7 h [33]. In any 3.2.2.1.1 Medicines Shortages Situation in the USA case, as a medicine from the hospital formulary has been Shortages increased sharply in the USA from 61 in 2005 to selected due to a favourable cost – benefit ratio, alternatives 178  in 2011 and further to 754  in 2014, with piperacillin-­ are in general cost-intensive compared to the standard prodtazobactam not being available for several months affecting uct. A simple intermediate substitution of a medicine on the 50% of the world market  following an explosion in the formulary costs 1800€, a definite s­ ubstitution between 3800€ Chinese manufacturing plant. The rate of shortages of anti- and 4690€ (figures from Germany) [28, 34–38]. microbials increased from 2001 to 2013, totalling 148 More than 500 shortages were registered in France in reported antibiotic shortages [11–16].  2017, and almost 1500  in Italy in 2018 [39, 40]. Between In 2011, the situation prompted authorities to intervene in 2012 and 2018, up to 63.4% of shortages in France were the market and remind manufacturers and suppliers of their related to medicines present at the market for an extended

3  Availability of Medicines

period of time. Anti-infective medicines for systemic use, central nervous system medicines, cardiovascular medicines, antineoplastic medicines and immune-­modulators, represent more than 50% of all shortages in Europe [41]. In 2015, a European Medicines Shortages Research Network addressed causes and debugging strategies by the bottom-up approach of COST (cooperation in science and technology) Action CA15105 which joined together many stakeholders and particular interests along the supply chain. The COST platform was sustained by nationally funded research projects which aim to respond to clinical, financial and quality of life interests, to achieve analytical clarity on disruption causes, to simulate decision making in order to anticipate new shortages, to reflect on best coping practices, and to approach to improvements of the situation by novel approaches such as System Dynamics and the repromotion of hospital pharmacy manufacturing and preparation. In Switzerland, the national funding of the COST Action focused on round table negotiations with the stakeholders. The aim of this national research project was to contribute to improvements of medicines supply security by proposing to the political actors and to the interested population solutions for the most important root causes, i.e. the identification of erroneous incentives and stepping out from coping strategies to true solutions [42–44].

Compared to 86% of hospital pharmacists in 2014 reporting medicine shortages to be a problem in everyday healthcare services provision, 90% and 95% of them reported the same problem in 2018 and 2019, respectively [45]. A significant increase with 91.8% hospital pharmacists in 2018, compared to 86.2% in 2014 in Europe stressed out that medicines shortages pose a significant problem in their hospital pharmacy [45].

In 2019, 95% of hospital pharmacists, 72% of physicians, 62% of nurses and 89% of other healthcare professionals from 39 European countries faced problems in delivering healthcare due to shortages, as many as in 2012. More than 80% of hospital pharmacists experienced shortages with products from one manufacturer more than three times according to the EAHP Survey in 2019, with delays in care (42%), suboptimal treatment (28%), cancellation of care (27%) and increased length of stay (18%) as major consequences for the patients. This was confirmed by the patients themselves in one of the first research conducted in Europe on patients’ perspectives related to shortages and healthcare professionals coping strategies [45, 46].

29

The major challenge is to override the economic incentive system in place which is aligned in such a way that participating stakeholders are motivated to manoeuvre themselves into a deadlock situation. A critical issue today is that the key players do not collaborate sufficiently to guarantee a security of supply of essential medicines. What could support an improvement of supply security is a systems perspective to understand and loosen the deadlock situation as well as to create innovative incentives on a legal and regulatory level. In order to provide the optimal treatment and appropriate substitute, healthcare professionals need to have public access to information on medicine shortages, which have their root causes in the industrial step of the pharmaceutical supply chain, as to prevent patient harm and promptly mitigate shortages [47]. Based on EAHP Survey from 2019, medicines mostly affected by shortages were antimicrobials (63%), oncology medicines (47%) and anaesthetics (38%) [45]. Small markets are particularly sensitive to shortages. High registration and regulation affairs cost for market admission may tempt suppliers to economise in countries with low volumes of sales. One of the biggest Swiss university hospitals experienced 172 cases of medicines shortage in 2011, i.e. 3 cases per week, with the involvement of 51 suppliers, and with multiple shortages for some products. An out-of-stock medicine was not available between 21 and 335 days. Withdrawal from the market in a country such as Switzerland may be an alert for an upcoming critical situation in the European Union [31].

Deterioration of medicines supply safety is as noticeable in Switzerland as it is at the global level. This fact was recognised at an early stage of medicines shortages. With the Postulate Heim (12.3426) of 4 June 2012, co-signed by 28 members of parliament and adopted on 28 September 2012, the Swiss Federal Council was commissioned to analyse the supply situation of medicines in Switzerland in a report and to show how the Confederation can support the cantons in the supply of medicines. In the report on the security of medicine supply of 20 January 2016, the Federal Council concluded that the supply of medicines in Switzerland can be described as good to very good. However, the number of not available medicinal products – although registered at Swissmedic – increased from July 2017 (270 shortages notified) threefold to 767  in January 2020. When Covid-19 pandemia became a global threat in February and March 2020, the Swiss population and economy was made aware of (continued)

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a major national supply problem, not only with life-­ saving medicines, but also with further medicinal products and protection material such as FFP2 masks and cover-all suits. The inability to supply the Swiss population sufficiently made evident, that medicines supply safety depends too much on the outside-­ European international provision and that neither Europe nor Switzerland had enough own sources [42].

3.2.2.1.3 General Worldwide Supply Chain Disruptions As a result of the Covid-19 pandemic, worldwide supply chains were and are still heavily disturbed. Goods apart from medicinal products such as electronic chips and motherboards, or car components, suffered from disruptions in raw material, production, or transportation. Suez Canal blockade by a stranded container ship or low lorry drivers’ resources after Brexit in the UK were encountered. Basically, patterns as seen for medicinal products, emerged more and more with a certain delay in non-health sectors. Reengineering of parts of the different supply chains may be more promising if a holistic approach could be chosen for all global industrial sectors.

3.2.2.2 Causations of Medicines Shortages Situations Drivers of shortages pose significant risks to patient treatment [48, 49]. A recent case of the potential human carcinogen N-nitrosodimethylamine (NDMA) found in valsartan and ranitidine, demonstrated how difficult it is to predict manufacturing problems at local or global scale, especially when there is a single manufacturer that produces medicines for numerous Marketing Authorisation Holders (MAHs). Consequently, unexpected shortages were provoked, which only underlined the need for healthcare professionals to be promptly informed on potential shortages as to mitigate them properly [50–53]. On the other hand, limited capacity or discontinuation in production, followed by the pharmaceutical mergers allows more predictability and makes shortages more manageable [48]. The supply chain can be parted into processes such as production of active ingredients, manufacturing, wholesaling, clinical need, and measures of poor clinical, financial and quality of life outcomes arising from shortages. Causes are multifaceted ranging from production disruptions, natural disasters, discontinuations, difficulties created by various restrictive and disincentive legal, trade and pricing frameworks, unfavourable decision making in medicines production and trade, insufficient stocks, as well as conflicts of interest of stakeholders. Some of the claimed causes are occurring as a result of pitfalls arising at the roots of the sup-

ply chain. It is ultimately required to identify these root causes to prevent shortages effectively. The most “famous” among a list of multifactorial reasons [48] which have induced a medicines shortage, were: • Quality or availability problems related to active ingredients or to production processes or equipment (e.g. heparin contamination [54] and propofol case [55]) • Demand spikes (e.g. oseltamivir following flu pandemic scenarios [56]) • Unintended consequences of contracting by large buyers leading to the loss of small suppliers • Overstocking due to panic buying (especially when alternatives are lacking) • Parallel trade of medicines [57, 58] • Discontinuation decisions taken by industry, possibly related to pricing or other macro-economic factors (like high cost and low gain) • Globalisation of supply chains creating new vulnerabilities • Covid-19 • Lacking alternatives The latter may be explained by the fact that capital bound in a stock is considered as an important item with potential to optimise a financial balance. The risk of losing capital is reinforced by the availability of new technologies and new products, which might diminish or degrade the stock’s value due to a loss of demand for old products. However, medicines are not comparable to electronic or technical devices with short half-lives. There is no doubt that general economic rules are hardly applicable, one to one, for medicines and in no way for special product groups such as antidotes, narcotics, antineoplastics, total parenteral nutrition, and anti-­ infectives, if no equivalent and equally expensive medicine is available. Thus, commercial items and lean production are not convincing arguments for small stocks. It is obvious that most medicines in short supply represent highly active ingredients and the shortage is linked to safety and quality issues. Deviations from GMP uncovered on inspections requiring improvements and investments in a manufacturing plant may play an important role in decision making about maintaining production or not. The risk and the consequences for the supply chain, which arises from cases of a major quality problem and paralysis of a big manufacturing plant after a merger of several smaller sites, is more threatening as less alternatives will be available. The risk of affecting a global market will be clearly higher in case of one big facility affected instead of many smaller ones. It is even worse, if production is relocated into “low-cost” countries, which have less or no experience in a reliable industrial production free from major operational disruptions. From a delivery, security and ethical point of view, the economic pressure on medicines production has led to a disastrous situ-

3  Availability of Medicines

ation, which is to everyone’s disadvantage (clinical, financial and health outcomes). An option for pharmacies to immediately cope with the vacuum caused by a stop of industrial manufacturing is only possible if the equipment and quality assurance of its production is regularly updated and the capacity of those still able to produce is sufficient to cover the needs of non-producing pharmacies as well. One of the important deliverables of the Swiss COST Action research project was a mind map summarising ­causations attributed to the supply chain steps. The original mind maps in English can be downloaded from the EAHP website [59]. In addition to the pure medicines shortages research performed, important pitfalls arising from the Covid-19 pandemic have been identified [9]: • Contingencies initiated by states led to disastrous situations –– The legal basis for the government’s decision is the epidemics act. –– State-controlled non-professional supply by-passes traditional established supply-chains for vaccines programs or masks supply. –– Vaccination programs lasted months instead of weeks. • EMA and/or Swissmedic should request from licence holders to stock-keep APIs and designate backup API suppliers from licence holders. • Industrial research-active industry tends to concentrate on high-return-on-investment products such as blockbusters, ATMP, gene- and cell-therapies, and to abandon market authorization for small molecule APIs. Industry should rather transfer licenses for small-sales-volume products to small-and-medium enterprises in order to adapt the production scale to the enterprise size. • No comprehensive GPS monitoring of international medicinal products transportation existed during the pandemic waves. Locating freshly produced, stranded medicinal products, or stockpiled pools of potentially available medicinal products was not done or was not possible.

3.2.2.3 Approaches to Prevent and Manage Medicines Shortages Situations 3.2.2.3.1 Approaches to Exploit Alternative Medicinal Products Sources As no one of the actors of the supply chain is capable of covering the entire pathway alone, stakeholders need to exchange views, communicate and seek common solutions. Therefore, EMA and HMA in 2019 adopted two joint guidelines related to shortages (“Guidance on detection and notification of shortage of medicinal products for Marketing Authorisation Holders (MAHs) in the Union (EEA) and “Good practice guidance for communication to the public on medicines’ availability issues”). Both documents emphasise

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the need of establishing proper communication channels between MAH, the Regulatory Authorities and the public, aiming at providing sufficient information on medicines affected by shortages in terms of its characteristics, availability of alternatives, affected population of patients and patient’s safety risks involved due to substitution or interruption/delay of treatment [60, 61].

Relief of shortages suffering may arise from less restricted importation frames. Import options depend on the current national legislation and are always related to a lag time for delivery, if substitution cannot be an option. For example, Swissmedic, may temporarily approve imports of EMA-admitted medicines from another European country for an intermediate interval of time in which the local supply chain is interrupted. There are further disadvantages related to importation, in addition to the extra administrative effort. The importing country may be causing a shortage in the exporting country if they are prepared to pay a higher price. In some countries, an imported product can be excluded from reimbursement, if the assurance company is not in agreement.

The role of pharmacists to cope with medicine shortages is a determining one if consequences such as decreased safety and worse outcomes are to be prevented. The Swiss Association of Public Health Administration and Hospital Pharmacists (GSASA) has edited guidelines to cope with medicine shortages [62] and, supported by the most important Swiss Associations and Federations of pharmacists (Swisspharma), physicians (FMH), and hospitals (H+), has signed an agreement with the leading associations of pharmaceutical industry (ASSGP, Intergenerica, Interpharma, Scienceindustries, and Swiss Association of Importers of Proprietary Medicines (VIPS)) to readily provide pharmacies with active ingredients for extemporaneous individualised preparations and small scale stock production of commercially not available formulations or dosages [63]. Whatever the reason for a shortage may be, adaptation from both sides is highly recommended, i.e. from the supplier and from the supply chain responsible in a hospital. All pharmacies should have an up to date, written policy for managing shortages [64, 65]. That policy should include the need for a risk assessment, which will assess the impact of the shortage and the actions that should be taken to limit those effects. Pharmacists have a responsibility not to do anything that will exacerbate a shortage situation. They have a responsibility to co-operate with any nationally agreed scheme to reduce the effect of such shortages.

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• For the future, it is indispensable to build high capacities to buffer shortages. Economic concerns such as low stock-bound capital must have less weight. –– Incentives for stockpiling, for losses due to expiry date, for rolling stocks, et cetera might be subsidised by the state. –– Short one-step supply pathways better than multiple serial or parallel small stores. • Backup compounding and preparation options should be exploited (Fig. 3.1). An important deliverable of the Swiss COST Action research project was a mind map summarising systematic attempts at a solution to prevent medicines shortages. This mind map has been submitted to the competent authorities in Switzerland that have to warrant the national economic supply (FONES.  Federal Office for National Economic ­ Supply). The original mind maps in English can be downloaded from the EAHP website [66].

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3.2.2.3.2 Approaches to Mitigate Medicines Shortages COST Action CA15105 produced a toolkit for healthcare professionals aiming at providing a more structured approach to manage shortages. It involves processes that need to be conducted before and throughout a shortage, including medicine substitution and patient follow-up and monitoring (Fig. 3.2) [67].

The evaluation of the health risks stemming from shortages followed by therapeutic substitution should be conducted by pharmacists, physicians and other healthcare professionals through a systematic approach in order to evaluate healthcare professionals’ readiness in mitigating shortage's impact on patient care. This could be achieved via providing the series of preconditions necessary for a successful shortage management (Fig. 3.3) [68]. Risk-mitigation strategies aiming at proactively assessing risks stemming from shortages, have recently received a growing awareness [69]. However, these risks do not involve clinical risks occurring just after or prior to medicine substitution due to a shortage. A variability in implementing a variety of risk assessment techniques in German hospitals has been reported, with more than 30% of hospitals not applying either FMEA or RCA within clinical risk management [70]. Developing systems aimed at gathering information on the shortages should not be the sole tool to manage shortages. Providing proactive measures for existing an emerging shortage should be also in place as to address clinical and safety risks occurring when a patient does not receive therapy or appropriate alternatives [69]. Therefore, proactive risk assessment is crucial in detecting and understanding all risks related to potential medicine shortages in respective healthcare settings assuring patient safety and optimal health outcomes [71]. European health authorities and the pharmaceutical industry supported by the European Medicine

Fig. 3.1  Backup compounding and preparation options. The current supply chain from an industrial manufacturer via pre-wholesaler by direct-to-hospital supply to the patient is disrupted in a shortage situation (green dotted line). Alternative supply options are provision of bulk material (red lines and bold green line) by the manufacturer,

start-ups, universities, a national supply source (in Switzerland FONES), or the use of high purity substances such as biochemical, food, or analytical qualities (orange lines). As long as raw material is available, hospital pharmacies will be able to provide medicinal products

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Organizational assessment

Follow-up/patient monitoring

Substitution protocols

Communication assessment

Historical data analysis

Fig. 3.2  Shortages mitigation cycle in a healthcare facility

Fig. 3.3  List of procedural and organisational outputs needed for a successful mitigation of shortages

Agency (EMA) and Parenteral Drug Association (PDA) proposed a prospective risk assessment-based approach to manage potential shortages, focused on their prevention through production and quality control assessment [72]. On the other hand, risk assessment should allow for considering all causes of shortages, their frequency and duration as well as utilisation patterns of a particular medicine affected by a shortage in a respective healthcare setting. Furthermore, the risk assessment’s outputs and proposed mitigation strategy require effective and open communication among healthcare professionals involved in managing shortages [35]. Such an approach based on comprehensive risk assessment may provide a proactive management/prevention of shortages and enable identification, assessment and control of risks emerging from shortage, hence preventing and reducing harm to patients. It is conducted via medicine’s criticality assessment based on its therapeutic indication, likelihood of shortages, clinical needs of a patient and

a­ vailability of potential alternatives. Moreover, a set of measures aimed at controlling/correcting risks related to shortages is expected to be delivered throughout risk triage [72]. Guidelines dedicated to managing shortages in the USA, Australia and Europe, developed by the ASHP, the TGA and the EMA are based both on risk assessment in manufacturing/supply chain, and in therapeutic substitution when providing alternative treatment [49, 60, 61, 71, 73]. In the UK, the NHS' Department of Health and Social Care, performs risk assessment within medicine’s procurement on a national scale, avoiding duplicated risk assessment at local hospital level [74]. Furthermore, the Rapid Response Report issued by the National Patient Safety Agency's (NPSA) proves how important for healthcare professionals is to proactively assess risk factors related to treatment delay, which may occur due to a shortage and cause patient harm from delayed and omitted doses of medicines [75]. Meanwhile, the Dutch Ministry of Health has announced

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new regulations for stock keeping of medicines. This capacity increase is aiming at a 10 week supply in place by January 2023 (personal mail communication). 3.2.2.3.3 Systems Dynamics’ Contributions to Forecast Supply Chain Threats

Simplicity is the ultimate sophistication (Leonardo Da Vinci)

Nature is an inspiring prototype for laminar flow. Natural laws are demonstrating where interventions in the supply chain should go. A river has a steady flow as long as the riverbed is broad and obstacles impede flow only marginally. The situation changes when the river has to pass a gorge. The flow becomes wild and turbulent. The same is applicable for congestions in traffic situations. Following nature’s laws, losing the capacity to provide sufficiently the downstream need with narrow diameters of the supply channels equals high risk for supply security. For supply chain management this means that medicines availability is at high risk of shortages in case of mergers of the producing industry, insufficient scale of production plants, low afflux of starting material, of minimal stocks, tendering, narrow channels, scarce channels. It has been detected that a formerly available back-up system, i.e. the hospital pharmacy production, is being resurrected in many hospitals, as no intermediate scale production site is able to offer sufficient capacity to rapidly fill gaps arising from shortages. Medicinal products’ supply chain is a complex object for which forecasting is not possible with simple linear methods or equations. Linear foresight of medicine use suffers from inaccuracies such as incomplete variables included in the linear models. Typically, this was seen when bovine spongiform encephalopathy (BSE) depleted the biologic source of both milk and gelatine supply. Nobody would deny that the world has become more complex during the past decades due to technological change and globalisation. With digitisation, interconnectivity between people and things has rapidly increased. Dense networks now define our technical, social, and particularly, business environments. Complex objects have to be addressed by methodologies capable of accounting for the complexity. The idea of applying complexity science to management was first discussed in the 1990s. Popular literature propagated the ideas of complexity theory—in particular, the notion of the “butterfly effect” by which a small event in a remote part of the world could trigger a chain of events that would add up to a disruptive change in the whole system. Managers’ eyes were opened to the reality that organisations are not just complicated but complex. Complex systems can be found anywhere multiple actors interact, are subject to feedback dynamics, and are influenced by time delays between cause and effect [76]. It is much more precise to simulate complex networks by differential rather than linear equations, which should include the most important variables that might have an input on stocks along the supply chain. System Dynamics

(SD) is a time-dependent simulation tool that captures important system variables and their interactions as explicitly defined differential equations. Qualitative causal maps are a first step to understand the system’s dynamics, but are in most cases not sufficient. Such qualitative causal maps focus on including different perspectives on a challenge, e.g., medicine shortages, that needs to be managed. However, they cannot help to estimate the time-delays, magnitudes, or the impact of policy interventions. For this, simulation modelling using the system dynamics methodology is necessary. System Dynamics (SD) is one of the most popular, widespread and validated simulation (computational) methods and cannot be overlooked when discussing forecasting of supply chain threats. The basic idea of SD is to capture the underlying characteristics of complex dynamic systems to understand them better and foster desirable developments [77]. To capture all these characteristics SD-models must represent nonlinearities, long-term patterns, feedback dynamics, and the internal structure of a system. This is technically achieved by mapping the system’s stockand-flow structure. The use of SD is particularly appropriate because the modelling method has its roots in the field of supply chain management and forecasting. Remarkable in this area is the concept of demand reinforcement or the bullwhip effect. More recently, the concept of remanufacturing has gained attention with many contributions on closed value chains in consumer electronics and consumer appliances [78, 79]. Some consumer products, termed essential consumer goods, are crucial to sustaining health or even life. A shortage in supply of essential consumer goods can have tangible negative impacts on society. A simulation performed as part of the project applies this topic to the case of inexpensive, generic, injectable oncological medication shortages in Europe. Cancer patient outcomes including survival rates, as well as treatment costs, are significantly influenced by oncological medicines shortages. This simulation (Fig. 3.4) proposes the first causal model showing the underlying structure of the European inexpensive, generic, injectable oncological medications supply chain. It identifies the most common causes of supply shortages and develops a quantitative supply chain model with the ability to simulate the most relevant causes of identified shortages. Finally, key performance indicators are proposed to evaluate the sustainability of the supply chains in question from several perspectives. With this simulation model, a first forecasting model for the complex medicine supply chain has been developed. Even though the (continued)

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Fig. 3.4  Aggregate structure of the medicines sourcing section of the hospital pharmacy echelon (Model of cytotoxics supply chain in a hospital pharmacy)

problem of medicine shortages is well structured, documented, and universally acknowledged, a lack of data in the specifically modelled situation has deterred any quantitative solution-oriented studies. However, a structural model can provide reliable insight in cases where data is unavailable or unreliable through relying on structural validation. Therefore, the simulation calls for a quantitative comparison and robust sensitivity analysis of all primary and secondary causes of medicines shortages using the proposed model. Furthermore, both existing and new policy recommendations regarding oncological medicines shortages in Europe should be studied quantitatively [80].

3.2.3 Bioequivalence Considerations for Coping with Shortages Medicines Reconciliation at the patient admittance seeks to match a patient’s medication with the hospital assortment, Medication Review to assess the effects of the current medication with the objectives of a personalised pharmacological treatment. Substituting some of the medicines outside the hospital’s formulary is a current task in hospital pharmacies. It is also a current option to overcome shortage situations. However, alternatives are not always feasible and available. When shortages arise, risk increases through substitution from

other excipients, other concentrations, foreign language vials, or untranslated package leaflets. Generic substitution is defined as the mutual substitution of medicinal products having the same active ingredient, the same strength, and the same dosage form. Different salt forms of the same medicinal product are considered to be the same active substance, unless the salt forms in question exhibit substantial differences in terms of efficacy and activity. [81] The term pharmaceutical alternative is used to define the medicinal product with the same active ingredient, although the dosage form, salt form or strength may vary, such as substitution from a tablet with immediate release to controlled release, or from capsule to oral solution. Therapeutic substitution is the mutual substitution of medicinal products with different active ingredients, both of which may or may not belong to the same therapeutic group. In general, medicines, which passed bioequivalence testing, should be substitutable with their generically equivalent, when needed. The European Medicines Agency (EMA) and the Food and Drug Administration (FDA) consider products to be bio-equivalent if, based on the same molar dose, a generic substitute or pharmaceutical alternative exhibits a similar rate and degree of availability at the site of action, and can thus be said to have a similar efficacy and degree of safety. (continued)

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Market approval of generic medicines requires pharmacokinetic bioequivalence studies. In bioequivalence studies, the product to be investigated is compared to an innovator product. Products are regarded as bio-­equivalent if the 90% confidence interval of the AUC-­ratio and Cmax are within 80–125% of the reference product. However, in conjunction with certain active substances or certain situations, it may be preferable to avoid even the slightest risk (e.g. ciclosporine). Classical bioequivalence studies have limited value in indicating equivalent efficacy and safety for biosimilars (generic version of biological medicines).

3.3 Availability of Medicines with a Market Authorisation 3.3.1 Market Authorisation (Formerly “Registration”) In Europe as in many other parts of the world, medicines can only be marketed if they are authorised [82–84]. A company, which wants to market a medicinal product, has to apply for a marketing authorisation at the European Medicines Agency for the European Union [85] or at the Medicines Agency of a country. The Medicines Agencies scientifically evaluate the medicine and grant an application if they have safety, quality and efficacy assessed positively. The process, which formerly was called registration of medicines, now is to be spoken of as granting of a Marketing Authorisation. And the company is the Marketing Authorisation Holder (MAH). The applicant has to be authorised for manufacture, import, wholesaling, export or trading in foreign countries, according to the activities and the locations of the business. The applicant has to submit a product dossier with all necessary data defined in a guideline [86]. Such an authorisation is limited in time. It is renewed after an inspection. It nominates the Qualified Persons and specifies limitations or conditions. To be allowed to produce a medicinal product the manufacturer or the importer needs a Manufacturing License, which is bound to compliance to GMP (see Chap. 35). If the Medicines Agency judges positively, the European Commission or the National Authorities grant a Marketing Authorisation for the entire European economic area (EEA; EU Member States plus Switzerland, Norway, Iceland and Liechtenstein) or just for the country itself. Conversely, local authority’s approval does not grant any authorisation for other EU member states. Non Member States ratify EU legislation such as on the pharmacopoeia to adapt national legislation and may have treaties with the EU, USA, Australia

or Singapore [87, 88]. European registration is possible for all medicines which meet certain requirements [89]. It is however compulsory for specific medicinal products such as biotechnologicals, orphan medicinal products, antineoplastics or medicines for autoimmune diseases. The product is recognisable by a EU-authorised medicinal product registration number (for example: EU/1/04/276/001). Product information on European authorised medicines can be found at the EMA Regulatory and procedural guidance index [90]. This information comprises: • A list of authorised presentations of the medicinal product • The summary of product characteristics (SmPC) • The patient leaflet and labelling of the product • The European Public Assessment Report (EPAR) A medicinal product with a national marketing authorisation has a national registration number, e.g. RVG 11,985 in the Netherlands. Product information about nationally authorised medicines can normally be found on national websites. National Medicinal Agencies refer to the website of the EMA if the product has obtained a European Marketing Authorisation.

3.3.2 Reimbursement The manufacturer is allowed to market a product with a Marketing Authorisation. The company sets the price of the medicine. This is done either by a calculation which takes into account the manufacturing and marketing costs, including a profit allowance, or it is set in comparison to competing products of the same kind, especially, if the authorities negotiate with the company about that price. National pricing and financing policies are guided by a WHO policy [91]. Regulations for reimbursement are still nationally determined. In many countries the approaches are more or less the same: the type of health insurance system, pharmacoeconomic data, the effectiveness of the medicine, and the need in relation to similar medicines are determinant. The cost of a medicine for patients may be regulated differently from the community situation. The inclusion in clinical guidelines of a specific medicine is of major importance in order to obtain reimbursement. The key questions by the assessor are about an added benefit and about the medical value. In the Netherlands, the medical value is assessed unofficially by means of the Dunnings Funnel, which evaluates the candidates by defined criteria, e.g. necessity, effectiveness, safety, cost-­effectiveness commonly calculated as incremental cost-effectiveness ratio (ICER), and social arguments such as budget impact or own responsibility [92]. However, pharmacoeconomic studies consider often added values only, but not the harm that is put

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on patients. Harm seems to cost as much as three times the gain. The societies’ willingness to pay for an additional quality-­adjusted life year gained (QALY) varies from country to country ranging from 20.000 to 100.000 euro for the western world, also depending on the economy [93–97]. The added medical benefit may be assessed in comparison with existing therapies in terms of effectiveness, adverse effects, experience, applicability and ease of use. In France, the first step of reimbursement decision and price fixing process is confirming the medical benefit obtained (SMR, service médical rendu) which determines the reimbursement percentage, whereas the second step evaluates the improvement of the medical benefit over existing medicines (ASMR, amélioration du service médical rendu), which is used for price negotiations [98]. In contrast to the methods of healthcare evaluation in other countries, the UK National Institute for Health and Care Excellence (NICE) does not evaluate all interventions as they reach the market. NICE has published guidelines on how it will select interventions for review. This includes the following key questions [99–101]: • Is the technology likely to result in a significant health benefit, taken across the National Health Service (NHS) as a whole, if given to all patients for whom it is indicated? • Is the technology likely to result in a significant impact on other health related government policies (e.g. reduction in health inequalities)? • Is the technology likely to have a significant impact on NHS resources (financial or other) if given to all patients for whom it is indicated? • Is the institute likely to be able to add value by issuing national guidance?

Many countries, e.g. Switzerland, have compulsory social accident and health insurance systems for every citizen. The choice of the insurance company is free. The insurer has to accept every request and is not allowed to reject applicants with increased risks in the basic part. Rejection is only possible for coverage by complementary insurances. Physicians, pharmacists, midwives, chiropractors, laboratories, hospitals, several institutions for acute or chronic care for in- or outpatients, or ambulance transporters are care providers approved from the concordat of insurers. Care providers are licensed to bill the insurer for approved services at prefixed rates according to lists such as TARMED and SwissDRG (German modification) issued by the Federal Office of Public Health (FOPH) [102, 103]. To be put on the list of pharmaceutical specialties, a request has to be addressed to the Swiss Federal Social

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Insurance Office, which is advised by the Swiss Federal Drug Commission. Applicants have to follow a manual and submit several documents, e.g. a summary of product characteristics, the grant of marketing authorisation, key facts, clinical overview, non-clinical overview, most relevant clinical studies, epidemiologic data of the disease to be treated, clinical guidelines, and pharmacoeconomic studies [104]. It is stipulated in the Swiss federal act on health insurances, that medicines and care are required to be efficacious, appropriate and economic to be reimbursed [105]. The latter requirement is checked by means of price comparisons between the requested Swiss price and those applied in Denmark, Germany, the Netherlands, Great Britain, France, and Austria [104]. The costs of materials, duration of preparation, quality control, investment in premises, training, quality assurance et cetera determine the basic cost of pharmacy preparation. As with the reimbursement of licensed medicines there is a distinction between in-patient and out-patient supply. Pharmacy preparations used in hospitals could be considered to be part of the reimbursement for the therapy as a whole. Anyhow, the hospital pharmacist normally has to find his payment within the hospital organisation. In community pharmacy most pharmacy preparations are reimbursed by the health insurer, according to the Tax price with a surcharge according to the performance cost system. Reimbursement for unlicensed medicines will be handled differently in most European Countries. There may also be differences between the reimbursement for hospital and public pharmacies.

Within the patient access and reimbursement schemes, risk sharing is fixed as outcome-based or financial-based agreement between the payer and the manufacturer. Financialbased agreements are possible on a fixed price, on a pricevolume ratio, on a price by diagnosis, on capitation fee, or on dose-quantity limits. Outcome-based agreements can be divided into evidence-development-based, conditional treatment continuation-based, or performance-based schemes. Most of these schemes are applied in Europe and Australia, followed by Canada and the United States [106, 107]:

• Evidence development schemes (34 schemes in use in 2010, regrouped into coverage-with-study or coverage-with-appropriateness determination approaches) –– Example taxanes: In 2000 in the UK, the use of taxanes for adjuvant treatment of early breast cancer was limited to randomised clinical trials. (continued)

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–– Example temozolomide: In 2001 in the UK, this active ingredient was only recommended as an initial chemotherapy for patients with brain cancer included in a clinical trial. –– Example risperidone: In 2003  in France, costs were covered, if evaluation studies on whether it helps patients stay on the medications were performed. In case of failure the manufacturer was to refund costs to the French ministry of health. –– Example human papillomavirus quadrivalent vaccine: In 2007  in Sweden, the manufacturer was asked to provide every 6 months additional data on ongoing and planned studies in order to determine the cost-effectiveness from a long-­ term perspective. • Conditional treatment continuation schemes (10 schemes in use in 2010) –– Example bortezomib: For the multiple myeloma indication, in the UK the manufacturer agreed in 2007 to reimburse the NHS in either cash or product for patients who did not respond, i.e. those who do not show a 50% decrease in serum M protein, after four cycles. Responding patients received additional four cycles. In 2009, the same agreement was fixed with the Scottish Medicines Consortium. –– Examples sunitinib and sorafenib: A hospital discount of 50% applies in Italy to the first 3 months of treatment. For responding patients the treatment is then reimbursed and the discount dropped. –– Examples of Alzheimer’s disease medicines: In Italy, during the first 3 months, patients starting Alzheimer’s disease medicines are assessed for short-term effectiveness. The medicines are provided free of charge by the manufacturer. If treatment goals are met after 3 months, treatment is continued for a maximum of 2 years and the costs reimbursed by the Italian Drugs Agency (AIFA). • Performance-linked reimbursement schemes (14 schemes in use in 2010, regrouped into pricing review, try-before-you-buy, or no cure  – no pay principles) –– Example statins: In 1998  in the US and in 2000 in the UK, rebates were agreed and refunds were promised if LDL cholesterol could not be lowered. –– Example bosentan: In 2004  in Australia, the price of bosentan for pulmonary arterial hyper-

tension was linked to the survival of patients followed in an observational study. –– Example risedronate sodium: In the US in 2009, the manufacturer agreed to reimburse for the costs of treating-related fractures.

In the past decade, pharmacotherapy has seen progresses and developments arising from new knowledge in the genome. New techniques such as CRISPR-CAS enable today’s gene- and cell-therapy which promises recovery from an inborn error. The economic outcome of these new therapies is not yet known. New price models such as payfor-­performance might limit expenses for public health. Otherwise, as these inherited diseases actually in the focus of gene- and cell-therapy are only indicated for a few patients, total cost may be kept more or less equilibrated, as it is the product of price and amount (Cost = Amount * Price). Few patients and high prices may yield similar total costs as low prices and high amounts.

3.4 Availability of Investigational Medicinal Products The manufacturing of investigational medicines goes together with phases I–III of the Clinical Trial Investigation, where pharmacokinetics and toxicology at different dosages is investigated and compared with the standard treatment or placebo treatment in a small group of healthy volunteers first, in a limited group of patients afterwards, and finally in a large group of patients. After completing investigation, the new medicine can be offered for approval and admission to the market (market authorisation). In phase IV Authorised Medicines are evaluated for the authorised indications, side effects and long-term value and will be monitored in clinical practice. This may occur by pharmacovigilance or by outcomes research in specific patient populations. As described in Table 3.4, currently 15 years may pass until a new chemical entity reaches the market. In the clinical phase of development of new chemical entities, medicines are developed by hospitals, universities, or pharmaceutical companies and administered to humans as “Investigational Medicinal Products (IMP)”. Each specific investigation has to be approved by an Ethics Committee. In the Netherlands, a national committee for clinical research has to assign a certificate of incorporation. In Europe, the administration of IMPs to human beings was regulated by Directive 2001/20/EC. On January 31, 2022, the new Clinical Trial Regulation No 536/2014

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Table 3.4  Phases of clinical research

Years approximately Test population

Purpose

Yield

Discovery Preclinical testing 6.5

Clinical trials Phase I 1.5

Laboratory and animal studies

20–100 healthy volunteers Determine safety and dosage

Assess safety, biological activity and formulations 5000 compounds evaluated

Phase II 2

Launching Phase III 3.5

100–500 patient volunteers

1000–5000 patient volunteers

Evaluate effectiveness, look for side effects 5 enter trials

Confirm effectiveness, monitor adverse reactions from long-term use

came into effect. It deals with the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. In addition to a large number of changes concerning the organisation of Clinical Medicines Research, this Regulation also includes an important change concerning the preparation of medicines for research (Article 61, fifth paragraph). For a number of processes, a GMP manufacturer’s license for investigational medicinal products is no longer required, provided the research takes place within a hospital or institution and in the same Member State. In short, it concerns [108]: 1. Repack or relabel 2. Prepare Radiopharmaceuticals for Diagnostic Application 3. Magistral or officinal preparations Appropriate regulations must be drawn up for each country to ensure that these processes take place properly so that the protection of test subjects and the reliability of data are guaranteed [108].Research with a non-licensed medicine without such an approval is not allowed. In Switzerland, a new act on human research entered into force as from 2014 [109]. The dossier of an IMP is called the Investigational Medicinal Product Dossier (IMPD). It describes the technological, pharmacological and toxicological properties of the product as well as the method of preparation. Importing or preparing IMPs by a manufacturer or a pharmacist requires a license/authorisation [110]. An authorisation as a wholesale trader in medicinal products is required, if the IMP originates from another ERA state (European Research Area). A Manufacturing Authorisation is requested, if the medicine is imported from a country outside the ERA. These authorisations are specific for a dosage form or for a preparation process. Preparation and quality control should be performed according to the IMPD. A Qualified Person (QP, see Chap. 25) has to release the product after import, preparation and quality control and to guarantee that all quality requirements are met.

Drug agency 1.5

Phase IV

Review process, approval

Additional post-marketing testing

1 approved

Pharmacies don’t need a Manufacturing License if the preparation of an IMP is limited to operations such as reconstitution, dilution and labelling, which have to be performed for the purpose of administration to the patient as defined in the IMPD.  These activities however must be carried out within the institution where this clinical trial is carried out and by a pharmacist who is employed within this institution [111].

In Switzerland, IMP production needs a Swissmedic manufacturing authorisation. To obtain such an authorisation for manufacturing in the frame of clinical trials, plants, fix and mobile installations, equipment, as well as qualifications and validations must be inspected by Swissmedic. The qualified person needs to be certified for his scientific background and GCP skills. The authorisation can be limited to a limited kind of galenic forms, e.g. non-sterile forms. Pure reconstitution and storage are facilitated, meaning that a mere cantonal manufacturing licence for small production scale is needed, as long as no further actions such as randomisation and blinding are executed.

3.5 Availability of Unlicensed Medicines Unlicensed medicines are medicines, including pharmacy preparation, which do not have a Marketing Authorisation. Patients who suffer from a disease, for which no licensed medicinal product is marketed, or who cannot enter a clinical trial, but one is either in a clinical trial or available abroad, may exceptionally get the unlicensed medicines from the manufacturer. This happens on the legal basis of a ­compassionate use program either on a named patient basis or to cohorts of patients. This regulation applies to patients

40

with a chronically or seriously debilitating disease or whose disease is considered to be life threatening. Compassionate use is a treatment option that allows the use of an unlicensed medicine. Compassionate use programmes cannot enter a clinical trial. They are intended to facilitate the availability to patients of new treatment options under development. To qualify for a compassionate use programme, the manufacturer calls on the national authorities for permission. The manufacturer must submit a request for the granting of a marketing authorisation or he must perform research in the context of a research programme with a cohort. Compassionate use procedures are also applicable for unlicensed medicines withdrawn from the market or for off-label use of licensed medicines. Reimbursement has to be clarified from case to case (see Sect. 3.3.2). Several options to get authorisations for named patients have been applied in the past and still are in practice in order to maintain the supply chain with the most important medicines. As long as they are classified as IMPs and thus not allowed on the market, patients may be treated in some countries, e.g. Switzerland, in a parallel trial programme or within an extended access. Procedures follow those for compassionate use and requests have to be submitted to the ethical committee as well. A parallel trial programme will always require Ethical Approval and would therefore be a Clinical trial in the UK.  Single cases different from compassionate need an authorisation but do not need an ethical committee approval. No marketing authorisation is needed, if the required medicine is a part of an approved formulary (formula magistralis or formula officinalis) produced on a small scale [112, 113], or if it is produced according to an own formula in small scale for own clients (see Sect. 3.11). Medicines from foreign countries made available to tourists from the same country to continue an existing treatment, are free from authorisation requests as well. In case of life-threatening urgencies, health professionals have the obligation to assist the affected person. If procedures will not resolve a problem in time, the use of unlicensed medicines may be approved by phone or mail contacts of inspectorates or of another direct supervising authority. Off-label use of a licensed medicine and unlicensed use of not-admitted or not-marketed medicines have several uncertainties in common. For neither one of them the intended use is described nor approved by the authorities (different indication, different dose, different application mode, different patient population, different pharmaceutical items, e.g. expiry date, solvent, etc.). Thus, the responsibility is attributed to the treating physician and to the (preparing) pharmacist, if he is or can be aware of the indication for which the medicine is given. They act under the obligation and duty of care and have to consider the state of the art. Adverse events have to be notified to the authorities. The legitimation of having acted the selected way must be justi-

H. Jenzer et al.

fied. Informed consent of the patient must be available. Information about reimbursement granting or rejection must have been given. The pharmacist’s duty is to validate the prescription, to consult the prescriber, to produce according to GMP, PIC/S or approved quality guidelines, and be responsible for the formula (Table 3.5), in the case of a prepared medicine [114]. Table 3.5  General requirements for off label and unlicensed use of medicines. Authorisations may differ according to national and local ordinances Authorisation Type status Off label use I Medicine with a market authorisation in the own country (Market Admission covering local use)

Legal basis

Requirements

Responsibility of No special treating physician authorisation Obligation and needed duty of care Prescription and Information of dispensing the patient according to Liability approved state of Notification the art of pharmaceutical and medical sciences Special II Medicine with authorisation market authorisation in a needed Authorisation for foreign country import needed Unlicensed use (compassionate use, parallel trial, extended access, individual case, medicines withdrawn from market) Small amounts No special I Medicine not Responsibility of authorisation admitted to own treating physician needed market, but Obligation and Authorisation for admitted in an duty of care import needed extra-European Information of To be used within country (USA, the patient the approved Canada, Liability indications Australia, New Notification Physicians and Zealand) pharmacist with II Medicine not allowance for admitted to own retail trade market, but admitted in an extra-European country (other than USA, Canada, Australia, New Zealand) III Medicine without market authorisation worldwide Market authorisation not needed Formula magistralis medicine according to prescription for individual patient or patient group Formula officinalis medicine according to an approved monograph Own formula medicine produced in small amounts for own clients or patients

(continued)

3  Availability of Medicines

41

Table 3.5 (continued) Type I

Authorisation status Active ingredient known, used according to scientifically approved indication

II

Active ingredient known, used in an indication beyond scientifically approved knowledge

III

Active ingredient not yet rated “for human use”

Legal basis Authorisation to produce needed

Requirements Strictly small scale Manufacturing according to c-GMP/PIC/S guidelines Responsibility, obligation and duty of care attributed to physician and pharmacist Liability Notification Documentation of scientific knowledge on the active ingredient Strictly small scale Manufacturing according to cGMP/PIC/s guidelines Responsibility, obligation and duty of care attributed to physician and pharmacist Liability Notification Notification to ethical committee Documentation of scientific knowledge on the active ingredient Strictly small scale Manufacturing according to c-GMP/PIC guidelines Responsibility, obligation and duty of care attributed to physician and pharmacist Liability Notification

3.6 Availability of Orphan Medicines The pharmaceutical industry decides on the basis of a cost-­benefit analysis, if the development and placing on the market of a medicinal product is profitable. The development of medicines for rare illnesses or for minor-

ity special patient populations (“neglected patients”), therefore generally does not get funded. Industrial providers however offer innovations for very small groups of patients at very high prices, e.g. products from recombinant technologies e.g. coagulation factor VII, monoclonal antibodies for oncology or immunology, products for gene- and cell therapy, and many more. Governments have designed programs to stimulate the development of these medicines.

3.6.1 Orphan Medicines Disorders which are rare, are called orphan diseases and the medicines intended for these diseases are called orphan medicines. An orphan disease is a serious, life-threatening or chronically debilitating condition which affects less than 5000–10,000 patients in the 750 million inhabitants in the EU [115]. Governments try to stimulate the development of orphan medicines with economic incentives through legislation on orphan medicines. It was hoped that this stimulant would encourage the market. However, the market is failing in this respect [116]. In trade, sellers get paid for what they sell. In care, providers get paid for what they do. No orphan medicinal product will be available without economic encouragement, at least the coverage of development and production costs. The European legislation is based on the economic motivation to put a medicinal product on the market. Public health arguments are secondary. If the market fails, health care and tax payers should take over and care for the patient in another way, e.g. by attribution opportunities and flexibility to prepare medicines in a pharmacy. Many case studies support a simplified handling for pharmacy prepared compounded medicines with a long history of effective use [117].

In some countries, enterprises can be commanded to provide medicines. This had been the case in the nineties with cladribine (2-CdA, 2-chlorodesoxy-­ adenosine), which was provided first by a current industrial supplier in the USA to treat hairy cell leukaemia as an alternative to interferon-alfa. Cladribine was not available in Europe at that time, neither as a product nor as an active substance. It took several weeks until the six-­step synthesis was developed and a hospital pharmacy product could be made available. The US-price of the marketed syringe was some 20 times as much as could be attained later by hospital pharmacy production with the specially synthesised substance [118].

42

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Today, the EU encourages the development of orphan medicines [119] with: • Advice and support on research protocols • EU-funded research • Free pre-submission meetings with persons or companies (“sponsors”) on authorisation applications • Reduction on the registration fee • Centralised EU procedure • Market exclusivity for 10 years • After-designation support To be eligible for these incentives, products should be designated through the orphan designation procedure. The EMA through its Committee for Orphan Medicinal Products (COMP) assesses at request by the manufacturer, if a substance might be designated as an orphan medicine for a specified orphan disease. The whole orphan designation procedure comprises the following steps [120]: • Sponsor notifies the Agency of intent to file. • Pre-submission meeting/ teleconference. • Submission of application; validation by the Agency (day 1). • Assessment/COMP meeting/ possible hearing/COMP opinion adopted (by day 60 or 90). • Opinion sent to the European Commission. • Commission decision granted (within 30 days). • Publication in EU Register on the Commission’s website; publication of public summary of opinion on the Agency’s website. After a positive assessment the manufacturer must follow the normal registration procedure, albeit that the clinical studies normally will be continued after the market authorisation has been granted due to the small number of patients. National incentives may be provided, e.g. reimbursement options. In Portugal, France and Belgium, all orphan medicinal products are reimbursed, in the Netherlands most of them (95%) [121].

Designated orphan products, indications and more than 1224 active substances are registered. Sixty are authorised for 52 rare diseases, 25 are withdrawn or suspended, 9 expired. Oncological products dominate. Within this class, no orphan medicinal product authorisation has been attributed to axitinib, crizotinib, erlotinib, gefitinib, lapatinib, pazopanib, vandetanib, vemurafenib. An orphan medicinal product authorisation has been assigned to dasatinib, imatinib, nolotinib, sorafenib [122].

3.6.2 Neglected Patients For many diseases active substances are available, and yet groups of patients will not receive the medicines they need. This refers not only to patients who cannot pay for the medicines, but also to various special patient groups, e.g. children and elderly. They need doses or dosage forms which differ from the available licensed medicines. In the wake of the WHO and DNDi, following the World Health Assembly in 2012 [123–125], the EU, national Governments and universities call for attention to be given to the development of appropriate medicines for these neglected patients. For the development of more medicines for children funding programmes have been started such as ERA-NET PRIOMEDCHILD in the EU [126] and in the Medicines for Children Research Network (MCRN) in the Netherlands and the UK [127]. From the WHO-report Priority Medicines for Europe and the World [128, 129]: … There is a wide range of existing evidence-based, very often off-patent, technologies that are heavily underutilised. Such technologies could be used to improve the ‘patient-friendly’ performance of a number of existing medicines, the use of medicines in paediatrics and geriatrics, and other areas where individualised time-dosing of medicines is required, e.g., patients with impaired liver or kidney functions, or patients with compromised immune systems…

Whereas agreements on patents and authorised production can be negotiated in cases of shortages (see section on shortages), this has so far not yet been possible in cases of national versus pharmaceutical industry interests on behalf of neglected patients. Patented medicines block the production of more affordable generic versions while more and more patients become sick or die because the medicines they need to stay alive are simply too expensive. Recently, much attention has been attracted by India’s efforts to increase access to medicines and implement a patent system in line with its public health needs. India is a critical producer of affordable medicines. Competition among generic producers in India has brought the price of medicines to treat diseases such as HIV, tuberculosis and cancer down by more than 90%. The majority of the antiretroviral medicines purchased by the U.S. government’s global AIDS program come from India, and more than 80% of the HIV medicines non-profit aid organisations use to treat more than 280,000 people with HIV in 21 countries are generics from India. The policies and decisions by India’s patent offices and courts to limit abusive patenting practices and increase access to affordable generic medicines are (continued)

3  Availability of Medicines

43

approved temporarily for importation in out-of-stock situations are made available in some countries like The Netherlands and Switzerland on resp. KNMP/Farmanco [133] or Swissmedic [134, 135]. From those medicines prepared in one of a selection of European hospital pharmacies, half to three-quarters are available in the market in another EU country, North America or Australia [136]. Although European legislation has been aimed at decreasing trade barriers since 2001, the purchase of medicines from other countries is anything but simple. A patient is allowed to travel abroad and buy an authorised medicine for personal use and import it into Europe, however, a pharmacist can only import a medicinal product if the amount does not exceed a maximal need for 1 month, or in larger amounts if he has a wholesale import authorisation. Finally, the complicated rules for reimbursement (in some Countries) and the amount of time the whole process takes, renders import a laborious way to make medicines available for the patient. If an imported medicinal product has been granted a Marketing Authorisation, the pharmacy can purchase it from a wholesaler established in the country or from the manufacturer. The packaging must meet the labelling requirements in the subject country, and the patient leaflet has to be written in one of the country’s languages. In a hospital, the patient leaflet and/or usage information are less important if information and skill is more readily available from a permanent pharmaceutical assistance and documentation than outside of a hospital. The pharmacist will then dispense the product to the patient. As a second option, a pharmacist or a whole3.6.3 Improving Accessibility in Lowsaler or a manufacturer can ask permission to import from and Middle-Income Countries the Competent Authority under the terms of the named International cooperation focuses on improving and acceler- patient regulation and on the following conditions: ating access to essential therapeutic products in resource • The physician considers it necessary that the patient constrained countries by strengthening the regulatory sysbelonging to his medical practice is treated with the tems. The Marketing Authorisation for Global Health medicinal product. Products is one component of this cooperation. Its approach • There is no adequate alternative medication for the medicis to involve regional National Medicines Regulatory inal product on the market. Agencies in this cooperation. In the past few years there have • The physician has requested a pharmacist to deliver the been many efforts to improve the accessibility of low-­ medicine in writing using the national model form. income-­countries to international pharmaceutical markets. • The pharmacist has presented the written request of the WHO, the European Parliament, EMA, and/or Swissmedic physician to the Competent Authority. together with foundations such as the Bill and Melinda Gates • The quantity of the medicinal product and the period durFoundation support and guide governments and authorities ing which it may be delivered to the doctor, has been of such countries through the regulatory strengthening to determined by the Competent Authority. facilitate market access [131, 132]. • The manufacturer, wholesaler or pharmacist keeps track of the quantity of the medicinal product, the name of the physician, the number of patients for whom it is intended, 3.7 Medicines Import and on the medicinal side effects observed. The costs of medicines purchased from abroad have to be If a patient needs a medicine, which is not on the national borne by the budget of the institution. In some Countries market, it may be imported from abroad or prepared in a these imported medicines are not reimbursed from social pharmacy. Lists of medicinal products made available and health insurance, unless the patient has an allowance or is subject to increased political pressure from the US government and pharmaceutical industry. Among the critical decisions can be found a 7-year-battle to claim a patent on the salt form of the cancer medicine imatinib, judged by the Indian Supreme Court as non-patentable, and a generic version of a kidney cancer medicine, which was made available for 97% less than the patented version. India’s health ministry has set up an independent expert committee to identify exorbitantlypriced medicines for which further compulsory licenses may be issued, relying on the Agreement on Trade Related Aspects of Intellectual Property (TRIPS) and the Doha Declaration on TRIPS and Public Health, both of which defend access to existing medicines by allowing countries to use flexibilities such as patent oppositions and compulsory licenses to overcome intellectual property barriers. The country must now deal with pressure from the multinational pharmaceutical industry trying to sue India in a foreign tribunal. The US Government has a policy of negotiating and exerting pressure on governments to give foreign investors the right to sue governments ‘known as Investor-State Dispute Settlement’ for high amounts of damages if a law or policy harms their investment [130].

44

H. Jenzer et al.

covered by an extra private insurance, specifically for that medicinal product.

3.8 Preparation of the Remaining Necessary Medicines A patient may need medicines which are not commercially available, neither in the country nor abroad, or which are temporarily not available, although a Marketing Authorisation is granted. To provide the necessary care to the patient, these medicines may be prepared by the pharmacist, either from raw materials or through adapting a licensed product. The need for this combined production-and-care task of the pharmacist is endorsed worldwide. Various references and lists from hospital pharmacy production units are published online [137]. The Formularium der Nederlandse Apothekers contains formulations for 200 medicines, which are prepared in the pharmacy because they are frequently needed but not on the market. It does not contain all the required pharmacy preparations. The total number of required, rational medicines which pharmacies have to prepare out of raw materials is estimated at 50 to more than 500. The estimate depends on the concepts ‘required’ and ‘rational’ (see Table  3.6 for examples of the vast variety of medicines provided by a Swiss University hospital pharmacy). Specials (unlicensed medicines) are being produced according to GMP and PIC/S guidelines and are becoming more and more important to produce, whereas extemporaneous preparations, prepared according to less strict standards, are becoming less common. There is a need for consensual standards of preparation practices and common monographs for preparations [138, 139]. The development of standard formulations is costly, but considerably cheaper than developing a medicine with a Marketing Authorisation. Table 3.6  Examples of the vast variety of medicines provided by pharmacy preparations only (extracted from a Swiss University Hospital’ internal list) Sterile products (large volume liquids ≥100 ml, aseptically prepared) Cardioplex injection solution PCA Fentanyl 20 mcg/ml injection solution Sterile products (large volume liquids ≥100 ml, autoclaved) Mepivacaine HCl 0.5%, 1% injection solution PCA Ketamin 5 mg/ml infusion solution PCA Ketamin 2 mg/ml/ MORPHIN 2 mg/ml infusion solution

Table 3.6 (continued) PCA Morphine HCl 2 mg/ml infusion solution PDA forte (or standard) infusion solution Polyelectrolyte infusion concentrate Sterile products (small volume liquids  90°) Fig. 6.11  Equilibrium of forces at the point P due to surface and interfacial tensions. The force vectors are shown as arrows

this will not happen. The particles can float when the air is not replaced. This phenomenon is called flotation. Poorly wettable and floating particles often adhere to the wall of the bottle neck. As a result, dosing is difficult with such systems. Pharmaceutical examples of poorly wettable substances are: phenytoin, sulfur, zinc oxide and barium sulfate. By adding a surfactant, the interfacial pressure can be reduced by which wetting is improved. To reduce the risk of foaming, surfactants that lower the interfacial pressure only moderately are mostly used. To improve wetting, surfactants with an HLB larger than 15 are used, such as sodium dioctyl sulfosuccinate (Aerosol OT ®), ethoxylated castor oil, poloxamer, sodium salts of higher alcohol sulfates (sodium lauryl sulfate) and polysorbates, but also polymers with interfacial activity as, for example hydrogel formers as methylcellulose, hypromellose, etcetera. A further discussion of these substances can be found in Chap. 7. In practice, propylene glycol or a thickening agent will lower the interfacial tension to a sufficient extent.

6.4.3 Micelle Formation and Solubilisation Surfactants are not only applied to reduce the surface or interfacial tension. They can also be used to increase the solubility of substances. When dissolved in water above a certain minimum concentration, aggregates of surfactants are formed, also called micelles. Lipophilic substances can be brought into solution (solubilised) using these micellar solutions. Micelles can be prepared as follows. Consider an aqueous solution of which the surfactant concentration is gradually increased. At low concentration of the surfactant, the molecules are predominantly located at the surface. If the concentration is increased, more of the surfactant molecules will be present at the surface and the surface tension will decrease. Above a certain concentration, however, the surface will be full and the extra molecules will migrate into the bulk of the solution. When this occurs, the surface tension will not further decrease. The surfactants molecules that migrate into the bulk of the solution form micelles. The structure of the micelles is such that the lipophilic part of the surfactant molecules is at the inside of the micelle, so that the thermodynamically unfavourable contact of the lipophilic part of the surfactant mol-

6  Physical Chemistry

ecules with the water molecules is minimal. The minimum concentration at which micelles are formed is called the critical micelle concentration (CMC). The exact shape of the micelles and the CMC differ from substance to substance but are usually spherical. Micelles have the size of colloids and also behave physico-chemically as such. This behaviour is discussed in more detail in Sect. 6.5.1. In an oil phase, micelles with the inverted structure can be formed, i.e. the hydrophilic part of the surfactant molecules is oriented towards the inside. These micelles are also called reverse micelles. Many poorly water soluble substances can, molecularly disperse or absorb into the core of the micelles. These micellar solutions are optically clear. This is called solubilization (Fig.  6.12). Examples from the Dutch formulary FNA are oral aqueous preparations with vitamin A (retinol palmitate) or D (cholecalciferol (Table  6.15)). Another example is a licensed oral mixture with ciclosporin.

109

Solubilisation may also be undesirable. Solutions containing polysorbate cannot be preserved with for example methyl or propyl parahydroxybenzoate. The preservative effect of these substances is inhibited by solubilisation or even nullified. With sorbic acid/sorbate, preservation is possible, provided that a higher than conventional concentration is used.

6.5 Disperse Systems Many liquid and semi-liquid pharmaceutical preparations are disperse systems. Disperse systems are defined as systems in which a substance is distributed as particles (discontinuous) into a dispersion medium (continuous). Three types of disperse systems will be discussed which are pharmaceuTable 6.15  Cholecalciferol oral solutiona 50.000 IU/mL [22] Cholecalciferol concentrate (oily form) 1000,000 IU/g Citric acid monohydrate Polysorbate 80 Potassium sorbate Star anise oil Syrup BP Water, purified Total

The order of mixing the components in this preparation is important in order to achieve solubilisation: first polysorbate to cover the flask with a layer, then carefully adding and mixing the cholecalciferol concentrate and star anise oil. The ratio between the amount of polysorbate and the cholecalciferol concentrate is also important.

This solution is actually a solubilisate

a

Fig 6.12  Micelle formation and its effect on the solubility of poorly water soluble substances

5.0 g 0.48 g 25 g 0.6 g 0.22 g 12.5 g 60.2 g 104 g (= 100 mL)

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tically relevant: colloidal systems, suspensions and emulsions. In both colloidal systems and suspensions, solid particles are dispersed in a liquid. The difference is that in colloidal systems the particles do not settle, while they do in suspensions. This difference is caused by the size of the particles. In colloidal systems, the particles are so small (1 nm – 1 μm) that the Brownian motion (diffusion caused by thermal energy) is stronger than the force of gravity so that they remain suspended in the liquid and do not settle. In suspensions, the particles are larger (>1 μm) and as a consequence the force of gravity is stronger than the Brownian motion which makes them settle (if the density of the particles is larger than that of the dispersion medium). Emulsions consist of non-miscible liquids. Two types of emulsions will be discussed: oil drops disperse in water (oil-in-water emulsion or o/w emulsion) and water drops disperse in oil (water-in-­ oil emulsion or w/o emulsion). There are also more complex structures such as w/o/w emulsions and bi-continuous systems. However, these systems will not be discussed.

6.5.1 Colloidal Systems 6.5.1.1 Lyophilic and Lyophobic Systems Colloidal systems can be divided into lyophilic and lyophobic systems. Lyophilic colloids have a strong affinity with the dispersion medium by which a solvation shell around the particle is formed. This process is called solvation and if the dispersion medium is water it is called hydration. A polysaccharide dissolved in water is an example of a lyophilic colloidal system. The solvation shell is formed by hydrogen bonds between the hydroxyl groups of the polymer molecules and the water molecules. Pharmaceutical examples are solutions of dextran, used as plasma expanders. Micelles are also lyophilic colloids. Example of such a system is the aqueous cholecalciferol oral mixture (Table  6.15). In these preparations, a lipophilic fluid is dissolved in an aqueous medium by incorporating it in micelles. Because this type of colloids falls apart on dilution to concentrations below the CMC, they are also known as association colloids. Lyophobic colloids have no affinity with the dispersion medium. Thus, in this type of colloids no solvation shell is formed around the particles. An example of lyophobic particles are colloidal gold particles (with a diameter of 1 nm – 1 μm) disperse in water. There are no hydrogen bonds or other interactions between the gold particles and the water molecules, so the solvation shell is missing. If the dispersion medium is water, lyophilic colloids and lyophobic are also referred to as hydrophilic and hydrophobic colloids, respectively. 6.5.1.2 Stabilisation of Colloidal Systems Basically, colloidal systems are not thermodynamically stable. The particles have the tendency to attract each other by Van der Waals forces and aggregation can take place. Yet

W. Hinrichs and R. van Gestel

there are many colloidal systems that can be stored for extended periods of time without this happening. This is because two stabilising mechanisms may play a role. Around lyophilic colloids a solvation shell is formed, which acts as a protective layer around the particles. This protective layer prevents the two particles from approaching each other too closely. In addition, the particles repel each other when they are electrostatically charged. This repulsion is not fully determined by the charge at the surface of the particle (Nernst potential) but by the charge at a small distance from the particle which is called zeta or ζ-potential. During the diffusion of the particle through the dispersion medium a layer of the dispersion medium around the particle is dragged along with it. Therefore, it is not the charge of the particle, but the charge of the particle together with this layer of dispersion medium that is relevant for the stability of the system. If the particle is charged and when ions are present in the dispersion medium, there will be more ions of opposite charge (counter ions) in the near vicinity of the particle than ions of the same charge due to electrostatic attraction. The charge of the particles is therefore neutralised to a certain extent. This neutralisation increases with increasing ionic strength. This implies that the zeta-potential is smaller than the Nernst potential and decreases with increasing ionic strength. If the dispersing medium contains polyvalent counter-­ions, the zeta-potential and the Nernst potential can even have opposite charges. The zeta-potential can also be influenced by the absorption of specific ions from the dispersion medium onto the surface of the colloidal particle. For example, if a positively charged surfactant adsorbs onto a positively charged colloidal lyophobic particle, the zeta-potential becomes larger than the Nernst potential. Moreover, the adsorption of surfactants onto lyophobic particles has a second effect. Because only the lyophobic part of the surfactant adsorbs onto the lyophobic particle, its lyophilic part is oriented towards the dispersion medium. This lyophilic part forms a protective layer by which the particles can approach each other less easily. This effect is called steric stabilisation. Surfactants usually do not adsorb onto lyophilic particles. However, by covalently linking hydrophilic polymers to their surface, we can also achieve steric stabilisation of lyophilic colloidal particles. A detailed description of the forces of attraction and repulsion can be found in literature [5, 21]. So a lyophilic colloidal system can be stabilised by two mechanisms, namely by a solvation shell and by electrostatic repulsion. This implies that a lyophilic colloidal system with a zero zeta-potential does not necessarily have to be unstable. This is because the stabilising effects of the solvation shell may be sufficient. A lyophobic colloidal system, however, lacks a solvation shell. A lyophobic colloidal system can therefore only be stable if the zeta-potential is sufficiently high (positive or negative).

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6.5.1.3 Destabilisation of Colloidal Systems A sol is a colloidal system in which the repulsion forces Table 6.16  Carbomer Gel pH 6.5 [23] between the colloidal particles dominate in such a way that Carbomer 35000 1 g they can move freely with respect to each other. Lyophilic Disodium edetate 0.1 g colloidal particles can be destabilised either by making the Propylene glycol 10 g particles more lyophobic or by reducing the zeta-potential or Trometamol 1 g Water, purified 87.9 g both. Lyophobic colloidal particles, however, can only be Total 100 g destabilised by reducing the zeta-potential. Lyophilic colloidal particles can be rendered more lyophobic by adding a fluid which is miscible with the dispersion medium but in groups by which the negative charge is neutralised which the colloidal particles are lyophobic (for example, and the hydrophilisation is counteracted. To prevent ethanol when the dispersion medium is water). The zeta-­ this, disodium edetate is added in (aqueous) carpotential of colloidal particles (lyophilic or lyophobic) can bomer gel pH 6.5 NRF (Table 6.16). be reduced by adding an electrolyte to the system. When a 2. At high ionic strength the (absolute) zeta-potential sol is partially destabilised, the forces of attraction are stronof carbomer will decrease, which may result in preger than the forces of repulsion. As a result, the particles will cipitation and is an example of salting-out of a no longer be able to move freely with respect to each other, colloid. but they will form a continuous three-dimensional network extending throughout the dispersion medium. Such a structure is called a gel and it is called a hydrogel if the dispersion Carbomer, carmellose sodium, hydroxypropylcellulose medium is water. This sol-gel transition can be observed by and other cellulose derivatives are examples of well-known the flow behaviour. Because the colloidal particles in sols polymers that form hydrogels. An overview of different gel move more or less freely with respect to each other, formers can be found in Chap. 7. Newtonian or pseudo-plastic flow behaviour can be observed. Gels exhibit a yield stress because first the continuous three-­ dimensional structure must be broken down before flow can DLVO-Theory occur. In this case plastic flow behaviour can be observed. Because the colloidal particles in a gel cannot move freely The destabilisation of colloidal systems can also be with respect to each other, a gel can be considered as a pardescribed with the DLVO (Deryagin-Landau-Verwey-­ tially or controlled destabilised sol. However, when sols are Overbeek) theory. This theory has been proposed for extensively destabilised a compact aggregate will be formed, lyophobic colloidal systems but can also be applied which will start to float or sediment depending on the density qualitatively to lyophilic colloidal systems. If the difference with the dispersion medium. They are no longer potential energy is plotted as a function of the distance considered as colloidal systems. This process is called of two particles, a curve is obtained as shown in salting-­ out when it is induced by the addition of an Fig. 6.13. electrolyte. This curve is established by adding the potential energies resulting from the attraction and repulsion forces to each other (with a negative potential energy meaning attraction and a positive potential energy repulsion). Suppose that two particles approaching Carbomer is a special hydrogel former. The chemical each other have too little thermal energy to pass the name for carbomer is polyacrylic acid. As such the maximum. In this situation they approach each other to polymer is poorly soluble in water. However, when a distance where the secondary minimum is located monovalent bases (e.g. NaOH) are added, the carboxand thus attract each other. Now two situations can ylic acid groups are deprotonated. By deprotonation occur: the polymer becomes negatively charged and thereby 1. The particles have sufficient thermal energy and hydrophilised and forms a hydrogel. they spontaneously diffuse away from each other. Carbomer in combination with monovalent bases, This kind of system is a sol. Such a situation is also however, is not extremely hydrophilic as it also forms called deflocculation. a gel in ethanol. 2. The particles have insufficient thermal energy and Addition of salts may have two effects: remain at the same distance. This kind of system is 1. Divalent ions such as calcium and magnesium form cross-links between deprotonated carboxylic acid (continued)

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W. Hinrichs and R. van Gestel CH3

Repulsion HO

Potential energy

2

O a

O

O b

a

H

Fig. 6.14 Chemical structure of poloxamer

a c

Distance

3 b

1

Attraction Fig. 6.13 Potential energy between two particles as a function of their distance. (a): repulsion due to zeta-potential; (b): attraction as a result of Van der Waals forces; (c): net potential energy curve; primary minimum, maximum and secondary minimum are indicated by 1, 2 and 3, respectively. (Source: Recepteerkunde 2009, reprinted by permission of the copyrights holder)

a gel, because external energy (in the form of yield stress) is needed to bring the particles at a greater distance from each other. This is called reversible aggregation or flocculation. Suppose a lyophobic colloidal system that behaves like a sol and it is destabilised by decreasing the zetapotential. At a certain point, a sol-gel transition will take place. The reduction of the zeta-potential by the addition of electrolyte is expressed in the energy curve by a lowering of the potential energy in the secondary minimum. The addition of a certain amount of electrolyte will result in such a lowering of the potential energy in the secondary minimum that the particles have insufficient thermal energy to spontaneously diffuse away from each other. However, addition of electrolyte also results in a lowering of the maximum of the potential energy curve. Therefore, when a huge amount of electrolyte is added, it is possible that the particles have sufficient thermal energy to pass the maximum. The particles approach each other now to a distance where the primary minimum is located. Compact aggregates are formed and there is no longer a colloidal system. Because the attractive forces are so high, the original colloidal system cannot be restored by adding external energy. This process is called irreversible aggregation or coagulation.

A great deal of research has been performed into the use of poloxamers for the controlled release of active substances [24]. Poloxamers, also referred to as Pluronics or Lutrols, consist of triblock copolymers having a central hydrophobic polypropylene oxide block and on both sides a hydrophilic polyethylene oxide block (Fig. 6.14). By varying the length of the blocks, polymers with different physical properties can be achieved. At low temperatures, these polymers are generally soluble in water and form sols. When the temperature is increased, however, a sol-gel transition may take place. This is caused because, with increasing temperature, the thermal energy and thus also the Brownian motion of the molecules increases. As a result, the hydrogen bonds between the water molecules and the polymer become weaker. The stabilising effects of the solvation shell will therefore decrease and the attraction forces will become dominant, resulting in gelation. The temperature at which the solgel transition takes place depends on the composition of the polymer (length of the three blocks) and the concentration. In addition, the sol-gel transition temperature can be influenced by the addition of other substances. For example, the sol-gel transition temperature will be greatly reduced by the addition of a small amount of carmellose sodium. This makes it possible to prepare a solution of poloxamer (and an active substance) that behaves as a sol at a low temperature, for example room temperature or lower, but transforms into a gel at body temperature. Therefore, the solution can be administered at low temperature as a free flowing liquid to a patient after which a gel is formed in situ by the increase of the temperature. Because the gel slowly erodes in vivo, the active substance is slowly released. In principle, different routes of administration for this delivery system are possible. Preparations based on poloxamers have been studied for e.g. parenteral (subcutaneous and intramuscular injection), rectal, vaginal, nasal, ocular, and dermal administration. E.g. a poloxamer based morphine-containing hydrogel for the treatment of large-scale skin wounds has been developed [25].

6.5.1.4 Protein Solutions as an Example of Colloidal Systems Until the beginning of the twenty-first century, in pharmacy, the particles in a colloidal system usually did not consist of active substances but of excipients, such as viscosity enhancers. The number of publications in the pharmaceutical literature on colloidal systems in which the

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dispersed particles solely consist of an active substance or consist of carrier systems in which an active substance has been incorporated, however, has increased dramatically in recent years. Important medicines within this so-called nanotechnology are biologicals, in particular therapeutic proteins. Protein solutions are becoming ever more popular within pharmacy. This is due to the fact that the unravelling of the human genome and the developments in the field of biotechnology offer access to a growing number of proteins that can be used for the treatment of various diseases and disorders. Due to their specific physico-chemical properties, these medicines must be handled in a different way from the classical medicines, which are usually relatively small organic molecules. The specific three-dimensional structure of proteins is essential for their therapeutic action. The structure of proteins can be described at four levels: 1. Proteins are polymers built up from amino acids. The sequence of the amino acids is called the primary structure. 2. Parts of the protein form specific three-dimensional structures, for example alpha-helices (spiral like structures) and beta-sheets (plate like structures), which are called the secondary structure. The secondary structure is mainly stabilised by hydrogen bonds. 3. The relative orientation of the structural elements with respect to each other is called the tertiary structure. This structure is stabilised by hydrogen bonds, disulfide bonds, electrostatic interactions and hydrophobic interactions. 4. In some cases, several chains of amino acids, also referred to as polypeptide chains, form complexes. For example, insulin forms hexamers in the presence of zinc ions. The relative orientation of the polypeptide chains with respect to each other in such a complex is called the quaternary structure. Some proteins also contain, besides amino acids, oligo- or polysaccharides. These substances are called glycoproteins. One of the major problems with proteins is that they are usually not stable. Physical or chemical changes may lead to changes in the three-dimensional structure. This may not only cause a loss of efficacy but it can also have dramatic effects such as the induction of antibodies and severe immune responses. Some practical advice to improve the stability of proteins is given below. Protein solutions should not be stored at a pH which is equal to their iso-electric point. At the iso-electric point, the amount of deprotonated carboxylic acid groups and protonated amino groups are equal and thus the net charge of the particle is zero. In that situation the zeta-potential is zero and irreversible aggregation can easily occur. For the same reason, the electrolyte concentration in the solution should not be too high. A very low or high pH is not recommended

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because the hydrolysis of proteins is both acid and base catalysed. The oxidation of many proteins is catalysed by the divalent metal ions, in particular Fe2+ and Cu2+. Divalent metal ion catalysed oxidation of proteins can be prevented by the addition of disodium edetate to complex these ions. However, certain divalent metal ions can also act as stabilisers for specific proteins. Proteins can in particular irreversibly adsorb onto hydrophobic surfaces. Storage of a protein solution in polypropylene vials is therefore not recommended. In addition, protein solutions are sensitive to shear forces. The use of peristaltic pumps during the preparation of formulations should therefore be avoided. By refrigerated storage and transportation, the degradation processes of protein solutions can be slowed down, and thus their shelf life increases. However, freezing must be prevented since ice formation can damage proteins. Alternatively, proteins can be stabilised by freeze-drying them together with sugars. The stabilizing action of sugars as well as the freeze drying procedure is elucidated in Sect. 6.5.1.5. Summarising, physical degradation of proteins can be caused by: • Aggregation • Denaturation • Adsorption onto surfaces • Precipitation Chemical degradation can be caused by: • Deamidation • Oxidation • Hydrolysis • Racemisation • Reduction disulfate bridges/disulfide exchange

6.5.1.5 Stabilisation of Proteins by Freeze Drying Them Together with Sugars As mentioned in Sect. 6.5.1.4 proteins in solution are unstable. As most degradation pathways require molecular mobility, it is obvious to bring the protein in the dry state, e.g. by freeze drying. The freeze drying process, however, can be detrimental for the protein and therefore stabilising excipients are required. It is well known that sugars can act as such excipients, with the disaccharides sucrose and trehalose being the two most often applied sugars. Two theories have been described to explain the stabilising effects of sugars: the water replacement theory and the vitrification theory (although refinements to these theories have been proposed [26]). According to the water replacement theory, hydrogen bonds between the protein and water molecules are gradually replaced by hydrogen bonds between the protein and the hydroxyl groups of the sugar molecules by which the original three-dimensional structure of the protein is maintained. According to the vitrification theory, the protein is incorporated in a sugar matrix in which the translational molecular mobility is strongly reduced, thereby also reducing most

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degradation processes. For both stabilisation mechanisms, the sugar molecules should form a tight coating around the protein molecules. Therefore, the sugar molecules should be oriented towards the irregular surface of the protein, and thus not towards each other in a specific way like in a crystal lattice. Such random orientation of molecules is also referred to as amorphous. An amorphous material can be either in the rubbery or in the glassy state, i.e. when a glass is heated to above a certain temperature (the glass transition temperature; Tg) it changes into a rubber. While in the rubbery state the molecules have a high translational mobility, in the glassy state it is very low. The rubbery or glassy state, however, are no equilibrium states. Consequently, the material is prone to crystallisation. Due to the high translational mobility of the molecules in a rubber, crystallisation is indeed likely to occur sooner or later. Due to its low translational molecular mobility, this is not the case for a glass during pharmaceutical relevant time scales. Therefore, a material in the glassy state is called kinetically stable. For two reasons, the sugar should be in the glassy state to optimally stabilise the protein. First, according to the vitrification theory, the sugar molecules should have a low translational mobility and therefore in the glassy state. Second, with respect to the water replacement theory, the sugar should also be in the glassy state, as crystallization of the sugar will break up hydrogen bonds between the sugar and the protein. As a consequence, the sugar molecules do not form a tight coating anymore and protein stabilisation is lost. In addition, mechanical forces during the crystallization process may deteriorate the protein structure. As a glass or a rubber do not represent equilibrium states, they are not included in a phase diagram, instead a state diagram applies. Detailed information on such state diagrams can be found in [27]. Basically, freeze drying concerns a process where a solution is cooled until it is fully solidified after which water is removed by reducing the pressure. During cooling, water will crystallize to form ice. However, not all water will crystallize as part of it will form a glass together with the sugar, Fig. 6.15  Phase diagram of water with emphasis on the sublimation curve

W. Hinrichs and R. van Gestel

the protein and possibly other components of the solution, e.g. buffers. The Tg of solutions containing sucrose or trehalose is around −30 °C. Therefore, such solutions should be cooled to below this temperature to avoid crystallization of the sugar. For the same reason, cooling should also be fast. However, extremely fast cooling is not preferred as due to fast nucleation, small ice crystals are formed which may be detrimental for the protein due to a large specific interfacial area where protein molecules can accumulate and unfold. As a rule of thumb, a cooling rate of 1–2 °C/min is advised [28]. Freeze drying of protein/sugar solutions thus implies the removal of these two types of water; ice crystals and water within the glass. This can be achieved by applying a reduced pressure. Water from ice crystals is removed by sublimation while water in the glass is removed by evaporation. Sublimation of water molecules from ice crystals is a relatively fast process as these molecules are directly exposed to the environment. On the other hand, evaporation of water molecules from the glass is a relatively slow process as the diffusion of these molecules through the glass to the environment is hindered by the presence of the sugar, protein and potentially other molecules. Therefore, the removal of water molecules from the solidified solution can be divided into two subsequent stages: primary drying which is the sublimation of water from the ice crystals, and secondary drying which is the removal of water from the glass, although this distinction may in practice not be that strict. Nevertheless, the freeze-drying process should be initiated at a temperature below the Tg of the solution to avoid crystallisation of the sugar. However, primary drying should be performed at a temperature as high as possible to achieve a drying process of acceptable rate. The pressure should not be too low as at very low pressures the capacity of the atmosphere in the freeze dryer for water vapour is very low. As a result, the driving force for sublimation is low and therefore also the sublimation rate. However, the pressure should be below the sublimation curve (Fig.  6.15). This implies that when the temperature is below −30 °C, a pressure lower than around

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40 Pa should be applied. After primary drying is completed, the slower secondary drying process continues. Because during drying the sugar/water ratio of the glass increases, the Tg of the glass gradually increases (the Tg’s of pure sucrose and trehalose are around 85 and 120  °C, respectively). This means that the temperature of the sample can be gradually increased as long as the glass transition curve is not passed. Furthermore, the pressure should be decreased as much as possible, as the capacity of atmosphere above the samples for water vapour is not rate limiting anymore but the diffusion of water molecules through the glass. After the freezing-­ drying process is completed, a highly porous cake with a white appearance and a volume equal to the original solution will be obtained. The high porosity is the result of the fact that during freezing ice crystals are formed everywhere in the solution, and ultimately, the glass will be situated in the interstices between these ice crystals. As a consequence, after the freeze-drying process, a mirror image of the ice crystals will be obtained as the molecules in the glass show a low translational mobility. Such a highly porous cake is very advantageous, as due to its very large specific surface area, reconstitution, e.g. for the preparation of an injection, proceeds fast with no or minimal agitation. In this respect, it should be emphasised that vigorously shaking a protein solution should be avoided as it creates a large liquid-air interface where protein molecules tend to accumulate and unfold. Furthermore, the cake appearance can also indicate whether or not the freeze-drying process was successful. E.g. when the Tg is passed during secondary drying, the glass will be turned into a rubber. Due to the high translational mobility of the molecules in the rubbery state, the porous cake will collapse and the product will appear as a translucent or white crystalline layer at the bottom.

Below, some practical advice for freeze-drying protein/sugar solutions using lab-scale freeze dryers is given. Usually, glass vials are used to charge them with solutions to be freeze-dried, with potentially the possibility to stopper them within the freeze dryer after the drying process depending on the type of freeze dryer used. Freezing of solutions in the glass vials can be achieved by immersing them in liquid nitrogen or by placing them on a pre-cooled shelf of the freeze dryer. When the samples are frozen on the shelf, the shelf temperature is usually set at −50 to −60 °C to obtain a sufficiently fast cooling rate. The drying process can be regarded as an erosion process, meaning that water is gradually removed from the top to the bottom of the vial. Therefore, the height of the solution in the vial should not be too large to avoid a

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long drying time. Typically, a maximal height of approximately 1  cm is recommended. In that case, using a robust freeze-­drying program, the total drying time would be around 2  days, i.e. 1  day of primary drying and 1 day of secondary drying. However, the drying process time can be shortened by adjusting the program settings depending on the formulation characteristics, i.e. type of sugar, sugar/protein ratio, total solid concentration, etcetera and the height of the solution. After the freeze-­drying process is completed, the samples can be collected in two ways. First, when the vials can be stoppered in the freeze dryer, the pressure within the freeze dryer is increased to about 0.8  atm with either air or nitrogen via an inlet after which the vials are stoppered. After further increasing the pressure to ambient conditions, the freeze dryer is opened and the vials are removed. Second, the pressure within the freeze dryer is increased to ambient conditions via an inlet. Thereafter, the freeze dryer is opened and the vials are removed and subsequently stoppered. It should be emphasised that, depending on the relative humidity of the environment, stoppering of the vials should be performed immediately after collection. During the freeze-drying process, not all water will be removed, and the final product usually contains a few percent of water. Therefore, the Tg of a freeze dried product will be substantially lower than that of a fully anhydrous product. Furthermore, sugar glasses are highly hygroscopic and can therefore absorb substantial amounts of water from the environment. This can result in a drop in the Tg to below ambient temperature followed by crystallisation. E.g. sucrose and trehalose already crystallise at 25  °C within a few hours when exposed to 30 and 45% relative humidity, respectively [29].

6.5.2 Suspensions Suspensions are regularly used as a dosage form. Examples can be found in oral suspensions (co-trimoxazol suspension), dermatological preparations (zinc oxide or calamine lotions like Zinc oxide lotion (Table 6.17)), parenteral preparations (corticosteroid injections, medroxyprogesterone injection) Table 6.17  Zinc oxide cutaneous suspension [30] Zinc oxide Propylene glycol Ethanol (90%) BP Talc Water, purified Total

13.8 g 13.8 g 23 g 13.8 g 50.6 g 115 g (=100 mL)

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W. Hinrichs and R. van Gestel

and a suspension in the form of a solid dispersed in a melted fat base as in the case of suppositories. As with colloidal systems, suspensions consist of particles dispersed in a liquid. As a result, the physico-chemical properties of suspensions are, in principle, similar to those of colloidal systems. As described in the introduction to Sect. 6.5, the main difference is that the particles in a suspension are larger (>1 μm) than in a colloidal system (1 nm – 1 μm). As a result, the particles settle in a suspension (if the density of the particles is greater than the density of the dispersion medium, which is generally the case) while this is not the case in a colloidal system. Fast sedimentation of particles in a suspension has major drawbacks. Pouring out a partially settled suspension in several portions or at different times leads to too low particle concentrations in the first portions and too high in later portions. In the past this has had fatal consequences, when a 4 months old boy got a threefold dose of spironolactone [31].

6.5.2.1 Sedimentation Behaviour The sedimentation rate of the particles in a suspension can be calculated using Stokes’ law: v=

2r 2 ( ρ1 − ρ2 ) g



9η

(6.15)

where v is the sedimentation rate, r the radius of the particle, ρ1, the density of the particle, ρ2, the density of the medium, g the acceleration due to gravity and, η the viscosity of the medium. From this equation, it can be deduced that the rate of sedimentation decreases as the particle size decreases, the differ-

Fig. 6.16 Schematic representation of deflocculated (a) and flocculated (b) sedimentation. (Source: Recepteerkunde 2009, ©KNMP)

ence in the density of the particles and the medium decreases and the viscosity increases. When applying this equation, the zeta-potential of the particles has also to be taken into account. Again the curve can be used in which the potential energy is plotted as a function of the distance of two particles, as discussed for colloidal systems (Fig. 6.13). The difference with colloidal systems is that the maximum in the curve for suspensions is generally higher. As a result, coagulation or irreversible aggregation almost never occurs in practice. Usual situations are either reversible flocculation or aggregation when the zeta-­potential is small or deflocculation when the zetapotential is large. The sedimentation behaviour is largely affected by whether or not flocculation or aggregation occurs, as described below. In a deflocculated system the particles will not aggregate and therefore settle separately from each other. Because, according to Stokes’ law, the sedimentation rate increases with particle size; large particles will arrive earlier on the bottom of the container than smaller particles. Because the particles do not attract each other, the voids between the large particles are gradually being filled up with the small particles. Therefore, a very compact sediment (cake) is slowly built up from the bottom of the container (Fig. 6.16a). If the suspension also contains particles smaller than 1 μm (the colloidal fraction of the suspension), these particles will not settle but will continue to be suspended in the liquid so that the liquid above the sediment remains cloudy. The sediment exhibits dilatant flow behaviour. In a flocculated system, the particles do attract each other and aggregates will be formed anywhere in the fluid.

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These aggregates have very open structures. This is because when a particle approaches an aggregate, it will be immoTable 6.19  Chloramphenicol Oral Suspension 33 mg/mL [32] bilised by the attractive forces at the outside of the aggreChloramphenicol palmitate 5.75 g gate. This makes diffusion of the particle to possible void Carmellose sodium M 1 g spaces in the inside of the aggregate impossible. As everyPolysorbate 80 0.5 g Propylene glycol 2 g where in the fluid aggregates are formed, a large and loose Cacao syrup (local standard) 15 g sediment is formed (Fig.  6.16b). This typical way of setSyrup B.P. 15 g tling of flocculated suspensions may be called sedimentaEthanol (90%) BP 1 mL tion, but more precisely subsidencing as is suggested by Vanillin 0.02 g [5]. Because the aggregates rapidly increase in size the subWater, purified Ad 100 mL sidencing also progresses rapidly. Any further settling and compaction of the sediment is unlikely to occur. Once the sedimentation has been completed, a very open sediment is A preparation that illustrates the versatile function of a obtained due to the cavities in the aggregates. As a result, at surfactant in a suspension is the Chloramphenicol Oral the same volume fraction of particles, the volume of the Suspension 33 mg/mL ex-FNA (Table 6.19). sediment of a flocculated suspension will be much larger In this preparation, first a gel of carmellose is prethan in a deflocculated suspension. The liquid above the pared in a portion of the cold water using a rotorsediment is clear because particles smaller than 1  μm are stator mixer. Then chloramphenicol palmitate is dissolved in a mixture of hot polysorbate 80 and proincluded in the aggregates. The sediment exhibits plastic pylene glycol. Polysorbate 80 thus functions here as flow behaviour. a part of the solvent mixture. The hot clear solution Both deflocculated and flocculated systems have advanis added to the aqueous gel under intensive stirring tages and disadvantages. In a deflocculated system sedimentation proceeds slowly but once it is completed, it is very with the rotor-­stator mixer. During this process the difficult to disperse the very compact sediment. The disadchloramphenicol palmitate crystallises to form vantage of a flocculated system is the high sedimentation microcrystals. The size of these microcrystals is not rate. The sediment, however, is easy to disperse because it only determined by the intensity of stirring but also has a very open structure. by the presence of polysorbate 80, which acts as the In practice, therefore, the objective is to achieve an intersurfactant. During storage polysorbate 80 also inhibmediate form by the addition of a controlled amount of elecits any crystal growth. In addition, in this suspension trolyte or surfactant. When the particles strongly repel each design, polysorbate 80 acts as a deflocculating agent other, an electrolyte can be added. By decreasing the zeta-­ and prevents, by wetting chloramphenicol palmitate, potential, the repulsive forces will decrease. When the partiflotation and sticking of the active substance to the cles attract each other too strongly a surfactant can be added. bottleneck. As the lyophobic part of the surfactant molecule adsorbs onto the surface of lyophobic colloids its lyophilic part will be oriented into the dispersion medium. By steric stabilisation, the attraction forces are decreased. The properties of 6.5.2.2 Influencing Sedimentation Behaviour flocculated and deflocculated suspensions are summarised in Ideally the sedimentation rate of pharmaceutical preparaTable 6.18. tions is as low as possible. On the basis of Stokes’ law, it is clear which variables can be varied to accomplish this. The Table 6.18  Properties of a deflocculated and a flocculated suspension gravitational acceleration cannot be reduced, nor the density of the particles. However, the particle size, the density Deflocculated suspension Flocculated suspension and the viscosity of the dispersion medium may be Sediment built up from the bottom Subsidencing sediment adjusted. Slow sedimentation Fast sedimentation Compact sediment Open sediment A first method to reduce the sedimentation rate is particle Small volume sediment Large volume sediment size reduction. This can be accomplished by milling. On a Possibly cloudy fluid above Clear fluid above sediment small scale, this is possible by using a mortar and pestle, if sediment electrostatic charging and agglomerating can be managed. Flow behaviour sediment: Dilatant Flow behaviour sediment: On a larger scale, high-tech equipment has been developed Plastic for this (see Chap. 28). The precipitation method is another Sediment difficult to disperse Sediment easy to disperse

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method to reduce the particle size. It is a useful method when no milling equipment is available or when electrostatic charging will be a problem. In the precipitation method, at first the active substance is dissolved and then its solution is brought into the supersaturated state. As a result, the dissolved substance will precipitate. The size of the precipitated particles will decrease when the degree of supersaturation increases or when the rate at which supersaturation has been achieved increases, or both. Supersaturation can be created in different ways. The solubility of many active substances is pH dependent. As described in Sect. 6.1.1, active substances with for example one or more acid groups are generally poorly soluble at a low pH but their solubility will be better at a high pH. This property can be used by preparing a solution of the active substance at high pH and then adding an acid to the solution by which it becomes supersaturated. Obviously, the opposite strategy can be used for active substances containing one or more amine groups: first the active substance is dissolved at low pH and then a base is added. Thus in both cases a solution of the active substance in ionised form is prepared. Then, the active substance in the form of its free acid or base (non-ionised form) is formed by changing the pH and supersaturation is achieved. In another precipitation method, two different liquids are used that are miscible with each other, but in which the solubility of the active substance substantially varies. Firstly, the active substance is dissolved in the liquid in which the active substance dissolves well. Subsequently, supersaturation is achieved by adding the second liquid to the solution in which the active substance is poorly soluble. In a third precipitation method, the fact that most substances are more soluble at a high than at a low temperature is to be made use of. A saturated solution is made at a high temperature after which it is cooled until supersaturation is achieved. This last method is the least suitable because in practice it is often difficult to cool rapidly. The chloramphenicol palmitate suspension as described in Table 6.19 is an example of a suspension prepared by precipitation. Chloramphenicol palmitate precipitates when the solution in a hot mixture of polysorbate 80 and propylene glycol is mixed with the cold aqueous gel. By vigorous stirring during the final step, small particles are obtained. A second method to reduce the sedimentation rate is to increase the density of the dispersion medium, for example, by the addition of syrups or a solution of sorbitol. A third method to reduce the sedimentation rate is to increase the viscosity of the dispersion medium, which is almost always achieved by the application of polymers. But it must be kept in mind that accurate dosing by the patient of a specific amount of the suspension is more difficult when the viscosity increases. To avoid inadequate dosing the prep-

W. Hinrichs and R. van Gestel

aration can be delivered together with a dosing/measuring syringe instead of a measuring cup or spoon.

Most corticosteroids nasal sprays (licensed preparations) are suspensions in which croscarmellose sodium is used as a viscosity enhancer. The inhalation liquids for nebulisation with the same type of active substances however only contain polysorbate and sorbitanlaureate to stabilise the suspension. For atomisation in jet nebulisers, the liquid should not be too viscous, in order to prevent clogging of the nebuliser.

6.5.2.3 Particle Size Stability The size of the particles in suspensions is not stable. During time, the particle size will increase by temperature fluctuations and by the so-called Ostwald ripening. Because most substances are more soluble at a high than at a low temperature, small particles present in a suspension will dissolve when the temperature increases. When subsequently the temperature decreases again the solution will become supersaturated. The undissolved larger particles will act as nuclei for precipitation and grow. Ostwald ripening is happening because the solubility of a substance in the near vicinity of small particles is greater than in the near vicinity of large particles. The relationship between the solubility and the size of the particles is given by the Ostwald-Freundlich equation:



 2 ⋅γ ⋅ M  Cs ,curved = Cs , flat ⋅ exp    R ⋅ T ⋅ ρ ⋅r 

(6.16)

where Cs,curved and Cs,flat is the solubility near a small particle and an infinitely large particle, respectively, γ the interfacial tension between the particles and the dissolution medium, M the molecular weight of the substance, R the gas constant, T is the temperature (in K), ρ the density of the substance, and r the radius of curvature of the particles. Due to the differences in solubility, differences in concentration in the dispersion medium arise and the dissolved molecules diffuse from the small particles to the large particles. As a consequence, the dispersion medium around the large particles becomes supersaturated and the dissolved molecules will precipitate onto these particles. Because the dissolved molecules around the small particles are diffusing away, the dispersion medium is no longer saturated and molecules from the small particles will dissolve. Thus, small particles become smaller and eventually disappear and large particles are getting bigger. A second effect is that irregularly shaped particles in suspensions become spherical.

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From the above it can be concluded that by both temperature fluctuations and Ostwald ripening the particle size will increase faster when the particle size distribution is larger. It is therefore desirable that the particle size distribution in a suspension is as small as possible.

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their slow dissolution, can be improved by converting them into the glassy state.

6.5.3 Emulsions

6.5.2.4 Polymorphism, Pseudo-Polymorphism, Emulsions can often be found as dermatological preparaGlassy State tions, and sometimes as injections and oral preparations. Solids may exhibit polymorphism, which means that they They make combinations of immiscible liquids possible, can exist in different crystal modifications which differ in typically of fatty/lipophilic components and water. The fat/ their physical properties [3, 20, 33, 34]. No less than eleven lipophilic ingredients can act as an active substance, for different crystal modifications of phenobarbital are known. It example, in creams to keep the skin hydrated. They can also depends on the physical conditions such as temperature serve as a solvent for other substances such as diazepam in which crystal modification is stable. The other modifications Diazemuls® injection or for fat soluble vitamins in parenteral are metastable. For substances that exhibit polymorphism, nutrition (see Chap. 21). the solubility of the metastable form is higher than that of the The physico-chemical properties of emulsions are basistable form. This means that if the metastable modification is cally similar to those of suspensions, with the essential difin equilibrium with the solution (i.e. saturated for the meta- ference that in emulsions the dispersed phase consists of a stable form), the solution is supersaturated for the stable liquid instead of a solid. This difference has important consemodification. In other words, the stable form can grow over quences. Similar to a suspension, an emulsion exhibits a time at the expense of the metastable form. Some fats also large interface between the dispersed phase and the dispersexhibit polymorphism [35]. The preparation method and the ing medium. It requires energy input to create an interface. storage temperature will influence for example the melting This implies that energy is liberated when the interfacial area behaviour of suppositories, and thereby probably also the is reduced. Since this is thermodynamically advantageous, release rate. the system will attempt to minimize the interfacial area. Besides polymorphism, pseudo-polymorphism also Because liquids are ‘deformable’ the dispersed drops in exists. In pseudo-polymorphism, a substance is found in emulsions will therefore have a strong tendency to coalesce. crystal modifications whose hydration or solvation state dif- This coalescence may eventually result in ‘breaking’ of the fers. There may therefore be crystal lattices in which more or emulsion. When breaking occurs, the two phases will be less water or other solvent molecules are included. Similar to present as two liquid layers. The stability of an emulsion can polymorphism, the substance in the form of one pseudo-­ be improved by adding surfactants. The driving force of the polymorph is more soluble than in the other. Erythromycin is disperse drops to coalesce becomes smaller because less an example of a substance which exhibits pseudo-­ energy will be liberated. Specifically applied in emulsions, surfactants are referred polymorphism. It exists in an anhydrous form and as a hydrate. In Erythromycin Eye Ointment FNA (Table  6.20) to as emulsifying agents. According to the rule of Bancroft, the anhydrate is used, because this form dissolves faster in the HLB of the emulsifying agent determines which type of emulsion is obtained, water in oil (w/o) or oil in water (o/w). the fatty ointment base. Besides in the crystalline form, a substance may also exist According to this rule, the phase in which the emulsifying in the glassy state. In the glassy state, the molecules are not agent dissolves better will be the dispersion medium. An oriented in a specific manner towards each other as they are emulsifying agent with an HLB   7 an o/w solubility and thereby also the dissolution rate of a substance emulsion. This can be explained as follows. When an emulin the glassy state is better and higher than in crystalline form sifying agent is more soluble in oil than in water (HLB  7, the hydrophilic part Paraffin, liquid 39.8 g Paraffin, white soft 51.2 g occupies a larger volume and an o/w emulsion is obtained. Wool fat 5.97 g The stability of an emulsion increases when the emulsifyTotal 100 g ing agent molecules form a more compact layer at the inter-

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face. A very compact layer can be achieved by making use of two different emulsifying agents, one of the o/w-type and one of the w/o-type. One emulsifying agent occupies the cavities in the interface that the other emulsifying agent cannot fill. Such combinations of emulsifying agents are referred to as mixed layer emulsifying agents or emulsifying agent complexes. The HLB of two emulsifying agents can be calculated by multiplying the weight fraction of each emulsifying agent by its HLB value and adding them together. Thus the HLB of a mixture of two emulsifying agents A and B can be calculated as follows: HLBmixture = f A × HLB A + f B × HLBB (6.17) where f A and f B are the weight fractions of the emulsifying agents A and B, respectively; HLBA and HLBB are the HLB values of the emulsifying agents A and B, respectively.

When two emulsifying agents are combined, one with an HLB of 4.7 and the other with an HLB of 10.3, in a weight ratio of 40/60, the HLB of the whole will become 8.1 (HLBmixture = 0.40 x 4.7 + 0.60 x 10.3 = 8.1). According to the rule of Bancroft, with this combination an o/w emulsion will be obtained.

The Bancroft rule should be interpreted as a general rule. In practice, however, there are many exceptions. In addition, the type of emulsion that is formed will also depend on the volume ratio of the two phases, the method of preparation, the electrolyte concentration, etc.

6.6 Osmosis Osmosis is the transport of water through a semi-permeable membrane as a result of a difference in the concentration of solutes on either side of the membrane. A semi-permeable membrane is only permeable to water; dissolved dissociated or undissociated substances cannot pass through it. Living cells are provided with a membrane through which water transport can take place. This must be taken into consideration when the envisaged dosage form for an active substance is a solution. If a solution is administered to a patient, water transport across the cell membrane of the cells in the near vicinity of the site of administration should be avoided as much as possible. This is because extensive water transport across cell membranes may lead to irritation and cell damage. The risks for this are, in particular, present with parenteral preparations and irrigations, but also in the case of preparations for eye, middle ear, and nose. In this section the water transport across membranes is dealt with in more

W. Hinrichs and R. van Gestel

detail. Methods are given to prevent net water transport across cell membranes after the administration of solutions.

6.6.1 Osmotic Pressure When an aqueous solution and pure water in two different compartments are separated from each other by a semipermeable membrane, a spontaneous transport of water molecules across the membrane into the solution will take place. This spontaneous transport is caused by the attractive forces between the solute molecules and the water molecules. As a result, water molecules are forced through the pores of the semi-permeable membrane. By this water transport, the liquid level in the compartment of the solution will rise, while it will fall in the compartment of pure water. The rise of the liquid level in the solution compartment will, however, not continue indefinitely because the difference of the fluid levels creates a hydrostatic pressure difference that leads to a driving force for water transport in the opposite direction, i.e. across the membrane to the compartment containing pure water. At a given moment the driving forces for transport of water from the solution to pure water and from pure water to the solution are equal, and the liquid levels in the two compartments do not change anymore. The process of transport of water through a semipermeable membrane due to a concentration difference is called osmosis and the final pressure difference between both sides of the membrane is called osmotic pressure. Basically, the osmotic pressure should be expressed in Pascal, but in practice the words osmolality or osmolarity are used to indicate osmotic pressure, both with osmole as unit. Osmotic pressure is a colligative property. A colligative property solely depends on the concentration of the dissolved molecules or ions and is independent of the nature of the solute. Freezing point depression is also a colligative property and can be indirectly used to determine osmotic pressure. In practice, it is much more difficult to determine the osmotic pressure of a solution than to measure its freezing point depression. The freezing point of a solution can be measured and the osmotic pressure can be calculated from it. The molar freezing point depression of water is 1.86 °C. Blood freezes on average at −0.54 °C. Plasma and tear fluid have the same freezing point. The osmolarity of blood, plasma and tear fluid is thus equal to: 0.54 = 0.290 osmole ( 290 mosmole ) 1.86

(6.18) In literature, also a freezing point depression of blood of 0.52 °C or 0.56 °C has been reported. Based on these values, it can be calculated that the osmolarity of blood, plasma and tears will be 280 or 300 mosmol, respectively.

6  Physical Chemistry

The osmotic pressure has the unit of Pascal (N/m2) but in clinical practice this unit is not used as such. Measurements and calculations are performed with concentrations expressed as osmols or milliosmols, which are abbreviated as “osmol” and “mosmol”, respectively. In the clinical setting 1 osmole means a concentration of 1 mol of a non-dissociable substance per kg of solvent or per litre of solution. If this concentration is expressed as mol per kg of solvent (molality) it is called osmolality. If the concentration is expressed as mol per litre of solution (molarity) it is called osmolarity. Since the concentration of, in particular, parenteral preparations is more commonly expressed as mole per litre solution than mole per kilo solvent, usually the osmolarity of injections and infusions is given. The difference between osmolarity and osmolality in dilute aqueous solutions is usually not significant, because the density of water is 1 kg per litre, and the volume fraction of the solute is usually negligible. In highly concentrated solutions, however, there is a clear difference between osmolality and osmolarity. But highly concentrated solutions are clinically hardly relevant.

6.6.2 Iso-osmotic and Isotonic If two aqueous solutions with different concentrations of dissolved substances are separated from each other by a semipermeable membrane, there is a net transport of water from the solution with lower concentration molecules or ions to the solution with the higher concentration of molecules or ions. The solution with the lower concentration is called hypo-osmotic, while the solution with the higher concentration is hyper-osmotic in relation to the other. When the concentrations of dissolved substances in the solutions on either side of the semi-permeable membrane are equal to each other, there will be no net transport of water across the membrane. In such a case we call the two solutions iso-osmotic. When cells are brought into contact with a solution and a cell membrane would behave as a semi-permeable membrane, the solution within the cell will try to become iso-­ osmotic to that outside of the cell. This water transport will cause damage to the cell. It must therefore be ensured that there is little or no net water transport from the solution into the cell or vice versa. If an active substance is administered in a low concentration solution, the osmotic value will be

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less than that of the blood. To achieve an iso-osmotic concentration, NaCl or glucose can be added. When the active substance has to be administered in a high, hyper-osmotic concentration, consideration should be given to reducing the concentration by dilution. If this is not possible, then, under certain conditions a solution with a hyperosmotic concentration can be administered, preferably into a vein with a good flow so dilution will take place swiftly (see Chap. 21). The cytoplasmic membrane of an erythrocyte or a corneal epithelial cell and other physiological membranes, however, do not always behave as a semi-permeable membrane. Cell membranes are to some extent also permeable to some molecules other than water. Some molecules or ions, such as urea, ethanol, and ammonium salts, are able to pass through a cell membrane at a relatively high rate. If an erythrocyte for example is placed in an iso-osmotic solution of ammonium chloride, the transport of ammonium chloride across the cell membrane occurs quickly until its concentration in- and outside the cell is equal. For this reason, solutions containing that type of molecules may be iso-osmotic with the cell content, but nevertheless show water transport when brought into contact with cells. On the other hand, a net water transport does not necessarily occur when the cell content is not iso-osmotic with the environment. If certain ions or molecules do not stay at one side of the (cell) membrane, their contribution to the pressure difference will not be the same as in the case of a ‘perfect semi-permeable’ membrane. If net water transport occurs from the environment to the cell the solution outside the cell is called hypotonic. And vice versa, when a net water transport occurs from the cell to the environment the solution outside the cell is hypertonic. If no net water transport takes place, both solutions are called isotonic. Iso-osmotic is a physico-chemical concept and only depends on the concentration of dissolved molecules and ions. Isotonicity is the concept that takes into account, as well, the properties of the biological membrane in relation to the type of dissolved substances. Thus isotonicity should be interpreted as a physiological concept. Therefore, in this context it is better to speak of selectively permeable instead of semi-permeable. For most applications or routes of administration (bio-membranes), the number of substances for which there is a difference between iso-osmotic and isotonic is limited. For this reason, terms such as hypertonic and hypotonic are commonly used while actually hyper- or hypo-­ osmotic, respectively, are meant.

6.6.3 Non-ideal Solutions On the basis of paragraph Sect. 6.6.1, it would be expected to calculate as follows: if the composition of the fluid is given in millimoles, determine whether or not the dissolved sub-

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W. Hinrichs and R. van Gestel

stances dissociate and if so how many ions are formed. For example, a solution of 1  mmol of glucose in 1  L of water yields 1 mosmol, but a solution of 1 mmol of NaCl or 1 mmol CaCl2 in 1  L of water yields 2 or 3  mosmol, respectively. After summing the contributions of all components it can be verified whether or not the total strength is approximately 300 mosmol. This way of calculating only applies to so-called ideal solutions. In an ideal solution of substance A in a solvent B, the interactions between A and B, A and A, and B and B are equal. In practice, however, non-ideal solutions are more common. As a result, at an equal concentration of molecules or ions, the osmolarity of a non-ideal solution can be different from that of an ideal solution. This difference in osmolarity is expressed by a correction factor f. This correction factor is specific to each substance and in dilute solutions independent of the concentration. At very high, clinically irrelevant, concentrations, the correction factor may change due to association of the dissolved components. The osmolarity of a solution can be calculated as follows: G ×f M

In a preparation, the active substance (if present in dissolved form) and the excipients (e.g. buffering agents, preservatives, antioxidants, and disodium edetate) all contribute to the osmotic value of a preparation. If 290 mosmol is taken as the iso-osmotic value, a solution of the substances A, B, … is iso-osmotic with blood under the following condition:



GA G G × fA + B × fB +…+ H × fH = 0.290 MA MB MH

(6.20)

where GA, GB, .... are the concentrations of the solutes in grams per litre, MA, MB, .... the molecular weights of the dissolved substances, and fA, fB, ..... the correction factors associated with dissociation of the solutes. To make a solution iso-osmotic, an excipient can be added. In (6.20) this excipient is indicated with an H.

6.6.4 Calculation of Osmotic Value

(6.19) where G is the concentration of the solute in grams per litre and M the molecular weight of the dissolved substance. The f-values are mentioned in Table 6.21 as group averages.

If an active substance or excipient substantially contributes to the osmotic value, it may be necessary to calculate this contribution. This can be done in practice by three different calculation methods. The choice of the method depends on which physical characteristics of the substances are available.

Table 6.21  Dissociation types and f-values of various substances

Method 1: If the molecular weight and the dissociation type (f-value, Table 6.21) are known, the osmotic value can be calculated using a part of Eq. 6.16, namely:

Dissociation type Non-dissociating

Molar freeze point depression (in °C/ mol) 1.9

4.8

f-value Examples 1.0 Glycerol Glucose Sorbitol Urea 1.05 Alkaloids Bases Boric acid 1.05 Magnesium sulfate Zinc sulfate 1.8 Sodium chloride Silver nitrate Phenobarbital sodium 2.3 Sodium sulfate 2.5 Zinc chloride

5.2

2.7

6.0

3.2

7.6

4.0

Weak electrolytes

2.0

Di-divalent electrolytes

2.0

Mono-monovalent electrolytes

3.4

Mono-divalent electrolytes Di-monovalent electrolytes Mono-trivalente electrolytes Tri-monovalent electrolytes Tetraborate

4.3

Sodium citrate Aluminium chloride Borax



GA × fA MA

Method 1 Is Exemplified by the Calculation of the Osmotic Value of Betaxolol 1% Eye Drops Suppose that no iso-osmotic concentration of the substance (betaxolol) is known. The osmotic value can then be calculated using the molecular weight and the type of dissociation. Betaxolol hydrochloride has a molecular weight of 343.9. The degree of dissociation and the pKa cannot be easily found in the literature. Based on its chemical structure, however, it can be concluded that this is a salt of a secondary amine. The so-called f-value of this type of molecule is 1.8. The contribution of betaxolol hydrochloride is then (G/M) × f = (10/343.9) × 1.8 = 52 mosmol per litre. Betaxolol  hydrochloride therefore contributes for (52/290)  ×  100%  =  18% of the iso-osmosis. As a consequence, excipients should contribute for the remaining 82% to make an isotonic solution.

6  Physical Chemistry

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Method 2: If the iso-osmotic concentration of a substance is known, the osmotic value can be easily calculated. In Martindale, these values are often specified in the description of substances [11]. In the Merck Index and in the Handbook of Injectable Drugs, the iso-osmotic concentrations for a large number of substances are listed in a table [6, 39].

Method 2 is exemplified by the calculation of the osmotic value of Pilocarpine Eye Drops 2% FNA (Table 6.22). Table 6.22  Pilocarpine eye drops solution 2% [40] Pilocarpine hydrochloride Benzalkonium chloride Borax Boric acid Disodium edetate Water, purified

2 g 0.01 g 0.375 g 0.7 g 0.1 g Ad 100 mL

Method 3 is exemplified by the calculation of E value and NaCl equivalents for a thiamine-injection 25 mg/ mL (Table 6.23):

A 4.1% w/v solution of pilocarpine hydrochloride is iso-osmotic (293 mosmol as determined by measuring its freezing point depression). A 2% w/v pilocarpine hydrochloride thus contributes to about 50% of the iso-­osmotic value (the osmolarity as determined at pH 6 is 147 mosmol). The other 50% should be provided by the excipients. Iso-osmotic stock solutions for the preparation of eye drops could be very useful for the purpose of easy calculation. The stock solution Boric acid-benzalkonium solution FNA is nearly isoosmotic (boric acid is iso-osmotic at a concentration of 19 mg/mL). The contribution to the osmotic value of the benzalkonium chloride 100 mg/L is too small and can be neglected in the calculations. Without adjusting the pH, 50% v/v of Boric acid-benzalkonium solution would be needed. But because the stability of pilocarpine is optimal at pH  6.5, the pH is adjusted with 3.75 mg/mL borax to 6.5. As 3.75 mg/mL borax contributes 15% to the osmotic value, 35% is left for the Boric acid-benzalkonium solution.

Method 3: If no iso-osmotic concentration is known, it can be calculated with the aid of the sodium chloride equivalent, also known as tonicic equivalent or E-value. The sodium chloride equivalent is defined as: E=



freeze point depression per gram of compound A freeze point depresssion per gram NaCl

For each substance, the E value can be calculated if the dissociation type of that substance is known [41]. In practice, tables are used in which the E-values for a large number of substances are listed. These tables can be found in references [6, 39]. The calculation using E-values proceeds as follows. The concentration of each of the solutes, expressed as a percentage, is multiplied with the corresponding E value. The product thus obtained, gives for each substance in the amount used the amount of NaCl which corresponds to the osmotic value. The sum of the products of all individual components represents the strength in NaCl equivalents of the total solution. Because the overall strength of the solution should be 0.9 NaCl equivalents, the relative contribution of the active substance to the osmotic value is known. The amount of iso-­ osmotic stock solution to be added can be calculated as described above.



(6.21)

Table 6.23  Calculation of E value an NaCl equivalents for a thiamine injection solution Thiamine-hydrochloride Disodium edetate

Per 100 mL 2.5 g 0.01 g

E 0.21 0.20

NaCl-eq 0.525 0.002

This gives a total of at E = 0.527 sodium chloride equivalents. 0.9  g of sodium chloride per 100  mL is iso-osmotic. This means that almost 0.373  g per 100 mL should be added.

6.6.5 Importance of Osmotic Value in Dosage Forms With the aid of the three methods described in Sect. 6.6.4 it can be calculated whether or not a pharmaceutical preparation is iso-osmotic. Hypo-osmolarity can usually be avoided as it can be compensated by the addition of excipients in calculated quantities. Hyper-osmolarity may be inevitable due to dosage reasons, for example when a high dose of an active substance has to be administered in a small volume. The extent to which hyper-osmolarity is tolerated will depend on the route of administration and administration site. The tolerance for parenteral administration, for example, increases in the order: subcutaneous