1
Q
Medicines Act 1968 - related to extemporaneous prep
A
Sections 7 & 8
- manufacture or assemble any medicinal product
- sell, supply or export any medicinal product
- procure the manufacture or assembly of any medicinal product for sale, supply or exportation
Section 9
Does not apply to doctors or dentists
Section 10
Exemptions for pharmacists
2
Q
What is the orange Guide (1971)
A
- promote Good Manufacturing Practice by recommending steps taken by manufacturers to ensure that their medicinal products are of the good quality
- Uniting the main pharmaceutical regulations, directives and guidance expected when making medicinal products
- Compliance is a legal requirement within the EEA
3
Q
Breckenridge Report (1976)
A
Increasing frequency of IV administrations plus increasing complexity of reconstitution and administration requirements, plus increasing complexity of drug regimens equals increased potential for error
Conclusion – reconstitute centrally within the hospital pharmacy
Result – CIVAS/TPN/Chemotherapy
4
Q
Farwell Report (1995)
A
- Detailed approved operational procedures
- Defined responsibilities, competencies, training and performance of staff involved in the activity
- Control of all materials, including containers, devices and packaging, used in the processes.
- Consistent approach to product presentation including labelling
- Full documentation of systems and processes and other product-related issues, e.g., customer complaints
5
Q
QAAPS (5th Edition)
A
Quality Assurance of Aseptic Preparation Services
- NHS response to loss of Crown Immunity and to MCA “Guidance to the NHS on the licensing requirements of the Medicines Act 1968.”
- Nationally agreed quality standards for preparation of aseptic products within the NHS
6
Q
Supervision & Responsible Pharmacist Regulations
A
- Responsible Pharmacist regulations do not apply easily to Section 10 aseptic activities
- Permission to carry out activities under Section 10 exemption from Medicines Act requires pharmacist supervision but not physical presence
- Supervision for aseptic preparation is not specifically defined
- Scope to define “good practice” for this area
- Product approval pilot outcome to redefine good practice based on evidence
7
Q
Section 10 exemption vs. MHRA Specials licence
A
Specials manufacturer licence
Preparation by any suitably trained person
Extended expiry
Batches prepared for stock
Final check and release must be done by separate people (any registered)
External MHRA inspection
Section 10 exemption
Prepared or directly supervised by a pharmacist
Max 7 day expiry
Prepared against a prescription
Final check and release done together by any suitably qualified person
8
Q
What is a quality management system?
A
Quality Management System (QMS) –
A structured system that documents processes, procedures, and responsibilities for continuously delivering high-quality products and services that meet regulatory and customer requirements.
The objective of a quality management system is to provide a framework that improves communication, collaboration, and consistency while also reducing waste, and promoting continuous improvement.
9
Q
What is a quality management system for pharmaceutical products?
A
Manufacturers must make medicines that are fit for their intended use and do not put patients at risk due to inadequate safety, quality or efficacy
The manufacture of pharmaceutical products requires the establishment and implementation of an effective ‘quality management system’ (QMS)’
The basis of an effective QMS in the production of pharmaceutical products must include the concepts of :
Good Manufacturing Practice (GMP)
Quality Control (QC)
Quality Assurance (QA)
10
Q
What do I need to know about PQS?
A
Applicants to become a Qualified Person (QP) will be expected to demonstrate a thorough understanding of the following:
- the basic principles of QA;
- the design criteria for effective QMS
- auditing and self inspections
- deviations and change control
- documentation and record keeping
- the interpersonal skills necessary to implement an effective QMS
- the concepts of risk management
- the principles of design, selection, qualification and maintenance
- the principles of purchasing and supplier certification
11
Q
What is Good manufacturing practice (GMP)?
A
- Good manufacturing practice (GMP) is the minimum standard that a medicines manufacturer must meet in their production processes
Products must:
- be of consistent high quality
- be appropriate to their intended use
- meet the requirements of the MA
12
Q
What is Good manufacturing practice (GMP)
Legal framework?
A
- The legal framework for GMP are stated in a number of EU Directive’s which set out the principles and guidelines of GMP in the EU and UK.
- The GMP regulations establish mandatory, minimum requirements
- For the preparation of medicines, the RP is responsible for GMP
- Compliance is not an option or a matter of choice
- Complying with GMP is the lowest acceptable quality standard
13
Q
What is Quality Control?
A
- The quality of a drug is critical for patient safety and effective treatment.
- If a drug is contaminated or not pure, it could cause harm to patients.
- If a drug is not potent enough, it may not be effective in treating the condition for which it was intended
QC is part of Good Manufacturing Practice which is concerned with:
- Inspecting, Sampling, and Testing the final product for adherence to specified quality standards.
- Products are examined and tested against predetermined criteria to identify and correct deviations from quality standards.
- Products may be tested during different stages of manufacture.
- QC covers detailed documentation of test results and release procedures.
- QC provides a feedback loop for future process enhancements
- QC ensure that the necessary and relevant tests are carried out and that materials are not released for use, until their quality has been judged to be satisfactory.
- QC involves identifying product defects and fixing these problems
14
Q
What is Quality Assurance?
A
- Quality Assurance (QA) is a systematic approach aimed at ensuring the quality of a product throughout its lifecycle
- QA in manufacture is a series of well-defined and documented processes, providing a foundation for consistent, high-quality products.
- Quality assurance aims to prevent mistakes and defects and manage quality through defining processes, establishing standards and developing guidelines
- Each step of production should be carried out by a validated process aimed at assuring quality.
- QA focuses on defect prevention, aiming to reduce errors in the final product by identifying and mitigating potential risks early in the process.
- QA is focused on the entire process of manufacture
15
Q
How do we design an effective PQS?
A
- Manufacturers must make medicines that are fit for their intended use and do not put patients at risk due to inadequate safety, quality or efficacy
- The basis of an effective QMS in the production of pharmaceutical products must include the concepts of :
- Good Manufacturing Practice (GMP)
- Quality Control (QC)
- Quality Assurance (QA)
16
Q
How do you know your PQS is working?
A
Key Performance Indicators
- Statistical Process Control
- Trends
- People surveys
- Deviations
- Opinions
- Audits
- Customer Feedback
17
Q
Limitations of PQS
A
- Cost of quality
- Documentation
- Processes
- Detail
- Knowledge Management
18
Q
Specials and unlicensed medicines
A
- Medicines Licensed in Europe or elsewhere but not on sale in this country
- Medicines for a specified patient in accord with a prescriber’s instructions
- Medicines obtained from holders of a manufacturer’s “specials” licence e.g. hospital or a commercial: liquid formulations, low dose products for children, colour or allergen free
- Re-packed medicines generally used in accordance with the licence (changing the packaging means it is no longer licensed)
- Product is not a medicine but used to treat a rare condition (e.g. metabolic disorders)
- Prepared under a Section 10 exemption.
19
Q
Licensed vs Specials - Legal differences
A
- If medicine is used within the terms of the licence (e.g. at the stated dose and for the indication specified in the SPC) any untoward effects are the legal responsibility of the manufacturer
- If a patient experiences a side effect (even one not specified in the SPC) then patients would have grounds to prosecute the manufacturer
- This is not the case for a pharmaceutical special
- As there is no SmPC, the prescriber takes full responsibility in law for any adverse effects caused by the medicine (unless proven faulty)
20
Q
Legal Matters
A
- Manufacture and sale or supply of medicines was first brought under legal control by The Medicines Act 1968
- Subsequently incorporated into European law by EEC Directive 65/65 amended following Brexit in Jan 2021, but essentially the same
- Updated into Human Medicines Regulations 2012 which requires that:
- All Medicines are licensed before they may be sold or supplied in the UK (with post Brexit amendments 2019 and 2020) (with section 10 exemptions)
21
Q
Conditions of section 10 exemptions
A
As a pharmacist you must have:
Bona fide unsolicited order
Product is formulated for a specified patient in accordance with the requirement of a practitioner registered in the UK
As a pharmacist you must be sure:
- Product is for use by your individual patients on their direct personal responsibility
broadly includes any form of extemporaneous dispensing, including TPN compounding, IV additives and cytotoxic reconstitution
- If a ‘special’ is manufactured in the UK, the manufacturer must hold a manufacturer’s (specials) licence from the MHRA and / or an Investigative Medicinal Products (Clinical Trials) Licence
- Pharmacies must have the appropriate equipment and facilities available to produce a high quality, safe product
- Serious adverse drug reactions reported to MHRA (Yellow Card Scheme
22
Q
A ‘special’ may not be advertised
A
- Because “specials” have no product licence they cannot be offered for sale by a manufacturer, but must be procured or commissioned by a purchaser
- “Specials” manufacturers can advertise their services only
- The Medicines for Human Use (Advanced Therapy Medicinal Products and Miscellaneous Amendments) Regulations 2010 amended the legislation and allowed price lists be published
- Because of the bespoke nature of some specials, it’s not be possible for all unlicensed medicines to be included in price lists
23
Q
Risk assessment: what’s on it?
A
- The risk assessment for unlicensedmethods should state what the risks are
and whether an equivalent relevant licensed product exists and is available
It should also include (GphC standard)
formula from a recognised source e.g.
- Pharmacopeia
- Method validation
- Calculation verification
- Need/use of specialist equipment
- Contamination & hygiene measures
product-specific risks
- Suitability of premises
- Staff skills / knowledge / training / competence
24
Q
Essential records must be kept
A
A record should be kept, including as a minimum
- name of product;
- specification;
- prescriber’s name, if appropriate;
- manufacturer and (if different) supplier;
- date ordered;
- quantity ordered;
- batch number received
- Retained for least 5 years
25
Transmissible Spongiform Encephalopathies
- TSEs = neurodegenerative diseases caused by a prion (always fatal)
- All manufacturers, importers and exporters of unlicensed medicinal products for human use are required to comply with the provisions of the Regulations
- If an unlicensed medicine (special or extemp) is supplied and is proved to carry a risk from TSE and any harm to a patient is caused, those making or importing or marketing that product would be held liable
26
3 measures to minimise contamination
- Environment is suitable for medicine preparation
- Specific steps taken to ensure that risk of chemical cross-contamination and microbial contamination is eliminated or minimised
- Use knowledge and awareness to inform practice
27
Liability with specials
- Unlike medicines with an MA (i.e. licensed), assumptions of quality, safety and efficacy cannot be made about unlicensed products
- Individual unlicensed medicinal products do not go through the same processes of independent scrutiny as licensed products
- Manufacturers of unlicensed medicines might not have been able to obtain all the necessary evidence of compliance for all their products
- Users (i.e. prescribers and pharmacists) need a process for assessing the risk, quality and suitability of unlicensed specials and extemps.
- This is usually in the form of a policy or SOP
28
Policy with specials
=- It is usual for a senior pharmacist to have overall responsibility for controlling the procurement and supply of specials
- The policy should detail the responsibilities of all staff involved in commissioning, purchase and supply of unlicensed medicines
- Records should be kept e.g. product; specification; prescriber, supplier; date & quantity ordered; when received, batch number
Complaints and Recall
- A system for handling complaints is required
- Concerns are raised when you suspect that medicines are not fit for purpose.
- Systems need to be in place so that you can demonstrate that you can effectively manage an appropriate response and take action
29
Biopharmaceuticals (‘biologics’)
Proteins
Antibody based:
‘Whole’ antibodies (monoclonals)
Antibody-drug conjugates (ADCs)
Fusion proteins
Antibody fragments
Simple peptides (e.g. insulin)
Glycoproteins (e.g. Filgrastim)
Cytokines (e.g. Erythropoetin)
Enzymes (e.g. pancreatin, streptokinase)
Vaccines
Gene therapy
30
Monoclonal antibodies (‘mAbs’)
- Quaternary glycoproteins ~150kDa
- Typically, IgG1 but can be IgG2/4
- Multiple mechanisms of action
- mAbs are recombinant proteins from mammalian cells – typically hamster ovary cells.
- IgG1 are the easiest to develop (less potential for isomers) and have the most potent ADCC/CDCC effects.
- IgG4 useful if you do not want much Fc activity.
- IgG1 and IgG4 both have 16x disulfide bonds. IgG2s have 18 (2 extra bonds linking heavy and light chains in the hinge region).
IgG3 is not used as they are cleared from the body too quickly (3x faster)
31
Monoclonal antibodies glycosylation
- Glycan molecule attached to Asn297 side chain
- Oligosaccharide molecule: typically 8-12 sugars
Glycosylation pattern on mAbs affects
- Pharmacodynamics
- Pharmacokinetics
- Bioavailability
- Oligosaccaride groups are relatively small contribution to size MAB’s 5% ish however big impact on function and behaviour. Correct glycosylation is fundamental to correct functioning
- Removal of sialic acid results in Galactose exposure which promotes active excretion. Loss of alpha 1,6 fucose on IGG results in enhanced ADCC activity.
Also the growth media of the cells (sugars available in the ‘nucleoside pool’)
Sugars will depend on the species used to manufacture the mAb – effects immunogenicity
32
Monoclonal Antibodies – Biosimilars
A biologic medicine that is similar to an already licensed biologic in terms of quality, safety and efficacy.
Specifically developed and licensed to treat the same disease(s) as the original innovator product.
33
Fusion proteins
Typically consist of
Fc portion of an IgG antibody
A target receptor (e.g. TNFR)
Examples: abatacept, aflibercept, etanercept
34
Antibody-drug conjugates (ADCs)
- Highly-potent cytotoxic agents conjugated to mAb
- Attached via Cys or Lys residues
- Only 13 currently on UK market
- pH sensitive linkers, enzymatic cleavable linkers, glutathione sensitive linkers, non-cleavable linkers,
- Lysine, Cysteine or engineered residue attachment
- Thio-bridges linkers improve stability
- Low DAR reduces molecule potency
- High DAR reduces molecule half-life but increases toxicity & aggregation
35
New nomenclature of mAbs
-tug
Conventional full antibodies
-bart
Artificial full antibodies
-ment
Antibody fragment
-mig
Multi-specific biologicals
-fusp
Antibody cytokine fusion (protein)
36
Biopharmaceutical safety with biologics
- Biologics are generally less hazardous than conventional cytotoxic chemotherapy drugs
- Risk of immunogenic reactions
- Potential for teratogenic effects (many can cross placenta)
- ADCs should be treated as cytotoxic
37
Biopharmaceutical manipulation
- Compounding a biopharmaceutical into a ready-to-use medicine drastically changes the drug environment
- Generally, protein-based medicines such as antibodies are formulated as free-dried powders lyophilisates; but this must be changed to make patient friendly
38
Degradation pathways of proteins
Chemical degradation leads to physical degradation
- Handling and storage has the potential to disrupt ‘weak bonding’ which can result in physical degradation
- Adsorption onto bag
- Chemical modification of individual residues involved in higher-order structure stabilisation
- Denaturation
- Aggregation
- Fragmentation (e.g. reduction of –S-S- bridges leads to chains falling apart)
39
Biopharm chemical degradation
- Deamidation affects asparagine and glutamine residues where a nitrogen atom in polypeptide backbone react with the primary amide on the a/a side chain, resulting in loss of an amine group.
- Oxidation is the addition of oxygen to a molecule, typically methionine but solvent accessible tryptophan, cysteine, lysine and histidine will also be oxidised
- Deamidation of asparagine drives conversion to aspartic & iso-aspartic acid, which has been associated with reduced stability and aggregation due to altered charge states
- Acid hydrolysis occurs at pH 6 leading to the production of fragments, increased rates of aggregation and loss of monomer API. This appears to stop at pH 8
40
Protein aggregation
- Protein aggregation is the abnormal association of proteins into larger insoluble aggregate structures
- 0 mAb monomers are around 10 nm in length
- Soluble aggregates can be detected by specialised techniques that use laser diffraction
- Insoluble aggregates up to approx 50um can be detected by microscopic techniques such as microflow imaging
- Aggregates above 50um may be detectable to the human eye
- Effectiveness of antibody treatment is reduced
- Increased likelihood of immunogenic reactions in patients
- In severe cases, micro-vessel occlusion can occur
41
Antibody fragmentation
- The peptide bond is incredibly stable
- Disulphide bonds can be broken during API manufacture
- Peptide bond half-live is over several hundred years, when disulphide bonds are broken it forms fragments impurities in the product
42
5 examples of environmental stress
- Photo Degradation
- Thermal Degradation
- Freeze-Thaw
- Temperature Cycling
- Oxidative Stress
43
What materials are used in syringes?
Syringes
- Polypropylene barrel (PP)
- Polycarbonate, polyisoprene or rubber/latex plunger
- Silicone oil
44
What materials are used in IV bags?
Infusion Bags
- Polyvinyl Chloride (PVC)
- Polyethylene & Polypropylene (PO)
- Ethylene vinyl acetate (EVA)
- Polyamide (PA)
45
What is the impact of container materials?
'Polyolefin' (PO) collectively describes polyethylene and polypropylene, and any polymer with the chemical formula CnH2n produced from a hydrocarbon monomer unit. PO and EVA are widely used alternatives to PVC, where use has declined over time as was deemed inferior for pharmaceutical device applications.
PVC is more likely to interact with drugs and cause instability than POs
46
Formulation Conditions
High concentration more protein-protein interaction & adsorption
Low concentration less stable during freeze-thaw/lyophilisation
Lyophilisation
Loss of 10-20% activity upon reconstitution
Diluent
WFI: Drives intermolecular force attraction due to lowered tonicity
5% Glucose: Glycation, not suitable for acidic biotherapeutics
0.9% NaCl: Reduces intermolecular force attraction
pH
Irreversible crosslinking outside pH 4 – 10
Impacts oxidation rate
High viscosity protects from physical stress during manufacture
Extreme viscosity increases protein-protein interactions
During storage of therapeutic mAbs, glycation can be introduced by reducing sugars in the formulation.
47
Protective Excipients
- Mabs are generally highly water soluble, and do not require co-solvents to enhance this
- Detergents prevent proteins from adsorbing onto surface of container
- Surfactants: Reduce aggregation rate
- CAA binding to cationic sites on the antibody and stabilising the folded state and strengthening the electrostatic repulsion between antibodies thus preventing association
- Reducing sugars and certain disaccharides should be excluded as they react with primary amines in the protein molecule (maillard reaction)
- Cu and Fe have deleterious effects on proteins - Metals ions drive oxidation from manufacturing but also needle exposure
48
49
Potential routes of exposure:
- Ingestion (Consuming)
- Inhalation (Breathing)
- Dermal (Absorption through skin)
- Mucosal membranes (moist lining of organs & cavities)
- Percutaneous (needle puncture)
50
Defining hazardous drugs
- Carcinogenicity
- Teratogenicity
- Reproductive toxicity
- Organ toxicity at low doses
- Genotoxicity (Older Cytotoxics)
51
Latency Periods
The latency period following exposure may be years
It may be many more years before risks linked to occupational exposure are fully understood
Safe handling techniques have reduced potential exposure, de-risking handling hazardous materials
52
Hierarchy of control
Assess risk
Eliminate (e.g. resheathing)
Substitute (e.g. powders for liquids)
Engineering controls (e.g. room design)
Administrative controls (e.g. training)
PPE
53
Decontamination
Removal
- Aqueous clean
- Detergent
- Validated method
Denaturation
- Biologics
- Bleach or alkaline agents
54
Spillages
- Risks & procedures depend on area and nature of spill
- Incident reporting / documentation
- Proper disposal of contaminated equipment
55
Environmental Monitoring
Monitor key areas for contamination;
– surfaces of work area (and surroundings)
– starting materials
– finished products
Link results to audits & training
56
57
The role of Pharmacy in aseptics
Supply medicines ‘ready to use’
Supply medicines of the appropriate quality
Must not present a microbiological or particulate hazard to the patient
Use technical expertise to supply a stable preparation with an appropriate presentation and formulation
Supply within legal boundaries
Supply medicines via the appropriate route
58
How do patient factors affect formulation?
Patient type e.g. premature, elderly, sick, healthy
Dose range
Access routes
Volume
Rate of administration
Other drugs
Setting (hospital, homecare)
59
How do drug properties affect formulation?
Concentration
Volume required
Impact of infusion bag overage
Solubility
Co-solvents/ surfactants / buffers required to maintain solubility
Physical stability
Vibration
Tonicity
Isotonic ideal
Stability
pH
solution/solid
Catalyst
Diluent
Light
Storage Temperature
Room
Refrigeration
Freeze/ thaw
60
How does the container affect formulation?
Adsorption
Formulations with polysorbates to solubilise the drug
Oxygen permeability
Moisture permeability
Closure of container (microbiological)
Rate of administration
61
Assigning expiry & formulation
SmPC
Generated by Company.
Available on the MHRA website
Dose & Administration information
Reconstitution details & stability
Pharmaceutical Particulars
Excipients, incompatibilities, shelf life, storage, handling instructions
Not written for aseptic process
Displacement values omitted
Microbiological stability provided
62
The role of the worksheet in the PQS
Our documentation is as important as our products – Why?
Essential, mandatory part of GMP – Regulatory.
Without documentation our products cannot be released.
Documentation provides batch traceability.
Documentation provides a real time record of what was happening at any point in time.
Ensures consistency – defines the system.
To support and record effective training.
Reduces errors and misunderstanding created by verbal communication.
63
PQS requirements
By signing a GMP document you are confirming that you have completed or checked a particular task.
Sign only if you have performed the actions (DO NOT sign on anyone else’s behalf or their say so)
Read documents carefully prior to signing.
Only complete tasks which you have been trained on and are competent to do.
Never copy a previous entry.
Never discard raw data
64
Labelling a specials product
- Risk of administering wrong drug or dose to patient if the label does not correspond with the contents.
- Risk of administering an unstable product if the expiry date is incorrect.
- Professional appearance, clarity & placement to avoid obscuring graduations
- Reconciliation process is important
65
66
What are the risks?
Infection / sepsis
Thrombophlebitis
Extravasation
Air embolism
Dose errors
Incorrect drug given
Incorrect site
Incorrect rate
Incorrect formulation
67
Head space - vials
Impact on reconstitution volume
Larger head space enables more solution to be added
Improved dissolution and more effective wetting of powder
Less air improves dissolution
Less viscous & easier to remove
less drug remaining in vial
68
Dead space
The term "high dead space" refers to the fluid remaining within the needle and between the syringe hub and the plunger
This space can be as high as 84 microlitres in conventional syringe/needless
Beware of ‘dead-space’ contribution to errors
Incorrect quantity of solution (> patient receiving incorrect dose – low or high)
69
Air in syringe
Risk of air embolism in patient
Fatality is dependant on volume and rate
Incorrect volume of solution (patient receiving low dose)
Implications for stability & infusion rate
70
Incomplete bung seal
Reduction in safety barriers to user
Risk of Integrity of syringe being compromised
Infection
71
Drug in the bung
Risk of contamination to user
Integrity of syringe has been compromised exposing the contents of syringe to microbiological contamination
72
Drug in the hub
Risk of exposure to Cytotoxic drugs
Creates a fluid pathway for microbiological contamination into the solution
73
Documentation rules
Make records in real time
Write dates and numbers consistently
Use black and blue pen
Complete all gaps with N/A or lined through and sign & date
When an error is made, the whole word/number needs to be lined through & the correct word/number rewritten (sign + date)
A check signature confirms you actually saw / checked everything was correct
Do not make copies of documents unless you are authorised
74
75
What is an aseptic area?
A highly controlled clean environment which has been specially designed, constructed and maintained to prevent microbial and particulate contamination of pharmaceutical products
76
use of cleanroom
Highly controlled environment
Minimise viable and non–viable contamination (particulates)
Filtered and re-circulated air
Use HEPA filters (removes particles above 0.5 micron)
Controlled temp. & humidity.
At positive pressure
Graded A-D
77
How are rooms ranked A-D?
A - high risk operations
B - background support of A
C - Less critical operations (prep)
D - Less critical/background operations (cleaning)
78
5 sources of microbial contamination in aseptics
People
Workspace
Starting materials & consumables
Storage
Aseptic process
79
How can people cause contamination?
People produce respiratory droplets which contain bacteria
People shed dead skin particles which carry bacteria
Shedding increases with movement
80
How can starting materials cause contamination?
Viable microorganisms in the starting materials or the consumables used for the aseptic process will be transferred to the product.
81
How can storage cause contamination?
Contamination can be introduced during storage
Paper and cardboard harbour fungal and bacteria spores
Uncovered items will collect dust
82
How can aseptic process cause contamination?
Operator
Staffing – (too many? too few?)
Supervision
Transfer disinfection - between grades of room (usually through a hatch)
Storage of opened ampoules
Number of sterile manipulations performed
83
Minimising risk of contamination: 1 People
Sterile clothing- PPE
Tuck in to gloves and boots.
No outdoor clothing
No infections/skin lesions/, open wounds
No wristwatches, make-up, jewellery,
Regularly decontaminate hands
Minimise movement (shedding).
Lighting/ Temp/ Humidity
Management
Optimise staff number
Good work flow
Training
84
Minimising risk of contamination: 2. Work space
Filter air - HEPA filter
Maintain rooms at positive pressure
Perform aseptic operations in a BSC or Isolator (Grade A).
Work areas must be clean, disinfected, dry & tidy
Use disinfectant in rotation
Correct preparation and ‘In-use’ dilutions
Correct contact time
Regular use of sporocide
Grade A & B areas: Sterile disinfectants
Regular monitoring required
85
Minimising risk of contamination:
3. Starting materials & consumables
Starting materials: sterile products with a product license
Consumables: pre-sterilised by the manufacturer & packaged correctly
Remove from paper/cardboard packaging where possible
Sterility maintained by the operator
86
Minimising risk of contamination: 4. Storage
Products stored appropriately:
- Minimise time between prep. & admin.
- Max. expiry = 7 days
(longer if prepared in a licensed facility)
Store at 2-8oC where possible
87
Validation & monitoring for aseptic processing
Aseptic processing is tightly controlled through
(i) Validation of equipment, processes, techniques & staff
(ii) Use of SOPs, monitoring, training & competency assessment
88
What are the three types of validation?
Facility validation
Process validation
- simulate aseptic operation using microbiological
media e.g. simulated broth fill
Must represent the process you are validating
Cleaning validation
- confirms removal of microbial, chemical,
biological & viral contamination
89
Microbial monitoring
Performed to a set schedule throughout whole Aseptic unit.
And performed during each session of aseptic manufacture
Settle Plates.
Swab 10x10cm work area with moistened swab.
Finger dabs-
Performed by each operator at the end of each session
Assess contamination.
Knowledge of labs ‘usual’ level.
Knowledge of labs ‘usual microbiome’
Record results and check limits
90
Common contaminants
Settle plates
G+ves: Bacillus, Staphylococcus, Micrococcus, Streptomyces
(Skin and environmental bacteria)
Moulds: Cladosporium, Aspergillus, Penicillium
Finger dabs
G+ves: Staphylococcus, Micrococcus, Streptococcus
91
What to do if levels exceeded.
You will know the typical numbers of organisms you expect in your facility.
Alert levels and action levels are set for all tests
Alert levels – 2.5% outside ‘normal’ limits (QA book)
Action levels – 5% outside limits
Perform regularly & assess trends
For levels 7.5% outside limits:
Apply Deviation Management through PQS
92
93
What are radio pharmaceuticals?
Radioactive drugs which are administered to patients for:
Diagnostic purposes
Therapeutic purposes
Used for imaging or non-imaging
Uses ionising radiation - Gamma, beta, alpha
94
Nuclear decay
Alpha Decay
Ejects a doubly charged Helium nucleus He2+
Beta Decay
Excess neutrons gain stability by converting neutron to a proton + negatron (nuclear electron or beta particle)
Gamma
No particles emitted only gamma photons
95
Nuclear vs xray
Isotopes are emitting from inside the patient
Isotopes show function
Isotopes show change as it happens
X-rays pass through the image
X-rays show structure only
X-rays only show changes post event
96
The Gamma Camera
Detects gamma radiation
Collimator - absorbs scatter to give clearer image
Sodium Iodide crystal
Produces a light pulse
97
Radionuclides
99m Technetium
140 Kev energy
6hr half life
201 thallium
68-80 Kev
71 Hr half life
111 Indium
370Kev
2.6 days half life
123 Iodine
13hrs half life
159 Kev
131 Iodine
8 day half life
364Kev, 600Kev
67 Gallium
78 Hr half life
93,194,296 Kev
98
Tc-99m
Nuclear istope for radio-imaging
Easy to manufacture
Readily available
Short half life
Gamma emitter
Low energy range
Decays to stable isotope
Combines with a wide range targeting tracers
99
Additional roles of the Radiopharmacist
Clinical Pharmacy
E.g. Adjuvant drugs
Drug Information
E.g. Breast feeding
Teaching and training
Research and development
Clinical trials
100
Kidney Scan
A MAG3 renal scan is a non-invasive imaging test that uses a radioactive tracer called MAG3 to assess kidney function, urine flow, and identify potential blockages
101
DMSA - DIMERCAPTOSUCCINIC ACID
Binds to heavy metals in body
Passes through glomerulus but reabsorbed in distal tubules
65% bound to renal tubules
Function & renal outline
Renal scarring
Used extensively in paediatric nephrology
102
Lung scan - V/Q scan
A ventilation-perfusion scan is a nuclear medicine test that assesses how well air and blood flow in your lungs
VENTILATION
Inhale Krypton-81 gas and traced
PERFUSION
Inject MAA into vein, see how blood travels
103
Pertechnetate ( TcO4)
Pertechnetate (TcO4-) is a radioactive chemical used in thyroid imaging
Technetium has similar size and shape to Iodine
Stomach – Meckels diverticulum
104
Organic phosphate complex
Homogenous distribution of tracer throughout skeleton
Uptake by hydroxyapatite crystals
Uptake dependent upon bone turnover
Bone Metastases lead to areas of increased uptake in the skeleton as bone is replaced by tumour cells.
Eventually pathological fractures occur
105
Colloids
a mixture in which one substance consisting of microscopically dispersed insoluble particles is suspended throughout another substance
particle size denotes usage
Liver colloids: not used now replaced by CT
Bone marrow and Lymphatics
Standard lymphoscintigraphy
Sentinel Node Localisation
106
Defecating Proctoscintigraphy - Radioactive porridge
The ideal pseudostool
80 mls P.R.
Pooh in the potty
Calculate the pooh rate
Draw the pooh curve
107
108
ATMP
Advanced Therapy Medicinal Product
Biological medicine that is classified as one of the following (or combination of):
Gene therapy
Somatic cell therapy (SCT)
Tissue Engineered Product (TEP)
109
Gene Therapy
A biological medicinal product which contains an active substance which contains or consists of a recombinant nucleic acid used in, or administered to human beings, with a view to regulating, repairing, replacing, adding or deleting a genetic sequence; and its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence.
110
Somatic cell therapy (SCT)
A biological medicinal product which contains or consists of cells or tissues that:
1)have been substantially manipulated ex vivo, or
2) - are not intended to be used for the same essential function(s) in the recipient and the donor.
111
Tissue Engineered Product (TEP)
A biological medicinal product that contains or consists of cells or tissues administered to human beings with a view to regenerating, repairing or replacing human tissue. A tissue engineered product may contain cells or tissues of human or animal origin, or both. The cells or tissues may be viable or non-viable. It may also contain additional substances, such as cellular products, bio-molecules, bio-materials, chemical substances, scaffolds or matrices.
112
ATMPs starting products
ATMPs may be autologous (starting material is from the intended recipient), allogeneic (starting material originates from a donor) or xenogeneic (starting material is of animal origin).
ATMPS can also be classed as a Combined product; this is a combination of any of the above with a medical device.
113
ATMP regulation
Medicines subject to the same requirements as other medicinal products
Chief Pharmacist is responsible for governance and management of ATMPs
Current usage is in clinical trials, and as licensed and unlicensed medicines.
114
Role of Pharmacy in ATMPs
To oversee governance arrangements
To ensure ATMPs are of appropriate quality for intended use
Collaborative working with Human Tissue Authority (HTA) designated individual within organisations to develop collaborative process to provide appropriate governance and handling of ATMPs
115
ATMP Governance Considerations
ATMPs are innovative products often with novel administration procedures
Scrutiny by organisational multidisciplinary committee e.g. Medicines Management, New Interventional Procedures committee, ATMP committee
For gene therapy – review by Genetic Modification Safety Committee
116
Pharmacy Practicalities
Storage
-80oC freezer
nitrogen vapour storage dewar (-150oC)
Handling
Sensitivity of cellular product
Patient specific
COSHH category 2 biohazards
Training
Dedicated staff (may be outside of pharmacy)
Delivery
May be directly to end user
Pharmacy oversight required
Preparation
Specialist components & training
Consideration for appropriate facilities
Risk assessment for location
May be outside of pharmacy
Logistics
Short shelf life
Planning and liaison with MDT
117
Pharmacy Arrangements
Option appraisal for product management
Use of appropriate expertise
Regulatory and Manufacturing authorisations
Good Clinical Practice oversight
Patient safety
Robust governance
Staff skills and training
118
Manufacture, supply & handling
Facilities for manufacture may be outside of pharmacy
SOPs required for safe handling
Handling will be dependent on product
Supply my not be directly from pharmacy
Pharmacy have overall responsibility for medicine manufacture, supply & handling
119
Gene Therapy Medicinal Products
Pharmacy process for initiating GTMP
Protocol
Risk assessment
Technical feasibility assessment
Genetic Modification Safety Committee approval
Confirmation of class and containment
Standard Operating Procedures
In vivo GTMP – injected directly into a specific tissue or administered intravenously
Ex vivo GTMP – sample of patient’s cells removed and incubated with viral vector to form engineered cells. The genetically modified cells are classed as a medicine. E.g. CAR-T cell therapy
120
Routes of Gene Therapy Administration
1. In vivo administration:
Inhalation (eg via aerosol)
Oral
Intramuscular injection
Subcutaneous injection
Intravenous injection
Intranodular injection
2. Ex vivo administration:
Target cells removed from the patient, transduced in cell culture, then genetically altered cells are returned to the patient
121
Gene therapy medicinal products
GTMPs are designed to introduce genetic material into cells to:
Compensate for abnormal genes
Make a beneficial protein which then multiplies and exerts a positive effect
Introduce a normal copy of the gene to restore the function of the protein if a mutated gene causes a necessary protein to be faulty or missing.
122
Types of Vectors for Gene Transfer
Plasmid DNA
Retroviruses
Adenoviruses
Adeno-associated vectors
Vaccinia/fowlpox vectors
Poxviruses
Herpes Simplex virus
Salmonella
Lentivirus
123
Advantages of adenoviruses
Enters dividing and non-dividing cells.
Not integrated into host
genome.
Transient therapeutic DNA expression.
124
Disadvantages of adenoviruses
Host immune response
Limited insert size.
Transient therapeutic DNA expression limits applications.
125
Advantages of Retrovirus
Well characterised.
Efficient gene transfer.
Long-term expression of therapeutic gene.
126
Disadvantages of retroviruses
Safety issues.
Limited insert size.
Random integration of therapeutic gene.
127
Advantages of adeno-associtaed viruses
Integrates into host at specific site.
No immune response.
128
Disadvantages of adeno-associtaed viruses
Difficult to produce viral stocks.
129
Risks associated with Gene Therapy
Viral vectors can infect healthy cells
New gene might be inserted in the wrong location in the DNA, possibly causing cancer or other mutations
Introduction of DNA to patient’s reproductive cells.
Over expression of gene product.
Immune reaction caused by viral vector.
Transmission of viral vector from the patient to other individuals or the environment.
130
Considerations When Handling Gene Therapy In Clinical Settings
Regulatory bodies
Classification of risk & risk assessment
Biological containment level
Routes of exposure
Minimise staff exposure, risk to patient and contamination of environment
Integrity of product
Accepted national practice
Standard operating procedures (SOPs)
131
HSE Genetically Modified Organisms (Contained Use) Regulations 2014
Came into force on 1st October 2014
Describes the law applying to GMOs
Containment measures & controls
Role of the competent authority (HSE)
Risk assessment
Classification of contained use work
Accident reporting
132
HSE Definitions - Genetically Modified Organisms (GMOs)
A genetically modified organism is defined as an organism (with the exception of humans) in which ‘the genetic material has been altered in a way that does not occur naturally by mating and/or natural recombination’ using ‘recombinant nucleic acid techniques involving the formation of new combinations of genetic material by the insertion of nucleic acid molecules, produced by whatever means outside an organism, into any virus, bacterial plasmid or other vector system and their incorporation into a host organism in which they do not naturally occur but in which they are capable of continued propagation’.”
133
Classification of Risk
GMOs are classified as one of four classes (1, 2, 3 and 4), based on the risk to human health and the environment.
Class 1 activities involve the least and class 4 the highest risk.
Class 1 activities are unlikely to result in harm to humans or the environment (no or negligible risk).
Work with any agent able to cause human disease is categorised as class 2 (low risk) or higher (class 3 = moderate risk; class 4 = high risk).
134
Staff Training
All staff handling gene therapy must be appropriately trained.
Employees must be aware of the risk associated with the therapy and have an option not to be involved.
Staff handling gene therapy should not be pregnant, breastfeeding or immunosuppressed.
Document & update staff training.
Involve Occupational Health.
135
Pharmacy Supply of gene therapy
Supply from pharmacy department
Storage - freezers
Transport – containment, spillage
Defrost
Shelf life at room temperature
Reconstitution and dilution
136
Pharmacy handling of gene therapy
Specific gene therapy aseptic unit facilities
Minimises risk to environment
Minimises microbial contamination
Reduces medication errors
Personal protective clothing
Containment measures
Follow SOPs, SPS and HSE guidance
137
Near patient delivery of gene therapy
No pharmacy aseptic facilities
Pharmacy storage and dispensing
Nursing handling and administration
Class 1 handled in clinical areas
Class 2 handled in side rooms
Class 1 & 2 defrosted & drawn up at bedside
Personal protective clothing
Dilutions at bedside with pharmacy prepared worksheets – undertaken by trained & competent staff
Roles & responsibilities clearly documented
138
Practical barriers to near patient delivery of gene therapy medicines
Risk assessments
Standard Operating Procedures
Safe storage – pharmacy or clinical area?
Temperature monitoring
Transport
Training and competency assessment
Spillage and waste disposal
Aseptic facilities
139
Implementation and Management of ATMPs SOP
Introduction of ATMP
Risk Assessment
Committee Assessment and Approval
Occupational Health
Training
140
Handling ATMP Gene Therapy Medicines SOP
Handling procedure
Administration – class 1 and class 2
Waste disposal
Spillage decontamination
Accidental Exposure
Incident reporting
Training
141
Car-T Cell Therapy
Patient-specific (autologous) cell therapies
Patient’s own T lymphocytes - genetically modified to express a chimeric antigen receptor to confer antigen specificity
Genetic modification by manufacturer
Using viral vector derived from a retrovirus or a lentivirus, which carries the new gene for the chimeric receptor (ex vivo gene therapy)
Car-T Cell Therapy commissioned sites
142
Licensed Car-T Cell Therapy (CDF)
Axicabtagene ciloleucel (Yescarta)
Large B Cell lymphoma
Tisagenlecleucel (Kymriah)
B-cell acute lymphoblastic leukaemia (ALL) Childhood leukaemia
Specifically developed for each individual patient
Involves reprogramming the patient’s own immune system cells which then target the cancer.
Trials have shown cure in some patients
143
Car-T Cell Therapy manufacture
Procurement of patient cells – pharmacy oversight required
License under Human Tissue Authority (HTA)
Secure supply chain to link donor material to final product throughout manufacture
Received frozen at cryogenic temperatures (<-155oC) in vapour phase nitrogen (VPN)
Preparation step post-defrost
144
145
Why does community pharmacy need to innovate?
Pharmacy funding has been reducing in real terms
More items to be dispensed with less resource
Pharmacists are expected to undertake more services
Paper heavy industry
Duplication of tasks
Increase in skilled tasks
146
The growth of online pharmacy
Online pharmacies make up 6 of the top 10 pharmacies for items dispensed each month.
In 2023-24 they accounted for over 32,700,000 items. In 2024-25 it has risen to over 37,000,000.
Growth of these pharmacies accelerated quickly during the pandemic.
At these scales, digital innovation is crucial to maintain safety, service levels and drive profitability.
147
Improving patient outcomes
Fast uptake of new services (Covid vaccination clinics)
Improved patient experience
Access to patient data
Better support for vulnerable patients
Patients are able to take more ownership of their medications
148
Diversifying the role of the pharmacist
Digital services pharmacist roles
Reduction in time spent in the dispensary
Increasing focus on the patients with the greatest need
Remote working
Portfolio working
149
Types of innovation
- vending machines
- dispensing robots
- monitored dosage systems
- prescription apps
- AI
- digital services
150
Barriers to innovation
Cost is the biggest barrier
Although more efficient, the upfront cost of most digital solutions is too high for many pharmacy companies and they do not have the capital to invest
Integration
New technology needs to be able to work with legacy systems
Capability
New technology requires up skilling and adds in extra complexity to an operation
Patient adoption
Patients can be reluctant to move use new systems
151
Future trends
Additional Role Reimbursement Scheme (ARRS)
Independent Prescribers (IP)
Specialist services
Essential and enhanced services
152
153
What is the progesterone-only pill
They increase the volume and viscosity of cervical mucus, thereby preventing sperm penetration into the upper reproductive tract
They also suppress ovulation by suppressing mid-cycle peaks of luteinizing hormone and follicle-stimulating hormone.
Menstrual irregularities are a common side effect and often a reason for women stopping the POP.
take continuously
154
What is the combined pill
Act on the hypothalamic-pituitary axis to reduce the production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). With no surge in LH and FSH to stimulate the ovaries, ovulation does not occur.
Also have contraceptive effects on cervical mucus and the endometrium
Less chance of menstrual irregularities (usually gives you good period control), but some women do experience side effects.
The 7-day interval causes oestrogen and progestogen concentrations to fall, which causes the endometrium to slough, mimicking menstruation
There is no health benefit from having this hormone-free interval
Tailored regimens can be used based on patient preference. The use of CHC in this way is off-label.
Multiphasic combined oral contraceptives (COCs) should not be used in these tailored regimens.
155
Community Pharmacy Contraceptive Service
PGDs in place that allow us to continue or initiate the supply of oral contraceptives.
Pharmacists must be familiar with at least one online shared decision-making contraception consultation tool.
Complete CPPE training on contraception, emergency contraception and sexual health
Declare competence
156
Emergency contraception in community pharmacy
EllaOne (Ulipristal acetate) or Levonelle (levonorgestrel) can be bought OTC
Also can be available as a locally commissioned service
PGD in place to allow supply of POM levonelle, or sale of EllaOne
Free of charge to some women, usually under 25, but depends on service specification
Consultation: Hx, MEC, informed choice, STIs, safeguarding, regular/LARC contraception
Advanced supplies?
Ethics: Who are you going to provide it to
157
Why do people take HRT?
Hormone Replacement Therapy – used to control symptoms associated with the menopause
In menopause, periods stop due to the change in hormone levels, and this change in hormone levels can cause an array of unwanted symptoms
158
HRT in Community Pharmacy
HRT pre-payment certificate: £19.80/year (vs £9.90/item)
Logistical issues currently!
SSP (Serious Shortage Protocols): HRT supply issues
Estradiol 10mcg vaginal tablets: >50y/o; last period over 1-year ago
159
160
Pharmacy (Preparation and Dispensing errors – Hospital and Other Pharmacy Services) Order 2022
Aim of this Order is to remove the threat of criminal penalties for inadvertent (accidental or unintentional) preparation and dispensing errors by pharmacy staff working in hospitals and similar settings
Under the 1968 Medicines Act, there are already ‘defences’ pharmacy professionals can use if they are responsible for an accidental or unintentional preparation or dispensing error that since 2018 pharmacy staff working in registered pharmacies have been able to use.
The Order now includes pharmacy staff working in hospitals and certain other pharmacy settings, such as care homes, some Integrated Care Boards (ICBs), some ambulance trusts, prisons, and other places where people are lawfully detained.
To benefit from the defences set out in the Order, the hospital (or other pharmacy setting listed in the Order) must have a Chief Pharmacist (or equivalent) in post, with the appropriate skills, training, and experience.
161
Never Events
Defined as Serious Incidents that are “wholly preventable” because guidance or safety recommendations that provide strong systemic protective barriers are available at a national level and should have been implemented by all healthcare providers
barriers that must be successful, reliable and comprehensive safeguards or remedies – for example, a uniquely designed connector that stops a medicine being given by the wrong route.
162
What are the 5 Medication Never Events
Mis-selection of a strong potassium solution
Administration of medication by the wrong route
Overdose of insulin due to abbreviations or incorrect device
Overdose of methotrexate for non-cancer treatment
Mis-selection of high strength midazolam during conscious sedation
163
The NHS Patient Safety Strategy
Patient safety is about maximising the things that go right and minimising the things that go wrong for people experiencing healthcare.
Describes how the NHS will continuously improve patient safety over the next five to ten years.
It is human to make mistakes
need to continuously reduce the potential for error by learning and acting when things go wrong.
164
Patient Safety Incident Response Framework
Sets out the NHS’s approach to developing and maintaining effective systems and processes for responding to patient safety incidents for the purpose of learning and improving patient safety.
Principles all Trusts to adopt:
Compassionate engagement and involvement of those affected by patient safety incidents
Application of a range of system-based approaches to learning form patient safety incidents
Considered and proportionate responses to patient safety incidents
Supportive oversight focused on strengthening response system functioning and improvement
165
Blame Myths -Perfection and Punishment
The Perfection Myth
“If we try hard enough we will not make errors”
The Punishment Myth
“If we punish people when they make errors they will not make them again”
We do not yet know enough about how the interplay of normal human behaviour and systems determines patient safety
Blame can be disguised within otherwise valid approaches to improvement such as training and reflection. When these are recommended for one individual only, the underlying assumption is that they alone are the problem that needs fixing.
This individual approach does not prevent future errors
166
Understanding Causes of Error
Person centred approach
Individuals who make errors are ‘careless, at fault, reckless’
Blame and punishment
Remove the individual = improve safety
Systems approach
Poor organisational design sets people up to fail
Focus on the system rather than the individual
Change the system = improve safety
167
Human Factors Approaches
Avoid reliance on memory
Make things visible
Review and simplify processes
Standardise common processes and procedures
Routinely use checklists
Decrease the reliance on vigilance
MPharm3 SL32114
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