Q0SM Flashcards
(158 cards)
1
Q
what requirements are needed to manufacture to a high standard
A
sterile
• Pyrogen-free (pyrogens are substances that induce fever)
÷Microbial by-products such as endotoxins
• No particulates
Glass, fibres, precipitate, floaters (particulates that float instead of sink)
• Containers
Transparent (so we can see any contamination)
2
Q
why use injectables
A
• Rapid drug action required
-
e.g. emergencies
• Patient unco-operative, unconscious, or unable to tolerate oral medication
– Drugs i– Fluids
– Electrolytes – Nutrients
I
• Drug ineffective by other routes
poorly absorbed, inactivated, irritant, etc.
i-
- e.g. local anaesthetic at dentist’s surgery
molecular weight/charge/fat solubility can affect absorption • Local action
• Prolonged action required
- e.g. goserelin (Zoladex) implant (28 days and 12 weeks)
3
Q
what are the problems associated with injections
A
Problems with injectables
• Once administered, generally can’t remove
-
Overdose, adverse effects
• More difficult and expensive to produce
Sterile, pyrogen-free, particulate-free • Poor compliance
Pain, discomfort, inconvenient • Can require trained personnel
IV, IM (generally)
4
Q
what are the different type of injections
A
Small volume parenterals (SVPs)
1 – 50 mL
= Not necessarily administered IV
Not necessarily isotonic Not necessarily at physiological pH • Large volume parenterals (LVPs) Up to 1000 mL = IV infusion over prolonged period Isotonic → Solvent can be water or vegetable oil • Sterile suspensions and emulsions Continuous phase can be water or oil • Powders for injection or infusion = Require a diluent Not IV SC, IM
0.9% NaCl or 5% dextrose
5
Q
what are the different routes
A
ntravenous — into the vein (small or large volume) Subcutaneous or hypodermic (up to 2ml) Intramuscular (2-5ml; >5ml in divided doses) Intradermal or intracutaneous (~0.1ml)
6
Q
what are the different routes
A
intra-articular— joints
Intrasynovial — joint fluid area I Intraspinal — spinal column
Intrathecal — spinal fluid Intra-arterial — arteries Intracardiac— heart
7
Q
what is Methylprednisolone acetate (Depo-Medrone)
A
Injection (aqueous suspension) 40mg/ml Dose
\ By intra-articular injection, 4-80mg, according to size, where appropriate may be
repeated at intervals of 7-35 days, also for intralesional injection
-
Can also be given IM
8
Q
what is IV
A
Veins of forearms
Small volume (bolus)
Large volume infusions (up to a litre, use of indwelling catheters) Appropriate rate (flow rates range from 42-150ml/h)
Generally aqueous solutions (must not precipitate as solid particles can block capillaries)
9
Q
what are the advantages of IV route
A
Rapid onset of action (no absorption has to occur)
Controlled duration of action (for infusions)
100% bioavailability — accurate dosing
Suitable for large volumes — max 3L per day for adult
Suitable for high molecular weight compounds — e.g. monoclonal antibodies such as trastuzumab (Herceptin) protein average weight = 145531.5
10
Q
what are the uses of IV
A
Emergencies
- Bolus delivery (drug toxicity and irritation)
Fluid, electrolyte replacement
Due to shock, severe bleeding, dehydration Nutrient supplement
l Comatose patient
11
Q
what are the different types of IV administration
A
iv bolus or iv push
intermittent infusion
continuous infusion
12
Q
what does IV bolus or IV push entail
A
peated at intervals
Basically the typical IV injection that we know
13
Q
what does intermittent infusion entail
A
Drug diluted in 25-100ml of fluid and infused over 15-60mins at spaced intervals e.g. every 6h
/
consistent blood levels compared to a continuous
intravenous injection
Can also have a secondary IV line — this line ‘piggybacks’ (joins) with the original line
→ Careful here — have to make sure the fluids can be mixed otherwise a precipitate may form in the tube blocking the delivery of drug to the patient, or even go into the patient and block their capillaries
> Thispiggybacktechniquemeansthatthepatientdoes not require multiple IV sites
14
Q
what does continuous infusion entail
A
Drug added to large volume parenteral (LVP, up to 1000ml)
:and slowly and continuously infused
Excellent control over the drug plasma levels over a long period of time
Any toxicity and irritancy of the drug is minimised because :it is diluted
However, requires monitoring of the patient
Can’t use unstable drugs because they might start to :degrade inside the LVP due to temperature inside the room for example
Can’t use with fluid restricted patients
:Can’t use with poorly soluble drugs that have been dissolved in water miscible solvents or hydro alcoholic solutions because it is quite likely that they might precipitate out of this kind of infusion bag
15
Q
what are disadvantages of IV route
A
Discomfort, fear, poor compliance Possibility of infection
Possibility of tissue damage Administration by trained personnel only Drug can’t be retrieved
, Dose can be very different to oral route
16
Q
what are the different Types of IV products (almost all are aqueous solutions)
A
Parenteral nutrition (PN) Lipid emulsions Amino acid solutions Carbohydrates
Monoclonal antibodies
Cancer treatment
Large molecular weight molecules
I
Heparin
17
Q
Stealth liposomes (e.g. Doxorubicin HCl)
A
IV infusion
90% of drug is encapsulated in lipids
Drug is inside liposome, which is pegylated Surface-bound methoxy polyethylene glycol Gives it a longer half life + changes toxicity profile These are nano sized particles
18
Q
subcutaneous route
A
Patient should rotate where :they get subcutaneous
injections (not always in the same place)
Inject through skin into loose SC tissue — NOT muscle Aqueous solution or aqueous suspension e.g. insulin
Drug enters capillaries via diffusion and/or filtration Blood supply is important
/ Vasoconstrictor — restricts the blood supply and the drug will remain where it was injected rather than moving away into the circulation
- Exercise — blood flows faster after exercise and could lead to inconsistent absorption
E.g. subdermal implant of etonogestrel (Nexplanon)
19
Q
Goserelin matrix implant (Zoladex
A
SC into upper abdominal wall
Continuous release over 28 days
Goserelin dispersed in matrix
Matrix is copolymer of D,L-lactic and glycolic acids
20
Q
IM route
A
Aqueous solution or suspension
Oily (oleaginous) solution or suspension also possible
:
Rarely anything other than IM
Works well for drugs that aren’t water soluble Inject deep into skeletal muscles
Onset of action is less rapid
Absorption rates can vary widely (usually slower with an oily suspension)
Volume should be less than 5ml for the gluteus muscle, less than 2ml for the deltoid muscle
Oily injections — sustained release
: Progesterone (sesame or peanut (arachis) oil)
Testosterone enantate (sesame oil)
I
Can be made into a depot preparation — only needs to be given 2-3 weeks
21
Q
long acting IM depot injections
A
Nandrolone decanoate (Deca-durabolin) Testosterone enantate Testosterone proprionate, phenylproprionate, isocaproate (Sustanon 100) Testosterone proprionate, pehylproprionate, isocaproate, decanoate (Sustanon 250) Testosterone undecanoate (Nebido)
22
Q
ester at position 17
A
Decreases water solubility (as the chain gets longer) Increases oil solubility (as the chain gets longer) Deactivates molecule - Can’t bind to androgen receptor Ester cleaved/hydrolysed in blood \ Restores -OH group and can attach to receptor I / I / of ziÉ Diffusion + partitioning
In order for this drug to become active, we need the ester steroid complex to diffuse to the edge of the droplet and partition out of the droplet
Enzymes in the muscle tissue will hydrolyse the ester away and we are left with the steroid, which can now be reactivated and have a clinical effect
23
Q
droplet surface area
A
Can influence release rate (p’kinetics) Affected by
: Force of injection
Viscosity and surface tension of oil phase
: Size of needle
Environment into which its injected
24
Q
Half life of oily depots vs. Oil viscosity
A
Higher viscosity oil has a longer half life than lower viscosity oil
25
intradermal route
corium of skin — more vascular layer of skin beneath the epidermis Anterior forearm, back
Diagnostic purposes usually
- Tuberculin & allergy testing
26
what are the 3 type of injectables
Controlled release
Needle-free technologies
Targeted delivery
27
needle free delivery
Devices propel small jet of liquid or powder under high pressure Most are gas powered (CO2 or N2)
Some are spring powered
Intradermal, subcutaneous and intramuscular tissues!
28
needle free delivery of insulin
Uses pressure from a spring — without the use of a needle
Not pain free (bruising)
Good for people with needle phobias
Good for people who do not dispose of needles properly after use or that reuse needles!
29
what are powder injections
Delivers dry powder
No need for ‘cold chain’
Powders more stable than liquids
‘Cold chain’ is when the drug needs a constant temperature during transportation, once that ‘chain’ is broken the drug is useless
30
Applications of needle-free devices
Current applications include the delivery of insulin, vaccines, growth hormones etc. Gene delivery in the future?
31
needle free devices
```
Expensive, due to small market share
Price should decrease
Market should increase with
More drugs
: Increased patient awareness and acceptance
Prevention of needle-stick injuries
: Lack of special disposal requirements
Standardisation of devices
```
32
what is meant by marketing authorisation
A license that is required by law for any pharmaceutical product, issued by the regulator for that country
33
who is the regulator in the uk
MHRA – medicines and healthcare products regulatory agency
34
Why is licensing necessary?
Guarantees the medicine is safe and effective for human use, which must be proven by extensive testing before the MA will be given. Guarantees product quality
35
What does the MA stipulate?
Details of exactly which patients, conditions and clinical situations the medicine can be used for, including specific doses
36
what are specials
These are unlicensed medicines
| It is used for patients with unique clinical requirements or unusual circumstances
37
manufacturing specials
Made by a company who have a Specials Manufacturing License (MS) from the
MHRA
• Normally made according to a specific prescription
• Must comply with certain standards and keep specific records
• Companies can also perform limited batch manufacturing of specials
38
what does unlicenced medicine and unlicenced use mean
UNLICENSED MEDICINE = medicine with no MA at all (applies to specials) UNLICENSED USE = using a medicine with a MA, in a way that is different to the conditions stipulated on the MA
39
what is the need for specials
Always situations where patient requirements are unique
• Doesn’t merit applying for a full marketing authorization (costly & takes years for approval)
• To avoid extemporaneous (made on the spot in the pharmacy e.g. mixing together a cream) preparation
40
who might need specials
Babies and children
-people with swallowing difficulties
• Long-term or permanent feeding tubes
• Allergies and intolerances
-specific treatment required but no licensed product available in the UK
• To avoid extemporaneous prep in a pharmacy
41
licence first
Under MHRA rules we should always use a licensed product where possible
This means we must consider using a licensed product in an unlicensed way, before resorting to use of a special
42
what are the options
Licensed product, used within the conditions of the license. If not suitable... 2. Is there an alternative licensed product? E.g. someone with hypertension, allergic to ACE-I, could use A2RBs or CCBs. If not suitable...
3. Is there a licensed product you can use in an unlicensed way? E.g. different age group, indication, crush tablets. Can you import? If not suitable...
4. Consider use of a special
43
Batch manufacture of specials – when needed
Common liquids for children
:• Ophthalmic preparations – eye drops, ointments
• Many preservative-free products (many IV drugs, because some preservatives
can cause nerve toxicity)
• Non-routine parenteral products
• Epidural infusions
• Dermatology preparations that would be made extemporaneously
44
what does the law say about specials
Specials have exemption for need for MA
• Manufactured and supplied in accordance with prescriber specifications
patients fall into category of having spcial needs
• Clear reasons why licensed alternative is not clinically appropriate
45
what are the pharmacists responsibilities in terms of specials
Patient care is always your primary concern
:• Ensure all medicines prescribed and supplied are safe, effective and appropriate for
condition
• Make certain no other licensed alternatives can be used
:• Should always be an exception, never routine supply
• Patient and prescriber made fully aware of unlicensed status, patient must share the
decision to use a special
• Ensure the quality of the special product
/Use reputable specials manufacturers
• Keep all records in relation to purchase and supply
• You share accountability with the prescriber!
46
how do you make a clinical assessment about specials
Need to establish that this patients clinical situation is different from normal
• Should NOT be in relation to cost
• Should NOT be in relation to simple convenience, must be justifiable
• Allergy, severe intolerance, administration route limitations, refractory to all other treatments etc.
47
give an example of when you would use a special
Phenobarbitone is used for neonatal seizures
• Licensed phenobarb liquid available is a 15mg/5ml suspension
• Phenobarbitone suspension contains 38% alcohol, 20mg dose equivalent to a glass of wine!
• 50/5ml special is available which is alcohol Shorter expiry date, more unstable...
• BUT its justified to use the special because the licensed product would seriously harm a sick baby
48
what are the 5 principles of professional practice guide
Establish the patient’s special clinical need
:2. Understand patient’s experience
3. Identify a preparation and supplier
4. Ensure effective governance is in place (keep all the references, request the receipts to ensure legal requirements are fulfilled)
5. Monitor patient and review need for the special
49
what are the disadvantages about specials
No robust testing like a licensed medicine, can’t guarantee safety and efficacy
• Short expiry dates and instability are common, especially if preservative-free
• Very expensive – GPs struggle to fund them in the long-term for chronic diseases
50
what can pharmacists do to safeguard patients when supplying specials
Have up to date SOPs and follow them
• Use reputable companies
• Check product compliance certificates (for single prescriptions)
• Check product analysis certificates (when dealing with batches)
• Question and report to MHRA if in doubt
keep all records and documents
51
what does sterile mean
The COMPLETE absence of life (so any detectable contaminations means “non sterile”)
• There are no degrees of sterility (concepts like ‘more sterile’ or ‘very sterile’ are inappropriate and display a lack of understanding of the concept)
52
what does sterilisation mean
Destruction or physical removal of all microorganisms in a product
• How can we destroy or remove microbial cells from a product?
53
what are the different sterilisation process
• Elevated temperature (moist heat - autoclaving; dry heat) -
-
• Reactive gas (e.g. ethylene oxide) I
• Irradiation (e.g. ionizing radiation such as Gamma rays) -
54
what is terminal sterilisation
Make product under non-sterile conditions using non-sterile ingredients; sterilize it at the end pf the process
55
what is aseptic manufacturing
Make the product from sterile ingredients under sterile conditions - clean rooms
56
what is the kinetics of antimicrobial action
Microorganisms and microbial structures show different sensitivity to sterilization agents • e.g. heat or radiation
Vegetative forms of bacteria and fungi, and larger viruses, show a greater sensitivity to sterilization
Compared with small viruses and bacterial or fungal spores
Reference organisms for testing sterilisation efficiency are usually bacterial spores
• e.g. Geobacillus stearothermophilus - formerly known as Bacillus stearothermophilus - for testing moist heat sterilisation
57
what happens when a microbial population is exposed to a killing process
Microbial populations generally lose viability in an exponential fashion (independently of the initial number of organisms)
58
what are survivor curves
The constant K tells us how quickly cells are being killed – distinct microorganisms have distinct k constants at different temperatures
59
what is meant by the d value
Resistance of an organism to a sterilizing agent can also be described by the D-value
Time needed to kill 90% of the population For heat treatments:
• D value is the time taken at a fixed temperature to achieve a 90% reduction in viable cells
For radiation treatments:
• D value is the radiation dose required to achieve a 90% reduction in viable cells
Examples of D-values of biological indicators of sterilization
Steam sterilisation of G. stearothermophilus:
D121 ≥ 1.5 min (it takes 1.5 mins to kill 90% of organisms at 121 degrees) Dry heat sterilisation of Bacillus atrophaeus:
D160 ≥ 2.5 min
Ionising radiation of Bacillus pumilus:
D ≥ 1.9 kGy
-
-
:
60
what is the inactivation factor
The D-value is used to indicate rate of kill – but it does not quantify the amount of microbial killing
A parameter that quantifies the amount of microbial killing is the inactivation factor (IF):
D-value (and k constant) for the same organism changes with temperature
61
what is meant by the z value
Z-value represents the increase in temperature needed to reduce the D-value of an organism by 90%
Or the number of degrees Celsius required to change a D-value by one factor of ten
:
Z-values found by experiment are normally within the range 10-14 degrees Celsius for different microbial species
Values very close to 10 degrees are so commonly observed that this figure (10 degrees) is often adopted in calculations to design steam sterilization processes
62
what is meant by the F value
The F value uses 121 degrees as a reference temperature
Expresses a heat treatment at any temperature in terms of an equivalent number of minutes exposure at 121 degrees
For example, a steam sterilisation cycle with an F value of 8 would have a killing effect equivalent to that of 8 minutes at 121°C
To calculates F values we need to know the Z-value (but measuring Z-values by experiments is time-consuming)
Since z-values are often close to 10 degrees, a value of z=10 is frequently assumed in F calculation
-
The part of the equation in red gives the killing effect at temperature T, relative to that at 121 degrees
This killing effect is referred to in textbooks as the lethal rate
63
summarise d z and f values
D → time to kill 90%
z → increase in temp needed to change D value
by factor of 10
F → time required to kill a known population under
specified conditions ( 121°C )
64
what is meant by sterile
‘Sterile’ means no surviving organisms
• Killing of microorganisms is a time-dependent process (influenced by duration of biocidal action and initial bioburden)
• True sterility (=zero survivors) can only be achieved after an infinite exposure period
65
what is meant by sterility assurance
sterility assurance will not guarantee sterility
we refer to the likelihood of a product being stable-probability of a single organism remaining to contaminate a processed product
Sterility Assurance Level (SAL): probability of a single surviving organism remaining to
• A sterilization process will not guarantee sterility
• We refer to the likelihood of a product being stable – probability of an organism surviving
the treatment process
contaminate a processed product
Most frequent standard for pharmaceutical products: sterility assurance level (SAL) of 10-6 Probability of a non-sterile unit is 1 in 1 million units processed
66
Quality control of sterile products is usually ‘assured’ by combining process monitoring and performance criteria:
Bioburden determinations • Environmental monitoring
| • Validation and monitoring of sterilization procedures • Sterility testing
67
what is meant by bioburden
Bioburden: concentration of organisms in a material
• Microbial contamination during manufacture and growth of populations initially present in materials should be restricted – for this reason manufacturing processes usually include
:extreme temperature and pH values, and organic solvent exposures
68
benefits of low pre-sterilisation bioburden
Reduced exposure of the product to high sterilization temperatures (minimizes degradation
of actives and excipients)
• Greater probability of the product passing the bacterial endotoxins test (BET) – autoclaving does not destroy endotoxins; high bioburden means high endotoxin concentration
• Shorter autoclaving cycles use less energy – and also translate into more autoclave runs per day
69
how can you determine the bioburden of pharmaceutical products
Bioburden determinations
:• Use of standard microbiological methods e.g. pour and spread plates and membrane
filtration
• Application of these methods to raw materials and manufactured medicines may need distinct adjustments e.g. due to presence of solid particles, formulation, viscosity and presence of antimicrobial agents
Environmental monitoring
• Levels of microbial contamination in manufacturing areas are monitored – microbial numbers should not exceed specified limits
• Microbial load in atmosphere may be determined by ‘settle plates’ or by use of air samples – which cause a volume of air to be passed over an agar surface
• Contamination on surfaces, including equipment, may be measured using swabs or contact plates
70
validation and monitoring of sterilisation processes
Calibration and testing of all the physical instruments used to monitor the process e.g. thermocouples, pressure gauges and timers
Evidence that the steam is of the desired quality e.g. chamber temperature is that expected for pure steam at the measured pressure
• Conduct of leak tests and steam penetration tests – using both an empty chamber and a chamber filled with the product to be sterilized in the intended load conformation
:• Production of data to demonstrate repeatability – typically for 3 runs
• Comprehensive documentation of all sterilization aspects
71
what are the uses of biological indicators
Standardised bacterial spore preparations
I• After the sterilization process, the suspensions or spores on carriers are aseptically
transferred to an appropriate nutrient medium – which is incubated and examined for signs of growth
72
what is meant by sterility testing anf what are its principles
A sterility test assesses whether a sterilized product is free from microorganisms
Principles of sterility testing
• Placing the product (or a sub-sample) into a suitable liquid culture medium
I
Methods of sterility testing Direct inoculation
• Samples are introduced into nutrient media
Membrane filtration
surfaces
• If, after incubation, there are no signs of microbial growth (measured as turbidity) the item passed the test
73
what is direct inoculation
Samples are introduced into nutrient media
Alternatively, concentrated culture medium may be added to the test fluid in its original container (more sensitive test)
74
what is meant by membrane filtration
Recommended by most pharmacopoeias
:• Involves filtration of fluids through a sterile filter (pore size of 0.45 micrometers, filter is transferred into culture liquid media)
• Water soluble solids can be dissolved in a suitable diluent and processed the same way – oil soluble products may be dissolved in suitable solvents
• Testing must be performed under aspetic conditions e.g. laminar airflow cabinet
• Control tests are necessary to confirm the adequacy of facilities – by sampling of air and surfaces
• Necessary to use negative controls – samples known to be sterile
Where an antimicrobial forms part of the product, it must be inactivated before sterility testing
75
what are the different methods of antimicrobial inactivation
Specific inactivation
• An appropriate neutralizing agent is incorporated into the culture media
Dilution
• The antimicrobial agent is diluted in the culture medium to a level it ceases to have any
:activity
Membrane filtration
• The product is filtered through a membrane filter
I
-
• Membrane retains any contaminating microorganisms, is washed and transferred to liquid media, method traditionally used with antibiotics
76
what is meant by positive control
is essential to show that microorganisms will grow under the conditions of the test
• European Pharmacopoeia suggests the use of several designated strains as positive controls
77
what are the limitations of sterility testing
Destructive test – problem when testing large, expensive or delicate products
• Procedure intended to demonstrate a negative – failure to detect growth could be
consequence of using unsuitable media or incubation conditions, or presence of antimicrobials
• No attempt is made to detect viruses
• Expensive test – need of expensive clean rooms, equipment and qualified staff
• Low sensitivity – statistical process in which part of a batch is randomly sampled, dependence of sample size
78
Parametric release of pharmaceutical products
Sterilisation processes involving e.g. heat and irradiation are very well characterized
e.g. physical measurements can be accurately made
• Authorities place considerable reliance on the validation and performance of sterilisers
and sterilization cycles (due to limitations of sterility tests)
• A sterilization cycle will be validated to have a sterility assurance level (SAL) of 10-6 or less
• In these cases, sterility can be assured by ensuring that the manufacturing process as a whole conforms to established protocols
. If the process has satisfied the required parameters, it may permit the parametric release of the product – release based upon process data, and batches of terminally sterilized products may be released without being subjected sterility tests
I Sterility assurance failures are not uncommon and there are several product recalls each year
79
what is meant by microbial strain
Taxonomic sense
A strain is made up of the descendants of a single isolation in pure culture and usually is made up of a succession of cultures ultimately derived from an initial single colony
Definition in nature
A strain is an isolate or group of isolates that can be distinguished from other isolates of the same genus and species by phenotypic characteristics or genotypic characteristics or both
80
How can we differentiate microorganisms below the species level?
Phenotypic typing methods
Based on the analysis of phenotypic characteristics Antibiotic resistance typing
: Phage typing (phages are viruses affecting bacteria) — phages are species specific and sometimes they may be strain specific
Serotyping (method where we study cell surface antigens) — a serotype is a group of organisms within a species that have the same type and number of cell surface antigens
:
Genetic typing methods — genotyping
Based on the analysis of genetic characteristics Electrophoretic methods e.g. PCR fingerprinting Sequence-base typing e.g. single gene sequencing Other methods e.g. whole genome sequencing
-
:
81
:Most genotyping methods involve a Polymerase Chain Reaction (PCR)
Reagents needed:
DNA template (extracted from a culture or sample) DNA polymerase
Nucleotide bases (dNTPs)
Primers flanking the region of interest
Water
Polymerase buffer
Exponential amplification of nucleic acids by a series of alternating heating and cooling steps
Depending on the primer we are using, they will promote the amplification of certain specific regions of the genome
At the end of the reaction we will have millions of copies of the region of interest With so many copies, we can then do other tests with these DNA fragments
82
amplification of nucleic acids
Analysis of amplified DNA fragments typically involves an electrophoresis in agarose or polyacrylamide gel
Fragments are separated according to their sizes
Gels are visualised under UV light (after staining with e.g. ethidium bromide)
83
What is MLST
Multilocus sequence typing (MLST) is an unambiguous procedure for characterising microbial isolates — using the sequences of internal fragments of usually seven house-keeping genes Approx 450-500 base pair internal fragments (regions) of each gene are used — as these can be accurately sequenced on both strands using an automated DNA sequencer
For each house keeping gene, the different sequences present within a microbial species are assigned as distinct alleles (numbers)
For each microbial isolate, the alleles at each of the loci define the allelic profile or Sequence Type (ST) — each isolate is characterised by a series of 7 numbers which correspond to the alleles at the seven house keeping loci
Most bacterial species have sufficient variation between house keeping genes to provide many alleles per locus — allowing billions of distinct allelic profiles to be distinguished using seven house keeping loci
The allelic profile of isolates can easily be compared to those in a large central database via the Internet
MLST typing demonstrated that the bacteria isolates from the patients were linked to the use of the ultrasound gel and isolate grown from the gel — they were highly genetically related to each other
84
what is GMP & HACCP
The foundation for ‘sound’ manufacture is GMP or rather cGMP
• The basis for safety is a Hazard Analysis of Critical Control Points (HACCP) and a Hazard and Operability study (HAZOP)
• ICH Quality Guidelines (Q-series) aim to address concerns of actually producing the medicine
85
HACCP
Hazard Analysis of Critical Control Points means: :• ICH Q9 - Risk Management
• Points of weakness
• Point of loss of control
Points of external influence
→ Flagged-up “notifiers” at these points
→ Involves testing point (analysis) as part of a regime of QC
86
what are the 7 point system of HACCP
1.Conduct a hazard analysis
2. Establish critical control points or CCP’s (based on a decision tree): e.g. temperature, time, Aw, pH, particle size, pressure
3. Establish critical limits /thresholds; so that each CCP has 1 or more limits
4. Establish procedure to monitor CCP
5. Establish corrective action in event of exceeded limits (why and what will be done?)
6. Record keeping, full documentation
7. Verification of findings in terms of effective working of HACCP policy
• Limits for: content of drug, impurities, toxins, microbes (bacteria, fungi, other pathogens)
87
quality control
A number of key activities are used routinely in quality control
• Physical sampling
:Confidence and reproducible sample recovery
Laboratory tests using valid analytical methods (VAM’s) - System suitability
• Routine in- and on-process tests
- “Magic eye” is a detector that can pick up certain features – metal, colour, obscuration,
“smart” materials
Rapid tests – impedence/DEFT (direct epifluorescent filter technique) (microbiology),
limit tests (chemical analysis), product ‘history’ markers Manual sorting (not very good)
88
Propagation of error
Errors can be additive or multiplicative
• Additive, routine variability
• Multiplicative, multifactor-driven increasing change
89
Sampling schema
```
Sampling
Physical sampling (recovery) is associated with QC testing, and a strategy for sampling (plan) is associated with manufacturing
```
90
Analytical storage containers
Plastic containers are taken into the production area for sampling purposes, glass is generally not allowed because of the risk of contamination of product by shards
• The compounds that can leach out of non-inert plastic sample containers are:
– Bisphenol A (BPA), which is used in tough polycarbonate products as an antioxidant
– Plastic softeners called phthalates. – Vinyl chloride monomer from PVC
91
Lot sampling in manufacture
• Inert container, blank/control
• Avoidances: sifting, carry-over, de-/adsorption, atmospheric addition, volatilisation • Procedural modes
• Continuous mode sampling
– Portion
– Continuous flow (liquid/gas) trapping • Batch mode sampling
– Auger, Quartering (aka successive reduction), Coning, Rifling, Sampling “thief” (see examples to follow)
– Random (can random really be random?)
92
Sampling and recovery error
Sample preparation, consistency, stabilize sample > Error in sampling – sampling is major contributor to
Sifting – small particles fall to the bottom, big particles stay at the top, these don’t have the same chemical composition Ratholing – there is an air bubble in the sample
93
The FOUR most important features limiting analysis:
Cost
• Time
• Staff skill base
• Equipment
94
Process analytic
Use of analysis of cleaning validation • Surface techniques
– Contact, settle
– Swab or rinse (recovery studies), common ;– Air impingers
• Measurement: use a modified product assay
– Chromatographic: HPLC, LC-MS, common
– Total organic carbon (TOC)
– UV-vis (NIR)
– pH/conductimetry
– Colony counts, microbial load (DEFT, nephelometry, etc)
95
Cleaning validation
```
Safety factors (F)
certain substances are highlighted specifically: penicillins, cephalosporins, potent steroids, cytotoxic, allergenic, endotoxins should use < LOD for best analytical method available
```
96
t he Statistical Process
```
Sterility: quality control
Monitoring quality by application of statistical methods in all stages of production
i
;
:
:
:Statistical Process Control (SPC)
Probabilistic modeling
• Is my process out of specification?
:
• On what basis do I pass or fail the batch? • Have I taken enough samples?
• Inter-relationship – between failure and productivity
• Probability – that the batch/unit in a batch will fail • Significance – how significant is the failure
}
improved
tighter
evaluation
control
• Decision making
• Chance variation – random variation
• Assignable cause – variation due to underlying bias • Outliers
• Trends
• Pattern established
-
:probabilistic modelling
• Is the process changing with time?
• Do I pass or fail the batch?
• What are the consequences of making an erroneous judgment?
```
97
six sigma
DMAIC: define goals (D), measuring using standards (M), analyse causality (A), improve results (I), control and correct (C)
:• Relates to Shewhart cycle: D+M=P, A=D, I=C, C=A
• Design: DMADV, define, measure, analyse, design, verify
• Total quality management (TQM)
98
when do you use six sigma
We use six-sigma instead of 3 because we can have shifts up to 1.5 standard deviations due to random fluctuations within the data
- Using six-sigma gives us this safety margin
99
Process statistics
sometimes we find that normal frequency data is not appropriate
I
• The data is skewed to one side
Out of control: centerline is shifted due to bias e.g. machine error Bimodality: there are 2 discrete populations
100
control charts
the control chart
• Shewhart, origin and example
```
Basic types based on variables
• X-type
• R-type
• CuSum
• Regression
```
Based on attributes
• NP, C, U and P-type
101
what are the different types of error Type I and Type II errors are 2 well-known concepts in quality “science”, that are related to hypothesis testing and the fractional probabilities of making a judgment, that also have a variety of names
```
Type I errors are also called
• Producer’s error (the producer disposes of acceptable goods)
• Alpha error
• False alarm
• False negative
```
```
Type II errors are also called
• Consumer’s error (the producer accepts dangerous sub-standard goods)
• Beta error
• Misdetection
• False positive
```
102
Charts based on variables
Moving average – as Shewhart Chart but average represents 4 measurements and is constantly updated for new “complete” sets of data, uses a weight constant for a weighting of data and defining limits
:• Uniformly weighted moving average (UWMA): larger values of weight actually guard against small shifts
• Exponentially weighted moving average (EWMA): small values of weight are used to guard against small shifts
103
Process Capability and Six-Sigma
For variable control charts we often want to include process capability indication.
.
• Where sigma (s) is the estimated process standard deviation, and USL and LSL are the upper
and lower specified limits
/
• If the process is not centred, an adjusted index Cpk is used
I
Six-Sigma
Six-Sigma hierarchy
1. Champions - institutions incorporation/vision (Expert, rare)
2. Master black belts
3. Black belts - quality perspective
4. Green belts
5. Golden belts -some knowledge of quality
6. White belts – novice
7. Can involve effectiveness (E) = quality improvement (Q) x acceptance (A)
• Cost of poor quality (CoPQ) descriptive parameter - may account for 15-25% total cost i.e. wastage
• CoPQ ICEBERG ANALOGY - total costs. Top of the iceberg: 1/8 = traditional costs. Immersed fraction = 7/8. Due to lost operations (scrappage) and the hidden "factory" and other hidden costs
6:-Sigma’s Defectives for the Pharmacist
Defect per million opportunities (DPMO)
• 690,000 DPMO = 1 sd (= 10,350,000 wrong prescriptions/year) - POOR/NON-COMPETITIVE
:• 308,357 DPMO = 2 sd
• 66,807 DPMO = 3 sd
:• 13,333 DPMO = 3.7 sd, 99% good: (= 200,000 wrong prescriptions/year) - INDUSTRY
STANDARD
• 6,210 DPMO = 4 sd - INDUSTRY STANDARD BEST
/
-
• Distribution of respective quality characteristic or variable (e.g., depth of blister well) is normal, and the process is perfectly centred (i.e., the mean is equal to the control chart centreline), then this index can be interpreted as the proportion of the range (the process width) that falls within limits.
.
• For a “sound" process, the Cp index should be >1.0, i.e., the specification limits will be larger than 6 times the sigma limits, so that over 99.9999998% of all items should be expected to be within the acceptable specifications.
104
what is the six sigma heirarchy
Six-Sigma hierarchy
1. Champions - institutions incorporation/vision (Expert, rare)
2. Master black belts
3. Black belts - quality perspective
4. Green belts
5. Golden belts -some knowledge of quality
6. White belts – novice
7. Can involve effectiveness (E) = quality improvement (Q) x acceptance (A)
105
Cost of poor quality (CoPQ) descriptive parameter
* Cost of poor quality (CoPQ) descriptive parameter - may account for 15-25% total cost i.e. wastage
* CoPQ ICEBERG ANALOGY - total costs. Top of the iceberg: 1/8 = traditional costs. Immersed fraction = 7/8. Due to lost operations (scrappage) and the hidden "factory" and other hidden costs
106
Quality control of sterile medicines
High pressured steam use (clean room and laminar flow; 121-134°C; 12D): – Solutions
– Suspensions
– Proprietary (in hospital) products
• Is 6-sigma relevant? sterility is 2×10-7%, is this acceptable?
Alternative or combination practice - via non-heat methodologies – are they applicable? – g-irradiation (60Co, 137Cs), electron beam
– Ethylene oxide
– Less common: H2O2, peracetic acid, UV, microwave, hyperthemal, hyperbaric
107
Prediction of quality and defectives
How do you spot the odd ones out?
Strategy to detect non-conformance • Pinpoint (hard) or :
• Trend (easier)
108
Chart definitions
QL, acceptable quality level - arbitrary value selected by producer (usually relates to non- conforming units in population associated with alpha)
UQL, unacceptable quality level
• AOQL, average outgoing quality level
• LTPD, lot tolerance percent defective, arbitrary ”worst quality” level selected by the consumer (usually relates to non-conforming units in population associated with beta)
-
:
109
Sampling / sampling plans
* AQLs, accept if x i
| * UQLs reject if >x
110
Rejection-acceptance:
type I error (false alarm, throw away a perfectly good product)
– Type II error (failure to detect upset product)
– alpha - risk of error (producers’) reject good: probability of type I error – beta - risk of error (consumers’) accept bad: probability of type II error
111
Sampling interpretation
Hypotheses
– H0 = proportion of defectives is as stated (£ AQL)
– H1 = proportion of defectives has changed from those stated (>AQL)
• Process is stable when we do not reject H0
• Process is NOT stable when we reject H0
– H0 is true but we think it is false, P = alpha - type I error – H0 is false but we think it is true, P = beta - type II error
112
sampling and validity
```
A plan and strategy for:
1. Effective sample
2. Reproducible sample
3. Representative sampling
Error in 75% of cases at sampling point is responsible for poor outcome/data
```
113
Definitions of plan acronyms
AQL, defining quality we would accept; associated with probability, P(alpha)
• LTPD, what we do not want; associated with probability, P(beta)
:
114
Sampling plans
Provide an effective check on quality
• AQL’s; UQL’s; a ; b - important parameters
• AQL - UQL = close; a-b = small
/AQL-UQL= far apart; a-b=large
I
• Single – a sample is taken from a batch and tested, if it fails, disregard the batch
:• Double – a sample is taken from a batch and tested, if it fails, take another sample and
test it again
• Multiple – a sample is taken from a batch and tested, if it fails, take another sample and test it again, repeat
• Sequential uses an applied handicap (H) & penalty (b)
115
the Operating Characteristic Curve (OCC)
An OCC is simply an x-y plot of the probability of accepting a batch of product (y-axis) against quality, usually defined by the proportion of defectives in a given sample e.g. percentage (x-axis)
116
Preparing an OCC experimentally
From experimental data it is possible to produce an operating characteristic curve (OCC)
• An OCC is simply an x-y plot of the probability of accepting a batch of product (y-axis) against quality, usually defined by the proportion of defectives in a given sample e.g. percentage (x-axis)
* The average chosen can be taken from a graph and can be the modal, median or arithmetic mean of the values.
* A quality controller ha
117
Process Errors
. Come from “wear and tear” on equipment e.g. rotary tablet press and tamping pins. They are made of metal and change shape over extended productions
2. Changing or changed environment or treatment
3. Operational or operator methodological inconsistency e.g. human measurement and robotic measurement
4. Physico-chemical changes in stored raw materials, packaging and API
118
what is the difference between sterility and sterilisation
sterility and sterilization
• Sterility: absence of microorganisms
• Sterilization: complete removal or destruction of all living organisms
• Sterility testing cannot guarantee sterility!
• Must use validated processes
• Aim for high sterility assurance levels (10-6)
• Sterilization isn’t an alternative to good manufacturing practices
119
Why is it important that certain preparations are sterile?
some preparations are placed inside the body – injections, implants, sutures, dialysis
fluids etc.
• Some come into contact with broken skin and mucosal surfaces
These pose a threat of infection • Risk of product degradation
120
what are the Properties of ideal sterilization method
High antimicrobial activity (giving high sterility assurance level)
Easily controllable/measurable/
understood physical conditions for
microbial inactivation
• Terminal sterilization – product is sterilized in its final container before being shipped
• Material compatibility
• No hazard to operator • No toxic residues
• Short processing time • Low cost
121
There are 2 strategies for making sterile products:
Terminal sterilization: Make the product under non-sterile conditions using non-sterile ingredients then sterilize it at the end of the process
• Aspetic manufacturing: Make the product from sterile ingredients under sterile conditions
122
There are 2 strategies for making sterile products:
Terminal sterilization: Make the product under non-sterile conditions using non-sterile ingredients then sterilize it at the end of the process
• Aspetic manufacturing: Make the product from sterile ingredients under sterile conditions
123
Terminal sterilization and parametric release (PR)
Wherever possible, sterilization in the final container is preferred (terminal sterilization)
• PR: “ a system of release that gives the assurance that the product is of the intended
quality based on the information collected during the manufacturing process and on the
compliance with specific GMP requirements related to PR”
PR may be permitted for products sterilized using certain processes – no sterility test
• PR requires permission to be granted
124
give examples of items that require sterilisation
```
• Dry powders
• Oils
• Disposable plastic gloves
• Delicate equipment • Thermolabile liquids
• Indwelling medical devices (catheters, sutures, artificial prostheses) • Wound dressings
• Contaminated blankets • Wastes
.
• Ampoules of water for injection
• Infusion pack
```
125
what methods for sterilization recommended by the British Pharmacopoeia
```
Dry heat
• Steam sterilization • Ionizing radiation
• Gas sterilization
• Media
• Filtration
```
126
what is a prion
: A prion is a type of protein that can trigger normal proteins in the brain to fold abnormally. These are generally not our primary consideration in the sterilization process
• Our main aim is to eliminate bacterial endospores
• If we are able to destroy endospores, then we can also destroy anything that comes below it by default
• Endospores can generally survive boiling for hours, there is very little inactivation below 80 degrees
• Fungal spores can survive at 60 degrees for hours but tend to die at 80 degrees • Non-sporing bacteria have a D60 of about 1-5 mins
• Viruses rarely survive above 50-55 degrees for more than about 30 mins
• Mammalian cells wouldn’t survive more than a few hours at 40-45 degrees
127
why is the cooling stage important in the heat sterilisation cycle
The cooling stage is very important to protect the integrity of the product and also for safety reasons
128
what is dry heat sterilisation
Sterilization by thermal conduction (outside of the item heats up, the heat is conducted
through the whole item until the whole item is the same temperature) • Suitable for heat stable and moisture sensitive products
• Process:
1. heat up period
2. Sterilization period (holding time)
3. Cool down period
Action through coagulation and oxidative processes that takes place inside the cells
• SAL of 10-6 or better
129
Sterilisation parameters for dry heat
160 degrees for 2 hours
170 degress for 1 hour
180 for 30 mins
250 for 30 mins for endotoxin removal
130
what are endo toxins
All endotoxins are pyrogens but all pyrogens are not endotoxins
• Pyrogens are substances that cause fever
:• Endotoxin is a lipopolysaccharide (structural component) found in the outer membrane of
gram negative bacteria only
• Lipopolysaccharide:
1. Comprises lipid A, which is embedded into this phospholipid membrane
2. This is linked via Ketodeoxyoctonate (KDO) to core polysaccharides
3. And these are linked to O polysaccharides – these are the ones that have the antigenic
nature (they vary between cells)
• 160 degrees for 2 hours
• Depyrogenation is when we remove that lipopolysaccharide/that endotoxin/that pyrogen
131
what are the features of dry heat sterilisation ovens
Open mesh shelving – so the air can flow and move around the objects to ensure even
temperature
• Temperature recorder
Overheat cut out – so it doesn’t get too hot
• Thermally insulated chamber
• Cycle counter
• Forced cooling and filtered air
• Thermocouple inlet – to ensure we achieved the right temperatures
• Door interlock and automatic non-interruptible cycle – prevents under processing
:• Steriliser hold period timer initiated by chamber temperature (separate from the chart recorder)
• Fault indication
132
what are alternative dry heat sterilisation
Unidirectional airflow tunnels: allows for continuous throughput of material
• Radiant heat tunnels
133
application for dry heat sterilisation
For heat-stable, non-aqueous materials that cannot be sterilized by steam
• Overheat cut out – so it doesn’t get too hot
• Glassware
Metal instruments
• Non-aqueous thermostable liquids e.g. some oily injections • Thermostable solids
• Depyrogenation of glassware
134
what are the advantages and disadvantages of dry heat sterilisation
:
• Effective method – heat conduction reaches all surfaces
• Where hydration is undesirable
• Protection of cutting edge e.g. sharps
• Avoids ‘wet pack’ problems (wet packaging)
• No chemical residue
• Depyrogenation possible
Disadvantages
• Less efficient than steam at the same temperature
• Limitations for plastic/rubber items
• Uneven/slow heat transfer
• Cost of prolonged cycles
• Limited packaging materials due to high temperatures
• Oxidation may occur
135
what are the properties of steam
Moist heat sterilization is carried out in an instrument called an autoclave
• Autoclaves use dry saturated steam
Saturated steam: in thermal equilibrium with the water which has produced it (steam on
phase boundary)
• Dry steam: water vapour, no liquid water
• Steam condenses onto articles releasing latent heat
• Superheated steam: inefficient sterilizing agent
:o If the steam is too dry and we keep increasing the temperature its not efficient, because it then has to cool down to an appropriate temperature to release its latent heat
• Steam containing air will be at a lower temperature than pure steam – air removal is crucial to the success of the process
:• Steam contains latent heat, when in contact with a product, it releases this heat onto the product
• Key parameters: steam, pressure, temperature and time
136
what is autoclaves
```
Downward displacement (also called bottled fluid sterilisers, bench-top autoclaves) – these tend to be used for bottles of aqueous fluids
• Porous loads (also called high speed pre-vacuum sterilisers)
```
137
what is the process for moist heat sterilisation
air removal and steam admission (we don’t do this with dry heat sterilisaation)
• Heating up and sterilizing stage
• Drying/cooling
138
Main construction features of a large-scale steam steriliser
This is a downward displacement autoclave
:
• Steam jacket: to help heat up the autoclave or cool it down I
• The steam enters the autoclave, passes through a baffle, goes up the top of the autoclave and pushes down, forcing the cold air out
• Temperature sensitive valve allows cold air to exit until the air inside is all an even temperature
• Its really important that the steam has direct contact with the article
139
How do we generate those high temperatures inside the autoclave?
By increasing the pressure
• If we lower the pressure, water boils at a lower temperature
• If we increase the pressure, water boils at a higher temperature
Parameters for steam sterilization
o Reference conditions: 121°C for 15 minutes, 15 P.S.I (pans per square inch) o 126°C for 10 minutes, 20 P.S.I
o 134°C for 3 minutes, 30 P.S.I
o SAL of 10-6 or better
Quality of the water is really important
In order to achieve those temperatures (above), the steam needs to be pure, so no contaminating air
We use dry saturated steam in an autoclave – the steam is at the same temperature that produced it (phase boundary)
140
What would happen to the phase boundary line if we have a mixture of steam and air in the autoclave?
the phase boundary line would move downwards
o At the same pressure, we will have a lower temperature
o This is because air contributes to the partial pressure of the system but not to the temperature in the chamber in the way steam does
o So if we have air present, it provides a pressure component without providing the temperature component
141
what are the adverse effects of air on steam
Air is driven off from water and can be trapped in items such as porous loads e.g.
:blankets, so we don’t get direct contact of the steam with the article because the air is
preventing heat flow
• Air is a poor conductor of heat and inhibits heat flow
• Air reduces steam temperature at a given pressure (not saturated) • The sterilization temperature will not be achieved
142
Applications
```
Applications
Gravity displacement autoclaves:
• Laboratory media
• Water
• Pharmaceutical products
• Medical waste
• Non-porous articles
```
143
if we have porous loads: High-speed pre-vacuum (HPV) sterilisers
Porous loads contain trapped air which must be removed for efficient sterilization –
:achieved with a vacuum pump (instead of waiting for the steam to push the air out, its not
strong enough)
• Requires contact between materials and steam
• Applications: heat-stable items, dressings, gowns, plastics, packaging materials permeable to steam and air
144
what are advantages and disadvantages of steam sterilisation
```
Advantages
non toxic
• Inexpensive
• Rapidly microbiocidal
• Sporicidal
• Efficient at heating and penetrating the load
:Disadvantages
• Deleterious effects on materials, e.g. change of shape or corrosion
```
145
what is radiation
Radiation
• Radiation is energy travelling through space :• 2 main types of radiation
Electromagnetic: gamma rays, xrays, ultraviolet, infra red, microwaves, visible light
Particulate: alpha particles, beta particles (high speed electrons), neutrons, protons
• Some forms of radiation are ionizing – they can add or remove electrons from molecules, producing electrically charged ions
146
Units of radiation
Activity of a source is measured in becquerel (Bq). 1 bq =1 nuclear disintegration per second (replaces curie [ci], 1 Ci= 3.7 x 1010 Bq) :•Absorbeddoseismeasuredingray(Gy). 1Gyistheabsorptionof1jouleofenergyper Kg of material (rad [radiation absorbed dose] is still often used (1 Gy = 100 rads)
Energy of radiation is measured in electron volts (eV) or millions of electron volts (MeV)
147
gamma rays: ionising radiation
onising radiation has enough energy to remove electrons and create charged molecules
• Short wavelength, ionising, high energy & highly penetrating
• Usually 60Co source
• g-rays bombard the materials which results in emission of lower energy photons and
electrons
:
:
• Activity of a source is measured in becquerel (Bq). 1 bq =1 nuclear disintegration per second (replaces curie [ci], 1 Ci= 3.7 x 1010 Bq) :•Absorbeddoseismeasuredingray(Gy). 1Gyistheabsorptionof1jouleofenergyper Kg of material (rad [radiation absorbed dose] is still often used (1 Gy = 100 rads)
* Items pass in a zig-zag pattern around the source
* Exposure times long
* Standard reference dose is 25 kGy
* Specialised process with high safety control
148
how are gamma rays generated
Cobalt 60 source
• As it decays, cobalt source emits one electron with energy of 0.31 MeV and it produces 2 photons of energy (the gamma rays) with energies of 1.17 MeV and 1.33 MeV
149
Cobalt irradiation facilities
he source is stored 4 meters underground, within 2m thick concrete, in a pool of water
:• Source hoist: able to raise the source up to a conveyor belt where the product will pass by on the conveyor belt
•The cobalt 60 is stored in rods called pencils, many pencils form the radioactive source
• When we are done, we lower the source back down into the ground
150
Sensitivity of organisms to ionizing radiation
Resistance to radiation is genetically determined by how
well the cell can repair itself (DNA damage caused by the
radiation)
I
radiation is due to the production of free radicals
:• If we have increased levels of oxygen, we get higher levels
of kill
• Dehydration increases resistance
:
-
• Oxygen is a big factor, much of the damage caused by
• Freezing increases resistance
• Some organic materials provide a protective environment, such as sulfhydryl groups in amino acids/proteins
151
what are the lethal effects of radiation
```
Direct hits – direct alterations to the target (usually DNA) Indirect effects – free radical and peroxide formation H2O 'H2O++e-
H2O+ > ●OH + H+
e-+H20 , OH-+H●
2H● >H2
2●OH >H2O2
H ● +O2 > ●HO2 (hydroperoxyl radicals)
```
152
Application of gamma radiation
```
Thermolabile products – products which cannot withstand high heat
• Single-use technologies
• Disposable syringes
• Range of plastics (polypropylene, styrene, acrylonitrile, polyethylene, latex)
• Labware & culture media
• Intravenous infusion sets
• Adhesives and dressings
• Prostheses
• Unit-dose ointments
• Dry pharmaceutical products
• Metal instruments
```
153
what are the advantages and disadvantages of radiation
```
High penetrability
• ‘Cold’ process
• Not dependent on humidity, temperature, pressure or vacuum
• Does not generate residuals
• Does not generate radioactivity
```
```
:Disadvantages of gamma radiation
• Specialised facilities/training
• High costs
• Safety consideration – risk to operator
• Deleterious effects on products
• No inactivation of endotoxin
```
154
Deleterious effects on products
Plastics cross-linking, chain scission, odour formation, discolouration, embrittlement, stiffening, softening, enhanced or reduced chemical resistance, increased or decreased melting point (e.g. FEP, PTFE and PVA affected)
☹ Glass may also be affected
☹ Pharmaceutical products may undergo alteration/degradation
☹ Aqueous environments ]damage through radiolysis of water
155
Accelerated electrons
High energy electron beam generated by accelerating electrons form a hot filament through
an evacuated tube under high potential difference
arious machines produce electrons with energy of 5-10MeV
• Rapid dose delivery therefore shorter process times (seconds/minutes) than for gamma
• Less penetrating than gamma rays – may not be suitable for all products
• Direct ionization of molecules
156
UV radiation
Not ionizing because it doesn’t have enough energy
157
Less lethal and damaging than ionising radiation
Causes excitation not ionisation
| • Induces linkages between adjacent pyrimidine bases – :dimer formation (usually thymine)
158
application of UV radiation
```
Poor penetrating power, not practical for pharmaceutical/medical products
application as a disinfection agent
• Air
• Work areas & surfaces
• Manufacturing-grade water
• Microbiological safety cabinets
```
