Q0SM Flashcards
what requirements are needed to manufacture to a high standard
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)
why use injectables
• Rapid drug action required
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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)
what are the problems associated with injections
Problems with injectables
• Once administered, generally can’t remove
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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)
what are the different type of injections
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
what are the different routes
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)
what are the different routes
intra-articular— joints
Intrasynovial — joint fluid area I Intraspinal — spinal column
Intrathecal — spinal fluid Intra-arterial — arteries Intracardiac— heart
what is Methylprednisolone acetate (Depo-Medrone)
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
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Can also be given IM
what is IV
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)
what are the advantages of IV route
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
what are the uses of IV
Emergencies
- Bolus delivery (drug toxicity and irritation)
Fluid, electrolyte replacement
Due to shock, severe bleeding, dehydration Nutrient supplement
l Comatose patient
what are the different types of IV administration
iv bolus or iv push
intermittent infusion
continuous infusion
what does IV bolus or IV push entail
peated at intervals
Basically the typical IV injection that we know
what does intermittent infusion entail
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
what does continuous infusion entail
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
what are disadvantages of IV route
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
what are the different Types of IV products (almost all are aqueous solutions)
Parenteral nutrition (PN) Lipid emulsions Amino acid solutions Carbohydrates
Monoclonal antibodies
Cancer treatment
Large molecular weight molecules
I
Heparin
Stealth liposomes (e.g. Doxorubicin HCl)
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
subcutaneous route
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)
Goserelin matrix implant (Zoladex
SC into upper abdominal wall
Continuous release over 28 days
Goserelin dispersed in matrix
Matrix is copolymer of D,L-lactic and glycolic acids
IM route
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
long acting IM depot injections
Nandrolone decanoate (Deca-durabolin) Testosterone enantate Testosterone proprionate, phenylproprionate, isocaproate (Sustanon 100) Testosterone proprionate, pehylproprionate, isocaproate, decanoate (Sustanon 250) Testosterone undecanoate (Nebido)
ester at position 17
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
droplet surface area
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
Half life of oily depots vs. Oil viscosity
Higher viscosity oil has a longer half life than lower viscosity oil
intradermal route
corium of skin — more vascular layer of skin beneath the epidermis Anterior forearm, back
Diagnostic purposes usually
- Tuberculin & allergy testing
what are the 3 type of injectables
Controlled release
Needle-free technologies
Targeted delivery
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!
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!
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
Applications of needle-free devices
Current applications include the delivery of insulin, vaccines, growth hormones etc. Gene delivery in the future?
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
what is meant by marketing authorisation
A license that is required by law for any pharmaceutical product, issued by the regulator for that country
who is the regulator in the uk
MHRA – medicines and healthcare products regulatory agency
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
What does the MA stipulate?
Details of exactly which patients, conditions and clinical situations the medicine can be used for, including specific doses
what are specials
These are unlicensed medicines
It is used for patients with unique clinical requirements or unusual circumstances
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
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
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
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
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
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…
- 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…
- Consider use of a special
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
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
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!
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.
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
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
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
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
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)
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?
what are the different sterilisation process
• Reactive gas (e.g. ethylene oxide) I
• Irradiation (e.g. ionizing radiation such as Gamma rays) -
what is terminal sterilisation
Make product under non-sterile conditions using non-sterile ingredients; sterilize it at the end pf the process
what is aseptic manufacturing
Make the product from sterile ingredients under sterile conditions - clean rooms
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
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)
what are survivor curves
The constant K tells us how quickly cells are being killed – distinct microorganisms have distinct k constants at different temperatures
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
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:
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
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
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
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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
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 )
