sterile products Flashcards
what are the criteria that defines sterility
absence of viable microorganisms, endotoxins within limits, no detectable particles (perfectly clear)
what are the types of products that require sterility
parenteral, ophthalmics, preparations for irrigation
what are endotoxins
lipopolysaccharides produced by gram neg bacteria that causes the release of pro inflamm mediators IL and cytokines
what are pyrogens and what are the most common types of pyrogens
pyrogens are substances that causes fever and most common pyrogens are endotoxins
what is meant by sterility assurance level
it indicates the probability of one viable microorganism present in a certain number of drug products
what value indicates high sterility
SAL of 10^-4
what value indicates low sterility
SAL of 10^-1 to 10^-3
what are the types of sterility testing
sterility test (suitability test, growth promotion test), endotoxins test, bioburden, visible/non visible particles
what is meant by inactivation factor
degree to which the viable microorganism is reduced by the sterilisation treatment applied
what is the process of suitability testing (under sterility testing)
perform sterility test but spike the test with known quantities (<100cfu) of known microorganisms -> positive and negative controls -> incubate all tests for 3-5d -> compare levels of turbidity (if turbidity in test sample comparable to positive control -> success)
what is an isolator used for
advances aseptic processing for high potency drugs like chemo drugs, uses insulator of neg pressure
what is the difference between neg pressure and pos pressure insulator
neg pressure = air pressure inside < outside -> air enters but substance cannot exit
pos pressure = air pressure inside > outside -> air leaves and cannot reenter = protect product
what are examples of aerobic bacteria
s. aureus, bacillus, p, aeruginosa
what are examples of anaerobic bacteria
clostridium, aspergillus, candida
what are examples of growth medium
trypticase soy broth, fluid thioglucollate medium
what are the criteria under the growth promotion test (sterility testing)
- each lot of growth medium used in sterility test procedure will support the growth of < 100 viable microorganisms
- portion of each media lot must be incubated and assessed for sterility according to incubation parameters (temp and time)
if media cannot promote growth = fail, if media is non sterile = fail
what is a false positive result
think that product is not sterile as see something in final product but it came from outside and not from system
what is a false negative result
medium does not support growth so think that product is sterile
what is the most common endotoxins test
limulus amoebocyte lysate test (LAL test)
what is the principle of LAL test
reaction between lipopolysaccharide and a substance (clottable protein) contained within amoebocyte cells from the lysis of blood of the horseshoe crab
what is meant by endotoxin limit conc and how to calculate
ELC = K/M where K is max endotoxin dose in kg (usually 5EU/kg) and M is max recc dose in kg
what is meant by maximum valid dilution and how to calculate
MVD = ELC/ method sensitivity lambda
MVD refers to how much you can dilute the sample before notable to determine if number of endotoxin units is high or low enough and is dependent on lambda which varies for different methods
look at example for ELC and MVD calc
what is meant by safety factor
the range of working dilution between MVD and the first dilution fitting the specs
what is meant by bioburden
conc of microorganisms in a material (total number of organisms per ml/g)
what is the limit of bioburden
no more than 10CFU/100ml
what are the potential process design and control strategy risk mitigation measures that can reduce the amount of bioburden
- reduce microbial load prior to and on sterile filter, remove bioburden using pre filters
- limit hold time and room temp storage
- implement aseptic handling techniques where appropriate
- select and validate sterile filter membranes with high microbial retention capabilities (> 10^6CFU/cm2)
- increase effective filter surface area by using larger single filter or multiple filters in series
- limit batch volume to be sterile filtered
- test integrity of sterilising filters pre and post use
what are the potential process design and control strategy risk mitigation measures that can reduce the amount of bioburden
- reduce microbial load prior to and on sterile filter, remove bioburden using pre filters
- limit hold time and room temp storage
- implement aseptic handling techniques where appropriate
- select and validate sterile filter membranes with high microbial retention capabilities (> 10^6CFU/cm2)
- increase effective filter surface area by using larger single filter or multiple filters in series
- limit batch volume to be sterile filtered
- test integrity of sterilising filters pre and post use
what is meant by D value
amount of time required to have at least 1 lg reduction (to reduce a microbial population by 90%)
what are the equations to calculate bioburden
- log (N/N0) = -kt
- log (1/10) = -kD
- D = 1/K where K is death rate constant
- N = SAL of 10^-6 where N is number of cells surviving at time t
what are the concerns regarding presence of sub-visible/ visible particles
concerns with adverse reactions like mechanical obstruction or injection site reactions (phlebitis, granuloma)
what are the possible sources and nature of sub-visible/ visible particles
- extrinsic - environmental conditions like manufacturing equipment, primary packaging, hair, fibers, glass, rubber
- intrinsic - formulation related like API, proteinaceous, excipients, gas bubbles
what are the types of tests that can test for sub-visible/ visible particles and which test is preferred
light obscuration particle count test, microscopic particle count test
what are the types of tests that can test for sub-visible/ visible particles
light obscuration particle count test, microscopic particle count test
which test is preferred for detecting sub-visible particles
light obscuration particle count test
what is the principle of light obscuration particle count test
use suitable apparatus based on the principles of light blockage which allows automatic determination of size of particles and number of particles according to size
apparatus calibrated using dispersion of spherical particles of known sizes between 10-25microm
powders for parenteral use reconstituted with particle free water or with appropriate solvent without contamination of particles
how are large and small volume parenterals tested in light obscuration particle count test
large volume parenterals are tested single units, small volume (<25ml) will have 10 or more units combined in a cleaned container to obtain a total volume of not less than 25ml to be tested
what should the result be that indicates preparation complies with the light obscuration particle count test
number of particles present in the units tested does not exceed 6000 per container >equal 10microm and does not exceed 600 per container >equal 25microm
what is the principle of microscopic particle count test
use of a suitable binocular microscope which is equipped with an ocular micrometer calibrated with an objective micrometer
sensitivity depends on kind of microscope used
what is an ocular micrometer
a circular diameter graticule and consist of a large circle divided by crosshairs into quadrants, transparent and with black reference circles 10 and 25 microm in diameter
what is the criteria that indicates preparation complies with the microscopic particle count test
sub-visible particles: no more than 6000 per container >equal 10microm, no more than 600 per container >equal 25microm
visible particles: essentially free of visible particles
what are the components in ensuring a sterile preparation
safety - freedom from adverse toxicological concerns
sterility - freedom from microbial contamination
non pyrogenic - freedom from pyrogens, endotoxin contamination
particle free - freedom from visible particle contamination
stability - physical, chemical, microbiological
compatibility - packaging, formulation, other diluents
tonicity - isotonic with biological fluids
what are examples of sterile products
sterile powders, injections, IV bags, multi dose vials, patient controlled analgesia, epidurals, irrigations, albumin, plasma protein fraction, immunoglobulins, ophthalmics
what are sterile powders
drugs in powdered form are necessary if unstable in liquid form, must be reconstituted with a sterile diluent before administration
what to look out for when dealing with sterile powders
expiration date, type and amount of solvent to be used in ml, stability of formulation upon reconstituation, storage
what are the advantages of injections
- good for drugs that are poorly absorbed or inactivated in GIT
- good for drugs that are unpleasant
- immediate physiological action
- easy to control onset, duration and therapeutic response (circumvent intestinal absorption)
- easy to administer to unconscious or uncooperative patients
what are the disadvantages of injections
- must be sterile
- tissue toxicity arising from local irritation
- frequent administration may pose difficulties and cause non compliance
- may require skilled personnel for administration
- difficulty in correcting errors
what are the requirements for injections
- sterile and bacterial endotoxins below allowable limits
- standards for particulate matter
- limit additives use
what are examples of additives used in injections
vehicles, antimicrobial agents as preservatives, tonicity adjusting agents, buffers, antioxidants, dispersing agents and surfactants
what are examples of preservatives used in injections
phenols, chlorocresol, thimerosal, phenylmercuric chloride, benzalkonium chloride, benzethonium chloride, benzyl alcohol, chlorbutanol, methyl paraben, propyl paraben, butyl paraben
what are examples of dispersing agents used in injections
tween 80, pluronic f68, lecithin, sodium carboxymethylcellulose, methylcellulose, acacia, gelatin
what is meant by the term preservatives
inhibit bacterial growth, stable and compatible with other excipients
what is meant by the term dispersing agents
prevent agglomeration and promote solubilisation, stable and compatible with other excipients
what is the content in IV bags
base solution with medication dilution before administration
what are the types of IV and the differences between them
- small volume IV (IV piggybacks)
- administered over a short time at specific intervals
- consist of base fluid and medication
- 50 to 250ml - continuous preparation of large volume IV
- infused at a continuous rate
- mostly base fluid with no additives - continuous preparation of IV drips
- infused at a very slow rate
- usually ordered by amount of drug to be infused over given time frame
what is the critical step for multi dose vials
must label date and time opened, initials of person who opened it on vial and must check expiration date when about to use
what are patient controlled analgesia
IV pain medication administered via device either continuous administration or button operated, devices are calibrated to prevent overdose
what are epidurals
inserted IT for pain control in surgery or obstetrics, must be preservative free as can cause paralysis, consist of anesthetic alone or with narcotic
what are irrigation preparations
used in surgery to irrigate open surgical sites, usually contains abx like gentamicin, must be sterile
what are albumin preparations
sterile solution for a single dose administration that contains 25% human albumin, used to treat hypovolemic shock and neonatal hyperbilirubinemia, last up to 4h once open
what are plasma protein fraction (ppf) preparations
sterile solution for single dose IV administration containing 5% plasma proteins, used to treat hypovolemic shock and hypoproteinuria
what are immunoglobulins preparations
sterile, lyophilised, single dose preparation of Ig, used for patients with primary defective or suppressed immune systems and at risk for infections, must be reconstituted before administration
what are ophthalmics
prepared using aseptic filtration technique before being packaged into dropper, instilled onto external surface of eye (topical)/ inside eye (intraocular)/ adjacent (periocular)
