C2-Sterile dosage forms Flashcards
what are the qualifications for parenteral preparations?
Stability of the API during storage and administration
API content and identity accurrency
no microorganisms
limits of pyrogens and ednotoxins
free of visible particles
adequte tonicity, ph
Container size classifications
SVP= small volume parenteral ( < =100 ml) LVÜs= larger voulme parenteral (>=100 ml)
glass types?
type 1 (2-100 ml), have highest quality and high resistance of hydrolytic attack
Antimicrobial, when should it be used?
in all multiple-dose
single dose without a terminal sterilization (may be added)
injections (> 15 ml) no preservatives)
Antioxidants?
ascorbic acid and sodium bisulfits
prevention of oxidative degradation
why are parenteral applications important
due to fast onset of and length of the drug action
action can be control with injectables
what does sterility means?
the absence of viable and actively multiplying microorganisms
on what does the release of the batch depends?
on the validated process
what is a SAL
Sterility assurance level, used to express the probability of a mO to survuve in the product
meaning of a paramerically release
the release is based on the process parameter of the sterilization proces, which are already validated
sterilization processes
steam, dry heat, radiation
steam sterilization process
end product is treated using water vapour as energy conductor
why do we have a shorter sterilization time in steam processing
due to better conduction of water vapor than dry air, (7-fold higher).
temperature in steam and dry heat sterilization
steam temperatur is lower, due to higher energy conductor
what is the case, if sterilization is possible?
sterile filtration and aseptic manufacuring
when is sterilie filtration used?
when steam and dry heat sterilization is not possible
why can’t we used ionizing radiation
due to instabilities of drug susbstance and excipients
On which products can raidation sterilization used?
non-aqueous liquif
when do we used aspetic conditions?
if steam or sterile filtrated is not possible
when do we used dry sterilization process
STANDRAD 160 °c; 2h
METAL AND GLASSS EQUIPMENT
OIL PREPARATION
SAl, on what does the probability of surving of MO depends?
enviroment, the count, type and the resistance of MO
what can be done to ensure high sterility level?
filtration beofre sterilization can be conducted
what can influence the resistance of the MO
pH and antimicrobial compound
number of MO in the prodcut can be affect by the water content
what is the SAL required by Ph.Eur.
10-6
What’s the D-value
decimal reduction value, define as the rate at which the MO are killed during sterilization
what does the D-value meanse?
the number of germs can be reduced at the giving rate by one log
on what does the d-value depends?
on the germs type and procedure
D-value of 15 mins is asign to which baterial?
for geobacillus stearothermophilus or bacillus atrohaeus
what does spore means?
there are heat reistance
Equation for D-value?
D121°C * 10 ^ (121-T/Z)
Z-value?
the temperature coefficient, temerature different at which the D-value is change to the tenfold
F-value?
the time to achive an effective sterilization procedure
Equation for the F-value, when the bioburden is giving
F=n*D–>F=[log(N0)-log (N)] *D
which filter are used for the filter integrity tests?
cartidge and flat filer membranes
on what does the filtration process based?
on the filterion medium, type of filter, pore size, amerial and applied pressure
how can the filter be differentiated?
sepration mechanism
pore structure
property of the filter
PES filter?
Polyether sulfone, asymmetrical structure, hydrophilic
suitbale for aqueous media
classification of the filter integrity test?
destructive and non-destructive
name a destructive test and explained
bacterial challenge test, carried out as a full flow analysis
filter is exposed to > 10^7 CFU/cm of a specific test organism
WFI mixed with the test O-pumped towards the filter to be tested
solution flows through a second filter, transfering it to a agar plat
Non-destrutive test can be divided in ?
convection and diffusion
Bubble point?
convection test
the sterile filter membrane is wetted with the medium, the filter is pressurized with air at the non-sterile side. the diffusion rate highly increses at the bubble point
diffusion tests?
forward flow test, where the gas diffusion needs to stay below the bubble point pressure
pressure hold test?
a pressure is set on the unsterile side
the requirement for the pressure hold test?
intact filter, the pressure stays the same, the bubble point est can follo
otherwiese,there will be a decrease of the pressure over time
what does a redudeant filtration mean?
a two sterile filtration steps
Bublle point test (before and ) after the filteration of the product while the transfer (zone B) from production in zone C, filling in zone A
what are the requirment inorder to start the validation process
germ count of the raw material
on what should the validation based on?
on worst-scenario, to reduce the probability of an error
was have to be tested after setting the CP
efficiency of the sterilization process and the controllability of the parameter
where are the clean rooms zones mesntioned?
Annex 1, GMP
Grade A
high risk operations (aseptic preparation and filling of products
what is require in G A
the laminar air flow
Grade B
aseptic preparation and filling, background enviroment for the grade A
Grade C and D
less critical stages
Ventilation type
GA: LAF, HEPA-filter
GB/GC: turbulent dilution flow HEPA filter
GD: turbulent dilution flow
Laminar air flow
air comes from the high efficiency particulate (HEPA) filter , filter size of 0.3 µm
Process of the LAF?
it carries off emitted particles within seconds and prevent their entrance from outside
what does the LAF provides
horizontal and vertical, provides only product protection
cabinet/banche provides?
the product against contamination from the ambient air, also from working peronnel from aerosols
air flow in the cabinets
the air flow passes into the work zone and enter into the exhaust slits at the front and back egde of the working area
How is the safety cabine arranged?
Was the results of this arrangment?
it is arrange in a way that the exhaust capacity is higher than the supply rate of the filter air
the stucking of the air from the internal space and that of the ambient air, which prevent both the entrace and the exist of the suspended particles
Pyrogen testing
trigger hyperthermia due to release of interleukins
What is major group of pyrogens?
endotoxins
what are endotoxins?
cell wall constituents of Gram-negative bateria
what are other pyrogenic substnaces
living organism (viruses, fungi and bacteria) and non-living, rubber, metal ions, plans
what is the important pyrogenic moiety of the endotoxin?
phosphorylated polysaccaride tighly connected to the lipid component
test of pyrogens
rabbit test and limulus-amoebocyte-lysate-test (LAL
monocyte activation test
used of mannitol in medecine?
infusion solution indicted for osmotic diuretic
it is a hypertonic solution introducing new solute in the plasma, which increase the tonicity of the plasma
which method can be used to monitor the clean room?
Glove print, settle plate and volumetric air sample method and surface sampling (swabs and contact plates)
CFU stands for?
colony forming unit
which tool is used to determine the airbone particle concentration?
Light scattering and airbone particle counter
test for sterility of the product is?
used of membrance filtration and by direct incoculation
membrane filter test for which product?
aqueous preparation, alcoholic or oily preparations
pore size of the membrane filter
50 mm
direct inoculation?
the test sample is diretly inoculated into the culter medium
particle contamination
visible and nonvisible particles
method for visible particles
used of a simplex device, light diffraction
nonvisible particles
based on counting the number of particles, using a light absorption method or microscopy
tes for Euhydrie in the Ph.Eur.
no test mentioned in the Ph. Eur.
ph for infusion, injections and opthalmic
infusion: 3.5-9.5
injections: extreme acidic or alkalic range
opthalmic: 5.5-11
Hypotonic
solution has lower tonicity, resulting in the influx of water in the blood cells, increasing of the pressure inside the cells
plasmolysis
occur by hypertonic solution influx of water into the plasma
osmotic pressure?
the pressure required to stop osmosis
osmosis?
influx of water through a semipermeable membrane to equalize the solute concentration on boh sides of the membrane
what does colligative property means?
property of the solution depends on the number of sollute particle in solution and not on their physical nature
example of colligative property
osmotic pressure,
boiling point
freezing point depression
on what is the osmotic pressure related to?
to the molar concentration of solute M
R, gas constant and T absoulte temperature
what is added to th equation of the OP when we have an electrolytes?
the van’t hoff factor
what is used to determine the osmotic pressure of a solution
by measuring the freezing point depression, an indirect method
freezing point os proportional to what?
it is directly propertional to the molality of the solut (Raoult’s law)
step Determination of FPD?
- first determine the freezing temperatures of the pure solvent and that of the solution
what is used to determine FPD?
electronic osmometer
- process in the osmometer
- the solution is cooled down to its freezing point by mesnd of a cooling block in the device
what happend during the cooling process?
the solution is not rigidfied
what happend after the cooling process?
the solution is uncooled to a certain temperature, where cystallization occure due to mechanical trigger
what is the regidification point?
it is a point where the temp increase due to the occurrence of crystallization
how is the fluid called at the regidification point
regidifying fluid
till which point do the temperature rise?
till ine mmelting point.
what happend after the meltinng point is reached?
the solution solidified
when does the solidification takes places?
in cases where one has a pure solvent
which maximum temepertaure is reach, if we don’t have a pure solvent?
the freezing point temp. of the solution is reached and not the melting point temp.
why does the freezing point decreases
because only the crystals of the our solvent will seperate and thus making the solution more concentrated
Apart from the Raoult Law method, which other method is used to calculate the freedzing point depression?
DAC-method,
NaCL equivalent method
White-Vincent-Method
nonogram
Osmolality for infusion, injections and ophthalmic
infusion: 900 mOsmol/kg
injections: 600 mOsmol/kg
Ophthalmic: 275-300 mOsmol/kg
when do we used membrane filtration and filter integrity?
when sterilization by other methods is not possible
what has to be done with filters
it has to be sterilzed by a validated produre
how can you test the integrity?
forward flow, bubble point and water intrusion test
what is a filter integrity tests
it is used to investigate the compliance to the respective filter specifications of the manufacturer
in which law is the bubble point test beaded on?
know the eqaution
on the laplace law
when is the bubble point reached, when using a syringe?
when a continous bubble hain is coming out of the filtrate side
importnat guidelines and cocuments regarding asecotic processing
EU GMP Annex 1, 17
What is a parenteral drug association technical report?
it provide informtion regarding vaidation of sterilization processes and bioburden recovery, steilizing filteration of liquid, package integrity.
whar are media fills?
it is define as a limiation of the contatmination risk to 10-03, it is relavent during the validation of aseptic manufacturing
how are contaminations tried to be avoided?
using validated porcesses and room concepts
when are suspension preparation suitable?
where the API has a low solubility in water
what is a nonogram,
it is used to calculte the amount oFNacl, by creation a calibration.
what is the blow fill technology?
used to formed plastic containers, which are the filled with sterile filter poduct ans asepticall sealed
forming filling and sealing are conducted under aseptic conditions without interrupting the operations sequence.
