unit 5 Flashcards
dosage forms of therapeutic agents that are free of viable microorganisms.
Sterile products
unique dosage forms of drugs as they are injected through the skin or
mucous membranes into the internal body compartments.
Parenteral products
Sterile preparations
parenteral, ophthalmic and irrigational preparations
sterile liquids, semisolids, or solid preparations
intended for the administration upon the eyeball and/or conjunctiva
in the conjunctival sac
Opthalmics
pH: Ideally for opthalmic
pH 7.4) or slightly more alkaline
Opthalmic prep. tolerate solutions with pH as low as___to improve absorption and stability
3.5
used to treat local disorders of the eye
EYe drops
are used to treat
intraocular disorders like glaucoma.
Ocular solutions
are used for rinsing the eye or impregnating eye
dressings
Eye lotions
sensitive to microorganisms which is why ocular solutions must be sterile.
Occular tissues
Injectable route of administration, drugs are commonly injected
into the veins, muscles or skin butcan also be injected in the
arteries, joints, joint fluid areas, spinal column, spinal fluid or heart.
Parenteral
included under
certain conditions such as in multidose products.
Benzyl alcohol
pH of most licensed parenteral
solutions is between __
3and 9
Parenteral solutions must be ___ and ___
sterile and pyrogen-free.
important to ensure that theproduct is in its optimum shape to produce its
desired therapeutic outcome
(isotonicity testing
Used when wider range of tonicity can be tolerated as dilutionwith
body fluid occurs.
Smaller volume
- the solution must be aqueous, as oildroplets can occlude the pulmonary
microcirculation.
Intravenous
- the solution canbe aqueous or non-aqueous.
Intramuscular and subcutaneous
- are sterile solutions, emulsions or suspensions prepared by
dissolving emulsifying or suspending the active ingredients and other
additives in water for injection or other suitable non-aqueous vehicle
or in mixture of two, if they are miscible.
Injections
are sterile solid substances (including freeze- dried or lyophilized materials) which
are distributed in their final containers which, when shaken with the prescribed volume of the
appropriate sterile liquid, rapidly form clear and practically particle-free solutions or uniform suspension.
Powder for injections
These are sterile aqueous solutions or emulsions with water as continuous phase.
Intravenous Infusion
When a drug is infused intravenously at a constant rate, a __
will be reached progressively in the most frequently most of the cases follows first
order kinetics.
plateau concentration
True or false
The amount of drug in the body then rises, but as the drug concentration increases,
so does the rate of elimination.
True
True or false , the rate of elimination will keep rising until it matches the rate of infusion.
True
amount of drug in the body is then constant and is said to have reached a ___
steady state or plateau.
sterile solid preparations of size and shape for implantation into
body tissues so as to release active ingredient over an extended period of
time.
Implants
man-made devices, in contrast to a transplant, which is
a transplanted biomedical tissue.
Implants
are sterile solutions that are intended for administration by
injection or by IV infusion only after dilution with suitable dilution with a suitable liquid.
Concentrated solutions for injections
Aqueous Vehicles for Sterile Products
Water for Injection
Sterile Water for Injection
Bacteriostatic Water for Injection
It is intended to be
used within 24 hours
after collection
Water for Injection
Single dose containers not
larger than 1 liter
Sterile for water injection
agents such as
benzyl alcohol may cause gasping
syndrome (multiorgan failure).
Bacteriostatic
Use Not more than 30 ml of the water
Sterile water for injections
Total solid contents
not more than 1
mg/100 ml
Water for Injection
It is packaged in prefilled syringes
or in vials
Bacteriostatic water for injections
Single dose units:
ampoules, infusions and prefilled disposable syringes
multiple dose vials types of packaging
Multiple dose units:
production and control of Small volume parenterals:
volume < 100 ml
: volume ≥ 100 ml
Large volume parenterals
are topical preparations used intra-operatively during procedures.
Irrigation solutions
indicated for washing or bathing surgical incisions, wounds, and body tissues, including
body cavitie
Irrigation
most important
requirement of irrigation preparation.
sterility
Processing of Parenteral Preparations
1.Cleaning of
Containers and
Equipment
2. Collection of
Materials
3.Preparation of
Parenteral Products
4. Filtration
5. Filling the
preparation in
the final
container
6. Sealing the
container
7. Sterilization
and Evaluation
8. Evaluation of the
parenteral preparation
9. Labeling &
packaging
Physical and Chemical Tests for Sterile Products are Categorized into:
1. Identity tests
2. Quality tests
3. Purity tests
4. Potency tests
used to conform the actual presence of compound for
example color formation, precipitatio
Identity test
These tests are the physical methods used to measure accurately the characteristic properties of drug.
For example: Absorbance, refractive index.
Quality tests
designed to estimate the level of all known and significant impurities and contaminants
in the drug substance under evaluation. For example: Tests for clarity of solutions, Acidity, Alkalinity.
Purity tests
are assays that estimate the quantity of an active ingredient in the drug.
Potency tests
is employed to test the package integrity.
Leakage test
reflects its ability to keep the product in and to keep potential
contamination out
Package integrity
employed to detect incompletely sealed ampoule so that they may be discarded.
Leakers test
Types of Leaker Test:
(Visual Inspections, Bubble Test, Dye Test, Vacuum Ionization)
easiest leaker test method to perform.
§ The method is used for the evaluation of large volume parenterals.
Visual Inspections
The test package is
submerged in liquids.
§ A differential pressure
is applied on the
container.
Bubble Test
location of the leaks can be observed in this method.
Bubble test
The test container is
immersed in a dye bath.
Dye test
dye used in dye test
0.5% to 1% methylene blue
The dye test can be optimized by use of a ___
surfactant and or a low viscosity fluid
Disadvantages: destructive and slow
Dye test
useful for testing leakage in the
vials or bottles sealed under
vacuum
Vacuum ionization
used for testi
Vacuum ionization
presence of residual gas
present will glow
for
stability purposes
Freeze-dried products
function of headspace vacuum level in vacuum ionization
Glow intensity
indicative of vacuum while the purple glow indicative of no
vacuum.
Blue glow
method is used for the lyophilized vials of biopharmaceuticals.
Vacuum ionization
aka: Particle Containment Test or Detection of Particulate Matter
Clarity test
defined as the quality of transparency or purity
Clarity
test is performed to check the particulate contamination of injections and infusions
consists of extraneous, mobile and undissolved particles, other than gas bubbles, unintentionally
present in the solution.
Clarity test
Small volume injections (<100 ml) in ≥ 10 um and ≥ 25 um Particle size
3000 per container 300 per container
Large volume injections
(>100 ml) in ≥ 10 um and ≥ 25 um
Particle size
12 per ml 2 per ml
Visual inspection by naked eye
Test for Visible Particles
gives the qualitative estimation of
the particulate matter
Visual inspection
• This test is performed to check particulate contamination of injections and infusions (ie: presence of
extraneous, mobile undissolved particles, other than gas bubbles)
Test for Sub-visible Particles
This test is based on the principle of light
blockage which allows an automatic
determination of the size of particles and the
number of particles according to size.
• Method 1: Light Obscuration Particle Count
equipped with an ocular micrometer calibrated with an objective micrometer, a mechanical stage and, 2 suitable illuminators. in MICROSCOPIC PARTICLE COUNT
TEST
binocular microscope
true or false;
ACCEPTANCE STANDARDS of Light Obscuration Particle Count ;if the average number of particles present in the units tested does not exceed 25 per milliliter equal to or greater than 10 µm and does not exceed 13 per milliliter equal to or greater than 25 µmin more than 100ml
false
true or false;
ACCEPTANCE STANDARDS of Light Obscuration Particle Count if the
average number of particles present in the
units tested does not exceed 6000 per
container equal to or greater than 10 µm
and does not exceed 600 per container
equal to or greater than 25 µm in LESS than 100 mL:
true
true or false
ACCEPTANCE STANDARDS of MICROSCOPIC PARTICLE COUNT
TEST in MORE than 100 mL:
The preparation complies with the test if the
average number of particles present in the
units tested does not exceed 24 per milliliter
equal to or greater than 10 µm and does not
exceed 2 per milliliter equal to or greater
than 25 µm
false
true or false
ACCEPTANCE STANDARDS of MICROSCOPIC PARTICLE COUNT
LESS than 100 mL:
The preparation complies with the test if the
average number of particles present in the
units tested does not exceed 3000 per
container equal to or greater than 10 µm
and does not exceed 100 per container
equal to or greater than 25 µm
false
are fever producing substances. They are metabolic by-products of microbial growth and
death.
Pyrogens
produce more potent endotoxins
Gram negative bacteria
are heat stable lipopolysaccharides (LPS) present in bacterial cell walls, not present in cellfree bacterial filtrates.
Endotoxins
doses of Pyrogen: asymptomatic inflammation reaction Moderate doses: fever & changes in plasma
composition
low dose
doses of Pyrogen: asymptomatic inflammation reaction Moderate doses: fever & changes in plasma
composition
low dose
doses of Pyrogen: cardiovascular dysfunction, vasodilation, vasoconstriction, endothelium dysfunction, multiple
organ failure & finally death.
High doses
This test consists of measuring the rise in body
temperature evoked in rabbits by the injection of a
sterile solution of the substance being examined.
IN VIVO PYROGEN TEST (RABBIT TEST)
The thermometer is inserted into the rectum of the rabbit to a depth of about ----------(B.P specification) or ------- (USP specification)
5 cm or 7.2cm
All the glassware, syringes and needles must be thoroughly washed with water and heated
in a hot air oven at -------- for 30 minutes or at ----------for an hour.
250°C and 200°C
test Before using a
rabbit for the first time in a pyrogen test, condition it not more than seven days before use
sham test
true or false
record the temperature at 1-minute intervals between 1 and 3 hours subsequent to the
injection and determine the maximum temperature.
false - 30 minutes
the mean of two temperature readings (recorded at an interval of 30 minutes)
Initial Temperature
the highest temperature recorded three hours after the injection of the
preparation
Maximum Temperature
True or falseTotal of 8 rabbits is used in pyrogen in vivo
true
true or false
Product passed the test if no rabbit from the three showed an individual rise of
more than 0.6°C, and the sum of the rise in temperature of the three rabbits did not exceed 2.4°C otherwise, test the product in 5 more rabbits (Stage 2).
false 1.4 C
true or false
Product passed the test if no rabbit from the eight showed an individual rise of
more than 0.6°C, and the sum of the rise in temperature of the eight rabbits did not exceed 3.7°C otherwise, the test failed.
true
aka: Bacterial Endotoxin Test (BET)
IN VITRO PYROGEN TEST (LIMULUS AMEBOCYTE LYSATE TEST)
aqueous extract of blood cells
(amoebocytes) from the horseshoe crab,
Limulus polyphemus.
LIMULUS AMEBOCYTE LYSATE TEST
true or false;
The concentrated pyrogens make the gel more turbid and thicker.
true
true or false;
proteins must be diluted to
appropriate concentration before the test to avoid false positive results.
true
Methods of LAL Test
1. Gel- Clot Method
2. Turbidimetric Method
3. Chromogenic Method
provides very simple positive or negative result and a qualitative LAL test for detection of Gram-negative bacteria endotoxins.
Gel Clot LAL test
used to adjust the pH of in vitro test
sample at 7.
potassium phosphate 2mEq/ml
true or false in pyrogen in vitro gel;
If precipitate or solid remains are
intact, the sample is considered to contain endotoxin. If the liquid flows down the side
of the tube, the result is negative for endotoxins.
true
quantitative LAL test that works on the principle
of measuring the wavelength of light passing through the solution using spectrophotometric
methods.
Turbidimetric Method
turbidity wavelength of
light passing through the solution is measured using
spectrophotometric methods.
true or false';
More turbidity= lower concentration of pyrogens
false
quantitative LAL test that mixes the LAL reagent with a chromogenic
reagent to produce a synthetic chromogenic substrate which is then added to the test sample and incubated.
chromogenic method
in chromogenic test, thepresence of endotoxins is indicated by the formation of a ----------- of the solution.
yellow coloration
true or false;
The more endotoxin present, the more yellow the solution will become.
true
Chromogenic test can be quantitated using a ------------- or ---------------- to reveal
the specific endotoxin concentration.
spectrophotometer or absorbance plate reader
true or false;
LAL test does not detect non-endotoxin pyrogens
true
defined as the freedom from the presence of viable microorganisms.
sterility test
carried out under strict aseptic conditions in order to avoid accidental
contamination of the product during test.
sterility test
2 methods of Sterility Testing
(1) Membrane Filtration Method and (2) Direct Inoculation Method
true or false:
Membrane Filtration Method
After filtration the membrane is removed aseptically from the metallic holder and divided into two halves.
The first half is transferred into 100 ml of culture media meant for fungi and incubated at 20 ̊to 25 ̊c for not
less than seven days.
The other half is transferred into 100ml of fluid thioglycolate medium and incubated at 30 to 32 ̊c for not
less than 7 days.
false 35
true or false:
Membrane Filtration Method;
(More colonies/ More
turbidity= greater concentration of viable microorganism
true
true or false:
DIRECT INOCULATION METHOD
Incubate the inoculated media for not less than 14 days, unless otherwise specified in the monograph at
300c - 350c in the case of ---------
fluid thioglycolate medium
true or false:
DIRECT INOCULATION METHOD
Incubate the inoculated media for not less than 14 days, unless otherwise specified in the monograph at 200c - 250c for ----------
soybean casein digest medium.
primarily intended for culture of anaerobic
bacteria
can also detect aerobic bacteria
FLUID THIOGLYCOLATE MEDIUM
suitable for culture of both fungi and
aerobic bacteria
SOYBEAN CASEIN DIGEST MEDIUM
INCUBATION TIME
AND
TEMPERATURE
14 days at 30-35°C
FLUID THIOGLYCOLATE MEDIUM
Final pH = 7.1
FLUID THIOGLYCOLATE MEDIUM
contains L-cysteine
trypticase peptone
dextrose
yeast extract
sodium chloride
sodium thioglycolate
resazurin
agar
purified water
FLUID THIOGLYCOLATE MEDIUM
contains
Trypticase soya broth
Trypticase peptone
Phytone peptone
Sodium chloride
Dipotassium phosphate
Dextrose
Purified water
SOYBEAN CASEIN DIGEST MEDIUM
Final pH = 7.3
SOYBEAN CASEIN DIGEST MEDIUM
are used as a Quality Control measure which helps in the monitoring of
conditions necessary to kill a specified number of microorganisms by a given sterilization process
Biological Indicators (BI)
are used as a Quality Control measure which helps in the monitoring of
conditions necessary to kill a specified number of microorganisms by a given sterilization process
Biological Indicators (BI)
Moist Heat (autoclave)
B. stearothermophilus
Method of Sterilization used in B. subtilis
Dry Heat (oven)
Method of Sterilization used in B. stearothermophilus
Ethylene oxide
Bacteria Used inRadiation
Both B. stearothermophilus & B. subtilis + B. pumilus
Apparatus Used
pH
pH meter
apparatus Viscosity
Ostwald viscometer
Osmolality apparatus (count of the number of particles in a fluid sample)
Osmometer
Conductivity apparatus (conductivity of vehicle used in sterile preparation)
(Pure Water 0.55mS/cm)
Conductometer
Temp. for Heat Sterilization apparatus (To maintain the constant temperature during heat sterilization of product)
Thermometer, Digital Thermometer
