Parenterals are the sterile dosage forms intended for administration other than enteral route (parenteral = per+enteral) and exerts their action by directly entering into the systemic circulation.
The quality of parenterals is the
sum of all parameters that contribute to safety, efficacy and therapeutic
efficacy of the drug.
The USP compendial requirements has recommended the following
tests for parenteral products
1. Weight variation or content uniformity
2. Particulate matter in injections
3. Bacterial endotoxin test
4. Pyrogen test
5. Sterility test
2. Particulate matter in injections
3. Bacterial endotoxin test
4. Pyrogen test
5. Sterility test
1. Weight variation or content
uniformity test
This test is intended for sterile
solids used for parenteral preparation. The weight of 10 individual sterile
units is noted and the content is removed from them and empty individual
sterile unit is weighed intern. Then net weight is calculated by subtracting
empty sterile unit weight form gross weight. The content of active ingredient
in each sterile unit is calculated by performing the assay according to the
individual monographs. The content in 10 sterile units is calculated by
performing the assay. The dose uniformity is met if the amount of active
ingredient is within the range of 85-115.0% of label claim as determine
by the content uniformity method or weight variation method. The dose
uniformity is also met if the potency value is 100% in the individual monograph
or less of label claim multiplied by average of limits specified for potency in
individual monograph divided by 100 provided that the relative standard
deviation in both the cases is equal to or less than 6.0%.If one unit is
outside the range of 85-115.0%, and none of the sterile unit is outside the
range of 75-125.0% and if the relative standard deviation of the resultant is
greater than 6.0% then, the fore mentioned test is carried for 20 more sterile
units. The sterile units meet the requirements if not more than one unit is out
side the range of 85-115%, no unit is outside the range of 75-125.0% and the calculated
relative standard deviation is NMT 7.8%.
2. Particulate matter in injections
The preparations intended for
parenteral use should be free form particulate matter and should be clear when
inspected visually. Two methods are described by USP according to the filled volume of the product to be
tested.
For large volume parenterals (LVP's), a filtration followed by microscopical examination procedure is used. For small volume parenterals (SVP's) a light obscuration based sensor containing electronic liquid-borne particle counter system is used.
The USP standards are met if the LVP's under test contain NMT 50 particles per ml of 10 µm, and NMT 5 particles per ml of 25µm in an effective linear dimensional fashion.
The USP standards are met if the SVP's under test contain NMT 10,000 particles per container of 10 µm, and NMT 1000 particles per container of 25µm in an effective spherical diameter.
For large volume parenterals (LVP's), a filtration followed by microscopical examination procedure is used. For small volume parenterals (SVP's) a light obscuration based sensor containing electronic liquid-borne particle counter system is used.
The USP standards are met if the LVP's under test contain NMT 50 particles per ml of 10 µm, and NMT 5 particles per ml of 25µm in an effective linear dimensional fashion.
The USP standards are met if the SVP's under test contain NMT 10,000 particles per container of 10 µm, and NMT 1000 particles per container of 25µm in an effective spherical diameter.
3. Bacterial Endotoxin test
LAL (Limulus Amebocyte Lysate) test
is used to characterize the bacterial endotoxin that may be present. The USP
reference standard contains 10,000 USP endotoxins per vial. The LAL reagent is
used for gel-clot formation. The test is performed using stated amounts of
volumes of products, standard, positive control, and negative control of
endotoxin. The tubes are incubated at 37±10C FOR 60±2 minutes. When
the tubes are inverted at 1800C angle, formation of firm gel
confirms positive reaction. While formation of a viscous gel that doesn't
maintain its integrity or absence of a firm gel confirms negative reaction. The
test is invalid if the standard endotoxin or positive product control doesn't
show end point within ±1 two fold dilution from label claim sensitivity of LAL
reagent or if the negative control shows gel-clot end point.
4. Pyrogen test
It is performed by using rabbits as
test animals. Initially 10 ml/kg body weigh of animal is injected through rat
vein at 37±20C within ten minutes from start of administration. The
temperatures are recorded at 1, 2 and 3 hours after injection. The requirements
of USP are met if the rise in temperature of individual rabbit is NMT 0.60C
and the sum of rise in temperature of three rabbits is NMT 1.4C. If any one
rabbit shows a rise in temperature of 0.60C and sum of rise in
temperature of three rabbits exceeds 1.40C then the test is repeated
using 5 rabbits. The requirements are met if 3 out of 8 rabbits shows an
individual rise in temperature of NMT 0.60C and sum of maximum rise
in temperature of 8 rabbits is NMT 3.7C.
5. Sterility test
Growth promotion medium and
incubation conditions are selected based on the test microorganism according to
USP and is listed in table 1. The sterility test is done using direct transfer
and membrane filtration techniques. Membrane filtration technique is suitable
for liquids, soluble powders with bacteriostatic or fungi static properties,
oils, creams and ointments. Sterility test by direct transfer is performed by
aseptic transfer of specified volume from test container (table 2) to culture
medium and incubated for 14 days and visual observation of medium is done on 3rd,
4th, 5th, 7th, 8th and 14th
day. A membrane filter with porosity of 0.45µm with diameter of 47mm with flow
rate of 55-75 ml of water per minute at a pressure of 70 cm of mercury should
be used. The test meets the requirements when no growth is observed and if
growth is observed then the test is repeated in the second stage and generally
second stage is repeated with double the number of specimens tested in first
stage when the test was found to be conducted under faulty or inadequate
aseptic techniques.
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