1.0
OBJECTIVE
1.1
To lay down a standard procedure to be followed for conducting an Abnormal Toxicity Test in
Experimental Animals by the method prescribed in Indian
Pharmacopoeia (I.P.)-2018.
2.0
SCOPE
2.1
This Standard Operating Procedure (SOP) shall be
applicable for conducting Abnormal Toxicity Tests in
Experimental Animals by the I.P.-2018 method in the Animal House Facility.
3.0
RESPONSIBILITY
3.1
Head- Animal House Facility / Study Director
3.2
All Personnel involved in Study
4.0
DEFINITIONS
4.1
Nil
5.0
PROCEDURE
5.1
Pre-Experimental
Activities
5.1.1
IAEC approval for conducting abnormal toxicity test of
test item shall be taken as per the currently running version of SOP…… Study shall be
initiated after getting approval from the IAEC committee for the conduct of
experiment.
5.1.2 A detailed Study Plan for the study shall be prepared by
following recommended method prescribed.
5.1.3
Study personnel shall be given study-specific training
if any (if required) as per the currently running version of SOP……….
5.1.4
After getting approval of study plan from sponsor,
required number of data recording sheets (DRS) formats shall be issued from
QAD.
5.1.5
Animal requisition shall be given to the animal house
facility and animals shall be issued as per the currently running version of SOP………...
5.1.6
After issue animals shall be acclimatized to standard
laboratory conditions for a period of at least 5 days as per the current
running version of SOP………..
5.1.7
After completion of the acclimatization period animals
shall be randomized and grouped by the following SOP………….
5.1.8
Numbering and identification of animals shall be
carried by following the currently running version of SOP……………...
5.1.9
If test item needs to be formulated (prepared) /
diluted in any vehicle then dose calculation and formulation of test item shall
be carried out as per the sponsor’s instruction / recommended procedure.
5.2
Experimental
Activities
5.2.1
Animal
requirements and housing conditions
5.2.1.1
For
Test Item/s other than vaccines and antisera
5.2.1.1.1
5-10 healthy adult mice preferably of the same
variety weighing 17-22 g shall be used for test item/s other than vaccines and
antisera.
5.2.1.1.2
Animal shall be housed individually in an
area of uniform temperature (25±2 °C), possibly with uniform humidity, and free
from disturbances likely to excite them.
5.2.1.1.3
The animals shall be given ad libitum water
and food, commonly used for laboratory animals.
5.2.1.2
For
Vaccines and Antisera
5.2.1.2.1
5-10 healthy adult mice weighing 17-22 g and
2-4 adult guinea pigs weighing 250-350 g shall be required.
5.2.1.2.2
Animal shall be housed individually in an
area of uniform temperature (25±2 °C), possibly with uniform humidity, and free
from disturbances likely to excite them.
5.2.1.2.3
The animals shall be given ad libitum water
and food, commonly used for laboratory animals.
5.2.2
Administration
of doses
5.2.2.1
For
Test Item/s other than vaccines and antisera
5.2.2.1.1
For test item/s other than vaccines and
antisera, the test item shall be prepared in water for injection (WFI) or
sterile normal saline (NS) or as per recommended method by the sponsor with the final dose of 0.5 mL/animal volume.
5.2.2.1.2
Test items shall be administered aseptically
to each animal in a single dose over a period of 15 to 30 sec. (unless
otherwise stated in the individual monograph) through intravenous (i.v.) route by
following the currently running version of SOP………….
5.2.2.1.3
If one of the animals dies or show signs of
ill-health during the specified observation period of 24 hrs or within the time
specified in the individual monograph, the test shall be repeated.
5.2.2.2
For
Vaccines and Antisera
5.2.2.2.1
For vaccines and antisera test item shall be
prepared/used as per individual monograph.
5.2.2.2.2
Unless otherwise prescribed in the individual
monograph inject intraperitoneally one human dose but not more than 1.0 ml
into each of five healthy mice, weighing 17 g to 22 g, and one human dose but
not more than 5.0 ml into each of two healthy guinea pigs weighing 250 g to 350
g.
5.2.2.2.3
The human dose is that stated on the label or
in the accompanying information leaflet of the preparation under examination.
5.2.3
Observations
5.2.3.1
Clinical signs of toxicity after dosing shall
be recorded as per the current running version of SOP………… and data shall be
recorded in associated format to the SOP. All animals shall be observed
individually after dosing at least once during the first 30 minutes,
periodically during the first 24 hours, with special attention given during the
first 4 hours, and daily thereafter, for the time as specified in the individual
monograph, except where they need to be removed from the study and humanely
killed for animal welfare reasons or are found dead.
5.2.3.2
Animals shall be observed daily during the observation period for mortality as per SOP…….. and observation shall be recorded
in associated format to SOP.
5.2.3.3
Individual weights of animals shall be
determined shortly before the test substance is administered and daily
thereafter. Bodyweight shall be recorded as per the currently running version of SOP…………
and data shall be recorded in associated format to SOP. At the end of the test
surviving animals shall be weighed and then humanely killed.
5.2.3.4
All test animals (including those that die
during the test or are removed from the study for animal welfare reasons) shall
be subjected to a gross necropsy as per the current running version of SOP…………. and
all gross pathological changes shall be recorded in associated format to SOP.
5.2.3.5
All observations shall be systematically
recorded, with individual records being maintained for each animal.
5.2.3.6
Animals found in a moribund condition and
animals showing severe pain or enduring signs of severe distress shall be
humanely killed. When animals are killed for humane reasons or found dead, the
time of death shall be recorded as precisely as possible.
5.2.4
Interpretation
of Results
5.2.4.1
For
Test Item/s other than vaccines and antisera
5.2.4.1.1
The substance passes the test if none of the
mice die within 24 hours or within the time specified in the individual
monograph.
5.2.4.1.2
If more than one animal dies, the preparation
fails the test.
5.2.4.1.3
If one of the animals dies, repeat the test.
5.2.4.1.4
The substance passes the test if none of the
animals in the second group die within the time interval specified.
5.2.4.2
For
Vaccines and Antisera
5.2.4.2.1
The preparation passes the test if none of
the animals die or show signs of ill-health in 7 days following the
injection. If more than one animal dies, the preparation fails the test. If one
If the animals die or show signs of ill health, repeat the test.
5.2.4.2.2
The preparation passes the test if none of
the animals in the second group die or show signs of ill health in the time
interval specified.
5.2.4.2.3
If one of the animals dies or show signs of
ill-health during the specified observation period of 7 days or within the time
specified in the individual monograph, the test shall be repeated.
5.3
Data And
Reporting
5.3.1
Individual animal data shall be provided. Additionally,
all data shall be summarized in tabular form, showing for each test group the
number of animals used, the number of animals displaying signs of toxicity, the
number of animals found dead during the test or killed for humane reasons, time
of death of individual animals, a description and the time course of toxic
effects and reversibility.
5.3.2
Statistical analysis, if required shall be carried out
by using a licensed version of Graphpad instant 3.01 or by Graphpad 7.04 by
following its user manual.
5.4
Test report
5.4.1 Draft test report shall be prepared and shall include the following information, as appropriate:
5.5 Archive
5.1.1 After the approval of the draft study report from a sponsor, study file and all related materials / raw data shall be achieved.
5.6 Flow chart
for conducting Abnormal Toxicity Test in Experimental Animals (By I.P.-2014
Method)
5.7 Checklist of
SOPs required for conducting Abnormal Toxicity Test in Experimental Animals (By
I.P.-2018 Method)
6.0
ENCLOSURES
6.1
Nil
7.0
ABBREVIATIONS
7.1
SOP :
Standard Operating Procedure
7.2
AHF :
Animal House Facility
7.3
DRS : Data Recording sheets
7.4
I.P. : Indian
Pharmacopoeia
7.5
QAD : Quality Assurance
Department
8.0 REFERENCES
8.1 Section 2.2.1, Indian Pharmacopoeia, 2018.
9.0 REVISION HISTORY
END OF
DOCUMENT
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