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in process quality control test for ophthalmic and parenterals
1. IN-PROCESS QUALITY CONTROL TEST FOR
OPHTHALMIC AND PARENTERALS
MQA103T
Guided by : Presented by:
Dr. Bhavna Patel Henisha Patel
Department of pharmaceutical science,
Quality Assurance 1
3. Ophthalmic preparations are specialized sterile dosage forms
designed to be instilled onto the external surface of the eye (topical),
administered inside (intraocular) or adjacent (periocular)to the eye or
used in conjunction with an ophthalmic device.
The most commonly employed ophthalmic dosage forms are
solutions , suspension and ointments
Newest: gels, gel-forming solution , ocular inserts , intravitreal
injection and implants.
Definition
3
4. • Prior to World war II, &into the 1950’s, ophthalmic preparations were
mostly compounded by the pharmacist for immediate use.
• Even until 1953, there was not a legal requirements by FDA that all
manufactured ophthalmic solutions be sterile.
• But in the past 50 years, a modern pharmaceutical industry
specializing in ophthalmic preparations has developed to support the
advances in diagnosis and treatment of eye diseases, eye surgery and
contact lenses.
HISTORICAL BACKGROUND
4
8. Planned system
Controlling procedures involved in manufacturing of the dosage
forms starting from raw materials purchase to dispatch of the product
in ideal packaging.
OBJECTIVE
It monitors all the features of the product that may affect its quality
and prevents errors during processing.
IPQC is concerned with providing accurate ,specific & whole
description of the procedures to be employed from raw materials to
the finished products.
WHAT DO YOU MEAN BY IPQC
8
9. 1)Uniformity of volume
2)Metal particles
3)Insoluble particulate matter test
4)Particle size
5)Sterility test
6)Pyrogen test
7)Leaker test
8)Uniformity of weight
Various IPQC Tests:
9
10. Pour completely the contents of each container into calibrated
volume measures of the appropriate size and determine the volume
of contents of 10 containers.
(1) UNIFORMITY OF VOLUME
For 10
containers
Average net volume of the
content is not less than
labelled amount
take 1
container
Not less than 91% & not
more than 109% of the
labelled amount
10
11. e:g. where, labelled amount is 50ml or less
95.5% and not more than 104.5% labelled amount
If these requirements are not met, determine the net volume of the
contents of 10 additional containers.
11
12. Required only for ophthalmic ointment
The presence of metal particles will irritate the corneal or
conjunctival surfaces of the eye.
It is performed using 10 ointment tubes.
The content from each tube is completely removed onto a clean 60-
mm-diameter petri dish which possesses a flat bottom.
The lid is closed and the product is heated at 85 C. for 2hr.
Once the product is melted and distributed uniformly, it is cool at
room temperature.
The lid is removed after solidification.
(2)Metal particles
12
13. The viewing surface is illuminated using an external light source
positioned at 45° C. on the top.
The entire bottom surface of the ointment is examined, and the
number of particles 50um or above are counted using a calibrated
eyepiece micrometer.
13
14. Fit membrane filter on to the membrane filter holder
Filter under reduced pressure 200 ml of the purified water for particulate
matter test at the rate of 20 to 30 ml / min.
vacuum apply
until the surface of the membrane is free from water
remove membrane
dry it below 50°C
(3) INSOLUBLE PARTICULATE MATTER TEST
14
15. filter is dried, place it under the microscope
Adjust the microscope to get the best view of the particles that are
equal to or greater than 150 µm. Ascertain that the number is not
more than 1.
15
16. Introduce a suitable quantity of the preparation into a counting cell
or with a micropipette onto a slide, as appropriate and scan under
microscope an area corresponding to 10 µg of the solid phase.
For practical reasons, it is recommended that the whole sample is
first scanned at low magnification (e.g. 50X) particles greater than 25
µm are identified.
These larger particles can then be measured at a
larger magnification (e.g. 400X)
(4)Particle size
16
17. Remove labels wash the container dry.
Weigh the container along with its contents.
Empty the containers as completely as possible.
Rinse with water + ethanol and dry at 100°C to a constant weight.
Allow to cool in desiccators and weigh.
The difference between the weights represents the weight of the
contents.
Repeat the procedure with further 19 containers and determine the
average weight. Not more than two of the individual weights deviate
from the average weight by more than 10% and none deviates by
more than 20%.
(5) UNIFORMITY OF WEIGHT:
17
18. IPQC records:
1. Visual inspection:
Description ________________________________________________________
Total no of filled, sealed & sterilized containers rejected
__________________
Nature of defects
____________________________________________________
Name of worker who examined:
(I ). ________________________________________________
(ii). _______________________________________________
(ii). _______________________________________________
DOCUMENTATION
18
19. Batch Packaging & Labeling Records:
Product name_______________________ Batch no _______________________
Strength___________________________ batch size ______________________
Category___________________________ mfg. date _______________________
MFG no____________________________ exp. date _______________________
Batch Packaging & Labeling Records
Description of packaging______________________________________________
Pre-coding of labels & printed packaging materials,
examined & verified by _______________________________________________
No. of pre-coded ____________________________________________________
(ii). Printed packaging material received __________________________________
Result of bulk finished products ________________________________________
Sign. Of officer _____________________________________________________
19
20. TESTS IP BP USP PH.EUR JP
sterility No growth in 14
days
No growth in 14
days
No growth in 14
days
No growth in 14
days
No growth in 14
days
Uniformity of
volume
50 ml or less
±9% 50 to 200
ml ±4.5% 200 to
300 ml ±3%
- - - -
Particulate
matter
- - ≥ 25µm -2 can
be present
- ≥ 25µm -2 can
be present
Particle size
-
No particle
should be ≥ 90
µm
-
No particle
should be ≥ 90
µm
No particle
should be ≥ 90
µm
Delivered mass
or volume
- - - Not less than
100%
-
Specification of eye drops and eye lotion according to different pharmacopoeia:
20
23. Parenteral dosage form
are sterile, pyrogen free
solutions or dispersions
(emulsions or suspensions)
of one or more active
ingredients in a suitable
vehicle.
The unique attributes of
the parenteral dosage
form: rapid absorption and
distribution, high
bioavailability, zero
enzymatic degradation in
the gastrointestinal tract,
and an ability to be
administered to
unconscious patients.
Definition
23
25. Types/CALSSES OF PARENTERAL
• They includes
ampules and vials of
1ml,2ml,3ml up to
30ml.
• The most widely
used small volume
parenterals are
various insulin
preparation used
for treatment of
Diabetes Mellitus.
Small volume
parenteral
(SVP):
• It designed to
provide
Fluids,Calories and
Electrolytes or a
combination of
these.
• Volume:100 –
1000mL
• Used in cases when
the patient cannot
consume oral
nutrition for long
periods.
Large volume
parenteral
(LVP):
• Dry powders are
available in market
are soluble in water
or any other sterile
solvent for injection
prior to use.
• They are suitable
for certain
formulations which
degrade by
hydrolysis.
Powder
parenteral:
25
26. Sterile
free from pyrogenic (endotoxin) contamination
free from visible particulate matter (especially Injectable solutions)
Isotonic
Shelf life
All products must be stable, not only chemically but also physically.
Parenteral preparation characteristic:
26
28. The quality of product must be maintained .so there are various
official tests for check the quality.
- They may be divided into 3 categories;
Various IPQC Tests:
For raw materials
For
intermediates(IPQC)
For finished product
28
29. (1) For raw materials:
-Purity
-Identity
-Assays for different compounds(given in individual monograph in
pharmacopoeia)
- Label checking
(2) For intermediates(IPQC):
- Content of solution
-pH
- Color
-Clarity
-Environmental control
-Temperature & humidity control
29
30. (3) For finished product:
-Sterility testing
-Pyrogen testing
-Leak testing
- Particulate matter testing
-Uniformity of weight
-Uniformity of content
30
31. (1) CONTENT OF SOLUTION
The amount of the active ingredient(s)
In a suitable dose volume;
Volume in container
FOR POWDERS:
The amount of active Ingredient(s);
Net contents (e.g. number of dosage unit)
FOR INTERMEDIATE (IPQC)
LABELED SIZE
0.5 ml
1.0 ml
2.0 ml
5.0 ml
10 ml
20 ml
50 or more
31
32. (2) pH measurement
Two different types of methods used in measurement of pH
(1)Dip a piece of pH paper into the sample
(2)pH meter:
-pH meter is initially calibrated with respective buffer
capsule than the pH of sample is measured.
32
35. Personnel should be permitted into aseptic area only after following
rigid prescribed procedure.
Surface disinfection personnel:
-Must be inherently neat, orderly, reliable and alert.
-Should be in good health.
Air control: (HEPA filters)
-It is composed of glass fibers and filters.
-It is 99.97% efficient removes particals of 0.3um size and larger.
(5) Environmental control
35
36. Sources Control
People Total body covering in critical area and partial covering in non
critical area.
Adequate personal flow and restricted access to aseptic and
critical environment.
Minimum movement of personal.
Adequate operation procedure for personal.
Barrier Adequate sterilization procedure
Protective laminar flow equipment
Barrier and separation between high risk and low risk
operation.
Adequate operation procedure to assure proper handling,
cleaning, and sterilization of machinery and equipment
Material Adequate material control and selection
Adequate sterilization and filtration procedure
Air Adequate air filtration system
Adequate monitoring of air cleanliness level.
Adequate air system validation procedure.
36
37. (6) Temperature and humidity control
Maintained as requirement of particular product.
Cleanroom Environmental Monitoring
Sr.no. Test Frequency
1 Particle Monitoring in air 6 monthly
2 HEPA Filter Integrity Testing Yearly
3 Air Changes Rate Calculation 6 Monthly
4 Air Pressure Differentials Daily
5 Temperature and Humidity Daily
6
microbiological monitoring by settle plates and / or
swabs in aseptic areas
Daily, and at
decreased
frequency in
other areas
37
38. (1)sterility testing :
-Essential characteristic of parenteral
WHAT DO YOU UNDERSTAND BY STERILITY?
- The test intended for detect absence of viable forms of microbes in
preparation.
Steps for sterility testing :
(1)Direct transfer method:
(2)membrane filtration method:
FOR FINISHED PRODUCTS
38
39. (1)Direct transfer method:
traditional sterility test method
which involves a direct inoculation of required volume of a sample
in two tests tube containing a culture medium that is FTM, SCDM.
This method is simple in theory but difficult in practice.
Direct inoculation of the culture medium suitable quantity of the
preparation to be examined is transfer directly into the appropriate
culture medium and incubate for not less than 14 days.
39
40. (2)membrane filtration method:
It is official in U.S.P. 1970.
This method basically involves filtration of Sample through membrane
filters of porosity 0.22 micron and Diameter 47mm.
The filtration is assisted under Vacuum, after filtration completion the
membrane is cut into 2 halves and one halve is placed in two test tubes
containing FTM, SCDM medium.
Interpretation:–If no visible evidence of microbial growth in culture
medium in test tube then it is interpreted that the sample representing lot
is without intrinsic contamination.
40
41. Pyrogenic -means producing fever
Pyrogens – fever inducing substances
Having nature:
-endogenous(inside body)
-exogenous (outside body)
When the volume to be injected in a single dose is 10 ml or more,
Injections comply with the test for pyrogens.
Mainly 2 tests:
1) Rabbit test
2) LAL test
(2)Pyrogen
41
42. 1) Rabbit test :
This test basically involves the injection Sample solution which is to
be tested into a Rabbits. Which are use as test animals through ear
vein.
This test is performed in separate area designed solely for this
purpose under environmental conditions similar to animal house should
be free from disturbances that likely to excite them.
42
43. Test Animals:
Use healthy and adult rabbit
preferably of the same variety
fed on a complete and balanced diet and not showing loss of
body weight during the week preceding the test.
Initially this test is performed on 3 Rabbits but if required results
are not obtained this test is repeated on 5 additional Rabbits
with same sample solution administer to initial 3 rabbit.
Then Rectal temperature is recorded at 1,2,3 hrs. subsequent to
injection.
43
44. Procedure:
Record the temperature of each animal 90 min before the injection
and continue for 3 h after the injection for every 30 min.
Record the "initial temperature" of each rabbit and temperature
after 30 min. Rabbits showing a temperature variation greater than
0.2°C between two successive readings in the determination of
"initial temperature" should not be used for the test. Do not use any
rabbit having a temperature higher than 39.8°C and lower than 38°C.
Inject the solution slowly into the marginal vein of the ear of each
rabbit over a period not exceeding 4 min.
The volume of injection is not less than 0.5 ml/kg and not more than
10 ml/kg of body weight.
44
45. • The difference between the "initial temperature" and the "maximum
temperature" which is the highest temperature recorded for a rabbit
is taken as it’s response.
• When this difference is negative, the result is counted as a zero
response.
45
47. 2) LAL test:
Gel clot formation will be checked.
Thus the LAL reagent is prepared.
Equal volumes of test solution and LAL reagent are
mixed in glass test tubes. after incubation at 37 C for
1 hr., the tubes are observed for clot formation after
inventing them.
gel like mass formed give a positive test
Thus if the pyrogen present then gel formation occur otherwise not.
47
48. Main advantages of LAL test :
Particularly useful for:
Radiopharmaceuticals and cytotoxic agents
Products with marked pharmacological or toxicological activity in
rabbit (e.g. Insulin)
Blood products which sometime give misleading results in the rabbit
Water for injection where LAL test is potentially more stringent and
readily applied
Alternative to animal model
48
49. This test is generally applicable to ampoules, not used for the vials or
bottles because the rubber closure used in it are not rigid however
bottles are often sealed while a vacuum is being pulled so that the
bottles remains evacuated during its shelf life.
The container should be properly sealed so the interchange
between the contents of the container (ampoule) & environment can
not occur.
Here from the leakage microbes can also enter from it.
The content may leak outside & also spoil the appearance of
package
That’s why the leak test is preferred.
(3) LEAK TEST
49
50. Method:
First fill the ampoules & seal it properly.
Then put into the container filled with colored dye solution.
Put this container into the vacuum chamber for 30 min.
Then check it,
If leakage may be there then the dye solution penetrate into ampoules
Instead of vacuum chamber autoclave may also be used
it fulfill 2 purposes
I . Sterilization purpose
II . For study of leak testing
Thus the leakage will examine
50
51. Particulate matter refers to the extraneous, mobile ,undissolved
particles, other than gas bubbles , unintentionally present in
solution.
Particulate count is done by:
(I)Light obscuration particle count test
(ii)Microscopic particle count test
(4) PARTICULATE MATTER
51
53. Limit:
Sample particle in µm max. No of
Preparation in container 10 25 %
More than 100 ml 25 3%
Preparation in container 10 6000 per
With 100 ml 25 600 per
container
Preparation in container 10 6000 per
Less than 100 ml 25 600 per
container
53
54. This method is suitable for revealing the presence of particles (10 μm
or more)
A suitable microscope, filter assembly and membrane filter for
retention of particles will be there.
The procedures should be done in a laminar air-flow cabinet or
hood preferably in a controlled-air environment. Free from foreign
particles.
(ii)Microscopic particle count test
54
55. Sampling:
Where the volume of liquid in a container is very small, the test
solution may be prepared by mixing the contents of a suitable
number of containers and diluting to 25 ml with water.
Large-volume
parenteral
Single units should
be tested
Small-volume
parenteral(<25ml)
10 or more units
should be
combined
55
56. Process:
Invert the container of the preparation under examination 20
times successively in order to mix the contents.
Wash the outer surface of the container and remove the
closure carefully, avoiding contamination of the contents.
Filter the content through membrane filter slowly
Remove the content from membrane filter with flat-ended
forceps, place it on slide and allow it to dry in air after the filter
has been dried, place the slide on the stage of the microscope,
and scan the entire membrane filter under reflected light.
Count the number of particles that are equal to or greater
than 10 μm, the number of particles equal to or greater than
25 μm and the particles equal to or greater than 50 μm.
56
57. Limit:
Sample particle in µm max. No of particle
Preparation in container 10 12 %
More than 100 ml 25 2%
Preparation in container 10 3000 per container
With 100 ml 25 300 per container
Preparation in container 10 3000 per container
Less than 100 ml 25 300 per container
57
58. Unless otherwise stated in the individual monograph, suspensions
for injection that are presented in single dose containers and that
contain less than 10 mg or less than 10 per cent of active ingredient
comply with the following test.
For suspensions for injection containing more than one active
ingredient carry out the test for each active ingredient that
corresponds to the above conditions.
Determine the content of active ingredient(s) of each of 10
containers taken at random, using the method given in the
monograph or by any other suitable analytical method of equivalent
accuracy and precision.
(5) Uniformity of content
58
59. Remove label - wash the container - dry.
Weigh the container along with its contents.
Empty the containers as completely as possible.
Rinse with water + ethanol and dry at 100°C to a constant weight.
Allow to cool in desiccators and weigh.
The difference between the weights represents the weight of the
contents.
Repeat the procedure with further 19 containers and determine the
average weight. Not more than two of the individual weights deviate
from the average weight by more than 10% and none deviates by
more than 20%.
(6) UNIFORMITY OF WEIGHT
59
60. IPQC records
1. Visual inspection:
Description
________________________________________________________
Total no of filled, sealed & sterilized containers rejected
__________________
Nature of defects
____________________________________________________
Name of worker who examined:
(i ). ______________________
(ii). _____________________
(ii). _____________________
DOCUMENTATION
60
61. www.pharmpress.com/files/docs/Remington
Pharmaceutical dosage forms parenteral medications volume 2
edited by Kenneth E. Avis, Leon Lachman
Sterile Pharmaceutical Manufacturing by Groves Gisan
Aseptic Pharmaceutical Manufacturing by M.J.Groves
THE INDIAN PHARMACOPOEIA,
GOVT. OF INDIA, MINISTRY OF HEALTH & FAMILY WELFARE,
“Monograph of parenteral”, Volume 2, 2007,Pg no,39-42
International Journal of Pharmacy Teaching & Practices 2012, Vol.3,
Issue 2, 261-265.
REFERENCE
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