IN PROCESS QUALITY CONTROL (IPQC) means controlling the procedures involved in manufacturing of the dosage forms starting from raw materials purchase to dispatch of the quality product in ideal packaging

1. IPQC FOR PARENTERALS
Prepared by:
Mr. Petkar Kaleem Mazhar (Roll no: 27)
Ms. Patil Komal Dagadu (Roll no: 26)
M. Pharm – Quality Assurance.

2. PURPOSE OF IPQC:
 To ensure detectable and significant human errors.
 Equipment failure and idiosyncrasies.
 Abnormal interpretation.
 Adoption of given procedures.
IN PROCESS QUALITY CONTROL:
 IPQC means controlling the procedures involved in manufacturing
of the dosage forms starting from raw materials purchase to
dispatch of the quality product in ideal packaging.
 It monitors all the features of the product that may effect its quality
and prevents errors during processing.
 It is the activity performed between QA and QC.

3.  PARENTERALS
 A parenteral dosage form can be defined as a sterile drug product
which is presented in the form of solutions, suspension, emulsion,
or reconstituted lyophilized powder, suitable for administration by
injection through skin or mucous membrane.
What are parenterals?
Greek para= “Beside” and enteron= “Intestine”, because it
bypasses the intestines.
.

4.  FLOW CHART OF PARENTERALS FROM PRODUCTION
TO MARKET.
MANUFACTURING OF PRODUCTS.
STERILIZATION OF PRODUCTS.
ASEPTIC SUB-DIVISON AND SEALING.
ONLINE TESTING.
CAPPING / OUTER SEALING.
INSPECTION
QUARANTINE.
FINISHING LABELING AND PACKAGING.
WAREHOUSE
MARKET.

5.  Types of parenterals
1. Small volume parenterals (SVPs): They are given as multiple
dose.
Small volume parenterals contains-
a. Ampoules,
b. Vials.
C. Dry powders.
a. Ampoules b. Vials c. Dry
powders

6. 2. Large volume parenterals (LVPs): They are designed to provide
fluid, calories and electrolytes. They are of 4 types.
a. Hyperalimentation solution.
b. Cardioplegic solution.
c. Peritoneal dialysis solution.
d. Irrigating solution.

7. IPQC TESTS
FOR
PARENTERALS
CLARITY
TEST
CONTENT
UNIFORMITY
PYROGEN
TEST
LEAKAGE
TEST
STERILITY
TEST
PH AND
ASSAY
CONTENT
 IPQC TESTS FOR PARENTERALS.

8.  IPQC FOR PARENTERAL PRODUCTS
 Clarity Test (For particulate matter):
➡ Visual method.
➡ Coulter counter method.
➡ Light obscuration technique.
 Leakage Testing (For package integrity):
➡ Visual methods.
➡ Bubble test.
➡ Dye test.
➡ Vacuum ionization method.
 For fill volume.
 PH.

9.  IPQC FOR PARENTERAL PRODUCTS
 Pyrogen testing.
➡Rabbit fever response test.
➡Limulus amoebocycte lysate test.
 Sterility test.
➡Membrane filtration method.
➡Direct inoculation method.
 Test for packaging containers.
1. For glass containers:
➡Water attack test.
➡Powder glass test.
2. For plastic containers:
➡Leakage test, collapsibility test, transparency test and
water vapor permeability test.
 Assay for drug content.

10.  CLARITY TEST
Visual method:
A. In visual inspection, each injectable is
inspected visually against white and black
backgrounds. The white background aids in
detection of dark colour particles.
B. The light or reflective particles will appear
against the black back ground.
C. A magnifying lens at 2.5 × magnification set
at the eye level facilitates the inspection.
Microscopic examination enhances detection
of particulate matter in injectable.
D. Acceptance Standards is that each container
checked must not contain any visible
particulate matter.

11.  CLARITY TEST
 Coulter counter counts the particles in a sample based on the
change in the electrical resistance. Particle size detection limit in
this instrument is from 0.1 to 1000 micrometer.
 The powder sample requires pretreatment such as dispersion in
an electrolyte to form a very dilute suspension.
 The suspension is usually subjected to ultrasonic agitation to
avoid particle agglomerates.
 A dispersant may also be added to aid particle deagglomeration.
 Particles below 0.2μm can also be detected.
 This test is not recommended by FDA for parenteral.
 Coulter counter method.

12. xdzdzd
Limits for detection of subvisible particulate matter as prescribed in USP.
Particle size SVP LVP
Less than equal to 10μm 3000/Container 12/ml
Less than equal to 25μm 300/Container 2/ml

13.  Light obscuration method
 Tungsten lamp produces a constant collimated beam of light that
pass through a small rectangular passageway and impinges onto a
photodiode.
 Liquid can flow through the passageway between the light source
and photodiode.
 If a single particle transverses the light beam there results a
reduction in normal amount of light received by the photodiode.
 This reduction of light and the measurable decrease in the output
from the photodiode is proportional to the area of the particle
interrupting the light flow.
 Thus light obscuration principle measures particle size based
diameter of circle having equivalent area.

14.  Leakage test
 Used to test package integrity.
 Leakage test is employed to detect incompletely sealed
ampoule and vials so that they may be discarded.
WHAT IS THE NEED?
➡Presence of capillary pores or tiny cracks can cause
microbes or other contaminants to ender in the ampoules.
➡Change in temp during storage can cause expansion and
contraction of the ampoule and thereby causing interchange
of its contents if any opening exists.
➡Leakage test is done by visual inspection, bubble test and
dye bath test.

15.  LEAKAGE TEST
A. DYE BATH:
 The test container is immersed in a dye bath. Vacuum and
pressure is applied for some time.
 The container is removed from the dye bath and washed. The
container is then inspected for the presence of dye either visually
or by means of UV spectroscopy.
 The dye used may be of blue, green, yellowish-green color.
 The dye test can be optimized by use of a surfactant and or a low
viscosity fluid in the dye solution to increase the capillary
migration through the pores.
 The dye test is widely accepted in industry and is approved in drug
use. The test is inexpensive and is requires no special equipment
required for visual dye detection.
 However, the test is qualitative, destructive and slow. The test is
used for ampoules and vials.

16.  Leakage test
B. VISUAL INSPECTION:
 Visual method is the easiest leak test method to perform. But this
method is least sensitive.
 The method is used for the evaluation of large volume parenteral.
To increase the sensitivity of the method, the visual inspection of
the sample container may be coupled with the application of
vacuum to make leakage more readily observable.
 This method is simple and inexpensive. However, the method is
insensitive, operator dependent, and qualitative.
 Sometimes, the method is used in combination with pressure and
/or temperature cycling to accelerate leakage to improve
sensitivity.

17. C. BUBBLE TEST:
 The test package is submerged in liquids. A differential pressure is
applied on the container. The container is observed for bubbles.
 Sometimes, surfactant added liquid is used for immersion of test
package. Any leakage is evident after the application of differential
pressure as the generation of foaming in immersion liquid. The method
is simple and inexpensive.
 The location of the leaks can be observed in this method. However, it is
relatively insensitive and the findings are operator dependent and are
qualitative.
 The optimized conditions can be achieved using a surfactant immersion
fluid along with the dark background and High intensity lighting.
Generation of a differential positive pressure of 3 psi inside the vial and
observation of any leakage using magnifying glass within a maximum test
time of 15 minutes. Positive leak test result. Air bubbles
 Leakage test

18.  pH
 Checking the bulk solution, before
filling for drug content, PH< color,
clarity and completeness of solution.
 The pH of a formulation must be
considered from following
standpoints:
1. The effect on the body when the
solution is administered.
2. The effect on stability of the product.
3. The effect on container-closure system.
 pH measurement:
1. pH is measured by using a pH meter.
2. pH meter is initially calibrated with
respective buffer capsule then the pH of
the preparation is measured.

19.  STERILITY TEST
A. MEMBRANE FILTRATION METHOD:
 Sterilization of filtration system and membrane filtration of
examined solution under aseptic conditions.
 Filtration of the sample through a membrane filter having the
nominal size of 0.45µ and a diameter of 47mm.
 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 35 ˚c for not less than 7 days.

20.  STERILITY TEST
➡DISADVANTAGES:
1. This method cannot differentiate
the extent of contamination between
units if present because all product
contents are combined and filtered
through a single filter and cultured in
single test tube.
2. There exists a higher probability of
inadvertent contamination in
manual operations .

21. B. Direct inoculation method:
 Required quantities of liquid is
removed from the test containers
with a sterile pipette / sterile syringe.
 Aseptically transfer the specified
volume of the material from each
container to vessel of culture medium
 Mix the liquid with medium but
not aerate excessively

22. ➼Fluid thioglycolate medium(FTM):
FTM provides both aerobic and anaerobic environments
within the same medium. FTM is an excellent medium for
the detection of bacterial contamination.
Thioglycolate has the advantage of neutralizing the
bacteriostatic properties of mercurial preservatives
incubation of the media: 14 days at 30 -35°C
➼Soybean casein digest medium:
Soybean casein digest medium primarily intended for the
culture of both fungi and aerobic bacteria specific role of
some ingredients. incubation of the media: 14 days at 20 -
25°C
 TYPES OF MEDIUM USED:

23.  Pyrogen test
A. RABBIT FEVER RESPONSE TEST:
➡ Principle: The test involves measurement of rise in body temperature of
the rabbits following the intravenous injection of a sterile solution of the
substance to be tested. The body temperature of the rabbits increases if
pyrogens are present in the injected test solution.
➡Procedure: Preparation of the sample:
I. Warm the solution to About 37 ± 2 o c before the injection
II. In the case of lyophilized products dissolve it in normal saline solution.

24. ➡ Determination of initial temperature of rabbits:
I. Insert a clinical thermometer into the rectum of each rabbit
and normal readings of body temperature are taken prior to
the injection of test solution.
II. Two such readings are taken at an interval of 30 minutes
and the mean is calculated.
III. This mean reading is taken as the initial temperature of the
rabbits or as a control.

25. ➡Determination of the response of rabbits:
I. The test solution is injected into the ear vein of each rabbit.
II. The volume of injection is 10 ml/kg of the body weight.
III. This volume varies according to the test substance and is
prescribed in the individual monograph.
IV. Record the temperature of each rabbit at an interval of 30
minutes for 3 hours after the injection.
V. This is the maximum temperature recorded for that rabbit.
VI. The difference between maximum temperature and initial
temperature is taken as its response.
VII. If this difference is negative, it is taken as a zero response.

27. ➡INTERPRETATION OF THE RESULTS:
 The test is carried out on the first group of 3 rabbits; if necessary
on further groups of 3 rabbits to a total of 4 groups, depending on
the results obtained
 Intervals of passing or failing of products are on the basis of
summed temperature response.
➡ The Result of pyrogen test:
If above tests not passes the sample is said to pyrogenic.
No, of rabbits Individual Temp,
Rise (°C )
Temp. rise in group
(°C )
Test
3 Rabbits 0.6 1.4 Passes
If above not passes
3+5=8 rabbits
0.6 3.7 Passes.

28.  Limulus Amebocyte Lysate Test (LAL Test)
 PRINCIPLE:
The addition of solution containing endotoxin to a solution of lysate produce
turbidity . The rate of reaction depends upon concentration of endotoxin , the pH and
the temperature.
The endotoxin reference standard is the freeze dried. The test is based on the
primitive blood- clotting mechanism of the horseshoe crab.
 LAL Test is done by 3 methods:
1. Gel clot technique 2. Kinetic Turbidimetric 3. Chromagenic technique

29. If the solid remains intact the product is
considered to contain endotoxin.
I. Gel clot bacterial endotoxin
First of all, we have to prepare test
tubes of 4 samples dilutions.
Then LAL reagent is added to the
equal volume of the test tubes.
After that the test tubes are agitated and
then allowed to incubate for 1 hr at 37 C.
After incubation the tubes are
inverted

30. 2. Kinetic turbidimetric technique.
The sample is taken
LAL reagent is added to the
sample.
Produce gel-clot
This result in turbidity
 It is a photometric assay
measuring the increase in
turbidity caused by the
reaction of endotoxin and
the lysate.
 A spectrophotometer is
used in this regard.
 In this method turbidity is
developed after cleavage of
an endogenous substrate.

31. 3. Chromogenic method
 The chromogenic method is also
photometric assay measuring the
colour, developed by the
chromophore and released by the
chromogenic substrate by the
reaction with endotoxin lysate.
 The resulting colour of the reaction is
measured using spectrophotometric
method to reveal the concentration of
the endotoxin in the sample.
 The chromogenic reagent used in this
method is a peptide connected to p-
nitroaniline, a yellow clottable
coagulant.
Procedure:
First of all, the LAL reagent is
mixed with all chromogenic
reagent.
The mixture is then
added to the test sample
to create the test
solution.
The test solution is
then allowed to
incubate.
If endotoxin is
present, the
enzymatic rxn of the
LAL reagent break
the peptide bond
and releases yellow
colour

32.  TEST FOR PACKAGING CONTAINERS
I. For glass containers:
a. Water attack test:
I. Rinse 3 or more containers with high purity water. Fill each
container to 90% of its capacity with high purity water.
II. Cap all the flasks with borosilicate glass beaker, place in the
autoclave at 121 C for 60 min
III. cool the flask, decant the water from the flask into a clean vessel
IV. add 5 drops methyl red solution, titrate immediately with 0.02 N
sulfuric acid .
V. Record the volume of 0.02N Sulfuric acid used to neutralize the
extract from 10 g of the prepared specimen of glass

33. b. Powder Glass test:
I. Use crushed glass containers in 250-ml conical flask, add 50 ml
high purity water, cap the flask with borosilicate glass beaker
II. Place the containers in the autoclave and close it securely hold
temperature at 1210c±2 0c for 30 min., counting from the time
this temperature is reached.
III. cool the flask, decant the water from the flask into a clean
vessel, and wash the residual powdered glass with high purity
water, add 5 drops methyl red solution, titrate immediately
with 0.02 N sulfuric acid .
IV. Record the volume of 0.02N Sulfuric acid used to neutralize
the extract from 10 g of the prepared specimen of glass.

34. II. For plastic containers:
a. Collapsibility test:
Container is checked weather it has enough durability to
hold the drug and does not collapse or break open.
b. Transparency test:
Fill five empty containers to their nominal capacity with
diluted suspension as described in IP 1966. The cloudiness
of the diluted suspension in each container is detectable
when viewed through the containers as compared with a
container of the same type filled with water.

35. C. Water vapor permeability test:
i. Fill five containers with nominal volume of water and
heat seal the bottles with an aluminium foil-poly ethylene
laminate or other suitable seal.
ii. Weigh accurately each container and allow to stand
(without any overwrap) for 14 days at a relative humidity of
60+5% and a temperature between 20 and 25 °C
iii. Reweigh the containers. The loss in weight in each
container is not more than 0.2%.

36.  Assay for drug content.
 Assay is performed according to method given In the
monograph of that parental preparation in the
pharmacopeia.
 Assay is done to check the quantity of medicament present
in the parenteral preparation.
 So we can know the exact amount of medicament present
such that it can perform its action.
 We should follow the official monograph IP/BP/USP for
performing the assay.