The document discusses in-process quality control (IPQC) and final product quality control (FPQC) tests for parenteral pharmaceuticals. It defines parenterals as sterile dosage forms intended for administration other than orally to directly enter systemic circulation. The types of parenterals are described based on volume and packaging. Important IPQC tests are outlined including conductivity, pH, temperature monitoring and volume filled verification. Key FPQC tests for parenterals involve sterility testing, pyrogen testing, clarity evaluation, leakage assessment, uniformity of content and weight tests, and extractable volume determination. Methods for each test are concisely explained.

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ROSHAN H. KHETADE
FOR PARENTERALS
IPQC & FPQC
SKB College of pharmacy

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CONTENTS
Introduction to parenteral
Types of parenteral
What is IPQC
Importance of Quality Control
IPQC tests for parenterals
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Introduction to Parenterals
Greek para = "beside" and enteron = "intestine", it bypasses
the intestines.
 Parenterals are the sterile dosage form intended for
administration other than enteral route and exert their action
by directly entering into the systemic circulation.
Parenteral are
◦ Sterile
◦ Pyrogen-free &
◦ Free from particulate matter which are injected into the
internal body compartment.
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Types of parenterals
A} Based on the volume
a) Small volume parenterals: volume ≤ 100 ml,
b) Large volume parenterals: volume ˃ 100 ml {101ml-1000ml}
B} Based on types of packaging
a) Single dose units: ampoules, infusions and prefilled disposable
syringes.
b) b) Multiple dose units: multiple dose vials.

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Powder for
injections
Injections Infusions
CATEGORIES
5
Implants Concentrated
solutions for
injections
Eg. Enbrel Tegamet
Eg. Parazeal IV
Afymol
Eg. Doxil, Daunasome,
Botox
Eg. Glidel, Durin,
Duros, Eg. Mitoxantrone Inj.
USP

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 IPQC means controlling the procedures
involved in manufacturing of the dosage
forms starting from raw material purchase
to dispatch of the quality product in ideal
packaging.
It monitors all the features of the product
that may affect its quality and prevent
errors during processing.
It is the activity performed between QA
and QC.
In Process Quality control

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77Importance of Quality Control
To minimize human errors.
Provides accurate, specific and definite
description of the procedure to be employed.
 It is a planned system to identify materials,
equipments processed and operations.
Is to detect the errors if and when it does occurs.
Is to enforce the flow of manufacturing and
packing operations according to established routes
and practice.

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88IPQC tests
It provides for the authorization of approved raw materials for manufacturing
and these test are generally called as IPQC which includes physical,
chemical, microbiologic and biologic tests.

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99IPQC and FPQC tests for parenterals
Conductivity measurement
pH measurement
Temperature for heat sterilized product
Volume filled
 QUALITY CONTROL PARAMETERS OF PARENTERAL
PHARMACEUTICALS:
I. Sterility Test
II. Pyrogen test
III. Clarity test
IV. Leakage Test-non pharmacopoeia test
V. Test for Uniformity of Content
VI. Uniformity of weight
VII.Extractable volume

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Conductivity measurement:
1 Conductivity is measured by conductometer.
2 It measures the conductivity of vehicle used in sterile
preparation.
3 Conductivity of pure water is 0.55 microsiemens /cm.
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

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1111 Temperature for heat sterilization:-
1. It is important to maintain the constant temperature during heat sterilization of
product.
2. The tempraturechanges may cause some undesirable changes like change in
potency,change in isotonicity.
3. The temperature can be determined by normal thermometer.
 Volume filled :–
An injection container is filled with a volume in slight excess of the labeled size.

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I. Sterility Test:
• The tests for sterility are intended for detecting the presence of viable
microorganism in pharmaceutical preparation that is designed to be sterile.
Method of testing:

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1313Culture media

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14141.Method A (Membrane filtration):
• Method A (Membrane filtration) is preferred where the substance
under examination is
1. An oil
2. An ointment that can be put into solution.
3. A non bacteriostatic solid not readily soluble in the culture
medium, and
4. A soluble powder or a liquid that possesses bacteriostatic and /or
fungistatic properties.
• For liquid products where the volume in a container is 100 ml or
more, method A should be used.

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1. Sterilization of filtration system and membrane
filtration of examined solution under aseptic
conditions.
2. Filtration of the sample through a membrane filter
having the nominal size of 0.45µ and a diameter
of 47mm.
3. After filtration the membrane is removed aseptically
from the metallic holder and divided into two
halves.
4. 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.
5. The other half is transferred into 100ml of fluid
thioglycolate medium and incubated at 30 to 35 ˚c
for not less than 7 days.
The procedure of membrane filtration

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16162.Method B: Direct inoculation method
• This method is only used when membrane filtration is not possible the sample
is inoculated directly into the media or the device is placed directly into the
media
• Process:
1Aseptically opening each sample container from a recently sterilized batch of
product.
2. Using a sterile syringe and needle to withdraw the required volume of sample
for both media from the container
3. Injecting one-half of the required volume sample into a test tube containing the
required volume of FTM and the other half volume of sample into a second test
tube containing the required volume of SCD.

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1818Interpretation of Results
Interpretation of results At the end of the incubation period the following
observations are possible:
• No evidence of growth; hence the preparation being examined passes the test
for sterility.
• If the material being tested renders the medium turbid so that the presence or
absence of microbial growth cannot be easily determined by visual
inspection,14 days after incubation , transfer portion (< 1 ml) of the medium
to fresh vessels of the same medium and then incubate original and transfer
vessel for not less than 4 days.
• If No evidence of microbial growth is found- complies with test for sterility.

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1919II. Pyrogen test
Test for pyrogens can be carried out by in-vitro and in-vivo methods.
A) Rabbit test (in-vivo) B) LAL test (Limulus amoebocyte
lysate) (in-vitro)

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A) Rabbit test (in-vivo)
a) Preliminary Test (Sham Test):-
Injecting intravenously 10 ml per kg body weight
of a pyrogen-free saline solution warmed to about
38.5° C. Record the temperatures of the animals,
beginning at least 90 minutes before injection and
continuing for 3 hours after injection of the test
solution. Any animal showing a temperature
variation of 0.6°C or more must not be used in
the main test. Selection of animals is done in it.
b) Main Test: Carry out the test using a group of
three rabbits.

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2121
• Procedure:-
1. Inject the solution under examination
slowly into the marginal veins of the ear
of each rabbit over a period not
exceeding 4 mins.
2. Record the temperature of each animal
at half hour intervals for 3 hours after
injection.
3. The difference between the initial
temperature and the maximum
temperature which is the highest
temperature recorded for a rabbit is
taken to be its response.
• Preparation of the sample:- Dissolve the substance in or dilute with pyrogen free
saline solution . Warm the liquid to approximately 38.5° before injection.

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2222

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2323B) LAL test (Limulus amoebocyte lysate) (in-vitro)
• The LAL (limulus amebocyte lysate) Assay is an in vitro assay used to detect the
presence and concentration of bacterial endotoxins in drugs and biological products.
Procedure:-
◦ Equal volume of LAL reagent and
test solution (usually 0.1 ml of each) are mixed in a
depyrogenated test-tube
◦ Incubation at 37°C, for1 hour
◦ Remove the tube and invert in smooth motion at
180° angle
◦ Observe the result

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2424Interpretation of Result
• The tubes are incubated at 37±1°C FOR 60
±2 minutes.
• When the tubes are inverted at 180ºC
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.

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2525III. Clarity test:
1. VISUAL INSPECTION BY
NAKED EYE:
◦ Each injectable is inspected
visually against White and Black
Backgrounds.
◦ The White background aids in
detection of dark colored particles.
◦ The light reflective particles will
appear against the Black
background.
Medical-Pharmaceutical-Drug-Clarity-
Tester

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26262. Coulter Counter method:
• The sample solution is added to an
electrolyte solution which is drawn
through a small orifice.
• As particle passes through the
orifice it displaces its own volume
of electrolyte.
• Particle detected by the increase in
electrical resistance.
• Voltage pulses are proportional to
the particle size.
• Particles below 0.2µm can also be
detected.

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IV. Leakage Test (visual inspection, bubble test, dye
tests )
• The test is used for ampoules and vials.
• Leakage test is employed to test the
package integrity. Package integrity
reflects its ability to keep the product in
and to keep potential contamination out.
• Leakage occurs when a discontinuity
exists in the wall of a package that can
allow the passage of gas under pressure or
concentration differential existing across
the wall. Leakage test can be done by dye
bath test( using methylene blue solution)

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• It is detected by producing negative
pressure within an incompletely sealed
ampule, usually in a vacuum chamber,
while the ampule is entirely submerged
in a deeply colored dye solution.
• The pressure inside chamber causes
penetration of dye in and it is being
visible after the ampule has been
washed externally clear it of dye.

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V. Test for Uniformity of Content
As per IP&BP : - Determine the content of active ingredient(s) of each of 10
containers taken at random, using the method given in the monograph.
• The preparation under examination complies with the test if the individual
values thus obtained are all between 85 and 115 per cent of the average value.
• The preparation under examination fails to comply with the test if more than one
individual value is outside the limit 85 to 115 per cent of the average value
• or if any one individual value is outside the limits 75 to 125 per cent of the
average value.
• If one individual value is outside the limits 85 to 115 per cent but within the
limits 75 to 125 per cent of the average value, repeat the determination using
another 20 containers taken at random.

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• The preparation under examination complies with the test if in the total sample of
30 containers not more than one individual value is outside the limits 85 to 115
per cent and none is outside the limits 75 to 125 per cent of the average value.
As per USP:-
Stage1: Take 10 units randomly and perform the assay. It passes the test if the
relative standard deviation (RSD) is less than
6% and no value is outside 85-115%. Fails the test if one or more values are outside
75-125%.
Stage2: Take 20 more units and perform the assay procedure. Passes the test if RSD
of all the 30 tablets is less than 7.8%, not
more than one value is outside 85-115%, and no value is outside75-125%. Or else
the batch fails the test.

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3131VI. Uniformity of weight:
• Uniformity of weight: Remove labels and wash the container and dry.
• Weigh the container along with its contents.
• Empty the containers as completely as possible.
• Rinse with water and with 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%.

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3333VII. Extractable volume :
Extractable volume (IP):-
• Where the nominal volume does not exceed 5 ml, the containers comply with
the requirements of Method 1 and where the nominal volume is greater than 5
ml, the containers comply with the requirements of Method 2. Suspensions
should be shaken before the contents are withdrawn; oily injections may be
warmed but should be cooled to 25º C before carrying out the test
• Method 1- Use 6 containers, 5 for the test and 1 for rinsing the syringe used.
• Inspect the 5 containers to be used in the test visually and ensure that each
contains approximately the same volume of the preparation.
• Using a syringe with a capacity not exceeding twice the volume to be
measured and fitted with a suitable needle, take up a small quantity of the
liquid under examination from the container reserved for rinsing the syringe,
and discharge it from the syringe whilst the needle is pointing upwards so as to
expel any air.

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3434
Withdraw as much as possible the contents of one of the containers reserved for
the test and transfer, without emptying the needle, to a dry graduated cylinder of
such capacity that the total combined volume to be measured occupies not less
than 40 per cent of the nominal volume of the cylinder. Repeat the procedure
until the contents of the 5 containers have been transferred and measure the
volume. The average content of the 5 containers is not less than the nominal
volume and not more than 115 per cent of the nominal volume.
Method 2 — Transfer the contents of not less than 3 containers separately to dry
graduated cylinders such that the volume to be measured occupies not less than
40 per cent of the nominal volume of the cylinder and measure the volume
transferred.

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• The contents of each container are not less than the nominal volume and not
more than 110 per cent of the nominal volume
• Multiple dose containers labelled to yield a specific number of doses shall
contain a sufficient excess to permit the withdrawal of the designated number
of doses.
Extractable volume (BP)
• Single dose container:
 Select 1 container if the nominal volume is 10 ml or more,
 3 containers if the nominal volume is more than 3 ml and less than 10 ml,
 5 containers if the nominal volume is 3 ml or less
 Take up individually the total contents of each container selected into a dry
syringe of a capacity not exceeding 3 times the volume to be measured, and
fitted with a 21-gauge needle not less than 2.5 cm in length

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 Take up individually the total contents of each container selected into a dry syringe
of a capacity not exceeding 3 times the volume to be measured, and fitted with a
21-gauge needle not less than 2.5 cm in length. Expel any air bubbles from the
syringe and needle, then discharge the contents of the syringe without emptying the
needle into a standardized dry cylinder (graduated to contain rather than to deliver
the designated volumes) of such size that the volume to be measured occupies at
least 40 per cent of its graduated volume. Alternatively, the volume of the contents
in millilitres may be calculated as the mass in grams divided by the density.
 For containers with a nominal volume of 2 ml or less, the contents of a sufficient
number of containers may be pooled to obtain the volume required for the
measurement provided that a separate, dry syringe assembly is used for each
container. The contents of containers holding 10 mL or more may be determined by
opening them and emptying the contents directly into the graduated cylinder or
tared beaker.

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3737
 The volume is not less than the nominal volume in case of containers examined
individually, or, in case of containers with a nominal volume of 2 ml or less, is
not less than the sum of the nominal volumes of the containers taken
collectively.
Multi-dose container: (BP)
• For injections in multi-dose containers labelled to yield a specific number of doses
of a stated volume, select one container and proceed as directed for single-dose
containers using the same number of separate syringe assemblies as the number of
doses specified. • The volume is such that each syringe delivers not less than the
stated dose

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1UNIVERSAL TESTS FOR PARENTERAL
PREPARATIONS:
a Description
b Identification
c Assay
d Impurities
a Description:-
This test is often called appearance on a specification and is a qualitative description
of the parenteral preparations. For example, the description of parenteral
preparations .

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B Identification:- The purpose of the
identification or identity test is to verify the
identity of the active pharmaceutical
ingredient (API) in the parenteral
preparations. This test should be able to
discriminate between compounds of closely
related structures that are likely to be present.
C Assay :- This test determines the strength or content of the API in the parenteral
preparations and is sometimes called a content test
D Impurities This test determines the presence of any component that is not the API or an
excipient of parenteral preparations. The most common type of impurities that are measured is
related substances, which are processed impurities from the new drug substance synthesis,
degradation products of the API, or both.

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• United states pharmacopeia (2000) volume 2.
• Indian pharmacopeia (1996) volume 2.
• Lachman.L, Liberman HA, Kaniz JL, The Theory and practice of industrial
pharmacy Bombay, Varghese publication House.
• Md. Sahab Uddin et al., 2017 - Quality control parameters of parenteral
pharmaceuticals based on pharmacopoeias.
• Amrutha et al., 2017- In-Process and Finished Products Quality Control Tests
for Sterile and Non Sterile Dosage Form.
• Powerpoint presentations from slideshare.
References

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