PHARMACEUTICAL QUALITY

ASSURANCE
Quality Assurance and Quality Management concepts

BP606T
Unit-3
Part-1

(QUALITY CONTROL: Quality control test for containers, rubber closures and secondary packing
material)

Snigdha Rani Behera

Associate Professor
ARKA JAIN UNIVERSITY
 Quality control test for containers
Definition:
 Any material that is used for packaging of products for their distribution and sale is
said to be packaging material.
 Pharmaceutical packaging is the means of providing protection, presentation,
identification, information and convenience to encourage compliance with a course
of therapy.
 The commonly used packing materials are container, closure and cartoon or outer
box.
 The containers mostly made of glass, plastic, metal or paper.
 The material for closure may include cork, Glass, Plastic, Metal or Rubber.

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 There are three type of packaging material.
1. Primary packaging material: Comes in contact with the product e.g. Bottles,
vials, ampoules, tin etc.
2. Secondary packaging material: Used to cover primary packs e.g. Cartons, boxes,
etc.
3. Tertiary packaging material: It is used to bulk handling and shipping. E. g. Barrel,
container, edge protector.
 There are various tests for determination of quality, integrity and compatibility of
packaging materials.
 The specification and requirement of quality testing depends on type of
pharmaceutical materials used.

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 1.Crushed glass test
Quality control test for Glass
container
2.Whole container test

a. Powder glass test

3.Chemical resistant
of glass container
b. Water attack test
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 4. Hydrolytic resistance of glass
containers

5. Light Transmission test

6.Arsenic test
Quality control test for
Glass Container
7. Thermal shock test

8. Internal bursting pressure test

9. Leakage test

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 ARKA JAIN University, Jamshedpur, Jharkhand
• General purpose Soda lime Glass (used for non-parenteral products (to be Type-IV
taken orally or by inhalation) as the vial)
• Soda lime silica Glass (with only moderate hydrolytic resistance, suitable Type-III
for non-aqueous preparations for parenteral use, for powders for parenteral
use (except for freeze-dried preparations) )
• Treated Soda lime silica Glass (with a high hydrolytic resistance, suitable Type-II
for most acidic and neutral, aqueous preparations)
• Neutral or borosilicate Glass (with a high hydrolytic resistance, suitable Type-I
for most preparations not for parenteral use)
1.Crushed glass test:
 The container is crushed and sieved to produce uniform particles of which a definite weight of
taken. 
 The control of the particle size and weight of powder ensures that a constant surface area is
exposed to the solution. 
 Because all of the glass (not just the surface layer) is examined and extraction is enhanced by
the rough surfaces of the particles, this is a severe test, and, if a glass passes, it is unlikely that
containers made from it will give trouble while is use.
 This test can be used for determining the nature of a glass or for distinguish between two
types of glasses, such as neutral or surface – treated.

2.Whole container test:

 It is used in the USP for treated soda-lime containers only. 
 The containers are simply filled with the test solution and exposed to the test conditions.
 Glassware may pass the whole container test more easily because the surface layer of a
container is smooth and less reactive.
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 In this test, surface area does not increase as much as volume with the increase in
container size, consequently, the small sized containers are more attacked by the
leaching of the alkali from the surface.
3.Chemical resistant of glass container:
 USP and IP provide two tests to determine the chemical resistance of glass
containers.
 It is divided in to two types. a. Powder glass test
b. Water attack test
 a. Powder glass test: From the glass containers, alkaline constituents (oxides of
sodium, potassium, calcium, aluminum, etc.) are leached into purified water under
conditions of elevated temperatures.
 When the glass is powdered the leaching of alkali can be enhanced in the powdered
is critical.
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 The principle involved in the powdered glass test in estimate the amount of alkali
leached form the glass powder.
 The amount of acid that is necessary to neutralize the released alkali (a specified
limit) is specified in the pharmacopoeia.
 The basic analysis is acid-base titration using methyl red indicator.
Step-1: Preparation of glass specimen:

Few containers are rinsed thoroughly with purified water and dried with stream of
clean air

Grind the containers in a mortar to a fine powder and then pass through sieve no,20
and 50.
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Step-1: Washing the specimen:

10 gm of the above specimen is taken in to 250 ml conical flask and wash it with 30
ml of acetone

Repeat the washing

Decant the acetone and dried after which it is used which it is used within 48hr

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Procedure:
10g specimen/ sample is added with 50 ml of purified water in a 250 ml conical Flask

Placed in autoclave at 121º c ± 2º c for 20 mins

Cooled under running water

Solution decant in to another conical flask

Then the sample(Residue) washed again with 50 ml of high purity water and again
decanted
Titrated immediately with 0.02 N Sulphuric acid using 5 drops of methyl red indicator

Record the volume of 0.02 N Sulphuric acid

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 Volume of Sulphuric acid consumed

Volume of 0.02 N
Tests Container
Sulphuric acid

Type-I 1.0
Powder glass Test Type-II 8.5
Type-III 15.0
Type-II (100 ml or below) 0.07
Water attack test
Type-II (above 100ml) 0.02

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b. Water Attack Test:
 This test is used only with containers that have been exposed to sulphur dioxide
fumes under controlled humidity conditions.
 Such a treatment neutralizes the surface alkali.
 The principle involved in the water attack test is to determine whether the alkali
leached form the surface of a container is within the specified limits or not.
 Since the inner surface is under test entire container (ampoule) has to be used.
 The amount of acid that is necessary to neutralize the released alkali from the surface
is estimated, the leaching of alkali is accelerated using elevated temperature for a
specified time.
 Methyl red indicator is used to determine the end point. The basic is acid-base
titration.

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Procedure:
 Rinse 3 or more containers twice with high purity water.
 Fill each container to 90% of its overflow capacity with water.
 Cap all the flask, autoclave at 121°C for 30min.
 Then it is cooled and the liquid is decanted which is titrated with 0.02N sulphuric
acid using methyl red as an indicator.
 Measure the volume of sulphuric acid.

ARKA JAIN University, Jamshedpur, Jharkhand

4.Hydrolytic Resistance of Glass Container:
Rinse container at least 3 times with CO2 free water with the same to their filling
volume . Fill and cover the vials and keep in autoclave.

Heat to 100ºc for 10 min. and allow the steam to issue from the vent cork.

Rise the temp. from 100ºc to 121ºc over 20 min. maintain the temp. at121ºc to 122ºc
for 60 min. Lower the temp. from 121ºc to100ºc for 40 min.

Remove the container from autoclave, cool & combine the liquids being examined.

Measure the volume of test solution in to conical flask and titrate with 0.01N HCL
using methyl red as an indicator.
Perform blank titration with water and the difference between the titration represents
the volume of HCL consumed by the test solution.
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5. Light Transmission test:

The glass container is cut circular sections from two or more areas with circular saw

Wash and dry each sample taking care not to scratch the surfaces

Place the specimen in a spectrophotometer with its cylindrical walls parallel to the slit
in such a way that the light beam is perpendicular to the surface of the section

Measure the transmittance of the section

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 The observed light transmission does not exceed the limits given in the below
table intended for parenteral use.

Size, ml % Light transmission at any

wavelength between 290 to 450
1 25
2 20
5 15
10 13
20 12
50 10
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6.Arsenic test:
 This test is for glass containers intended for aqueous parenterals.

The inner and outer surface of the containers is washed with fresh distilled water for 5 mins

Then similar steps followed as performed in the hydrolytic test, previously described, till
obtaining the final combined solution

10 ml from the final combined volume is pipette out and to it 10ml of HNO3 is added and dried
in an oven at 130ºc

10 ml of hydrogen molybdate is added and refluxed for 25 minutes

It is cooled and absorbance is measured at 840nm

The absorbance of the test solution should be less than the absorbance obtained using 0.1 ml of
arsenic standard solution (10 ppm)
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7. Thermal shock test:
Place the glass containers in upright position in a tray

Immerse the tray into a hot water for a given time and transfers to cold water bath,
temp of both are closely controlled.

Examine cracks or breaks before and after test

The amount of thermal shock a bottle can withstand depends on its size, design and
glass distribution
Small bottles withstand a temp differential of 60ºc to 80ºc and 1pint bottle 30ºc to
40ºc.

A typical test uses 45ºc temp difference between hot and cold water
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8. Internal bursting pressure test:

The test container is filled with water and placed in side the glass chamber

A scaling head is applied and the internal pressure automatically raised by a series
of increments each of which is held for a set of time

The bottle can be checked for predetermined pressure level and test continues until
the container finally bursts

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9. Leakage test:

Drug fill container filled with colored solution (due to the addition of dye)

Which is at high pressure compared to the pressure inside the glass container so that
the colored solution enters the container if any cracks or any breakage is present

Then it conclude leakage is there

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Quality control test for Plastic container
 Quality control test for plastic may be done by any / both of the procedure.
1. Chemical Examination 2. Biological Test

1. Leakage
test
1. Implantation
test
5.Transparency 2. Collapsibility
test test

Intra - cutaneous Systemic

3. Clarity of test injection test
6. Water vapor
aqueous
permeability test
extract
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 10 containers are filled
1. Leakage test with water and fitted with
intended closures

The test is said to be passed if They are kept inverted at

there is no sign of leakage room temperature for 24
from any container. hours.

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 2. Collapsibility test:

A container by collapsing
inward during use, yield at This test is applicable to
least 90% of its normal containers which are to be
contents at the required rate of squeezed in order to remove
flow at ambient temperature the contents.

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 A suitable container is
3. Clarity of taken at random, and
unlabeled, unmarked
aqueous extract and non-laminated
portions is selected.
The processed sample is taken
in to the flask, previously
cleaned with chromic acid and
rinsed with distilled water
250ml of distilled water is
added to the flask, covered and
autoclaved at 121°C for 30
mins
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These portions are cut
into strips, none of which
has a total surface area of
20cm²
The strips are washed free
from extraneous matter by
shaking them with at least two
separate portions of distilled
water for about 30 secs.
The extract is cooled and
examined. It should be
colorless and free from
turbidity.
 Fill five containers with
nominal volume of water and
4. Water vapor heat seal the bottles with an
Permeability test aluminum foil or other suitable
seal

Weigh accurately each container

and allow to stand (with out any
Reweigh the containers overwrap) for 14 days maintaining
humidity of 60 ±5 % and temp
between 20ºand 25º

The loss in weight in each

container is not more than 0.2%

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 Fill five containers to their nominal
5. Transparency test 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

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b. Biological Test:
 The USP has provided the biological test procedures for evaluating the toxicity of
plastic materials.
 This test consist of three phases

Implantation Test Systemic injection Intra- cutaneous

• Small pieces of Test
plastic material • Elutes using sodium
implanted intra- chloride injection
muscularly in are injected with
rabbits. and without alcohol
intravenously in
mice and injecting,
eluates using poly
ethylene glycol 400
and sesame oil
intra- peritoneally
in mice.
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Test
• Injecting all four
eluates
subcutaneously in
rabbits. The
reaction from test
samples must not
be significantly
greater than
nonreactive control
samples.
Quality control test for Metal container:
A metal bacteriological filter
Take 50 empty tubes filled
assembly fitted with filter
with ointment base, sealed &
paper & heated to melting
kept overnight
range of ointment base

Base from all tubes squeezed

Further wash with CHCL3
at certain rate & passed
and observed for particles.
through filter under vaccum

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Quality control test for Closures:
 Closures are used to prevent loss of material by Volatization, deterioration of the
product from moisture, oxygen or carbon dioxide.

1. Penetrability Compatibility Extractive Test

Test Test

• It is measured by • This test is • In this test, the

using the piercing performed to check closure is boiled
machine. the compatibility of with water for four
• Piercing force the rubber closures hours under reflux
with various types of and the water
must not exceed a
the substance. evaporated to
stated value. • Since it is necessary dryness.
to ensure that there
• The residue must
is no interaction
between the contents not exceed the
of the bottle and the specified amount.
clouser.

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 Quality control test for Closures:
Preparation of sample:

The closures are washed in 0.2% w/v of anionic surface active agents
for 5 mins.

Rinsed five times with distilled water and 200ml water is added to it.

It is subjected to autoclave at 119ºc to 123ºc for 20 to 30 min and

covered with aluminum foil.

Cooled and solution is separated from closures

(Solution A).
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 ARKA JAIN University, Jamshedpur, Jharkhand
• This test is applicable to closures intended to be pierced with
hypodermic needle capped and stand for 16 hr. test
• For dry preparation close vials with closures. Inject with hypodermic
needle (1ml) and take 1 ml air, Pass liquid through filter.
3. Fragmentation
• Count no of fragments, must not more than 10 and for butyl rubber
closures it is not more than 15.
• When treated clousers are subjected to sterilization test at 64ºc to 66ºc 2. Sterility Test
and a pressure of about 0.7 KPA for 24 hr.
• 50 ml of Solution A is evaporated to dryness on a water bath and dried Evaporation
at 105ºc. 1. Residue on
• The residue weighs not more than 4 gm.
 ARKA JAIN University, Jamshedpur, Jharkhand
• 20ml of Solution A is added with 0.1 ml bromothymol blue when
it is added with a small amount of 0.01M NaOH which changes
the color from blue to yellow.
6. PH of aqueous extract
• The volume of NaOH required is not more than 0.3ml and if it
done with HCL , the volume should not more than 0.8ml.
aqueous extract
• Solution A is not more opalescent than opalescent standard OS3
and not more than 0.8ml.
5. Clarity and color of
• Pierce 10 times with hypodermic needle and immerses in 0.1%
methylene blue solution, maintain the pressure of about 27 KPA
and restore to atmospheric pressure and stand for 30 min.
4. Self stability Test
• Rinse outside and observed for traces of colored solution.
• Traces of colored solution should not be found.
 ARKA JAIN University, Jamshedpur, Jharkhand
• 20ml of solution A is added with 1ml of 1M
sulphuric acid and 20ml of 0.002M kmn04 and
boil it for 3 min then cool and add 1 gm KI
which is titrated with sodium thio sulphate using
8. Reducing substances
starch as an indicator.
• Blank is done and difference between titration
volumes not more than 0.7ml.
• It must be done within 4hrs of preparation of
solution A
• It filtered through 0.5µ filter and it absorbance is 7. Light absorption test
measured at 220nm to 360nm.
• Blank is done without closures and absorbance is
not more than 2.
Quality Control test of collapsible Tubes:
• Water filled in the tube and closed tightly.
• External surface is wiped off and tube is kept inverted on filter
1. Leakage test paper at base.
• Allow to stand for 1 hr. Filter paper shows absorption at any time
during test period.

• a. Powder of adhesion: Tube was spitted along the length and flattened.
Cotton wool soaked in acetone was rubbed over lacquer surface for 20
min. Lacquer should not lift from surface and cotton wool shall remain
2. Lacquer curing test colorless.
• b. Flexibility test: The tube was folded in such a manner that internal
lacquer surface is outside. The lacquer costing should not be peeled off
when the folded position is rubbed with finger.

• 10 tubes are taken as test sample. Then it filled and crimped subjected to
3. Lacquer compatibility 45c for 72 hr. Tubes were allowed to cool and cut lengthwise.
• a. Product compatibility: Content should not show change in color or gas
test formation.
• b. Lacquer compatibility: Lifting or peeling of lacquer is checked .

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Quality control of Strip and blisters:

The strips and After sometime

The 3/4th of water is blisters were place vacuum was
poured in in side the released and strips,
desiccators desiccators and blisters were taken
vacuum is applied out

If there is no leakage The contents of

The water present
, the contents will strips and blister
over the outer
not be wetted. This packages were
surface of the
indicates the perfect removed and was
packages was wiped
sealing of the checked for
off with tissue paper
packages. presence of moisture
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Quality control tests for Cartons:

• This is used to assess the strength of

erected package there by estimating the
degree of protection that it confers on the
1. Compression contents.
• This is useful for products with no
inherent strength in one plane or another.

• The carton should spring open in to its

original shape without a need for
2. Carton unreasonable force.
opening force • If the carton does not spring open or
buckles in on itself, it may cause
problems on cartooning machine.
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 THANK YOU
STAY SAFE
&
STAY HEALTHY
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