Primary Packages For Pharmaceuticals-8249242526

Draft General Chapter uploaded on 11th April 2017
For Forthcoming IP (2018)

6. PRIMARY PACKAGES FOR PHARMACEUTICALS
6.1. INTRODUCTION
6.1.1. Terminology
6.2. CONTAINERS
6.2.1. Plastic Containers
6.2.1.1. Plastic Containers for PARENTERAL Preparations
6.2.1.1.1. Sterile Plastic Containers for Blood and Blood Components
6.2.1.1.2. Sterile PVC (Polyvinyl chloride) Containers for Blood and Blood Components
6.2.1.1.3. Sterile PVC (Polyvinyl chloride) Containers for Blood containing an
Anticoagulant Solution
6.2.1.2. Plastic Containers for NON-PARENTERAL Preparations
6.2.1.2.1. Polyethylene Terephthalate (PET) Containers
6.2.1.2.2. Polyethylene (HDPE & LDPE) Containers
6.2.1.2.3. Polyvinyl Chloride (PVC, non-plasticized) Containers
6.2.1.2.4. Polyvinyl Chloride (PVC, plasticized) Containers
6.2.1.2.5. Polypropylene (PP) Containers
6.2.1.2.6. Containers based on Cyclic Olefins
6.2.1.2.7. Poly(ethylene-vinyl acetate) (PEVA) Containers
6.2.1.2.8. Polycarbonate (PC) Containers
6.2.1.2.9. Polyamide 6 (PA-6) Containers
6.2.1.3. Plastic Containers for OPHTHALMIC Preparations
6.2.2. Glass Containers
6.2.3. Metal Containers
Collapsible Metal Tubes For Ophthalmic Ointments
6.3. CLOSURES FOR CONTAINERS
6.4. LABELS ON CONTAINER
6.4.1. Basic Statutes Governing Labelling
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6. PRIMARY PACKAGES FOR PHARMACEUTICALS
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6.1. INTRODUCTION
Pharmaceutical products are delivered to the intended consumers in a variety of packages.
A package for a pharmaceutical is a form that is intended to contain, protect/preserve the contents throughout the
shelf life; aid in the safe, efficient transportation and distribution; and to inform the user about the drug substance or
drug product. A package comprises a container that usually has a closure (e.g. cap, lid, dispensing system) and a
label (e.g. a separate label or printed matter). The closure may or may not have a liner.
A package is also conventionally referred to as a container-closure system.
NOTE 1:
This section covers the primary package i.e. the materials that come in direct contact with pharmaceutical contents.
Secondary and tertiary packaging is not addressed in this pharmacopoeia.
This chapter deals with the specific requirements, guidance and information on containers used for packaging of
pharmaceutical products. The materials that are used in the manufacture of containers, particularly plastic
containers, the raw materials and additives used and the formulations employed should be agreed with the users of
the containers.
A container-closure system for pharmacopoeial article is intended to contain a drug substance or drug product with
which it is, or may be in direct contact.
A container-closure system for pharmacopoeial article must be chosen with care and after taking into consideration
the nature of the articles and the likely effects of transportation and storage, even for short periods of time.
A container-closure system for pharmacopoeial article should be designed so that the contents may be removed in a
manner suitable for the intended use of the article in it. It should also provide an adequate degree of protection,
minimise the loss of constituents and should not interact physically or chemically with the contents in a way that
will alter their quality to an extent beyond the limits given in the individual monograph, or present a risk of toxicity.
The choice of a container-closure system for pharmacopoeial article is also governed by the likely period of storage
of the article during which its quality will not be compromised to a degree where it will be unfit for use. Under the
heading Storage, the pharmacopoeia indicates the measures to be taken to protect the article from contamination and
deterioration during its entire shelf-life. Technical Specifications for the package to be used for any article have not
been given but in certain cases, the type of package that is recommended is stated in terms that have the following
meanings.
6.1.1. Terminology
a. Package. A package comprises a container that usually has a closure (e.g. cap, lid, dispensing system) and
a label (e.g. a separate label or printed matter). The closure may or may not have a liner.
A package is also conventionally referred to as a container-closure system.
b. Well-closed Package. A container-closure system for a pharmacopoeial article that protects the contents
from extraneous solids and liquids and loss of the article in process of handling, shipment, storage and
distribution.
c. Airtight or Tightly-closed Package. A container-closure system for a pharmacopoeial article that protects
the contents from contamination by extraneous solids, liquids, or vapours, loss or deterioration of the article
from effervescence, deliquescence or evaporation during handling, shipment, storage and distribution. A
tightly-closed container-closure system for a pharmacopoeial article must be capable of being tightly re-
closed after use.
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d. Hermetically Sealed Package. A container-closure system for a pharmacopoeial article that is impervious
to air or any other gas under normal conditions of handling, shipment, storage and distribution, e.g. sealed
glass ampoule, gas cylinder etc. A hermetically sealed container-closure system must be used for a single
dose.
e. Light-resistant Package. A container-closure system for a pharmacopoeial article that protects the contents
from the effects of actinic light by virtue of the specific properties of the material of which it is made.
Alternatively, a clear and colourless or a translucent container may be made light-resistant by means of an
opaque (light-resistant) covering and/or in such cases, the label on the container should bear a statement
that the opaque covering or storage in dark place is needed until the contents have been used up.
f. Single-dose Package. A container-closure system for pharmacopoeial article that holds a quantity of the
preparation intended for total or partial use as a single administration.
g. Multi-dose Package. A container-closure system for a pharmacopoeial article that holds a quantity of the
preparation suitable for two or more doses.
h. Sealed Package. A container-closure system for pharmacopoeial article closed by fusion of the material of
the container.
i. Tamper-evident Package. A container-closure system for a pharmacopoeial article fitted with a device or
mechanism that reveals irreversibly whether the container has been opened.
The user of the container-closure system must obtain an assurance from the supplier that the composition of the
closure does not vary from batch to batch and that it is identical to that of the container used during compatibility
testing. When the user is informed of changes in the composition, compatibility testing and biological testing must
be repeated, totally or partly depending on the nature of the changes.
A container-closure system for a pharmacopoeial article is available in different forms. However, one of the form is
container which is widely used for pharmaceuticals. The details are given below:
6.2. CONTAINERS
Containers for pharmaceutical products are made of a variety of materials such as different types of plastics, glass,
metal and their combination. This section covers the guideline for each type of these container materials.
6.2.1. Plastic Containers

The commonly used plastic resins conforming to Indian Standards for the manufacture of plastic container and
closures are Polyethylene terephthalate (PET) (IS 12252), Polyethylene (IS 10146), Polyvinyl Chloride (IS 10151),
Polypropylene (IS 10910), Cyclic Olefins, Polyamides [nylon 6 (IS 12247)], Polycarbonate (IS 14971), Poly
(ethylene-vinyl acetate) (IS 13601). However, if the manufacturer of pharmacopoeial articles intends to use plastics
made from polymers other than listed above, it should be justified and authorised by appropriate competent
authority.
The resin identification codes as mentioned in IS 14534 may be visibly marked on the plastic containers and/ or the
label, wherever possible.
The plastic containers should be manufactured from materials that do not include in their composition any
substances that can be extracted by any contents in such quantities so as to alter the efficacy or stability of the
product or present a toxic hazard. Recycling of excess material of well-defined nature and proportions may be
permitted after appropriate validation.
A summary of the manufacture and usage of plastic container and closures is provided in the Table 1.
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Table 1 - Overview of the life cycle (stages) of Plastic Materials for Pharmacopoeial Articles
Stakeholder Activity Involved Governing Regulations Examples

in force
Plastic Resin Monomers BIS Standards on Polyethylene terephthalate (PET) = IS 12252
Manufacturers (Raw material) composition of various Polyethylene (PE) = IS 10146
packaging polymers Polyvinyl chloride (PVC) = IS 10151
conversion into (plastic resins) Polypropylene (PP) = IS 10910
Polyamides [nylon 6] = IS 12247
Polycarbonate = IS 14971
Polymer Poly (ethylene-vinyl acetate) = IS 13601
(Plastic Resin)
Manufacturers Addition of BIS Standard for Resin Bottles, Containers, Tubes, Caps, Closures
of Packaging Colourant/ Additives Identification Codes and other forms of Packages
components to Resin if needed IS - 14534 Identification Codes
(Convertors) and converting the Code No.1 = PET
mixture into shaped Code No.2 = HDPE (High Density PE)
articles Code No.3 = V (PVC, Polyvinyl Chloride)
(Plastics Articles) Code No.4 = LDPE (Low Density PE)
Code No.5 = PP
Code No.6 = PS (Polystyrene)
Code No.7 = Other plastics
Manufacturer of Filling of The Drugs and Substances, Preparations, Articles
Pharmacopoeial Pharmaceutical Cosmetics Act, 1940
Articles Formulations The Drugs and
(Users) (Packaged Products) Cosmetics Rules, 1945
Patients, Health care chain (Doctors,

Consumer Consumption/ Usage ˗ Hospitals)
All Plastic Waste Various responsibilities on Manufacturers,

stakeholders Disposal Management Rules, 2016 Local Bodies, Citizens, etc.
The selection of a suitable plastic container should be based on a knowledge, obtained from the supplier of the raw
materials used and of the composition of the plastic so that potential hazards can be assessed. The plastic container
chosen for any particular product should be such that the ingredients of the product in contact with the plastic
material are not significantly adsorbed on its surface and do not significantly migrate into or through the plastic.
Type samples (specimen) of the intended container should be packed with the product and tested under conditions
that reproduce those that would be encountered in use. These tests should include examination of the product to
ensure absence of any sensory, chemical or physical change, an assessment of changes in the quality of contents due
to permeability of the plastic, detection of changes in pH, an assessment of the effects of light, chemical tests and
where necessary, biological tests. Containers from bulk production should conform to the type sample (specimen) in
every respect. It should be ensured that there is no change in the composition or any change in the manufacturing
method used by the manufacturer and more importantly, that no use is made of post-consumer recycled material.
It must be emphasized that changes in the composition of the plastic or reworking or inadequate control of
processing can bring about changes which may invalidate the results of type testing. Samples from production
should be tested to ensure conformance to type samples (specimen) and test schedules should be designed to check
deviations from the characteristic of the type sample (specimen).
The biological and chemical tests described below are intended for plastic containers in which pharmaceutical
formulations are packaged. It should be appreciated that these tests by themselves are not sufficient to establish
safety or suitability of the plastic containers for the preparations and it is necessary to consider the results of the tests
in conjunction with the information given above. Specification should be agreed with the container manufacture and
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should be revised if the composition of the plastic or the ingredient quality is altered or the processing treatment is
changed.
It shall be the responsibility of the user/manufacturer to ensure the compatibility of the pharmaceutical
products with the package and stability of the product in the package system. Towards this the user /
manufacturer shall have in place a system of quality assurance with the supplier / convertor to ensure
compliance of the components of the package with the requirement stated in this chapter at all times. The
user should take the “risk-based approach” to determine the testing and its frequency required to ensure this.
Applicability of Biological Tests for Plastic Packages

- Packages used for oral and topical dosage forms do not need any biological testing.
- In vitro testing described in Appendix 2.2.23 is applicable to the packages used for all dosage forms except
for oral and topical dosage forms.
- Packages that meet the requirements of the in vitro tests are not required to undergo any further in vivo
testing (2.2.24).
- Packages that do not meet the requirements of the in vitro tests where applicable are required to undergo
further in vivo testing.
Packages that do not meet the requirements of the biological reactivity tests [(2.2.23) and (2.2.24), if appropriate]
are not suitable as packages for pharmaceutical use.
6.2.1.1. Plastic Containers for Parenteral Preparations
General Requirements
Material. Plastic containers for parenteral preparations are manufactured from one or more polymers. The polymers
most commonly used are polyethylene, polypropylene and polyvinyl chloride. Only virgin plastic material, which is
practically odourless, is used in the manufacture of the containers. Additives such as antioxidants, lubricants,
plasticisers, stabilisers, etc. may be used but no pigment may be used for purposes of colouring.
Characteristics. The containers may be bags or bottles. They have a site suitable for the attachment of an infusion
set designed to ensure a secure connection. They may have a site that allows an injection to be made at the time of
use. They usually have a part that allows them to be suspeended and which will withstand the tension occurring
during use. Although it may not be feasible to include parameters for construction and design of containers in terms
of size, shape and weight, for example those meant for large volume parenterals (LVP), of different materials and
made on different machines, both manufactured indigenously and internationally, involved in the production of such
plastic containers, nevertheless the integrity of neck and shoulders of the containers should be suitably and
appropriately strengthened and it shall be the responsibility of such LVP manufacturers to ensure that the containers
withstand the stress conditions and rigors of transportation and packaging. The containers must withstand the
sterilisation conditions to which they will be submitted. The design of the container and the method of sterilisation
chosen are such that all parts of the containers that may be in contact with the infusion are sterilised. The containers
are impermeable to micro-organisms after closure. The containers are such that after filling them, they are resistant
to damage from accidental freezing which may occur during transport of the final preparation. The containers are
and remain sufficiently transparent to allow the appearance of the contents to be examined at any time, unless
otherwise justified and authorised.
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Labelling. The label accompanying a batch of empty containers states (1) the name and address of the
manufacturer; (2) a batch number which enables tracing the history of the container and of the plastic material of
which it is manufactured.
Visual inspection. The empty containers display no defects that may lead to leakage and the filled and closed
container shows no leakage.
NOTE 2:
For satisfactory storage of some preparations, the container should be enclosed in a protective envelope. The initial
evaluation of storage is then to be carried out using the container enclosed in the envelope.
Tests on Containers
Leakage test. Fill ten containers with water, fit with the intended closures and keep them inverted at room
temperature for 24 hours.
There are no signs of leakage from any container.
Collapsibility test. This test is applicable to containers which are to be squeezed in order to remove the contents. A
container, by collapsing inward during use, yields at least 90% of its nominal contents at the required rate of flow at
ambient temperature.
NOTE 3:
For Parenterals in Plastic Containers, other suitable means of ensuring package integrity may be used.
NOTE 4:
Plastic Containers for Parenteral Preparations shall be governed by all considerations covered in details in the
Plastic Containers for Non-parenteral Preparations (6.2.1.2).
Tests using Special Solution “S”

Preparation of Special Solution “S”
Fill a container under examination to its nominal capacity with water and close it, using the usual means of closure;
otherwise closed using a suitable sheet / foil of aluminium. Heat in an autoclave so that a temperature of 121± 2°C
is reached within 20 to 30 minutes and maintain at this temperature for 30 minutes. If heating at 121 °C leads to
deterioration/deformation of the container, heat at 100 °C for 2 hours.

Note: Use solution S within 4 hours of its preparation.
Blank. Prepare a blank by heating water in a borosilicate-glass flask closed by an aluminium foil at the temperature
and for the time used for the preparation of solution S.
Tests Using Solution “S”
Clarity and Colour of solution S. Solution S is clear (2.4.1) and is colourless (2.4.1).
Acidity or Alkalinity. To a volume of solution S corresponding to 4% of the nominal capacity of the container add
0.1mL of phenolphthalein solution. The solution is colourless.
Add 0.4mL of 0.01M sodium hydroxide. The solution is pink. Add 0.8mL of 0.01M hydrochloric acid and 0.1mL of
methyl red solution. The solution is orange-red or red.
Light absorption. The light absorption in the range 230nm to 360nm of solution S using a blank prepared as
described under Solution S is not more than 0.20 (2.4.7).
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Reducing substances. To 20.0mL of solution S add 1mL of dilute sulphuric acid and 20.0mL of 0.002M potassium
permanganate. Boil for 3 minutes. Cool immediately. Add 1g of potassium iodide and titrate immediately with
0.01M sodium thiosulphate, using 0.25mL of starch solution as indicator.
Carry out a titration using 20.0mL of the blank prepared as described under Solution S.
The difference between the titration volumes is not more than 1.5mL.
Transparency. Fill the container previously used for the preparation of solution S to its nominal capacity with a 1 in
200 dilution of the standard suspension (2.4.1) when made from polyethylene or polypropylene. For containers
made of other plastics, use a 1 in 400 dilution.
The cloudiness of the suspension is perceptible when viewed through the container and compared with a similar
container filled with water (2.4.1).
6.2.1.1.1. Sterile Plastic Containers for Blood and Blood Components

Plastic containers for the collection, storage, processing and administration of blood and its components are
manufactured from one or more polymers, if necessary with additives. The composition and the conditions for
manufacture of the containers are approved/ registered by the appropriate competent authorities in accordance with
the relevant national legislation and international agreements.
When the composition of the materials of the different parts of the containers corresponds to the appropriate
specifications, their quality is controlled by the methods indicated in the specifications, described under Plastic
Containers for Parenteral Preparations (6.2.1.1).
Materials other than those described in the Pharmacopoeia may be used provided that their composition is
authorised by the Licensing Authority and that the containers manufactured from them comply with the
requirements prescribed for Sterile Plastic Containers for Human Blood and Blood Components.
In normal conditions of use the materials do not release monomers, or other substances, in amounts likely to be
harmful and do not lead to any abnormal modifications of the blood. The containers may contain anticoagulant
solutions, depending on their intended use, and are supplied sterile.
Each container is fitted with attachments suitable for the intended use. The container may be in the form of a single
unit or the collecting container may be connected by one or more tubes to one or more secondary containers to allow
separation of the blood components to be effected within a closed system.
The outlets are of a shape and size allowing for adequate connection of the container with the blood-giving
equipment. The protective coverings on the blood-taking needle and on the appendages should be such as to ensure
the maintenance of sterility. They should be easily removable but should be tamper-proof.
The capacity of the containers is related to the nominal capacity prescribed by the national authorities and to the
appropriate volume of anticoagulant solution. The nominal capacity is the volume of blood to be collected in the
container. The containers are of a shape such that when filled they may be centrifuged.
The containers are fitted with a suitable device for sending or fixing which does not hinder the collection, storage,
processing or administration of the blood.
The containers are enclosed in sealed, protective envelopes.
Description. The container is sufficiently transparent to allow adequate visual examination of its contents before
and after the taking of the blood and is sufficiently flexible to offer minimum resistance during filling and emptying
under normal conditions of use. The container contains not more than 5mL of air.
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Tests
Solution S1. Fill the container with 100mL of sodium chloride injection. Close the container and heat it in an
autoclave so that the contents are maintained at 110°C for 30 minutes.

If the container under examination contains an anticoagulant solution, first empty it, rinse the container with 250 mL
of water for injections at 20±1ºC and discard the rinsings.
Solution S2. Introduce into the container a volume of water for injections corresponding to the intended volume of
anticoagulant solution. Close the container and heat it in an autoclave so that the contents are maintained at 110 °C
for 30 minutes. After cooling, add sufficient water for injections to fill the container to its nominal capacity.
If the container under examination contains an anticoagulant solution, first empty it and rinse it as indicated above.
Resistance to centrifugation. Introduce into the container a volume of water, acidified by the addition of 1mL of
dilute hydrochloric acid, sufficient to fill it to its nominal capacity. Envelop the container with absorbent paper
impregnated with a 1 in 5 dilution of bromophenol blue reagent or other suitable indicator and then dried. Centrifuge
at 5000rpm for 10 minutes.
No leakage is perceptible on the indicator paper and no permanent distortion occurs.
Resistance to stretch. Introduce into the container a volume of water, acidified by the addition of 1mL of dilute
hydrochloric acid, sufficient to fill it to its nominal capacity. Send the container by the sending device at the
opposite end from the blood-taking tube and apply along the axis of this tube an immediate force of 20 N (2.05
kgf). Maintain the traction for 5 seconds. Repeat the test with the force applied to each of the parts for filling and
emptying.
No break and no deterioration occurs.
Leakage. Place the container that has been submitted to the stretch test between two plates covered with absorbent
paper impregnated with a 1 in 5 dilution of bromophenol blue reagent or other suitable indicator and then dried.
Progressively apply force to the plates to press the container so that its internal pressure (i.e. the difference between
the applied pressure and atmospheric pressure) reaches 67 kPa within 1 minute. Maintain the pressure for 10
minutes.
No signs of leakage are detectable on the indicator paper or at any point of attachment (seals, joints, etc.).
Vapour permeability. For a container containing an anticoagulant solution, fill with a volume of sodium chloride
injection equal to the volume of blood for which the container is intended.
For an empty container, fill with the same mixture of anticoagulant solution and sodium chloride injection. Close the
container, weigh it and store it at 5 ± 1°C in an atmosphere with a relative humidity of 50 ± 5% for 21 days.
At the end of this period the loss in weight is not more than 1%.
Emptying under pressure. Fill the container with a volume of water at 5 ± 1°C equal to the nominal capacity. Attach a
transfusion set without an intravenous cannula to one of the connectors. Compress the container so as to maintain
throughout the emptying an internal pressure (i.e. the difference between the applied pressure and atmospheric
pressure) of 40 kPa.
The container empties in less than 2 minutes.
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Speed of filling. Attach the container by means of the blood-taking tube fitted with the needle to a reservoir
containing a suitable solution having a viscosity equal to that of blood, such as a 33.5% w/v solution of sucrose at
37°C. Maintain the internal pressure of the reservoir (i.e. the difference between the applied pressure and
atmospheric pressure) at 9.3 kPa with the base of the reservoir and the upper part of the container at the same level.
The volume of liquid which flows into the container in 8 minutes is not less than the nominal capacity of the
container.
Resistance to temperature variations. Place the container in a suitable chamber having an initial temperature of
20°C to 23°C. Cool it rapidly in a deep-freeze to –80°C and maintain it at this temperature for 24 hours. Raise the
temperature to 50ºC and maintain for 12 hours. Allow to cool to room temperature. The container complies with the
tests for Resistance to centrifugation, Resistance to stretch, Leakage, Vapour permeability, Emptying under pressure
and Speed of filling described above.
Transparency. Fill the empty container with a volume equal to its nominal capacity of the standard suspension
(2.4.1), diluted so as to have an absorbance at 640nm of 0.37 to 0.43 (dilution factor about 1 in 16) (2.4.7).
The cloudiness of the suspension must be perceptible when viewed through the bag, as compared with a similar
container filled with water.
Extractable matter. Tests are carried out by methods designed to simulate as far as possible the conditions of
contact between the container and its contents which occur in conditions of use.
The conditions of contact and the tests to be carried out on the eluates are described, according to the nature of the
constituent materials, in the particular requirements for each type of container.
Haemolytic effects in buffered systems
Stock buffer solution. Dissolve 90.0g of sodium chloride, 34.6g of sodium phosphate and 2.4g of sodium
dihydrogen phosphate dihydrate in water and dilute to 1000mL with the same solvent. Prepare three buffer solutions
as follows
Buffer solution Ao. To 30.0mL of stock buffer solution add 10.0mL of water.
Buffer solution Bo. To 30.0mL of stock buffer solution add 20.0mL of water.
Buffer solution Co. To 15.0mL of stock buffer solution add 85.0mL of water.
Introduce 1.4mL of solution S2 into each of three centrifuge tubes. To tube I add 0.1mL of buffer solution A o, to
tube II add 0.1mL of buffer solution B o and to tube III add 0.1mL of buffer solution Co. To each tube add 0.02mL
of fresh, heparinised human blood, mix well and warm on a water-bath at 30±1°C for 40 min. Use blood collected
less than 3 hours previously or blood collected into either an Anticoagulant Citrate Phosphate Dextrose Solution
(CPD solution) or Anticoagulant Citrate phosphate Dextrose Adenine Solution (CPDA solution) less than 24 hours
previously.
Prepare further three solutions as follows:
3.0mL of buffer solution Ao and 12.0mL of water (solution A1),
4.0mL of buffer solution Bo and 11.0mL of water (solution B1),
4.75mL of buffer solution Bo and 10.25mL of water (solution C1),
To tubes I, II and III add, respectively, 1.5mL of solution A 1, 1.5mL of solution B1 and 1.5mL of solution C1. At
the same time and in the same manner, prepare three other tubes, replacing solution S 2 by water.
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Centrifuge simultaneously the tubes to be examined and the control tubes at exactly 2500g in the same horizontal
centrifuge for 5 minutes. After centrifuging, measure the absorbance of the liquids at about 540nm (2.4.7), using the
stock buffer solution as blank. Calculate the haemolytic value as a percentage from the expression
Aexp × 100
A100
where, A100 = absorbance of tube III,

Aexp = absorbance of tube I or II or of the corresponding control tubes.
The solution in tube I give a haemolytic value not greater than 10% and the haemolytic value of the solution in tube
II does not differ by more than 10% from that of the corresponding control tube.
Sterility. Introduce aseptically into the container 100mL of sodium chloride injection and shake the container to
ensure that the internal surfaces have been entirely wetted. Filter the contents of the container through a membrane
filter. Complete the test as described under Method of Test for aqueous solutions (2.2.11), paragraph 2, beginning at
the words ‘After filtration, ……..’.
Pyrogens. Solution S1 complies with the test for pyrogens (2.2.8). Inject 10mL of the solution/kilogram of the
rabbit’s weight.
Abnormal toxicity. Solution S1 complies with the general test for abnormal toxicity (2.2.1). Inject 0.5mL of the
solution into each mouse.
Container and Closures. Sterile plastic containers for human blood and blood components are packed in protective
tamper-evident envelopes. On removal from its protective envelope the container shows no leakage and no growth
of micro-organisms. The protective envelope is sufficiently robust to withstand normal handling.
The protective envelope is sealed in such a manner that it cannot be opened and re-closed without leaving visible
traces that the seal has been broken.
Labelling. The label states that once withdrawn from its protective envelope, the content must be used within 10
days.
A part of the label is reserved for the information required concerning the blood or blood components for which the
container is intended to be used.
The ink, or other substance used to print the labels or the writing must not diffuse into the plastic material of the
container and must remain legible up to the time of use.
6.2.1.1.2. Sterile PVC (Polyvinyl chloride) Containers for Blood and Blood Components
Sterile PVC (Polyvinyl chloride) containers for blood and blood components should meet the requirements
described under the introductory part of section 6.2.1.of chapter 6.2. They also comply with the tests described
under Sterile Plastic Containers for Blood and Blood Components and with the following additional tests.
Acidity or Alkalinity. Introduce into the container a volume of water for injections corresponding to the intended
volume of anticoagulant solution. Close the container and heat in an autoclave so that the contents are maintained at
110ºC for 30 minutes. Cool and add sufficient water for injections to fill the container to its nominal capacity
(solution A). To a volume of solution A corresponding to 4% of the nominal capacity of the container add 0.1mL of
phenolphthalein solution; the solution remains colourless.
Add 0.4mL of 0.1M sodium hydroxide; the solution is pink. Add 0.8mL of 0.01M hydrochloric acid and 0.1mL of
methyl red solution; the solution is orange-red or red.
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Light absorption. Heat water for injections in a round bottom flask in an autoclave at 110ºC for 30 minutes
(solution B). Measure the light absorption of solution A in the range 230nm to 360nm using solution B as blank. The
absorbance is not more than 0.30 at any wavelength from 230nm to 250nm and not more than 0.10 at any
wavelength from 251nm to 360nm (2.4.7).
Ammonium. Dilute 5mL of solution A to 14mL with water in a test-tube, if necessary make alkaline with 2M
sodium hydroxide and dilute further to 15mL with water. Add 0.3mL of alkaline potassium mercuri-iodide solution,
stopper the tube, mix and allow to stand for 5 minutes. When viewed vertically, any yellow colour produced is not
more intense than that obtained by treating a mixture of 10mL of ammonium standard solution (1ppm NH4) and
5mL of water in the same manner (2ppm).
Chlorides. 15mL of solution A complies with the limit test for chlorides (2.3.12). Prepare the standard using a
mixture of 1.2mL of chloride standard solution (5ppm Cl) and 13.8mL of water (0.4ppm).
Extractable di(2-ethylhexyl)phthalate
Extraction solvent. Ethanol diluted with water to have a relative density of 0.9389 to 0.9395 (2.4.29), measured with
a pycnometer.
Stock solution. Dissolve 0.1g of di(2-ethylhexyl)phthalate in the extraction solvent and dilute to 100mL with the
same solvent.
Standard solutions
(a) Dilute 20mL of stock solution to 100mL with extraction solvent.
(b) Dilute 10mL of stock solution to 100mL with extraction solvent.
(c) Dilute 5mL of stock solution to 100mL with extraction solvent.
(d) Dilute 2mL of stock solution to 100mL with extraction solvent.
(e) Dilute 1mL of stock solution to 100mL with extraction solvent.
Measure the absorbance of the standard solutions at the maximum at about 272nm, using the extraction solvent as
blank and plot a curve of absorbance against the concentration of di(2-ethylhexyl)phthalate (2.4.7).
Extraction procedure. Using the donor tubing and the needle or adaptor, fill the empty container with a volume
equal to half the nominal volume with the extraction solvent, previously heated to 37ºC in a well-stoppered flask.
Expel the air completely from the container and seal the donor tube. Immerse the filled container in a horizontal
position in a water-bath maintained at 37±1ºC for 60±1 minute without shaking. Remove the container from the
water-bath, invert it gently ten times and transfer the contents to a glass flask. Immediately measure the absorbance
at the maximum at about 272nm, using the extraction solvent as blank (2.4.7).
Determine the concentration of di(2-ethylhexyl)phthalate in milligrams/100mL of the extract from the calibration
curve. The concentration does not exceed
10mg/100mL for containers of nominal volume greater than 300mL but not greater than 500mL;
13mg/100mL for containers of nominal volume greater than 150mL but not greater than 300mL;
14mg/100mL for containers of nominal volume upto 150mL.
Oxidisable substances. Immediately after preparation of solution A, transfer to a borosilicate-glass flask a quantity
corresponding to 8% of the nominal capacity of the container. At the same time, prepare a blank using an equal
volume of the freshly prepared solution B in another borosilicate-glass flask. To each solution add 20.0mL of
0.002M potassium permanganate and 1mL of 1M sulphuric acid. Allow to stand at room temperature, protected
12
from light, for 15 minutes. To each solution add 0.1g of potassium iodide. Allow to stand protected from light for 5
minutes and titrate immediately with 0.01M sodium thiosulphate, using 0.25mL of starch solution as indicator.
The difference between the two titrations is not more than 2.0mL.
Residue on evaporation. Evaporate to dryness 100mL of solution A in a borosilicate-glass beaker, previously

heated to 105°C. Evaporate to dryness in the same conditions 100mL of solution B. Dry to constant weight at
105°C.
The difference between the weights of the residues is not more than 3mg.
6.2.1.1.3. Sterile PVC (Polyvinyl chloride) Containers for Blood containing an

Anticoagulant Solution
Unless otherwise authorised as described in the introductory part of section 6.2.1 of chapter 6.2, the nature and
composition of the material from which the containers are made complies with the requirements described under
Sterile PVC (Polyvinyl chloride) containers for blood and blood components (6.2.1.1.2).
Sterile plastic containers containing an anticoagulant solution are used for the collection, storage and administration
of blood. Before filling they comply with the description and characteristics described under Sterile PVC (Polyvinyl
chloride) containers for blood and blood components (6.2.1.1.2).
After addition of the anticoagulant solution the containers comply with the tests described under Sterile Plastic
Containers for Blood and Blood Components (6.2.1.1.1) and with the following additional tests:
Light absorption. Measure the light absorption of the anticoagulant solution from the container in the range 250nm
to 350nm using an anticoagulant solution of the same composition that has not been in contact with a plastic
material as blank.
The absorbance at the maximum at about 280nm is not more than 0.5 (2.4.7).
Extractable di(2-ethylhexyl)phthalate. Carefully remove the anticoagulant solution by means of the flexible
transfer tube. Using a funnel fitted to the tube, completely fill the container with water, leave in contact for 1
minute, squeezing the container gently and empty completely. Repeat the rinsing.
The container then complies with the test described under Sterile PVC (Polyvinyl chloride) containers for blood and
blood components (6.2.1.1.2).
Volume of anticoagulant solution. The volume does not differ by ±10% from the stated volume when determined
by emptying the container and collecting the anticoagulant solution in a graduated cylinder.
6.2.1.2. Plastic Containers for Non-parenteral Preparations
Tests on Containers
The container used for packaging of pharmaceutical formulations shall meet all the test requirements detailed below.
Leakage test, Collapsibility test. Comply with the tests described under Plastic Containers for Parenteral
Preparations (6.2.1.1).
The following tests are applicable to containers intended for filling oral liquids.
Clarity of aqueous extract. Select unlabelled, unmarked and non-laminated portions from suitable containers,
taken at random, sufficient to yield a total area of sample required, taking into account the surface area of both sides.
Cut these portions into strips, none of which has a total area of more than 20cm2. Wash the strips free from
13
extraneous matter by shaking them with at least two separate portions of distilled water for about 30 seconds in each
case, then draining off the water thoroughly.
Select cut and washed portions of the sample with a total surface area of 1250cm 2, transfer to a flask, previously
cleaned with chromic acid mixture and rinsed with several portions of distilled water and add 250mL of distilled
water. Cover the flask with a beaker and autoclave at 121°C for 30 minutes. Carry out a blank determination using
250mL of distilled water. Cool and examine the extract; it is colourless and free from turbidity.
Non-volatile residue. Evaporate 100mL of the extract obtained in the test for Clarity of aqueous extract to dryness
and dry to constant weight at 105°C.
The residue weighs not more than 12.5mg.
Tests on Container Material

The following tests are done:
- on portions of the container that are unlabelled, unprinted or non-laminated or
- on the granules of plastic in the case of containers made by the ‘form-fill-seal’ process.
6.2.1.2.1. Polyethylene Terephthalate (PET)

Polyesters are polymers containing ester linkages generated due to the condensation of di-acids and di-ols. A
prominent example in the class of polyesters is Polyethylene terephthalate (PET).
PET is a polymer which comprises at least 85% units of terephthalic acid or dimethyl terephthalate condensed with
ethylene glycol. Co-monomers such as isophthalic acid, dimethyl isophthalate or diethylene glycol may also be used
in the PET polymerisation.
Production of PET
The polymerisation of PET is catalysed with catalyst (usually certain metal oxides), at temperatures greater than
280°C and high vacuum. The manufacturing process of the PET pellets (resin) shall ensure that the residual
acetaldehyde content is not greater than 10ppm.
The resin is then given shape into bottles or any other shape through a conversion process involving injection
moulding and blow moulding.
The resin and its conversion into PET containers may involve the use of colourants conforming to Indian Standards
IS-9833 and/or additives conforming to IS-12252.
The manufacturers of containers should receive the certificate of analysis for each lot of resins procured from to
confirm the quality of resins that the grade of resins used is as agreed and meets the relevant specification. The
certificate of analysis from the resin manufacturer shall provide the necessary assurance about the quality of resin.
Quality assessment of PET Containers

The container used for packaging of pharmaceutical formulations shall meet all the test requirements detailed below.
A] IDENTIFICATION OF CONTAINER MATERIAL
Test 1 – By FTIR Spectrophotometry

Dissolve 50mg of the PET container specimen under examination in 2mL of solvent blend of phenol and
tetrachloroethane (60:40 w/w) with heating followed by centrifuging or 1,1,1,3,3,3-hexafluoropropan-2-ol
or other appropriate solvent systems. Apply several drops of this solution on a glass plate. Keep this plate
on a water-bath in a fume cupboard to produce a thin film of about 15mm by 15mm. Allow the solvent to
14
evaporate completely. Remove the film using a stream of water and a scraper. Dry the film in an oven
(typically at 100-105°C for about 1 hour).
Examine the film by infrared absorption spectrophotometry (2.4.6). The spectrum should show absorption
maxima substantially at about 3053cm-1, 1955cm-1, 1725cm-1, 1613cm-1, 1455cm-1,1410cm-1, 1265cm-1,
1020cm-1, 973cm-1, 875cm-1, and 730cm-1.
Note: Substantial, as opposed to exact, allows for minor spectral differences arising from the natural
compositional and/or physical variation and/or instrumental capabilities.
Test 2 – By UV Spectrophotometry
Reflux 100mg of the PET container under examination with 250mL of a 20% w/v solution of potassium
hydroxide in a 50% v/v solution of ethanol for 30 minutes in a round bottom flask. Allow to cool and dilute
to 100mL with water. Filter if necessary. Dilute 1.0mL of the filtrate to 100mL with water.
Examine this solution in the range 210nm and 330nm (2.4.7), the absorption maximum should be at about
240nm.
Test 3 – By Differential Scanning Calorimetry (2.4.31)

Compare the thermogram of the sample with that obtained with PET and the melting peak temperature
obtained from the thermogram of the sample does not differ from that of the reference thermogram by more
than 8.0°C.
B] CHEMICAL TESTS
B1] TESTS USING SPECIAL SOLUTIONS
Preparation of Special Solutions for Subsequent Tests on PET

Select unlabelled, unmarked and non-laminated portions from suitable containers, taken at random,
sufficient to yield a total area of sample required, cut these portions into strips, none of which has a total
area of more than 1cm2.
Solution S1 (Aqueous Extract)

Place 10g of the sample in a round bottom flask. Add 200mL of water and heat at 50°C for 5 hours. Allow
to cool and then decant the solution.
Use solution S1 within 4 hours of its preparation.
Solution S2 (Ethanolic Extract)

Place 10g of the sample in a round bottom flask. Add 100mL of ethanol (95%) and heat at 50°C for 5
hours. Allow to cool and decant the solution.
Solution S3 (Acidic Extract)

Place 20g of the sample in a round bottom flask. Add 50mL of 0.1M hydrochloric acid and heat at 50°C for
5 hours. Allow to cool and decant the solution.
15
Solution S4 (Alkaline Extract)
Place 20g of the sample into a round bottom flask. Add 50mL of 0.01M sodium hydroxide and heat at 50°C
for 5 hours. Allow to cool and decant.
TESTS USING SPECIAL SOLUTION S1
B1.1] Appearance
Solution S1 has to be clear (2.4.1).
B1.2] Absorbance of solution S1 (2.4.7)
- In the UV- range (220nm to 340nm): absorbance should be not more than 0.20
- In the visible range (400nm to 800nm): absorbance should be not more than 0.05
B1.3] Acidity
To 50mL of solution S1 add 0.15mL of BRP indicator solution. The solution turns yellow. Not more than
0.5mL of 0.01M sodium hydroxide is required to change the colour of the indicator to blue.
B1.4] Alkalinity
To 50mL of solution S1, add 0.2mL of methyl orange solution. The solution turns yellow. Not more than
0.5mL of 0.01M hydrochloric acid is required to reach the beginning of the colour change of the indicator
to orange.
B1.5] Reducing substances
To 20mL of solution S1, add 2mL of 0.5M sulphuric acid and 20mL of 0.002M potassium permanganate.
Boil for 3 minutes. Immediately cool to room temperature. Add 1.0g of potassium iodide, 0.25mL of starch
solution as indicator and titrate with 0.01M sodium thiosulphate. Perform a blank titration using 20mL of
water.
The difference in volume used in the 2 titrations is not greater than 0.5mL.
TESTS USING SPECIAL SOLUTION S2
B1.6] Appearance
Solution S2 has to be clear and colourless (2.4.1).
B1.7] Absorbance of solution S2 (2.4.7)
In the visible range (400nm to 800nm): absorbance should be not more than 0.05.
B1.8.] Extractable Metals
NOTE 5:
a) For quantitative determination of the extractable metals described hereunder, Inductively Coupled
Plasma Spectrometry (2.4.42) may be used. Alternatively, Atomic Absorption Spectrometry (2.4.2) can
be used provided it has the appropriate sensitivity.
b) Extractable metals are measured using special solutions S3 and S4.
16
c) Permissible limits mentioned in the paragraphs below are extractable metals in the PET/Plastics. These
have been expressed as ppm (µg of extracted metal/ /g of PET/Plastics in the special solutions, after
appropriate calculations).
NOTE 6:
The above extractable elements have been chosen to be estimated based on their historical presence in
various PET manufacturing processes.
TESTS USING THE SPECIAL SOLUTION S3
B1.8.1] Aluminium. Not more than 1ppm.

Reference solutions. Prepare the reference standard solutions of aluminium (200ppm Al) with 0.1M
hydrochloric acid.
Wavelength. 396.15nm, the spectral background being taken at 396.25nm.
Verify the absence of aluminium in the 0.1M hydrochloric acid used.
B1.8.2] Barium. Not more than 1ppm.

Reference solutions. Prepare the reference standard solutions of barium (50ppm Ba) with 0.1M
hydrochloric acid.
Wavelength 455.40nm, the spectral background being taken at 455.30nm.
Verify the absence of barium in the 0.1M hydrochloric acid used.
B1.8.3] Cobalt. Not more than 1ppm.

Reference solutions. Prepare the reference standard solutions of cobalt (100ppm Co) with 0.1M
hydrochloric acid.
Verify the absence of cobalt in the 0.1M hydrochloric acid used.
B1.8.4] Manganese. Not more than 1ppm.

Reference solutions. Prepare the reference standard solutions of manganese (100ppm Mn) with 0.1M
hydrochloric acid.
Verify the absence of manganese in the 0.1M hydrochloric acid used.
B1.8.5]Titanium. Not more than 1ppm.

Reference solutions. Prepare the reference standard solutions of titanium (100ppm Ti) with 0.1M
hydrochloric acid.
Wavelength 323.45nm or 334.94nm, the spectral background being taken at 323.35nm.
Verify the absence of titanium in the 0.1M hydrochloric acid used.
B1.8.6] Zinc. Not more than 1ppm.

Reference solutions. Prepare the reference standard solutions of zinc (100ppm Zn) with 0.1M hydrochloric
acid.
Verify the absence of zinc in the 0.1 M hydrochloric acid used.
17
TESTS USING THE SPECIAL SOLUTION S4
B1.8.7] Antimony. Not more than 1ppm.

Reference solutions. Prepare the reference standard solutions of antimony (100ppm Sb) with 0.01M sodium
hydroxide.
Wavelength. 231.15nm or 217.58nm, the spectral background being taken at 231.05nm.
B1.8.8] Germanium. Not more than 1ppm.

Reference solutions. Prepare the reference standard solutions of germanium (100ppm Ge) with 0.01M
sodium hydroxide.
Wavelength 206.87nm or 265.12nm, the spectral background being taken at 206.75nm.
B2] OTHER TESTS
B2.1] Substances soluble in dioxane. Not more than 3.0%

Place 2g of the material to be examined in a round bottom flask. Add 20mL of dioxane and heat under
reflux for 2 hours. Evaporate 10mL of the solution to dryness on a water-bath and then dry the residue at
100-105°C.
The residue weighs a maximum of 30.0mg.
B2.2] Sulphated ash (2.3.18). Not more than 0.5% determined on 1.0g.
B2.3] Total Terephthaloyl moieties. Not more than 1ppm

Polyethylene terephthalate extracting media. (1) 50% ethanol(dilute 125mL of ethanol (95%),
with Purified Water to 238mL, and mix), (2) n-heptane and (3) water.
For each extracting media fill a sufficient number of test containers to 90% of its nominal capacity to
obtain not less than 30mL.
Fill a corresponding number of glass bottles with each extracting medium for use as a blank. Fit the bottles
with impervious seals, such as aluminium foil, or apply closures. Incubate the test packaging system and
the glass bottles at 49°C for 10 days. Remove the test systems and glass bottles and store at room
temperature. Do not transfer the extracting medium samples to alternative storage vessel.
Determine the absorbance of 50% ethanol extract at the wavelength of maximum absorbance at about
244nm (2.4.7). For the blank use corresponding extracting medium blank.
Determine the absorbance of n-heptane extract at the wavelength of maximum absorbance at about 240nm
(2.4.7). For the blank use corresponding extracting medium blank.
The absorbance of the 50% ethanol and n-heptane extracts does not exceed 0.150, corresponding to not
more than 1ppm of total terephthaloyl moieties.
B2.4] Ethylene glycol. Not more than 1ppm

Periodic acid solution. Dissolve 125 mg of periodic acid in 10mL of water.
Dilute sulphuric acid. To 50mL of water, slowly add and with constant stirring 50mL of sulphuric acid,
allow to cool to room temperature.
Note: Dilution of sulphuric acid produces substantial heat and can cause the solution to boil. Perform this
addition carefully sulphur dioxide gas will be evolved. Use fume hood is recommended.
Sodium bisulphite solution. Dissolve 100mg of sodium bisulphite in 10mL of water.
18
Disodium chromotropate solution. Dissolve 100mg of disodium chromotropate in 100mL of sulphuric
acid.
Reference solution. Dissolve quantity of ethylene glycol in the water, to obtain a solution containing
0.0001% w/v of ethylene glycol.
Test solution. Use the water extract from Total Terephthaloyl moieties
Procedure. Transfer 1mL of the reference solution, test solution and purified water extracting medium in
three separate volumetric flasks. Add 0.1mL of periodic acid solution to each flask swirl to mix, and allow
to stand for 60 minutes. Add 1mL of sodium bisulphite solution to each flask, and mix. Add 0.1mL
of disodium chromotropate solution to each flask, and mix. (Note- All the solutions should be analysed
within 1 hour after addition of disodium chromotropate solution) Slowly add 6mL of sulphuric acid to each
flask, mix, and allow the solutions to cool to room temperature. Dilute each solution with dilute sulphuric
acid to volume, and mix. Measure the absorbance of the resulting solutions at the maximum at about
575nm (2.4.7), using water extracting medium as the blank.
The absorbance of the Sample solution does not exceed that of the Standard solution, corresponding to not
more than 1ppm of ethylene glycol.
C] BIOLOGICAL TESTS
Applicability of the test.

1. PET Containers to be used for the packaging of dosage forms other than oral and topical shall comply with
the requirements stated in 6.2.1.
2. PET Containers to be used for the packaging of oral and topical dosage forms do not require the biological
tests.
6.2.1.2.2. Polyethylene
A] Identification of Container Material
 High-density polyethylene
Test 1 – By FTIR Spectrophotometry (2.4.6)

Determine the infrared spectrum from 3800cm−1 to 650cm−1 (2.6–15 µm). The specimen exhibits an
absorption spectrum that is substantially equivalent to that of High-Density Polyethylene RS. Substantial, as
opposed to exact, equivalence allows for minor spectral differences arising from the natural compositional
and/or physical variation among polymers of this class. Substantial equivalence is achieved when all
differences between the sample and RS spectra can be explained in the context of such natural
compositional and/or physical variations.

The thermogram of the specimen is similar to the thermogram of High-Density Polyethylene RS, and (Tg)
the melting peak temperature obtained from the thermogram of the specimen does not differ from that of
the RS by more than 6.0°.
19
 Low-density polyethylene

absorption spectrum that is substantially equivalent to that of the Low-Density Polyethylene RS.
Substantial, as opposed to exact, equivalence allows for minor spectral differences arising from the natural
compositional and/or physical variation among polymers of this class. Substantial equivalence is achieved
when all differences between the sample and RS spectra can be explained in the context of such natural

The thermogram of the specimen is similar to the thermogram of Low-Density Polyethylene RS, and
(Tg) the melting peak temperature obtained from the thermogram of the specimen does not differ from that
of the RS by more than 8.0°.
B] Chemical Tests
Preparation of Special Solutions for subsequent tests on Polyethylene
Solution S1 (Water extraction)

Place 25g of the test material in a borosilicate glass flask with a ground-glass neck. Add 500mL of purified
water, and boil under reflux conditions for 5 hours. Allow to cool to ambient temperature, and filter the
extracting solution through a sintered-glass filter. Collect the filtrate in a 500mL volumetric flask and dilute
with purified water to volume; the diluted solution is Solution S1.
Use Solution S1 within 4 hours of preparation.
Solution S2 (Toluene extraction)

Place 2.0g of the test material in a 250mL borosilicate glass flask with a ground-glass neck. Add 80mL of
toluene and boil under a reflux condenser for 1.5 hours, stirring constantly. Allow to cool to 60 °C and add
120mL of methanol with continued stirring. Pass the resulting solution through a sintered-glass filter. Rinse
the flask and the filter with 25mL of a mixture of 40 volumes of toluene and 60 volumes of methanol add
the rinsing to the filtrate, and dilute to 250mL with the same mixture of solvents to produce Solution S2.
Prepare a blank solution.
Solution S3 (Acid extraction)

Place 5g in a borosilicate glass flask with a ground-glass neck. Add 100mL of 0.1M hydrochloric acid, and
boil under a reflux condenser for 1 hours with constant stirring. Allow to cool and the solids to settle,
decant the solution into a 100mL volumetric flask, and dilute to volume with 0.1M hydrochloric acid; the
diluted solution is Solution S3.
Tests Using Special Solutions
B.1] Absorbance (2.4.7)

Determine the spectrum between 220 and 340nm in Solution S1.
Absorbance should be not more than 0.2.
20
B.2] Acidity or alkalinity
To 100mL of Solution S1 add 0.15mL of BRP indicator solution. Determine the titration volume of 0.01M
sodium hydroxide required to change the colour of the indicator to blue. To a separate, 100mL portion
of Solution S, add 0.2mL of methyl orange solution. Determine the titration volume of 0.01M hydrochloric
acid required to reach the beginning of the colour change of the indicator from yellow to orange.
Not more than 1.5mL of 0.01N sodium hydroxide is required to change the colour of the indicator to blue.
Not more than 1.0mL of 0.01N hydrochloric acid is required to reach the beginning of the colour change of
the indicator from yellow to orange.
B.3] Plastic Additives

These tests should be carried out in whole or in part as required due to the stated composition of the
material.
B.3.1] Phenolic Antioxidant

Solvent mixture. Mixture of equal volumes of acetonitrile and tetrahydrofuran.
Sample solution S2A. Evaporate 50mL of Solution S2 to dryness under vacuum at 45°C. Dissolve the
resulting residue with 5.0mL of the solvent mixture. Prepare a blank solution from the blank solution
corresponding to Solution S2.
Sample solution S2B. Evaporate 50mL of Solution S2 to dryness under vacuum at 45°C. Dissolve the
residue with 5.0mL of methylene chloride. Prepare a blank solution from the blank solution corresponding
to SolutionS2.
Reference solutions of the following reference solutions; prepare only those that are necessary for the
analysis of the phenolic antioxidants stated in the composition of the substance to be examined.
Reference solution (a). A 0.01% w/v of Butylated Hydroxytoluene RS and 0.024% w/v of Plastic Additive
01 RS in the solvent mixture.
Reference solution (b). A 0.024% w/v of Plastic Additive 02 RS and 0.024% of Plastic Additive 03 RS in
the solvent mixture
Reference solution (c). A 0.024% of Plastic Additive 04 RS and 0.024% of Plastic Additive 05 RS in
methylene chloride
Reference solution (d). A 0.01% of Butylated Hydroxy toluene RS in the solvent mixture
Reference solution (e). A 0.024% of Plastic Additive 01 RS in the solvent mixture
Reference solution (f). A 0.024% of Plastic Additive 06 RS prepared in the solvent mixture
Reference solution (g). A 0.024% of Plastic Additive 02 RS prepared in the solvent mixture
Reference solution (h). A 0.024% of Plastic Additive 03 RS prepared in the solvent mixture
Reference solution (i). A 0.024% of Plastic Additive 04 RS prepared in methylene chloride
Reference solution (j). A 0.024% of Plastic Additive 05 RS prepared in methylene chloride
Test A
Determine by liquid chromatography (2.4.14).
If the substance to be examined contains additive butylated hydroxytoluene and/or additive ethylene
bis[3,3-bis[3-(1,1dimethylethyl)-4-hydroxyphenyl]butanoate
Chromatographic system
21
- a stainless steel column 25cm x 4.6mm, packed with octadecylsilane bonded to porous silica
microparticles (5µm)
- mobile phase: a mixture of 70 volumes of a acetronitrile and 30 volumes of water
- flow rate: 2.0mL/minute
- spectrophotometer set at 280nm
- injection volume: 20µL
Inject reference solution (a). The test is not valid unless the resolution between the peaks due to additive
butylated hydroxytoluene and additive ethylene bis[3,3-bis[3-(1,1-dimethylethyl)-4-
hydroxyphenyl]butanoate] peaks is not less than 8.0.
Inject Sample solution S2A corresponding blank solution, Reference solution (a), and Reference solution
(d), Reference solution (e), or both. Run the chromatogram for about 30 minutes.
The peak areas of Sample solution S2A are less than the corresponding peak areas of Reference solution
(d) or Reference solution (e).
Note: Sample solution S2A shows only peaks caused by antioxidants stated in the composition and minor
peaks that also correspond to the blank solution.
Test B
If the substance to be examined contains one or more of the following antioxidants pentaerythrityl
tetrakis[3-(3,5-di tert-butyl-4-hydroxyphenyl)propionate; 2,2,2″,6,6,6″-hexa-tert-butyl-4,4,4″-[(2,4,6-
trimethyl-1,3,5-benzene-triyl)trismethylene]triphenol; octadecyl 3-(3,5-di-tert-butyl-4-
hydroxyphenyl)propionate; tris(2,4-di-tert-butylphenyl) phosphate; 1,3,5-tris(3,5-di-tert-butyl-4-
hydroxybenzyl)-s-triazine-2,4,6(1H,3H,5H)-trione
Carry out the test as described in Test A with the following modifications
microparticles (5µm),
- mobile phase: a mixture of 60 volumes of acetronitrile 30 volumes of tetrahydrofuran and 10
volumes of water,
- flow rate: 1.5mL/minute,
- spectrophotometer set at 280nm,
Inject reference solution (b).The test is not valid unless the resolution between the peaks due to additive
pentaerythrityl tetrakis[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate and additive 2,2’,2″,6,6’,6″-hexa-
tert-butyl-4,4’,4″-[(2,4,6-trimethyl-1,3,5-benzene-triyl)trismethylene]triphenol peaks is not less than 2.0.
Inject Sample solution S2A corresponding blank solution, Reference solution (b), and any Reference
solutions of the antioxidants listed above that are stated in the composition. The peak areas of Sample
solution S2A are less than the corresponding peak areas of Reference solutions of the antioxidants that are
listed above and that are stated in the composition.
22
Test C
If the substance to be examined contains additive octadecyl-3-(3,5-di-tert-butyl-4-
hydroxyphenyl)propionate and/or additive tris(2,4-di-tert-butylphenyl) phosphite.
- mobile phase: a mixture of 50 volumes of methanol, 40 volumes of 2 propanol and 5.0 volumes
of water
- spectrophotometer set at 280nm injection volume: 20µL
Inject reference solution (c). The test is not valid unless the resolution between the peaks due to additive
octadecyl-3-(3, 5-di-tert-butyl-4-hydroxyphenyl) propionate and additive tris(2,4-di-tert-butylphenyl)
phosphite peaks is not less than 2.0.
Inject Sample solution S2B corresponding blank solution, Reference solution (c), and any Reference
solutions (i) or Reference solution (j) of the antioxidants listed above that are stated in the composition. The
peak areas of Sample solution S2B are less than the corresponding peak areas of Reference solutions of the
antioxidants that are listed above and that are stated in the composition.
Note: Sample solution S2B shows only peaks caused by antioxidants stated in the composition and minor
B.3.2] Non-phenolic Antioxidant

Determine by thin-layer chromatography (2.4.17), coating the plate with silica gel GF254.
Mobile phase A. Hexane
Mobile phase B. Methylene chloride
Methylene chloride, acidified. To 100mL of methylene chloride add 10mL of hydrochloric acid, shake,
allow to stand, and separate the two layers. Use the lower layer.
Sample solution S2C. Evaporate 100mL of Solution S2 to dryness under vacuum at 45 °C. Dissolve the
resulting residue with 2mL of methylene chloride acidified.
Reference solution (m). A 0.6% w/v of Plastic Additive 08 RS in methylene chloride. Dilute 2mL of the
solution with methylene chloride, acidified to 10 mL.
Reference solution (n). A 0.6% w/v of Plastic Additive 09 RS in methylene chloride. Dilute 2mL of the
solution with methylene chloride, acidified to 10mL.
Reference solution (o). A 0.6% w/v of Plastic Additive 10 RS in methylene chloride. Dilute 2mL of the
Reference solution (p). A 0.6% of Plastic Additive 10 RS, and 0.6% of Plastic Additive 09 RS in methylene
chloride. Dilute 2mL of the solution with methylene chloride, acidified to 10mL.
Apply to the plate 20µL of sample solution S2C, reference solution and the reference solution
corresponding to all the phenolic and non-phenolic antioxidants expected to be present. Development the
plates Over a path of 18cm with Mobile phase A and over a path of 17cm with Mobile phase B
23
respectively. After development, dry the plate in air and examine under ultraviolet light at 254nm and spray
with alcoholic iodine solution.
The test is not valid unless the chromatogram obtained with reference solution (p) shows two separate spot.
Any spot in the chromatogram obtained with sample solution S2C is not more intense than the spot in the
same position in the chromatogram of the corresponding reference solution.
B.3.3] Amides and Stearates

Use sample solution as sample solution S2C as described in Non-phenolic Antioxidants.
Reference solution (r). A 0.2% of Stearic Acid RS prepared in methylene chloride.
Reference solution (s). A 0.2% of Plastic Additive 12 RS prepared in methylene chloride.
Reference solution (t). A 0.2% of Plastic Additive 13 RS prepared in methylene chloride.
Test A
Determine by thin-layer chromatography (2.4.17), coating the plate with silica gel GF254
Mobile phase. a mixture of 75 volume of trimethylpantane and 25 volumes of alcohol
Apply to the plate 10µL of sample solution S2C, reference solution (r). Develop the plates over a path of 10
cm with Mobile phase. After development, dry the plate in air and examine by spray with 2% 2,6-
dichlorophenol-indophenol sodium in dehydrated alcohol heat in an oven at 120 °C for a few minutes to
intensify the spots.
Any spot corresponding to additive stearic acid in the chromatogram obtained with sample solution S2C (R f
= about 0.5) is not more intense than the spot in the same position in the chromatogram of reference solution
(r).
Test B
Mobile phase B. A mixture of 95 volumes of methylene chloride and 5.0 volumes of methanol.
Apply to the plate 10µL of sample solution S2C, reference solution (s) and reference solution (t). Develop
the plates Over a path of 13cm with Mobile phase A and Over a path of 10cm with Mobile phase B
respectively. After development, dry the plate in air and examine by spray with 40% phosphomolybdic acid
in alcohol heat in an oven at 120°C for a few minutes to intensify the spots. Any spot corresponding to
additive oleamide or erucamide in the chromatogram obtained with sample solution S2C (R f = about 0.2) is
not more intense than the spot in the same position in the chromatogram of reference solution (s) and
reference solution (t).
B.4] Total organic carbon

The total organic content of Solution S1 is measured according to the general methodologies outlined
in Total Organic Carbon (2.4.30).
The method used to perform the total organic carbon analyses should have a limit of detection of 0.2mg/L
(ppm) and should have a demonstrated linear dynamic range from 0.2 to 20mg/L (which encompasses the
total organic carbon limit). A linear range with a higher upper concentration can be used if linearity is
established. If sample extracts exceed this upper linear range, they must be diluted appropriately for
analysis.
24
The difference between the sample and blank total organic carbon concentrations is not more than 5mg/L.
B.5] Extractable Metals

Solution S3 is used for extracting acid extractable metals.
Procedure for extract analysis
Instrumentation and methods are those specified in Elemental Impurities (2.3.13A)
Aluminum. Solution S3 contains not more than 0.4mg/L (ppm), corresponding to 1µg/g.
Arsenic, cadmium, lead, mercury, cobalt, and nickel. Report the measured value in Solution S3 at
values above 0.01mg/L (ppm), corresponding to 0.025µg/g. If the measured values are below these values,
report the result as less than 0.01mg/L (ppm), corresponding to less than 0.025µg/g.
Chromium. Solution S3 contains not more than 0.02mg/L (ppm), corresponding to 0.05µg/g.
Titanium. Solution S3 contains not more than 0.4mg/L (ppm), corresponding to 1µg/g.
Vanadium. Solution S3 contains not more than 0.04mg/L (ppm), corresponding to 0.1µg/g.
Zinc. Solution S3 contains not more than 0.4mg/L (ppm), corresponding to 1µg/g.
Zirconium. Solution S3 contains not more than 0.04mg/L (ppm), corresponding to 0.1µg/g.
6.2.1.2.3. Polyvinyl Chloride, Non-Plasticized

absorption spectrum that is substantially equivalent to that of the Polyvinyl Chloride, Non-plasticized RS.

The thermogram of the specimen is similar to the thermogram of Polyvinyl Chloride, Non-plasticized RS,
and the melting peak temperature obtained from the thermogram of the specimen does not differ from that
of the RS by more than 8.0°. Note that the results of the DSC analysis are strongly dependent on the
amount of plasticizer in the test article.
B] Chemical Tests
Preparation of Special Solutions for subsequent tests on Polyvinyl Chloride

Place 25g of the test material into a borosilicate glass flask. Add 500mL of purified water, cover the flask's
neck with aluminium foil or a borosilicate beaker, and heat in an autoclave at 121 ± 2°C for 20 min. Allow
the solution to cool and the solids to settle, decant the solution into a 500mL volumetric flask, and dilute
Solution S2 (Tetrahydrofuran extraction)

Dissolve 5.0g of the test material in 80mL of tetrahydrofuran and dilute to a volume of 100mL with the
same solvent. Filter if necessary; the solution may remain opaque. Slowly and drop wise add 70mL ethanol
25
to 20mL of this solution. Cool the mixture in ice for 1 hours. Filter or centrifuge the mixture, collecting
residue A. Wash residue A with ethanol. Collect the washings and add them to the solution remaining after
filtration or centrifugation. Transfer the solution to a 100mL volumetric flask and dilute to volume with
ethanol. This process produces Solution S2. Prepare a blank solution.


Evaporate 100mL of Solution S1 to dryness. Dissolve the residue in 5mL of hexane. If necessary, pass
through a filter that has been previously rinsed with hexane. Determine the spectrum between 250 and 330
nm in the dissolved residue.
Polyvinyl chloride, non-plasticized contains 1-phenyleicosane-1, 3-dione for dry dosage forms for oral
administration
Dilute 1.0 volume of Solution S2 to 10 volumes with ethanol prior to measurement. In all other situations,
analyze Solution S2 with no further preparation. Determine the spectrum between 250 and 330nm in the
dissolved residue
Absorbance should be not more than 0.25 for containers for non-injectable aqueous solutions.
Absorbance should be not more than 0.30 for containers for dry dosage forms for oral administration
B.2] Plastic Additives and Stabilizers

The supplier of the material must be able to provide sufficient compositional information to establish
whether the material meets the specifications for additives and stabilizers.
B.2.1] Vinyl Chloride

Determine by gas chromatography (2.4.13).
Test solution. Place 1.0g of the test material in a 50mL vial, and add 10.0mL of the internal standard
solution. Close the vial, and secure with a stopper. Shake by avoiding contact between the stopper and the
liquid. Place the vial in a water bath at 60±1°C for 2.0 hours.
Internal standard solution. Inject 10µL of ethyl ether into 20.0mL of N,N-dimethylacetamide by
immersing the tip of the needle in the solvent using a microsyringe. Immediately before use, dilute the
solution with N,N-dimethylacetamide to 1000 times its volume.
Vinyl chloride primary solution:
NOTE—Prepare under a ventilated hood.

Place 50mL of N,N-dimethylacetamide in a 50-mL vial, stopper the vial, secure the stopper, and weigh to
the nearest 0.1mg. Fill a 50-mL polyethylene or polypropylene syringe with gaseous vinyl chloride, allow
the gas to remain in contact with the syringe for about 3 min, empty the syringe, and fill again with 50mL
of gaseous vinyl chloride. Fit a hypodermic needle to the syringe, and reduce the volume of gas in the
syringe from 50 to 25mL. Inject the remaining 25mL of vinyl chloride slowly into the vial, shaking gently
26
and avoiding contact between the liquid and the needle. Weigh the vial again; the increase in mass is about
60mg (1µL of the solution obtained contains about 1.2µg of vinyl chloride). Allow to stand for 2 hours.
Store the primary solution in a refrigerator.
Vinyl chloride standard solution.

To one volume of the Vinyl chloride primary solution add three volumes of N,N-dimethylacetamide.
Reference solutions. Place 10.0mL of the Internal standard solution in each of six 50mL vials. Close the
vials, and secure the stoppers. Inject 1, 2, 3, 5, and 10µL, respectively, of the Vinyl chloride standard
solution into five of the vials. The six solutions thus obtained contain, respectively, 0, 0.3, 0.6, 0.9, 1.5, and
3µg of vinyl chloride. Shake, avoiding contact between the stopper and the liquid. Place the vials in a water
bath at 60 ± 1°C for 2 hours.
- a stainless steel column 3m x 3.0mm, packed with with silanized diatomaceous earth for gas
chromatography impregnated with 5% m/m of dimethylstearylamide and 5% m/m of polyethylene
glycol 400
- temperature:
 column. 45°C
 inlet port. 100°C
 detector at 150°C,
- flow rate: 30mL/minute using nitrogen as carrier gas
Inject 1mL of the head space of each vial containing the test solution and the Reference solutions.
Calculate the amount of vinyl chloride in the test solution by comparing the test result of the Sample
solution with the test results of the Reference solutions. Calculate the amount of vinyl chloride in the test
material by dividing the amount of vinyl chloride in the test solution by 1.0g, producing a result in µg/g or
ppm.
Not more than 1ppm. Note that vinyl chloride is not an additive but is monitored as a residual monomer.
B.2.2] Tin in Tin-Stabilized Materials

Reference solution U. 0.081% of Plastic Additive 18 RS prepared in tetrahydrofuran. Dilute 20mL to
100mL with ethanol.
Test solution. In a test tube, add 0.1mL of Solution S2, Add 0.05mL of 1M hydrochloric acid, 0.5mL of
potassium iodide solution, and 5mL of ethanol. Mix thoroughly and wait for 5 min. Add 9mL of water and
0.1mL of a 5-gram/ /L solution of sodium sulphite and mix thoroughly. Add 1.5mL of dithizone solution
freshly diluted 100-fold with methylene chloride, shake for 15 sec and allow to stand for 2 min.
Standard solution. Use 0.1mL of Reference solution U through the same procedure as the 0.1mL
of Solution S2.
Compare the violet colour in the lower layer of the Sample solution to the violet colour in the lower layer
of the Standard solution. The colour in the Sample solution should not be as intense as the colour in
the Standard solution.
Not more than 0.25 weight %.
27
B.2.3] Tin in Non Tin-Stabilized Materials
Test solution. In a test tube, add 0.1mL of Solution S2, Add 0.05mL of 1M hydrochloric acid, 0.5mL of
potassium iodide solution, and 5mL of ethanol. Mix thoroughly and wait for 5 min. Add 9mL of water and
0.1mL of a 5-gram/ /L solution of sodium sulphite and mix thoroughly. If the solution is not colourless, add
the sodium sulphate in 0.05mL fractions Add 1.5mL of dithizone solution freshly diluted 100-fold with
methylene chloride, shake for 15 sec and allow to stand for 2 min.
Standard solution. Use 0.05mL of Reference solution U through the same procedure as the 0.1mL
of Solution S2.
Compare the violet colour in the lower layer of the Sample solution to the violet colour in the lower layer
of the Standard solution. The colour in the Sample solution should not be as intense as the colour in
the Standard solution.
Not more than 25µg/g (ppm).
B.3] Related Substances (Residual Monomers / Residual Solvents)
B.3.1] Chlorine Content

50.0mg of the test material is processed using Oxygen Flask method (2.3.34). Absorb the combustion
products with 20mL of 1M sodium hydroxide. To this, add 2.5mL of nitric acid, 10mL of 0.1M silver
nitrate solution, 5mL of ferric ammonium sulphate solution, and 1mL of dibutyl phthalate. Titrate with
0.005M ammonium thiocyanate solution until a reddish-yellow colour is obtained. Carry out a blank
titration.
Calculate the titration volume by subtracting the volume of titrant used in the blank from the volume of
titrant used in the Preparation. Each mL of 0.005M ammonium thiocyanate is equal to 6.25mg of polyvinyl
chloride. The chlorine content, in weight%, is calculated as follows:
Chlorine content (weight %) = {[titrant volume (in mL) × 6.25 mg/mL]/weight of sample (mg)} × 100%
Not less than 80% by weight, expressed as polyvinyl chloride.

The method used to perform the total organic carbon analyses should have a limit of detection of 0.2mg/L
total organic carbon limit). A linear range with a higher upper concentration can be used if linearity is
analysis.

Instrumentation and methods are those specified in Elemental Impurities (2.3.13A).
Aluminum, arsenic, lead, cadmium, mercury, cobalt, nickel, vanadium, and zinc: Report the measured
value in Solution S3 at values above 0.01mg/L (ppm), corresponding to 0.025µg/g. If the measured values
are below these values, report the result as less than 0.01mg/L (ppm), corresponding to less than 0.025µg/g.
28
Additional acceptance criteria for materials used as containers for non-injectable aqueous solutions.
Barium: Solution S3 contains not more than 0.10mg/L (ppm), corresponding to 2µg/g.
Cadmium: Solution S3 contains not more than 0.03mg/L (ppm), corresponding to 0.6µg/g.
Zinc: Solution S3 contains not more than 5mg/L (ppm), corresponding to 100µg/g.
6.2.1.2.4. Polyvinyl Chloride, Plasticized

absorption spectrum that is substantially equivalent to that of the Polyvinyl Chloride, Plasticized RS.

The thermogram of the specimen is similar to the thermogram of Polyvinyl Chloride, Plasticized RS,
and(Tg) the melting peak temperature obtained from the thermogram of the specimen does not differ from
that of the RS by more than 8.0°. Note that the results of the DSC analysis are strongly dependent on the
amount of plasticizer in the test article.
B] Chemical Tests
Preparation of Special Solutions for subsequent tests on Polyvinyl Chloride

Place 25g of the test material into a borosilicate glass flask. Add 500mL of purified water, cover the flask's
neck with aluminium foil or a borosilicate beaker, and heat in an autoclave at 121 ± 2°C for 20 min. Allow
the solution to cool and the solids to settle, decant the solution into a 500-mL volumetric flask, and dilute
Solution S2 (Tetrahydrofuran extraction)

Dissolve 5.0g of the test material in 80mL of tetrahydrofuran and dilute to a volume of 100mL with the
same solvent. Filter if necessary; the solution may remain opaque. Slowly and drop wise add 70mL ethanol
to 20mL of this solution. Cool the mixture in ice for 1 hours. Filter or centrifuge the mixture, collecting
residue A. Wash residue A with ethanol. Collect the washings and add them to the solution remaining after
filtration or centrifugation. Transfer the solution to a 100mL volumetric flask and dilute to volume with
ethanol. This process produces Solution S2. Prepare a blank solution.

29

Evaporate 100mL of Solution S1 to dryness. Dissolve the resulting residue in 5mL of hexane to produce
the hexane sample. Pass the hexane sample, if necessary, through a filter previously rinsed with hexane.
Determine the spectrum between 250 and 310nm in the hexane sample.

sodium hydroxide required to change the colour of the indicator to blue. To 100mL of Solution S1 add 0.2
mL of Methyl orange solution. Determine the titration volume of 0.01M hydrochloric acid required to
reach the beginning of the colour change of the indicator from yellow to orange.

Determine by thin-layer chromatography (2.4.17), coating the plate with silica gel GF254 (1 mm thick)
Additives are di(2-ethylhexyl) phthalate, N,N″-diacylethylenediamines, epoxidized soya oil, and epoxidized
linseed oil. Vinyl chloride monomer (VCM) is also monitored, although it is a residual monomer and not an
additive.
Mobile Phase. Toluene.
Solution A1. Add 2.0g of the test material to 200mL of peroxide-free ether and heat under a reflux
condenser for 8 hours. Separate the resulting residue B and extraction solution A by filtration. Evaporate
extraction solution A to dryness under reduced pressure in a water bath at 30°C, producing residue C.
Dissolve residue C in 10mL of toluene.
Precipitate B2. Dissolve residue B in 60mL of ethylene chloride heating on a water bath under a reflux
condenser, producing solution D. Filter the resulting solution D. Add the filtered solution D drop wise and
with vigorous shaking to 600mL of heptanes heated almost to boiling. Separate by hot filtration the
coagulum B1 and the organic solution E. Allow solution E to cool; separate the precipitate B2 that forms
upon cooling, and pass through a tared sintered-glass filter (pore size of 16–40µm).
Reference solution (u) 0.01% of Plastic Additive 14 RS prepared in toluene.
Reference solution (v) 0.01% of Plastic Additive 15 RS prepared in toluene.
Reference solution (w) 0.01% of Plastic Additive 16 RS prepared in toluene.
Additive di(2-ethylhexyl) phthalate.

Apply to the plate 0.5mL of solution A to the plate as 30mm × 30mm. Apply 5µL reference solution (u).
Develop the plates over a path of 15cm with toluene. After development, dry the plate in air and examine
under UV light at 254nm. Locate the zone corresponding to additive di(2-ethylhexyl) phthalate, Plastic
Additive 14 RS (Rf about 0.4). Remove the area of silica gel corresponding to this zone, mix with 40mL of
ethyl ether, and shake for 1 min. Filter, rinse filter with two quantities each of 10mL of ethyl ether, add the
rinsing to the filtrate, and evaporate to dryness. The residue weighs not more than 40mg.
Residue is not more than 40 mg
30
Additives epoxidized soya oil and epoxidized linseed oil.
Apply to the plate 0.5mL of solution A to the plate as 30mm × 30mm. Apply 5µL reference solution (v)
and reference solution (w). Develop the plates over a path of 15cm with toluene. After development, dry
the plate in air and expose to iodine vapor for 5 min. locate the zone corresponding to additive epoxidized
soya oil, Plastic Additive 15 RS and epoxidized linseed oil, Plastic Additive 16 RS (Rf 0.0). Remove the
area of silica gel corresponding to this band. Similarly, remove a corresponding area of silica gel as a blank
reference. Separately mix both samples with separate 40mL portions of methanol, shaking for 15 min.
Filter, rinse the filter with two quantities of 10mL of methanol, add the rinsing to the filtrate, and evaporate
to dryness. The difference between the masses of both residues is not more than 10mg.
Epoxidized soya oil : The difference between the masses of both residues is not more than 10mg.
Epoxidized linseed oil: The difference between the masses of both residues is not more than 10mg.

The method used to perform the Total Organic Carbon analyses should have a limit of detection of 0.2
mg/L (ppm) and should have a demonstrated linear dynamic range from 0.2 to 20mg/L (which
encompasses the total organic carbon limit). A linear range with a higher upper concentration can be used if
linearity is established. If sample extracts exceed this upper linear range, they must be diluted appropriately
for analysis.
The difference between the sample and blank Total Organic Carbon concentrations is not more than 5
mg/L.

Arsenic, cadmium, lead, mercury, cobalt, nickel, and vanadium: Report the measured value in Solution
S3 at values above 0.01mg/L (ppm), corresponding to 0.025µg/g. If the measured values are below these
values, report the result as less than 0.01mg/L (ppm), corresponding to less than 0.025µg/g.
Barium: Solution S3 contains not more than 0.25mg/L (ppm), corresponding to 5µg/g.
Calcium: Solution S3 contains not more than 35mg/L (ppm), corresponding to 0.07 weight %.
Tin: Solution S3 contains not more than 1mg/L (ppm), corresponding to 20µg/g.
Zinc: Solution S3 contains not more than 100mg/L (ppm), corresponding to 0.2 weight %.
B.6.1] Vinyl Chloride

Internal standard solution. Using a microsyringe, Inject 10µL of ethyl ether into 20.0mL of N,N-
dimethylacetamide by immersing the tip of the needle in the solvent. Immediately before use, dilute 1.0
volume of the solution to 1000 volumes with N,N-dimethylacetamide.
Test solution. Place 1.0g of the test material in a 50mL vial, and add 10.0mL of the internal standard
solution. Close the vial, and secure with a stopper. Shake, avoiding contact between the stopper and the
liquid. Place the vial in a water bath at 60 ± 1°C for 2 hours.
31
Vinyl chloride primary solution:
Note—Prepare under a ventilated hood.
Place 50mL of N,N-dimethylacetamide in a 50-mL vial, stopper the vial, secure the stopper, and weigh to
the nearest 0.1mg. Fill a 50-mL polyethylene or polypropylene syringe with gaseous vinyl chloride, allow
the gas to remain in contact with the syringe for about 3 min, empty the syringe, and fill again with 50mL
of gaseous vinyl chloride. Fit a hypodermic needle to the syringe, and reduce the volume of gas in the
syringe from 50 to 25mL. Inject the remaining 25mL of vinyl chloride slowly into the vial, shaking gently
and avoiding contact between the liquid and the needle. Weigh the vial again; the increase in mass is about
60mg (1µL of the solution obtained contains about 1.2µg of vinyl chloride). Allow to stand for 2 hours.
Store the primary solution in a refrigerator.
Vinyl chloride standard solution. To one volume of the Vinyl chloride primary solution add three volumes
of N,N-dimethylacetamide.
Reference solutions . Place 10.0mL of the Internal standard solution in each of six 50mL vials. Close the
vials, and secure the stoppers. Inject 1, 2, 3, 5, and 10µL, respectively, of the Vinyl chloride standard
solution into five of the vials. The six solutions thus obtained contain, respectively, 0, 0.3, 0.6, 0.9, 1.5, and
3µg of vinyl chloride. Shake, avoiding contact between the stopper and the liquid. Place the vials in a water
bath at 60 ±1°C for 2 hours.
- a stainless steel column 3.0m x 3.0mm, packed with silanized diatomaceous earth for gas
chromatography impregnated with 5% m/m of dimethylstearylamide and 5% m/m of polyethylene
glycol 400
- temperature:
 column. 45°C
 inlet port. 100°C
 detector at 150°C
- flow rate: 30mL/minute using nitrogen as carrier gas
Inject 1mL of the head space of each vial containing the test solution and the Reference solutions.
Calculate the amount of vinyl chloride in the test solution by comparing the test result of the Sample
solution with the test results of the Reference solutions. Calculate the amount of vinyl chloride in the test
material by dividing the amount of vinyl chloride in the test solution by 1.0g, producing a result in µg/g or
ppm.
Not more than 1ppm.
Note that vinyl chloride is not an additive but is monitored as a residual monomer.
6.2.1.2.5. Polypropylene

absorption spectrum that is substantially equivalent to that of the Homopolymer Polypropylene RS.
32

The melting peak temperature in the thermogram does not differ from that of the Homopolymer
Polypropylene RS by more than 12.0°C
B] Chemical Tests
Preparation of Special Solutions for subsequent tests on Polypropylene

NOTE- Use Solution S1 within 4 hours of preparation.

Place 2.0g of the test material in a 250-mL borosilicate glass flask with a ground-glass neck. Add 80mL of
toluene and boil under a reflux condenser for 1.5 hours, stirring constantly. Allow to cool to 60°C and add

Place 5g in a borosilicate glass flask with a ground-glass neck. Add 100 mL of 0.1M hydrochloric acid, and


of Solution S, add 0.2mL of Methyl orange solution. Determine the titration volume of 0.01M hydrochloric
33
material.

Solvent mixture. Mixture of equal volumes of Acetonitrile and Tetrahydrofuran.
resulting residue with 5.0mL of the Solvent mixture. Prepare a blank solution from the blank solution
to SolutionS2.
Reference solutions of the following reference solutions, prepare only those that are necessary for the
01 RS in the solvent mixture.
the solvent mixture.
methylene chloride
Reference solution (d). A 0.01% of Butylated Hydroxytoluene RS in the solvent mixture
Reference solution (h) A 0.024% of Plastic Additive 03 RS prepared in the solvent mixture
Reference solution (i) A 0.024% of Plastic Additive 04 RS prepared in methylene chloride
Reference solution (j) A 0.024% of Plastic Additive 05 RS prepared in methylene chloride
Test A
microparticles (5 µm),
- mobile phase: a mixture of 70 volumes of a acetronitrile and 30 volumes of water
- flow rate: 2.0 mL/minute,
- spectrophotometer set at 280 nm,
Inject reference solution (a).The test is not valid unless the resolution between the peaks due to additive
34
(d), Reference solution (e), or both. Run the chromatogram for about 30 minutes. The peak areas of Sample
solution S2A are less than the corresponding peak areas of Reference solution (d) or Reference solution (e).
Test B
microparticles (5 µm)
volumes of water
- spectrophotometer set at 280 nm
Test C
hydroxyphenyl)propionate and/or additive tris(2,4-di-tert-butylphenyl) phosphite
- mobile phase: a mixture of 50 volumes of methanol, 40 volumes of 2 propanol and 5.0
volumes of water
35
Inject reference solution (c).The test is not valid unless the resolution between the peaks due to additive
octadecyl-3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate and additive tris(2,4-di-tert-butylphenyl)
B.3.2] Non-Phenolic Antioxidant

Mobile phaseA. Hexane
Sample solution S2C: Evaporate 100mL of Solution S2 to dryness under vacuum at 45°C. Dissolve the
resulting residue with 2mL of methylene chloride acidified.
Reference solution (m). A 0.6% w/v of Plastic Additive 08 RS in methylene chloride. Dilute 2mL of the
solution with Methylene chloride, acidified to 10mL.
Reference solution (n): A 0.6% w/v of Plastic Additive 09 RS in methylene chloride. Dilute 2mL of the
solution with Methylene chloride, acidified to 10mL.
Reference solution (o). A 0.6% w/v of Plastic Additive 10 RS in methylene chloride. Dilute 2mL of the
Reference solution (p). A 0.6% of Plastic Additive 10 RS, and 0.6% of Plastic Additive 09 RS in methylene
plates Over a path of 18 cm with Mobile phase A and over a path of 17cm with Mobile phase B
respectively. After development, dry the plate in air and examine under ultraviolet light at 254nm and spray
with alcoholic iodine solution. The test is not valid unless the chromatogram obtained with reference
solution (p) shows two separate spot. Any spot in the chromatogram obtained with sample solution S2C is
not more intense than the spot in the same position in the chromatogram of the corresponding reference
solution.

Reference solution (t) A 0.2% of Plastic Additive 13 RS prepared in methylene chloride.
36
Test A
dichlorophenol-indophenol sodium in dehydrated alcohol heat in an oven at 120°C for a few minutes to
intensify the spots. Any spot corresponding to additive stearic acid in the chromatogram obtained with
sample solution S2C (Rf = about 0.5) is not more intense than the spot in the same position in the
chromatogram of reference solution (r).
Test B
Mobile phase B. A mixture of 95 volumes of Methylene chloride and 5.0 volumes of methanol.
additive oleamide or erucamide in the chromatogram obtained with sample solution S2C (Rf = about 0.2) is

The method used to perform the Total Organic Carbon analyses should have a limit of detection of 0.2
mg/L (ppm) and should have a demonstrated linear dynamic range from 0.2 to 20mg/L (which
encompasses the total organic carbon limit). A linear range with a higher upper concentration can be used if
linearity is established. If sample extracts exceed this upper linear range, they must be diluted appropriately
for analysis.
The difference between the sample and blank Total Organic Carbon concentrations is not more than 5mg/L.

Aluminum: Solution S3 contains not more than 0.4mg/L (ppm), corresponding to 1µg/g.
Chromium: Solution S3 contains not more than 0.02mg/L (ppm), corresponding to 0.05µg/g.
Titanium: Solution S3 contains not more than 0.4mg/L (ppm), corresponding to 1µg/g.
Zinc: Solution S3 contains not more than 0.4mg/L (ppm), corresponding to 1µg/g.
37
6.2.1.2.6. Cyclic Olefins

absorption spectrum that is substantially equivalent to that of Cyclic Olefin Polymer Reference Standard
(RS) or Cyclic Olefin Copolymer RS. Substantial, as opposed to exact, equivalence allows for minor
spectral differences arising from the natural compositional and/or physical variation among polymers of
this class. Substantial equivalence is achieved when all differences between the sample and RS spectra can
be explained in the context of such natural compositional and/or physical variations.

Given the amorphous nature of these polymers and their compositional variety, material-to-material
variations in the melting peak temperature can be anticipated. Thus, it is neither recommended nor required
that differential scanning calorimetry (DSC) be performed.
B] Chemical Tests
Preparation of Special Solutions for subsequent tests on Cyclic Olefins




38

material.
Solvent mixture. Mixture of equal volumes of Acetonitrile and Tetrahydrofuran.
resulting residue with 5.0mL of the Solvent mixture. Prepare a blank solution from the blank solution
to SolutionS2.
Reference solutions of the following reference solutions; prepare only those that are necessary for the
01 RS in the Solvent mixture.
the Solvent mixture
methylene chloride
Reference solution (d). A 0.01% of Butylated Hydroxytoluene RS in the solvent mixture
Reference solution (h). A 0.024% of Plastic Additive 03 RS prepared in the solvent mixture
Reference solution (i). A 0.024% of Plastic Additive 04 RS prepared in methylene chloride
Reference solution (j). A 0.024% of Plastic Additive 05 RS prepared in methylene chloride
Test A
39
- mobile phase: a mixture of 70 volumes of acetronitrile and 30 volumes of water
Inject reference solution (a).The test is not valid unless the resolution between the peaks due to additive
(d), Reference solution (e), or both. Run the chromatogram for about 30 minutes. The peak areas of Sample
solution S2A are less than the corresponding peak areas of Reference solution (d) or Reference solution (e).
Test B
Chromatographic system Determine by liquid chromatography (2.4.14). Carry out the test as described
in Test A with the following modifications
volumes of water
Test C
hydroxyphenyl)propionate and/or additive tris(2,4-di-tert-butylphenyl) phosphite
Chromatographic system Determine by liquid chromatography (2.4.14). Carry out the test as described
in Test A with the following modifications
40
- mobile phase: a mixture of 50 volumes of methanol, 40 volumes of 2 propanol and 5.0
volumes of water
- flow rate: 1.5mL/minute,
Inject reference solution (c).The test is not valid unless the resolution between the peaks due to additive
octadecyl-3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate and additive tris(2,4-di-tert-butylphenyl)
B.3.2] Non-phenolic Antioxidant

Sample solution S2C: Evaporate 100mL of Solution S2 to dryness under vacuum at 45°C. Dissolve the
resulting residue with 2mL of Methylene chloride acidified.
Reference solution (m). 0.6% w/v of Plastic Additive 08 RS in methylene chloride. Dilute 2mL of the
Reference solution (n): 0.6% w/v of Plastic Additive 09 RS in methylene chloride. Dilute 2mL of the
Reference solution (o). 0.6% w/v of Plastic Additive 10 RS in methylene chloride. Dilute 2mL of the
Reference solution (p). 0.6% of Plastic Additive 10 RS, and 0.6% of Plastic Additive 09 RS in methylene
plates Over a path of 18cm with Mobile phase A and over a path of 17cm with Mobile phase B
respectively. After development, dry the plate in air and examine under ultraviolet light at 254 nm and
spray with alcoholic iodine solution.
The test is not valid unless the chromatogram obtained with reference solution (p) shows two separate spot.
Any spot in the chromatogram obtained with sample solution S2C is not more intense than the spot in the
same position in the chromatogram of the corresponding reference solution.
41
B.3.3] Copolymer of Dimethyl Succinate and (4-Hydroxy-2,2,6,6-tetramethylpiperidin-1-yl) ethanol
Solvent mixture. 89 volume of Hexane and 11 volumes of ethanol.
Sample solution S2D. Evaporate 25mL of Solution S2 to dryness under vacuum at 45°C. Dissolve the
residue with 10mL of toluene and 10mL of a 10% w/v solution of tetrabutylammonium hydroxide in a
mixture of 35 volumes of toluene and 65 volumes of anhydrous ethanol. Boil under a reflux condenser for
3 hours. Allow to cool, and filter.
Reference solution (q). 0.06% w/v of Plastic Additive 11 RS prepared in toluene. Add 1.0mL of this
solution to 25mL of the blank solution corresponding to Solution S2 and evaporate to dryness under
vacuum at 45°C. Prepare a blank solution from the blank solution corresponding to Solution S2. Dissolve
the residue with 10mL of toluene and 10mL of a 10% w/v solution of tetrabutyl ammonium hydroxide in a
mixture of 35 volumes of toluene and 65 volumes of anhydrous ethanol. Boil under a reflux condenser for 3
hours. Allow to cool, and filter.
- a stainless steel column 25cm x 4.6mm, packed with aminopropylsilane bonded to porous
silica microparticles (5µm)
- mobile phase: a mixture of 89 volume of hexane and 11 volumes of ethanol
Inject reference solution (q).The test is not valid unless the resolution between the peaks due to diol
component and the diluents peaks is not less than 7.0.
Inject Sample solution S2D corresponding blank solution and Reference solution (q). Run the
chromatogram for about 30 minutes. The peak areas of diol component in Sample solution S2A are less
than the corresponding peak areas of Reference solution (q).

Test A
dichlorophenol-indophenol sodium in dehydrated alcohol heat in an oven at 120°C for a few minutes to
intensify the spots. Any spot corresponding to additive stearic acid in the chromatogram obtained with
sample solution S2C (Rf = about 0.5) is not more intense than the spot in the same position in the
chromatogram of reference solution (r).
42
Test B
additive oleamide or erucamide in the chromatogram obtained with sample solution S2C (R f = about 0.2) is
B.4] Total Organic Carbon

The method used to perform the Total Organic Carbon analyses should have a limit of detection of
0.2mg/L (ppm) and should have a demonstrated linear dynamic range from 0.2 to 20mg/L (which
encompasses the TOC limit). A linear range with a higher upper concentration can be used if linearity is
analysis.

Aluminium: Solution S3 contains not more than 0.4mg/L (ppm), corresponding to 1µg/g.
Titanium: Solution S3 contains not more than 0.4mg/L (ppm), corresponding to 1µg/g.
Zinc: Solution S3 contains not more than 0.4mg/L (ppm), corresponding to 1µg/g.
6.2.1.2.7. Poly (Ethylene-vinyl Acetate)

absorption spectrum that is substantially equivalent to that of Poly(ethylene-vinyl acetate) RS. Substantial,
as opposed to exact, equivalence allows for minor spectral differences arising from the natural
43
The thermogram of the specimen is similar to the thermogram of Poly(ethylene-vinyl acetate) RS, and the
melting point temperature obtained from the thermogram of the specimen does not differ from that of the
RS by more than 6.0°.
B] Chemical Tests
Preparation of Special Solutions for subsequent tests on Poly(ethylene-vinyl acetate)


120 mL of methanol with continued stirring. Pass the resulting solution through a sintered-glass filter.
Rinse the flask and the filter with 25mL of a mixture of 40 volumes of toluene and 60 volumes of methanol
add the rinsing to the filtrate, and dilute to 250mL with the same mixture of solvents to produce Solution
S2. Prepare a blank solution.

decant the solution into a 100mL volumetric flask, and dilute to volume with 0.1 M hydrochloric acid; the


Not More than 1.0mL of 0.01N hydrochloric acid is required to reach the beginning of the colour change of

material.
44
B.3.1] Phenolic Antioxidants
Solvent mixture: A mixture of equal volumes of acetonitrile and tetrahydrofuran.
Sample solution S2E. Evaporate 50mL of Solution S2 to dryness under vacuum at 45°C. Dissolve the
resulting residue with 5.0 mL of the Solvent mixture. Prepare a blank solution from the blank solution
Sample solution S2F. Evaporate 50mL of Solution S2 to dryness under vacuum at 45°C. Dissolve the
to Solution S2.
Reference solution (k). A 0.01% of Butylated Hydroxytoluene RS, 0.016% of Plastic Additive 02 RS,
0.016% of Plastic Additive 03 RS, and 0.016% of Plastic Additive 04 RS in the solvent mixture.
Reference solution (l). A 0.016% of Plastic Additive 04 RS and 0.016% of Plastic Additive 05 RS in
methylene chloride
Note: Of the following reference solutions, prepare only those that are necessary for the analysis of the
phenolic antioxidants stated in the composition of the substance to be examined
Test A
- mobile phase: a mixture of 70 volumes of tetrahydrofuran, 60 volumes of acetronitrile, and 10
volumes of water
- flow rate: 1.5 mL/minute
Inject reference solution (k).The test is not valid unless the resolution between the peaks due to Plastic
Additive 02 RS and Plastic Additive 03 RS peaks is not less than 2.0 and the column efficiency is not less
than 2500 theoretical plates calculated for Butylated Hydroxytoluene RS.
Inject Sample solution 12 corresponding blank solution, Reference solution (k), Run the chromatogram for
about 30 minutes. The peak areas of Sample solution 12 are less than the corresponding peak areas of
reference solution (k).
Note: Sample solution S2E shows only peaks caused by antioxidants stated in the reference solution (k) and
minor peaks that also correspond to the blank solution.
Test B
If the chromatogram obtained via Test A for Test solution S2E shows a peak with the same retention time
as the last antioxidant eluted from Reference solution K.
45
- mobile phase: a mixture of 45 volumes of 2 propanol 50 volumes of methanol and 5.0 volumes of
water
Inject reference solution (l). The test is not valid unless the resolution between the peaks due to Plastic
Additive 04 RS and Plastic Additive 05 RS peaks is not less than 2.0.
Inject Sample solution S2F corresponding blank solution, Reference solution (l). The peak areas of Sample
solution S2F are less than the corresponding peak areas of Reference solution (l).
Note: Sample solution 13 shows only peaks caused by antioxidants stated in the reference solution (l) and
minor peaks that also correspond to the blank solution.
B.3.2] Amides and Stearic Acid

Sample solution S2G: Evaporate 100mL of Solution S2 to dryness under vacuum at 45°C. Dissolve the
resulting residue with 2.0mL of acidified methylene chloride.
Reference solution (r) A 0.2% of Stearic Acid RS prepared in methylene
Reference solution (s) A 0.08% of Plastic Additive 12 RS prepared in methylene chloride
Test A
Mobile phase. a mixture of 75 volume of trimethylpantane and 25 volumes of ethanol.
Apply to the plate 10µL of sample solution S2G, reference solution (r). Develop the plates over a path of
10 cm with mobile phase. After development, dry the plate in air and examine by spray with 2.0 % w/v 2,
6-dichlorophenol-indophenol sodium in dehydrated alcohol and heat in an oven at 120°C for a few minutes
to intensify the spots. Any spot corresponding to additive stearic acid in the chromatogram obtained with
sample solution S2G is not more intense than the spot in the same position in the chromatogram of the
corresponding reference solution (r).
Test B
Apply to the plate 10µL of sample solution S2G, reference solution (s) and reference solution (t). Develop
additive oleamide or erucamide in the chromatogram obtained with sample solution S2G is not more
intense than the spot in the same position in the chromatogram of reference solution (s) and reference
solution (t).
46
B.4.1] Vinyl Acetate

Test solution: Place 0.25 to1.0g of the test material into a 300mL conical flask containing a magnetic
stirrer. Prepare an extraction blank starting with an otherwise empty 300mL conical flask. Add 40mL of
xylene and boil under a reflux condenser with stirring for 4 hours. After heating, continue stirring, allowing
the solution to cool to the point that precipitation starts. Slowly add 25mL of alcoholic potassium
hydroxide. Boil again under a reflux condenser for 3 hours with continued stirring. While stirring, allow the
solution to cool, rinse the condenser with 50mL of water and add 30 mL of 0.05M sulphuric acid to the
flask. Transfer the contents of the flask to a 400-mL beaker, rinsing the flask with the following:
2.0 quantities, 50mL each, of a 200gram/ /L solution of anhydrous sodium sulphate
3.0 quantities, 20mL each, of water
Add the rinsings to the flask.
Titrate the excess sulphuric acid in Test solution with 0.1M sodium hydroxide, determining the endpoint
potentiometrically (2.4.25). Carry out a titration of the extraction blank.
Determine the amount of titrant (mL) required by subtracting the titrant volume used for the extraction
blank (mL) from the titrant volume used for the extract (mL). Determine the amount of vinyl acetate by
multiplying the volume of titrant required by the quantity 8.609mg/mL. The content of vinyl acetate is
calculated as:
Content of vinyl acetate (weight%) = [amount of vinyl acetate (mg)/weight of material extracted (g)]/10.
Content of vinyl acetate
For containers: Not more than 25% by weight
For tubing: Not more than 30% by weight

The method used to perform the Total Organic Carbon analyses should have a limit of detection of 0.2mg/L
TOC limit). A linear range with a higher upper concentration can be used if linearity is established. If
sample extracts exceed this upper linear range, they must be diluted appropriately for analysis.

All metals: Report the measured value in Solution S3 at values above 0.01mg/L (ppm), corresponding to
0.025µg/g. If the measured values are below these values, report the result as less than 0.01mg/L (ppm),
corresponding to less than 0.025µg/g.
47
6.2.1.2.8. Polycarbonate

Determine the infrared spectrum from 3800 cm−1 to 600 cm−1 (2.6–16 µm). The specimen exhibits an
absorption spectrum that is substantially equivalent to that of the Polycarbonate RS. Substantial, as opposed
to exact, equivalence allows for minor spectral differences arising from the natural compositional and/or
physical variation among polymers of this class. Substantial equivalence is achieved when all differences
between the sample and RS spectra can be explained in the context of such natural compositional and/or
physical variations.

The thermogram of the specimen is similar to the thermogram of Polycarbonate RS, and the melting peak
temperature obtained from the thermogram of the specimen does not differ from that of the RS by more
than 8.0°. Note that the results of the DSC analysis are strongly dependent on the amount of plasticizer in
the test article.
B] Chemical Tests
Preparation of Special Solutions for subsequent tests on Polycarbonate



Determine the spectrum between 220 and 340nm in Solution S1
Absorbance should be not more than 0.20

48
Not more than 1.5mL of 0.01M hydrochloric acid is required to reach the beginning of the colour change of
B.3.1] Residual Solvents

By Head Space Gas Chromatography (2.4.13):
Test solution. Weigh 1.0g of the test material and place it in a 20-mL headspace vial. Add 10mL of N, N,-
dimethylformamide, cap the vial closed, and sonicate for 4 hours. Cool to room temperature. Prepare a
sample blank in a similar fashion.
Residual solvents primary solution. Weigh 500mg each of dichloromethane, toluene, and ethylbenzene and
1250mg of chlorobenzene into a 50mL volumetric flask; dissolve and adjust with N,N,-dimethylformamide
to volume.
Residual solvents stock solution. Transfer 5mL of the Residual solvents primary solution into a 100mL
volumetric flask; adjust with N, N-dimethylformamide to volume.
Reference solutions. Pipet 0, 2, 3, 4, 5, and 6mL of the Residual solvents stock solution into individual
100mL volumetric flasks, dilute with N-N-dimethylformamide to volume and mix well. The six reference
standards thus obtained (Reference solution blank and WS1 through WS5) contain, respectively, 0, 10, 15,
20, 25, and 30mg / /L of dichloromethane, toluene, and ethylbenzene and 0, 37.5, 50, 62.5, and 75mg/ /L of
chlorobenzene.
- a capillary column 30m × 0.32mm, packed with 100% bonded and cross linked polyethylene
glycol (5µm)
- temperature:
 column: Start at 50°C, hold for 20 min. Heat to 165°C at 6°C/min, hold for 20 min
 inlet port.140 °C
 detector 250°C
- flame ionization detector
- flow rate. adjust to provide a constant pressure of 10 psi, using Helium as carrier gas
- Injection volume: 1µL, split
Head space conditions
Temperatures
- Thermostating: 115°C
- Needle: 110°C
- Transfer: 120°C
- Thermostating, 60 min
- Pressurization, 0.5 min
- Injection, 0.1 min
- Withdrawal, 0.2 min
- Carrier gas pressure, 20 psi
Conditioning. Inject the reference solution blank three times into the chromatographic system.
49
Inject reference solution WS3 five times into the chromatographic system. The test is not valid unless, the
relative standard deviation of the peak areas in the chromatogram obtained with reference solution WS3 for
is not less than 5.0%. The symmetry factor for the caprolactam peak obtained for the third injection must be
between 0.8 and 1.3.
Rinsing. Inject the Reference solution blank once.
Calibration, front of bracket. Inject each of the five Reference solutions once. Construct a linear calibration
curve of the peak areas obtained for the Reference solutions versus their analyte concentrations for each
analyte. The correlation coefficient (r2) obtained for the best-fit linear regression line must be not less than
0.99.
Rinsing. Inject the Reference solution blank once.
Sample. Inject each test solution once, including the blank. Inject not more than six test solutions.
Rinsing: Inject Reference solution blank once.
Calibration, back of bracket: Inject each of the five Reference solutions once.
Calculations: Construct a linear calibration curve of the peak areas obtained for the Reference
solutions versus their analyte concentrations (using the front and back of the bracket). The correlation
coefficient (r2) obtained for the best-fit linear regression line must be not more than 0.99. Calculate the
amount of each analyte in the test solution by putting the peak area obtained for the test solution into the
calibration curve.
Calculate the amount of each in the test material by multiplying this result by a factor of 10 and dividing
the product by the weight of the test material in g, producing a result in µg/g.
Analyte (µg/g) = (Analyte in Sample solution (mg/L) × 10) ÷ weight of test material, g.
B.3.1] Bisphenol A
[NOTE—Bisphenol A is monitored although it is a residual monomer and not an additive.]
Test solution. Weigh 1.0g of the test material and place it in a 250mL round-bottom flask. Add 50mL of
methylene chloride and heat at 50°C for 1.0 hours under a reflux condenser to dissolve the test material.
Cool the solution to room temperature and slowly add 75mL of methanol to the room-temperature solution,
with continuous stirring. Place in a refrigerator for 2 hours to cool the resulting solution. Filter the cooled
solution through a sintered-glass filter. Wash the round-bottom flask and the filter twice with 15mL of
methanol. Evaporate the filtrate to dryness under vacuum at 45°C. Dissolve the residue in 5mL of
methylene chloride. Add 0.5mL of this solution and 0.5mL of N,O-bis(trimethylsilyl)trifluoroacetamide to
a 1.5-mL vial and close the vial immediately. Heat the closed vial at 40°C for 2 hours and then cool to
room temperature. Prepare a sample blank in a similar fashion.
Bisphenol A primary solution. Weigh 20mg of Bisphenol A RS in a 200mL volumetric flask; dissolve and
dilute with methylene chloride to volume.
Reference solutions. Pipet 0, 5, 10, 20, 30, and 40mL of the Bisphenol A primary solution into six 100mL
volumetric flasks. Dilute with methylene chloride to volume and mix well. The six reference standards thus
obtained (Reference solution blank and WS1 through WS5) contain, respectively, 0, 5, 10, 20, 30, and 40
mg/ /L of Bisphenol A.
Add 0.5mL each of the Reference solutions and 0.5mL of N,O-bis(trimethylsilyl)trifluoroacetamide to
separate 1.5-mL vials and close the vials immediately. Heat the closed vials at 40°C for 2 hours and then
cool to room temperature.
50
- a capillary column 25m × 0.25mm, packed with 100% dimethylpolysilxane (0.25µm)
- temperature:
 column: 250°C
 inlet port
 detector 300 °C
- flow rate: adjust to provide a constant pressure of 13 psi, using Helium as carrier gas
- Injection volume: 2µL, split
Head space conditions
Temperatures
- Thermostating: 115°C
- Needle: 110°C
- Transfer: 120°C
- Thermostating, 60 min
- Pressurization, 0.5 min
- Injection, 0.1 min
- Withdrawal, 0.2 min
- Carrier gas pressure, 20 psi
Conditioning. Inject the reference solution blank three times into the chromatographic system.
Inject reference solution WS3 five times into the chromatographic system. The test is not valid unless, the
is not less than 5.0%.
Rinsing: Inject the Reference solution blank twice.
Calibration, front of bracket: Inject each of the five Reference solutions once. Construct a linear calibration
curve of the peak areas obtained for the Reference solutions versus their bisphenol A concentrations. The
correlation coefficient (r2) obtained for the best-fit linear regression line must be not less than 0.98.
Rinsing: Inject the Reference solution blank once.
Sample: Inject each test solution once, including the Sample blank. Inject not more than six test solutions.
Rinsing: Inject the Reference solution blank once
Calibration, back of bracket: Inject each of the five Reference solutions once.
Calculations: Construct a linear calibration curve of the peak areas obtained for the Reference
solutions versus their bisphenol A concentrations (front and back of bracket). The correlation coefficient
(r2) obtained for the best-fit linear regression line must be not less than 0.98. Calculate the amount of
bisphenol A in the Sample solution by putting the peak area obtained for the Sample solution into the
calibration curve.
Calculate the amount of bisphenol A in the test material by multiplying this result by a factor of five and
dividing the product by the weight of the test material in g, producing a result in µg/ /g,
Bisphenol A (µg/ /g) = (Bisphenol A in test solution (mg/ /L) × 5) ÷ weight of test material
Not more than 100µg/g.
51
The method used to perform the TOC analyses should have a limit of detection of 0.2mg/L (ppm) and
should have a demonstrated linear dynamic range from 0.2 to 20mg/L (which encompasses the TOC limit).
A linear range with a higher upper concentration can be used if linearity is established. If sample extracts
exceed this upper linear range, they must be diluted appropriately for analysis.
The difference between the sample and blank Total Organic Carbon concentrations is not more than 5
mg/L.

Arsenic, lead, cadmium, mercury, cobalt, nickel, and vanadium: Report the measured value in Solution
values, report the result as less than 0.01mg/L (ppm), corresponding to less than 0.025µg/g. Additional
acceptance criteria for certain metals are provided as follows.
6.2.1.2.9. Polyamide 6

Determine the infrared spectrum from 3800cm−1 to 600cm−1 (2.6–16µm). The specimen exhibits an
absorption spectrum that is substantially equivalent to that of the Polyamide 6 RS. Substantial, as opposed
to exact, equivalence allows for minor spectral differences arising from the natural compositional and/or
physical variation among polymers of this class. Substantial equivalence is achieved when all differences
between the sample and RS spectra can be explained in the context of such natural compositional and/or
physical variations.

The thermogram of the specimen is similar to the thermogram of Polyamide 6 RS, and the melting peak
temperature obtained from the thermogram of the specimen does not differ from that of the RS by more
than 8.0°. Note that the results of the DSC analysis are strongly dependent on the amount of plasticizer in
the test article.
B] Chemical Tests
Preparation of Special Solutions for subsequent tests on Polyamide 6

52
with purified water to volume; the diluted solution is Solution S1. Use Solution S1 within 4 hours of
preparation.

Place 5 g in a borosilicate glass flask with a ground-glass neck. Add 100mL of 0.1M hydrochloric acid, and
Solution S3 (Phenol extraction)

Dissolve 1.0g of the test material in 50mL of phenol by heating at 50°C for 4 hours with constant stirring.
This process produces Solution S3. Prepare a blank solution.

Determine the spectrum between 220 and 340 nm in Solution S1.
Absorbance should be not more than 0.25

To 100 mL of Solution S1 add 0.15 mL of BRP indicator solution. Determine the titration volume of 0.01
M sodium hydroxide required to change the colour of the indicator to blue. To a separate, 100mL portion
B.3] Free Base Functions
Perchloric acid in 70% phenol. Dissolve approximately 0.72g (target 0.710–0.7250g) of perchloric acid
in 50mL of phenol.
Titrate 50mL of solution S3 with Perchloric acid in 70% phenol, determining the end-point
potentiometrically (2.4.25). Carry out a blank titration using phenol as extraction blank.
The difference between the titration volumes, extract versus extraction blank, is not more than 0.4mL.
B.4.1] Caprolactam.
Determine by gas chromatography (2.4.13).
Test Solution. Dissolve 1.0g of the test substance in sufficient quantity of formic acid. Dilute to 10mL with
same solvent.
Caprolactam primary solution. Dissolve 125mg of Caprolactam RS in formic acid and dilute to 50mL
with same solvent.
Reference solutions. Pipet 0, 2, 4, 6, 8, and 10mL of the Caprolactam primary solution into six 20mL
volumetric flasks. Dilute with anhydrous formic acid to volume. The six reference standards thus obtained
53
(blank and WS1 through WS5) contain, respectively, 0, 250, 500, 750, 1000, and 1250 mg/ /L of
caprolactam.
- a capillary column 2m × 4mm, packed with silanized diatomaceous earth for gas chromatography
impregnated with 10% m/m of polyethylene glycol 20000
- temperature:
 column. 170 °C
 inlet port.
 detector 250 °C
- flow rate 25mL/min. using Helium as carrier gas
Conditioning. Inject 1µL of the Reference solution blank three times into the chromatographic system.
Inject Reference solution WS4 five times into the chromatographic system. The test is not valid unless, the
is not less than 5%. The symmetry factor for the caprolactam peak obtained for the third injection must be
between 0.8 and 1.3.
Rinsing. Inject 1µL Reference solution blank once.
Calibration, front of bracket: Inject each of the five Reference solutions once. Construct a linear calibration
curve of the peak areas obtained for the Reference solutions versus their caprolactam concentrations. The
correlation coefficient (r2) obtained for the best-fit linear regression line must be not less than 0.98.
Rinsing. Inject 1µL the Reference solution blank once.
Sample. Inject 1µL each test solution once. Inject not more than six test solutions.
Rinsing. Inject 1µL Reference solution blank once.
Calibration, back of bracket. Inject 1µLeach of the five Reference solutions once.
Construct a linear calibration curve of the peak areas obtained for the Reference solutions versus their
caprolactam concentrations (both front and back of bracket). The correlation coefficient (r2) obtained for
the best-fit linear regression line must be not less than 0.98. Calculate the amount of caprolactam in the test
solution by putting the peak area obtained for the test solution into the calibration curve. Calculate the
amount of caprolactam in the test material by multiplying this result by a factor of 10 and dividing the
product by the weight of the test material in g, producing a result in weight %.
Not more than1%.

The method used to perform the Total Organic Carbon analyses should have a limit of detection of
0.2mg/L (ppm) and should have a demonstrated linear dynamic range from 0.2 to 20mg/L (which
encompasses the Total Organic Carbon limit). A linear range with a higher upper concentration can be
used if linearity is established. If sample extracts exceed this upper linear range, they must be diluted
appropriately for analysis.
54
Arsenic, lead, cadmium, mercury, cobalt, nickel, and vanadium: Report the measured value in Solution
values, report the result as less than 0.01mg/L (ppm), corresponding to less than 0.025µg/g. Additional
acceptance criteria for certain metals are provided as follows.
6.2.1.3. Plastic Containers for Ophthalmic Preparations

Plastic containers for ophthalmic preparations are made from plastic composed of a mixture of homologous
compounds having a range of molecular weights. Such plastics frequently contain other substances such as residues
from the polymerisation process, plasticisers, stabilisers, antioxidants, lubricants and pigments. For deciding the
suitability of a plastic for use as a container for opthalmic preparations, factors such as the composition of the
plastic, processing and cleaning procedures, contacting media, adhesives, adsorption and permeability of
preservatives, conditions of storage, etc. should be evaluated by appropriate additional specific tests.
Plastic containers for ophthalmic preparations comply with the following tests.
Leakage test; Collapsibility test. Comply with the tests described under Plastic Containers for Parenteral
Preparations (6.2.1.1).
Clarity of aqueous extract; Non-volatile residue. Comply with the tests described under Plastic Containers for
Non- Parenteral Preparations (6.2.1.2.).
Eye irritation test. This test is designed to evaluate responses to the instillation of extracts of material under
examination in the eye of a rabbit.
Extracting media– (a) Sodium Chloride Injection (b) Vegetable Oil.
Test animals. Select healthy, albino rabbits having no visible eye irritation and not previously used for an eye
irritation test. The animal house should be designed and maintained so as to exclude sawdust, wood chips, or other
extraneous materials that might produce eye irritation. Examine both eyes of the animals before testing and use only
those animals without eye defects or eye irritations.
To test the suitability of the rabbit ocular system in use for a given set of samples, select one test animal and proceed
as shown under procedure using 100µL of a blank prepared as directed under Systemic injection test in one eye and
100µL of sterile water for injection in the other eye. The rabbit ocular system is suitable if no significant differences
are found between the two eyes.
Procedure. Use three albino rabbits for each extract to be examined. Restrain the animals firmly but gently until
quiet. Gently pull the lower lid away from the eyeball to form a cup, and instil about 100µL of sterile water for
injection. Hold the lid together for about 30 seconds. Instil in to the other eye 100µL of the sample extract prepared
as directed underSystemicinjection test. Examine the eyes 24, 48 and 72 hours after instillation. The requirements of
the test are met if the sample extract shows no significant irritant response during the observation period over that
with the blank extract and the rabbit ocular system is suitable. If irritation is observed in the control eyes treated with
sterile water for injection or if the rabbit ocular system is shown not to be suitable, repeat the test using three
additional rabbits. In the repeat test, all the rabbits meet the test requirement.
55
Biological Tests. Perform the test for Biological Reactivity, In Vitro (2.2.23). Materials that meet the requirements
of this test are not required to undergo testing as described in test for Biological Reactivity, In Vivo (2.2.24).
6.2.2. Glass Containers

Glass containers may be colourless or coloured.
Neutral glass is a borosilicate glass containing significant amounts of boric oxide, aluminium oxide, alkali and/or
alkaline earth oxides. It has a high hydrolytic resistance and a high thermal shock resistance.
Soda-lime-silica glass is a silica glass containing alkali metal oxides, mainly sodium oxide and alkaline earth oxides,
mainly calcium oxide. It has only a moderate hydrolytic resistance.
According to their hydrolytic resistance, glass containers are classified as:
– Type I glass containers which are of neutral glass, with a high hydrolytic resistance, suitable for most
preparations whether or not for parenteral use,
– Type II glass containers which are usually of soda-lime-silica glass with high hydrolytic resistance resulting
from suitable treatment of the surface. They are suitable for most acidic and neutral, aqueous preparations
whether or not for parenteral use,
– Type III glass containers which are usually of soda-lime-silica glass with only moderate hydrolytic resistance.
They are generally suitable for non-aqueous preparations for parenteral use, for powders for parenteral use
(except for freeze-dried preparations) and for preparations not for parenteral use.
Glass containers intended for parenteral preparations may be ampoules, vials or bottles. The glass used in the
manufacture of such containers complies with one of the requirements for hydrolytic resistance given below.
Containers of Type II or Type III glass should be used once only. Containers for human blood and blood
components must not be re-used. Glass containers with a hydrolytic resistance higher than that recommended for a
particular type of preparation may generally also be used.
Containers for parenteral preparations are made from uncoloured glass except that coloured glass may be used for
substances known to be light - sensitive; in such cases, the containers should be sufficiently transparent to permit
visual inspection of the contents.
Hydrolytic resistance
The tests to be done for defining the type of glass are given in Table 2.
Table 2
Type of container Test to be done
Type I and Type II glass containers Test 1 (surface test)
to distinguish from Type III glass
containers
Type I and Type II glass containers Tests 1 and 2
where it is necessary to determine
whether the high hydrolytic resistance
is due to the chemical composition
or the surface treatment
Test 1. Carry out the determination on the unused containers. The number of containers to be examined and the
volumes of test solution to be used are given in Table 3.
56
Table 3
Nominal capacity Number of containers Volume of test
of container (mL) to be used solution to be used
for titration (mL)
Up to 3 At least 20 25.0
5 or less At least 10 50.0
6 to 30 At least 5 50.0
More than 30 At least 3 100.0
Remove any debris or dust from the containers. Rinse each container at least twice with water at room temperature.
Just before the test rinse each container with freshly prepared distilled water and allow to drain. Complete the
cleaning procedure from the first rinsing in not less than 20 minutes and not more than 25 minutes. Fill the
containers to the brim with freshly prepared distilled water, empty them and determine the average overflow
volume.
Heat closed ampoules on a water-bath or in an air-oven at about 50°C.Fill the ampoules with freshly prepared
distilled water to the maximum volume compatible with sealing them by fusion of the glass and seal them. Fill
bottles or vials to 90% of their calculated overflow volume and cover them with borosilicate glass dishes or
aluminium foil previously rinsed with freshly prepared distilled water. Place the containers in an autoclave
containing water so that they remain clear of the water. Close the autoclave, displace the air by passage of steam for
10 minutes, raise the temperature from 100°C to 121°C over 20 minutes, maintain a temperature of 121°C for 60
minutes and reduce the temperature from 121°C to 100°C over 40 minutes, venting to prevent vacuum.
Remove the containers from the autoclave and cool them in a bath of running tap water. Carry out the following
titration within 1 hour of removing the containers from the autoclave. Combine the liquids from the containers under
examination, measure the volume of test solution specified in Table 2 into a conical flask and add 0.15mL of methyl
red solution for each 50mL of liquid. Titrate with 0.01M hydrochloric acid taking as the end-point the colour
obtained by repeating the operation using the same volume of freshly prepared distilled water. The difference
between the preparations represents the volume of 0.01M hydrochloric acid required by the test solution. Calculate
the volume of 0.01M hydrochloric acid required for each 100mL of test solution, if necessary. The result is not
greater than the value stated in Table 4.
Table 4
Capacity of container Volume of 0.01M
[corresponding to 90% hydrochloric acid /100mL of
average overflow test solution
volume (mL)]
Type I or Type
II glass III glass
(mL) (mL)
Not more than 1 2.0 20.0
More than 1 but not more than 2 1.8 17.6
More than 500 0.20 2.2
57
Test 2. Examine the number of containers indicated in Table 2. Rinse the containers twice with water and then fill
completely with a 4% v/v solution of hydrofluoric acid and allow to stand at room temperature for 10 minutes.
Empty the containers and rinse carefully five times with water. Carry out the procedure described under Hydrolytic
resistance. Compare the results with the limiting values given in Table 3. For Type I glass the values obtained with
the hydrofluoric acid-treated containers are closely similar to those stated in the Table for Type I or Type II glass.
For Type II glass the values obtained with the hydrofluoric acid-treated containers greatly exceed those given in the
Table for Type I or Type II glass and are similar to those given for Type III glass.
Arsenic. Glass containers for aqueous parenteral preparations should comply with the following test. Carry out the
test on ampoules the inner and outer surfaces of which are washed five times with freshly distilled water.
Prepare a test solution as described in the test for Hydrolytic resistance for an adequate number of containers to
produce 50mL. Pipette 10mL of the test solution from the combined contents of all the containers into a flask, add
10mL of nitric acid and evaporate to dryness on a water-bath. Dry the residue in an oven at 130°C for 30 minutes.
Cool, add to the residue10.0mL of hydrazine-molybdate reagent, swirl to dissolve and heat under reflux on a water-
bath for 20 minutes. Cool to room temperature. Determine the absorbance of the resulting solution at the maximum
at about 840nm (2.4.7), using 10.0mL of hydrazine-molybdate reagent as the blank. The absorbance of the test
solution does not exceed the absorbance obtained by repeating the determination using 0.1mL of arsenic standard
solution (10ppm As) in place of the test solution (0.1ppm).
6.2.3. Metal Containers
Collapsible Metal Tubes for Ophthalmic Ointments-Metal collapsible tubes comply with the following test for
metal particles.
Select a sample of 50 tubes from the lot to be tested and clean each tube by vibration and/or “blowing”. (A lot may
be either the tube manufacturer’s day’s production or a consignment delivered to the tube user). Fill the tubes with a
suitable molten eye ointment base, close the open end of each tube by a double fold and allow the filled tubes to cool
overnight at a temperature of 15°C to 20°C.
Assemble a metal bacteriological filter with a 4.25-cm filter paper of suitable porosity supported on suitable
perforated plate in place of the standard sintered carbon disc and heat it in a suitable manner to a temperature above
the melting range of the base. Remove the caps from the cooled tubes and apply uniform pressure to the closed
end of each tube in turn, in such a manner that the time taken to express as much of the base as possible through
each nozzle is not less than 20 seconds. Collect the extruded base from the 50 tubes in the heated filter, applying
suction to the stem of the filter in order to draw the molten base through the filter paper. When the entire melted
base has been removed, wash the walls of the filter and the filter paper with three successive quantities, each of
30mL, of chloroform, allow the filter paper to dry and immediately mount it between glasses for examination.
Examine the filter paper under oblique lighting with the aid of magnifying glass with a graticule of 1mm squares,
one of which is sub-divided into 0.2mm squares and note (a) the number of all metal particles 1mm in length and
longer, (b) the number in the range 0.5mm to less than 1mm and (c) the number in the range 0.2mm to less than 0.5
mm.
Carry out two further examinations with the filter paper in two different positions so that the lighting comes from
different directions and calculate the average number of metal particles counted in each of the three ranges specified.
Give each metal particle detected on the filter paper a score as follows and add the scores together.
58
Particles 1 mm and above 50
Particles 0.5 mm but less than 1 mm 10
Particles 0.2 mm but less than 0.5 mm 2
Particles less than 0.2 mm Nil
The lot of tubes passes the test if the total score is less than 100 points; if the total score is more than 150 points, the
lot fails the test. If the total score is between 100 and 150 (inclusive), the test is repeated on a further sample of 50
tubes and the lot passes the test if the sum of total scores in the two tests is less than 150 points.
6.3. CLOSURES FOR CONTAINERS

A closure for a container for an aqueous parenteral preparation or for a sterile powder is a packaging component
which is in direct contact with the drug. A rubber closure is made of materials obtained by vulcanisation (cross-
linking) of elastomers with appropriate additives. The elastomers are produced from natural or synthetic substances
by polymerization - polyaddition or polycondensation. The nature of the principal components and of the various
additives such as vulcanisers, accelerators, stabilising agents, pigments, etc. depends on the properties required for
the finished closure. The requirements of this chapter do not apply to closures made from silicone elastomer, to
laminated closures or to lacquered closures.
Rubber closures are used in a number of formulations and consequently different closures possess different
properties.
NOTE 9: Closures made from plastics will be governed by all requirements covered in 6.2.1. and its subsections.
The closures chosen for use with a particular preparation should be such that the components of the preparation in
contact with the closure are not adsorbed onto the surface of the closure to an extent sufficient to affect the product
adversely. The closure should not yield to the product substances in quantities sufficient to affect its stability or to
present a risk of toxicity. The closures should be compatible with the preparation for which they are used throughout
the shelf-life of the product.
It shall be the responsibility of the user/manufacturer to ensure the compatibility of the pharmaceutical products and
stability of the product in the package system. Towards this the user / manufacturer shall have in place a system of
quality assurance with the supplier / convertor to ensure compliance of the components of the package with the
requirement stated in this chapter at all times. The user should take the “risk-based approach” to determine the
testing and its frequency required to ensure this.
The following test procedures apply to rubber closures which comprise wads (flat rubber discs), plugs (with or
without skirt or flange) and caps (rubber covers held in position on the outsides of the containers by the tension of
the rubber) so as to form with their appropriate seals an effective barrier against micro-organisms after sterilisation.
Identification of the type of rubber used for closures is not covered in the following tests. The tests given distinguish
elastomer and non-elastomer closures but do not differentiate the various types of rubber.
Description. Rubber closures are elastic and either translucent or opaque; the colour depends on the additives used.
They are homogeneous and practically free from flash and adventitious materials such as fibres, foreign particles
and adhering rubber pieces.
Identification
A. Heat 1g to 2g in a heat-resistant test-tube over an open flame to dry the sample and continue heating until the
vapours formed are condensed near the top edge of the test-tube. Deposit a few drops of the condensate on a
59
potassium bromide disc and examine by infrared absorption spectrophotometry (2.4.6), comparing with the
spectrum obtained with the type (standard) sample.
B. The total ash (2.3.19) is within ±10% of the value obtained with the type sample (specimen).
Preparation of samples. Wash the closures by agitation in a 0.2% w/v solution of an anionic surface-active agent
for 5 minutes at room temperature. Rinse five times with water, place a number of the washed closures
corresponding to a surface area of about 100cm2, in a suitable container of borosilicate glass or inert material, and
add 200mL of water/100 cm2, surface area of the closures and weigh. Cover the mouth of the container with
aluminium foil or a borosilicate glass beaker and heat in an autoclave so that a temperature of 119°C to 123°C is
reached within 20 to 30 minutes and maintain at that temperature for 30 minutes. Cool to room temperature over
about 30 minutes and make up to the original weight with water for injection. Shake and immediately separate the
solution from the closures by decantation (Solution A).
Prepare a blank in the same manner using 200mL of water for injection.
Dry the treated closures at 64°C to 66°C at a pressure not exceeding 0.7 kPa for 24 hours.
Appearance of solution. Solution A is not more opalescent than opalescence standard OS3 (2.4.1), and not more
intensely coloured than reference solution BYS6 (2.4.1).
Acidity or alkalinity. To 20mL of solution A add 0.1mL of bromothymol blue solution. Not more than 0.3mL of
0.01M sodium hydroxide or 0.8mL of 0.01M hydrochloric acid is required to change the colour of the solution to
blue or yellow respectively.
Light absorption. Carry out the test within 4 hours of preparing solution A. Filter solution A through a membrane
filter with a nominal pore size of 0.5µm and reject the first few mL of the filtrate. Measure the light absorption of
the filtrate in the range 220 to 360nm (2.4.7), using as the blank a solution prepared in the same manner as solution
A but using 200mL of water without the closures. The absorbance is not more than 2.0; if necessary, dilute the
filtrate before measurement and correct the results for the dilution.
Reducing substances. Carry out the test within 4 hours of preparing solution A. To 20mL of solution A, add 1mL
of 1M sulphuric acid and 20mL of 0.002 M potassium permanganate and boil for 3 minutes. Cool, add 1g of
potassium iodide and titrate immediately with 0.01 M sodium thiosulphate using 0.25mL of starch solution, added
towards the end of the titration, as indicator. Repeat the operation using 20 mL of the blank prepared in the test for
Light absorption. The difference between the titration volumes is not more than 7.0mL.
Heavy Metals (2.3.13). 20mL of solution A complies with the limit test for heavy metals, Method A.
Residue on evaporation. Evaporate 50mL of solution A to dryness on a water-bath and dry at 105°C. The residue
weighs not more than 4.0mg.
Volatile sulphides. Place closures, cut if necessary, with a total surface area of 20±2cm2 in a 100-mL conical flask
and add 50mL of a 2% w/v solution of citric acid. Place a piece of lead acetate paper over the mouth of the flask
and maintain the paper in position by placing over it an inverted weighing bottle. Heat in an autoclave at 121±2°C
for 30 minutes. Any black stain on the paper is not more intense than that of a standard prepared at the same time in
the same manner using 0.154mg of sodium sulphide and 50mL of a 2%w/v solution of citric acid.
Sterilisation test. The closures ‘prepared’ in the aforementioned manner shall not soften or become tacky and there
shall be no visual change in the closure.
60
Fragmentation test. This test is applicable to closures intended to be pierced by a hypodermic needle. For closures
that are intended to be used for aqueous preparations, place a volume of water corresponding to the nominal volume
minus 4mL in each of 12 clean vials, close the vials with the ‘prepared’closures, secure with a cap and allow to
stand for 16 hours. For closures that are intended to be used for dry preparations, close 12 clean vials with the
‘prepared’ closures. Using a lubricated, long-bevel (bevel angle of 10°C to 14°C) hypodermic needle with an
external diameter of 0.8mm (21 SWG) fitted to a clean syringe, inject 1mL of water into the vial and remove
1 mL of air; carry out this operation 4 times for each closure, piercing each time at a different site. Use a new needle
for each closure and check that the needle is not blunted during the test. Pass the liquid in the vials through a filter
with a nominal pore size of 0.5µm. Count the number of fragments visible to the naked eye. The total number of
fragments is not more than 10 except in the case of butyl rubber closures where the total number of fragments is not
more than 15.
Self-sealability. This test is applicable to closures intended to be used with multidose containers. Fill 10 suitable
vials with water to the nominal volume, close the vials with the ‘prepared’ closures and secure with a cap. For each
closure, use a new hypodermic needle with an external diameter of 0.8mm (21 SWG) and pierce the closure 10
times, piercing each time at a different site. Immerse the vials upright in a 0.1% w/v solution of methylene blue and
reduce the external pressure by 27kPa for 10 minutes. Restore the atmospheric pressure and leave the vials
immersed for 30 minutes. Rinse the outside of the vials. None of the vials contains any trace of coloured solution.
Biological Tests. Perform the test for Biological Reactivity, In Vitro (2.2.23). Materials that meet the requirements
of this test are not required to undergo testing as described in test for Biological Reactivity, In Vivo (2.2.24).
6.4. LABELS ON CONTAINER
6.4.1. Basic Statutes Governing Labelling
Requirements on Labelling of the packages/container for pharmaceuticals shall be governed as/the following
provisions:
- Labelling requirements as/the Drugs & Cosmetics Act, 1940 and the Drugs & Cosmetics
Rules, 1945 as amended from time to time.
- Section on Labelling covered in General Notices in the applicable version of the Indian
Pharmacopoeia.
61

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Draft General Chapter uploaded on 11th April 2017

For Forthcoming IP (2018)

6.2.1. Plastic Containers

Stakeholder Activity Involved Governing Regulations Examples

Patients, Health care chain (Doctors,

All Plastic Waste Various responsibilities on Manufacturers,

Applicability of Biological Tests for Plastic Packages

6.2.1.1. Plastic Containers for Parenteral Preparations

Tests using Special Solution “S”

deterioration/deformation of the container, heat at 100 °C for 2 hours.

Tests Using Solution “S”

6.2.1.1.1. Sterile Plastic Containers for Blood and Blood Components

autoclave so that the contents are maintained at 110°C for 30 minutes.

Haemolytic effects in buffered systems

where, A100 = absorbance of tube III,

Residue on evaporation. Evaporate to dryness 100mL of solution A in a borosilicate-glass beaker, previously

6.2.1.1.3. Sterile PVC (Polyvinyl chloride) Containers for Blood containing an

6.2.1.2. Plastic Containers for Non-parenteral Preparations

Tests on Container Material

6.2.1.2.1. Polyethylene Terephthalate (PET)

Quality assessment of PET Containers

A] IDENTIFICATION OF CONTAINER MATERIAL

Test 1 – By FTIR Spectrophotometry

Test 3 – By Differential Scanning Calorimetry (2.4.31)

B1] TESTS USING SPECIAL SOLUTIONS

Preparation of Special Solutions for Subsequent Tests on PET

area of more than 1cm2.

Solution S1 (Aqueous Extract)

Solution S2 (Ethanolic Extract)

Solution S3 (Acidic Extract)

TESTS USING SPECIAL SOLUTION S1

Solution S1 has to be clear (2.4.1).

B1.2] Absorbance of solution S1 (2.4.7)

B1.5] Reducing substances

TESTS USING SPECIAL SOLUTION S2

Solution S2 has to be clear and colourless (2.4.1).

B1.7] Absorbance of solution S2 (2.4.7)

B1.8.] Extractable Metals

b) Extractable metals are measured using special solutions S3 and S4.

TESTS USING THE SPECIAL SOLUTION S3

B1.8.1] Aluminium. Not more than 1ppm.

B1.8.2] Barium. Not more than 1ppm.

B1.8.3] Cobalt. Not more than 1ppm.

B1.8.4] Manganese. Not more than 1ppm.

B1.8.5]Titanium. Not more than 1ppm.

B1.8.6] Zinc. Not more than 1ppm.

B1.8.7] Antimony. Not more than 1ppm.

B1.8.8] Germanium. Not more than 1ppm.

B2] OTHER TESTS

B2.1] Substances soluble in dioxane. Not more than 3.0%

B2.3] Total Terephthaloyl moieties. Not more than 1ppm

B2.4] Ethylene glycol. Not more than 1ppm

Applicability of the test.

A] Identification of Container Material

Test 1 – By FTIR Spectrophotometry (2.4.6)

Test 2 – By Differential Scanning Calorimetry (2.4.31)

Test 1 – By FTIR Spectrophotometry (2.4.6)

Test 2 – By Differential Scanning Calorimetry (2.4.31)

Solution S1 (Water extraction)