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INTRODUCTION
Packaging is a process by which the pharmaceuticals are suitably packed so that they should
retain their therapeutic effectiveness from the time of packaging till they are consumed.
Packaging may be defined as the art and science which involves preparing the articles for
transport, storage display and use. Pharmaceutical packaging is the means of providing
protection, presentation, identification, information and convenience to encourage compliance
with a course of therapy.
Composition of package:
(a) Container
(b) Closure
(c) Carton or Outer
(d) Box
2. Testing Packages
a. Mechanical Mechanical tests are applied mainly to outer packaging for protection from
transportation hazards. They consist of the use of a standardized test procedure to compare
the effect of different protective materials to prevent damage to the contents.
b. Environmental- Packages are subjected to conditions that reproduce the environment and
some evaluation is made at suitable intervals. Such procedures may be applied to testing
closures for water vapour transmission.
There are various tests to ensure that the resultant product will comply with its specification.
Tests applied to the environment or to equipment, as well as to products in process, may also
be regarded as a part of in-process control.
PRINCIPAL INSTRUMENTAL TECHNIQUES EMPLOYED FOR PACKAGING CONTROLS
i. Spectrophotometry
ii. Chromatographic Methods
iii. Thermal analysis techniques
iv. Gas transmission analysis
v. Leak detection
vi. Physical test methods
vii. X-ray Fluorescence Analysis
IDEAL REQUIREMENTS OF GOOD PACKAGE:-
1. They should be able to hold the product without loss on account of leakage, spoilage or
permeation.
2. They should afford protect against environmental conditions like light, air and moisture
during storage.
3. They should not have any permeability for gases.
4. They should possess sufficient strength to withstand shocks of handling, transportation
etc.
5. They should facilitate efficient safe and convenient use of contents.
6. The material must not interact with the contents.
7. The containers should afford protection from moulds, bacteria etc.
8. The cost of material should be as low as possible without compromising the quality.
9. They should facilitate easy identification.
10. They should afford protection from moulds, bacteria etc.
11. The container should not absorb or adsorb any material containing.
12. The closure should provide air tight closing to the container.
13. The closure should be compatible with the preparation.
Airtight containerA container that is impermeable to solids, liquids and gases under
ordinary conditions of handling, storage and transport. If the container is intended to be
opened on more than once, it must be so designed that it remains airtight after re-closure.
Hermetically Sealed container. A container 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.
Light-resistant container. A container that protects the contents from the effects of
actinic light by virtue of the specific properties of the material of which it is made.
Multidose containerA container that holds a quantity of the preparation suitable for two
or more doses.
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.
Glass is a common material to be used in either no sterile or sterile liquid dosage forms. It
leaches alkali from its surface. Leaching of alkali can be reduced but cannot be zero. Hence,
a limit test for alkalinity is to be performed before using it for a particular product.
EVAUATION PARAMETERS:-
(A) Crushed glass test:
This test is official in USP. The container is crushed and sieved to produce uniform particles
of which a definite weight of taken. The control of the particle size and weight of powder
ensures that a constant surface area is exposed to the solution. Because all of the glass (not
just the surface layer) is examined and extraction is enhanced by the rough surfaces of the
particles, this is a severe test, and, if a glass passes, it is unlikely that containers made from
it will give trouble while is use. Nevertheless, the technique is tedious and is not applicable
to surface treated containers (sulphured or siliconed) because crushing would expose the
alkaline glass below the surface. This test can be used for determining the nature of a glass
or for distinguish between two types of glasses, such as neutral or surface treated.
(B) Whole-Container test:
This test is official in European, British and International Pharmacopoeias. it is used in the
USP for treated soda-lime containers only. The containers are simply filled with the test
solution and exposed to the test conditions. Glassware may pass the whole container test
more easily because the surface layer of a container is smooth and less reactive.
In this test, surface area does not increase as much as volume with the increase in container
size, consequently, the small sized containers are more attacked by the leaching of the alkali
from the surface.
Type I 1.0
1. Powdered Glass Test Type III 8.5
Type NP 15.0
3. Sorption: It may be defined as bonding of a solute to a plastic .This process involves the
removal of constituents from the drug product by the packaging material. Sorption may lead
to serious problem for drug preparation in which important ingredients are in solution. Since
drug substances of high potency are administered in small doses, losses due to sorption may
significantly affects therapeutic efficacy of the preparation.
4. Chemical Reactivity: Certain ingredients that are used in plastic formulations may react
chemically with one or more components of a drug product. At times ingredients in the
formulation may react with the plastic. Even micro quantities of chemically incompatible
substance can alter the appearance of the plastic or the drug product.
A. TESTS ON PLASTIC CONTAINER
3.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 20 cm2. Wash the strips free from 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.
4.Transparency test: Fill five empty containers to their nominal capacity with diluted.
suspension as described in IP 1966. The cloudiness of the diluted suspension in each
container is detectable when viewed through the containers as compared with a container of
the same type filled with water.
5.Water vapour permeability test: Fill five containers with nominal volume of water and heat
seal the bottles with an aluminum foil-poly ethylene laminate or other suitable seal. Weigh
accurately each container and allow to stand (without any overwrap) for 14 days at a relative
humidity of 60+5% and a temperature between 20 and 25 0C Reweigh the containers. The
loss in weight in each container is not more than 0.2%.
PLASTIC CONTAINERS FOR OPHTHALMIC PREPARATIONS:-
Plastic containers for ophthalmic preparations comply with the following tests:
1 Leakage test; Collapsibility test Clarity of aqueous extract; Non-volatile residue
Comply with the tests described under Plastic containers for Non-parenteral Preparations.
2 Systemic injection test; Intracutaneous test Comply with the tests described under Plastic
containers for Parenteral Preparations.
3 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.
B. TESTS ON PLASTIC MATERIAL
PHYSICO-CHEMICAL TESTS:-
The following tests are based on the extraction of the plastic material, and it is essential that
the designated amount of the plastic be used. Also, the specified surface area must be
available for extraction at the required temperature.
1. Appearance
2. Light absorption
3. pH
4. Non-volatile matter
5. Residue on ignition
6. Heavy metals
7. Buffering capacity
8. Oxidisable substances
BIOLOGICAL TESTS: -
The USP has provided its procedures for evaluating the toxicity of plastic materials Essentially
the tests consist of three phases:
Systemic injection test: Injecting eluates using sodium chloride injection, with and
without alcohol intravenously in mice and injecting eluates using poly ethylene glycol 400 and
sesame oil intraperitoneally in mice.
Intracutaneous test: Injecting all four eluates subcutaneously in rabbits. The reaction
from test samples must not be significantly greater than nonreactive control samples.
2.3 METAL CONTAINERS
The materials used for various pharmaceutical drug delivery systems include tin plated steel,
mild steel, stainless steel, tin free steel, aluminum and its various alloys..Tin is frequently
used in the production of aerosolcans by electroplating it onto sheet steel to improvecorrosion
resistance and facilitate soldering. Incontrast; aluminum is used in its pure form as foil.Often,
aluminum foil is used as an impermeable layerin a multilayer laminate that may include paper
and plasticsas well. Aluminum foil can be formed intorigid containers, semi rigid containers,
blister construction,or laminates.
Metals have a number of advantages over otherpackaging materials. Like glass, metal is
nearly totallyimpermeable to gas and water. In addition, metalcontainers are extremely
strong and are shatterproof. For applications requiring malleability such as collapsibletubes,
metal offers relatively easy manufacturingand very easy use .Metals can also be fashioned
into more complex delivery systems such as metered-dose inhalers, dry powder inhalers,
aerosol administration devices, and even ready-to-use needles. The primary disadvantages of
metals relate to their cost and quality control. Metals are inherently more expensive to
purchase and to fabricate into a useful container. Metals also are prone to the development of
pinhole defects during manufacturing that can drastically compromise their barrier
propertiesespecially in particularly thin sections. Not only can these defects be deleterious
to the container, but they can also compromise the quality of the pharmaceutical.
Types of closures:-
1. Thread screw cap
2. Lug cap
3. Crown cap
4. Pilfer proof closures
Materials used for making closures:-
1. Cork
2. Glass
3. Plastic
4. Metal
5. rubber
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 vulcanization (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, stabilizing agents, pigments, etc. depends on the
properties required for the finished closure.
Rubber closures are used in a number of formulations and consequently different closures
possess different properties. 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.
3.Self sealability test: Applicable to multidose containers fill 10 vials with water close them
with prepared closures and secure with a cap. For each closure use a new hypodermic needle
and pierce 10 times each time at different site immerse the vials upright in methylene blue
(0.1%) solution and reduce external pressure 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.
4.Extractive test: In this test, the closure is boiled with water for four hours under reflux and
the water evaporated to dryness. The residue must not exceed the specified amount.
5. Compatibility test: This test is performed to check the compatibility of the rubber closures
with various types of the substances, since it is necessary to ensure that there is no
interaction between the contents of the bottle and the closure.
6.Light absorption Filter solution A through membrane filter. Measure the light absorbance of
filtrate in the range 220 to 360 nm using a blank solution (prepared in the same manner as
solution A). The absorbance is not more than2.
7. Light absorption : Filter solution A through membrane filter.Measure the light absorbance
of filtrate in the range 220 to 360 nm using a blank solution (prepared in the same manner as
solution A). The absorbance is not more than2.
4. PACKAGING DESIGN AND SPECIFICATIONS
INTRODUCTION
Quality control of a packaging component starts at the design stage. All aspects of a pack
development that may give rise to quality problems must be identified and minimized by
good design.
PACKAGING DESIGN
(A) Component Shape and Dimension
Standardizing both component shape and size should be the policy. There are many
components that can be standardized such as ampules, vials, cartons, labels and leaflets.
Rubber plugs and plastic bottles can be standardized with respect to shape and size, varying
only in the material of construction. There will be a variety of sizes of components depending
on the dosage, but again the same shape could be used but with different dimensions.
(B)Packaging Validation Trials
When the components have been identified for a particular product, the validation of
packaging operation is required. This is to ensure that a consistent pack quality is obtained at
the required packaging rate.
(C) Material of Construction
The material of construction requires careful consideration, particularly when the product is
in contact with the container. It is necessary to ensure that the product does not deteriorate
or does not become contaminated as a result of being in contact with the container, or that
the product does not affect the integrity of the pack.
(D) Component /Product Validation
Once a formulation has been agreed, the pharmaceutical company has to perform
compatibility studies between the product and container to ensure the product degradation
does not occur during the product market life. The container has to be capable of protecting
the product from environment.
1. Sterile product validation:-
a) Product and pack compatibility- the components must be washed and sterilized through
a validated procedure. The vials must be filled with the sterile product under sterile conditions
and terminally sterilized if this is a part of the intended product operation. Components
performance should be monitored during the compatibility trials to ensure that deterioration
has not occurred.
b) Seal integrity- the seals of each vial should be examined before the experiment to
ensure that there are no defectives, and then each vial should be inserted into a tray
containing the challenge bacteria. The samples should be cycled through temperature and
pressure changes expected on the market for several weeks. Careful cleaning of the vials and
examination of contents for sterility will determine the seal quality.
c) Product stability- it is unlikely that a compatibility problem, particularly with the film
coated tablet, will occur, although it is necessary to check up full life of the product. There is
possibility that either the smell or taste of tablets will be affected.
COMPONENT SPECIFICATIONS
Every detail concerning a component specification must be communicated to and agreed
upon with the manufacture, including packaging, transportation, and labeling requirements. If
any of the details are missing confusion or mistakes may occur.
The main specifications requirements are the component drawing, artwork (printed
components only) and the quality control testing and standards.
Quality control testing and standards- There are two classes of components:-
1. Primary in contact with the product, e.g., ampules, vials, plastic bottles, polymer
coated foils
2. Secondary not in contact with the product, e.g., cartons, labels, leaflets
Compatibility and costumer usability- This involves checking that each component forming a
pack fits together and functions correctly. Example eye dropper pack
1. The nozzle must have a good interference fit into the bottle and allow one drop at a
time deliver through the hole in the nozzle when inverted, but must not leak from the fitted
position.
2. The cap must screw into position , and leakage must not occur when the bottle is
squeezed into the inverted position, i.e., a sterile seal is maintained.
Chemical testing- The majority of chemical testing is required on primary components. The
type of testing required depends on the type of component used.
1. Glass vials and Ampules The USPXXII requirements for glass containers are chemical
resistance and light transmission. The requirements vary from country to country, but
basically testing determines whether the correct type of glass has been used for the
manufacture and its suitability for use with pharmaceutical products.
2. Plastic primary components- the testing is more extensive with plastic components,
requiring both biological and physicochemical tests. This is because plastic components
contain other substances, such as plasticizers, stabilizers, antioxidants, pigments, lubricants
and possibly residues from polymerization. Therefore, for components that are in direct with
the product, this testing is required to ensure that the product is not affected during its life.
5. PHARMACEUTICAL PACKAGING
The quality control of components in pharmaceutical premises starts at the receiving stage.
Once the component s are considered acceptable by the packaging material laboratory, the
control of components quality must be maintained through each stage of handling and use ,
that is from the component storage and preparation to the filling , packaging, and dispatch of
the product.
PACKAGING AREA
The packaging operation can involve many complex operations, all of which require careful
control if product quality and security are to be maintained. The packaging operation means
either the filling and packaging of non sterile products or the packaging stage of filled sterile
products.
A. Area standard
Depending on the type of product and packaging operation, the standard requirement of the
packaging area will vary, although there are several basic standards required:-
1. Each packaging line should be in separate room.
2. There should be covered floors and ceilings for easy cleaning.
3. The packaging operators should wear non fiber shedding overalls that have a tight fit
around the neck and sleeves. There should be no external pockets above waist height.
4. The filling part of the packaging operation should be enclosed and supplied with filtered
air.
5. Basic precautions prior to filling can be operated, such as blowing the container with
filtered air immediately before filling. Washing of containers should not be necessary,
provided that the correct production and operation standards are in use in the supplier
premises .
B. Packaging instructions
1. Packaging specifications
The following details must be included in the specifications:
The product name, strength, and reference code to be packaged.
The pack size and number of product items to be included in each pack, that is, the
number of tablets, ampules, vials, etc.
A description and reference of each packaging item to be included in the pack.
Special precautions to be taken during the operation. For example the packaging of a
moisture sensitive tablet may need to be performed under low humidity conditions.
Detail the in-process control system to be operated. This will vary depending on the
complexity of the packaging operations.
3. Customer requirements
The customer order may be to package all the product in each of the batches allocated or in
an exact number of packs. The quantities of components required for each batch to be
packaged need to be stated. This quantity must include overages based on expected wastage
due to line set up, breakdowns , and in-process checks.
C. Product quality and security
Once the packaging line is set up and the correct packaging instructions are available,
product quality and security must be maintained throughout the packaging stage. It can be
done in following ways:
1. Critical devices a critical device is any device that unless it is working correctly, could
affect product quality. Each device must be identified and calibrated or challenge on a regular
basis to ensure that it is working within specified limits.
2. Bar coding all the printed items (printed containers , labels , and cartons ) should be
bar coded , with the code reader said to read each item immediately to including into the
pack. With the ampules and vials , a ring coding system or a similar method should be used.
3. Miss printing and missing component detectors if these detectors have been proven
to work correctly, they can give additional assurance of a satisfactory pack on the market.
6.(A) PACKAGING MATERIAL SPECIFICATIONS:-
Specifications of packaging materials may contain below mentioned particulars:-
(i) Printed strip rolls
* Common name
* Code number
* Description
* Colour scheme and design
* Quality of printed matter
* Seal quality
* Effect of heat
* Name of approved supplier
* Frequency of re-inspection of stored material
* Precaution
* Date of issue of specification
(ii) Cartons
* Name (name of the drug and strength)
* Code number
* Description
* Dimensions (length, width, height)
* Colour scheme
* Quality of printed matter
* Printed matter
* Gram per square meter
* Suitability
* Name of approved supplier
* Frequency of re-inspection of stored material
* Date of issue of specification
(iii) Bottles
* Common name
* Code number
* Description
* Total height
* Neck height
* Body diameter
* Type of glass
* Overflow capacity
* Suitability
* Name of approved supplier
* Date of issue of specification
Particular attention should be given to ensure that different products are not packed in close
proximity unless there is physical segregation. The written procedures should include
following features, which will prevent mix-ups and cross contamination:
1. Before packaging operations begin, steps should be taken to ensure that the work area,
packaging lines, printing machines and other equipments are clean and free from any
products, materials or documents previously used.
2. Identification of drug product with lot or control number that permits determination of
the history of the manufacture and control of the batch.
3. The name and lot number of the product being handled should be displayed at each
packaging station or line.
4. All the products, labels, labeling and packaging material should be checked on delivery
to the packaging department for quantity, identity, and conformity with the packaging
instructions.
5. Examination of the packaging and labeling materials for suitability and correctness
before start up of packaging operations and documentation of such examination in the batch
production record.
6. Containers for filling should be clean before filling. Attention should be given for
avoiding and removing contaminants if any, such as glass fragments and metal particles.
7. Online control of the product during packaging should include at least checking the
following:
General properties of the packages.
Whether the packages are complete and the count is as per specification.
Whether the correct products and packaging materials are used.
Correct functioning of line controls.
8. Samples taken away from the packaging line should not be returned. They should
where appropriate, be destroyed (e.g. leak tested strips)
9. Product lots which have been involved in special events (rework or re inspection)
should be reintroduced into the process only after additional inspection and approval is
carried out by authorized personnel.
7. W.H.O GUIDELINES FOR QUALITY CONTROL OF PACKAGING MATERIALS
1. All the containers and closures intended for use shall comply with the pharmacopoeial
and other specified requirements.
3. Plastic granules should also comply with the pharmocopeial requirements including
physio-chemical and biological tests.
4. All the containers and closure shall be rinsed prior to sterilization with water for
injection according to written procedure.
5. The design of the closures, containers and stoppers shall be as such as to make an
airtight seal when fitted to the bottles.
6. It shall be ensured that containers and closures chosen for a particular product do not
affect the product adversely.
7. When the glass bottles are used, the written schedule of cleansing shall be laid down
and followed.
REFERENCES
1. INDIAN PHARMACOPOEIA 2007, Volume-1, published by The Indian Pharmacopoeia
Commission, Central Indian pharmacopoeia Laboratory Govt. Of India, Ministry of Health &
Family Welfare Sector-23, Raj Nagar, Ghaziabad-201 00 Page no. 363-371
2. UNITED STATES PHARMACOPOEIA 2007,Volume-1,Page no.661
3. Swarbrick James, ENCYCLOPEDIA OF PHARMACEUTICAL TECHNOLOGY, Volume
-1,Third Edition, Page no.2526-2541
4. Lachman leon, Lieberman H.A, Kanig J.L,THE THEORY AND PRACTICE OF INDUSTRIAL
PHARMACY, Third Indian Edition 1990, Varghese Publishing House, Dadar Bombay Page
no.711-732
5. Organization Of Pharmaceutical Producers Of India, QUALITY ASSURANCE GUIDE
Fourth Edition 2001, Chapter 11.5 Page no. 1-4
6. Banker G.S, Rhodes C.S, MODERN PHARMACEUTICS, Fourth Edition , Published by
Marcel Dekker, Page no.587-600
7. EUROPEAN PHARAMOCOPEIA5.0, Vol-1,page no.303-317
8. Jerkins W.A, Osborn K.J, PACKAHING DRUGS AND PHARMACEUTICALS, edition 1993,
Technomic Publishing Co.Inc., Page no. 1372-1389
9. Dean D.A, Evans E.R, and Hall I.H, PHARMACEUTICAL PACKAGING TECHNOLOGY