Selection and Evaluation Of

Pharmaceutical Packaging Materials

Tushar Prakash Naiknaware
[Link]
(Quality Assurance)
Roll No.14
Shri. D.D Vispute College Of Pharmacy &
Research Center
 Introduction
A Container Closure System must be designed to protect the drug during
actual conditions of Storage, Shipment and Use.
 It should be able to deliver the correct amount of product at the time of use.
 It must not interact with the product over its shelf life.

Effort required to develop or select the appropriate Container is based on:

 A Risk Assessment considering the Route of Administration.
 Class of Drug Product.
 Therapeutic Range.
 Chemical and Physical Stability of the drug substance.
 Drug Product Matrix.
 Packaging Component.
 Conditions of Storage and Use.
Some examples of Actual Events of Interaction between
containers and dosage forms:

 Migration of plastic additives to drugs

 Migration of preservatives
 Migration of drug to plastic or coating glass
 Migration of chemicals from heat seals, plastics, and foils
into drugs
 Degradation of components from sterilization
 Migration of inks, adhesives, and chemicals in paper into
inhalation solutions
Selection Of Container Closure System

To determine the appropriate container closure system, one should consider the
following:

 Preformulation information on the drug substance

 The nature of the dosage form
 Drug product information
 Container material qualification (CAS number, 21 CFR qualification, USP qualification,
etc.)
 Container/product compatibility
 Impact of the packaging operation on the drug product
 Ruggedness of the container system under actual conditions of packaging, shipping,
storage and use
 Performance
Packaging Materials

Types of Packaging Materials

Glass
Metals
Rubbers
Plastics
Material Type Example of Use
Glass Primary Metric Medical Bottle,
Ampoule, Vial

Plastic Primary Ampoule, Vial, Infusion

Fluid Container, Dropper
Bottle

Secondary Wrapper to Contain

Primary Pack

Cardboard Secondary Box to Contain Primary

Pack

Paper Secondary Labels, Patient

Information Leaflet
Glass

 Glass is composed of sand, soda ash, limestone and

cullet.
 Si, Al, Na, K, Ca, Mg, Zn and Ba are generally used into
preparation of glass.
Types Of Glass
 Type I (Neutral or Borosilicate Glass)
 Type II (Treated Soda Lime Glass)
 Type III (Soda Lime Glass)
 Type NP (General Purpose Soda Lime Glass)
Types Of Glass Properties

Type I • Highly resistant glass

• A substantial part of the alkali & earth
cations are replaced by boron and/or
aluminum & zinc.
• It is more chemically inert than the
soda-lime glass
• It is used to contain strong acids &
alkalies as well as all types of
solvents.
Type II • They are made of commercial soda-
lime glass that has been de-alkalized
or treated to remove surface alkali.
Type III • Containers are untreated & made up
of commercial soda-lime glass of
average or better-than-average
chemical resistance.
Type NP • Containers made up of soda-lime
glass are supplied for non-parenteral
products, those intended for oral or
topical use.
PACKAGE TYPE TYPE OF FORMULATION CAN BE PACKED MINIMUM QUALITY
OF GLASS THAT CAN
BE USED
Ampoule Aqueous Injectables Of Any pH Type I
Aqueous Injectables Of pH Less Than 7 Type II
Non-Aqueous Injectables Type III
Vial Aqueous Injectables Of Any pH Type I
Aqueous Injectables Of pH Less Than 7 Type II
Non-Aqueous Injectables Type III
Dry Powders For Parenteral Use (Need To Be Type IV
Reconstituted Before Use)
Bottles and Jars Tablets, Capsules, Oral Solids & Other Solids Type IV
For Reconstitution
Oral Liquids (Solutions, Suspensions, Type IV
Emulsions)
Nasal & Ear Drops Type IV
Certain Types Of External Semisolids Type IV
(Rubeficients, Local Irritants)
Blood & Related Products Type I
PACKAGE TYPE TYPE OF FORMULATION CAN BE MINIMUM QUALITY OF
PACKED GLASS THAT CAN BE
USED
Dropper Auxiliary Packaging Device With Certain Type IV
Kind Of Products
Aerosol container Aerosol product ( solution, suspension, Type I
emulsion or semisolid type)
Metals
 Metal Containers are used Solely for Medicinal Products for
Non-Parenteral Administration.
 Metal is Strong, Opaque, Impermeable to Moisture, Gases,
Odors, Light, Bacteria and Shatterproof, it is he ideal
packaging material for pressurized containers.
 It is Resistant to High and Low Temperatures.
 They include Tubes, Pack made from Foil or Blisters, Cans and
Aerosol and Gas Cylinders.
 Aluminum & stainless steel are the metals of choice for both
primary & secondary pharmaceutical packaging.
 Form excellent tamper-evident containers.
Rubbers

 Rubber is used in the pharmaceutical industry to make

closures, cap liners and bulbs for dropper assemblies.
 The rubber stopper is used primarily for multiple dose
vials and disposable syringes.
 Rubber closures for containers for aqueous parenteral.
 Preparations for powders and for freeze-dried
powders.
Type Of Rubber Advantages Disadvantages
Butyl Rubber • They are most Resistant to • Slow Decomposition
Aging & Chemical Attack. takes place above 130
• Permeability to Water Vapor & Celsius.
Air is Very Low. • Oil and solvent
• Water Absorption is Very Low. resistance is not very
good .
Nitrile Rubber • Oil resistant due to polar Nitrile • Absorption of
Group. bactericide and
• Heat resistant. leaching of extractives
are considerable.
Chloroprene Rubbers • This rubber is more polar hence -----------
oil resistant.
• Heat stability is good (up to 150
Celsius).
• Water absorption and
permeability are less.
Silicone Rubber • Heat Resistance (Up to 250 • They are very
Celsius). Expensive.
• Extremely Low Absorption and
Permeability of Water.
• Excellent Aging Characteristics.
Plastics

Advantages :
 Ease of manufacturing.
 Available in various types of quality.
 Freedom of design to which they lend themselves.
 Extremely resistant to breakage.
 Ease of Transportation.
 They are resistant to inorganic chemicals.
Disadvantages:
 They have disadvantages like interaction, adsorption, lightness and
hence poor physical stability.
 All are permeable to some degree to moisture, oxygen, carbon
dioxide, etc.
COMMONLY USED POLYMERS LESS COMMONLY USED POLYMERS
Polyethylene Polymethyl methacrylate
Polypropylene Polyethylene terephthalate
Polyvinyl chloride (PVC) Polytrifluoroethylene
Polystyrene Amino formaldehydes
Polyamides

Type of Plastic Polymer Properties Uses

Polyethylen LDPE • Ease of Processing Preferred Plastic for
e • Barrier to Moisture Squeeze Bottles
• Strength/Toughness
• Flexibility
HDPE • Stiffness Widely used in bottles
• Strength /Toughness for solid dosage forms
• Resistance to Chemicals
Polypropylene • Good Resistance to Heat Suitable for use in
Sterilization. closures, tablet
• Colorless and Odorless containers and
Thermoplastic Material. intravenous bottles.
• Excellent Resistance to
Strong acids & alkalis.
Type of Plastic Polymer Properties Uses
Polyvinyl chloride (PVC) • Versatility Used as Rigid Packaging
• Ease of bending Materials & Main
• Strength/Toughness Component of
• Resistance to Intravenous Bags.
Grease/Oil
• Resistance to
Chemicals
• Clarity
Polystyrene • Versatility Used for Jars for
• Insulation Ointments and Creams
• Clarity with low water content.
 Packaging Evaluation

 It is performed to investigate the Physicochemical

interactions that might occur between the product
and package.
 Packaging evaluation is designed to identify,
characterized and monitor interactions to achieve a
safe, unadulterated, stable and efficacious product.
 An Important step – to characterize the materials and
the chemicals that can migrate or extract from
packaging components to the drug product.
 To Establish suitability, Evaluation of Four Attributes is
Required -
 Tests For Glass

As per USP, Mainly Three Tests are done:

 Powder Glass Test
 Water Attack Test
 Hydrolytic Resistance Test
Water Attack Test

 The water attack test at 121C is performed on intact

containers.
 The containers are filled up to 90% of their overflow
capacity Containers are autoclaved for 60 min.
 Then content of container are cooled & from cooled
content 100m1 of the solution.
Steps-
 Rinse 3 or more containers with high purity water
 Fill each container to 90%of its overflow capacity
 Cap all the flasks, autoclave for 60 min
 Empty the contents & cool the contents in 250m1 conical
flask to a volume of 100m1
 Add five drops of methyl red solution
 Titrate with 0.02N Sulphuric acid while warm
 Record the volume consumed
 Volume should not exceed limits,
Types Of Glass & Their Limits

Types of General description Types of Limits Limits (ml

glass of glass test size ml of 0.20N)

1 Highly resistant Powdered All 1.0

borosilicate glass glass

2 Treated soda lime Water 100 or 0.7

glass attack less

      Over 100 0.2

3 Soda —lime glass Powdered All 8.5

glass

4 General —purpose Powdered All 15.0

soda lime glass glass
Hydrolytic Test

Type of container Test to be done

 This test is done for detecting
Type 1 & type 2 glass containers to
the type of glass
Test 1 (surface test)
distinguish from type 3 glass
containers

Type 1 & type 2 glass containers where Test 1 &2

it is necessary to determine whether
the high hydrolytic resistance is due to
the chemical composition or the
surface treatment
Test 1 – Surface Glass Test

 Wash containers with carbon dioxide free water

 Fill the containers with CO2 free water (90%)
 Close with aluminum foil
 Autoclave at 1009-1209C for 20 min
 Maintain at 120°C for 1 hr
 At lower temp for 40 min
 Remove containers & cool
 Titrate it within 1 hour
 Titrate with 0.01 M HCL (end point colourless)
 Repeat with same volume of CO2 free water
Volume Of Test Solution To Be Used

1 Up to 3 At least 20 25.0

2 5 or less At least 50.0

3 6 to 30 At least 50.0

4 More than 30 At least 100.0

Volume Of 0.01 M HCl Required By Test Solution
Capacity of container Corresponding Volume of 0.01M HCI for 100
to 90% avg over flow volume ml) ml of test solution
Type 1 or 2 Type 3 glass
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 2 but not more than 5 1.3 13.2
More than 5 but not more than 10 1.0 10.2
More than 10 but not more than 20 0.80 8.1
More than 20 but not more than 50 0.60 6.1
More than 50 but not more than 100 0.50 4.8
More than 100 but not more than 200 0.40 3.8
More than 200 but not more than 500 0.30 2.9
More than 500 0.20 2.2
Test 2

 Rinse container twice with water and with 4%volume

solution of HF
 Allow to stand for 10min
 Empty the container
 Rinse 5 times with water
 Carry out test similar test 1
 Tests For Plastic Containers

Leak test:
The plastic containers (non injectables and injectables):
 Fill 10 plastic containers with water and fit the closure.
 Keep them inverted at room temperature for 24
hours.
 No sign of leakage should be there from any
container.
Water permeability test:
 Fill 5 containers with nominal volume of water and sealed.
 Weigh each container.
 Allow to stand for 14 days at relative humidity of 60% at 20-25
degree Celsius.
 Again weigh the container.
 Loss of weight in each container should not be more than
0.2%.
Collapsibility Test:
 This test is applicable to the containers which are to be
squeezed for removing the contents.
 A container by collapsing inward during use, yield at least
90% of its normal contents at the required rate of flow at
ambient temperature.
 Tests For Rubber Closures

Preparation Of Sample (Solution-A):

 Wash closures in 0.2%w/v of an surface active agents
for 5min.
 Rinse 5 times with distilled water and add 200m1
water and is subjected to autoclave at 119 to 123 °C for
20 to 30m in covering with aluminum foil.
 Cool and separate solution from closure (solution-A).
I. Sterility Test:
When treated closures are subjected to sterilization
test at 64-66°C and a pressure of about 0.7 KPa for 24hr.
II. Residue On Evaporation:
50ml of solution A is evaporated to dryness at
105°CThen weigh the residue NMT 4mg.
III. Penetrability:
 This is measured to check the force required to make a
hypodermic needle penetrate easily through the closure.
 It is measured by using the piercing machine.
 The piercing force must not exceed a stated value.
 If it exceeds that stated value, the hypodermic needle
can be damaged as a result of undesirable hardness of
the closures.
IV. Fragmentation Test:

For closures for aqueous For closures for dry

preparations preparations

Place a vol of water corresponding to

the nominal vol minus 4 ml each of 12
clean vials
Close 12 clean
vials with the '
Close the vials with the 'prepared' prepared'
closures& allow to stand for 16 hours closures

Using a hypodermic needle with an external diameter of 0 8 mm inject 1 ml of

water into the vial and remove 1 m I of air

Carty out this operation 4 times with new neede each time
 Pass the liquid in the vials through a filter with a pores size of 0.5 um.

No of fragments is NMT 10 excepts In the case of butyl rubber closures

a here the total no of fragments is NMT 15

V. Self - Sealability Test:

This test is applicable to closures intended to be used with water.
 Close the vials with the 'Prepared' closures
 For each closure, use a new hypodermic needle with an external diameter
of 0.8 mm & pierce the closure 10 times, each time at a different site.
 Immerse the vials upright in a 0.1% w/v solution of methylene blue &
reduce the external pressure by 27KPa for 10 min.
 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 colored solution.
 Tests For Metal
I. Description:
Metallic tins having smooth inner surface. The upper surface is sealed
consists a clip to break the seal. The lower surface is open.
II. Dimensions:
Height- Measure the height in mm of 10 metallic tin, individually from
the lower surface edge to the upper rim.
Limit- Specimen metallic tins with tolerance-170mm±1Omm.
III. Diameter:
 Inner diameter- Measure the inner diameter of 10 metallic tins.
Limit- NLT 98mm.
 Outer diameter: Limit-NMT 105mm.
IV. Cleanliness Check:
It should not be dirty, damaged, stained or consist of any foreign
particles.