1. PACKAGING

2. PACKAGING
Packaging is the science, art, and technology of enclosing or protecting products for distribution, storage, sale, and use.
Packaging also refers to the process of design, evaluation, and production of packages.
Packaging may also be defined as the collection of different components (e.g. bottle, vial, closure, cap, ampoule, blister) which surround the pharmaceutical product from the time of production until its use.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

3. SELECTION CRITERIA FOR PACKAGING MATERIAL
There are many factors which need to consider when selecting a suitable type of pack for the product:
The product or pack contents
The application of the product
Content stability, and the need of protection form any environmental factors
Content reactivity ( with relevant to the packaging material)
Acceptibilty of the pack to the consumer or user
The packaging process
Regulatory, legal and quality issues
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

4. CHARACTERISTICS OF PACKAGING MATERIAL
The material selected must have the following characteristics:
Must meet tamper-resistance requirements
Must be FDA approved
Must be non-toxic
Must not impart odor/taste to the product
Must not reactive with the product
They must protect the preparation from environmental conditions
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

5. USES OF PACKAGING:
Physical protection: It protects from, among other things, mechanical shock, vibration, electrostatic discharge, compression, temperature, etc.
Information transmission: Packages and labels communicate how to use, transport, recycle, or dispose of the package or product. With pharmaceuticals, food, medical, and chemical products, some types of information are required by governments.
Marketing: The packaging and labels can be used by marketers to encourage potential buyers to purchase the product.
Convenience: Packages can have features that add convenience in distribution, handling, stacking, display, sale, opening, re-closing, use, dispensing, reuse, recycling, and ease of disposal.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

6. Barrier protection: A barrier from oxygen, water vapor, dust, etc
Barrier protection: A barrier from oxygen, water vapor, dust, etc., is often required. Permeation is a critical factor in design. Some packages contain desiccants or oxygen absorbency to help extend shelf life. Keeping the contents clean, fresh, sterile and safe for the intended shelf life is a primary function.
Security: Packaging can play an important role in reducing the security risks of shipment. Packages can be made with improved tamper resistance to deter tampering and also can have tamper-evident features to help indicate tampering. Packages can be engineered to help reduce the risks of package pilferage.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

7. TYPES OF PACKAGING
Primary packaging is the material that first envelops the product
and holds
it. This usually is the smallest unit of distribution or use and is the package
which is in direct contact with the contents.
Examples: Ampoules,Vials ,Containers ,Dosing dropper ,Closures
(plastic, metal) ,Syringe ,Strip package, Blister packaging.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

8. Secondary packaging is outside the primary packaging – perhaps used to group primary packages together.
Example: Paper and boards, Cartons ,Corrugated fibers ,Box manufacture)
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

9. Tertiary packaging is used for bulk handling , warehouse storage and transport shipping. The most common form is a palletized unit load that packs tightly into containers.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

10. TYPES OF PACKAGING MATERIAL
I) Glass
II) Metals
III) Rubbers
IV) Plastics
V) Fibrous material
VI) Films, Foils and laminates
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

11. Injectable formulations are packaged into containers made of glass or plastic.
Container systems include ampoules, vials, syringes, cartridges, bottles and bags. Ampoules are all glass while bags are all plastic.
The other containers can be composed of either glass or plastic and must include rubber materials such as rubber stoppers for vials and bottles, rubber plungers and rubber seals for syringes and cartridges.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

12. Parenteral dosage forms differ from all other dosage forms because they are injected directly into body tissue through the primary protective system of the human body, the skin and the mucous membranes.
They must be exceptionally pure and free from physical, chemical and biological contaminants.
These requirements place a heavy responsibility on the pharmaceutical industry to practice current good manufacturing practices(cGMPs) in the manufacture and packaging of parenteral dosage forms and upon pharmacists and other health care professionals to practice good aceptic practices(GAPs) in dispensing them for administration to patients.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

13. GLASS: Advantages DISADVANTAGES
Glass has been widely used as a drug packaging material.
Glass is composed of sand, soda ash, limestone,& cullet.
Si, Al, Na, K, Ca, Mg, Zn & Ba are generally used into preparation of glass
Advantages
They are hygienic and suitable for sterilization
They are relatively non reactive ( depending on the grade chosen)
It can accept a variety of closures
They can be used on high speed packaging lines
They are transparent.
They have good protection power.
They can be easily labeled.
DISADVANTAGES
It is relatively heavy
Glass is fragile so easily broken.
Release alkali to aqueous preparation
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

14. TYPE I GLASS TYPES OF GLASS: Type I ( Neutral or Borosilicate Glass)
Type II ( Treated Soda lime glass)
3) Type III ( Soda lime glass)
4) Type IV ( General purpose soda lime glass)
TYPE I GLASS
Least reactive.
Higher ingredients and processing cost therefore used for more sensitive pharmaceutical products such as parenteral or blood products.
Mostly ampoules and vials are made up of Type I glass.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

15. TYPE III AND TYPE IV GLASS
TYPE II GLASS
Higher chemical resistance but not as much as type I.
Cheaper than Type I.
Acceptable for most products accept blood products and aqueous pharmaceutical with a pH less than 7.
Type II and Type III glass
TYPE III AND TYPE IV GLASS
Have similar composition and are distinguished from each other on the basis of their hydraulic resistance
Type III has average or slight better than average resistance and is suitable for non- aqueous parenterals and non parenteral products.
Type III glass containers are normally dry
sterilized before being filled.
Type IV has lowest hydraulic resistance and is suitable for solid products, some liquids and semi solids and not for parenteral.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

16. TYPE OF FORMULATION CAN BE PACKED
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
Dry Powders For Parenteral Use (Need To Be Reconstituted Before Use)
Type IV
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

17. TYPE OF FORMULATION CAN BE PACKED
PACKAGE TYPE
TYPE OF FORMULATION CAN BE PACKED
MINIMUM QUALITY OF GLASS THAT CAN BE USED
Bottles
and
Jars
Tablets, Capsules, Oral Solids & Other Solids For Reconstitution
Type IV
Oral Liquids (Solutions, Suspensions, Emulsions)
Nasal & Ear Drops
Certain Types Of External Semisolids (Rubeficients, Local Irritants)
Blood & Related Products
Type I
Dropper
Auxiliary Packaging Device With Certain Kind Of Products
Aerosol container
Aerosol product ( solution, suspension, emulsion or semisolid
type)
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

18. Container Types
Glass
Glass is employed as the container material of choice for most SVIs. It is composed principally of silicon dioxide, with varying amounts of other oxides such as sodium, potassium, calcium, magnesium, aluminum, boron and iron.
Boric oxide will enter into the basic structure of glass formed by silicone oxide and persist as loosely bound, so thereby relatively free to migrate. These migratory oxides may be leached into a solution in contact with the glass.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

19. QUALITY CONTROL TESTS FOR GLASSES
CHEMICAL RESISTANT OF GLASS CONTAINERS
A) POWDERED GLASS TEST: It is done to estimate the amount of alkali leached from the powdered glass which usually happens at the elevated temperatures. When the glass is powdered, leaching of alkali is enhanced, which can be titrated with 0.02N sulphuric acid using methyl red as an indicator
Step-1: Preparation of glass specimen: Few containers are rinsed thoroughly with purified water and dried with stream of clean air. Grind the containers in a mortar to a fine powder and pass through sieve no.20 and 50.
Step-2: Washing the specimen: 10gm of the above specimen is taken into 250 ml conical flask and wash it with 30 ml acetone. Repeat the washing, decant the acetone and dried after which it is used within 48hr.
Procedure:
10gm sample is added with 50ml of high purity water in a 250ml flask. Place it in an autoclave at 121⁰C±2⁰C for 30min.Cool it under running water. Decant the solution into another flask, wash again with 15ml high purity water and again decant. Titrate immediately with 0.02N sulphuric acid using methyl red as an indicator and record the volume.

20. B) WATER ATTACK TEST:
This is only for treated soda lime glass containers under the controlled humidity conditions which neutralize the surface alkali and glass will become chemically more resistant.
Principle involved is whether the alkali leached or not from the surface of the container.
Procedure: Rinse thoroughly with high purity water. Fill each container to 90%of its overflow capacity with water and is autoclaved at 121⁰C for 30min then it is cooled and the liquid is decanted which is titrated with 0.02N sulphuric acid using methyl red as an indicator. The volume of sulfuric acid consumed is the measure of the amount of alkaline oxides present in the glass containers.
TESTS
CONTAINER
VOL.OF 0.02N H2SO4
Powdered glass test
Type I
Type II
Type III
1.0
8.5
15.0
Water attack test
Type II(100ml or below)
Type II(above 100ml)
0.07
0.02
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

21. 2) HYDROLYTIC RESISTANCE OF GLASS CONTAINERS:
Rinse each container at least 3times with CO2 free water and fill with the same to their filling volume. Also fill & Cover the vials and bottles and keep in autoclave. Heat to 100⁰C for 10min and allow the steam to issue from the vent cork. Rise the temp from 100⁰C to 121⁰C over 20min. Maintain the temp at 121⁰C to 122⁰C for 60min.Lower the temp from 121⁰C to 100C over 40min venting to prevent vacuum.
Remove the container from autoclave, cool and combine the liquids being examined. Measure the volume of test solution into a conical flask and titrate with 0.01M HCl using methyl red as an indicator. Perform blank with water and the difference between the titration represents the volume of HCl consumed by the test solution.
TABLE 1
Nominal capacity
of container (ml)
Number of containers to be used
Volume of test solution to be used for titration (ml)
5 or less
at least 10
50.0
6 to 30
at least 5
More than 30
at least 3
100.0
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

22. STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

23. A typical test uses 45C temp difference between hot and cold water
THERMAL SHOCK TEST:
Place the samples in upright position in a tray. Immerse the tray into a hot water for a given time and transfers to cold water bath, temp of both are closely controlled. Examine cracks or breaks before and after the test. The amount of thermal shock a bottle can withstand depends on its size, design and glass distribution
A typical test uses 45C temp difference between hot and cold water
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

24. INTERNAL BURSTING PRESSURE TEST:
The most common instrument used is American glass research increment pressure tester .The test bottle is filled with water and placed inside the test chamber. A scaling head is applied and the internal pressure automatically raised by a series of increments each of which is held for a set of time. The bottle can be checked to a preselected pressure level and the test continues until the container finally bursts.
LEAKAGE TEST:
Drug filled container is placed in a container filled with coloured solution (due to the addition of dye)which is at high pressure compared to the pressure inside the glass container so that the coloured solution enters the container if any cracks or any breakage is present.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

25. PLASTICS
According to British standards institutes plastics represents;
“ A wide range of solid composite materials which are largely organic, usually based upon synthetic resins or upon modified polymers of natural origin and possessing appreciable mechanical strength. At a suitable stage in their manufacturing, most plastics can be cast, molded or polymerized directly into shape”.
Classes of plastics:
There are two classes of plastics, reflecting the behavior with respect to individual or repeated exposure to heating and cooling.
Thermoplastics
Capable of being shaped after initial heating and solidifying by cooling.
Resistant to breakage and cheap to produce and providing the right plastics are chosen will provide the necessary protection of the product in an attractive containers.
E.g. Polystyrene, polyethylene and polyvinyl chloride.
Thermosets
They need heat for processing into a permanent shape. During heating such materials form permanent crosslinks between the linear chains, resulting in solidification and loss of plastic flow.
E.g. Phenolic, urea and melamine are representative of thermosets.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

26. Used for many types of pack including;
Uses
Used for many types of pack including;
rigid bottles for tablets and capsules, squeezable bottles for eye drops and nasal sprays, jars, flexible tubes and strip and blister packs.
Advantages
Least expensive than glasses
Ease of transportation
No risk of breakage
Flexible
Light in weight
Disadvantages
They are not as chemically inert as Type -I glass.
They are not as impermeable to gas and vapour as glass.
They may possess an electrostatic charge which will attract particles.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

27. TYPES OF PLASTICS POLYETHYLENE POLYPROPYLENE
This is used as high and low density polyethylene
Low density polyethylene (LDPE) is preferred plastic for squeeze bottles.
Properties: Ease of processing , barrier to moisture, strength /toughness, flexibility, ease
of sealing.
High density poly ethylene (HDPE) is less permeable to gases and more resistant to oils, chemicals and solvents.
Properties: Stiffness, strength / toughness, resistance to chemicals.
It is widely used in bottles for solid dosage forms.
Drawback: prone to stress cracking in the presence of surfactants or vegetable or mineral oils.
POLYPROPYLENE
It has good resistance to cracking when flexed.
Good resistance to heat sterilization.
It is colorless, odorless thermoplastic material with excellent tensile properties even at high temperature.
Excellent resistance to strong acids and alkalis.
Low permeability to water vapour
Permeability to gases is intermediate between polyethylene HD and un-plasticized PVC
Suitable for use in closures , tablet containers and intravenous bottles.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

28. POLYSTYRENE POLYVINYL CHLORIDE
Versatility, insulation, clarity, easily foamed (“Styrofoam”).
It is also used for jars for ointments and creams with low water content.
Drawback: Chemicals like isopropyl myristate produce crazing(a fine network of surface cracks) followed by weakening and eventually collapsible of the container.
POLYVINYL CHLORIDE
Versatility , ease of blending, strength / toughness, resistance to grease/oil, resistance to chemicals, clarity.
Used as rigid packaging material and main component of intravenous bags.
Drawback: Poor impact resistance which can be improved by adding elastomers to the plastics but it will increase its permeability.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

29. Plastic Containers
Thermoplastic polymers have been established as packaging materials for sterile preparations such as large- volume parenterals, ophthalmic solutions and increasingly, small-volume parenterals.
Three principal problem areas exist in using these materials:
1. Permeation of vapors and other molecules in either
direction through the wall of the plastic container.
2. Leaching of constituents from the container to the
product.
3.Sorption(absorption and/or adsorption) of drug
molecules or ions on the plastic materials.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

30. Permeation, the most extensive problem, may be troublesome by permitting volatile constituents, water or specific drug molecules to migrate through the wall of the container to the outside.
This problem have been resolved, for example, by the use of an overwrap in the packaging of IV solutions in PVC bags to prevent the loss of water during storage.
Leaching may be a problem when certain constituent in the plastic formulation , such as plasticizers or antioxidants migrate into the product.
Sorption may be a problem in selective basis, that is, sorption of a few drug molecules occurs on specific polymers, for example, sorption of insulin and other protien, Vitamin A acetate etc has been shown to occur on PVC bags when these drugs were present as additives in IV admixtures.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

31. Adsorption(selective) extent
Plastic Polymers
Leaching extent
Potential leachables
Permeation extent
Potential agents
Adsorption(selective) extent
LDPE 2
Plasticizers, antioxidants 5
Gases, water vapors.
HDPE 1
antioxidants 3
PVC 4
HCl, specially plasticizers.
Polyolefins
Antioxidants
Polypropylene
Lubricants
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

32. Tests on the plastic containers
1 ) Leakage test for Injectable & Non-Injectable(IP 1996)
Fill the 10 containers with water and fit the closure.
Keep them inverted at RT for 24 hours.
No sign of leakage from any container.
2) Water vapor permeability test for injectable preparation(IP 1996)
Fill the 5 containers with nominal volume of water and seal.
Weigh the each container.
Allow to stand for 14 days at RH of % at 20 c to 25 c.
Reweigh the container.
Loss of the weight in each container should not be more than 0.2%.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

33. Test Toxicity Evaluation:
1) Implanting small pieces of plastic material intramuscularly in rabbits
2) Injecting the eluates using the sodium chloride injection with or without alcohol intravenously in the mice and injecting the eluates using the polyethylene glycol 400 and oil intraperetonially in mice
3) Injecting all four eluates subcutaneously in rabbits
The reaction from the test sample must not be significantly grater than non reactive control sample.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

34. PVC large volume IV infusion bag PVC small volume IV infusion bag
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

35. Various Containers for Parenteral Preparations in Brief
Ampoules
A parenteral product container made entirely of glass and intended for single use.
The ampoules can be broken at the neck restriction either by scoring or by having a ceramic point (ring or spot) baked on during the manufacture thus causing a weak point.
However breaking on the ceramic point can cause colored particles to fall into the product. This led to an alternative where the ampoule is scored and then has a colored ring above or below the score to indicate the break point( one point cut/open point cut method).
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

36. Vials
A glass or plastic container closed with a rubber stopper and sealed with an aluminum crimp. Vials are available for single dosing or for multiple dosing. Injection vials can be obtained in either neutral or soda glass and occasionally in treated soda glass.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

37. Type 1 Glass Vial for multi
HDPE Plastic Vials
Type 1 Glass Vial for multi
dosing purpose
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

38. Disposable Plastic/Glass Syringes
Syringes are devices for injecting, withdrawing or instilling fluids. Syringes consists of a glass or plastic barrel with a tight fitting plunger at one end, a small opening at the other end ac-comodates the head of a needle. Needle Gauge is the outside diameter of the needle shaft; the larger the number, the smaller the diameter. Gauges in common use range from 13 (largest diameter) to 27. Subcutaneous injections usually require a 24-gauge or 25- gauge needle. Intramuscular injections require a needle with a gauge between 19 and 22. Needles between 18 gauge and 20 gauge are commonly used for compounding parenterals.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

39. Disposable plastic syringe Disposable glass syringe
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

40. Prefilled Syringe
Prefilled Syringe: is a ready-to-use prefilled medication syringe with a needle attached, as with Insulin syringes, Interferon and some emergency drugs. As the pharmaceutical industry continues to seek out drug delivery methods that improve safety and efficiency while reducing costs, the traditional multidose or single-dose vial format for vaccines and injectables is starting to show its age. Developed markets are increasingly turning to packaging vaccines in prefilled, single-use syringes, with more and more companies recognising the benefits that come from this area's innovations. Prefilled syringes have been used to delivery drug categories like vaccines, therapeutic proteins, blood stimulants, erythroproteins and more.
"Syringes made from plastic-based cyclopoly olefin (COP) resin are becoming more common."
Advantages:
contamination prevention
ease of use and dosages
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

41. Cartridge Tubes
Cartridges are an ideal packaging for insulin and other drugs. They are used with pen or pump systems, auto injectors and needle free injectors.
The magnetic plungerless injection system is a hand held apparatus with a magnetically driven piston capable of displacing, moving and transferring liquid or gas through a cartridge chamber and into a sterile needle for injections. This apparatus works on the that a magnetic field penetrates glass and plastic walls of the cartridge. A magnet located outside of the cartridge walls and a Ferrous piston positioned inside of the cartridge create strong coupling with the piston repeating the movements of the magnet. Movement of the piston in one direction generates insertion of liquids and movement in the other direction generates extraction.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

42. Closures for Parenterals
Rubber Closures: These are used to seal the openings of cartridges, vials and bottles providing a material soft & elastic enough to permit entry & withdrawl of a hypodermic needle without loss of integrity of sealed container. Composition of Rubber Closure: It is made up of natural rubber (latex) & or a synthetic polymer, a vulcanising agent (sulfur), an accelerator (2-mercaptobenzothiazole), an activator (Zno), filler (carbon black/limestone) and other ingredients such as antioxidants & lubricants.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

43. The compatibility of rubber closures with the drug product is assessed by placing the closure in contact with the drug product & maintaining the samples at elevated temperature levels for planned periods of time. At prescribed intervals, samples are examined for quantitative and qualitative evidence of chemical/physical change either in the closure or in the product.
Physical Characteristics: Several properties of rubber closures are significant, particularly elastic, hardness & porosity. Rubber closures must be sufficiently elastic to provide a snug fit between the closure & the neck and lip of glass containers.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

44. The physical shapes of closures vary with their intended use
The physical shapes of closures vary with their intended use. The common shapes are flanged closure (center), slotted for freeze dried products, punctured for attachment of adapters for infusion sets & the plunger type for use with cartridge.
Testing of Rubber Closure: The USP describes physico chemical tests on aqueous extracts include pH, turbidity, residue on drying, Iodine number & heavy metals content. The biologic tests on saline, PEG 400 & cottonseed oil extracts include acute & chronic toxicity in mice & rabbits.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

45. Rubber Closures
There are a number of rubbers that may be used in pharmaceutical packing. Butyl rubber and chlorobutyl rubbers have the majority share of parenteral closure market. These materials offer the best resistance to permeation by oxygen and water vapor. Silicone rubbers have limited applications in pharmaceuticals as they are prone to tearing.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

46. Vial With Stopper :
Vials are mainly used for multiple dose parenteral preparation and are provided with the closure followed by aluminum seal to ensure the perfect air tight packing
Vial
Aqueous Injectable Of Any pH
Type I
Aqueous Injectables Of pH Less Than 7
Type II
Non-Aqueous Injectables
Type III
Closure:
Made from Butyl rubber ,Nitrile rubbers ,Neoprene, Silicon rubbers.
It has compression recovery, coring resistance, solvent resistance, heat resistant , radiation resistance with very low water absorption and permeability properties.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

47. Test of closure 1) Fragmentation test :
Place a volume of water corresponding to nominal volume minus 4 ml in each of 12 clean vials.
Close the vial with closure and secure caps for 16 hours.
Pierce the closures with 21 SWG hypodermic needle (bevel angle of 10 to 14) and inject 1 ml water and remove 1 ml air.
Repeat the above operation 4 times for each closure (use new needle for each closure).
Count the number of the fragments visible to the naked eye.
Total numbers of the fragments should not be more than 10 except butyl rubber where the fragments should not exceed 15.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

48. 2) Self sealability test for rubber closure applicable to multidose containers only.
Fill 10 vials with water with nominal volume and close the vials with closure, secure the cap.
Pierce the caps 10 times at different sites with 21 SWG hypodermic needle.
Immerse the vials in 0.1% w/v methylene blue solution under reduced external pressure (27K Pa) for 10 mins.
Restore the normal pressure and keep the container immersed for 30 mins.
Wash the vials. None of the vials should contain trace of colored solution
 3) Closure efficiency
Putting liquid in pack, inverting and applying a vacuum. A poor seal is detected by liquid seeping.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

49. Container-Closure Integrity Tests
Basic Principle
Advantages
Disadvantages
Acoustic Imaging
Ultrasonic energy focused onto sample submerged in water . Echo patterns produce images.
Visualize delamination
Expensive, Requires experts, not for porous materials.
Bubble test
Submerge package in liquid, pressurize and/or temperature cycling to accelerate leakage.
Simple, inexpensive, location of leaks can be observed.
Relatively insensitive.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

50. Container Closure Integrity Tests
Basic Principle
Advantages
Disadvantages
Helium mass spectometry
Helium is placed either inside or outside of the container and migration of helium is detected by mass spectometry.
Inert gas, extremely sensitive test
Expensive, expert personnel is required.
High Voltage Leak Detection(HVLD)
High voltage is applied to sealed container , increase in conductivity correlated to presence of liquid along the seal.
100% automatic inspection, non destructive.Used for ampoules, vials, syringes, blow/fill/seal containers.
Requires liquid fill products.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala

51. Container Closure Integrity Tests
Basic Principle
Advantages
Disadvantages
Residual Gas Ionization Test
High voltage field is applied to vials sealed under vaccum. The field causes residual gas to glow.
Used for Lyophilized products.
Inconsistencies in result.
Liquid Tracer Tests
Packaged immersed in solution of tracer chemical or dye. Pressure/vaccum or temp. cycling used to improve sensitivity. Leakage detected visually or mechanically
Operator independent, inexpensive
Destructive, Large sample numbers need.
STES, Sinhgad Instittute of Pharmaceutical Sciences, Lonavala