4202: Packaging Tecnology

Packaging Technology

Introduction

Packaging is an economical means of providing presentation, protection, identification/information, containment, convenience and compliance for a product during storage, carriage, display and use until such time as the product is used or administered. Pharmaceutical packaging provides protection for lifesaving drugs, surgical devices, blood and blood products, neutraceuticals, powders, poultices, liquid and dosage forms, solid and semisolid dosage forms.

Definitions

Packaging
Packaging is the process by which the pharmaceuticals are suitably packed so that they should retain their therapeutic effectiveness from the time of their packaging till they are consumed.

It is the art and science which involves preparing the articles for transport, storage, display and use.

Container

A container may be defined as a device in which the drug is enclosed and is in direct contact with the drug.

Closures

A closure is a device which seals the container to exclude oxygen, carbon-dioxide, moisture,
micro-organisms and prevent the loss of volatile substances.

Categorically differentiating pharmaceutical packaging

Primary Packaging: This is the first packaging envelope which is in touch with the dosage form or equipment. The packaging needs to be such that there is no interaction with the drug and will provide proper containment of pharmaceuticals. E.g. Blister packages, Strip packages, etc.

Secondary Packaging: This is consecutive covering or package which stores pharmaceuticals packages in it for their grouping. e.g. Cartons, boxes, etc.

Tertiary packaging: This is to provide bulk handling and shipping of pharmaceuticals from one place to another. e.g. Containers, barrels, etc.

Materials of construction refer to the substances (e.g., glass, high density polyethylene (HDPE) resin, metal) used to manufacture a packaging component.

A packaging component means any single part of a container closure system. Typical components are containers (e.g., ampules, vials, bottles), container liners (e.g., tube liners), closures (e.g., screw caps, stoppers), closure liners, stopper over seals, container inner seals, administration ports (e.g., on large-volume parenterals (LVPs)), overwraps, administration accessories, and container labels.

A primary packaging component means a packaging component that is or may be in direct contact with the dosage form.

A secondary packaging component means a packaging component that is not and will not be in direct contact with the dosage form.

A container closure system refers to the sum of packaging components that together contain and protect the dosage form. This includes primary packaging components and secondary packaging components, if the latter are intended to provide additional protection to the drug product.

A packaging system is equivalent to a container closure system.

A package or market package refers to the container closure system and labelling, associated components
(e.g., dosing cups, droppers, spoons), and external packaging (e.g., cartons or shrink wrap). A market package is the article provided to a pharmacist or retail customer upon purchase and does not include packaging used solely for the purpose of shipping such articles.

Quality refers to the physical, chemical, microbiological, biological, bioavailability, and stability attributes that a drug product should maintain if it is to be deemed suitable for therapeutic or diagnostic use. In this guidance, the term is also understood to convey the properties of safety, identity, strength, quality, and purity.

An extraction profile refers to the analysis (usually by chromatographic means) of extracts obtained from a packaging component.

A quantitative extraction profile is one in which the amount of each detected substance is determined.

Purposes of packaging

The package passes through a number of stages, beginning with the container manufacturer, thence to the product manufacturer, wholesaler, retailer and finally the consumer.

Therefore the packaging should perform the following purposes

1. Protect the contents from the environmental hazards: This includes

1. Light - protect the contents from light.
2. Temperature - withstand extremes of temperature.
3. Moisture - withstand extremes of humidity.
4. Atmospheric gases - protect the contents from the effect of atmospheric gases (e.g. aerial oxidation).
5. Particles - protect from particulate contamination.
6. Microorganisms - protect from microbial contamination.

2. Protects the content from the mechanical hazards: This includes

1. Vibration - Usually due to transportation.
2. Compression - this usually includes pressure applied during stacking.
3. Shock - such as impact, drops or rapid retardation.
4. Puncture - penetration from sharp objects or during handling operations.
5. Abrasion - this may create electrostatic effects.

3. To prevent the addition or loss of its contents: This includes

1. Protect the contents from both loss and gain of water.
2. Protect the contents from loss of volatile materials.
3. Must not shed particles into the contents.
4. Must not leach anything to the contents.

4. Provide pharmaceutically elegant appearance: This includes

1. In a competitive market the appearance of a package first draws the attraction of the consumers than its contents.
2. Must be easy to label and thus to identify the product.

5. Product identification

The package must also give clear identification of the product at all stages and again the life of the patient may depend upon rapid and correct identification in emergencies.

6. Convenience

The form of the package should be such that, it offers convenience at all stages of its life history.

Properties of packaging materials

The good packaging materials i.e. the containers and closures must meet the following criteria. (Ideal properties of containers and closures)

1. The material must give the container sufficient strength to withstand the extremes of temperature and pressure as well as to withstand handling while empty, while filling, closing, sterilizing, labelling, transport, storage and use by the consumer.

2. The material should be impervious to any possible contaminants; for example solids, liquids, gases vapours or microorganisms.

3. It should not interact with the contents. This includes migration, absorption, adsorption or extraction. e.g. Absorption of water from creams into cardboard boxes.

4. It should protect the contents from the loss of product due to leakage, spillage or permeation.

5. It should protect the contents from the loss of water and volatile materials.

6. The container must not impart its own colour, test or odour to the preparation.

7. It must not alter the identity of the product.

8. They must be FDA (Food & Drug Administration) approved,

9. They must meet applicable tamper-resistance requirements

10. They must be adaptable to commonly employed high-speed packaging equipment.
11. Must be cheap and economical i.e. they must have reasonable cost in relation to the cost of the product.
12. They must be convenient and easy to use by the patient.
13. They must be non-toxic and biodegradable.
14. The container and closure must not react either with each other or with the preparation.
15. Apart from all these a container and closure should be attractive in appearance and must have sale promotion and marketing value.

Shelf-life: The shelf life (t90) of a pharmaceutical product is the length of time the product may safely be stored on the dispensary shelf before significant decomposition occurs. This is important since, at best, drugs may decompose to inactive products; in the worst case the decomposition may yield toxic compounds. The shelf-life is often taken to be the time for decomposition of 10% of the active drug to occur, leaving 90% of the activity.

Factors influencing the choice of packaging

The choice of package is governed by the facilities available and by the ultimate use of the product.

Some of the important aspects include

1. The physical form of the product e.g. solid, semisolid, liquid or gas.
2. Chemical and physical characteristics of the drug entity, the excipients and the formulation;
3. Product detail covering any recognized routes of deterioration or degradation.
4. The dosage form and frequency of dosage,
5. The route of drug administration e.g. oral, parenteral, or external.
6. Type of patient (baby, child, teenager, adult, elderly, infirm etc.),
7. The stability of the product i.e. its protective needs.
8. Interaction of the product with the packaging materials.
9. Marketing requirements of the product.
10. The eventual channels of sale, i.e. where, when, how and by whom it is to be used or administered (e.g. doctor, dentist, nurse, patient etc.)
11. Whether the product is seasonal or has a year round use may be a further influence on pack selection.
12. The place of using the product, i.e. Clinic, Home, Hospital etc.
13. The distribution system, for example conventional wholesale/retail outlets, or direct to selected outlets.
14. The suitability of the manufacturing facilities may have to be considered for a number of reasons, i.e . New pack increased sales, improvements in GMP, revised product, new product etc.
15. Over all costs should be considered in order to make a cost effective quality product.

Types of Container

The containers can be classified into the following types.

1. Well closed containers: A well closed containers is used to protect the preparation from contamination by extraneous solids to prevent the loss of potency of active constituents and to prevent the loss of contents during transport, storage and handling.

2. Air-tight containers: Air-tight containers are used to protect the containers from atmospheric contamination of liquids, solids or vapors. They prevent the drugs due to efflorescence, deliquescence or evaporation.
3. Hermetically-Sealed containers: Hermetically sealed container is that which does not allow the air or other gases to pass through it. They are generally used for injectables.

4. Light-resistant containers: Light resistant containers are used to protect the drugs which undergo decomposition in the presence of light. For e.g .Amber colored glass or opaque glass.

5. Single dose containers: They are used to supply only one dose of the medicament. They are sealed in such a way that the contents cannot be removed without removing the seal; the contents so removed are consumed immediately. e,g. ampoules.

6. Multi dose containers: A multi dose container should hold a number of doses. It is sealed in such a way that success doses can be withdrawn easily without changing the strength, quality or purity of the remaining contents e.g multi dose vials.

7. Aerosol containers: Containers for aerosols must be strong enough to withstand the pressure evolved inside the container at the time of use of preparation.

Classification of containers according to their shapes

1. Glass / polyethylene bottles.

(i) Narrow mouth

(ii) Wide mouth

2. Dropper bottles/ droptainers

3. Collapsible tubes

4. Ampoules

5. Vials

6. Polythene packets for i.v. fluid.

7. Polythene / glass bottle for i.v. fluids

1. Glass / Polyethene bottles

• Wide mouthed bottles are used for containing solid dosage forms like powder, capsules, and tablets. To absorb the moisture sometimes silica-gel bags are given inside the bottle.
• For low viscosity liquids e.g. gargles, mouth washes, mixtures, elixirs narrow mouthed bottle is used. For high viscosity liquids or for suspensions wide-mouthed bottles are used.
• Liquid preparations for external uses like lotion, liniments, paints etc. are supplied in coloured fluted bottles in order to distinguish them from preparations meant for internal use.

2. Dropper bottles or droptainers: Eye drops, ear drops, nasal drops etc. should be dispensed in amber colour glass bottles fitted with a dropper. Now-a-days manufacturers prefer plastic droptainers. It is a single piece of squeezable container having an in built dropper.

3. Collapsible tubes: Ointments, pastes, gels are packed in plastic or metal tubes.
   
4. Ampoules: Ampoules are made of special type of neutral glass having low m.p. so that it can be heat sealed at low temperature.

5. Vials: Used for storing multi dose indictable preparation. The needle is passed through the rubber closure, the drug is drawn out. The rubber plug automatically seals the hole. Thus contamination of bacteria is checked.

6. Polyethene packets for infusion fluid: These flexible bags or packets are made of PVC, polyethylene or polypropylene.

7. Glass bottles for i.v. fluids: Previously glass bottles with big rubber stoppers were used.

Materials used for the making of containers

The following materials are used for the construction of containers and closure

1. Glass:  

1. Type I ( Neutral or Borosilicate Glass)
2. Type II ( Treated Soda-lime glass)
3. Type III ( Soda-lime glass)
4. Type IV- General Purpose soda lime glass
5. NP—soda glass (non parenteral usage)
6. Coloured glass
7. Neutral glass

2. Metals: a) Tin b) Iron c) Aluminium d) Lead.

3. Plastics: a) Thermosetting resins : (i) Phenolics

           (ii) Urea

            b) Thermoplastic resins: (i) Polyethylene

(ii) Polypropylene

(iii) Polyvinylchloride (PVC)

(iv) Polystyrene

(v) Polycarbonate

(vi) Polyamide (Nylon)

(vii) Acrylic multipolymers

(viii) Polyethylene terephthalate (PET)

4. Rubber: a) Natural rubber

b) Neoprene rubber

c) Butyl rubber.

5. Fibrous material
6. Films, foils and laminates

Glass and Glass Containers

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

1. They have good protection power as they are impermeable to atmospheric gases and moisture with a proper closure system.
2. They are relatively non-reactive (depending on the grade chosen).
3. They can be used on high speed packaging lines.
4. They can be easily labeled.
5. They are usually transparent.
6. Colored glass especially amber, can protect the photosensitive medicaments from light during their storage.  
7. They are hygienic and suitable for sterilization; as they can withstand the variation in temperature and pressure during sterilization.
8. They are neutral after proper treatment.
9. They do not deteriorate with age.
10. They are economical and easily available in various shapes and sizes.

Disadvantages

1. Glass is fragile so easily broken.
2. They are heavier in comparison to plastic containers.
3. Release alkali to aqueous preparation.
4. They may crack when subjected to sudden changes of temperature.
5. Some containers can impart alkalinity and insoluble flakes to the formulations.
6. Transparent glasses gives passage to UV-light which may damage the photosensitive drugs

Flaking

During flaking the alkali is extracted from the surface of the glass containers and a silica rich layer is formed which sometimes gets detached from the surface and can be seen in the contents in the form of shining flakes. This is a serious problem, especially in parenteral preparations.

              
Fig; Flacking                Fig: Weathering

Weathering

Weathering is a common problem with glass containers in which sometimes moisture condensed on the surface of glass container, can extract some weakly bonded alkali, leaving behind a white deposit of alkali carbonate. Further condensation of moisture will lead to the formation of an alkaline solution which will dissolve some silica resulting in loss of brilliance from the surface of glass  called weathering.

To prevent weathering, the deposited white layer of alkali carbonates should be removed as early as possible by washing the containers with dilute solution of acid and then washing thoroughly with water.

Types of glass

1. Type I ( Neutral or Borosilicate Glass)
2. Type II ( Treated Soda-lime glass)
3. Type III ( Soda-lime glass)
4. Type IV- General Purpose soda lime glass
5. NP—soda glass (non-parenteral usage)
6. Colored glass
7. Neutral glass

1. Type I-Borosilicate glass:

Highly resistant and chemically inert glass. Alkali’s and earth cations of glass are replaced by boron and/or aluminum and zinc. These are used to contain strong acids and alkalis.

2. Type II-Treated soda-lime glass:

These are more chemically inert than Type I glass. The glass surface is de-alkalized by
“Sulfur treatment” which prevents blooming/weathering from bottles.

3. Type III- Regular soda lime glass:

Untreated soda lime glass with average chemical resistance.

4. Type IV- General Purpose soda lime glass:

Glass is not used for parenterals, used only for products intended to be used orally or topically.                                                                                                          

Type of glass	Main Constituents	Properties	Uses
Type-I Borosilicate glass e.g. Pyrex, Borosil	SiO2 − 80% B2O3 − 12 Al2O3 - 2% Na2O+CaO - 6%	Has high melting point so can withstand high temperature Resistant to chemical substances Reduced leaching action	Laboratory glass apparatus For injections and For water for injection.
Type-II Treated soda-lime glass	Made of soda lime glass. The surface of which is treated with acidic gas like SO2 (i.e. dealkalised) at elevated temperature (5000C) and moisture.	The surface of the glass is fairly resistant to attack by water for a period of time. Sulfur treatment neutralizes the alkaline oxides on the surface, thereby rendering the glass more chemically resistant.	Used for alkali sensitive products Infusion fluids, blood & plasma. Large volume container
Type-III Regular soda-lime glass	SiO2 Na2O CaO	It contains high concentration of alkaline oxides and imparts alkalinity to aqueous substances Flakes separate easily. May crack due to sudden change of temperature.	For all solid dosage forms (e.g. tablets, powders) For oily injections Not to be used for aqueous injection Not to be used for alkali-sensitive drugs.
Type of glass	Main Constituents	Properties	Uses
Type NP Non-parenteral glass or General purpose soda-lime glass.			For oral and Topical purpose Not for ampoules.
Neutral Glass	SiO2 − 72-75% B2O3 − 7-10% Al2O3 − 6% Na2O − 6-8% K2O − 0.5 − 2% BaO − 2-4%	They are softer and can easily be moulded Good resistance to autoclaving Resistant to alkali-preparations (with pH upto 8) Lower cost than borosilicate	Small vials (<25 ml) Large transfusion bottles
Neutral Tubing for Ampoules	SiO2 − 67% B2O3 − 7.5% Al2O3 − 8.5% Na2O − 8.7% K2O − 4% CaO − 4% MgO − 0.3%	In comparison to neutral glass its melting point is less. After filling the glass ampoules are sealed by fusion and therefore the glass must be easy to melt.	Ampoules for injection.
Coloured glass	Glass + iron oxide	Produce amber colour glass Can resist radiation from 290           400           450nm       UV             Visible	For photosensitive products.

Metal and metal containers

Metals are used for construction of containers. The metals commonly used for this purpose are aluminium, tin plated steel, stainless steel, tin and lead.

Advantages

1. They are sturdy. (শক্ত)
2. They are impermeable to light, moisture and gases.
3. They can be made into rigid unbreakable containers by impact extrusion.
4. They are light in weight as compared to glass containers.
5. Labels can be printed directly on to their surface.

Disadvantages

1. They are expensive.
2. They react with certain chemicals
3. They may shed metal particles into the pharmaceutical product.

COLLAPSIBLE TUBES METAL

The collapsible metal tube is an attractive container that permits controlled amounts to be dispensed easily, with good enclosure, and adequate protection of the product. It is light in weight and unbreakable and lends itself to high speed automatic filling operations.  

Most commonly used are tin, aluminium and lead.

TIN

Advantages:

1. This metal is very resistant to chemical attack.
2. Readily coats a number of the metals e.g. tin-coated lead tubes combine the softness of lead with the inertness of tin and for this reason it was formerly used for packaging fluoride toothpaste.

Disadvantage:

Tin is the most expensive metal among tin, lead, aluminium and iron.

Uses:

1. Tin containers are preferred for foods, like milk powder containers are coated with tin.
2. Currently, some eye ointment still packaged in pure tin ointment tubes.

ALUMINIUM

Advantages:

1. Aluminium is a light metal-hence the shipment cost of the product is less.
2. They provide attractiveness of tin at somewhat lower cost.
3. The surface of aluminium reacts with atmospheric oxygen to form a thin, tough, coherent, transparent coating of oxide, of atomic thickness, which protects the metal from further oxidation.

Disadvantages:

1. Any substance that reacts with the oxide coating can cause corrosion e.g. products with the oxide coating can cause corrosion e.g. products of high or low pH, some complexing agents etc.
2. As a result of corrosion process H2 may evolve.

Uses:

1. Aluminium ointment tubes.
2. Screw caps
3. Aluminium strips for strip-packaging of tablet, capsules etc. Sometimes internally lacquered aluminium containers are used to stop the reaction with the content.

LEAD

Advantages:

1. Lowest cost of all the metals used in pharmaceutical containers.
2. Soft metal.

Disadvantage:

Lead when taken internally there is risk of lead poisoning. So lead containers and tubes should always have internal lining of inert metal or polymer.

Use:

With lining lead tubes are used for such product as fluoride tooth paste.

IRON

Advantages: Iron as such is not used for pharmaceutical packaging, large qualities of tin-coated steel, popularly called ‘tin’, combines the strength of steel with the corrosion resistance of tin.

Disadvantages: If an aqueous liquid can penetrate a pinhole or other fault in the layer of tin, which is virtually a short-circuited galvanic cell is set up and the intense chemical reaction which results brings about rapid corrosion of underlying steel. As a further measure the tin surface is lacquered.

Uses: Screw caps and aerosol cans.

Plastic and plastic containers

Plastics may be defined as any group of substances, of natural or synthetic origins, consisting chiefly of polymers of high molecular weight that can be moulded into a shape or form by heat and pressure.

Advantages

1. They are light in weight than glass and can be handled easily.
2. They are poor conductor of heat.
3. They have sufficient mechanical strength.
4. They can be transported easily.
5. Extremely resistant to breakage.
6. They are available in various shapes and sizes.
7. They are resistant to inorganic chemicals.
8. They have good protection power.
9. Flexible.
10. Variety of sizes and shapes.
11. Essentially chemically inert, strong, rigid, high quality, various designs.

Disadvantages

1. All are permeable to some degree to moisture, oxygen, carbon dioxide etc.
2. Most exhibit electrostatic attraction.
3. Allow penetration of light rays unless pigmented black etc.
4. Poor printing, thermostatic charge.
5. They cannot withstand heat without softening or distorting.(বিকৃত করা,)
6. They may interact with certain chemical to cause softening or distortion.
7. They may absorb chemical substances, such as preservatives for solution.
8. Over all they are prone to possible extraction, interaction, adsorption, absorption, lightness and hence poor physical stability.

Other possible negative features include:

1. Stress cracking: a phenomenon related to low density polythene and certain stress cracking agents such as wetting agents, detergents and some volatile oils;

2. Panelling or cavitation: whereby a container shows inward distortion or partial collapse owing to absorption of gases from the headspace, absorption causing swelling of the plastic, or dimpling following a steam autoclaving operation.

3. Crazing: a surface reticulation which can occur particularly with polystyrene and certain chemical substances (isopropyl myristate first causes crazing, which ultimately reaches a state of total embrittlement and disintegration).

4. Poor key of print: certain plastics, such as the polyolefins, need pre-treating before ink will key. Additives that migrate to the surface of the plastic may also cause printing problems.

5. Poor impact resistance: both polystyrene and PVC have poor impact resistance. This can be improved by the inclusion of impact modifiers, such as rubber in the case of polystyrene and methyl methacrylate butadiene styrene for PVC. However, both increase the permeability of each.

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 (On heating, they soften to a viscous fluid) 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. Polyethylene, polypropylene, polyvinylchloride, polystyrene, nylon (polyamide), polycarbonate, acrylic multipolymers, polyethylene terephthalate etc.

• Thermosets

When heated, they may become flexible but they do not become liquid; usually their shape is retained right up to the temperature of decomposition. Because of a high degree of cross-linking they are usually hard and brittle at room temperature.

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.

Examples of Plastics

Poly ethylene:          

This is used as high and low density polyethylene

Low density polyethylene (LDPE) is preferred plastic for squeeze bottles.

High density poly ethylene (HDPE) is less permeable to gases and more resistant to oils, chemicals and solvents. It is widely used in bottles for solid dosage forms.

Polyvinylchloride (PVC): Used as rigid packaging material and main component of intravenous bags.

Poly Propylene:  It has good resistance to cracking when flexed. Suitable for use in closures, tablet containers and intravenous bottles.

Polystyrene:  It is also used for jars for ointments and creams with low water content.

Drug-Plastic Consideration

A packaging must protect the drug without altering the composition of the product until the last dose is removed.

Drug plastic considerations have been divided into five separate categories:-

(1) Permeation, (2) leaching, (3) sorption, (4) chemical reaction, and (5) alteration in the physical properties of plastics or products.

1. PERMEATION

The transmission of gases, vapours or liquids through plastic packaging materials can have an adverse effect on the shelf-life of a drug.

1. Permeation of water vapour and O2 through the plastic wall into the drug can cause a problem if the dosage form is sensitive to hydrolysis and oxidation. Temperature and humidity influences the permeability of oxygen and water.

e.g. Nylons are hydrophilic in nature, and are poor barrier for  water while hydrophobic materials as polyethylene provide much better barriers.

2. Formulations containing volatile ingredients may change when stored in plastic containers due to the permeation of one or two ingredients through the walls of the containers. Often, the aroma of cosmetic products become objectionable and the taste of medicinal products changes.
3. Certain w/o emulsions cannot be stored in a hydrophobic plastic bottle, since there is a tendency for the oil phase to migrate and diffuse into the plastic.

2. LEACHING

Additives those are added in the plastics may leach into the content. Particular dyes may migrate into a parenteral solution and cause a toxic effect.

Release of a constituent from the plastic container to the drug product may lead to drug contamination, may catalyse some reaction in the solution - decomposing the drug.

3. SORPTION

This process involves the removal of constituents from the drug product by the packaging material. Drug substances of high potency are administered in small doses. In this case losses due to sorption may significantly affect the therapeutic efficacy of the preparation.

A common problem is the loss of preservatives. These agents exert their activity at low concentration, and their loss through sorption may be great enough to leave a product unprotected against microbial growth.

Factors influencing the characteristics of sorption from products are:

1. chemical structure of the solute,
2. pH,
3. solvent system,
4. concentration of solute,
5. temperature,
6. time of contact and
7. area of contact.

4. CHEMICAL REACTIVITY

Certain ingredients that are used in plastic formulations may react chemically with one or more components of a drug. Ingredients in the formulation may react with the plastic. Even micro-quantities of chemically incompatible substances can alter the appearance of the plastic or the drug product.

5. MODIFICATION

The physical and chemical alteration of the packaging material by the drug product is called modification. Deformation in polyethylene containers is often caused by permeation of gases and vapours from the environment or by loss of content through the container walls.

1. Oils have a softening effect on polyethylene and PVC.
2. Fluorinated hydrocarbons attack polyethylene and PVC. In some cases the content may extract the plasticizers, antioxidant or stabilizer, thus changing the flexibility of the package.
3. Plasticizers when extracted by some solvents renders the wall stiff.

Rubber

Natural rubber consists of long chain polymers of isoprene units linked together in the cis-position. Its most important source is the tree Hevea braziliensis from which a latex, containing 30 to 40% of rubber in colloidal suspension, exudes when shallow cuts are made in the bark.

The main types of rubber used for pharmaceutical products include natural rubber, neoprene, nitrile, butyl, chlorobutyl, bromobutyl and silicone rbber.

Categories of Rubbers

Mainly two types of rubbers are used

1. Natural rubber: Suitable for multiple use closures for injectable products as rubber reseals after multiple insertion of needle.

Disadvantages:

1. It doesn't well tolerate multiple autoclaving; whereby they become brittle and leads to relative degree of extractable material in presence of additives.
2. Risk of product absorption on or in to a rubber.
3. It has certain degree of moisture & gas permeation.

2. Synthetic rubber: Have fewer additives and thus fewer extractable and tends to experience less sorption of product ingredients.

Disadvantages:

1. They are less suitable for repeated insertions of needle because they tend to fragment
2. Sometimes the core pushes small particles of the rubber in to the product.

e.g. Silicone, butyl, bromobutyl, chlorobutyl etc.

Examples of Rubbers

BUTYL RUBBER

These are copolymers of isobutylene with 1-3% of isoprene or butadiene.

Advantages

1. After vulcanization butyl rubber possesses virtually no double bond, consequently they are most resistant to aging and chemical attack.
2. Permeability to water vapour and air is very low.
3. Water absorption is very low.
4. They are relatively cheaper compared to other synthetic rubbers.

Disadvantages

1. Slow decomposition takes place above 1300°C.
2. Oil and solvent resistance is not very good.

NITRILE RUBBER

Advantages:

1. Oil resistant due to polar nitrile group.
2. Heat resistant.

Disadvantage

Absorption of bactericide and leaching of extractives are considerable.

CHLOROPRENE RUBBERS (NEOPRENE)

These are polymers of 1:4 chloprene.

Advantages

1. Due to the presence of Cl group close to the double bond, resistant to oxidation.
2. This rubber is more polar hence oil resistant.
3. Heat stability is good (up to 1500°C).
4. Water absorption and permeability are less than for natural rubbers.

SILICONE RUBBERS

Advantages

1. Heat resistance (up to 2500°C).
2. Extremely low absorption and permeability of water.
3. Excellent aging characteristics due to their saturated chemical structures.
4. Poor tensile strength.

Disadvantages

1. They are very expensive.
2. experience permeability to moisture and gas

Fibrous Materials

The fibrous materials are the important part of pharmaceutical packaging.

• Fibrous materials include: Papers, Labels, Cartons, Bags, Outers, Trays for Shrink Wraps, Layer Boards On Pallets, etc.

• The Applications as well as Advantages of Cartons include:
• Increases display area
• Provides better stacking for display of stock items
• Assembles leaflets
• Provides physical protection especially to items like metal collapsible tubes.
• Fiberboard outers either as solid or corrugated board also find substantial application for bulk shipments.

Regenerated cellulose film, trade names Cellophane & Rayophane, is used for either individual cartons or to assemble a no. of cartons.

Films, Foils & Laminates

Regenerated cellulose film based on viscose ( chemical used for manufacturing of rayon)
& laminating two or more types of films, cellulose coatings, foil and paper play different roles such as supportive, barrier, heat seal & decorative.

For Example: Aluminum foil even in the thinnest gauges offers the best barrier properties, which are not approached even by the most impermeable plastics.

Plastics, as either films or coatings, can be used for decoration, flexibility, to provide various barrier properties, heat seal ability, see-through properties (i.e. transparency), and to protect the other plies within the lamination.

Metallization a relatively new process whereby particles of metal are laid down onto a surface under vacuum, can significantly improve the barrier properties of a material but these do not approach the properties of a pure foil.

In the newer technology Co-Extrusion a number of plastic plies are extruded in combination to produce cheaper laminations.

Uses of films, foils, laminations:

• Strip packs
• Blister packs
• Sachets
• Diaphragm seals for bottles
• Liners for boxes either attached or loose bag-in-box systems & bags.

Foil blisters:  When sealed with a metal foil-cover, the blister can provide a hermetic pack i.e. an isolated system, which excludes any exchange of gases between the product & surrounding atmosphere.

Both blister and strip packs appear to offer a reasonable degree of child resistance; particularly if the materials are opaque (opinion based on actual recorded poisonings or accidents).

Alu-alu foil is the best pharmaceutical packaging film for tablets, capsules, which is taking place of PVC film.

Characteristics:

1. Applicable to tablets, capsules, pills, etc.
2. It's a good substitute for PVC sheet.
3. No cracking, delamination or pinholes.
4. It has the quite good blocking properties effectively protecting drugs from water vapor, oxygen and ultraviolet.
5. It is particularly suitable for packing moisture-sensitive drugs or those sold in the hot and humid areas.
6. Taking out a part of the drugs from the drug boards without any impact on other
   well-packaged drugs.
7. It is used by cold-moulding packaging machines where it is easily shaped by changing the mold.
8. Nice appearance can upgrade drug's image

Tamper Resistant Packaging

A tamper resistant package is provided with an indicator or barrier before entering the package, so that if this indicator or barrier is broken, the buyer immediately gets the evidence that the product has been opened or tampered. Especially over the counter products require tamper resistant packaging.

The following packages are approved by FDA as tamper resistant packaging systems:

Film wrappers Blister package Strip package Bubble pack Shrink seals and bands Foils, paper or plastic pouches

Bottle seals Tape seals Breakable caps Sealed tubes Aerosol containers Sealed cartons.

1. Film Wrapper

Film wrapper can be categorized into:

I. End-folded wrapper:

This is formed by passing the product into a sheet of overwrapping film, which forms the film around the product and folds the edges in a gift-wrap fashion. The folded areas are heat sealed by passing against a heated bar.

Materials: Cellophane coated in both side by heat sealable polyvinylidene chloride (PDVC) or nitrocellulose-PDVC provides durable moisture barrier.

Polypropylene coated with heat sealable acrylic coating or polypropylene is added with heat sealable modifiers.

II. Fin seal wrapper

The seals are formed by crimping the film together and sealing together the two inside surfaces of the film, producing a ‘fin’-seal.

In this case heated bars never comes in contact with the package, hence much greater and more consistent sealing pressure can be applied and consequently better sealing integrity can be accomplished.

Materials: Polyethylene or Surlyn (Du Pont’s Ionomer resin)

III. Shrink wrapper

In this type of packaging the product is packed within a thermoplastic film that has been stretched and oriented during its manufacture and that has the property of reverting back to its unstretched dimensions once the molecular structure is ‘unfrozen’ by application of heat.

As the film unwinds on the over-wrapping machine, a pocket is formed in the center fold of the sheet, into which the product is inserted. An L-shaped sealer seals the remainder of the overwrap and trims off the excess film.

Materials: Heat shrinkable grades of polypropylene, polyethylene and polyvinylchloride (PVC).

2. Blister package       Discussed in details later.

3. Strip package

4. Bubble pack

The bubble pack can be made in several ways but is usually formed by sandwiching the product between a thermoformable, extensible or heat-shrinkable plastic film and a rigid backing material. This is generally accomplished by heat-softenting the plastic film and vaccum drawing a pocket into the film in a manner similar to the formation of a blister in a blister pack-age.

5. Shrink Banding

The heat-shrinkable polymer is manufactured as an extruded orienred tube in a diameter slightly larger than the cap and neck ring of the bottle to be sealed. The heat-shrinkable material is supplied to the bottle as a printed, collapsed tube, either pre-cut to a specified length or in roll from for an automated person.

6. Foil, Paper or Plastic Pouches

The flexible pouch is a packaging concept capable of providing not only a package that is
temper- resistant but also a package with a high degree of environmental protection. A flexible pouch is usually formed during the product filling operation.

7. Bottle seal

A bottle may be made temper-resistant by bonding an inner seal to the rim of the bottle in such a way that access to the product can only be attained by irreparably destroying the seal. Frequently used inner seals are glassine and foil laminates.

 
8. Tape Seals

Tape sealing involves the application of a glued or pressure-sensitive tape or label around or over the closure of the package, which must be destroyed to gain access to the packaged product. The paper used most often is a high density lightweight paper with poor tear strength.

9. Breakable Caps

Breakable closures come in many different designs. The roll-on cap design used in the past for carbonated  beverages uses an aluminium shell, which is placed over the bottle neck during the capping operation.

10. Sealed Tubes

Collapsible tubes used for packaging are constructed of metal, plastic or lamination of foil, paper and plastic. Metal tubes are still used for those products that require the high degree of barrier protection afforded by metal.

11. Aerosol containers

The aerosol container used for pharmaceutical products is usually made of drawn aluminium. The inside of the container can be specially coated if product compatibility is a problem. A hydrocarbon propellant in its cooled liquid phase is added to the container along with the product, and a spray nozzle contained in a gasketed metal ferrule is crimped over the opening of the aerosol container.
A length of polyethylene tube, called a dip-tube, is attached to the inside of the spray nozzle and dips into the product, drawing product into the spray nozzle when the sprayer is activated.

The spray nozzles are usually metered to allow a specific dose to be dispersed with each spray.

12. Sealed Cartons

Folding paperboard cartons have been used as a secondary package for OTC products for many years. The popularity of this packaging mode is based on both functional and marketing consideration.

CLOSURES

Closures are the devices by means of which containers can be opened and closed.

Proper closing of the container is necessary because

• It prevents loss   of material by spilling or volatilization.
• It avoids contamination of the product from dirt, microorganisms or insects.
• It prevents deterioration of the product from the effect of the environment such as moisture, oxygen or carbon dioxide.

Material used for closures

The closures for containers meant for storage of pharmaceutical products are generally made from the following basic materials.

• Cork
• Glass
• Plastic
• Metal
• Rubber

• Cork: Cork is essentially a wood obtained from the bark of oak tree. It is used for the manufacture of stoppers for narrow mouth bottles.

Fig: Cork

• Glass: As compared to cork glass is an ideal material for stoppers but they do not provide leak proof closure as well as can easily slip out of the neck of the closure during transport and handling.

• Plastic: As compared to cork, glass, rubber and metal Plastic closures are becoming popular day by day as they are unbreakable, light in weight and can be easily molded into various shapes and sizes.

• Metal: Tin plate and aluminum are mostly commonly used for the manufacture of closures but aluminum is mostly used for this purpose.

RUBBERS (Elastomers)

Excellent material for forming seals, used to form closures such as bungs for vials or in similar applications such as gaskets in aerosol cans.

Categories of Rubbers:

Natural rubbers: Suitable for multiple use closures for injectable products as rubber reseals after multiple insertion of needle.

Synthetic rubber: Have fewer additives and thus fewer extractable and tends to experience less sorption of product ingredients.

Unit Dose packaging

Blister Packing: In blister packing the unit dosage forms are enclosed in between transparent blisters and suitable backing material usually aluminum foil.

Strip Packing: In strip packing the unit dosage of drugs are hermitically sealed in between strips of aluminum foil and/or plastic film.

Blister package

The blister package is formed by heat-softening a sheet of thermoplastic resin and vacuum drawing the soften sheet into a contoured mold. After cooling, the sheet is released from the mold and proceeds to the filling station of the packaging machine. The semi-rigid blister previously formed is filled with product and lidded with a heat-sealable backing material.

The backing material may be of two types:

(i) A push-through type or (ii) Peelable type.

Materials

The blister is prepared from polyvinylchloride (PVC)

PVC / polyethylene combinations

polypropylene

polystyrene.

For commercial reason and for machine performance the blisters on most unit dose packages are made of PVC. For moisture protection PVC may be laminated with polyvinylidene chloride (saran) or polychlorotrifluoroethylene (Aclar) films. Under extremely humid condition Aclar coated PVC is preferred.

For push through type backing material aluminium foil coated with heat sealable coating is used.

For peelable type backing material polyester or paper is used as a component of the backing lamination. This peelable type backing material is tamper proof and child resistant.

Advantages of Blister Package:

1. Reduced costs and higher packaging speeds relative to other packaging materials. Blister packaging helps retain product integrity because drugs that are prepackaged in blisters are shielded from adverse conditions.
2. Opportunities for product contamination are minimal.
3. Each dose is identified by product name, lot number, and expiration date.
4. Blister packaging protects pharmaceuticals in the home better than bottles do.
5. Each tablet or capsule is individually protected from tampering until use.

Types of pharmaceutical blister packaging machine

Two basic types of pharmaceutical blister packaging machine exists

Cold Forming Blistering machine:

In the case of cold forming, an aluminum-based laminate film is simply pressed into a mold by means of a stamp. The aluminum will be elongated and maintain the formed shape.

Advantage of cold form foil blisters is that the use of aluminum is offering a near complete barrier for water and oxygen, allowing an extended product expiry date.

The disadvantages of cold form foil blisters are the slower speed of production compared to thermoforming and the lack of transparency of the package and the larger size of the blister card.

Example: ALU-ALU Machine

Operation:

The sequence involves;

1. Installing the Aluminium Foil,
2. Cold forming it into blister cavities via punch pins,
3. Loading the blister with the product,
4. Placing lidding material over the blister,
5. And heat-sealing the package.
6. Cutting into individual blisters

Thermo-cold forming blistering machine:

In the case of thermoforming, a plastic film or sheet is unwound from the reel and guided though a pre-heating station on the blister line. The temperature of the pre-heating plates (upper and lower plates) is such that the plastic will soften and become moldable.

Example: ALU-Tropical Machine

Operation:

The sequence involves;

1. Heating the plastic,
2. Thermoforming it into blister cavities,
3. Loading the blister with the product,
4. Placing lidding material over the blister,
5. And heat-sealing the package.
6. Installing the aluminium foil
7. Cold forming it into blister Pouch & seal it on thermoformed blister to give extra protection,
8. Cutting into individual blisters

Strip package

A strip package is a form of unit dose packaging that is commonly used for package is formed by feeding two webs of a heat-sealable flexible film through either a heated crimping roller or heated reciprocating plates. The product is dropped into the pocket formed prior to forming the final set of seals.

A continuous strip is formed, generally several packets wide. The strip packets are cut to the desired number of packets in length.

The product usually has a seal around each tablet. The seal can be rectangular, or “picture-frame format” or can be contoured to the shape of the product.

Since the sealing is usually accomplished between pressure rollers, a high degree of seal integrity is possible.

Materials:

High barrier materials e.g. foil laminations, saran-coated films.

For higher barrier applications a paper/polyethylene/foil/polyethylene lamination is commonly used.

When product visibility is important a heat-sealable cellophane or polyester can be used.

                                                                                           Fig: Strip Packaging Machine

Quality Assurance Aspects of Packaging

To ensure that patients and consumers receive high-quality drugs, the quality management system must take the following considerations into account if the required quality of packaging is to be obtained:

• The requirements of the national authorities and the relevant legislation
• The product
• The production process
• The manufacturers’ internal policies (safety, marketing, etc.).

Bad packaging which is the result of deficiencies in the quality assurance system for packaging can have serious consequences, and packaging defects can create problems that may result in drug recalls. Such defects may include breakage, and problems relating to printing or inks, or errors on labels and package inserts (patient information leaflets). The use of GMP and quality control will prevent the release of a defective medicinal product.

Packaging processes and equipment need validation/qualification in the same way as any other part of processing within a pharmaceutical facility.

Sampling and testing of packaging materials

Sampling:

Sampling is used;

• To check the correctness of the label, packaging material or container reference, as well as in the acceptance of consignments,
• Detecting adulteration of the medicinal product, obtaining a sample for retention, etc.
• The sampling procedure must take into account the homogeneity and uniformity of the material so as to ensure that the sample is representative of the entire batch.
• The sampling procedure should be described in a written protocol.

Testing programme:

          Quality control tests are intended to check the identity of the material concerned. Complete pharmacopoeial or analogous testing may also be carried out, as may special tests, where necessary. All written specifications for packaging materials and containers should include the nature, extent and frequency of routine tests. Routine tests vary according to the type of material and its immediate packaging, the use of the product, and the route of administration.

Nevertheless, such tests usually include the following:

• visual inspection (cleanliness, defects)
• tests to identify the material
• dimensional tests
• physical tests
• chemical tests
• microbiological tests

EVALUATION OF PACKAGING MATERIALS

A. Test for hydrolytic resistance (limit of alkalinity)

Because none of the glasses used for pharmaceutical containers is completely free from extractable alkali a test for its absence is impractical and limit tests must be used:

1. Crushed glass test

This test is done on all types of glass containers except surface treated glass (i.e. Type-II, sulfured or siliconed surface). The container is crushed and sieved to produce uniform particle size of which a definite weight is taken. Control of particle size and weight of powder ensures that a constant surface area is exposed to the solution.

The measured amount of glass powder is then taken in a resistant glass beaker, measured amount of distilled water was added, autoclaved for 1/2 an hour at 1210C. The water was then cooled and filtered. Filtrate is titrated with standard H2SO4.

2. Whole container test

In case of surface treated glass container the intact container is taken, filled with distilled water and exposed to the autoclaving condition. The extracts from several containers are pooled and titrated with standard HCl (according to I.P.)

Type	Description	Test used	Size (ml)	Limits Volume of 0.05 N H2SO4 to neutralize the extract from 10g of glass (ml)
I	Highly resistant Borosilicate glass	Crushed glass	All	1.0
II	Treated soda lime glass	Whole  Container	100 or less	0.7 0.2
III	Soda -lime glass	Crushed Glass	Over 100	8.5
N.P.	General purpose soda-lime glass	Crushed  glass	All	15.0

B. Metal containers for eye ointments (IP 66)

Metal collapsible tubes comply with the following test for metal particles. According to IP 50 empty tubes are taken, filled with ointment base, sealed and kept and kept overnight.

A metal bacteriological filter assembly fitted with a suitable filter paper and heated to the melting range of the ointment base.

Ointment bases from all the tubes squeezed at a certain rate, pooled and passed through the heated filter under vacuum. The filter paper is washed with chloroform.

The filter paper is dried and observed with magnifying glass under oblique light. The observations are noted as follows:

Particles 1 mm and above Particles 0.5 mm to 1 mm Particles 0.2 mm to 0.5 mm Particles less than 0.2 mm	50 10 2 Nil
Total score	62

The lot of tube passes the test if the total score is less than 100 points. If the score is above 150, the lot fails. If it is between 100 and 150 the test is repeated again with 50 more tubes. This time the lot will pass if total 100 tubes give 150 points.

C. Plastic containers

i) Leakage test

Ten containers are filled with water, fitted with the closures and are kept inverted at room temperature for 24 hours. There should be no signs of leakage from any container.

ii) Collapsibility test

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

iii) Transparency test

A 16-fold dilution of a standard suspension described in IP96 is prepared so as to give an absorbance at about 640 nm of 0.37 to 0.43.

Five empty containers were filled to their nominal capacity suspension in each container is detectable when viewed through the containers, as compared with a container of the same type filled with water.

iv) Water vapour permeability test

Five containers are filled with nominal volume of water and heat sealed with aluminium foil-polyethylene laminate or other suitable seal. Each container is accurately weighed and allowed to stand for 14 days at a relative humidity of 60 ± 5% and a temperature between 20 to 250C.

After 14 days it is weighed again. The loss in weight in each container is not more than 0.2%.

Other tests

This includes:

*Tests for Barium, heavy metals, tin, zinc, etc.

*Test on extracts

*Test on extracts

Specified volume of extracting medium is taken in it. Plastic of specified surface area is cut and extracted.

With the extract following tests are carried out:

1. Appearance of the extract - must be colourless.
2. Light absorption
3. Non-volatile matter.
4. Residue on ignition.
5. Heavy metals
6. Buffering capacity
7. Oxidisable substances.

*Bacteriological tests are carried out to determine the biological response of animals to plastics and other polymeric material by the injection or instillation of specific extracts from the material under test.

Glass Transition Temperature (Tg)

The maximum temperature below which a material become rigid, brittle solids and are said to be in ‘glassy-state’. In this condition they are not crystalline but are super cooled liquids of high viscosity. Above the glass temperature (Tg) thermoplastics soften and melt if heated to a considerably higher temperature than Tg. Other plastics are very highly cross-linked and for these thermosetting plastics Tg is so high that decomposition takes place before the material can soften and melt.

BIBLIOGRAPHY

Cooper and Gunn’s “Tutorial Pharmacy”;  Sixth Edition; Chapter 09; Pitman Medical Publishing co Ltd England.

“Guidance for Industry Container Closure Systems for Packaging” Human Drugs and Biologics; Chemistry, Manufacturing, and Controls Documentation; U.S. Department of Health and Human Services Food and Drug Administration; Center for Drug Evaluation and Research (CDER); Center for Biologics Evaluation and Research (CBER); May 1999

Liberman, Lachman and Kanig, “The Theory & Practice of Industrial Pharmacy” Third edition; chapter 24; Lea & Febiger, Philadelphia U.SA.

M. E. Aulton “Pharmaceutics: the science of dosage form design” Second edition, Chapter 36; Churchill Livingstone.

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