PAPER-III

NDDS (PART-I)

Pharmaceutical Packaging

SEMINAR ON PHARMACEUTICAL PACKAGING

GUIDED BY: Dr. R. K. PARIKH

PREPARED BY:M.PHARM SEM- II (2009-10)

DEPT. OF PHARMACEUTICS & TECHNOLOGY L.M.COLLEGE OF PHARMACY AHMEDABAD-09.

M.PHARM SEM-II (2009-10) L.M.COLLEGE OF PHARMACY, AHMEDABAD 09

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Pharmaceutical Packaging

Definition: PACKAGING: It is the science, art and technology of enclosing or protecting product for distribution, storage, sale, and use. It also refers to the process of design, evaluation and fabrication of the packages.  PHARMACEUTICAL PACKAGING: It can be defined as means for providing protection, presentation, identification, information, convenience, compliance and compatible unit, which maintain the integrity and stability of the product.

Definition as per USP XXVII: WELL CLOSED CONTAINER: It protects the contents from extraneous solid and from loss of the article under the ordinary condition of handing, shipment, storage and distribution.  TIGHT CONTAINER: It protects contents from the contamination by extr aneous liquid, solid or vapor from loss of the article and from efflorescence, deliquescence or evaporation.  HERMETIC CONTAINER: It is impervious to air or any other gas under the ordinary condition of handing, shipment, storage and distribution.  LIGHT RESISTANT CONTAINER: It protects the contents from the effect of light. A clear and colorless or translucent container may be made light resistant by means of opaque covering.  TAMPER EVIDENT CONTAINER: The container or individual carton of a sterile article intended for ophthalmic or optic use which cannot be used without destruction of the seal.

Role of Packaging: Protection against y Light y Reactive gases y Moisture  Presentation  Identification  Information  Compatible  Convenience
y Microbes y Physical damage y Pilferage y Adulteration

New concept:     
Packaging builds brand identity of the product. Packaging way to differentiate the product with others. Revolution in retail by display of the product. Patient convenience Innovation through pack design Packing that fulfill emotional needs.

Objectives of Packaging: Physical protection: Package may require protection from other things, shock, vibration, compression, temperature.
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 Barrier protection: A barrier from oxygen, water vapor, dust is required.  Containment or agglomeration: Small dosages are typically grouped together in one package for reasons of efficient packaging physical handling.  Information transmission: Information on how to use, transports, recycle or dispose of the package or product is often contained on the package or label.  Marketing: The packaging and the labels are used by marketers for the purpose of encouraging potential buyers to purchase the product.  Security: Packages can be made with improved tamper resistance to deter tampering and also can have tampered evident features to help indicate tampering.  Convenience: Packages can have features, which add convenience in distribution, hand ling, display, sale, opening, reclosing, use and reuse.

Importance of Packaging:    
Protect against all adverse external influences that can alter the properties of the product. Protect against biological contamination. Protect against physical damage. Carry the correct information and identification of the product. Tamper evident / Child resistance/ Anti counterfeiting.

Functions of Packaging: Containment y Not to leak, nor allow diffusion and permeation y Strong enough to hold the contents during handling  Protection y Light y y Moisture y y Oxygen y

Biological contamination Mechanical damage Counterfeiting

Criteria for the Selection of package type and package material:               

Stability Compatibility with the contents Strength of container and the degree of protection required Moisture-proofness Resistance to corrosion by Acids or Alkalis Resistance to grease Protection against salt Resistance to microorganisms Resistance to insects and rodents Resistance to differences in temperature Protection against light, fire and pilferage Odor retention and transmission Aesthetic effect Cost Machine suitability of packaging and the filling method Convenience of the packaging for the physician, pharmacist and finally the patient (size, weight, method of opening/re-closing, legibility of printing)
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Pharmaceutical Packaging

Types of Packaging: Packaging may be two types: Transport package or distribution package is the package form used to ship, store and handle the product or inner packages.  Consumer package is directed towards a consumer or household. According to the packaging material, packaging may be three types: y Primary packaging y Secondary packaging y Tertiary packaging

Primary Packaging
 Primary packaging material is the material that first envelops the product and holds it, that is those package components and subcomponents that actually come in to contact with the product or those that may have a direct effect on the product s helf life.  Material characteristics y Primary Packaging material should not have adverse effect on product due to chemical reaction, leaching, absorption or adsorption, particulate contamination. y It should not be affected by product. y It should not be influ enced by adverse manufacturing condition (sterilization, freezing). y It must preserve the physical properties of all dosage forms and protect them against damage or breakage. y It must not alter the identity of the product. y It must preserve the characteristics properties of the product to comply specifications. y It must protect product against undesirable or adulterating chemical, biological or physical entities.
Choosing appropriate primary pack  Product characteristics\sensitivity y Hygroscopicity y Physical degradation y Chemical degradation y Drug release properties  Selection of packaging material y Moisture barrier requirements y Light barrier requirements

y Mechanical properties y Photosensitivity y Gas liberation tendency y Dimensional aspects y y Gas barrier requirements Chemical properties

Secondary packaging material used external to the primary pack which provides physical
protection to ensure safe warehousing and mechanical protection required in shipment and transport.It has functions: y Protection from excessive y Transmission of reactive gases y Moisture y Light y Microbes y Protection to flexible container y Protection from rough handling during transportation
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Tertiary packaging is used for bulk handling and shipping.

Primary Glass bottles, jars Plastic bottles Strip packs Blister packs Pouches Ointment tubes Vials, ampoules Pre-filled syringes Aerosol containers Pre-filled inhalers Paperboard containers Wrappers Secondary Cartons Prescription dispensing containers Corrugated boxes Paper drums Shipping containers Injection trays Tertiary Barrel Container Intermediate bulk container Slip sheet Crate Edge protector Pallets Stretch wrap

Components of Packaging: Container: It refers in which the product or medicine is placed and enclosed. It remains in direct contact with the drug.  Closure: It tightly packs the container to exclude oxygen, carbon dioxide, moisture and microbes and prevents the loss of water and other volati le substances form the product.  Carton\outer: It is the outer covering, which gives secondary protection against mechanical and other environmental hazards and also serves for display of written information. The cartons are made up of cardboard, molded woo d pulp and expanded polystyrene.  Box: In the box, multiples of the products are packed. It provides primary defense against external hazards and have shock absorbing features. They are made up of thick cardboard and wood.

Symbols used on Package and Labels: Many types of symbols for package labeling are nationally and internationally standardized.  Some requirements symbols exist to communicate aspects of consumer use and safety.  Bar codes, Universal Product Code, RFID labels, Resin identification code , and Recycling direction are common to allow automated information management.  Resin identification code consist of arrow that cycle clockwise to form rounded triangle and enclosing a number where as the number inside the recycling symbol indicates about the number of recycling process applied on plastic material.

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NDDS (PART-I)

Pharmaceutical Packaging

TYPES OF PACKAGING MATERIALS:Type of Materials Glass Plastic Rubbers Paper\cardboards Metals Use Bottles, vials, ampoules, syringes, aerosol containers. Bottles, syringes, tubes, bags, laminates, pouches, lids, taps, stems, aerosol containers. Closures, vial wrappers, caps, plungers. Labels, inserts, display units, pouches, laminates, cartons, boxes, foil, gum tapes, paper drums. Collapsible tubes, foils, needles, aerosol containers, cans.

 The choice of the packaging material will depend upon:

y y y y y y y The dosage form desired. The degree of the protection required. Compatibility with dosage form. Presentation and aesthetics Customer convenience e.g. size, weight of dosage form. Filling method Sterilization method to be employed and cost.

 The choice of the packaging for a specific product is dependent upon:

y y y y y y y The nature of product and its compatibility with material. The type of patient: child, elderly, adult. The type of dose: granules, tablet, ointment. Method and the site of administration. Method of distribution: hospital, pharma cy, retailer. Capacity of packaging needed. Required shelf life and likely sales area.

PACKAGING MATERIAL:Packaging material must have following properties:

 Mechanical properties
y Container should be strong enough to withstand the shock during handling, filling, closing, storage and transport. y It can withstand heat during sterilization. y It should be impermeable to avoid any loss of product or contamination by liquid, gases, vapors and microbes.

 Physico-chemical properties
y y y y y y The container should not absorb substances from the product. It should protect light sensitive drug. It should be non -reactive with the contents of preparation. Container and closure should not react with each other and preparation. It should not impart its own color, taste and odor to the preparation. Closure must be easy to remove and replace.
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Pharmaceutical Packaging

y The materials used in the container should be F.D.A. approved.

 Biological properties
y The container should not produce any toxic effect. y It should not affect the therapeutic value of the product. y It should have suitable life, which should be comparable with the stability period of the product. y It should be able to withstand attack by insect and should not support mould growth.

 Economical aspect
y Cost wise the container and closure should be reasonable. y The cost of the container should be proportionate with the cost of the product.

 Pharmaceutical properties
y Dosage form of the product: solid, semisolid, liquid or gas. y The route of administration of preparation: oral, parenteral, external. y The stability of the product towards: light, oxygen, moisture, carbon dioxide and trace metals.

PRIMARY PACKAGING MATERIALS:PLASTIC

 A plastic packaging material is supposed to be strong, light, aesthetic, pilfer-proof, protective, easy to carry, convenient to open, use or administer, close, dispose, and tamper evident.  This can be used as homo or co-polymer or in combination with aluminum and board.  It is consists of polymers of high melting point, capa ble of being molded in to variety of shapes and forms by utilizing heat or pressure.  Advantage y It has very good mechanical strength. y They are non breakable. y Range of the plastic material available, which may satisfy requirement of the pharmaceutical packaging. y They reduce the cost due to their less weight. y Plastic containers are obtainable in multipurpose design. y Plastic are poor conductor of heat.  Disadvantage y Plastic are permeable to vapor. y The presence of many additives may bring about the drug-plastic interaction y Alteration in physical properties of the product. y The majority of the plastics are sensitive to heat & cause leaching.  Additives are present in plastic containers; y Emulsifier y Modifiers y Acceleration y Stabilizers y Flame retardants y Anti static agents y Mould release agents y Extenders y Antiblocking agent y UV absorbers y Catalyst y lubricants y fillers y Antioxidants y Opacifiers y Colorant y light excluders y Plasticizers y Antislip additives
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Pharmaceutical Packaging

 Plastic may be two types: y Amorphous plastics are more permeable to gases and moisture but are less inert. They offer good clarity, transparency, and hardness with possible brittleness. y Crystalline plastics have low permeability to gases and moisture and are more inert. They are opaque or translucent and more flexible.
Types of Plastic 1.Polyolefin( low density polyethylene) Properties -Flexible, very light, tough -Impermeable to water, vapors. -High permeability to gases. -Permeable to oil preservatives. -lack of transparency -Non-adherence of labels -Charged with static electricity. -More rigid, translucent and inert. -Easy handling and filling container. -High resistant to oils. -Sterilized by autoclaving. -Impermeable to water, vapors. Similar to H.D.P., but lighter, less opaque, more heat resistant, inert, impermeable to water vapors, flexible acquired original shape, low cost. -Less flexible than polyethylene. -More permeable to water vapors. -Less permeable to gases than polyethylene. -High clarity. -Hard rigid -Light material -Easy to mould -Permeable to water vapors -Not sterilizable -Excellent heat resistance -Impermeable to water vapors. -Expensive -Difficult to fabricate -Resistance to solvents and chemicals. Application Cosmetics, personal product, foods, tubes for topical ointment, bottles, and suppositories pack.

2. High density polyethylene (H.D.P.)

-Disposable syringes -Packaging of pharmaceutical preparation, infusion fluid, bottles, jars, closures, detergents, milk, food and cosmetics. -Disposable syringes -For dialysis fluids -Drugs & cosmetics -Syrup, juices, squeeze bottle -For retention enemas -Bottle jars -Suppositories -For retention enemas.

3. Poly propylene

4. Polyvinylidene chloride(P.V.C.)

5. Polystyrene

-Spoon -Bottles -Jars closures -Not suitable for sterile product. -Bottles -Jars closures -Packaging films and laminates

6.Polytetrafluoroethylene (P.T.F.E.)

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Pharmaceutical Packaging

7. Polyamides(Nylon)

8. Polycarbonate

-Very tough -non transparent -highly permeable to water vapors -heat resistance -Transparent -Stable -Heat resistant

-Packaging films and laminates

-Packaging films and laminates

GLASS
 Glass is composed of sand, soda ash, lime-stone and cullet. Where sand represents for pure silica, soda ash for sodium carbonate and lime-stone for calcium carbonate. Cullet is broken glass that is mixed with the batch, which acts as fusion agent for entire mixture.  A number of glass containers in pharmaceutical industry incl ude ampoules, bottles, vials, syringes and cartridges.  It is economical, chemical inert, impermeable with no diffusion or leakage, strong and rigid, recyclable, hygienic, sterilizable, easily washable, resistant to high temperature, compatible and transparent. It provides good light protection.  Advantages y Glass as a packaging material is chemically inert. y It imparts no odor and taste to the product. y It is non-corrosive. y It is strong and rigid. y It is impermeable to water vapors. y It is transparent and sparkles. y Glass posses FDA approval. y It does not undergo any change on aging.  Disadvantage y Glass is fragile. y It offers less pressure safety and impact resistance. y It has high cost due to the high weight. Types Properties Application
Type I Highly resistant, borosilicate glass Type II Treated sodalime glass Type III Soda-lime glass Alkalinity is removed by using boric oxide to neutralize the oxides of potassium and sodium. Obtained by treating the hot surface of the type III glass by sulfur dioxide/ammonium sulfate/ammonium chloride. It is an alkaline glass having a high percentage of lime and soda and no boric oxide as compare to the type I glass. -Preparation of Parenteral administration. -For alkali sensitive materials. -Chemical, glassware, ovenware. -Preparation for Parenteral administration. -For alkali sensitive materials. -For blood plasma. -Not generally used for parenteral preparation until and unless indicated. -Not for alkali sensitive materials. -Only for non-aqueous products.

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Pharmaceutical Packaging

Type NP General purpose soda-lime glass Colored glass

It has similar composition to that of the type III glass but has no similar properties. -In addition to glass composition, metal salts, carbon and sulfur or iron and manganese for Amber color. -Does not allow the UV rays to pass through it. As lead monoxide is used in manufacturing of glass cause lead poisoning.

Non parenteral article as oral or topical use. -Used for light sensitive material product. -Do not use for parenteral unless specified. -Used for liquid preparation. -Used when preparation meant for lead poisoning e.g. Na E.D.T.A. -Used for liquid preparation.

Lead free glass

Silicon treated

-Surface is treated with dimethyl siloxane. -As hydrophobic nature not welled so product do not cling to surface.

 Colored glass
y In colored glass, minerals like copper for red, blue or green, iron for black, tin for yellow are added. It also includes pale blue, dark blue, blue green, olive green, amber, yellow brown, red and black. y The color of the transparent material like glass is due to the absorption of light at certain wavelengths in visible spectrum. y There are several types of absorption: -Electron transfer between cations and anions. y Depending on the ions used, absorption can occur in either the visible or non -visible spectrum. y For e.g., Fe absorb around 1000 -1100 nm and gives the glass a blue tint. Cu can be formed by heat treatment and gives silver-yellow or golden-red color.

 Application y Glass is used for different containers ranging from ampoules, vials, cartridge tubes, disposable syringes and aerosol. y Ampoules are made up of neutral glass. There were one first unit dose containers but are being replaced by cartridge tubes and pre-filled syringes. y Vials are produced by soda glass when used for tablets and capsules. Injection vials can be obtained in neutral or soda glass of occasionally in treated soda glass.

Glass properties
1. Chemical properties  Sodium/alkali leaching 2. Electrical properties  Volume resistivity 3. Mechanical properties  Stress 4. Optical properties  Refractive index  Dispersion

 Alkali/Acid resistance  Surface resistivity  Density  Absorption  Transmission  Dielectric constant  Specific gravity  Reflectivity  Birefringence constant

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5. Thermal properties  Coefficient of thermal expansion (CTE)  Thermal conductivity  Specific heat

 Thermal shock  Softening point

METALS
 Metal containers are strong, unbreakable, opaque and impervious to water vapor, glass odor and bacteria. They are resistant to high and low temperature.  Due to their chemical reactivity, metals require the application of coating and lacquers to prevent the chemical reaction and corrosion.  Metals are also used for the formation of closures. Some of these closures are similar to those used on the glass and plastic container e.g. plastic & m etal screw closures and friction closures such as plug /slip lids.

 Aluminium
y It is the most abundant of the all metals. The chief source of it is bauxite ore. y It has excellent corrosion resistance due to the thin surface layer of aluminium oxide that forms when the metal is exposed to the air, preventing the further oxidation. The strongest aluminium alloy has less corrosion resistance due to galvanic reactions with alloyed copper. y It is good thermal and electrical conductor and is capable of being superc onductor.  Precaution: y Aluminium is neurotoxin that alters the function of the blood -brain barrier and cause the Alzheimer s disease. y Allergic reaction, vomiting and other symptoms of poisoning are occur.

 Aluminium foil
y It is the aluminium prepared in thin sheets, as a result of this, the foil is extremely pliable, and can be bent or wrapped around objects with ease. y It is sometimes known as al-foil or alu-foil and tin-foil, silver paper, Reynolds wrap. y Millions of the aluminium foil are u sed for protection and packaging of food, cosmetics and chemical products. y It gives slight tin taste to food wrapped in it. y It is most widely used for packaging of tablets and capsules. y It offers excellent barrier properties to the moisture, gas and light. y It is mainly suitable for blister packs and strip packs. y Aluminium foil laminated with paper or plastic is used as heat sealed membrane hermetically closing the container under the plastic screw cap and provides excellent barrier properties preventing moisture or gas transmission and tamper evident seal.

 Tin
y Tin is malleable, ductile, highly crystalline, silvery white metal. It resists corrosion from distilled, seal and soft tap water, but can be attacked by strong acids, alkalis, and by acid salts. y Tin can be highly polished and is used as protective coat for other metals in order to prevent corrosion or chemical action. y It combines directly with chlorine and oxygen and displaces hydrogen from dilute acids.
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y It is malleable at ordinary temperature but brittle when it is heated. y Tin foil was once common wrapping material for foods and drugs; replaced in early 20 th century by the use of aluminium foil, which is now referred to as tin foil.

 Lead
y It has dull luster and is dense, ductile, very soft, highl y malleable, bluish white metal that has poor electrical conductivity. y This true metal is highly resistant to corrosion. Due to these properties, it is used to contain corrosive liquid (sulfuric acid). y It can be toughened by adding a small amount of antimo ny or other metals to it. y It is very poisonous. It changes the optical characteristics of the glass and reduces the transmission of radiation.

 Collapsible metal tube

y The collapsible metal tube is an attractive container that permits controlled amount to be dispensed easily, with good reclosure, and adequate protection of the product. The risk of the contamination of the portion remaining in the tube is minimal because the tube is not suck back . Any ductile metal can be worked cold as suitable for collap sible tubes, but the most common ones in use are tin, aluminium and lead. y Small tubes are often made of tin even though the metal cost is higher. Laminates of tin coated lead provides appearance and oxidation resistance at lower prices. y Aluminium tubes offer significant saving in product shipping costs because of their light weight and provide attractiveness of tin at lower cost. y Lead has lowest cost of all the tubes metal and is widely used for the product as fluoride toothpaste. y Wax linings are most often used with water based products in tin tubes, and phenolics, epoxides, and vinyls are used with aluminium tubes, giving the better protection against alkaline materials than wax, but at higher cost.

 Laminates
y Laminates are combination of different plies put together to get some desired properties. These form thin films using minimum material are cost effective. y Any laminate may consist of number of plies selected from paper, cellulose, film foils coating, etc, depending upon: y Availability of the material. y Technical requirements. y Cost of base material. y Cost of lamination process and the yield. y Two laminations are widely used; include paper/foil/polythene and paper/foil/surlyn. y The main pharmaceutical application of lamination include, blister, str ip and sachet packaging are mainly child resistant packaging.

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CLOSURES
 A closure forms the most critical component of the container, as far as the stability and compatibility are concerned.  Though the primary function of closure system is to contain contents, safety and security may be necessary to prevent hazards resulting in leakage, seepage, pilferage, loss of quality, purity etc. by some source of contamination and impurity.  Mainly closures are made from elastomers (rubber). There are mainly four types of the rubber:  Butyl rubber (co-polymers of isobutylene and isoprene or butadiene). y Nitrile rubbers (butadiene -acrylonitrile co-polymers). y Chloroprene rubbers (Neoprene, polymers of 1:4 chloroprenes). y Silicon rubbers.  Butyl rubbers are cheap, chemical resistant, with desired aging properties and low water vapor permeability. It is not good for oils.  Nitrile rubbers are resistant to oil, heat treatment, vapor absorption and permeability but leaching and bactericide absorption is high.  Neoprene rubbers are resistant to oil and heat with low water absorption and permeability as compared to natural rubbers.  Silicon rubbers are costly but most heat resistant with very low water absorption and permeability, strength and aging properties.  Caps and over seals are used to secure the rubber closure to the container in order to maintain the integrity of the seal under normal condition of handling and storage.  These caps are usually made of aluminium and may be equipped with plastic top to facilitate opening. These forms tamper evident pack.  Closures may be achieved by a number of basic means or combination of it s including pressure, temperature and adhesion.  Pressure type closures make the use of mechanical and atmospheric pressure. Mechanical pressure is utilized in screw closures, plug seal, lever lid, etc. whereas atmospheric pressure is utilized in vacuum-sealed tin.  Use of temperature is made in case of closures e.g. welding, heat seals or electrical heat sealing.  Adhesion is made use of in the closures in t he form of solvents, adhesives, cold seal material etc.  The materials employed for the formation of closures include; y Materials like aluminium, aluminium alloys, tin plate, tin free steel, stainless steel. y Glass is used for formation of stoppers. y Rubbers and plastics (may be thermosetting or thermoplastic type). y Liners are generally used in the inner side of the containers. These are made from aluminium foil, tin foil, polyethylene, PVDC coating etc.

SPECIFIC TYPES OF CLOSURES: Tamper-evident closures

y Tampering include three aspects, namely altering, pilfering and falsifying the pharmaceutical product. y Tamper evident closures are designed to prevent the accidents and malicious tampering to create safe packaging.
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y These are used for products ranging from OTC drugs, toothpaste and topical and dermatological products, oral cosmetic liquids, contact lens solution and tablets. y Various types of tamper evident packaging include: y Film wrappers -Breakable cap ring systems y Blister packs -Sealed tubes y Bubble packs -Plastic bind end sealed tubes y Heat shrunk bands or wrappers -Sealed cartons y Plastic foil for plastic packs -Aerosol containers y Bottle with inner mouth seals -Metal and composite cans y Tape seals

 Child resistant closures

y Tragic accidents involving the drug intoxication of children has led to new legislation making it difficult for drug packaging to be opened by young children, while being easier for the adults to open. These are termed as child resistant closures. y These have proved effective in reducing child mortality from intoxication by oral prescription drugs. y International standards have been laid down by ISO and ECN (European committee for standardization for child resistant closures). y The three most common child resistant closures are press -turn, squeeze-turn and combination lock.

SECONDARY PACKAGING MATERIALS:PAPERBOARD

 Paperboard can be single or multi-ply. Paperboard used for the manufacture of folding cartons and rigid set-up boxes is often called boxboard. Paperboards used for the manufacture of corrugated fiberboard are called containerboard. It can be easily cut and formed, is lightweight, and is strong used in packaging. Sometimes it is referred to as cardboard, which is a generic, non-specific, lay term used to refer to any heavy paper pulp based board.  Production  Fibrous material is turned into pulp and bleached to create one or more layers of board, which can be optionally coated for a better surface and/or improved visual appearance.  Pulping  Mainly two methods for extracting fibres from its source are used: Mechanical Pulping is a two stage process which results in a very high yield of wood fibres. Chemical Pulping uses chemical solutions to convert wood into pulp, yielding around 30% less than mechanical pulping.  Bleaching y Pulp used in the manufacture of paperboard can be b leached to decrease colour and increase purity. Virgin fibre pulp is naturally brown in colour, because of the presence of lignin. Recycled paperboard may contain traces of inks, bonding agents and other residue which causes a grey coloration. y bleaching methods: y Bleaching by delignification using chlorine gas.
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y Ble c by oxidation us c e c ls suc as c lorine dioxide hydrogen peroxide or sodium hypochlorite y Bleaching by redu tion using chemicals such as sodium bisulphite

 Coatin In order to improve whiteness smoothness and gloss of paperboard, one or more layers of coating is applied. Coatings are made up of: a pigment like china clay, calcium carbonate or titanium dioxide, adhesive or binder & water, OBA (optical brightening agents . Classifi ations FBB/GC/UC (Foldin Box Board) which gives it a light yellow colour. SBB/SBS/SUS (Solid Bleached Board) which is white throughout. SUB (Solid Unbleached Board) is a board made from unbleached chemical pulp (yellow) or recycled material (grey). WLC (White Lined Chipboard) is a board made from virgin and recycled material (grey).
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UGA D FIBERBOARD

 Corru ated fiberboard is a paper-based material consisting of a fluted corrugated sheet and one or two flat linerboards. It is widely used in the manufacture of corrugated boxes and shipping containers, paper-like material usually over ten mils (0.010 inch, or 0.25 mm) thick. Paperboard and corrugated fiberboard are sometimes calledca dboa d, although cardboard might be any heavy paper-pulp based board.  Corrugated fiberboard can be specified by the construction (single face, singlewall, doublewall, etc), flute size, burst strength, edge crush strength, flat crush, basis weights of components (pounds per thousand s uare feet, grams per s uare meter, etc), surface treatments and coatings, etc.  Double and triple-wall corrugated board is also produced for high stacking strength an d puncture resistance.

BOX
 Boxes can be formed in the same plant as the corrugators. Alternatively, sheets of corrugated board may be sent to a different manufacturing facility for box fabrication. The corrugated board is creased or scored to provide controlled bending of the board. Most often, slots are cut to provide flaps on the box. Scoring and slotting can also be accomplished by die cutting.  Box co pression test The box co pression test measures the compressive strength of boxes made of corrugated fiberboard as well as wooden boxes and crates. It provides a plot of deformation vs compressive force. The BCT value is a measure of the strength of a shipping container and is measured in N ilonewton or pounds of force: deflection or deformation is measured in mm or inches.
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CARTON
 Carton is the name of certain types of containers typically made from paperboard which is also sometimes known as "cardboard . Many types of cartons are used in packaging. Sometimes a carton is also called a box.  Folding cartons are usually combined into a tube at the manufacturer and shipped flat (knocked down) to the packager. Tray styles have a solid bottom and are often shi pped as flat blanks and assembled by the packager.  Materials Cartons can be made from many materials: paperboard, various plastics, or a composite. Many cartons are made out of a single piece of paperboard. Depending on the need, this paperboard can be waxed or coated with polyethylene to form a moisture barrier. This may serve to contain a liquid product or keep a powder dry.

TERTIARY PACKAGING MATERIALS: Tertiary packaging materials is used for bulk handling and shipping. It includes barrel, crate container, edge protector, intermediate bulk container, pallets, slip -sheet, stretch wrap, big bag, bulk bags , or super sacks .  It mainly helps in bulk transportation.

PACKAGING REQUIREMENTS FOR INFECTIOUS SUBSTANCES: Packaging should include the following essential elements: y An inner packaging comprising: y Watertight primary receptacle of metal or plastics with leak-proof seal (e.g., a heat seal, skirted stopper, or a metal crimp seal). y Absorbent material in sufficient quantity to absorb the entire contents placed between the primary receptacle and the secondary packaging.  Storage No Storage of untreated BMW > 48 Hrs g y Waste stored in bags must be properly tied. y Placed in bins with vent. y Stored in Adequate thickness bags. y Use NaOCl & Formalin applicable and required. y Temperate climate: 72 hrs in winter 48 hrs in summer  Tropical climate: 48 hrs during winter 24 hrs during summer

PACKAGING OF SOLID DOSAGE FORM (Unit-Dose Packaging): Blister pack is a term for several types of pre-formed plastic packaging used for small consumer goods. The two primary components of a blister pack are the cavity or pocket made from a "formable" web, either plastic or aluminium - and the lidding, made from paper, carton, plastic or aluminium. The "formed" cavity or pocket contains the product and the "lidding" seals the product in the package.  Blister packs are commonly used as unit-dose packaging for pharmaceutical tablets, capsules or lozenges. Blister packs can provide barrier protection for shelf life requirements, and a degree of tamper resistance.
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 A series of blister cavities is sometimes called a blister card or blister strip as well as blister pack. In some parts of the world the blister pack is known as a Push-Through-Pack (PTP).  The main advantages of unit-dose blister packs over other methods of packing pharmaceutical products are the assurance of product/packaging integrity (including shelf life) of each individual dose and the possibility to create a compliance pack.

Materials - Pharmaceutical blister packs

 PVC y The most basic material for the forming web is PVC or Polyvinyl Chloride. The principal advantages of PVC are the low cost and the ease of thermoforming. The main disadvantages are the poor barrier against moisture ingress and oxygen ingress. In the case o f blister packaging the PVC sheet does not contain any plasticizer and is sometimes referred to as Rigid PVC or RPVC. In the absence of plasticizers, PVC blisters offer structural rigidity and physical protection for the pharmaceutical dosage form.  PCTFE y Polychlorotrifluoro ethylene or PCTFE can be laminated to PVC to obtain very high moisture barrier.  COC y Cyclic olefin copolymers (COC) or polymers (COP) can provide moisture barrier to blister packs, typically in multilayered combinations with polypropyl ene (PP), polyethylene (PE), or glycol-modified polyethylene terephthalate (PETg). Cyclic olefin resins are generally amorphous and are noted for good thermoforming characteristics. y Paper/PET/aluminium laminate is used for child resistant push -through packages.

Heat sealer
 A heat sealer is a machine used to seal products packaging, and thermoplastic materials using heat.  Hermetic seal A hermetic seal is a seal which, for practical purposes, is considered airtight. Electronic parts that are designed and intended to secure against the entry of microorganisms and other foreign bodies to maintain the proper functioning and reliability of their contents.       
Types of heat sealers Continuous heat sealers- (also known as Band type heat sealers) utilize heated moving belts. Impulse heat sealers- use a stationary element which is heated with each sealing cycle . Hot bar sealers- use one (or two) heated bars which contact the material to form a bond. Induction sealing is a non-contact type of sealing used for inne r seals in bottle caps. Ultrasonic welding uses high-frequency ultrasonic acoustic vibrations to workpieces being held together under pressure to create a weld. Good seals are a result of time, temperature and pressure for the correct clean material.

 Applications y Applications for hermetic sealing include semiconductor electronics, thermostats, optical devices, and switches. The food, chemical, and pharmaceutical industries all have
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applications for the use of such "airti ht" packaging, such as glass, metals, and high barrier plastics (with effective heat seals). Tin cans are hermetically sealed.  Factors affecting blister thickness: The nature of the material Softening temperature Hardening time Process Thickness of film.

Strips packaging
 This pack consists of one or two plies, made from regenerated cellulose, paper, plastic, foil or combination of these. Product is sealed between the two sheets along with a seal around each tablet/capsule and perforation of easy cutting.  The use of high barrier material like foil or saran-coated film with excellent seal formation , enables this packaging suitable for moisture-sensitive products.  Other lamination suitable for strip packaging is paper/polyethylene/foil/polyethylene.  Usually cellophane film which has heat sealable nature and transparency is used, especially when the visibility of the product is important.

AC AGING OF AREN ERAL LIQUIDS: Re uirements for product purity, activity, and shelf-life dictate high standards for injectable drug packaging particularly for highly active peptides and proteins.  Lyophilized proteins are sensitive to heat, light and chemical contaminants.  Fluoroelastomer coating on stoppers provide the barrier protection and safety from leaching.
4

 TYPES OF PAC AGES:y Vials and bottles y Ampoules y Prefilled syringes

5

BOTTLES & JARS

 Bottles are the containers in which the multiple dose parenteral preparation is packed. The material of these containers is glass & plastic.  Glass seal, which are tamper resistant, use an inner seal that bounded to the neck of the bottle.  Pressure sensitive inner seal and heat sensitive adhesives can also be used for the purpose of the tamper proof bottle packaging for which mainly aluminium foil is used for sealing.  Plastic bottles are used for Nasal & Ophthalmic packing.

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VIALS
 Vials made of glass y Vials are mainly used for multiple parenteral preparation. The vials are provided with the closure followed by aluminium seal to ensure the perfect air tight packing.  Different vials y Perfume sample vials. y Special designs for lyophilization. y OptiVial TM with its uniquely shaped bottom to eliminate leftover substances y Dual-chamber vials y Screw neck vials y Tablet vials.  Vials made of polymer y Vials made of advanced cyclic olefin copolymer (COC) of highest purity offer transparency comparable to glass. y Excellent barrier properties, high chemical resistance and breakage resistance make these vials ideal primary packaging for many different applications. y Sizes are available from 2 ml up to 100 ml.

CARTRIDGES
 Cartridges are used in large volumes and are an ideal packaging method for insulin and other drugs. They can be administered in the form of pen or pump systems. Sophisticated delivery systems require a rigorous level of precision and quality for all dimensional and functional aspects. Material for it is mainly glass. Cartridges for pen systems Cartridges for pump systems Dual-chambered cartridges for dual-component application Cartridges for auto-injectors Cartridges for needle free injectors Dental cartridges

PREFILLABLE POLYMER SYRINGES


This type of packaging system is employed on small dose parenteral preparation. Mainly diagnostic agents and vaccines are packed in this pack. The material for syringes is glass and plastic.

 Dropper pipettes in a wide range of shapes and colors are available. They can be ordered pre-washed and siliconized, as well as assembled with caps and droppers. Integrated printing avoids contamination, and the special packaging is ready for the sterilization process.  Material for it is glass with rubber cap.

AMPOULES
 Ampoules are a great primary packaging for a variety of drugs. The filled-in product is in contact with glass only and the packaging is 100% tamper proof. The break systems OPC (one-point cut) or the color break ring offer consistent breaking force. A wide variety of ampoule types from 0.5 to 50 ml. Up to 3 color rings can be placed on the stem or body for identification purposes. Printed ampoules with heavy metal free colors are available.
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Generally ampoules are made up from the glass. Recently plastic ampoules for water for injection are available in the market.

    

Type B straight-stem Type C funnel-tip Type D closed Double tip (1 25 ml) Fine tip (1 25 ml)

Sealing  Tamperproof sealing of the ampoule is essential. Two types of the seal like tip seal and pull seal.  Tip seal is made by melting sufficient glass at the tip of the ampoule neck to form bead of the glass and close the opening.  Pull seals are made by heating the neck of rotating ampoule below the tip, then pulling the tip away to form small, twisted capillary prior to being melted closed.  Pull sealing is slow but it prevents combustion products of flame from entering the ampoule at the time of sealing, as occur with tip sealing.

PACKAGING OF MEDICAL / SURGICAL DEVICES:The medical device packages are usually evaluated to meet the following requirements: y They must be capable of being sterilized economically. y They must withstand the shipping and handling environment. y They must be compatible with the procedures set up by the ho spitals. y Sterility y Environmental y Product resistance: oils, water, chemicals, gas, etc. y Physical: Dimensional stability (rigidity or flexibility, resists puncture, tearing, abrasion, impact and pressure, provides cushioning and structural support.

Evaluation of Medical Device Packages:

The Medical Device Packages Testing Laboratory is set up with the following principle goals: y To evaluate the component materials of container and the inner protective cushioning materials y To develop (through research) improved methods or concepts and improved package testing techniques.

The types of tests carried out for Medical Device Packages are as follows:
y y y Sterility Testing Manual handling Vehicle stacking y y y Loose-load vibration Vehicle vibration Drop test

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Compression

Package seal strength testing

PACKAGING OF AEROSOL
 Types of the materials for Aerosol containers: (a)Tin plated steel
1.Three piece-soldered side seam 2.Two piece-welded side seam or drawn (b) Aluminium 1.One piece-Extruded (c) Stainless steel (d) Glass uncoated (e) Plastic coated glasses (f) Plastic and synthetic resin  The parts of the containers packaging: 3.Drawn and ironed

2.Two piece-Extruded drawing

 Valve: The valve in the aerosol facilities the dispending of the product. Different types of valves dispensed the product as- sprays, solid streams and foams.  Types of valves: y Spray-any-way valves. y Tip-sealing valves y Metering valves y Vapor tap valves y Foam valves y Powder valves y Compressed gas valves  Actuators: The actuator is the molded part on the top of the valve stems that determining whether the product will be dispensed as a f oam, spray or stream. y Different types of actuators: y Solid stream actuator y Spray actuator y Foam actuator y Metered-dose inhalers  Dip tube: They are made from polyethylene. It should be inert with the ingredients of the product.  Product concentrate: They include solvents, antioxidants and surfactants.  Spray nozzle: It is metered to allow a specific dose to be dispensed with each spray. They are used for the inhalers.

Testing of Aerosols packaging containers

 Valve acceptance: The test procedure of metered valve having the following value: 54L or less, the limits are 15% 55 to 200L, the limits are 10% y Of the 50 individual deliveries, if four or more are outside the limits, the valves are rejected . y If three or two deliveries are outside the limits, another 25 valves are sampled and test is repeated. The lot is accepted if not more than one delivery is outside the specifications.

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 Weight checking: This is usually accomplished by periodically adding to the empty aerosol containers, which after being filled with concentrate, are removed and accurately weighed to check the accuracy of filling operation.  Leak testing: The testing of efficiency of the valve closure is accomplished by passing the filled containers through the water bath. Periodic checks are made of the temperature of the water bath and the results are recorded.  Spra testing: This method is based on the impingement of the spray on the paper that has been treated with a dye-talc mixture. The particles that strike the paper cause dye to go into solution and to be absorbed onto the paper. This gives the record of spray.
Cool the flask in running water. Decant the water. Wash the residual powdered glass (4 times with 15 ml high purity water). Add the decanted washing to main portion. Add 5 drops of methyl red solution as an indicator. Titrate immediately with 0.02 N sulfuric acid. Record the volume of 0.02 N sulfuric acid.
A

Volume doesn t exceed that indicated in table for the type of glass concerned.
B

Type of the glass I II III IV

Types of the test Powdered glass test Water attack test Powdered glass test Powdered glass test

Li its si e(ml) All 100 or less All All

Limits(ml of o.o2N) 1.0 0.7 8.5 15.0

Water attack test at 121 c (USP)

Rinse 3 or more containers twice with high purity water. Fill each container to 90 of its overflow capacity. Cap all the flasks, autoclave for 60 mins. mpty the contents and pool the contents in 250 ml conical flask to a volume of 100ml. Add the 5 drops of methyl red solution. Titrate with 0.02 N sulfuric acid while warm (complete titration within 60 mins). M.PHARM SEM-II (2009-10) L.M.COLLEGE OF PHARMACY, AHMEDABAD 09
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Record the volume consumed (corrected for blank obtained by titrating 100 ml of high purity water at same temperature and with the same amount of the indicator). Volume should not exceed that indicated in the table for the type of the glass concerned.

 Light transmission test

y A spectrometer is suitable sensitivity is used to cut the section of glass container. The transmittance of the selection is measured and observed light transmission is not expected to exceed the limits provided in the table. y Maximum % of light transmission at any wavelength between 2990nm and 450nm

Normal si e(ml) 1 2 5 10 20 50

Flame sealed container 50 45 40 35 30 15

Closure sealed container 25 20 15 13 12 10

Tests on the plastic containers

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.

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 60 + 5% at 20 c to 25 c. Reweigh the container. Loss of the weight in each container should not be more than 0.2%. 

Collapsibility test for Injectable and Non-Injectable preparation(IP 1996)

This test is applicable for those containers, which have to be s ueezed for the withdrawal of product. A container by s ueezing yields at least 90% of its nominal contents at re uire flow rate at ambient temperature.
R R R

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 Physicochemical tests
USP specifies the extracting medium; otherwise purified water is maintained at 70 c. After the extraction following tests are performed: y Non-volatile residue which measures organic and inorganic residue soluble in extracting medium. y Heavy metals: This detects the presence of metals such as lead, tin, zinc etc. y Buffering capacity: It measures the alkalinity/acidity of the extract. 

 Compatibility test
Compatibility components will not interact with the dosage form and may not show leaching. Regular screening is done by liquid chromatography, mass spectrometry, GC -MS etc. y Other changes like PH shift, precipitation, discoloration, which may cause the degr dation of a the product should be evaluated. 

 Measurement of diffusion coefficient through plastic

Stopcock A is first opened allowing evacuation of the system and this gives rise to a barometric leg in the manometer . As soon as A is closed, gas will diffuse through the membrane and mercury level will increase. The height of mercury level indicates diffusion of gas through the plastic.

Test on Rubber closures

 Closure efficiency
y y y y y Placing a desiccant in a packed stored under high RH. Putting liquid in side pack, storing at high temperature and low RH, detecting any moisture loss as reduction in weight. Checking of cap removal torque. Checking on compression ring seal in cap liner when a system contains a liners. Putting liquid in pack, inverting and applying a vaccum. A poor seal is detected by liquid seeping.

 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.

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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 solution of methylene blue 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.

Test for Blister and Strip packaging

 Leakage testing and package integrity testing
 Mainly two types of testing are involved for checking package integrity.

 Destructive type testing

Dip the packages in the pot containing the colored water (15-25 c) and place the pot in the vaccum chamber. Apply the vaccum of 33K Pa for strip packages and 24K Pa for blister packs for 30 sec. Return to the atmospheric pressure and remove the pot from the vaccum chamber. xamine the package for ingress of the water in to the package.
c

 Non-destructive type testing

y This type of testing equipment is based on a dry pressure vaccum procedure followed by detection of pack distortion (deflection) or non-distortion, i.e. packs with effective seals become concave them convex as positive pressur changes to negative pressure, while e leaking packs either do not change or show less or limited distortion, depending on the scale of the leakage.

 Pinholes and package integrity

y Pinholes are the common features of aluminium foil. It can be detected by wa vapor ter permeation. High water vapor permeation indicates the high numbers of the pinholes.

Tests for Paper and Boards

y y y y y y y y

Moisture content of paper and board Methods for determining the air permeability Test for the assessment of the odor for the packagi g material n Puncture resistance Roughness/smoothness Brightness Ash in paper and board Ink absorbency
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Test for carton

 Carton opening force: Hold the flat carton as delivered by its crease between thumb first figure and press. The carton should spring open in to the square position without the need for unreasonable force.

Package integrity test for Parenteral Preparation

Name of the test 1.ACOUSTIC IMAGING Method Ultrasonic energy is focused in to sample submerged in water or other solvent. Echo patterns produce image of package material. -Submerge package in liquid, applied differential pressure, observe for bubbles. -Apply surfactant, draw vacuum, and look for foaming Test tracer gas is used to measure leakage/permeation across a package seal. Gas is detected by coulometric detector (O2) or by photoelectric sensor (CO2 OR H2O). Helium is used as tracer gas for the detection and measurement of leakage using mass spectrometer. insideout method or sniffer probe method is used. High voltage is applied to sealed container. Increase in conductivity correlated to presence of liquid near detectors. Package is immersed in solution of tracer chemical or dye. -Pressure/vacuum or temperature cycling is used to improve the sensitivity. -leakage is detected by dye or chemical. Information Structural defects visible, such as channels, delaminations. Location of leak can be observed. Uses Construction materials, package and devices.

2.BUBBLE TEST

Pipes, large equipments, aerosol (warm water bath test). Screw-cap bottles, blister package, polymer and foil pouches.

3.GAS TRACER DETECTION

Provides total leakage and permeation information.

4.HELIUM MASS SPECTROMETRY

Provides information of microbial and liquid leakage.

Automotive parts, pacemakers, drums.

5.HIGH VOLTAGE LEAK DETECTION(HVLD)

Conductivity of package, humidity of testing site.

Glass and plastic ampoules, vials and syringes.

6.LIQUID TRACER TEST

Liquid and microbial leakage.

All types of packages.

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7.MICROBIAL CHALLENGE TEST

Containers are media filled, and seal is challenged with microorganisms.

8.NONINVASIVE MOISTURE AND OXYGEN ANALYSIS

9.RESIDUAL GAS IONIZATION TEST

IR is used to measure the powder moisture inside the unopened glass package. -Tunable diode laser light is passed through the package. Absorbed light is proportional to contents of oxygen or water. High voltage, high frequency field is applied to glass vials or bottles sealed under vacuum. The field causes residual gas to glow. Vacuum level is verified by glow or ionization current. Vials sealed with elastomeric closures are compressed at constant rate of strain. Stressstrain deformation curves are generated. Second derivative of the curve= RSF. Ultrasound echoes are used to create image of heat seals. Change in vacuum/pressure is measured inside the package or outside in sealed package chamber. Pressure/vacuum change greater than nonleaking package is indicative of reject. Look for leaks.

Presence of microbial growth is confirmed visually/ with instrumentation. Contents of oxygen and water.

Pharmaceutical industry.

Lyophilized and dry powder, validation of package integrity.

Gaseous contents of residual headspace.

Lyophilized product.

10.RESIDUAL SEAL FORCE(RSF)

RSF value.

Parenteral vials.

11.ULTRASONIC IMAGING 12.VACCUM/PRES SURE DECAY

Defects in sealing. Rigidity and porosity of package.

Heat seals. Food and medical package devices.

13.VISUAL INSPECTION

leakage

14.WEIGHT CHANGE

Filled, sealed container is stored at various stress condition checked over time for weight loss or weight gain.

Leakage. But leakage location can not detected.

Parenteral packages such as ampoules, vials and syringes. Vials, aerosols, solid or liquid dosage form packaging.

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REGULATORY ASPECTS OF PHARMACEUTICAL PACKAGING:Introduction

y FDA ensures the quality of drug products by carefully monitoring of drug manufacturers adhere to pharmaceutical regulatory comlience as per the cGMP. y Packaging is also the part of cGMP. The following characteristics are common requirements of most regulatory agencies: 1. Product or preparation related requirements: p Protection of the product p Protection of the consumer p Control of doses 2. Label related requirements: p Information to the receiver p Legal control of the product 3. Environmental aspects: p Packaging wastage p Ozone depletion 4. Consumer protection: p Child resistant closures p Tamper evident packaging

European Union (EU) and its guidelines

y Pharmaceutical packaging is a skill based industry directly related with marketing of product. p Initially glass was used inert no potential interaction with product, p With the introduction of plastics and tailor made packages - more scope for interaction between product and package so need more regulation.

The regulatory for over 150 countries may have differing requirements. The solution for this lies in the realization of the fact that out of the total market share, European union (EU) represents 30% of the market, US approximately 27% and Japan nearly 18%. These ads up to 75% of the market share. International conference for harmonization between these areas on certain issues may lead to a further improvement in the situation. The EU has been fairly successful in the pharmaceutical area while achieving: p Centralized system in place p Decentralized system in place p Harmonization of format p Increase acceptance outside EU, & p Harmonization of standards. Various EU guidelines applying to packaging are p CPMP list of allowed terms (III/359/91) p Notice to the applicants (updated 1998) p Plastic container guidance (III/9090) p Plastic in contact with food directive (90/128)
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FDA packaging guidelines

FDA packaging guidelines defines the types of containers to be used, dividing them into p Parenteral containers (glass/plastic) p Nonparenteral containers (glass, plastic & metal) p Pressurized containers p Bulk containers of API & drug products Also listed are closures including child resistant & tamper evident closure, liner, seal & elastomers when used for closure. According to FDA guidelines, for submitting documents for packaging for human drugs and biological the following are required. 1. Purpose: p Package must maintain standards, identity, strength, quality & purity for intended shelflife p Full information needed p Type of container/closure p Suitability for intended use p Submission of packaging information & date. 2. Environmental concerns: With increased environmental concerns there has been a considerable pressure to reduce contamination of environment with particular concern on amount of packaging & its disposal. Ozone depletion is also of concern with the use of pressurized containers. Regarding this aspects the increase in concerns has led to the European E Commission packaging waste directive which requires: y Reduction in quantity of waste y Reduction in harmfulness of waste y Increase in reuse of packaging y Recycling & recovery of packaging waste & y Reduction of the total packaging to be disposed of. y About one third of cost of medicine is accounted for the packaging materials. Packaging not only provides the protection to the product from contamination & physical damage but also helps in identification of product & display correct information. As whole plastics, glass, metal & paper are the most commonly used packaging material in pharmaceutical technology. Each one has its own pros and cons. The selection of the packaging material of the drug is mainly dependent on the p Nature of product p Machinability p Level of protection required p Shipment requirement p Stability p Dispensing of the dosage form. p Cost Basically pharmaceutical packaging is classified as p Primary packaging (bottles, jars, cans, stripes, blister, etc.) p Secondary packaging (cartons, corrugated boxes, etc) p Accessories (caps, closures & labels) Packaging further needs to be tamper evident, child resistant & customer friendly.
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Legal requirements for labeling and packaging

y Under the provisions of the Federal food, drug and cosmetic act 1940, i t is the responsibility of the manufacturer to provide the safety of a packaging material & to get approval before using it for any food & drug products. The FDA does not approve container as such, but only the materials used in the container. A list of substances considered Generally Recognized As Safe (GRAS) has been published by the FDA. A material that is not included under GRAS or prior sanctioned & is intended to be used with food, must be tested by manufacturer & the data must be submitted to FDA. The rules & regulations for labeling & packaging under the Drug and Cosmetics Act 1940 are given in the part IX of the act. According to act labeling & packaging of drug other than homoeopathic medicines is as under:

y y

Rule 94. Exemption of certain drugs from certain provisions of this part (1).
Labels on packages or containers of drugs for export shall be adapted to meet the specific requirements of the law of the country to which the drug is to be exported, but the following particulars shall appear in a conspicuous position on the innermost container in which the drug is packed & every other covering in which that container is packed: a) Name of the drug b) Name, address of the manufacturer and the license number c) Batch or lot no. d) Date of expiry, if any.

Rule 95. Prohibition of sale or distribution unless labeled:

Subject to the other provisions of these rules no person shall sell or distribute any drug.

Rule 96. Manner of labeling:

1. Subject to the other provision of these rules, the following particulars sha ll be either printed or written in indelible ink & shall appear in a conspicuous manner on the label of the innermost container of any drug & on every other covering in which the container is packed, namely: i. The name of drug p For drug in schedule F or F1 th e given therein p For official drugs letters I.P., B.P., etc. p For drug included in National Formulary of India N.F.I. ii. A correct statement of the net contents in terms of weight, measure, volume, no. of units in metric system. iii. The content of active ingredients p For oral liquid preparations in terms of content per single dose, dose being indicated in 5 ml. p For liquid parenterals ready for administration 1 ml of percentage by volume or per dose in the case of single dose container.
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p For drugs in solid form for parenteral units or weight per milligrams or grams. p For tablets, capsules, pills, etc. in terms of the content in each unit. p For other preparation percentage by weight or volume. iv. The name and address of premices of manufacturer. v. A distinctive batch no. The figure representing the batch no. being preceded by the words Batch No. or B No. or Batch or Lot No. or Lot vi. Every drug manufactured in India shall bear on its label the no. of the license under which the drug is manufactured. The figure representing the manufacturing license number being preceded by the words Manufacturing License Number or Mfg. Lic. No. or M.L. vii. Drugs specifies in the schedule P and their preparations including combinations with other drugs shall bear on label th e date of manufacturing & expiry date and the period between these two dates shall not exceed that laid down in the said schedule. viii. Drugs specified in schedule C(1) & their preparations including combinations with other drugs shall bear on the labels: p The date of manufacture p Date of expiry of potency fixed by the manufacturer p Where such drugs are imported also the No. of license under which the drug is imported preceded by the words Import License ix. Every drug intended for distribution to the medical profess ion as a free sample shall bear on the label of the container the words Physician s sample - not to be sold which shall be overprinted. x. If any preparation contains not less than 3% by volume of alcohol the quantity of alcohol shall be started in terms of the average percentage by volume of absolute alcohol in the finished products. xi. In addition to the other particulars which are required to be printed or written under these rules, the label of innermost container of the following categories of drugs & every other covering in which the container is packed shall bear a conspicuous red vertical line on the left side running throughout the body of the label which should not be less than 1 mm in width & without disturbing the other condition printed on the label under these rules, namely: Narcotic analgesics, hypnotics, sedatives, tranquillizers, corticosteroids, hormones, hypoglycemic, antimicrobials, antiepileptic, antidepresents, anticoagulants, anticancer drugs & all other drugs falling under schedule G, H, & X whether covered or not in above list. [provisions of this clause shall not apply to a) Preparation intended for animal treatment b) Preparation intended for external use c) Ophthalmic preparation & ear drops d) Sterile preparation such as sutures, surgical dressings & preparation intended for parenteral use.] 2. For mechanical contraceptives i. The particular to be printed or written on the label of mechanical contraceptive shall be as specified in schedule R.

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ii. The following particulars in addition to those specified in subrule (1) shall be either printed or written in indelible ink & shall appear in a conspicuous manner on the label namely: a) Date of manufacturing b) The date up to which the contraceptive is expected to retain its properties c) The storage condition necessary for preserving the properties of the contraceptive up to the date indicated in sub clause (b). 3. The particulars prescribed in sub rule (1) shall be printed or written in indelible ink either on the label borne by a container or vaccine lymph or on a label or wrapper affixed to any package in which the container is issued for sale.

Rule 97. Labeling of medicines

1. The container of medicine for internal use shall a) If contain substance specified in schedule G, is labeled with the words Caution: it is dangerous to take this preparation except under medical supervision - conspicuously printed & surrounded by a line within which there shall be no other words. b) If it contains substance specified in schedule H be labeled with the symbol Rx and conspicuously displayed on the left top corner of the label & also be labeled with following words: Schedule H drug- warning: To be sold by retail on the prescription of a registered medical practitioner only c) If it containing a substance specified in schedule H & comes within t he purview of the Narcotic drugs and Psychotropic substances Act, 1985 be labeled with the symbol NRx which shall be in red & conspicuously displayed on the left top corner & also labeled with words: Schedule H drug- Warning: To be sold by retail on the prescription of a Registered Medical Practitioner only d) If it contains a substance specified in schedule X be labeled with the symbol XRx which shall be in red conspicuously displayed on the left top corner of the label & be also labeled with the following words: Schedule X drug- Warning: To be sold by retail on the prescription of a Registered Medical Practitioner only 2. The container of an embrocating, liniment, lotion, liquid antiseptic or any other liquid medicine for external application shall be labeled with the words in capital FOR EXTERNAL USE ONLY 3. The container of a medicine made up ready only for treatment of an animal shall be labeled conspicuously with the words Not for Human Use; For animal treatment only & shall bear a symbol depicting the head of a domestic animal. 4. The container of a medicine prepared for treatment of human ailments shall if the medicine contains industrial methylated spirit, indicated this fact on the label & be labeled with the words- FOR EXTERNAL USE ONLY

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Rule 102. Non sterile surgical ligature and suture:

Every container of , and wrapper enclosing surgical ligature or suture which are nonsterile, shall bear a label on which are printed or written in a conspicuous manner in indelible red ink the words: Non-sterile surgical ligature(suture)- not to be used for operations upon the human body unless efficiently sterilized

Rule 104. Use of letters I.P. etc.:

The letters I.P. or recognized abbreviation of pharmacopoeias & official compendia of drug standards prescribed under these rules shall be entered on the label of the drug only for the purpose of indicating that the drug is in accordance with standards set out in such official books.

Rule 104A. Prohibition against altering inscriptions on containers, labels or wrappers of drug:
No person shall alter, obliterate or deface any inscription or mark made or recorded by the manufacturer on the container, label or wrapper of any drug.

Rule 105. Packing of drugs:

1. The pack sizes of drugs meant for retail sale shall be as prescribed in schedule P1 to these rules. 2. The pack sizes of drugs not covered by the schedule P1 shall be as given below: i. The pack sizes for Tablets/capsules shall be where the number o f tablet/capsules shall be where the no. of tablets/capsules is less than 10, such packing shall be made by the integral number, or numbers above 10, the pack sizes of tablets/capsules shall contain multiples of. ii. The pack sizes for liquid oral preparation shall be 30 ml. (pediatric only) / 60 ml. / 100 ml./ 200 ml. / 450 ml. iii. The pack sizes for pediatric oral drops shall be 5 ml. / 10 ml. / 15 ml. iv. The pack sizes for Eye/Nasal/Ear drops shall be 3 ml./ 5 ml. / 10 ml. v. The pack sizes for eye ointment shall be 3 gm/ 5 gm / 10 gm. Provided that the provisions of the pack sizes covered under this rule shall not apply to 1. Pack sizes of dosage forms not covered by the forgoing provisions of this rules 2. The imported formulations in finished form 3. Preparations intended for veterinary use 4. Preparations intended for export 5. Vitamins / tonics / cough preparations / antacids / laxatives in liquid oral forms, unit dose(including applicaps) 6. Pack sizes of dosage forms meant for retail sale to Hospitals, RMPs, Nursing Homes. 7. Physicians samples 8. Pack sizes of low volume I.V. fluids.

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Rule 105A. packing of drugs specified in schedule X:

The drugs specified in schedule X shall be marketed in packing not exceeding i. 100 unit doses in the case of tablets/capsules. ii. 300 ml. in the case of oral liquid preparations. iii. 5 ml. in the case of injections.

Rule 106. Diseases which a drug may not purport to prevent or cure (schedule J):
1. No drug may claim to prevent or cure or may carry any idea that it may prevent or cure one or more of the diseases or ailments specified in schedule J. 2. No drug may purport or claim to procure or assist to procure, or may convey any idea that it may procure or assist to procure, miscarriage in women.

RECENT TRENDS IN PHARMACEUTICAL PACKAGING:Major influences are: Product trends influencing pack trends Changes and trends in packaging materials Changes in packaging processes Other special considerations.

Product trends influencing pack trends

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Changes and trends in packaging materials

As changes to packaging materials occur relatively slowly, the materials which might be considered of historical value are still in wide usage. This particularly applies to the use of glass and metal, which extends back over several centuries. A slight reduction in the use of glass has occurred in recent years, and it is likely that this will continue as a slow downward trend. However, glass is generally seen as environmentally friendly, hence this trend could reverse. Metal containers are showing a much more serious usa ge drop in terms of containers for tablets and capsules, ointments, granules, powders, etc., and even survival as collapsible metal tubes is doubtful with the advent of laminated tubes. Rigid aluminium containers, other than aerosol containers, showed a rapid drop in usage some 8 10 years ago, when costs, compared with glass and plastic, became unfavourable. The conversion of bauxite to aluminium involves high energy levels. Although it has been accepted that no one plastic can offer the inertness of glass, particularly with reference to retention of certain preservatives, flavours and active ingredients, it is relatively easy to find a plastic which is suitable for a specific product albeit occasionally with a slightly reduced shelf life. Under this categor y various grades of PETP and PETG (polyester variants) are steadily growing in use. Since under normal handling polyester is much less prone to breakage and is lighter than glass, any cost premium can be readily offset. Polyesters generally show good retention of such volatile substances as menthol, camphor, esters of salicylic acid. Coated and multi -layer plastic containers offer further potential usage for liquid products. Silicon dioxide ( glass ) coated plastics are also of interest (SiO2 coatings). These arebeing closely followed by carbon diamond -like coatings. Although recognised as plastics, the thermosets play only a minor role as a packaging material and it was not until around 1953 onwards, when the first thermoplastics were used as low

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density polythene squeezee packs, that the real plastic revolution began. In 1996 five, in fact the most economical five, were the ones most widely used. These include the: polyethylenes (PE) LDPE, MDPE, HOPE, LLDPE, ULDPE, VLDPE polypropylenes (PP) homopolymers and copolymers of polypropylene polystyrenes (PS) crystal and to some extent impact modified polystyrene polyvinylchlorides unplasticised PVC and plasticised PVC polyesters PETP and PETG. These materials cover a wide range of properties, e.g. a range of densities 0.9 1.45, are clear to very hazy, hard, brittle to flexible, some virtually unbreakable; from highly permeable to ones of low permeability (with reference to moisture, gases, solvents, etc.), relatively inert to only fair inertness, etc.

Changes in packaging processes

In the past 25 years there have many progressive changes in packaging processes, and several significant improvements are detailed below.

Form fill seal processes for liquids and semi-liquids

The Bottlepack system (Rommelag, Germany) and a similar process by Automatic Liquid Packaging (USA) blow fill seal- continue to be successfully used for pharmaceutical products.. In use they usually operate in a clean area but also with a laminar flow type hood over the moulding-filling stations. With these precautions the unit can produce sterile non-preserved products. Output largely depends on the pack size, Special machines can also insert sterile components, e.g. rubber stoppers. Machines can handle PE, PP, PVC, PET , etc.

Other special considerations

There are occasions when demands or considerations related to a pack conflict. This applies to some of the general observations listed below, and in certain instances an acceptable compromise may be difficult to achieve. y Tamper-evidence y Child-resistance

References
 Pharmaceutical packaging technology, by U.K. Jain, D.C. Goupale, S. nayak.  Pharmaceutical packaging technology, edited by D.A. Dean, E.R. Evans.  Encyclopedia of pharmaceutical technology, edited by James swarbrick, 3rd edition, volume4.  Parenteral quality control, sterility pyrogen, particulate and package integrity testing, by Michael J. Akers, Daniel S. Larrimore, Dana Morton Guazzo, 3 rd edition.  The theory and practice of industrial pharmacy, edited by Leon Lachman, Joseph L. Kanig, 3 rd edition.  www.aclan packaging .com/  www.karishmainternational.com/  www.pharmainfo.net/pharmaceutical packaging  dir.indiamart.com/pharma-pack machines
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