by Mr. Girish.B, M.Pharm...
PACKAGING OF PHARMACEUTICAL PRODUCTS
Mr.Girish.B M.Pharm
[email protected]
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Packaging is a critical tool in the pharmaceutical industry for product delivery and regulatory compliance, many pharmaceutical companies will do all their packaging within a contamination free environment or Clean room. Pharmaceutical packaging is regarded as an integral part of the end pharmaceutical/drug product. Pharmaceutical Packaging Technology is structured to meet the needs of the global market, and assesses a wide range of current knowledge, catering for the requirements of the pharmaceutical industry as well as for pharmaceutical companies in emerging nations. Pharmaceutical packaging has to be carried out for the purpose of the safety of the pharmaceutical preparations in order to keep them free from contamination, hinder microbial growth, and ensure product safety through the intended shelf life for the pharmaceuticals. Girish.B KLEUCOP Belgaum
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The term ‘pack’ covers all the components involved the components enable the product to be stored, transported and displayed, and possibly assist use. A pack has a number of functions to perform during its life, including storage, carriage, display, sale, use, etc., all of which require in-depth consideration. A simple definition of a pack is: a pack is the “economical” means of providing for a product • presentation • protection • identification/information • convenience/containment/compliance
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The printed pack are likely to cover some of the following points: • type of product • product trade name • official name, i.e. compendium reference • strength • quantity • mode of usage/administration • batch number • expiry date or date of manufacture • shelf-life declaration • storage instructions • contra-indications—precautions • product licence number/manufacturing licence number • product category (OTC, ethical, etc.) • manufacturer’s name and address • bar code and/or similar security code • warnings (mandatory or voluntary) • product formulation, including excipients, preservatives, colourants, etc. Girish.B KLEUCOP Belgaum
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SCRAP CART MIST MARD S—shock C—compression R—rattle (vibration) A—abrasion P—puncture C—contamination/compatibility between pack and product A—ageing (certain combinations involving several sources) R—rodents or similar animal sources of contamination T—theft M—moisture (relative humidity (RH), rain, sea water) I—insects S—sunlight or any light sources T—temperature (extremes) M—microbiological A—atmospheric—gases, pressure differentials, dirt, dust, oxygen, carbon dioxide, etc. R—reuse/recycling/recovery/reduce, i.e. ‘the four Rs’ D—disposal—indirect hazards associated with ultimate disposal of pack-product including any pollution risks. Girish.B KLEUCOP Belgaum
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The pack must afford protection against • climatic, i.e. those associated with the surrounding atmosphere • biological—these involve microbiological (bacteria, moulds and yeasts), biological factors (insects, rodents, human pilferage, etc.) • mechanical, i.e. physical hazards associated with shock, compression, vibration, puncture, carriage, etc.—general handling • chemical—aspects of interaction and exchange between product and pack, i.e. compatibility
• use—professional and patient, including any possibilities of misuse or abuse. Girish.B KLEUCOP Belgaum
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Pack selection - Factors influencing choice of pack The product – physical and chemical characteristics of the drug, excipients, formulation, dosage and its frequency, mode of administration, type of patient The market – doctor, dentist, nurse, patient, clinic, home, hospital, home trade and export
The distribution system – whole sales, retail outlets Manufacturing facilities – new pack, increased sales, improvements in GMP, revised product, new product
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Packaging is the science, art and technology of enclosing or protecting products for distribution, storage, sale, and use. Packaging also refers to the process of design, evaluation, and production of packages. Packaging can be described as a coordinated system of preparing goods for transport, warehousing, logistics, sale, and end use.
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Packing Unit Dose Packing
Multi Dose Packing
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PACKAGING FORMS
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Different types of tertiary packaging Shippers Adhesive tapes
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Glass
Glass has been widely used as a drug packaging material Advantages Economical Variety of sizes and shapes
Essentially chemically inert, impermeable, strong, rigid Does not deteriorate with age Excellent barrier
Disadvantages Fragility Weight Leaching
Flacking
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Composition of glass Sand (silicon dioxide) Soda ash (sodium carbonate) Limestone (calcium carbonate) Cullet (broken glass) - aluminium, boron, potassium, magnesium, zinc, barium, oxygen Coloured glass may be obtained by solution or by colloidal dispersion. Amber: light yellowish to deep reddish brown, carbon and sulphur or iron and manganese dioxide Yellow: Compounds of cadmium and sulphur Blue: Various shades of blue, cobalt oxide or occasionally copper (cupric) oxide Green: iron oxide, manganese dioxide and chromium dioxide Opal: Involves fluorides or phosphates Girish.B KLEUCOP Belgaum
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Types of glass Type I—neutral, a boro-silicate type glass Type II—soda glass with a surface treatment
Type III—soda glass of limited alkalinity NP—soda glass (nonparenteral usage) or European Type IV
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Type I glass Neutral or borosilicate type glass has the following composition range: silica (SiO2),alumina (Al), sodium oxide (Na2O) or potassium oxide (K2O), boric oxide (B2O), calcium oxide (CaO), barium oxide (BaO), and possibly small quantities of magnesium oxide, ferric oxide and titanium dioxide. These types of glass require a higher working temperature, have a narrower working range and hence are more difficult to process (1700–1750°C). Borosilicate glasses with high boric oxide contents (over 12%) show reduced chemical resistance and are more prone to atmospheric weathering. Type I surface treated glass is also available with certain smaller tubular containers. Girish.B KLEUCOP Belgaum
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Type II glass Glass stored for several months in a damp atmosphere or extreme temperature variations , the wetting of the surfaced by condensed moisture results in salts being dissolved out of the glass – blooming or weathering. These are made of commercial soda lime had the surface treated, usually by a process of sulphating or sulphuring.
Type III glass Glass are untreated and made of commercial soda lime glass of average or better than average chemical resistant.
Type IV glass (NP) – general purpose Glass are made of commercial soda lime glass supplied for nonparenteral products, those intended for oral or topical use.
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Glass compositions (%) Material
Type I
Type II
Silica
66-74
66-75
Lime
1-5
6-12
Soda
7-10
12.5-19
Alumina
4-10
1-7
Boric oxide
9-11
-
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Lead free glass Lead monoxide – brilliance and clarity Cumulative poison Special cases – sodium calcium edetate, trisodium edetate injections Silicone treated glass Organic compounds containing silicon Good resistance to heat Good resistance to oxidation Chemically inert Free from colour, odour, toxicity Water repellency Advantages Not wetted Entire content can be withdrawn by syringe Disadvantage • Difficult to stick label – special fixative necessary • Chronic acids not to be used for washing – destroy film Girish.B KLEUCOP Belgaum
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Ampoules And Vials These are highly resistant glasses and widely used as glass ampoules and vials to package fluids for injection. One point cut ampoules Flat Based and Constricted Neck ampoules Flame cut ampoules Closed ampoules Ampoules with colour break band and identification bands
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BOTTLES Used in the dispensary as either amber metric medical bottles or ribbed(fluted )oval bottles. Available in various sizes. Amber metric medical bottles are used for packaging a wide range of oral medicines. Ribbed oval bottles attached are used to package various product that should not be taken orally includes liniments, lotions, inhalations and antiseptic solutions.
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Eye drop and dropper bottles for ear and nasal use are hexagonal-shaped amber glass container fluted on three sides. They are fitted with a cap, rubber teat and dropper as the closure. The bottles are used at a capacity of 3ml to 20ml.
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JARS Powders and semi-solid preparations are generally packed in wide-mouthed cylindrical jars made of clear or amber glass. Jars varies from 15ml to 500ml. Jars are used for packing prepared ointments and pastes.
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Syringe Graduated glass syringes
Stoppers Glass stoppers/lids
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Manufacturing of Glass
Blow process
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Evaluation of glass container Ampoules, Vials, Bottles, Syringes, containers for blood and blood components Tests for glass containers 1. Thermal shock test 2. Internal bursting pressure test 3. Annealing test 4. Vertical load test 5. Leakage tests 6. Autoclaving test (Powdered glass test) 7. Limit test for alkalinity (Water attack test) 8. Product and pack compatibility test 9. Measurement of wall and base thickness 10. Other tests: - Formal stability test with products, light transmission test, arsenic test….
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Type
General
Type of
Description
test
Limits Size
Ml of 0.01 m HCl
I
II III
NP
Highly resistant
Powdered
borosilicate glass
glass
Treated soda
All
1.0
Water
100 or less
0.7
lime glass
Attack
over 100
0.2
Regular soda
Powdered
lime glass
glass
All
8.5
All
15.0
General purpose Powdered soda lime glass
glass
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Powdered glass test Preparation of specimen for powder glass test Rinse thoroughly 6 or more containers Dry (clean dry air) Crush into fragments (25 mm) Divide 100g of coarsely crushed glass into 3 equal parts Place one portion in mortar Crush further Pass through sieve no 20 then 40 Transfer the retained portion Spread it on glazed paper Remove iron particle with magnet Wash it with 6/30 ml of acetone for 30 sec until free from agglomerations Decant acetone Dry the contents for 20 mins at 140°C Transfer to desiccators Final specimen to be used in powdered glass test
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Powdered glass test Test procedure Weigh accurately 10 gm specimen in a 250ml conical flask with high purity of water in bath at 90°C for 24 hrs or at 121°C for 1 hr. Add 50 ml of purified water into flask and to one similarly prepared blank. Autoclave for 10 mins Adjust temperature to 121°C Reduce the heat and wait to cool Cool the flask in running water Decant water from flask Wash the residue powdered glass with 4/15ml of high purity water Add the decanted washing to main portion Add 5 drops of methyl red solution Titrate immediately with 0.02 N Sulphuric acid Record the volume of 0.02 N Sulphuric acid and blank The volume does not exceed that indicated in the table for the type of glass concerned Girish.B KLEUCOP Belgaum
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Water attack test Rinse thoroughly 3 or more containers twice with high purity water Fill each container to 90% of its overflow Cap all the flask and autoclave for 60 mins Empty the content and pool the content in 250 ml conical flask to a volume of 100 ml Add 5 drops of methyl red solution Titrate with 0.02 N Sulphuric acid with warm Record the volume of 0.02 N Sulphuric acid and blank The volume does not exceed that indicated in the table for the type of glass concerned
Arsenic test Use as the Test Preparation 35 mL of the water from one Type I glass container or in the case of smaller containers, 35 mL of the combined contents of several Type I glass containers, prepared as directed for procedure under Water Attack at 121°C: the limit is 0.1 µg per g
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Plastic 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. Monomers which are relatively small molecules undergo a process known as polymerisation, a plastic or long chain polymer is produced. Girish.B KLEUCOP Belgaum
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General properties Amorphous materials give good clarity, transparency, hardness with possible brittleness, are usually more permeable to gases and moisture and are less inert. Crystalline materials are opaque or translucent, more flexible, with low permeability to gases and moisture and are more inert. Amorphous materials can be found as hard glassy plastics (polystyrene) or can be soft, flexible and rubbery (polyisoprene). This means that there is a temperature range where an amorphous material is in a glassy state and above which it is rubbery. This temperature is known as the glass-transition temperature (Tg).
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Advantages Less weight than glass, flexible Variety of sizes and shapes Essentially chemically inert, strong, rigid Safety use, high quality, various designs Extremely resistant to breakage Disadvantages Possible extraction, interaction Adsorption, absorption Permeable to moisture, oxygen … Poor printing Thermostatic charge Girish.B KLEUCOP Belgaum
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Types of Plastics Thermosets
Thermoplastics
Urea formaldehyde (UF) Phenol formaldehyde Melamine formaldehyde (MF) Epoxy resins (epoxides) Polyurethanes (PURs) Polyesters
Polyethylene{HDPE – LDPE} Polyvinylchloride(PVC) Polystyrene Polypropylene Nylon(PA) Polyethylene terepthalate(PET) Polyvinylidene chloride(PVdC) Polycarbonate Acrylonitrile butadiene styrene(ABS)
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Urea formaldehyde (UF) UF is made by the condensation polymerisation of urea and formaldehyde. It has been widely used for closures because of its good dimensional stability and good strength properties. Exhibits good resistance to alcohol, oils, grease and many organic solvents. Density 1.47–1.52. Phenol formaldehyde (originally Bakelite) (PF) PF is made by the condensation polymerisation of phenol and formaldehyde. Due to the volatile and toxic/irritant nature of formaldehyde, this is usually ‘fixed’ with ammonia giving hexamine. In certain cases some residues may remain in the moulding and be released into the product. As with UF, PF is mainly used for closures but due to the fact that the material is naturally dark, it is used for dark or deep colours and also provides good scratch resistant, exhibits low water absorption properties. PF is generally more resistant to heat and moisture than UF. Both UF and PF are used with a range of fillers, e.g. wood flour, synthetic fiber. Density 1.25–1.45. Girish.B KLEUCOP Belgaum
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Melamine formaldehyde (MF) Although offering better resistance to water and heat, it is considerably more expensive than UF and PF and has found few packaging applications. Epoxy resins (epoxides) Epoxy resins are polymers offering higher performance than most other thermosets. Their main packaging applications are for protective lacquers. Polyurethanes (PURs) Thermosetting polyurethanes are used as adhesives and to a limited extent as coatings or lacquers. They can be found as esters and ethers. Polyesters Polyester thermosetting resins are made by the polymerisation of dibasic acids with poly-functional alcohols. They offer high general strength, particularly when reinforced with glass fiber (GRP), excellent dimensional stability and good temperature resistance for temperatures. Used as closures, adhesives in laminations, protective lacquers, and enamels. Girish.B KLEUCOP Belgaum
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Polyethylene
A molecule of polyethylene is nothing but a long chain of carbon atoms, with two hydrogen atoms attached to each carbon atom. Sometimes some of the carbons, instead of having hydrogens attached to them, will have long chains of polyethylene attached to them called branched, or low-density polyethylene, or LDPE. When there is no branching, it is called linear polyethylene, or HDPE. Linear polyethylene is much stronger than branched polyethylene, but branched polyethylene is cheaper and easier to make.
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Polyethylene Polyethylene depending on density which ranges from 0.91 – 0.96 directly determines the physical characteristics of the container. Stiffness, Moisture vapour transmission, stress cracking, clarity/translucency. As density increases, material becomes more stiffer, higher melting temperature, less permeable to gases and vapors, less resistant to stress cracking. It is a good barrier against moisture but poor against oxygen and other gases. Polyethylene
Density
Ultra and very low density polyethylene
0.890–0.915
Low density polyethylene (LDPE)
0.910–0.925
Linear low density polyethylene (LLDPE)
0.915–0.930
Medium density polyethylene (MDPE)
0.926–0.940
High density polyethylene (HDPE)
0.940–0.965
Polypropylene (homopolymer/copolymer) (PP)
0.900–0.910
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Ethylene-based polymers Ethylene-vinyl acetate (EVA) EVA is a copolymer of ethylene and vinyl acetate which can have certain properties changed according to the proportion of each monomer. EVAs are soft, flexible compounds with high elongation and high impact strength even down to low temperatures. They are widely used in conjunction with LDPE and PP to increase flexibility and as an aid to heat sealing. EVA is also the basis for certain hot melts and is used as a compound lining in closures.
Ethylene vinyl alcohol copolymer (EVAL or EVOH) EVOH is now widely offered as an extrusion ply for coextruded laminations, where it provides a good bond and is increasingly popular as an excellent oxygen barrier. It has to be protected from moisture absorption since this significantly lowers its otherwise excellent barrier properties. Girish.B KLEUCOP Belgaum
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Polypropylene Does not stress crack under any conditions except for hot aromatic or halogenated solvents. These are good resistant to almost all types of chemicals. Suitable for boilable packages and for sterlizable products. • Excellent gas and vapor barrier • Lack of clarity, Brittleness at low temperature Polyvinyl chloride (PVC) PVC derived from vinyl chloride monomer. • Clear rigid PVC bottles, produced with crystal clarity • Provides good oxygen barrier, greater stiffness • Plasticizers, stabilizers, lubricants, colorants incorporated • Inexpensive tough clear material • Excellent barrier for oil, both volatile and alcohol, petroleum solvents • Not effected by acids or alkalis • Not be over heated, degrades 280° F
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Polystyrene • Rigid crystal clear plastic containers for solid dosage form • Low cost • Not used, higher water vapor transmission • Scratched, crack when dropped • Builds up static charge, Not to be used for hot items Nylon (Polyamide) • Made from a dibasic acid combined with diamine • Variety of nylons, type indicated by an identifying number (6/10) • Fabricated into thin walls, extremely strong • Excellent barrier to oxygen • Nylon 6, 6/6, 6/10, 11approved by FDA
Polyethylene terepthalate (PET) Reaction of terepthalic acid or dimethyl terepthalate ethylene glycol in the presence of catalyst • Bottle for carbonated beverages • Excellent impact strength, gas and aroma barrier • Cosmetics, mouth washes
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Additives (Plastics) Thermoplastics modified – addition of specific additives Lubricants – assist moulding/extraction (Zinc stearate)
Stabilizers – retard or prevent degradation of polymer by heat & light Plasticizers – softness &flexibility Antioxidants – retarding oxidation
Antistatic agents – prevent static charge Slip agents – reduce friction coefficient Dyes & Pigments – impart color
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DRUG – Plastic considerations Permeation Leaching Sorption
Chemical reaction Modification
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Sterilization of plastic packaging materials Agents – Steam, Gas, Irradiation Steam – polypropylene, HDPE Gas – 100% Ethylene oxide, 88/12% of Feron & Ethylene oxide, 80/20% or 90/10% mixtures of Carbon dioxide & Ethylene oxide Irradiation – cause degradation or cross linking of polymers Ex – PVC loses HCl
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Manufacturing of Plastic
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Manufacturing of Plastic
Injection stretch blow moulding
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Evaluation of plastics Plastics container for non-injectable preparations
Plastics container for injectable preparations Plastics container for noninjectable preparations • Leakage test • Collapsibility test • Clarity of aqueous extract • Non – volatile residue
Plastics container for injectable preparations • Leakage test • Collapsibility test • Water vapour permeability • Transparency
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Leakage test Fill 10 containers with water, fit with intended closures and keep them inverted at room temperature for 24 hrs. Collapsibility test Applicable to squeezable containers – yields at least 90% of its nominal contents at the required rate of flow at ambient temperature. Clarity of aqueous extract Select unlabelled, unmarked & non-laminated portions from suitable container randomly. Cut these portions in top strips (NMT 20 cm2). Wash them with distilled water. Transfer it in to a flask previously cleaned with chromic acid mixture and rinsed with distilled water. Add 250 ml of distilled water, cover the flask with a beaker and autoclave at121°C for 30 mins. Carry out a blank determination using 259 ml of distilled water. Cool and examine the extract. Girish.B KLEUCOP Belgaum
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Non-volatile residue Evaporate 100 ml of the extract obtained in the test for clarity of aqueous extract to dryness and dry to constant weight at temperature 105°C. The weight of the residue should not be more than 12.5 mg. Water vapour permeability test Fill 5 containers with nominal volume of water and heat-seal the bottles with an aluminium foil – polyethylene laminate or other suitable seal. Weigh accurately each container & allow to stand for 14 days at RH of 60±5% at 20 25°C. Reweigh the container. Loss of weight in each container should not be more than 0.2%.
Transparency Preparation of test specimen Prepare a 16 fold dilution of standard suspension. Test Fill empty containers to their nominal capacity with the diluted suspension. The cloudiness of the diluted suspension in each container is detectable when viewed through the containers, as compared with a container of same type filled with water. Girish.B KLEUCOP Belgaum
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TUBES Metal collapsible tubes, Plastic collapsible tubes & Laminated tubes
Metal tubes • Attractive container permits controlled amounts to be dispensed easily • Good reclosure, adequate protection to product • Less weight and unbreakable • High speed automatic filling operation
Commonly used metals – Aluminium, Tin, Lead
Tin • Most chemically inert (15%), expensive • Good appearance, compatibility
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Aluminium • Attractive, very less weight (60%) • Hardens in use, develop leaks
Lead • Lowest cost (25%) • Nonfood products • Adhesives, inks, paints, lubricants • Never be used alone
Linings • Interior flushed with wax type • Resins, epoxides • Vinyls, phenolics used with aluminium tubes
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Plastic tubes • Low cost, Light weight • Durable, Pleasant to pouch
• Flexible, Odorless, Inert • Unbreakable, Leakproof, Retain shape • Unique “suck-back” feature, printable • HDPE & LDPE, vinyls, polypropylene
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Laminated tubes Multilayer tubes with Aluminum foil / nylon / polyester act as barrier against oxygen, moisture, aroma loss and provide a glossy surface enhancing printing quality. Transparent stretch polypropylene and PET tubes with dispenser caps are designed. Different caps such as conical, fliptop, can be custom designed for an aesthetic look. Ex Depilatories, hand creams, hair care products, denture adhesives…. Girish.B KLEUCOP Belgaum
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CLOSURES Closures are the devices by means of which containers can be opened and closed. • Avoid material spilling or volatilization • Avoid contamination from dirt, microorganisms or insects • Deterioration moisture , oxygen or carbon dioxide The closures Cork Glass Plastic Metal Rubber
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Closures available in 5 basic designs 1. Screw-on, threaded or lug cap 2. Crimp-on (crowns) cap 3. Press-on (snap) cap 4. Roll-on cap (Pilfer proof) 5. Friction cap Variations of these basic types include Vacuum Tamperproof Safety Child-resistant Liner less types
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Cork closures Obtained from the bark of oak tree . cork is chemically inert and it does not impart any odor or flavor. It is used rarely because of growth of mold. Glass closures These closures are mainly used for reagent bottles in laboratories. Metal closures Made of aluminium and tin plate rubber
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PLASTIC CLOSURES Thermosets & Thermoplastics Thermosets – Phenolics & Urea – threaded closures Heat – softens – cures – hardens Permanent chemical change Fabricated by compression molding Phenolics color limitation – black / brown Urea – colors & brightness Thermoplastics (90%) – Polystyrene Polyethylene Polypropylene
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RUBBER CLOSURES Rubber – used as stoppers, cap liners, bulbs for droppers Multiple dose vials & disposable syringes Ideal qualities: Satisfactory hardness & elasticity Impermeable to water vapor Resistance to high temperature Resistance to oxidation Rust proof & oil resistance
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Ingredients of rubber closure:
Rubber Vulcanizing agent – sulphur, phenolics resins Accelerator / activator – thiazoles, stearic acid, zinc oxide Reinforce filler – calcium and magnesium carbonate Extended fillers – carbon black Softener / plasticizer – pine oil, mineral oil Pigments – oxides, sulfides of iron Lubricants – zinc stearate Special components - waxes
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Types of rubber closures: Natural – Long chain polymers of isoprene Synthetic – • Butyl rubber closure • Nitrile rubber closure • Chloroprene rubber closure • Silicon rubber closure Evaluation tests • Sterilization • Fragmentation • Self sealablity • Permeability • Compatibility • Acidity / alkalinity pH of aqueous extract • Light absorption • Reducing substances • Heavy metals • Residue on evaporation • Penetrability • Biological tests Girish.B KLEUCOP Belgaum
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CLOSURE LINERS Liner – an material inserted in a cap to effect a seal between the closure and container, made of resilient backing & a facing material Types – • Homogeneous liner One piece liner available as disk / ring of rubber or plastic Uniform & withstand high temperature sterilization • Heterogeneous / Composite liner Multi layers of different materials 2 parts Facing – contact with product Backing – cushioning & sealing Torque testing: Controlling cap tightness with Owens-Illinois torque tester can prevent evaporation / leakage of the product, breakage of a plastic molded closure & application of a cap too tight to be removed Girish.B KLEUCOP Belgaum
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BLISTER PACKAGE Blister packs are commonly used as unit dose packaging for pharmaceutical tablets, capsules etc…
Blister packs consist of two principal components : 1) A formed base web creating the cavity inside which the product fits 2) The lidding foil for dispensing the product out of the pack. Girish.B KLEUCOP Belgaum
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PACKAGING First Intent – Blister base MATERIALS (hierarchy of choice based on product stability) Material should preferably be opaque white unless clear is a specific market requirement (eg US, Japan) Polychlorotrifluoroethylene (Aclar) should be restricted to applications where cold form is not technically or commercially acceptable due to product or pack size, ie larger products (further guidance to be defined) 1. PVC 250m 2. PVC/PVDC 250m/60gsm
3. Cold Form 25 OPA/45 Al/ 60 PVC 4. PVC/Aclar® UltRx 2000
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There are two types of forming the cavity into a base web sheet: Thermoforming and Cold forming 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 preheating plates (upper and lower plates) is such that the plastic will soften and become moldable. - PVC
- Overlacquer - Print - Aluminium - Primer - Heat seal lacquer
- PVDC or Aclar
Lidding Foil – typically 20 micron Al
Film - eg PVC, PVC/PVDC, PVC/PE/PVDC, PVC/Aclar Product contact layers: For PVC or PVC/Aclar = PVC For PVC/PVDC = PVDC For Lid foil = heat seal lacquer Girish.B KLEUCOP Belgaum
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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, the lack of transparency of the package and the larger size of the blister card. Lidding Foil
Foil Laminate – e.g. OPA/foil/PVC, or OPA/foil/PP
- OPA Film - Primer/Adhesive - Aluminium foil - Primer/Adhesive - PVC (may be PP)
Product contact layers: For base = PVC (or PP) For lid foil = heat seal lacquer
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TROPICALISED BLISTER thermoform blister plus cold form tray once tray opened, in use life determined by primary thermoform blister high barrier before use Lidding Foil
Film – e.g. PVC, PVC/PVDC Foil Laminate – e.g. OPA/foil/PVC
Product contact layers: For PVC = PVC For PVC/PVDC = PVDC For Lid foil = heat seal lacquer
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Blister package design
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STRIP PACKAGE It is commonly used for the packaging of tablets and capsules. A strip package is formed by feeding two webs of a heat sealable flexible film through a heated crimping roller .The product is dropped into the pocket formed before forming the final set of seals. A continuous strip of packets is formed which is cut to the desired number of packets in length. The materials used for strip package are cellophane, polyester, polyethylene, polypropylene, polyvinylchloride. 82 g/m2 (25 m) Al foil/30 g/m2 LDPE or 25 g/m2 LDPE. Gives excellent moisture, gas and light protection. External foil image 30 g/m2 glassine/ink/poly/67 g/m2 Al foil (20 m) 25 g/m2 LDPE. Good protection— more subdued metallic image Girish.B KLEUCOP Belgaum
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Strip packaging
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Strip designs Strip designs are very basic, as the emerging units are invariably rectangular or square strips. The pocket portion can, however, be round, oval or square.
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FILM WRAPPER End folded wrapper
Fin seal wrapper Shrink wrapper
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End folded wrapper – formed by pushing the product into a sheet of overwrapping film, which forms the film around the product and folds the edges in a gift wrap fashion. Films used must be heat sealable – PVDC coated Cellophane, Polypropylene. Fin seal wrapper – seals are formed by crimping the film together and sealing together the two sides of the film producing a ―fin‖ seal. Seals are formed by compressing the material between two heater bars.
Shrink wrapper – a pocket is formed in the center fold of the sheet into which the product is inserted. The loosely wrapped product is then moved through a heated tunnel which shrinks the overwrap into a tightly wrapped unit. Polypropylene, Polyethylene, Polyvinylchloride…. Girish.B KLEUCOP Belgaum
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SACHETS Their use, initially as a replacement for powders in folded paper, was extended into granules, moisture sensitive solid products and liquids (particularly shampoos). Fabricated from a single web with a centre fold, using a three or four sided seal or two webs using a four sided seal. The reels may be fed horizontally or vertically and be sealed by a series of heated platens or rollers (cylinders) or a combination of the two. Difficult to tear plies, like PET, can be used provided a cut or V-notch is added to initiate the tear. Small sachets usually start with narrow seal margins of around 5 mm, but become wider as the weight of the contents increases. Sachets have the advantage that they can be used for liquid and semi-liquid packaging. Flow wraps are a further extension of a sachet-type pack. Girish.B KLEUCOP Belgaum
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PAPER: This can be used as a flexible wrap for products, or as a closure material for jars. Most paper materials are used with a liner applied either as a laminate or as a coating.
Foil: Foil is obtained from metal of 99% purity and above. The gauges range from 0.006 mm to 0.040 mm. The foil is annealed to give a soft foil with a ‗dead fold‘ property. Hard tempered (nonannealed) foil occasionally finds special applications, i.e. push-through lidding for blister packs. Lubricants are removed from hard foil by either solvent washing or controlled heating. For any nominal gauge +8% variation is normally allowed. Foil of 0.038 mm is guaranteed pinhole-free; 0.017 mm can be considered commercially free for most purposes. Ex: Alu, PVC, PVDC, EC… Girish.B KLEUCOP Belgaum
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CORRUGATED FIBERBOARD: is a paper-based construction material consisting of a fluted corrugated sheet and one or two flat linerboards. It is widely used in the manufacture of corrugated boxes.
CARTON: A carton is a type of suitable for food, pharmaceuticals, hardware, and many other types of products. Folding cartons are usually combined into a tube at the manufacturer and shipped flat (knocked down) to the packager.
Shippers: Shippers are used to carry large quantity of finished products for transportation.
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Blister packing machine
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Strip packing machine
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Bottle packing machine
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Tubes packing machine
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Sachet packing machine
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SYMBOLS USED ON PACKAGES AND LABELS Many types of symbols for package labeling are nationally and internationally standardized. For product certifications, trademarks, proof of purchase, etc.
Explosives
Substances liable to combustion
Flammable liquids
Oxidizing substances
Flammable solids
Toxic substances
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Corrosives
Miscellaneous danger goods 82
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REGULATORY REQUIREMENTS All packaging systems should pass the Federal Food, Drug and Cosmetic Act (FDA) regulations. When the FDA evaluates, the agency must be firmly convinced that the package for a specific drug will preserve the drug‘s efficacy, purity, identity, strength and quality for its entire shelf life. Under the provisions of FDA, it is the responsibility of the manufacturer to prove the safety of a packaging material and to get approval before using it for any product. A list of substances considered ―Generally Recognized As Safe‖ (GRAS) published by FDA are safe under specified conditions, assuming they are of good commercial quality. The FDA has published regulations (part 133) that implement the Current Good Manufacturing Practice (cGMP) requirements of section 501(a) 0f the act.
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REGULATORY REQUIREMENTS
• Presentation – e.g. for solid dose
• US prefer bottles • EU/RoW prefer blister packs
Child resistance requirements US Legal requirement with few exceptions Clear blisters, peel-push, tear notch, secondary CR pack
• Environment – EU Packaging and Packaging Waste Directive – US - no direct equivalent
EU/RoW Legal requirement in only 4 EU member states & for very limited list of products Push through blisters, opaque
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PACKAGING Key Regulatory Guidance - US
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PACKAGING Key Regulatory Guidance - EUROPE CPMP/QWP/4359/03 – Guideline on Plastic Immediate Packaging Materials - specific to plastics only
Guideline on Dossier Requirements for Type 1A and Type 1B Notifications
KEY POINT TO NOTE EU does NOT have a consolidated container/closure guideline (cf FDA) Girish.B KLEUCOP Belgaum
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TRENDS IN PHARMACEUTICAL PACKAGING Packaging of oral medicines generally conforms to requirements for easy dispensing, child resistance but senior-friendliness, but packs must also be identifiable, functional and very often hermetically sealed to cut the number of accidental poisonings. Gentle handling is also essential and packs should be hermetically sealed for higher product safety. A solution to achieve hermetically sealed packs for blister, blow-fill-seal pouches, vials and other products is to overwrap them into a horizontal flow wrap. New packaging lines will have to offer high flexibility while maintaining production levels. To meet validation requirements, pharmaceutical companies increasingly demand that machinery is modularized and standardized. This includes a standardized operating interface and control systems for all components. Such systems also have monitoring systems for maximum production safety standardization that is sufficient to produce high efficiencies. The entire packaging process needs to be harmonized and there is a huge optimization potential in this area.
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FUTURE CHALLENGES Moisture sensitive drugs increasing barrier requirements Novel delivery systems Emphasis on speed to market Control of R&D Expenditure/resource - number of stability studies Global - Regional - Local packs Anti-counterfeiting, illegal cross border trading Multiple studies for different packs vs. Year-on-Year manufacturing costs Pharmacogenomics - Personalised medicines Demographic change - Ageing population
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REFERENCES Dean DA, Evans ER, Hall H. Pharmaceutical packaging technology ,1st ed. Remington.The Science and Practice of Pharmacy, 21st ed,Vol-1. Leon Lachman, Lieberman AH, Kanig JL. The Theory and Practice of Industrial pharmacy,4thed. Hanlon J. Handbook of Packaging Engineering.4thed. H.C. Ansel, Introduction to Pharmaceutical Dosage Forms. Michael E Aulton, Pharmaceutics The Science Of Dosage form Design, 2nd ed. Girish.B KLEUCOP Belgaum
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Mr.Girish.B Asst. Professor Dept. of Pharmaceutics KLE University College of Pharmacy Belgaum-590010 Karnataka (INDIA) Phone: +919880547567
[email protected]
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