Packaging

Sterial Packaging : 

Sterial Packaging The form-fill-seal technology (blow-fill-seal technology) Pre-filled syringe system Lyophilization

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Blow-Fill-Seal Process: 1)Container Moulding: Polymer granules are continuously fed to a machine hopper through screw extruder. Within the extruder the polymer is subjected to high temperature (>160 oC) and pressure (up to 350 bar) and become molten. Then it is extruded through die and pin set to form an open ended tube of molten polymer known as parison. A mould set in two halves then moves over to the parison and closes around it. Molding is facilitated by vacuum The molded plastic is severed from the continuously extruding parison by a hot-knife, and is then shuttled within the mold set to the filling parison. Generally cutting of parison with hot-knife is associated with a problem of generation of particulate matter which is overcome by following technique.

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KleenKut™ (Technology for parison cutting): KleenKut™ parison cut-off mechanism, which is designed to prevent the generation of particulate matter at the source. The extruded parison does not cause microbial contamination of vials and confirms that non-viable particles 0.3µm to 10µm in size are significantly reduced in quantity compared with the volume of particles produced during the use of a hot-knife cut- off mechanism. KleenKut technology is available for both-low density and high-density polyethylene resin applications.

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2)Container Filling: The nozzle assembly lowers into the parison until the nozzles form a seal with the neck of the mould. Container formation is completed by applying a vacuum on the mould-side of the container and blowing sterile filtered air into the interior of the container. The patented electronic fill system delivers a precise dosage of product into the container. Viscous products, with apparent viscosities of less than 15,000 centipoises, and suspension products can be handled by blow-fill-seal machines with specially designed product fill systems. The precision fill accuracy achieved by electronically controlled time-pressure fills system.

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3)Container Sealing: Following completion of the filling process, the top of the container remains semi-molten, and the container are sealed by a second mold set, which forms the neck and closure of the BFS-containers.

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The main characteristic of the blow-fill-seal process: The isolation of the critical filling zone within the machine. Sterile air management within this critical zone (is typically verified through environmental monitoring for the presence of non-viable particulates). Better control of non-viable particulates will provide enhanced sterility assurance for the blow-fill-seal process. Advantages of FFS/BFS: The process takes place in a single machine under a controlled environment that enables the packaging of a parenteral solution in an aseptic manner with following advantages.. Overall product quality and product output. Low operational costs. High degree of sterility assurance.

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Minimum number of operating personnel. Relatively small space requirement. Problems regarding to storage of empty container is avoided. Product Applications: Blow-fill-seal technology has gained much market focus in recent years due to the increased focus on biologics, proteins and other complex solutions. These important products are thermolabile and cannot withstand with high temperature and hence conventional terminal sterilization is not an acceptable method to produce a ‘sterile’ product. Instead of bulk sterilization, sterilization by gamma irradiation or filter sterilization followed by direct packaging, the blow-fill-seal processes are often used successfully for these types of products.

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Blow-Fill-Seal Machine

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Pre-filled syringe systems Single-Chamber Syringe with Rigid Needle Shield (RNS) The pharmaceutical and biotech industry has registered a growing demand in the market segment of pre-filled syringe systems during the past ten years. Health-care experts consider these systems to be the state of the art for the parenteral administration of drugs. According to a study conducted by BD (Becton Dickinson and Company), nine out of ten persons surveyed prefer pre-filled application systems to conventional syringes. The decisive factors included: Their user-friendliness. Patient safety. Efficient use. The transfer into a pre-filled syringe or cartridge system is possible during all life cycles of a product.

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Advantages of pre-filled syringe systems - an overview For self-injecting patients, pre-filled systems mean a high degree of flexibility and independence, simple handling, the discrete appearance of the injector and reduction of injuries. In addition, there are other aspects, from the point of view of pharmaceutical companies and physicians, advantages of pre-filled syringe systems: Product differentiation in the market Cost savings from optimized drug use due to low overdosing requirements in pre-filled syringes in comparison to vials Reduced material requirements, simple storage and disposal Better patient compliance Simplified drug administration Simple administration and great convenience for hospital personnel Fewer needle injuries Reduced risk of microbiological contaminations

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Applications: Pre-filled syringes were used mostly for delivering insulin or human growth hormone. Now a days biotechnological products gaining popularity for the treatment of various diseases like multiple sclerosis, fertility, osteoporosis, hepatitis, rheumatoid arthritis, cancer, anemia, and hemophilia. Biotechnological products are generally available as injectable preparation and therefore pre-filled syringes are gaining popularity in market because its ease of use, ease of manufacturing and ease of dosing (generally unit dose pre-filled syringes are more used). In 2006, about 1.4 billion pre-filled syringes were sold, and by 2010 the quantity is expected to top 2.4 billion.

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Design of pre-filled syringes: Glass and plastic: Although plastic pre-filled syringes are gaining in popularity in Europe, glass barrels are still preferred in the United States. Glass pre-filled syringes are made of Type I borosilicate glass. Problem associated with glass container, Glass contains alkali ions, which can lead to a surface reaction that forms a small amount of sodium hydroxide which may cause detrioration of product Recently, more companies have been taken an interest in plastics, mainly owing to recent advances in their design and makeup. Original plastic syringes, which were introduced in the early 1990s, were made from polypropylene.

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But such materials were opaque and inspection of filled material was not possible to overcome such problems, several companies now offer syringe barrels made of cyclic olefin polymer or cyclic olefin copolymer, which is as clear as glass but less heavy and less likely to break. Cyclic olefin plastics also are more resistant than polypropylene to water transmission, which may help lengthen the shelf life of the drug product. The photo shows automated heat-tunnel unloading of pre-filled syringes.

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Lyophilization - a highly effective drying process

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Lyophilization-A Highly Effective Drying Process   The term lyophilization (freeze-drying) is the drying of a frozen material under a vacuum by means of freezing out the solvent (usually water) which then vaporizes in its frozen state (sublimation drying). Today, lyophilization is a common process for the careful drying and conservation of delicate materials such as food, flavors, and pharmaceuticals as well as biological materials. The final product of lyophilization is a very porous, stable and dry "lyo-cake". In the pharmaceutical field, lyophilization is an important and widespread process particularly for sensitive materials. They are highly active, but especially sensitive and can therefore only be preserved for longer periods by means of lyophilization

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As a basic principle, lyophilization has its advantages for filling if the medication is not sufficiently stable in solution and/or if the exact dosage is not possible using a dried filling. In addition, lyophilization could also be of benefit if a product possesses one or more of the following criteria: Instability with regard to humidity or oxygen Heat incompatibility

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Lyophilization is comprised of three procedual steps: 1.The freezing of the medication in the final container at very low temperatures, e. g. -60°C. 2.The main drying (by delivering energy under a high vacuum, water or the solvent is extracted from the agent. 3.Final drying. Automatic loading of a freeze-dryer

Newer techniques : 

Newer techniques Child resistant packaging Elder friendly Temper proof packaging

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Child resistant packaging(CRP) The provision of child-resistant packaging for pharmaceutical products is an emotive subject. The packaging that excludes the entry of children of less than 5 years age but not adults to access the contents of the pack. Legally : “ at least 80% of children between the ages of 20 and 42 months forming a test panel are unable to open the packaging within 10 minutes of receiving it” Up to now, all standards for testing for child-resistant compliance give a definition of such a package as being the immediate packaging which is resistant to opening by children (under 52 months old), but which does not pose difficulties for the elderly (over 65 years) to open and, where appropriate, to re-close properly.

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Peelable backing materials: Peelable backing materials-used to meet requirements of child-resistant packaging. Materials used: polyester or paper is used as a component of the backing lamination. Foil –component of backing lamination-barrier protection critical requirement-metallized polyester is replacing foil for some barrier applications Peelable backing materials: A peelable sealant compatible with heat-seal coating on the blister is also required since degree of difficulty in opening is a critical parameter for child-resistant packaging.

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Child-Resistant Stickpack It offers a single-use stickpack that features a child-resistant, yet senior-friendly, opening. The TearStick is a four-side-seal sachet made of plastic film that features a printed tear indicator with instructions. The tear indicator can also be combined with a fold-first or squeeze-first operation. The child-resistant tear-open feature can also be incorporated into other packaging formats, such as pouches and sachets.

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Cardinal health has patented certain child resistant containers like Slide pack: To open, the patient must insert their index finger through an opening, pull the plastic trigger to the right to expose the foil, hold and press the blister to push medication through the foil and release the trigger - thus prevention access again. E-Z tear:To access, the patient must remove a single dose at the perforation - which will tear at bubble blister only. Note: the child resistant foil will not puncture. RxBarrier™ pack:Blisters are protected by a PVC cover (barrier) to prevent child from biting individual cavities.

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Some of the "elder-friendly" concepts we expect to see include the conversion to square- or rectangular-footprint bottles from cylinders--to facilitate [container] opening and to resist rolling off countertops. Simillarly flexible pouches with larger fins that can be gripped more easily and pulled apart to open the pouch containing a unit dose. Unit-dose packaging itself would be a help. Other problem with geriatric patient is poor vision in dark in such cases glow-in-the dark inks can be used in printing packaging material. Missing dose is still a common problem for which a specially printed strips are designed on which the day & time is printed at which the drug is to be taken. Elder friendly packagings

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TAMPER PROOF PACKAING Tamper proof containers are those that resist the tampering of the product before consuming the product. Tampering includes three aspects, Altering, Pilfering and Falsifying They help in…. Receiving the products by patients “ as manufactured “ Preventing “ product browsing and sampling “

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TAMPER PROOF CONTAINER Film Wrappers Blister or Strip Packs Bubble Packs Heat Shrink Bands or Wrappers Foil, Paper, or Plastic Pouches Bottle Mouth Inner Seals Tape Seals Breakable Caps Sealed Metal Tubes or Plastic Blind-end Heat Sealed Tubes Cans In-Built Tamper-Evident Controls

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Other newer techniques involve, Shrink wrap or shrink film, is a material made up of polymer plastic film. When heat is applied to this material it shrinks tightly over whatever it was covering. Shrink bands are applied over parts of packages for temper resistance or labels. It can also combine two packages or parts. The most commonly used shrink wrap is polyolefin. It is available in a variety of thicknesses, clarities, strengths and shrink ratios. The two primary films are either crosslinked, or non crosslinked. Other shrink films include PVC and several other compositions. A shrink film can be made to shrink in one direction (unidirectional or mono-directional) or in both directions (bidirectional).

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Cooling the film sets the film's characteristics until it is reheated. this causes it to shrink back toward its initial dimensions. It can also be used for the product which cannot tolerate freezing. Various alarm signals can also be attached to such packs which rings when temp goes out of range.

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Time tracking packaging It is mainly for the products having shorter shelf life after opening the container once like eye drops. when opened, edible oil travels across the label at a consistent rate & provides a visible indicator of how long the product has been open & in use. When activated & applied over barcode of product, it slowly changes its colour as time passes or temp changes & when label become opaque or barcode is unreadable product is not safe to use. Other Time tracking include a time strip label which indicate how much shelf life remains.

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Regulation 0f Pharmaceutical packaging materials

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Why there is requirement for Regulation for Pharmaceutical packaging materials?? The various elements of the packaging of a pharmaceutical product is aimed at ensuring that medicines arrive safely in the hands of the patients for whom they are prescribed. It must be emphasized that packaging preserves the stability and quality of medicinal products and protects them against all forms of spoilage and tampering.

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FDA’S CURRENT FOCUS CMC CC Packaging Technical Committee Packaging Guidance for Industry CMC CC recent Packaging Initiative CMC CC= chemistry, manufacturing and control coordinating committee

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CMC CC PACKAGING TECHNICAL COMMITTEE CDER Office Of New Drug Chemistry Office Of Generic Drug Office Of Compliance Office Of Testing And Research Quality Implementation Staff CBER Office Of Compliance And Biologics Quality CVM Office Of New Animal Drug Evaluation

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Stability Testing of Drug Substances and Drug Products, draft, 1998 packaging for solid and liquid oral drugs ICH Common Technical Document-Quality (CTD-Q) S.6 and P.2.4 EN 13427:2004 Packaging - Requirements for the use of European Standards in the field of packaging and packaging waste The Federal Food, Drug, and Cosmetic Act : Section 501-505 The Code Of Federal Regulation : 21 CFR 211(Subpart E , Subpart F , Subpart G) 16 CFR 1700-1702 – Special Packaging Complaince Policy Guides That Concerns Packaging : Subpart 410, 430, 440-448, 450-457, 480 PACKAGING IN OTHER GUIDANCES

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PACKAGING GUIDANCE, 1999 Represents company’s current thinking on container closure systems for packaging of human and biological products. Does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfy the requirement of the applicable status, regulation or both. Provide guidance on general principles for submitting information on packaging materials used for human drugs and biologics

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The Federal Food, Drug, and Cosmetic Act (a) Section 501 : “ A drug or device shall be deemed to be adulterated “ if its container is composed, in whole or part, any poisonous or deleterious substance which may render the contents injurious to the health “ (b) Section 502 : A drug or device shall be deemed to be misbranded  If it is drug the name of which is recognized in an official compendium, unless it is packaged and labeled as prescribed manner (502(g))  If it is a drug and its container is so made, formed, or filled as to be misleading  If it is a drug and packaging or labeling is in violation of an applicable regulation issued pursuant to section 3 or 4 of the Poison Prevention Packaging Act of 1970

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The U.S consumer Product Safety Commission (CPSC) is responsible for enforcing the Poison Prevention Packaging Act (PPPA) in 1970. The PPPA requires special packaging of hazardous household substance to protect children from serious injury or serious illness from handling, using. Which Pdt requires Special Packaging ? Human oral prescription OTC drug preparation PPPA regulation establish performance standards and test methods that determine if a packaging system is child resistant and adult use effective.

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COMPLAINCE POLICY GUIDES THAT CONCERNS PACKAGING Subpart 410 :- Bulk Drugs 410.100 : Finished Dosage forms drug pdt. In bulk container Subpart 430 :- Labeling and Rapackaging 430.100 : Labeling for solid and liquid oral dosage forms 430.200 : Repackaging of drug pdts.- Testing/examination under CGMP Subpart 440-448 :- New Drugs 446.100 : Regulatory action regarding Approved New Drug and Antibiotic drug pdt. Subjected to Additional Processing or Manipulations. Subpart 450-457 :- OTC 450.500 : Tamper Resistant packaging requirements for certain OTC human drug products 450.550 : Control and accountability of labeling associated with Tamper Resistant packaging of OTC drug products. Subpart 480 :- Stability / Expiration 480.100 : Requirements for expiration Dating and stability testing 480.200 : Expiration dating of unit dose Repackaged drugs 480.300 : Lack of Expiration date of Stability data

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Requirements in the International Pharmacopoeia : Requirements for the Dosage form Containers : TABLETS :  Kept in well closed container & protected from light, moisture, crushing and mechanical shock.  Additional special recommendation for packaging, storage, transportation are specified in relevant individual monographs (E.g.. Effervescent Tablet ) CAPSULES :  Packaged and stored in a manner that protects them from microbial contamination.  should be protected from light, excess moisture, or dryness

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PARENTERAL PREPARATION :  Usually supplied in glass ampoules, bottles or vials , plastic bags and PFS which are colored in case of light sensitive substance.  Mostly containers are transparent to permit visual inspection  Closure should be equipped with a firm seal to prevent entry of microbes. TOPICAL SEMI-SOLID DOSAGE FORMS :  Containers should be made from a material that does not adversely affect the quality of the preparation  Containers should be of a design that minimize microbial contamination.  Use of suitable metal or plastic flexible tubes is preferred.  The preparation should maintain its pharmaceutical integrity throughout the shelf life when stored at the temp. indicated on the label.

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Stability aspect of packaging

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Stability aspect of packaging ‘A device for carrying and protecting the product from producer to user, thus it is involved in containment, convenience, compliance and confidence.’ The regulator, however, is interested in only some of these aspects. The regulator sees the pack as having the following characteristic. (1) Containing the product Protection of the product Protection of the consumer Dosage control (2) Carrying the label Legal control of the product Informing the recipient (3)Protecting the consumer Child resistant closure Temper-evidence

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SHELF LIFE: Shelf life of any product may, in certain instance, depend on and be influence by how and in what containers and material are stored, prior to and during processing, including bulk storage of the product, until the time when it is packed into the pack for sale. Good stability with a clearly defined shelf life profile: Occasionally drug have a limited shelf life irrespective of the pack used, but at the other extreme, some drug formulations are inherently stable and therefore a pack is needed only to prevent direct contamination, i.e. dirt, dust, bacteria etc from the outside atmosphere, and for containment.

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Traditionally pharmaceutical products have aim for a five years shelf life where practical, or at least three years. Generally stability is currently supported through the international conference on harmonization (ICH) guidelines

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Some factors that may influence the pharmaceutical pack: (1) Route or mode of administration: According to route of administration certain packaging features become desirable or necessary. (2)Type of pack/material: Type of pack can refer to either the basic materials employed, i.e. glass, plastic, metal etc. or the pack style/type, e.g. bottle, tube, blister etc. Pack may provide single use or multi use. Both group have influence on the product and have to be considered in terms of the material characteristic and the total packaging concept involving such factor as product compatibility, functional and aesthetic design, production performance, material costs, production costs and user convenience.

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(3) Mode of sale or market area: Sale a product by retail (community pharmacy), wholesale, health center, hospital, dental, health care center, special homes, home trade or export etc. Market may involved and be influenced by how an ethical product is spread for, i.e. privately, by national insurance or by some other form of reimbursement through governmental authorities (4) Administration To have the administration, the pack may be required to act as a dispensing aid or a device e.g. an aerosol, or a dropper assembly.

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PROTECTION The pack must afford protection against the following primary hazards. Climatic, i.e. those associated with the surrounding atmosphere Biological-these involved micro biological (bacteria, moulds and yeasts) and biological factors (insects, rodents, human pilferage, etc.) Mechanical, i.e. physical hazards associated with storage, carriage, etc-general handling. Chemical-aspect of interaction and exchange between product and pack i.e. compatibility, ingress and combination of these and the factors above. Use –professional and patient, including any possibilities of misuse or abuse.

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Formal Stability test: The final stage of any product-pack stability is usually a formal stability test includes analytical programme, packaging examination and pack analysis which forms important part of the procedure. Use of accelerated testing needs careful evaluation, as danger in the pack may occur that will lead to incorrect interpretation of result. For Ex. A closure on a pack may loosen and/or tight under broad cycling condition due to dimensional changes associated with temperature and relative humidity.

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Similarly, in a static condition test where samples are prepared at, say, 18˚C and then stored for a prolonged period at a higher (e.g. 40˚C 75RH) or lover temperature, differential expansion and/or contraction between container and closure may cause loosing or tightening of closure. Measurements are essential at all temperature as too often packs are allowed to equilibrate with the laboratory environment before being checked. The use of temperature above 45˚C or 50˚C tends to cause some changes with packaging materials which subsequently deterioration the product

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Container closure system: Tablet container closure system must provide functional protection against such factor as moisture, oxygen, light, volatility and drug/package interaction. Regulation requires that stability data for the solid dosage form be provided in the container in which it is to be marketed. The USP/NF has provided definition for various type of containers based on their capability to provide protection: light resistant, well closed and tight closed container.

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The USP/NF describe the quantitative tests to measure the permeation and light resistance of a container closure systems and establish limits for each test to define tight, well closed, and light resistant container. An understanding of the properties of the container closure systems and the types of protection necessary for the tablet product will be needed to establish the package selection. Glass and plastic are commonly used components for tablet packaging.

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GLASS: Glass shows a high degree of chemical inertness, resistance to decomposition by atmospheric conditions, and is completely impermeable to all gases, solutions and solvents. Umber or green shaded glass offers good resistances to ultra violate light, and amber glass shows the greater absorbance to infra red rays. Flint glass is transparent to light rays above 300 nm, whereas umber glass should out light rays upto 470nm. Since photolysis decreases with increase in wavelength, it is expected that amber glass would protect tablets against light.

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PLASTIC: The use of plastic or polymeric material packages for tablets has become very popular, especially with unit dose hospital packages for which aluminium foil is sometimes used. Polyethylene, high and low density polystyrene, polyvinyl chloride and poly propylene are among the commonly used polymeric materials to fit the different shapes and size of tablet packages. The major disadvantage of plastic containers is two way permeation through the walls. The degree of permeation varies from one polymeric material to another. Chemical and physical stability of the tablet dosage form can be influenced by penetration of the atmospheric water vapour or loss of moisture from the formulation.

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Gases such as oxygen and carbon dioxide in the air can permeate the plastic container walls, catalyzing drug degradation in tablets. Polymeric materials commonly used in strip and blister tablet unite dose packages includes cellophane, polyethylene, cellulose acetate, polyvinyl chloride, polypropylene, vinyl, and fluorinated hydrocarbon

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ONLINE TESTING: (1)Some testing procedures that are essential to be correct functioning of the line, such as those that detect that the pack is incomplete. No container (or film)-no fill No container, no allege filler- no closure No container- no label No container- no carton No leaflet- no carton. This means that if any part of the total pack structure does not feed to the line, the feeding mechanisms for the subsequent materials will not be activated.

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(2) Another essential area is the testing of the seal integrity of the closure. Level/tilt position of applied closure Inert gases sniffing’ of form, fill, and seal packs. (3) Another area considered essential for checking is ensuring that the correct identification is on the primary pack, i.e. barcode read or optical character verification (OCV) of the primary pack, leaflet, carton, outer casing or outer label.

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SUMMARY OF ICH GUIDELINES ON STABILITY AND POSSIBLE INFLUENCE ON THE PACK: Although the ICH guidelines make reference to stress condition, involving low and high temperatures, low and high humidities, freeze-thaw, varying light intensities, including cycling conditions, storage at a fixed temperature and humidity may not fully challenge the pack (and the product). A pack may therefore withstand continuous storage at 25˚C/60% RH, 30˚C/60% RH, 40˚C/75% RH etc., but fail under cycling or higher temperature stress conditions.

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However, packs are more likely to change if exposed to a multiplicity of challenges, e.g. Temperature and RH changes, vibration and compression (on a production line, in storage or distribution), the influence of oxygen, light. Packs which are to some degree permeable to moisture (as are most plastics) will lose or gain moisture according to whether they are exposed to a high or low relative humidity respectively 40˚C/75% RH may be particularly severe on a fully exposed blister pack and give an artificially low shelf life prediction.

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Packs removed from a simulated climatic condition also need to be checked for any signs of change/deterioration. Prior to opening During opening (peel strength, closure, torque/force etc.) After product removal. This is particularly relevant where extremes of temperature and cycling conditions are involved since closure efficiencies may vary according to the storage temperature. This can be critical where a product in its pack is allowed to equilibrate with bench conditions before it is subjected to analysis, so a trained packaging technologist is essential to this examination.

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The ultimate task of the pack is to produce confidence in the product in terms of convenience, preservation and protection from the environment. While ensuring that the product remains satisfactory in the fullest sense, i.e. integrity, identity, uniformity, safety, effectiveness etc. all at an economically acceptable art. CONCLUSION