|Year : 2013 | Volume
| Issue : 2 | Page : 98-110
Recent trends and future of pharmaceutical packaging technology
Nityanand Zadbuke, Sadhana Shahi, Bhushan Gulecha, Abhay Padalkar, Mahesh Thube
Department of Pharmaceutics, Government College of Pharmacy, Aurangabad - 431005, Maharashtra, India
|Date of Submission||08-Sep-2012|
|Date of Decision||29-Oct-2012|
|Date of Acceptance||27-Dec-2012|
|Date of Web Publication||14-May-2013|
Department of Pharmaceutics, Government College of Pharmacy, Aurangabad - 431005, Maharashtra
Source of Support: None, Conflict of Interest: None
| Abstract|| |
The pharmaceutical packaging market is constantly advancing and has experienced annual growth of at least five percent per annum in the past few years. The market is now reckoned to be worth over $20 billion a year. As with most other packaged goods, pharmaceuticals need reliable and speedy packaging solutions that deliver a combination of product protection, quality, tamper evidence, patient comfort and security needs. Constant innovations in the pharmaceuticals themselves such as, blow fill seal (BFS) vials, anti-counterfeit measures, plasma impulse chemical vapor deposition (PICVD) coating technology, snap off ampoules, unit dose vials, two-in-one prefilled vial design, prefilled syringes and child-resistant packs have a direct impact on the packaging. The review details several of the recent pharmaceutical packaging trends that are impacting packaging industry, and offers some predictions for the future.
Keywords: Pharmaceutical packaging, packaging materials, recent trends, future
|How to cite this article:|
Zadbuke N, Shahi S, Gulecha B, Padalkar A, Thube M. Recent trends and future of pharmaceutical packaging technology. J Pharm Bioall Sci 2013;5:98-110
|How to cite this URL:|
Zadbuke N, Shahi S, Gulecha B, Padalkar A, Thube M. Recent trends and future of pharmaceutical packaging technology. J Pharm Bioall Sci [serial online] 2013 [cited 2022 Jan 25];5:98-110. Available from: https://www.jpbsonline.org/text.asp?2013/5/2/98/111820
Packaging is defined as the collection of different components which surround the pharmaceutical product from the time of production until its use. Packaging pharmaceutical products is a broad, encompassing, and multi-faceted task. Packaging is responsible for providing life-saving drugs, medical devices, medical treatments, and new products like medical nutritionals (nutraceuticals) in every imaginable dosage form to deliver every type of supplement, poultice, liquid, solid, powder, suspension, or drop to people the world over. It is transparent to the end user when done well and is open to criticism from all quarters when done poorly. ,
Distribution of products is now more global than ever. Mass customization of packaging to permit its use in multiple markets is a topic that needs exposition and discussion. Environmental issues, including sustainability, will always be a subjective dimension to any packaging design.
Packaging is an emerging science, an emerging engineering discipline, and a success contributor to pharmaceutical industries.
Packaging can reside, or report through research and development (R and D), engineering, operations, purchasing, marketing, or the general administrative department of a company. For the majority of products produced in pharmaceutical industries it is probably the single largest aggregate purchase made by a company of materials critical to the protection, distribution, and sale of the product.
| Functions of Pharmaceutical Packaging|| |
- Containment - The containment of the product is the most fundamental function of packaging for medicinal products. The design of high-quality packaging must take into account both the needs of the product and of the manufacturing and distribution system. This requires the packaging: not to leak, nor allow diffusion and permeation of the product, to be strong enough to hold the contents when subjected to normal handling and not to be altered by the ingredients of the formulation in its final dosage form. 
- Protection - The packaging must protect the product against all adverse external influences that may affect its quality or potency, such as light, moisture, oxygen, biological contamination, mechanical damage and counterfeiting/adulteration.
- Presentation and information - Packaging is also an essential source of information on medicinal products. Such information is provided by labels and package inserts for patients.
- Identification - The printed packs or its ancillary printed components serves the functions of providing both identity and information.
- Convenience - The convenience is associated with product use or administration e.g., a unit dose eye drop which both eliminates the need for preservative and reduces risks associated with cross infection, by administering only a single dose.
| Categories of Pharmaceutical Packaging Materials|| |
- Primary packaging system is the material that first envelops the product and holds it i.e., those package components and subcomponents that actually come in contact with the product, or those that may have a direct effect on the product shelf life e.g., ampoules and vials, prefilled syringes, IV containers, etc.
- Secondary packaging system is outside the primary packaging and used to group primary packages together e.g., cartons, boxes, shipping containers, injection trays, etc.
- Tertiary packaging system is used for bulk handling and shipping e.g., barrel, container, edge protectors, etc.
| Materials used for Pharmaceutical Packaging|| |
Traditionally, the majority of medicines (51%) have been taken orally by tablets or capsules, which are either packed in blister packs (very common in Europe and Asia) or fed into plastic pharmaceutical bottles (especially in the USA). Powders, pastilles and liquids also make up part of the oral medicine intake. However, other methods for taking medicines are now being more widely used. These include parentral or intravenous (29%), inhalation (17%), and transdermal (3%) methods.
These changes have made a big impact on the packaging industry and there is an increasing need to provide tailored, individual packaging solutions, which guarantee the effectiveness of medicines. 
The present review article details several key trends that are impacting packaging industry, and offers some predictions for the future packaging encompassing solid oral dosage forms and injectables.
| Recent Packaging Technologies|| |
Aseptic blow-fill-seal (BFS) technology is the process by which plastic containers are formed, filled with sterile filtered product and sealed in an uninterrupted sequence of operations within the controlled sterile environment of a single machine. ,
The blow-fill-seal process is a robust, advanced aseptic processing technology, recognized by worldwide regulatory authorities for its inherent operational advantages over conventional aseptic production. Blow-fill-seal systems offer a unique combination of flexibility in packaging design, low operating cost and a high degree of sterility assurance. The machines require a minimum number of operating personnel and have a relatively small space requirement.
A variety of polymers may be used in the process, low and high-density polyethylene and polypropylene being the most popular. The innate ability to form the container/closure during the actual aseptic packaging process allows for custom design of the container to meet the specific needs of the application. This flexibility not only improves container ease of use, but provides a means of interfacing with many of today's emerging drug delivery technologies, most notably in the field of respiratory therapy.
Thermoplastic is continuously extruded in a tubular shape [Figure 1]a. When the tube reaches the correct length, the mold closes and the parison is cut [Figure 1]b. The bottom of the parison is pinched closed and the top is held in place with a set of holding jaws. The mold is then transferred to a position under the filling station.
The nozzle assembly lowers into the parison until the nozzles form a seal with the neck of the mold [Figure 1]c. Container formation is completed by applying a vacuum on the mold-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. The nozzles then retract into their original position.
Following completion of the filling process, the top of the container remains semi-molten. Separate seal molds close to form the top and hermetically seal the container [Figure 1]d. The mold opens and the container is then conveyed out of the machine [Figure 1]e.
The cycle is then repeated to produce another filled container. The filled containers are tested and checked to ensure that they meet the very strict specifications laid down for such products.
The duration of the complete cycle is between 10-18 seconds, depending on the container design and the amount of liquid to be filled.
| Advantages of BFS Technology|| |
BFS technology offers considerable advantages over conventional aseptic filling of preformed (plastic or other) containers, which are described as follows:
- BFS technology reduces personnel intervention making it a more robust method for the aseptic preparation of sterile pharmaceuticals.
- There is no need to purchase and stock a range of prefabricated containers and their closures. Bulk containers of plastic are required.
- Cleaning and sterilization of prefabricated containers and closures is not required. A clean, sterile container is made within the BFS machine as it is required for filling.
- The cost of material transport, storage and inventory control is reduced.
- Validation requirements are reduced.
- The technology allows the design of high-quality, custom-designed containers with tamper-evident closures in a variety of shapes and sizes.
- There is a large choice of neck and opening device shapes.
- A single compact BFS machine takes the place of several conventional machines, saving floor space. In addition, zones for transport to successive filling and closing procedures are not required because these operations all take place in the BFS machine itself.
- The operation of BFS machines is less labor intensive than conventional aseptic filling.
- The code numbers and variable data such as batch number and expiry date can be molded into the container itself rather than being added at a subsequent stage.
- The process lends itself to the production of single dose containers and therefore preservatives are not necessary as they are with multi-dose containers.
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 often cannot withstand exposure to high temperatures for extended periods of time without degradation of their active components. Conventional terminal sterilization, therefore, is not an acceptable method to produce a 'sterile' product. Bulk sterilization, sterilization by gamma irradiation or filter sterilization followed by direct packaging utilizing the blow-fill-seal process are often used successfully for these types of products.
| Anti-Counterfeit Packaging Technologies|| |
Counterfeiting means producing products and packaging similar to the originals and selling the fake as authentic products. Counterfeit is a problem of product security, with reference to packaging is not a problem in isolation; it is the part along with:
Duplication - i.e., copying labels, packaging, products, instructions and usage information,
Substitution - placing inferior products in authentic or reused packaging,
Tampering - by altering packages/labels and using spiked, pilfered, or stolen goods in place as real,
Returns and Warranty frauds they are addressed as Brand Theft.
| Anti-Counterfeiting Technology Solutions|| |
The current numbers of anti-counterfeiting solutions are many and new options are introduced in the market with some variations. An attempt is made to explain the technologies for easy understanding on product packaging.
1. Overt (visible) features
Overt features are intended to enable end users to verify the authenticity of a pack. Such features will normally be prominently visible, and difficult or expensive to reproduce. They also require utmost security in supply, handling and disposal procedures to avoid unauthorized diversion. They are designed to be applied in such a way that they cannot be reused or removed without being defaced or causing damage to the pack for this reason an overt device might be incorporated within a tamper evident feature for added security.
Tamper evident packaging systems
Some packages are inherently tamper proof, like a tin can hermetically sealed, an aseptically packed multilayer carton or a vacuum or the retort pack. The tamper evident packaging systems are:
a) Film wrappers
A transparent film with a distinctive design is wrapped securely around a product or product container. The film must be cut or torn to open the container and remove the product. Substrates options include ultra destructible films, voidable films that provides image when removed. e.g., Solvent sensitive papers.
b) Shrink seals and bands
Bands or wrappers with a distinctive design are shrunk by heat or drying to seal the cap and container union. The seal must be cut or torn to remove the product.
c) Breakable caps
Such caps break when an attempt is made to open it. These caps provide external tamper evidence and can also be combined with the internal seals thereby providing double security.
d) Sealed tubes
The mouth of the tube is sealed, and the seal must be punctured to obtain the product.
2. Covert (hidden) features
The purpose of a covert feature is to enable the brand owner to identify counterfeited product. The general public will not be aware of its presence nor have the means to verify it. A covert feature should not be easy to detect or copy without specialist knowledge, and their details must be controlled on a "need to know" basis. If compromised or publicized, most covert features will lose some if not all of their security value [Figure 2].
|Figure 2 : Encrypted text visible under special light as a covert feature|
Click here to view
Radio frequency identification (RFID) is hardly a new concept. For some, RFID is already a mainstream technology-it is used every day to pay tolls, secure building access, catch shop lifters etc., It allows the identification of objects through a wireless communications in a fixed frequency band. Three essential components in any RFID system are: the tag, the reader and the software. The tag is an integrated circuit containing a unique tracking identifier, called an electronic product code (EPC), which is transmitted via E.M. waves in the radio spectrum. The reader captures the transmitted signal and provides the network connectivity between tag data and the system software. The software can be tailor made for the purpose of anti-counterfeiting. For their track and trace usage, RFID tags are used [Figure 3].
a) Passive tag
When RFID tag is within the interrogation zone of the reader (i.e., interrogator) equipment; sufficient power is extracted from the interrogator to power up the tag or circuit, or a special reflective material. It then responds by transmitting data back to the interrogator.
b) Active tag
Such tags incorporate a battery to increase range for collating data, tag to tag communication, etc., But these are much more expensive.
c) Semi-active tag
In these tags batteries are used to back up the memory and data, but not to boost the range. With some active RFID tags, the batteries are only used when interrogated or when sending a homing pulse at fixed intervals to reduce cost and size.
4. Packaging designs: Materials/Substrates and other design options
There are variety of substrates used in the design of packages with intent to provide counterfeit and tamper evident features starting from litho paper, polystyrenes, destructive vinyl's, acetate films synthetic paper and coatings etc., There are many ways of incorporating covert markers within a substrate, such as visible or UV fluorescing fibers, or chemical reagents in carton board or paper. Watermarks can be embedded in leaflet paper, or metallic threads interwoven in the base material, possibly including an overt optically variable devices (OVD) feature. These require a dedicated supply source and large volume production, which, if affordable, results in a very effective option. Micro-encapsulated distinctive odors can be applied as an additive to an ink or coating to provide a novel covert or semi-overt feature, as well as sound chips creates special opportunities in the design.
b) Packaging designs
Packaging designs like sealed cartons, aerosol containers have inherent strength against counterfeiting
c) Sealing systems
Special caps such as the outer tamper evident system or the foil seal as an internal tamper evident feature are commonly used for pharmaceutical products. Sealing options are lever-lidded tins, secure packaging tapes, lined cartons and tear tapes/bands.
5. Security labels
Tamper evident and security labels play an important role in providing some relief to the consumers against fakes. In self adhesive labels the substrate mostly performs as a complimentary interaction of the substrate and the pressure sensitive adhesive. While passive security labels have been extensively used, today one can find a greater application of functional labels such as printing plus anti-theft. Some label options are:
a) Paper labels with security cuts
The substrate used for these labels is ordinary coated/uncoated paper. The security features are built in by the label printer at the converting stage. With the help of a special cutting die, the face material is given cuts at various angles so that by any ways one tries to remove these labels the paper will tear off. A general purpose permanent adhesive works fine with such labels. Care is taken to ensure that the adhesive will adhere well and firmly to the surface on which the label has to be applied.
b) Destructible labels
Needs a special substrate designed for the purpose. Most of the high-end applications use a specially made cellulose acetate film. The film is very intricately designed so that it has adequate strength to undergo conversion into label stocks in roll form. It is available both in clear and opaque formats and further converted into labels using aggressive pressure sensitive adhesives. The labels can be automatically dispensed on automatic label dispensers and when attempted to be removed, break-up into very small fragmented pieces. The cost effective vinyl have replaced acetate film. A combination of various synthetic polymers can be used to impart low inherent strength to the substrate.
c) Void labels and tapes
The most important of the tamper evident security labels and have text built into them. When as a self adhesive label they are removed, they exhibit the word VOID both in the removed film and the adhesive layer left behind. These substrates gain importance as there can be customization built into the labels produced with it. One can use polyester or biaxially-oriented polypropylene (BOPP) as face materials. Variety of colors, even metallization is possible. The text VOID could be replaced by the customers brand, emblem or a message, which would normally be invisible till the label is opened. Due to the versatility of things that can be done with the product, these label substrates have found widespread usage worldwide. The substrates can even be designed to work as tapes for the final outer corrugated cartons to prevent pilferage.
d) Self destructing paper label
The labels are very similar to destructible labels as mentioned earlier. In this case, the substrate used is of very weak strength paper of low grammage. The paper is also heavily loaded with fillers creating a weak and brittle paper. Labels made from such papers fragment into pieces when attempted to be removed. However, converting it is a very tricky issue when using these substrates due to the lack of strength. The papers are very difficult to source since most of the paper mills are trying to develop papers with very high strength.
e) Holographic labels
The labels form a very large and important part of the security label market and are an ideal choice for product authentication. The holographic foil that is an optically variable device is largely made using a polyester film base. The optical interaction of the holographic image and the human eye makes it ideal for brand promotion and security. These products reveal the holographic image when tilted in light. The image so revealed can be customized to the need of the brand owners to make the maximum impact. The hologram production involves development of complex origination process and a lot of innovation to make it difficult for counterfeiters to duplicate. Many holograms are designed such that besides offering brand authentication they also have tamper evident properties. The top polyester layer has a special coating that if the hologram is attempted to be removed, the top layer peels off leaving the hologram behind on the product [Figure 4].
f) Multi layered labels
The face stock of the labels is laminates of different substrates depending on the requirement of the security label, which can be film to a film or film to paper or other coatings. The layers are designed such that on separation they either exhibit tamper evidence by way of a one layer getting fiber tear or by complete separation and exhibiting a design or message. The various layers are bonded together by adhesive or heat seal coatings depending on the requirement of the design of the label. The segment of substrates can be vast and can be designed to the requirements of the user and offering variants as per the imagination of the designer or producer.
g) Transfer labels
The substrate consists of either polyester or BOPP. The film has a release coat over which the matter is printed and then adhesive coated. Such labels when applied and peeled off, the clear top layer comes off leaving the printed matter behind. This can also be designed such that some printing is subsurface and remains behind and some printed matter is on the top and comes off with the top layer.
h) UV fibers in paper
Here the substrate is paper and the security is built in at the paper mill during the paper making process. UV light sensitive fibers are incorporated into the pulp and evenly distributed in the paper. When labels made from such paper are exposed to UV light, the fibers glow indicating the genuineness of the labels. The volumes required for these substrates have to be large enough to allow the paper mill to produce a batch full of pulp that would eventually be converted into paper for security labels. The color of the fibers can be selected as per the wish or need.
i) Security threads
Thin micronic threads are introduced in the substrates either at the label stock making stage or they are separately built into two layers of paper laminated together. The threads can also be sensitive to UV light which will glow under UV light. e.g., currency notes.
j) Water mark
The mark that can be seen as an image in the paper when held against the light. The mark scan can also be built into the paper at the paper making stage in a paper mill. The volume has to be large enough to justify incorporating the markings in the paper making process. However, some converters do print these with inks where security requirements are not of a very strict nature.
6. Coding, printing and graphics
a) Coding and marking
For a long time, regulatory compliance drove the need for coding and marking on the packaged products starting with best before date. However, with an increasing awareness and greater printing and marking options like ink jet coding, laser coding and electrolytic etching for metal marking on can decide their use to evolve an overall anti-counterfeit feature. These provide the opportunities for online coding with flexibility, programmable options, time saving and low running costs. Depending on the exact requirements one can go for the touch dry contact coding, non contact coding or the permanent laser coding etc.
Traceability and counterfeiting measures can be improved by using a variable data on the labels i.e., to create unique marking of the packages, which can be made cost effective by using digital printing technology for producing on demand short run packed products.
b) Security graphics
Fine line color printing, similar to banknote printing, incorporating a range of overt and covert design elements such as guilloches, line modulation and line emboss. They may be used as background in a discrete zone such as an overprint area, or as complete pack graphics, and can be printed by normal offset lithography or for increased security by intaglio printing. Subtle use of pastel "spot" colors makes the design more difficult to scan and reproduce, and security is further enhanced by the incorporation of a range of covert design elements, such as micro-text and latent images.
Holograms were used first for promotional purposes during 80's and exhibited a phenomenal growth by 1996. Probably the most familiar overt feature is the "dove" hologram which has been used to protect credit cards for many years. A hologram normally incorporates an image with some illusion of 3-dimensional construction, or of apparent depth and special separation. Holograms and similar optically variable devices (OVD) can be made more effective when incorporated in a tamper evident feature, or as an integral part of the primary pack (e.g., blister foil). They can be incorporated into tear bands in over wrap films, or as threads embedded into paper substrates and hence may be usefully employed on secondary/transport packs. Several processes can be used to incorporate holograms into packaging; flexible, folding cartons or bottles. Methods include pressure sensitive, shrink, or glue applied labels, hot stamping, web transfer and lamination. Essentially selection options for the hologram are the image and media. The right combination of the two components produces a successful anti-counterfeiting marking that meets the desired objective.
a) Image choices
In the form of Parallax, 3-D perception, switching images, animated images, dynamic color effects, micro text, fine line patterns, machine readable image, hidden image readable through special reader.
b) Media or the form of delivery
The choices available are tamper evident, frangible, paper labels, induction wads, shrink sleeves, hot stamping foils, aluminum foils, PVC films, hologram tape/thread.
c) Optically variable devices
Optically variable devices (OVDs) also include a wide range of alternative devices, similar to holograms, but often without any 3D component. Generally, they involve image flips or transitions, often including color transformations or monochromatic contrasts. Like holograms, they are generally made-up of a transparent film which serves as the image carrier, plus a reflective backing layer which is normally a very thin layer of aluminum. Other metals such as copper may be used to give a characteristic hue for specialist security applications. Extra security may be added by the process of partial de-metallization, whereby some of the reflective layer is chemically removed to give an intricate outline to the image, as can be seen on many banknotes. Alternatively, the reflective layer can be so thin as to be transparent, resulting in a clear film with more of a ghost reflective image visible under certain angles of viewing and illumination. DOVID's (differentially optically variable image devices) that cannot be copied by electronic means are being used in decorative packaging and brand enhancement with security. DOVID's are generated through micro embossing, dot matrix mastering, photo resist interference, lithography, electron beam lithography and classical holography.
d) Color shifting security inks and films
These can show positive changes in color according to the angle viewing angle, and can be effective either as an overt graphic element or by incorporation in a security seal. Color shifting pigments are finely ground metallic laminates which need to be laid down in a thick opaque film to achieve the optical effect, and are therefore better suited to printing techniques such as gravure and screen printing rather than lithographic printing. Their security value lies in the specificity and dynamics of the color change (e.g., from blue to gold), combined with the difficulty and expense involved in manufacture. They are only available from a limited number of pigment suppliers, via a few specialist ink manufacturers. Positive authentication may involve forensic (microscopic) examination and embedded taggants. Color shifting films have been used for security applications, involving multi-layer deposition of thin films to build up a structure with unique diffractive properties, and vibrant color transitions. They can be applied as security seals or tamper evident labels.
e) Sequential product numbering
Unique sequential numbering of each pack or label in a batch can make counterfeits easier to detect in the supply chain. If printed visibly, it provides a semi-overt means of authentication by reference to a secure database, because duplicates or invalid numbers will be rejected. The main disadvantages of sequential numbering are that the sequence is predictable and easily replicated, and end users require some means of access to the database. The more secure option is serialization by means of a pseudo-random non-repeating sequence, and is discussed in the track and trace section.
f) On-product marking
On-product marking technologies allow for special images or codes to be placed on conventional oral dosage forms. The overt technologies can be difficult to replicate and offer a security technology at the pill level. The added layer of security is effective even when products are separated from the original package.
g) Invisible printing
Using special inks, invisible markings can be printed on almost any substrate, and which only appear under certain conditions, such as via UV or IR illumination. They can be formulated to show different colors with illumination at different wavelengths.
h) Embedded image
An invisible image can be embedded within the pack graphics which can only be viewed using a special filter, and cannot be reproduced by normal scanning means. The effects can be quite dramatic, and yet well hidden.
i) Digital watermarks
Invisible data can be digitally encoded within graphics elements and verified by means of a reader and special software. The data can be captured using webcam, mobile phone or other scanning equipment, but the digital information is not visible to the human eye, and attempts to replicate it will be detected by virtue of the degradation of the embedded data.
j) Hidden marks and printing
Special marks and print may be applied in such a way that escapes attention and is not easy to copy. Their effectiveness relies on a combination of secrecy and subtlety.
k) Anti-copy or Anti-scan design
Fine line background patterns appear as uniform tones, but when scanned or copied reveal a latent image which was not previously visible. Commonly used on secure documents to prevent photocopying, they may be applied to product packaging as a background tint.
l) Laser coding
The application of batch variable details by lasers coding requires special and expensive equipment, and results in recognizable artifacts which may be difficult to simulate. Laser codes can be applied to cartons and labels, and plastic and metal components.
8. Forensic markers
There is a wide range of high-technology solutions which require laboratory testing or dedicated field test kits to scientifically prove authenticity. These are strictly a sub-set of covert technologies, but the difference lies in the scientific methodology required for authentication.
a) Chemical taggants
Trace chemicals which can only be detected by highly specific reagent systems, but not normally detectable by conventional analysis.
b) Biological taggants
A biological marker can be incorporated at extremely low levels (parts per million or lower) in product formulations or coatings, or invisibly applied to packaging components. At such low levels they are undetectable by normal analytical methods, and require highly specific "lock and key" reagent kits to authenticate.
c) DNA taggants
Highly specific DNA "lock and key" reagent systems can be applied to packaging by a variety of printing methods. They require a "mirror image" recombinant strand to effect the pairing, and this reaction is detectable by a dedicated device. Security is further assured by hiding the marker and reagent pair in a matrix of random DNA strands, but the test is tuned to work only with one recombinant pair.
d) Isotope ratios
Naturally occurring isotopes are highly characteristic of the source compound, and accurately be determined by laser fluorescence or magnetic resonance techniques. They can provide a "fingerprint" of one or more of the product constituents, or alternatively a specific marker added with its own unique signature. Detection requires highly specialist laboratory equipment.
Micro-taggants are microscopic particles containing coded information to uniquely identify each variant by examination under a microscope. It may take the form of alphanumeric data depicted on small flakes or threads, or fragments of multicolored multilayered laminates with a signature color combination. These can be embedded into adhesives, or directly applied to packaging components as spots or threads.
The technologies allow microscopic application onto individual tablets. UV inks allow invisible printing onto any substrate including glass vials and ampoules and provide an excellent security.
9. Mass encoding/trace and track technologies
These involve assigning a unique identity to each stock unit during manufacture, which then remains with it through the supply chain until its consumption. The identity will normally include details of the product name and strength, and the lot number and expiry date although in principle it may simply take the form of a unique pack coding which enables access to the same information held on a secure database. The latter solution overcomes some of the concerns about privacy where the encoded data can be read at a distance by radio equipment.
In itself the track and trace label may not be immune to copying or falsification, but its security is greatly enhanced by the inclusion of unique and apparently random serialization, or non-sequential numbering, ideally at individual item level. If the serialization was sequential, then the level of security would be very low as the sequence is predictable, whereas "random" serialization using a highly secure algorithm or method of encryption overcomes this. Individual packs may still be copied, but the database will identify duplicates or invalid serials, as well as those which have been cancelled or expired, or which appear in the wrong market, or with invalid product details.
Individual products are encoded in an overt manner either through a barcode or a human readable form. Coding therefore becomes the essence in design process. Encoded products need the support of software solutions that permit product tracking through the various nodes in the LSCM operations. Options adopted for encoding are:
Barcode is a series of parallel, adjacent bars and spaces used to encode the small string of data. 2-D codes are also available now with possibility to encode large amount of information that makes it an option for anti-counterfeiting. Bar-coding when used with GS-1 standards, permit universal and unique identification of goods, services, assets etc., A bar code reader (scanner) decodes the bar code using intensity of the light reflected. While package printing gives emphasis to product appeal and acceptance by the consumer, barcodes captures the specific information that may contain information related to track and trace traceability, inventory management, security, identification etc., Bar-coding provides the means for automatic data capture of information. When used with international numbering standards, it permits universal and unique identification and security of packaged products. Barcoding works essentially with the optically scanning devices e.g., for the UPC bar code scanners use a helium neon (red) laser emitting at 660 nanometers to determine the contrast between the reflected light from the dark bars and light spaces. For their use as a system they also need the decoders, software's for coding. Universally GS-1 barcodes provide an access that could operate with countries/users who are the members of GS-1. However, due to some specific reason many retail chains use their proprietary codes. Use of barcodes as anti counterfeit option is attempted, especially with the possibilities to go for 2-D codes [Figure 5].
b) Digital mass serialization
The technology includes the generation of a random, pseudo random code in a sequential manner by the technology provider entered into their or the customers data base for later verification. These codes are provided to customers who in turn can apply them in different ways. These codes can be printed on the labels and then affixed on the product or can be used in a covert way on a pack. The authentication process involves matching the unique code on a product to those stored in the data base. If the code is present in the data base, then the then the product is authentic. This technology needs to be integrated with proper protocols and SOP's for its success with security features to its data base since it could be the weakest link in the technology.
c) Digital mass encryption
In all respects it is similar to the digital mass serialization (DMS) except for the way code is generated. In this process encrypted codes (defined) are produced by a cryptographic algorithm. The codes themselves do not carry or contain any product or logistical information. There is no need for maintaining a data base.
d) Auto identification systems
Smart packaging or auto identification systems are defined as small inexpensive label or tags that are attached onto primary packaging (e.g., treys, pouches bottles) or often onto secondary packaging (e.g., shipping containers) to facilitate communication through-out the supply chain for safety enhancements. Auto identification systems as per Ustandao are classified as optical character recognition (OCR), barcode system, chip cards, biometric systems and RFID as shown in [Figure 6]. Data carriers such as barcode labels and RFID tags are used to store and transmit data. Packaging indicators such as time temperature indicators, gas indicators, biosensors are used to monitor the external environment and whenever appropriate issue warnings.
|Figure 6: Auto identification of tags and barcodes with scanners, readers and phone|
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| Plasma Impulse Chemical Vapor Deposition|| |
Plasma impulse chemical vapor deposition (PICVD) was developed by Schott more than 10 years ago. It was the first CVD - based coating technology for the mass production of optical coatings on glass components (cold light mirrors, infrared reflective coatings and others). During the last few years, a modified PICVD-process for the deposition of three different functional coatings on plastics has been developed. The functions- anti-reflective, anti-scratch and easy-to-clean layers- are provided by only one technology-PICVD. This is a major progress compared for instance to the standard production line of polymer based eyeglass lenses, which uses a PVD process for anti-reflective coating, dip coating for anti-scratch and plasma polymerization for easy-to-clean coatings. Moreover, the development was extended to different kinds of plastics including optical polymers like polymethylmethacrylate (PMMA) and polycarbonate (PC). The PICVD coating technologies were not capable of depositing durable functional coatings on PMMA with a sustained adhesion to the substrate. A completely new layer system on PMMA with an adapted adhesive layer has been developed for these coatings. Durability has been proven by passing different types of functionality tests like tape test, grid test, climate tests or temperature shock tests. 
| Materials can be Coated Using Plasma Impulse Chemical Vapor Deposition|| |
Although developed 20 years ago by Schott Glass, PICVD has been very successful in coating high volume glass products, such as pharmaceutical vials, ampoules, syringes. To expand the application areas of PICVD) into plastics Schott HiCotec was set up as a new division. Very quickly it succeeded in modifying the original PICVD process and applying bonded homogeneous coatings - in particular glass-like SiO 2 and TiO 2 oxide coatings to a broad range of plastics (e.g., PET, PMMA, PC, COC, PP and HDPE). The result is that plastic can now have all the positive properties of glass. In the case of plastic lenses and display covers it is now possible to produce anti-scratch and antireflective coatings, while in the case of plastics packaging, a PICVD coating creates a barrier against the passage of gas oxygen can no longer get in, and released carbon dioxide cannot get out. Consequently, the contents have a longer shelf life with no effect on their taste. 
| Prefilled Syringes|| |
The use of prefilled syringes is a modern way to apply parenteral drugs. With the achievements in science and technology in the past twenty years an increasing number of injectables apply prefilled syringes. The benefits compared with vial-disposable syringe concepts are obviously convenience and ease of handling, as well as advantages in safety and a reduction of drug overfill.
The currently existing market of prefilled syringes is in the range of US$1-2 billion. The growth rate is to be expected to remain at a high level of more than 10% annually.
In the future, the pharmaceutical and biotech industries will ask for prefillable drug delivery systems for valuable potent drugs. Particularly, for biologicals the parenteral application will remain the most important route of application. The worldwide prefilled market is estimated to be one billion units. 
Prefilled syringes in the US market have been growing at a rate of 20% per year for at least five years. Studies indicate that the majority of healthcare professionals are demanding the convenience and safety that prefilled syringes provide. 
The primary driving factors behind the growth of prefilled syringes includes:
- Ease of administration; more convenient for healthcare professionals and end users; easier for home use; easier in emergency situations.
- Reduction of medication errors, misidentification; better dose accuracy.
- Increased assurance of sterility.
- Better use of controlled drugs such as narcotics.
- Lower injection costs- less preparation, fewer materials, easy storage and disposal.
- Elimination of vial overfills for products transferred to syringes for direct injection or addition to primary diluents.
- Removal of preservatives (i.e., thimerosal) from vaccine formulations.
- Product differentiation.
Today, prefills can be introduced at any point during a product's lifecycle to make it more desirable. Switching from vials to prefilled syringes, syringes to a nasal spray or a self injection system, prefills can work easily for products in development and those already on the market. At the same time, drug delivery systems must evolve and adapt to meet tomorrow's demands.
BD Medical-Pharmaceutical Systems markets a broad range of customizable, prefilled solutions for parental drug delivery such as BD Hypak Physiolis TM glass prefilled syringe, BD Accuspray™, BD Sterifill TSCF™, BD Preventis™ [Figure 7]. 
|Figure 7: BD Hypak PhysiolisTM glass prefilled syringe (reproduced with permission from BD)|
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| Safety Ampoule Breaker|| |
Ampoules are small glass vessels in which liquids for injections are hermetically sealed. They are opened by snapping off the glass top at the neck. The scoring at the neck does not always break where it is intended. This is due to the glass re-melding to some degree at the score line. When the cap is snapped off, glass chips can fly off and a jagged or sharp edge can cut the hands of the healthcare worker. Safer products exist removes the risk of broken glass cuts when breaking off the glass top.
SafeBreaK™ is a safety ampoule breaker [Figure 8] and it avoids dangerous glass filing required during breaking the ampoule. No gauze pads necessary to protect hands. SafeBreaK™ prevents cross contamination.
Snapit® invented by a Registered Nurse in Rockhampton, QLD, Australia [Figure 9]. Most people who work with ampoules have suffered an injury from breaking an ampoule. Furthermore, the very sharp edge on both the ampoule and the ampoule lid when the neck of an ampoule is snapped off can cause serious cuts. Snapit® reduces the risk of sustaining a sharps injury by keeping hands out of harms away. 
|Figure 9: Snapit® for open the ampoule (reproduced with permission from Quicksmart)|
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| Snap Off Ampoules|| |
Ampoules are small glass vessels in which liquids for injections are hermetically sealed. A typical pharmaceutical ampoule has a narrow neck between a cylindrical body and a conical tip.
Ampoule is a small, hermetically sealed glass or plastic container, e.g., one containing medication for parenteral administration. Snap off ampoule enables to break a piece from a whole ampoule.
Hisafe TM ampoules are manufactured with pre-fragilized systems like SafeCut TM OPC ampoules or SafeBreaK TM color ampoules for easy opening by doctors without cutter or filling. SafeCut TM ampoules open safely by using a predetermined breaking point to give a clean cut. SafeBreak TM ampoules come with color ring on its constriction which is used to open the ampoules easily by hand. 
| Two-In-One Prefilled Vials|| |
The innovative tamper-evident design of new EZ Fusion two-in-one prefilled vials enables consumers to easily determine authenticity of the product. Two-in-one prefilled vial consists of top and bottom chambers made of polypropylene, an insulating spacer, a stopper and tin cap [Figure 10]. Two-in-one vials enables consumers to easily determine authenticity of the product. There is less chance of contamination, and it provides a cost-effective solution versus traditional glass vials.
Two-in-one vial is a multi-chamber dispenser, which provides a closure solution for filling and separately packing the medication and water for injection, or for the compound injection packaging in a sterile vial. The mixture forms with a simple twist after removing the safety ring and flip-flopping the insulation spacer, then gently shaking the vial prior to usage. 
| Unit Dose Vials|| |
A unit dose is the amount of a medication administered to a patient in a single dose. Unit-dose packaging is the packaging of a single dose in a non reusable container. It is increasingly used in hospitals, nursing homes, etc., Medications in unit-dose packaging are easily identifiable and can be returned to the pharmacy if the medication is discontinued. 
Twist-Tip™ unit-dose vial incorporates a plastic squeeze-bulb with an integral twist-off tab. Once opened, the vial's contents can be dispensed through the opening by squeezing or pouring. 
Twist-Tip™ units are manufactured and filled by modified blow-ill-seal technology [Figure 11].
|Figure 11: Twist-Tip™ unit-dose vials (reproduced with permission from Unicep)|
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These unit dose vials are used in medical devices (in vitro diagnostics: buffers, reagents), oral health care (whitening gels, tooth conditioners, disinfectants, topical anesthetic, dental restorative materials, pharmaceuticals, ultrasonic cleanser concentrate), personal care products and cosmetics (shampoo, conditioner, lotions, skin creams) and veterinary ( medicines, topical applications). 
| Child-Resistant Packaging|| |
Child-resistant packaging (CRP) or C-R packaging is special packaging used to reduce the risk of children ingesting dangerous items. The CRP containers defy penetration by children but can be opened by adults. This is often accomplished by the use of a special safety cap with locking mechanism. 
The U.S. Consumer Product Safety Commission has stated in a press release that "There is no such thing as child-proof packaging. So you should not think of packaging as your primary line of defense. Rather, you should think of packaging, even child-resistant packaging, as your last line of defense."
It is required by regulation for prescription drugs, over-the-counter medications, pesticides, and household chemicals. In some jurisdictions, unit packaging such as blister packs is also regulated for child safety.
In developed countries like UK, it has been made compulsory to pack drugs like Aspirin, Paracetamol, Elemental iron, Contraceptives and many other drugs to be packed in CRP.
| Future of Pharmaceutical Packaging Technology|| |
A changing pharmaceutical industry
Changes in pharmaceutical industry research and manufacturing technologies have driven significant developments in packaging and delivery systems. An increase in the number of large-molecule, biopharmaceutical drugs in development pipelines has led to an increase in the need for injectable packaging and administration systems. The old glass and elastomer closure systems may not provide the effective barrier properties needed for high-value, life saving therapies. Component manufacturers have responded with new materials and technologies that ensure extended drug-product shelf-life. Many new biotechnology-derived drug therapies are unstable in liquid form and therefore are introduced as lyophilized or dry powder dosage forms. Lyophilized drugs need special stoppers for optimal performance in lyophilization chambers. The stoppers must solve the problem of the stopper sticking to the lyophilization shelf after the cycle is completed. In addition, lyophilized drugs typically are reconstituted at the point of care, thus requiring patient-friendly administration systems.
The increase in self-administered therapies
Decades ago, healthcare revolved around hospital care. Today, healthcare often revolves around the home - a situation that has largely resulted from cost constraints and the introduction of maintenance-type drugs for treating chronic conditions such as arthritis, cancer, multiple sclerosis, and other diseases that require frequent medication. Many of these maintenance therapies are delivered by injection, spurring a need for patient-friendly administration systems. These systems must ensure the potency of the drug, be tamper-evident, help deter counterfeiting, promote compliance with a dosing regimen, ensure dosing accuracy, and be as safe, easy to use and painless as possible.
An outgrowth of these changes is the move from the typical vial and disposable syringe to the prefillable syringe. With prefillables, dosing accuracy is ensured but they present some challenges for the industry. A pharmaceutical company needs a prefillable system that protects the integrity of the packaged drug product over time and will function as represented over the full shelf life of the drug product. The response from component manufactures was to develop syringe plungers with barrier films that minimize the interaction between the packaged drug and the components. At the same time, the industry has developed elastomers for molded plungers that maintain functional properties such as seal integrity, and break-loose and extrusion forces.
When self-administered drugs are in lyophilized or dry powder form, manufacturers must find methods or packaging systems that help prevent accidental needle stick injuries, inaccurate dosing, and drug spray-back. Manufacturers familiar with the drug administration process must provide delivery systems that simplify drug reconstitution, especially for non-professional caregivers.
Packaging and delivery systems as a differentiator for drug products will continue to become more important, especially in crowded therapeutic areas and for solving industry-wide problems such as drug-product counterfeiting. The market today is receptive to packaging systems that can provide track-and-trace capabilities and product authentication throughout the supply chain. Pharmaceutical seals are an ideal platform for these technologies. The wider use of technologies such as RFID tags embedded in the plastic button affixed to the seal, or ultraviolet inks applied to the seal, providing item-level security may be seen. The drive for cleanliness and purity will no doubt continue into the foreseeable future. With advances in material science, we can expect cleaner elastomeric formulations by utilizing BFS technology for manufacturing primary packaging and delivery-system components e.g., Respules TM , Twist Tip TM . The coatings with near-total barrier properties e.g., PICVD coatings may have a potential market.
Although predicting the future is problematic, but one prediction with confidence can be made: as pharmaceutical research continues to develop advanced, life-saving therapies, the systems used to package and administer those therapies will keep pace through advances in material science and innovative design.
| Conclusion|| |
In the era of globalization, it would be a challenge for the packaging industry, as the years ahead would witness the opening of the global channels, and to match the international standards and quality, it is necessary that packaging industry upgrades more in research to have a holistic approach to packaging that would go beyond functional aspect of packaging. Presently, very few pharmaceutical industries spend time and money on R and D in packaging. The conventional packages available do not serve the purpose of providing protection against counterfeiting and quality, and the industry seems to be sluggish in adopting the technical advances in the packaging, probably on account of the prohibitive cost factor. As packaging industry is directly or indirectly involved in the drug manufacturing process, it becomes ethically mandatory to understand and incorporate scientific methods in packaging. The pharmaceutical packaging trends are on the verge of innovative rapid growth provided the needs of the product, its security, cost and patient convenience is taken into consideration to build brand identity.
| References|| |
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11]
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