17.09.2021

The pharmaceutical package 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.


Packaging is defined as the collection of different components which surround the pharmaceutical raw material 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.[1,2]


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.

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.[3]


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.

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.


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 glass bottle (especially in the USA). Powders, pastilles and liquids also make up part of the oral veterinary 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.[4]


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.


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.[5,6]


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 1a]. When the tube reaches the correct length, the mold closes and the parison is cut [Figure 1b]. 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 1c]. 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.


Container sealing

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 1d]. The mold opens and the container is then conveyed out of the machine [Figure 1e].


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.


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 saccharin sodium.


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.


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.


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].


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].


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

a) Substrates

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].

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