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Pharmaceutical Manufacturing and Packing Sourcer

The Futures White

The global pharmaceutical industry faces a paradigm change in manufacturing demands. Simply put, there is a huge shift underway from high-volume ‘blockbuster’ products to low-volume (but often high value) ‘niche-buster’ products. This article presents a revolutionary new approach to the packaging of the smallest lots – one that is already in commercial operation.

Current Situation

The trend towards smaller lot sizes of packaged products is expected to accelerate in the coming years. Lots of 20,000 blisters or fewer are becoming the norm and lots of under 100 blisters are increasingly common. The logical end point of lots of single blisters is now conceivable. The trend is triggered by increasing demands for patient care in traditional and new therapeutic sectors. Markets that were previously considered too small are now being examined more closely. The development of new compounds with smaller numbers of potential patients is also an area of growing interest.

In the EU, legislation requires a pharmaceutical product to be labelled and packaged specifi cally for each state in which it is marketed. With 27 member states, each product has to be packed in up to 27 variants of language and text. Given that some member states represent comparatively small markets, the demand for packaging in small lots is signifi cant. Incentives through patent life extension are granted when a product is made available in every member state.

For the conventional packaging process, however, small lot sizes can mean a massive decline in productivity as measured by Overall Equipment Effectiveness (OEE). Because of the rapidly increasing number of format changes, the utilisation of the packaging lines drops, the running effi ciencies are affected and so the cost per unit of production rises disproportionately. Clearly, the remaining useful life of existing packaging lines – often high value assets – must be respected. In an ideal situation, a new process should provide a solution for the smallest lots while actually enabling an improvement of the performance of existing assets. The trend towards declining OEEs is illustrated in Figure 1.

Revolutionary Concept

The recent rapid advances in digital printing technologies and their application to packaging processes bring new opportunities. One such opportunity is a solution to the small lot question.

A radical option has been put forward that takes a fresh look at the complete supply chain. The ‘White Line’ is a packaging centre on which blisters of solid dose forms are produced and packed using either ‘white’ or ‘bright’ unprinted packaging materials or packaging materials pre-printed with standardised graphics – logos, for example. The market-specific data is digitally printed onto each component within the packaging line. With typical lot sizes of 1 to 2,000 blisters, text changes now take under 15 minutes from stop to re-start of the line. The quantity of packs to be produced is entered, along with the format information for the particular lot; the artworks are then downloaded to the line from the user’s registry, and the reconciliation at the end of the lot is automated.

This new approach means that the orders from each market for a particular product are combined into a single batch and run as part of a regular production cycle. It means that in the downtime between each market variant, artworks are downloaded to the line for the next run and an automatic reconciliation of the previous run is completed; there is no time to make a conventional reconciliation. There are no work-in-progress inventories of marketspecific components and the quantities to be produced are notified by the markets immediately before production.

The White Line completes the printing of the three components, verifies the printing and performs the packaging operation. Serialisation data and Braille are also printed on the ‘white’ carton as it passes through the process. The blisters themselves may be produced on a conventional blister packer that is integrated with the White Line or they may be produced elsewhere and automatically fed onto the White Line.

A Look in More Detail

The blisters arrive on a flighted conveyor. Verification of a pre-applied 2D matrix identifier takes place on this conveyor. Blisters then transfer onto a vacuum belt that transports them accurately one by one beneath the single, full width Drop on Demand (DoD) digital ink-jet printing head. Accurate alignment is ensured by the transfer mechanism. This process can run at up to 200 blisters per minute. Curing of the ink is by cold ultraviolet light, firstly in a ‘pinning’ stage to locate the ink onto the aluminium foil substrate and then a full curing stage. After transfer from the vacuum belt, camera inspection of the print area takes place with verification of critical elements of text. A buffering device is incorporated to ensure that no blisters are left partially printed in the event of a downstream machine stop. This part of the process is shown in Figure 2.

Leaflets are produced from a reel of blank paper that is printed on both sides in a toner print process before being fed as a web to the cartoner. After the inspection systems accept the leaflet print, a verification mark is printed on the leaflet that is read again prior to its insertion into the carton. The leaflet web is printed and inspected at a linear speed of around 20 metres per minute. A conventional reelfed leaflet insertion process then follows.

The magazine of the cartoning machine is loaded with conventionally formed, end-load cartons. The cartons are preprinted with standardised graphics. Each carton is transported in a single pass under four successive DoD printer heads. The first head prints the monochrome market-specific text and graphics on one side of the flat carton. The second head is for a different colour – usually red – to print the warning symbols required in some markets. Curing takes place after each print head and an inspection of the printed area is made before the carton is turned over to print the monochrome text and graphics on the reverse side of the carton, followed by the Braille text. Again, all print areas are inspected and verified. Serialisation data is printed by the same print heads which print the text and graphics on the carton. The complete process is shown diagrammatically in Figure 3.

Security Through Specialised Inspection Systems

In order to guarantee complete pharmaceutical security, multiple inspection systems are installed on the line to check each printing operation. At lot changes, the cameras, as well as the print heads, receive data files from the line management system. In this way, the downtime between lots can be minimised. The printed blister is inspected and verified by a camera before it reaches the cartoning machine. Any defective print is rejected and a further blister is printed to ensure the correct order quantity. The carton print is similarly verified. The print on the leaflet is verified by a line-scan camera approximately 4,000 pixels wide that generates an image of more than 20 megapixels. Areas of critical text are verified – including characters such as decimal points.

All print data is downloaded to the White Line in PDF files. Typically, nine such files are required per market variant. These are managed in a registry within the enterprise resource planning (ERP) system and accessed by the line operator when entering lot information at the White Line. Around half the downtime between lots is required for this data transfer process from ERP and for distribution within the White Line. A verification process ensures that the correct graphics have been printed onto the packaging components – the visual differences between market languages will not always be obvious to the line operator.

Drop on Demand Piezo-Electric Printing Technology

DoD print systems comprise a spray head, in which is mounted a row of several spray nozzles or orifices. These are arranged at right angles to the product surface to be printed. The spacing of the orifices, together with their diameter, determines the resolution of the printing system. In contrast to other printing technologies, the orifices are only activated as the print image requires, hence the system’s name.

The ink is fed by capillary action to an ink chamber in the print head. The surface tension of the ink prevents its escape through the small orifice. The upper part of the chamber is closed by a membrane, behind which is mounted a piezo-crystal. The piezocrystal has the property that its size changes when an electrical voltage is applied to it. This voltage may be applied as pulses or as a wave form. The level of the voltage produces smaller or larger movements that press against the membrane. The membrane in turn presses against the ink, creating an over-pressure that ejects a droplet from the orifice. Through the positioning of the orifices across the direction of travel of the substrate, full or broken lines can be produced. The second dimension of the image is produced through the movement of the substrate. The spraying process is shown diagrammatically in Figure 4 (page 21). A proprietary print head mounted above a continuously moving substrate is shown in Figure 5.

Case Study

A blister White Line as described above has recently been supplied by MediSeal GmbH of Schloss Holte, Germany, to a European packaging operation of a global pharmaceutical corporation. The line incorporated inspection systems from Seidenader GmbH, DoD printing systems from Atlantic Zeiser GmbH and toner printing systems from CSAT GmbH. The line is proven in a production environment as a solution for the packaging of the smallest lot sizes of blisters. A significant number of small lots per day can be readily achieved and the implications for the whole supply chain are being realised. At the same time, performance improvements on other lines have been gained.

The experience from this line to date indicates typical benefits that a user may realise:
  • An output of 10 or more small lots per shift results from 12-minute real time market changeovers. Output is measured in ‘lots per shift’ and not ‘packs per minute’
  • A revised artwork can be implemented immediately after approval. There is no lead time for the availability of printed packaging components beyond the time to download the new artwork to the White Line
  • The quantity to be produced is entered by the operator at the start of the lot. The whole supply chain thereby benefits from minimised inventories of market-specific product
  • ‘White’ packaging materials are required that can be ordered and stored in economic quantities. Multiple orders, at high cost, of small quantities of packaging components are eliminated, along with the risks of inventories becoming redundant at a later date
  • The White Line is operated by a single, qualified operator. Validated, automatic reconciliations, automatic distribution of artworks for each lot and relatively low line speed all contribute, as does a state-of-the-art mechanical design of the equipment for accessibility and operability

Small lot production is a daily challenge faced by many pharmaceutical packaging operations. White Line blister packaging offers a proven solution using a new combination of established technologies. By focusing the smallest lots onto a dedicated packaging line, new standards of customer service are achieved while additional operative capacity is released on the remaining, conventional blister lines of the packaging operation.

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Andrew Longworth joined Körber Medipak in 2004. His responsibilities include strategic sales and marketing development for the group, which supplies packaging and technology solutions to the pharmaceutical industry worldwide. Andrew holds a BEng in Mechanical Engineering from Imperial College, London. He has been engaged in the field of pharmaceutical packaging and production systems for over 25 years, and is an occasional contributor to journals and at conferences on these topics.
Andrew Longworth
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