Innovations in Pharmaceutical Packaging - Smart Blister Packs

Imagine a blister pack that shows a moving colour advertisement with sound. If a patient is partially sighted, he/she could press the package and it would play a recorded message giving the necessary dosage and patient details, which the pharmacist has put on the label. When it is time to take the tablets, the pack sounds an alert. By pressing the pack twice, the moving image scrolls through product information for those who can read it or speaks it out for those who cannot.

Although this may appear futuristic, comparable technologies are being developed by the electronics and packaging industries, and features that are genuinely useful and cost-effective may eventually reach blister packs. Discussing some of the remarkable technologies that are being used or are about to be used in pharmaceutical packaging reveals that reality and science fiction are much closer than many in the industry realize.

Devices

In the pharmaceutical supply chain, there are many devices available that monitor the condition of products and track their progress. For example, small electronic boxes can monitor and record the temperature of multipacks and shipping containers during transit and storage. Radio Frequency Identification (RFID) tags from WhereNet (Santa Clara, California, USA) can locate crates and containers by scanning at a range of hundreds of metres. Such devices can work in 3-D when necessary and are being used to rapidly locate items. However, because this RFID tag is highly sophisticated and incorporates an expensive interrogation system, each tag can cost upwards of $20 - although the benefits quickly pay off.

Figure 1: A standard blister pack with the Flying Null ribbon seen as the vertical dashed line on the right.

Non-electronic laminates and labels are available that monitor shock and even tilt in transit, recording whether goods were subject to unacceptable levels of movement. For smaller units, electronic smart labels from KSW Microtec (Dresden, Germany) and Technopuce (Luneville, France) combine RFID for tracking with temperature/time sensors. These credit card sized labels containing microbatteries cost approximately $2 each, making them more expensive than traditional ink-based temperature/time indicators; however, they are more reliable and accurate. For example, ink-based temperature/time indicators only change colour or graphics when alerting the occurrence of an unacceptable incident, but an electronic version can radio any number of alerts and keep records. Ink-based systems are sometimes subject to batch-to-batch variations and the effects of such variables as light, humidity and shelf-life; this is not the case with electronic indicators. In addition, an electronic system is more reliable and therefore preferred if evidence in court is needed. Environmentally safe, rechargeable microbatteries can be used to power the electronics.

Responsive inks

Responsive inks reveal words or colours to warn that something of interest has happened or is happening. New and improved responsive inks for temperature/time monitoring form the basis of diagnostic labels and are available from companies such as Lifelines Technology (Morris Plains, New Jersey, USA), Sherwood Technology (Nottingham, UK) and Food Guardian (Rickmansworth, UK). Responsive inks have been widely used on vaccines, antibiotics and insulin packaging. Companies developing responsive inks and non-electronic laminates have recently been particularly successful with versions that reveal temperature/time, humidity or successful completion of various types of sterilization.

Devices sensitive to other parameters are also becoming available. For example, colour changing indicators are available that detect the presence of pathogens, genetic modification markers or the occurrence of adulteration.

Responsive ink labels do not have a tracking function and are, therefore, used in conjunction with barcodes or RFID labels. RFID increasingly provides a lower cost of system ownership than barcodes, greater reliability and increased accuracy. RFID smart labels are now commonplace in tracking pallets, large containers and multipacks, recording their contents and status.

Electronic blister packs

RFID devices are rarely used in the primary packaging of pharmaceuticals, but the increasingly popular blister pack has virtually never supported modern diagnostic labelling or RFID devices because of the high expense. Monitoring the use of blister packs through to patient compliance has also been a distant dream. However, two companies, Flying Null (Cambridge, UK) and Information Mediary (Ottawa, Ontario, Canada), are offering very different yet complementary technologies tackling many key challenges in pharmaceutical packaging.

Combating counterfeits

Flying Null (FN) primarily seeks to assist pharmaceutical brand owners with implementing cost-effective, highly secure and automated anti-counterfeiting measures. According to the World Health Organization, counterfeit drugs account for more than 7% of the global supply of pharmaceuticals and mostly involve tablets and capsules. Some pharmaceutical companies have put this figure at 10% in developed nations and 30% in developing countries.

The FN solution (Figure 1) involves incorporating a ribbon (thread), similar to those found in banknotes, at intervals across the blister pack. It can be transfer printed in certain cases but a 20 mm polyester ribbon with a width of 1 mm is usually employed. This supports an active element, which is a metal alloy (>1 mm thick). However, unlike banknote security, this ribbon contains millions of unique pre-programmed digital identity codes, which are readable from a distance with the appropriate electronic device.

The amount of data, ribbon length and reading range are related but, as an indication, a tag 58 mm long, with 10000000 unique identities, can be read from a range of 20 mm through obstructions such as the metal of the blister pack and outer packaging. Encoding is done securely at the facility and the ribbon cannot be removed from the blister pack without destroying it.

Using the digital code on the ribbon, the contents of the blister pack can be authenticated remotely without breaking the tamper evident seal. RFID tags containing a microchip typically fail packaging tests such as hammering. However, the ribbon does not. Additionally, ribbons are also able to withstand a far greater temperature range than silicon chips.

Successful trials of the system in blister packs were recently completed by a major pharmaceutical manufacturer - the first time that this type of device has been successfully incorporated in blister packaging. Brand owners can now implement an advanced authentication solution, linking the code in the ribbon to the barcode and creating a unique encrypted identity for the pack as a whole. Using a handheld scanner, brand owners can ensure that the correct packs are in the correct boxes throughout the supply chain. The scanner has no moving parts, unlike a typical barcode reader, and is easy to use.

Separate trials have shown that such ribbons can also be successfully embedded within the induction seals of pharmaceutical bottles and containers. Conventional RFID uses an expensive microchip and reading problems can arise when the microchip is buried under the aluminium foil of a blister pack. Methods of embedding ribbons include:

• lamination of the thread into plain and fluted cartons, corrugated boards and labels

• lamination of discrete tags into plain and fluted cartons, corrugated boards and labels

• embedding threads during the paper making process

• using a transfer hot foil process.

The ribbon will be useful in identifying pharmaceutical grey markets, which typically employ parallel importing or smuggling. Parallel importing is the unauthorized, but not always criminal, importing of goods for resale, often through conventional sales channels. With pharmaceuticals that may be given away in developing countries but command a high price elsewhere, the pharmaceutical industry has one of the most severe problems of parallel importing - one that can threaten the funding of its research and development and, therefore, its viability.

Previously, there has been little protection against grey markets at the blister pack level. Grey markets in other industries, such as apparel and beverages, have been identified and shut down during the first year of using RFID on products.

Electronic compliance monitoring

Information Mediary supplies battery operated electronic devices (Med-ic) in blister packs that can be customized to record unacceptable levels of temperature and other parameters during transit. Most importantly, this system can obtain useful information regarding patient compliance, without requiring the patient to do anything new, by recording when each tablet is removed. Figure 2 shows such an electronic blister pack.

Figure 2: A book-type blister pack with an electronic content monitoring system (Information Mediary Inc).

Because this system is more expensive than the ribbon, it will not be deployed in large numbers of blister packs in the near future, but it should prove invaluable in trials to determine the efficacy of new medication and customized blister packs.

The US National Pharmaceutical Council estimates that patients' non-compliance with instructions on medication costs more than $100 billion annually in the US alone, and in 1990 it caused 125000 unnecessary deaths. Indeed, 11% of hospital admissions in the US were also attributed to non-compliance with the instructions on medication. According to Information Mediary, patients taking HIV medication correctly for 94% of the time actually half their chance of suppressing the virus when compared with those taking their medication 100% correctly. This illustrates how even minor mistakes in compliance can distort the results of trials of new formulations and endanger patients taking established medicines.

Variants of Information Mediary's systems can also be used:

• to control unauthorized sales and counterfeiting

• to warn of expiration

• to record data of interest for market research

• to assist in safety studies

• during security investigations.

Talking blister packs

ScripTalk RFID labels from Envision America (Normal, Illinois, USA) can be placed behind the printed label on certain pharmaceutical packaging in the US so that blind and partially sighted patients can use a reader that speaks the name of the patient, type, dose and timing. This customized RFID label is selectively applied to multipacks by pharmacists on an as needed basis; further developments will no doubt make it suitable for blister packs. However, like Med-ic, ScripTalk employs a microchip and costs are currently not low enough for it to become standard on all pharmaceuticals.

Patient requirements

Even with smart packaging technology, there remains a great gulf between what the blister pack offers and what many patients need. AstraZeneca has been sensitive to one aspect, which is the simplification of what to take when. The company has customized blow packs marked with instructions regarding when to take each tablet from its blister.

However, elderly patients and those with Parkinson's disease sometimes have problems opening blister packs. These patients often require a number of different tablets, usually from different manufacturers. One possible solution could be a single container that sounds an alarm when the medication needs to be taken. Ideally, an electronic record should be kept. Electronic tablet dispensers without a recording capability are obtainable but expensive. Because many patients live alone, they do not want to be dependent on someone coming to their house and filling customized containers.

Disposable electronics

Low cost disposable electronics are currently being developed. Figure 3 shows a disposable paper timer suitable for incorporating into pharmaceutical packaging. Manufactured by Power Paper Ltd (Einat, Israel), it is powered by an environmentally safe paper battery.

Figure 3: A paper timer set for a specific time relevant to the product that the package contains (Power Paper Ltd).

Looking ahead, several organizations believe the blister pack itself could be made into electronic circuits to perform a variety of functions such as those discussed earlier.

A team at the Polymer Centre of Sheffield University (UK) believes that the aluminium foil could constitute an electrode of a thin film electronic circuit grown on its surface by oxidation and deposition. In an alternative approach, proponents of polymer electronics have already created advanced circuits on polymer film by ink jet printing at high speed. In due course, they foresee these becoming feasible with everyday films such as those in blister packs. The smart blister pack has already arrived, and any further developments will simply make it more economic and more versatile.