Peter Harrop

RFID in healthcare is rapidly growing and predicted to become a $2.1 billion global business in 2016.

  This is partly a result of the increasing applications of the technology; for example, patient compliance-recording blister packs that electronically record when each pill is taken — or more strictly, when it is removed from the pack. Aardex (

) has a version where the pills in a plastic bottle are continuously weighed by a load cell in the base, which records when a pill is removed.  

These packages are used in drug trials and incorporate RFID so that a record can be linked to a specific patient. They deal with a problem arising from the fact that 50% of patients take their medication incorrectly, either in quantity, time or duration. In rheumatology the figure is 65%; arthritis and migraine is 7–15%; but most other afflictions are in the 40–60% range for noncompliance — a severe problem for the patient, those prescribing and those trialling the drugs. Indeed, the end-point must be smart packs that both prompt and record compliance, and yet are low cost, disposable and environmentally friendly. It is achievable, possibly commencing within 10 years as new printed electronics replace silicon chips and conventional electronic components.

Meanwhile, new finer silver conducting ink for sensors and interconnects can now be used in rapid litho, flexo and gravure printing. Semiconducting and dielectric inks are being developed by Merck (

) and others, and some of these will be suitable for high-speed printing of replacements for the silicon chip in labels and packaging within 10 years. Indeed, 60 organizations are developing printed transistor circuits. The printed alternatives are cheaper, more damage-tolerant and thinner. Packaging companies Dai Nippon Printing (

) are among those developing printed electronics for packaging. 

Marketing, patient and professional advantages

When two equally efficacious drugs enter the market, the one with better compliance is likely to be more widely used. Noncompliance is costly and risky. In the US, it: 					

Costs $100 billion and 125000 deaths annually.

Is responsible for 10% of hospital admissions (at an annual cost of $31 billion/380000 patients). 

Is responsible for 23% of nursing home admissions ($15 billion/3.5 million patients).

Costs the drug industry over  $8 billion annually in unfilled new and refill prescriptions (source: The National Institutes of Health [NIH]).

Unnecessary suffering and depressed sales of drugs 

Patients are often confused about the reasons for being prescribed the medication. After all, they spend an average of only 6 min when meeting their physician. Many patients also question whether their treatment is necessary.

They fail to get refills where prescribed, and 28% of over 45 year olds admit to discontinuing the prescribed medication prematurely — antidepressants are particularly bad in this respect.  

Drug companies have come to realize that spending heavily on creating new blockbuster drugs is risky and less cost-effective, whereas encouraging patients to take medication correctly benefits the patient, reduces the workload on physicians and hospitals, and sells more of existing, noncontentious drugs. 

The smart blister pack and plastic bottle reduce the amount of false data recorded in drug trials. Eventually, such packs will appear in the home — probably enhanced by self-adjusting electronic use-by dates (you overheated it for so long, therefore, dispose of it at this earlier date) and electronic monitoring of degradation in storage and transport.  

Drug packages that record when a given tablet was removed (and presumably taken) are at last receiving serious attention. The packages are starting to be used for two purposes — establishing compliance levels for existing drugs and improving the quality of information from trials of new drugs. In 2006, during a 6-month trial in 12 academic institutes, NIH tested the antibiotic Azithromycin using 30000 smart packages that recorded which tablet was taken and when. We estimate that these smart packages were sold for around $20 each to the trial operator. 

) performed the trial using smart blister packs from Information Mediary (http://

) has performed a drug trial, in this case using smart blister packs from Cypak (

), a company that uses packager MeadWestvaco (

) for some of its marketing. This first trial involved 200 patients and 20 pharmacies, and lasted for 3 months.  

In September 2006, Novartis commenced a second clinical trial with compliance monitoring packaging on its high blood pressure medication, Diovan 160, and will last for at least 12 months. Novartis is conducting this second trial to maintain and improve compliance on a wider scale than the first. The European Communications Consultancy Team (

) is conducting the trial. Based in The Netherlands, it designs medical consumer electronic devices. 

Ten thousand patients and 200 pharmacies in The Netherlands are involved in the project. There are an additional 400 pharmacies on the waiting list that ECCT expect to join once the trial has started. Dr Willem Kort, co-director of ECCT, reports that pharmacies in other European countries will also participate. "Pharmacies in Austria, France and Germany will join the project. We presented to the Ministry of Health in Austria and it reacted favourably. The Ministries of Health in France and Germany will follow quickly, and take the initiative with the technology," revealed Kort. 

Patients with compliance issues were nominated by their doctors for the trial. Those volunteering to improve their compliance, or get more guidance on how to take their medication, are also taking part. ECCT expects the Ministry of Health in Finland to also take the technology on now it has the chair of the European Commission.  

Although the first Novartis compliance trial, which ended in May 2006, used Cypak's Intelligent Pharmaceutical Packaging (IPP), Kort said that Cypak's technology will probably not be used in this trial. However, Cypak is still co-operating with the project, as is NXP (

ECCT is developing its own RFID blister pack system for compliance packaging, which will be launched soon. It can be applied to existing blister packs, saving cost. Meanwhile, it is also in talks with several intermediate technology companies to conduct the clinical trial. For example, the Information Mediary smart blister pack currently used in US drug trials may be a candidate, and Bang and Olufsen Medicom (

) in Denmark is also developing suitable products. 

The improved compliance benefits through smart packaging include:  					

Assisting the medical provider by explaining the optimal prescribed regimen. 

Enrolling the patient as a participant in their own therapy. 

Simplifying medication  administration for the patient. 

Providing interaction and prompting, reinforcement and cueing. 

Creating a permanent and continuous intervention that demands little involvement from the physician or pharmacist. 

Reducing the development of antibiotic-resistant bacteria.

The World Health Organization (WHO) estimates that counterfeit drugs annually cost the pharmaceutical industry $40 billion. The Centre for Medicines in the Public Interest projects global counterfeit drug sales to reach $75 billion in 2010 — a 92% increase on 2005. Drug counterfeits average 6–10% worldwide, according to WHO and the UN, and "Up to 15% in the global medicines supply chain" according to 2005 analysis by PloS Medicine. Russia, Africa and South America are significant markets for counterfeit medicines and more than 100000 people die from counterfeit drugs every year in China alone according to some reports. 

At the Rome (Italy) WHO meeting in February 2006, Nils Behrndt of the European Commission noted that 27 incidents of counterfeit drugs in the EU legitimate supply chain were identified between 2001 and 2005. Alexander Vladychenko, director general of social cohesion of the Council of Europe, noting the increasing sophistication of drug counterfeits said: "Counterfeit drugs are on the verge of becoming a silent pandemic." 

To combat this, RFID on each small package, with unique identification of that precise package ("mass serialization" under EPC global numbering and network), permits reverse audit, called "pedigree" by the pharmaceutical industry. Pedigree, combined with sophisticated software, ensures the origin and destination of even the smallest package is known at all times.  

FDA was expected to legislate on this within the next year or so when certain aspects are resolved, such as the best frequency to use. However, it has recently softened its stand, and is now unlikely to force through the necessary standards. Meanwhile, Pfizer (

) is RFID tagging, at item level, all Viagra for the US; GlaxoSmithKline (

) and others are following. They use high frequency (HF [13.56 MHz]) RFID because they get a guaranteed 99.95% read rate and no ghost reads. It is the most proven RFID frequency with over one billion of these tags in operation. Cardinal Health (

) and others have developed smart shelves in cabinets, refrigerators and trolleys that can read these HF tags for error prevention, automatic reordering and theft prevention.  

In addition, by the end of 2006, Wal-Mart (

) had taken delivery of over four million tagged drugs at item level for improving automation of stocktaking, customer service and theft prevention in its pharmacies. Company policy is to use ultra high frequency (UHF [in the US 915 MHz]) exclusively. However, Wal-Mart and the leading suppliers of UHF labels no longer recommend the so-called 'far field' versions, but support 'near field' UHF for items because it is just as insensitive to water and metal as HF (unlike far field UHF), but may give a lower cost label than HF.  

However, there are disadvantages. Near field UHF is unproven in mass production for these environments, and radio regulations will never allow it to be one frequency, bandwidth, signaling protocol or even power level, worldwide. In many countries, mobile phones and the military got there first and will not free up the same bands, although it is at least becoming legal in more areas and sometimes the permitted RFID power level is being increased. 

Articles

Drug companies have come to realize that spending heavily on creating new blockbuster drugs is risky and less cost-effective ...

Rapid progress in pharma RFID

Today's drugs are mainly supplied in pots or blister packs. Cosmetics and other skin treatments are usually supplied as ointments in pots or tubes, or as pots of powder. Many delivery systems act indirectly — for example, tablets take a drug to the bloodstream via the digestive system and painkillers may be required to travel through the body to find the site of the pain. This can mean that inflated doses may be required and unwanted side-effects could occur in more locations than with a direct system.  

				Smart skin patches are one of the new delivery systems for drugs and cosmetics that address these and several other problems associated with traditional methods, such as									

lack of automated records concerning compliance 

Demographic trends will make these challenges greater. For example, the percentage of the European population that will be 'dependent elderly' will rise from 20% to 30% by 2015. Figure 1 gives the dependent elderly as a percentage of the population from 1970-2050. The UK National Institute for the Blind estimates that 20% of people in the UK are currently sight impaired — a situation that will worsen with an increase in the elderly. A study in 

 found that nearly half of Americans older than 65 develop at least one of three chronic eye diseases, and the number of elderly is increasing rapidly. Even today, 100 million Americans are thought to have difficulty reading the instructions on medicines, reasons for which include poor printing, illiteracy, dyslexia and sight impairment. It is not prudent to let such people control the nature and timing of their medication if it can be avoided. 			

Traditional delivery systems for drugs and cosmetics rely heavily on humans administering the correct dosage at the right time, or in response to a subjective appraisal of need. Humans are notoriously bad at performing all these tasks.  			

The sick are even less reliable than the fit. Yet, since the time of Socrates more than 2000 years ago, it has been recognized that non-compliance with medication instructions can have severe effects. 

 has reported that if AIDS drugs are taken at the wrong time or in the wrong quantity for 5% of the time, then the chances of suppressing the virus are reduced by 50%. As that can mean that the patient dies 10-20 years earlier than would otherwise be the case, there is much at stake here.  

 Figure 1 Dependent elderly as a percentage of the population 1970-2050.			

It is not a problem that is confined to drugs. Skin care treatments that are incorrectly applied may be ineffective or, at the other extreme, they may cause adverse events, such as cancer. Skin care is an enormous market, having been worth $31 billion in 2001, and is predicted to grow by 24.6% through 2006, according to Power Paper (Einat, Israel). Here, the interest is in vitalizers that have rejuvenation effects and enhancers that boost delivery of the ointment through the skin. Figure 2 shows the level of non-compliance for various medical treatments. It averages 50% overall afflications.  

Drug trials are also imperilled by non-compliance. One may even be deciding whether to launch a new drug based on 50% corrupt data; that is, knowing that 50% of patients do not administer the drug correctly, but not knowing who they are. Add this to the fact that many drugs are only effective on one in three patients because of genetic and other differences, and one can be peering through a fog in assessing new formulations. 							

It can be distressing for unwell people to have to attempt to fulfil complicated instructions to prepare and administer a formulation, sometimes to a part of their body that they cannot see or easily reach. Most distressing for sufferers of severe forms of Parkinson's disease and diabetes is the need to inject themselves, deliberately causing pain — they may be shaking and may inadvertently inject at the wrong location, causing injury.  

Figure 2 Level of non-compliance for different medical treatments.						

An increasing number of these patients are required to be attached with a needle to an infusion pump all day, and sometimes all night too. The setting up procedure can be extremely challenging, with the mixing of liquids from ampoules in the correct amounts; remembering to have the pump switched off for part of the procedure; on for another part; and on when left in place. Even when medical staff follow the procedure, it is distressing for the patient.  

All invasive procedures, not least injections, can cause inflammation, lumps under the skin that may or may not be diffused by ultrasound or massage, and other complications such as infection. Also, needle-free injections using ultrasound syringes can have dosage problems and cause pain. Implants that deliver drugs can malfunction without it being immediately obvious or they may be rejected by the body. There is, therefore, a requirement for alternative approaches. 			

Skin patches to deliver drugs and ointments have long been used by physicians and veterinarians. For example, nicotine is delivered to help people stop smoking; oestrogen is delivered by transdermal patch as part of a contraceptive or to counter the symptoms of menopause; and animals are given drugs in skin patches to counter pain. These devices are first generation and are manufactured in large numbers. The patches only work with certain chemicals because the skin is a relatively impermeable barrier; absorption through it is very slow and varies with a variety of factors, such as temperature. 

Table I Examples of products incorporating ALZA transdermal technology.						

Enter the second generation devices, pioneered by companies such as ALZA (Mountain View, California, USA), Vyteris (Fair Lawn, New Jersey, USA) Empi (St Paul, Minnesota, USA) and Power Paper. These skin patches employ iontophoresis, which is the application of an electric bias to increase penetration. Applying a few volts for a short time can increase penetration by more than 16 times. A tiny electrical current is passed through the skin by electrodes in the patch, typically powered by a small laminar battery in the patch or, for larger quantities, a delivery system to the patch. For example, Power Paper uses its low cost, environmentally safe printed paper battery and printed resistor network.  			

The cost is low enough for the product to be disposable. This type of patch is usually pre-impregnated, but some versions can be reused as dispensers for ointment. This smart skin patch can even be a product in its own right with no impregnation because its dry activation removes wrinkles for a few hours: an effect greatly valued by some in the trials. This is a new Cinderella story wherein your wrinkles return at midnight! In the single year that the company has been demonstrating its electrical patches, it has signed production licences with five major corporations seeking more efficient delivery mechanisms for such products as antiwrinkle and antiblemish ointments. 

Power Paper has not yet applied for US Food and Drug Administration (FDA) approval to deliver drugs with its device, but ALZA and Vyteris have done so for their products in certain applications. Products now incorporating ALZA 

 transdermal technology include those in Table I. It is suitable for both local and systemic delivery, and is considered particularly beneficial with episodic onset of symptoms, and where precise and rapid delivery is required.  

Third generation skin patches are electronic rather than simply electrical devices. There are several reasons for this. For example, it has been found that regularly reversing the bias causes the ointment or drug to penetrate approximately 36 times faster than without iontophoresis; that is, twice as fast as with a simple unswitched electrical bias. Electronics can allow the dose to be adjusted even after loading and during treatment. Also, electronics in the device can permit timed doses and ultimately (with sensors) drug delivery according to monitored need. Thus, human intervention, and therefore, the main cause of errors, can be progressively eliminated. 			

The Vyteris controlled electrophoretic system is composed of a flexible adhesive pad consisting of two reservoirs that are prefilled respectively with the drug and saline to complete the circuit, and a dose controller. The first Vyteris product is designed to provide rapid, local dermal anaesthesia to minimize pain for medical needlestick procedures such as  insertion of IV catheters, hypodermic injections including immunizations, blood draws and dermatological surgery procedures. 

 is used with a small quantity of a vasoconstrictor epinephrine, and 99 doses can be delivered with the small battery. FDA approval was sought for this application in 2002. In 2004, both Vyteris and ALZA received FDA approval for iontophoretic delivery of these drugs. 

There is considerable scope for administration of Lidocaine in this way. In the US, there are more than 300 million needlestick procedures every year, of which 33 million are paediatric and 80 million are immunizations, according to Bruskin Research. Vyteris is to prioritize migraine and Parkinson's disease treatments as its next applications of iontophoresis. It reports that 23 million people in the US suffer severe migraine attacks and 1.5 million have Parkinson's disease. Currently, triptan compounds are taken orally for migraines and their action is unsatisfactorily slow with a possibility that there may be no protection against follow on attacks. The electronic control of these patches can ensure a strong first dose followed by a more modest follow on dose. 

The potential benefit of the dopamine and dopamine agonist orally administered treatments of Parkinson's disease is the reduction of patients experiencing nausea (50%) and those hallucinating (33%). There may be some hope of replacing the needlestick administration of the dopamine agonist apomorphine as well. This cannot be administered orally because it breaks down, yet it is the most efficient dopamine agonist currently known. Vyteris has also started clinical tests on the daily administration of parathyroid hormone to patients with osteoporosis and pulses of gonadotropin-releasing hormone every 90 min to women preparing for 

Microprojection arrays. ALZA has also had success with human growth hormone and vaccines. With some regimes, lower doses are effective compared with injection by syringe. In these cases, ALZA's 

. Here, a disposable, thin titanium screen has precision microprojections that, when applied to the skin, create superficial pathways through the skin's dead barrier allowing transport of macromolecules. It can be used as a passive skin patch or an electroactive one employing iontophoresis and is particularly appropriate for synthetic drugs, proteins and vaccines. The applicator is reusable. Further generations of skin patch could even involve arrays of needles to auto-inject timed doses of the more intractable drugs. Something of this nature may be necessary to assist the iontophoretic delivery of large molecules such as apomorphine. 			

However, before we have such speculative developments, it is appropriate to consider the closed loop system to replace timers. By this I mean the use of electronics in the patch to sense patient parameters and respond appropriately. The drug is administered according to need rather than the time of day. Diagnostic information linked to a unique identity number could even be radioed back to professional staff for review in critical cases. Disposable patches that do not deliver drugs, but simply radio back and/or record essential parameters against a unique electronic identity number will be another possibility. 							

With closed loop control it is not necessarily ideal to have the sensors at the same sites as the drug administration. Two or more smart patches signalling to each other may be more efficient. In late 2003, researchers at the University of Bremen (Germany) came up with an elegant solution to this. They told the World Congress on Medical Physics and Biomedical Engineering held in Sydney (Australia) that they have designed sensors that can share data by sending electrical signals through the body. Applications can include measuring pulse or blood chemistry. 			

This research was initially funded by EADS Astrium, the European space company. It hopes to use the technique to monitor astronauts' vital signs. The researchers believe there will also be applications in monitoring soldiers and firefighters.  

For all electronic skin patches, there is a need to reduce the cost if they are to be disposable and used in large volumes rather than in niche applications. The cheapest silicon chips have stuck at a price of 5-10 cents for more than 20 years and, with the cost of a fabrication facility for silicon chips growing exponentially beyond today's $3 billion dollars, it is not safe to assume that silicon chips will become much cheaper in the quantities required for patches. There are famines in the supply of silicon chips every 4 years or so and, at these times, the producers ration the simpler, low profit items first. Another problem with silicon chips is that other circuit components, such as batteries, lights and electronic chimes, cannot usually be made in the same process, so the reliability, cost and size problems of separately connected devices must be suffered.  			

However, help may be at hand with the new thin film transistor circuits, particularly the cheaper types. They consist of printed polymer circuits without the poisons used in the manufacture of silicon chips and are expected to be on the market by 2005. Electronically, they are crude devices that do not work at high frequencies, but they will be perfectly adequate for a host of disposable applications in medicine including most smart skin patches. More information regarding this and related technology can be found at the 

 conference and exhibition, 12-13 October,  Nice (France), and 

 (New Orleans, Louisiana, USA), 7-8 December. 

A new generation of drug delivery devices is being developed. Smart skin patches, it is claimed, will provider a safer and more user-friendly method of taking medication. This article highlights some recent developments in the field and analyses some of the many benefits the patches will provide to patients.

Smart Skin Patches

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. 	

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 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.	

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.			

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

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.	

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 record data of interest for market research

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.		

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.	

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.	

Packaging technology is moving into the 21st century with innovative and cost-effective developments, including sound, moving images and even tracking devices. What was once deemed science fiction is rapidly becoming science fact. This article explores the latest developments in blister pack technology, discussing the range of benefits to both pharmaceutical manufacturers and patients.