A number of commentators during the past few years have speculated that nanotechnology is the wave of the future in biotech and pharma. Predictions such as "The market could steeply rise after 2012, reaching potentially $220 billion by 2015 for these nanoenabled compounds"

  cause companies and their investors to take notice. There is, however, a large disparity between these predictions and the actions of the very companies that are in a position to make them a reality. For example, a Lux Research survey concluded that the pharma industry spends less than 0.5% of its research budget on nanotechnology and that only a sixth of companies had any nanotechnology strategy in place.

Nanotech appears to be following the classic technology adoption curves shown in 

. This shows the bellshaped Rogers Adoption Curve

  for any technology, overlaid by the Gartner Hype Cycle,

  which demonstrates technology acceptance. A new technology creates initial excitement that hypes its promise to be the next silver bullet. Usually, the hype is caused through a lack of understanding of the technology and its applications, which leaves the imagination to run wild and results in overstatement of the technology's promise. This is then followed by disillusionment when the reality does not match the hype. Finally, full adoption is achieved as the technology proves itself in the market.    

Table 1: Approved nano-enabled therapeutics.			

The estimates of the nano market (above) are likely to be part of the early 'hype' peak. We are now in the following trough, where expectations are low and there is a significant gap between early adopters and the early majority. 

Figure 1: Gartner Hype Cycle (blue)/Rogers Technology Adoption Curve (red).			

There are a number of early adopters of nanotechnology in the pharmaceutical industry. 

 shows the available nanotech formulations along with examples of approved drugs. Relative to the number of nonnano products on the market, the full list of approved nanoenabled drugs is very small and those that have made it to the market are effectively reformulations of existing generic drugs. These rarely allow significant returns on investment because of the low cost of the generic comparator drug used by health technology appraisal bodies such as The National Institute for Health and Clinical Excellence (NICE). Unless the reformulation drastically reduces toxicity or doseage (and, therefore, cost), the increased cost in comparison to the relatively minor change in quality adjusted life year (QALY) would make jumping the 'fourth hurdle' hard to achieve. 

It appears that the problem is one of risk. In the current market climate companies need to get their products to market quickly to allow as much market exclusivity time as possible — not to recoup their investment, as this is a sunk cost, but to recoup the cost of developing future drugs, which is becoming ever more expensive. The Tufts Center for Drug Development estimated that the cost of bringing a single drug to market was approximately $1.2 billion in 2008, compared with $802 million in 2000.

  If this trend continues, drug development will become a commercially untenable proposition for industry. Given these issues, companies will not adopt new technology — however brilliant the science is — unless they know it has a clear and fast route to approval. This is particularly poignant in drug formulation and other ratelimiting activities that occur postpatent filing; once a patent is filed, the clock is ticking on the product's life. If a product is going to be a $1 billion a year blockbuster, lost revenues will be at least $2.7 million for every day a product is held from the market. This produces a Catch 22 scenario; no one will take the risk to demonstrate a new technology, particularly if it is competing with existing and proven methods, so no one will see a clear adoption path and use it. 

This is very reminiscent of the fledgling biotech industry 15–20 years ago. Big Pharma was focussed on small molecules and did not want to risk bringing into their portfolio relatively unstable products that had to be injected, such as antibodies and proteins, and which were without a clear regulatory pathway. Now, 22 monoclonal antibodies have regulatory approval in the US, two of the top 20 global pharma companies are biotechs and pharmaceutical companies are buying up biotechs as soon as their products obtain clinical data. Are we rerunning the cycle with the nanotech industry? There are signs that we are, and if we have passed through the trough in 

, then now should be the right time to invest in nanotech. 

One thing is clear; even before the economic downturn, the pharma industry faced a challenge of getting drugs approved faster and cheaper. At the moment, it is not obvious as to whether nanotechnology can help achieve this. Early adopters, such as Abraxis and Elan, have started to clear a pathway, but, as yet, no company has developed a true nanodrug; one which was conceived as a nanoenabled product from first principles as opposed to using nanoformulation on existing products. 

The major question is how can such a high risk and highly regulated industry adopt this new and unproven technology? The UK is examining this question through the Nanotechnology Knowledge Transfer Network's (NanoKTN) NanoPharm Focus Group. The Steering Committee for this group was established with major industry stakeholders, including Pfizer, GlaxoSmithKline and AstraZeneca, with The Wellcome Trust, London School of Pharmacy, Cyclofluidic Ltd and the BioIndustry Association/BioProcessUK representing the research base and smaller companies. The group's aims are to unite the UK's nanotech and bio/pharma development community to examine this and other issues involved in nanotechnology adoption.  

In the drug discovery arena, which is prepatent, financial risk is lower and companies are more likely to risk developing a new technology if it holds promise for improved product discovery and development. In the pharma industry, nanotech is making a real difference in the development of tools to support drug discovery and early characterization of a new molecular entity's activity. Nanotech is also allowing the production of miniaturized high-throughput assays that use minute (picomolar) quantities of new compound and reagents. The benefits of these assays go further than just reducing the cost of reagents; they are also significantly faster because of the reduction in physical constraints, such as thermal mass, and can produce a greater degree of information than traditional assays.  

An example of this was recently published by McKendry's group at the London Centre for Nanotechnology, who demonstrated that microcantilevers can be used to assess the interactions between multiple bindings of vancomycin to the mucopeptide receptors of MRSA.

  The work gave the researchers an insight into the way the drug dimerizes and creates a rupture in the cell wall. This information would have been unavailable through traditional assays, and can allow better drug design in areas of the molecule away from the primary binding groups to increase dimerization potential and, in turn, increase the drug's potency. 

Nanotech has much to offer the pharma industry; if it follows previous technology examples, such as biotech, the successful early adopters will reap the rewards. However, there are still a number of hurdles to overcome, such as a clear regulatory pathway and a demonstration of value above and beyond current technologies, before it can become mainstream. There are significant efforts by industry and governments to help nanotech to jump the technology adoption gap quickly and ensure it can assist in developing the next generation of products, which are needed to solve significant unmet medical needs faced by patients and healthcare professionals.

is Theme Manager, Bionano & Nanomedicine, at NanoKTN (UK).

Why Big Pharma Is Missing the Nanotech Opportunity

4. J. Fenn, "When to Leap on the Hype Cycle," Gartner Group, 1 January (1995). 

, Tufts Center for Drug Discovery (2008). 

http://csdd.tufts.edu/InfoServices/OutlookReportsRequest.asp

, Tufts Center for Drug Discovery (2000). 

Articles

Manufacturing & Processing

A number of commentators during the past few years have speculated that nanotechnology is the wave of the future in biotech and pharma.

Nanotechnology: the next silver bullet?

Few industries now use untreated tap water in their production processes. Most find it necessary to purify tap water to a greater or lesser extent, as it can vary greatly depending on the source and the season. There are also increasing quality demands on production processes. Many applications where drinking water was previously suitable now require some form of water treatment. 

The level of treatment required will alter with the application and the feed water quality. In some 'simple' applications using filtration to remove large particles may be sufficient while other applications require more stringent levels of purification. Even apparently 'simple' requirements, such as the 'spot-free rinse' option in a car wash, requires quite a high water quality with a conductivity of around 10 μS/cm or better to ensure that no salt residues form when the water droplet dries. A similar quality standard is required to ensure laboratory or medical equipment emerges from a washer with no salt residues. 

The pharmaceutical, electronics and power generation industries use the highest purities of water. The water qualities required are so pure that if someone touches the water it would contaminate it and could not be used as it would fail the test analysis. The main impurities present in water can be divided into three categories:  					

Organic material, measured as total organic carbon (TOC).

Ionic material, measured by conductivity or the level of individual ions; for example, by ion exchange chromatography (IEC).

However, even within high purity water specifications there is some variation in the requirements. For example, pharmaceutical systems require reproducibility, reliability and documentation. Power generation requires very low conductivity and silica levels, and electronics manufacturers require the absence of any measurable impurities. The pharmaceutical industry and healthcare applications, such as renal dialysis, have standards defined by legal specifications outlined in Pharmacopoeias (Table 1). All other industries set water standards to meet the commercial and practical requirements of their manufacturing operations. 

Table 1 Pharmacopoeial specifications for bulk purified water (PW) and bulk water for injections (WFIs).			

Modern developments in water purification technologies, such as continuous electrodeionization (CEDI), ultrafiltration (UF) and ozone, have made it possible to achieve even higher purities of water. High purity water systems, such as those used in the electronics industry, are almost 100% pure water, with some impurities being measured in the parts per trillion (ppt) range. 

These improvements have also increased the demands on analytical technologies, which are used to monitor these systems, such as TOC and high performance liquid chromatography (HPLC). 

Most water systems consist of three sections: pretreatment, purification and distribution. The pretreatment system is designed to specifically meet the requirements of the site feed water supply and is used to remove impurities that may detrimentally affect the performance of the purification equipment. The purification system removes sufficient quantities of the remaining impurities in the pretreated water supply to achieve the final water quality required. The distribution system, typically including storage tanks and pipework, gets the water to the location(s) where it is required for the production process. 

 Much of the technology used in the pretreatment section is based on 'old' technology; for example, ion exchange-based water softening, which has been in use for almost 100 years. However, there is a growing increase in the use of newer membrane-based technologies. Not only are the municipal water companies installing membrane-based systems to help control contaminants, such as 

 but the use of UF membranes in on-site water systems is increasing, particularly where there may be a high organic level in the feed water. These organic materials can be detrimental to the performance of the purification technologies in the purification section; for example, by creating a fouling layer on membranes, coating ion exchange resins. 

TOC meters can measure the level of organic material in the feed water, but, unfortunately, there is not always a simple relationship between the TOC level in mains water and the likelihood of this water 'fouling' membranes. Therefore, TOC measurement tends not to be very useful in this section of a water plant. However, reducing the TOC level is usually beneficial to the overall system performance and using hollow fibre UF membranes in pretreatment systems can generally achieve this very successfully. UF membranes typically are considered to have an average effective molecular weight filtration range of 10000–200000 Da equating to a size of approximately 0.005–0.2 μm. 

UF membranes are available as spiral-wound modules or as hollow fibre modules. These hollow fibre membranes are usually 'double skinned'; that is, they have a UF membrane on the inside of the hollow fibre and the outside. The design of the UF system typically uses a cross flow configuration, where the feed water is recirculated internally. Permeate is taken off through the membranes and a portion of concentrate bled off to drain with the concentrated impurities. 

UF membranes provide a good balance of physical strength, resistance to fouling and 'cleanability' with economically viable flux rates (flux is a measure of flow per unit area of membrane). Figure 1 shows a UF system designed for this type of application. There are various methods of operating such a system, from a high cross flow and lower percentage conversions through to minimal or no cross flow with periodic backpulsing/backflushing and cleaning cycles. The system pictured is designed to operate with a cross flow, but includes the capability of backwashing the UF modules with permeate periodically, as well as performing chemical cleaning cycles. 

In this type of pretreatment application, the UF membranes remove contaminants across a wide range of particle sizes and are particularly effective at reducing the TOC levels. The UF membranes used in this application will typically have a molecular weight cut-off rating of 30000–100000 Da. 

 Reverse osmosis (RO) has been the key technology in most pure water systems for many years now and this membrane technology is very good at removing a high percentage of all contaminants present, frequently achieving 95–99% removal of ions and over 99.99% removal of organic and bacterial contaminants. 

To achieve the lower conductivity specifications required in many applications it is now common to follow the RO stage with a CEDI stage. In pharmaceutical water systems the use of CEDI with RO is now generally regarded as the standard combination to produce purified water or pretreat water for injections (WFIs).  

Most commercial CEDI devices comprise alternating cation and anion-permeable membranes with the spaces in between configured to create liquid flow compartments with inlets and outlets. The compartments bound by an anion membrane facing the positively charged anode and a cation membrane facing the negatively charged cathode are diluting compartments. The compartments bound by an anion membrane facing the cathode and a cation membrane facing the anode are concentrating compartments. To assist ion transfer in low ionic strength solutions, the dilute compartments are filled with ion exchange resins. A transverse direct current (DC) electrical field is applied by an external power source using electrodes at the bounds of the membranes and compartments. When the electric field is applied, ions in the liquid are attracted to their respective counter-electrodes. The result is that the diluting compartments are depleted of ions and the concentrating compartments are concentrated with ions. Figure 2 illustrates the typical configuration of a plate and frame EDI system. 

During the last few years, there has been a shift towards thicker diluting cells and modular system approaches, both of which have lowered costs. Thicker diluting cells reduce the amount of ion exchange membrane area necessary to treat a given amount of water, thereby reducing the overall cost of the modules. This has led to the use of layers of resin where the layers can be primarily cationic, primarily anionic material, mixed bed and so on. 

With layered CEDI technology, the goal of the individual layers is to remove their respective counter ions; that is, the anion resin layers remove anions and the cation resin layers remove cations. To maintain electroneutrality in a layer where cations are being transferred to the concentrate, water splitting must occur at the anion exchange membrane to provide hydrogen (H

 ) ions. A similar process happens in the anion layer at the cation membrane providing hydroxyl (OH

 ) ions to replace the removed anions. For this process to happen efficiently, layers must be enhanced to promote the water splitting reaction. In these enhanced layers, the acid or base created through water splitting can regenerate some of the ion exchange resin. It can also change the bulk pH in that particular layer. This is critical to the removal of species that are very weakly ionized at neutral or slightly acidic conditions, typical of CEDI feed waters. 

While not designed to remove residual TOC material, the fluctuations in pH through a layered bed system combined with the steady state of operation does result in, at worst, no addition of TOC and, at best, some reduction of TOC. Therefore, on most potable waters, the combination of RO and CEDI can result in product water that has a TOC level of as low as 5–20 ppb and a conductivity as low as 0.055 μS/cm. This technology was also incorporated into some laboratory water systems where a combined RO/CEDI unit produces water that is then further purified by a 'point of use' polisher unit using a combination of polishing technologies. Systems such as this are used to produce water for making up HPLC buffers and TOC meter test solutions. 

Industrial CEDI modules can be based on a 'plate and frame' design or a 'spiral' design and the resulting module incorporated into a system. Figure 3 illustrates an example of a skid-mounted purified water generation plant showing an LX CEDI module installed (bottom left in picture). Figure 4 shows plate and frame-type CEDI modules and a system of spiral-type EDI modules. The VNX module in Figure 5 is one of the latest CEDI developments, in which the 'plate and frame' concept is manifolded within a single housing, providing high flux in a compact unit. 

 Traditionally, in pharmaceutical water systems the main method for controlling bacterial levels was heat or chemical sanitants, such as peracetic acid or hydrogen peroxide. However, for systems operating at ambient temperatures there is now an increasing trend to use ozone in the distribution system to continually control bacteria. Using ozone also provides the additional benefit of reducing TOC levels in the product water. In most European pharmaceutical water systems, ozone is generated from a small side stream of water using an electrochemical method. In this system, the water is electrically split into hydrogen and oxygen. The oxygen is then converted into ozone and the ozone-rich water stream is fed into the return flow at the end of the distribution system. In this way, a residual ozone level is built up in the storage vessel and the ozone is then destroyed by an ultraviolet (UV) light as it enters the distribution loop. The pipework system may be sanitized by periodically turning off the UV light and allowing ozone to circulate around the distribution loop.  

Ozone is a very powerful oxidizing agent and works by attacking carbon–carbon bonds in any organic material. As this procedure continues, all the carbon chains can be broken down and the carbon produced is converted to carbon dioxide. This further reduces TOC in the product water and is a by-product of the use of ozone in pharmaceutical water systems because the TOC is already typically substantially less than the maximum allowed level of 500 ppb. However, it is one of the primary reasons for using ozone in a microelectronics water system where the objective may be to get to <1 ppb TOC levels.  

 HPLC is used to separate components of a mixture based on a variety of chemical interactions between the substance being analysed (analyte) and the chromatography column. There are four general types of HPLC:  					

When monitoring water systems the only type commonly used is IEC — the others may be used to separate organic compounds to help identify specific contaminants, but this procedure is more likely to be used in specialist problem-solving situations rather than routine monitoring. 

IEC is a process that allows the separation of ions and polar molecules based on the charge properties of the molecules. It can be used for almost any kind of charged molecule. IEC retains analyte molecules based on coulombic (ionic) interactions. The stationary phase surface displays ionic functional groups that interact with analyte ions of opposite charge. This type of chromatography is further subdivided into: 					

Cation exchange chromatography, which retains positively charged cations because the stationary phase displays a negatively charged functional group, such as a phosphonic acid.  					

Anion exchange chromatography, which retains negatively charged anions using a positively charged functional group, such as a  quaternary ammonium cation.

IEC is rarely used in monitoring pharmaceutical water systems, but it may be used in monitoring electronics water systems where the level of ionic contaminants may be in the part per trillion (ppt) range and the quantification of individual ions may be of interest in monitoring the performance of the purification system. 

 TOC analytical instruments measure the level of TOC present in the water. A typical analysis for TOC measures both the total carbon (TC) present, as well as the inorganic carbon (IC). Subtracting the inorganic carbon from the total carbon yields TOC. Another common variant of TOC analysis involves removing the IC portion first and then measuring the leftover carbon. This method involves purging an acidified sample with carbon-free air or nitrogen prior to measurement, and so is more accurately called nonpurgeable organic carbon (NPOC). 

Virtually all TOC analysers measure the CO

 formed when organic carbon is oxidized and/or when inorganic carbon is acidified. Oxidation is performed by a variety of methods: short wavelength (185 nm) UV lights, platinum (Pt)-catalyzed combustion or a UV/persulfate reactor. Once the CO

 is formed, it is measured by a detector: either a conductivity cell (if the CO

 is aqueous) or a nondispersive infrared cell (after purging the aqueous CO

 into the gaseous phase). Conductivity detection is only desirable in the lower TOC ranges in deionized waters and is the method normally used by instruments in high purity water systems. In contrast, nondispersive infrared (NDIR) detection excels in the higher TOC ranges. A variation described as membrane conductivity detection (MCD) can allow for measurement of TOC across a wide analytical range in deionized and nondeionized water samples. 

Modern high-performance TOC instruments are capable of detecting carbon concentrations well below 1 μg/L (1 ppb). This type of system can be quite expensive and, in a pharmaceutical application, requires additional validation documentation, routine system suitability testing and calibration. 

In high purity water systems arguably the best approach is to have the TOC meter fed continuously with a stream of water from the system being monitored; that is, operating on-line. This allows almost instantaneous monitoring of the TOC values, which can assist in trouble shooting system problems or identifying possible problems before they can affect the system. For example, an increase in TOC values may precede an increase in bacterial levels because the higher TOC levels indicate that more nutrient is available to support the growth of bacteria. The specification for purified water or WFI is <500 ppb and most modern systems can routinely achieve <30 ppb, significantly better than the design limit. It is typical for electronics water systems to produce water, at the points of use, with 1 ppb TOC or lower. However, pharmaceutical water systems based on using regenerable deionization systems rather than RO can sometimes struggle to achieve the <500 ppb limit when the TOC levels in the mains water are high. This is because there are no organic reduction technologies as effective as RO or UF. 

Modern water systems using the appropriate combination of technologies can reliably achieve very high levels of water quality. For electronics water systems the level of purity is almost limited by the accuracy of the monitoring devices available. For pharmaceutical water systems standard skid-mounted systems are available that can be fully factory tested and most of the validation work completed prior to arriving at site. On site they can be connected and commissioned with a reduction in the time and effort required.  

Modern instrumental techniques, such as TOC and HPLC, combined with programmable logic controllers, have substantially altered the way in which water systems are monitored and controlled. In many cases, it is no longer necessary for anyone to visit a water system plant room, except to perform routine functions, such as adding granular salt. 

Analytical Equipment

Traditionally, in pharmaceutical water systems the main method for controlling bacterial levels was heat or chemical sanitants...

Pure water technology

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. 

Supply Chain

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

The free radical theory of ageing, first postulated by Harman, is the most popular and widely tested.

  This theory is based on the chemical nature and ubiquitous presence of free radicals.

  In the cosmetic industry, the antioxidant coenzyme Q10 is widely used in anti-ageing products.

  Coenzyme Q10 is a lipid-soluble compound composed of a redox-active quinoid nucleus and a hydrophobic side chain containing 10 monounsaturated 

-isoprenoid units (Figure 1). The main biological function of coenzyme Q10 is to act as a redox component of transmembrane electron transport systems, such as the respiratory chain of mitochondria.

For the topical application of coenzyme Q10 a system that can deliver the antioxidant most efficiently into the skin is required. Therefore, investigations with different topical applied formulations, composed of NLCs, emulsion and liquid paraffin were performed for this study. 

NLCs are used as carrier systems for cosmetic ingredients and pharmaceutical drugs.

  They were developed following the success of solid lipid nanoparticles (SLNs). In contrast to emulsions, the solid particle matrix is composed of a blend of solid lipid and liquid lipid. The particle matrix is solid at body temperature, which protects the incorporated active ingredients against chemical degradation and allows the release of incorporated molecules to be modified.

  NLCs were developed in 1999/2000 and the first two cosmetic dermal products were introduced to the market at the end of 2005 (Nanorepair Q10 Cream and Nanorepair Q10 Serum [Dr Rimpler GmbH, Germany]). In 2006, more products were introduced to the market, for example, the day cream NanoVital (Dr Rimpler GmbH) and in the pipeline, IOPE the SuperVital products (cream, serum, eye cream [Amore Parcific/South Korea]). 

In this study, NLCs were investigated to compare possible advantages with a conventional oil/water (o/w) emulsion or liquid paraffin. The occlusion properties, as well as the penetration behaviour of incorporated coenzyme Q10 into the stratum corneum (SC), were analysed. 

NLCs were produced from the solid lipid cetylpalmitate (Henkel KGaA, Germany) and liquid lipid Miglyol 812 (Cognis Deutschland GmbH & Co. KG, Germany). The lipid blend was heated 5 °C above the melting point of the solid lipid and dispersed in an aqueous Tego Care 450 (Goldschmidt GmbH, Germany) solution at identical temperature (65 °C) by high-speed stirring. The pre-emulsion obtained was homogenized using a Micron LAB 40 (APV Homogeniser Systems, Germany). Cooling of the hot o/w nanoemulsion obtained led to the solidification of the lipid and the formation of NLCs. The reference emulsion was produced by substituting the cetylpalmitate with Miglyol 812 using the same high pressure homogenizer. Both formulations contained 25% (mass/mass [m/m]) coenzyme Q10 (BKI Internationaler Handel GmbH, Germany) calculated on the basis of the particle mass (i.e., 5% m/m in the total formulation). For the investigations, the formulations were diluted 1:10 with water to obtain a final coenzyme Q10 concentration of 0.5% m/m. As a second reference, a solution of 0.5% m/m coenzyme Q10 in liquid paraffin was used. 

The determination of the particle size of NLCs and the emulsion was performed by photon correlation spectroscopy (PCS) using a Zetasizer Nano ZS (Malvern Instruments, UK). Further investigations on particle size were performed by laser diffractometry (LD) using a Coulter LS 230 (Beckman-Coulter, Germany). PCS yields the mean particle size and the polydispersity index (PI) as a measure of the width of the particle size distribution. The LD data were evaluated using the diameter 50% (LD 50) and 95% (LD 95), which means that either 50% or 95% (volume distribution) of the measured particles are below this size.  

The particle charge was quantified as zeta potential using the Zetasizer Nano ZS. Measurements were performed in distilled water adjusted with sodium chloride to a conductivity of 50 μS/cm.

The occlusive effect of NLCs, emulsion and liquid paraffin was investigated using an 

  Water evaporation through a cellulose acetate membrane was measured and the occlusion factor (

) was calculated using the following equation:  

 is the amount of water evaporated through the cellulose acetate membrane without applying a formulation and 

 is the amount of water evaporated through the cellulose acetate membrane after applying a sample. For the evaluation of the occlusion factor, each sample was applied five times with a final amount of 10.2 mg/cm

 . The samples were stored at 32±1 °C and 60±5% relative humidity (RH). Water evaporation was investigated by weighing after 6, 24 and 48 h. If the applied formulation had no occlusive properties an occlusion factor of 0% would be obtained and for maximum occlusion an occlusion factor of 100% would be obtained.  

The penetration of coenzyme Q10 into the SC was studied using a  tape-stripping test. At the beginning all volunteers were asked to wash their arms and dry them afterwards. After an incubation time of 30 min at 20±1 °C and 45±5% RH, 150 mg of NLCs, emulsion and liquid paraffin containing 0.5% m/m coenzyme Q10 were applied to a 10.4 cm

  testing area on the volar forearm of five female volunteers with healthy skin in the testing areas. Thirty minutes after application the samples were washed off and the SC was removed with nine strips of Scotch Tape No. 90 (3M, MN, USA). Each tape was taken in a controlled way; that is, a 1 kg rubber weight was rolled over it 10 times. The coenzyme Q10 was extracted from the tape strips with 2 mL of acetone. The concentration of coenzyme Q10 was determined using HPLC. Strip 4 and 5, 6 and 7, 8 and 9 were analysed together. 

The NLCs and the emulsion had the same lipid content, were produced under the same conditions using the high pressure homogenization and possessed identical particle sizes (Figures 2 and 3). Figure 2 shows the PSC mean diameter and the polydispersity index of NLCs, and emulsion measured at six different time points during 1 month. The LD mean diameters (LD 50 and LD 95) for the formulations measured at the same time points as the PCS values are displayed in Figure 2. Both figures show that the particle size of NLCs and the emulsion are identical and remain constant during 1 month. Additionally, zeta potential measurements were performed. The zeta potential right after production was –54 mV for the NLCs and –57 mV for the emulsion. Zeta potentials in this range are related to no aggregation or to only little aggregation. 

Figure 4 shows the F values for NLCs, emulsion and liquid paraffin. The occlusion factor of the NLCs was much higher than the occlusion factor of the emulsion, although they had the same lipid content and particle size. This effect can be explained by the film formation of NLCs. NLCs showed a tendency to fuse, forming a dense film after application.

  NLC used for these investigations had a melting point of 47.5 °C, therefore, they are still solid at both room and skin temperature. After the water is evaporated from the NLC dispersion, only the solid NLC particles stay on the skin. The capillary force of the nanometer pores between the NLC particles are contractive, which promotes fusion and dense film formation.

  Thereby, the NLCs show the same occlusion properties as the highly occlusive liquid paraffin. It should be noted that the lipid content of the NLC dispersion was only 2%. The emulsion had relatively low occlusive properties although it had the same lipid content as the NLCs. 

With the tape stripping test it can be shown that the penetration of coenzyme Q10 from the NLCs and emulsion was much higher than from liquid paraffin (Figure 5). The NLCs showed the highest penetration of coenzyme Q10 into the SC. 

The shape of the curves obtained indicates a logarithmic relationship between the cumulative values of coenzyme Q10 and the tape strip numbers. Functions of the type can fit the data if a regression analysis is performed, where 

 is the cumulative percentage of the applied coenzyme Q10 found inside the SC, 

 the estimate equilibration coefficients (Table 1). 

Table 1 Parameters describing the logarithmic relation between the cumulative amount of coenzyme Q10 and the tape number for NLC, emulsion and liquid paraffin (p,

Drug Delivery

Coenzyme Q10-loaded NLCs: preparation, occlusive properties and penetration enhancement

Arecent survey by the Organisation for Economic Co-operation and Development (OECD) revealed that pharmaceuticals accounted for more than 10% of total health spending in most countries, but that in France they accounted for over 20% of healthcare spending despite the fact that it has one of the strictest pricing systems in Europe. A combination of low prices and a high level of government-reimbursement have given patients and physicians little incentive to cut consumption.

In France, the top therapeutic categories are cardiovascular (CV), central nervous system (CNS) and alimentary/metabolism.

  However, for the 12 months leading up to December 2006, these classes performed below expectations. The market for CV drugs actually declined by 4%, whilst those for CNS and alimentary/metabolism grew at approximately 2%. However, this picture appeared to mirror the general results for Europe's top five markets (Germany, France, UK, Italy and Spain). Promising categories for the French market include antineoplastic and immunomodulatory agents, and blood agents, which grew at 15% and 29% respectively for the 12 months leading up to December 2006.

Driven by a rapidly ageing population and a known high consumption of pharmaceuticals, the French pharmaceutical market has always appeared buoyant. Yet in practice, pharmaceutical companies have found the operating conditions in France to be tough, as governments continue to exert a downward pressure on profitability.

  For example, there has been visible encouragement for generics and it has been predicted that the French generics market may grow by over 20% per year by 2008.

  In contrast, annual growth for branded pharmaceuticals was less than 5% in 2006 and may be lower than 4% by the end of 2007.

  In recent years, growth rates for the French pharmaceutical market have tended to fall below industry expectations, and it is unclear whether this will improve in the future as cost containment continues to be popular among French politicians.

In 2004, French pharmaceutical production was valued at close to €35 billion and rose by 7.7% in 2006.

  Most French pharmaceutical exports go to the US, followed by Germany and Belgium. Out of total French pharmaceutical production, close to 44% is described as destined for EU member states. Despite continuing growth in production, the French pharmaceutical industry body, LEEM (Les entreprises du medicament) has described the operating environment as fragile.

The change in operating conditions is reflected by a steady decrease in the number of domestic pharmaceutical companies. In the 1950s there were around 1000 companies involved in the pharmaceutical sector, but this dropped to 339 in 2005.

  As in other parts of the world, the French market is dominated by the large multinationals. It has been estimated that the top 10 pharmaceutical companies represent over 50% of the French pharmaceutical market.

LEEM has also expressed concerns about the state of French pharmaceutical R&D, although in some areas the industry still performs well. For example, LEEM estimates the numbers of pharmaceutical staff have tripled in 20 years with 1000 new posts being created by the industry every year.

  At present, the industry employs approximately 100000 personnel with about 18% of these being involved in R&D functions.

  The number of personnel involved in R&D has increased from 14% in 2001, indicating favourable conditions for pharmaceutical research in France.

  In particular, demand for clinical R&D staff appears to be at an all time high. Figures from LEEM reveal that a considerable amount of clinical research is being conducted in France — especially in the cancer therapeutic area. They estimate that around 12000 pharmaceutical industry staff work on projects associated with breast cancer alone.

However, other signs are less encouraging and point to an erosion of France's underlying research base. For a start, the industry has seen a marked increase in the taxation of its income — between 1997 and 2001, industry figures reveal that the level of such taxes tripled.

  In an industry where sales growth is often in the double digit range, the French industry's figures have noticeably dipped, and companies link this to government cost containment and taxation policies.

  As the pharmaceutical industry uses its profits to determine the level of reinvestment in R&D, this has led to some multinational companies shifting new investment to foreign markets where they consider the conditions for long-term profitability more favourable.

The French Government has launched several initiatives to sustain innovation, including reforming the R&D tax credit scheme and creating a new fiscal status for emerging innovative companies. France has been examining initiatives launched by the UK and Spain to improve their R&D positions to develop its own national approach. The French government has also been following the progress of the EU-focused G10 Medicines Group, which seeks to improve R&D competitiveness in line with social and public health objectives.

In January 2004, the French government commissioned a fact-finding report entitled 

 detailing measures that could improve France's R&D position (Table 1). To compile the report, a delegation visited several countries representing major R&D centres to hear the views of different companies and organizations involved in the pharmaceutical and biotech sectors. The French government has also attempted to encourage emerging biotech companies through its 'young innovative company' scheme. To qualify for this status, a company must meet certain criteria such as spending at least 15% on R&D. In return they can get a substantive waiver on tax for a period of up to 8 years.

  The French biotech environment appears to be improving, with an estimated 400 start-ups in the country.

  Although this figure is similar to that in the UK and Germany, many of the French start-ups are at a very early stage compared with these European counterparts. 

Table 1 PharmaFrance recommendations.1			

Historically, France has been the major pharmaceutical producer in Europe. If the country is to maintain this position in the future then much will depend on the initiatives that have been undertaken by its government to revitalize the research environment. It will be keen to learn from the mistakes of neighbouring Germany, where the pharmaceutical industry has suffered a clear decline. 

1. R. Jones, The Chemical Industry and Globalization, ACS  Symposium Series, No. 942 (An American Chemical Society  Publication, 2006).  

2. IMS Health, "Drug Retail Monitor, 12 months to December 2006," (2006). 

3. IMS Health, "Generics Market Expected to Soar to $80 Billion by 2008," (2004). 

4. Anon, L'industrie pharmaceutique, Les entreprises du médicament (LEEM [2007]). 

Driven by a rapidly ageing population and a known high consumption of pharmaceuticals, the French pharmaceutical market has always appeared buoyant.

Fostering France's pharmaceutical recovery

A data package of nuclear magnetic resonance, infrared, ultraviolet and mass spectrometry (MS), plus elemental analysis, is the minimum you need to characterize a small molecule. It should be enough for publication if you are an academic, but if your compound is going into patients, you will need much more than this to satisfy the regulatory authorities. If the compound is a biopharmaceutical drug, then characterization becomes even more difficult because of the size of the molecules involved — be they recombinant proteins, monoclonal antibodies or DNA vaccines. Characterization is now one of the challenges faced by companies embarking on the manufacture of biosimilar drugs, as they must prove that their product has at least similar physical and chemical properties to the original. 

Unlike most small molecules, proteins can change their structure and composition depending on conditions, so characterization must take this into account. A change in pH or temperature may make a protein drug denature, or form a complex, or even a high molecular weight aggregate with other protein molecules. 

Changes in manufacturing conditions can lead to new patterns of glycosylation — the addition of sugar molecules to certain amino acid residues — which can alter the molecular weight and biological properties of the protein. A range of analytical technologies is required to capture these complexities, and there is still plenty of room for innovation.  

Proteins typically have molecular masses of several thousand Daltons, which used to be way beyond the scope of MS. However, this is a technology that has increased its power, while decreasing in price. The mass spectrometer can now accurately determine protein masses to within 1 Da. Given that most proteins have a molecular mass of several thousand Daltons, this is an impressive development, and MS is now the 'gold standard' in protein identification. 

But the mass of a protein cannot determine whether it has the correct three-dimensional (3D) structure, the one that will have the required biological activity. In biotech production, the host cell — be it microbial or mammalian — can generally be relied upon to produce the right amino acid sequence of the desired protein, but it cannot always follow through with folding it into the right shape. This is a particular problem with microbial production; mammalian cell hosts have more 'machinery' with which to perform post-translational modifications — that is, folding and glycosylation. Techniques such as light scattering, ultraviolet and visible spectroscopy, and circular dichroism can provide useful information on whether or not the protein has been folded correctly during its manufacture. Instruments, such as the Malvern Zetasizer (Malvern Instruments Ltd, UK), use light scattering to determine not just the size of a protein, but also its oligomeric state — monomer, dimer or more complex aggregate — in solution.  

Determining 3D structure, where each atom of a molecule is located in space, goes beyond knowing a molecular formula and is the only way of gaining insight into a small molecule or a biologic drug's pharmacological activity. X-ray crystallography (XRC) is another technology that has undergone amazing developments, with robotic handling allowing for routine, high throughput applications. However, the 3D structure of a protein in solution, where it is physiologically active as a drug, could differ from its structure in the solid state. And, although there are thousands of known protein structures from XRC in databases, some important proteins, such as the membrane proteins, cannot readily be crystallized. Efforts to understand and predict their structures depend upon mathematical methods and computer modelling, and these are still far more demanding than predicting small molecule structures.  

Changes in glycosylation, host cell protein content or folding from batch to batch are a particular problem in biotech manufacturing. But conventional manufacturing is not immune to dramatic changes in product with slight changes in manufacturing conditions. A drug may alter its polymorphic form; that is, the way the molecules are packed together in the crystal. The tale is probably well known enough by now, but when Abbott's HIV drug ritonavir began to precipitate out of its semisolid capsule formulation, the company's scientists learned that the drug molecule had changed its polymorphic form. The new form of ritonavir, induced by some slight change in manufacturing conditions, had different and less favourable properties compared with the form that had originally been marketed. Abbott was forced to find a way back to the original form, which it did. The result is that both companies and the regulatory authorities pay far more attention to the 'supramolecular' structure of small molecule drugs, which requires extra solid state analytical work with XRC and other techniques. In other words, looking at large-scale structures is as important for small molecules as it is for biologic drugs. 

One urgent requirement for characterizing biologic drugs is the development of high quality reference materials to which a product can be compared, and there are many efforts being devoted to this goal. For instance, the UK's National Institute for Biological Standards and Controls states that its mission is to safeguard public health by helping ensure the quality of biological medicines. At the heart of this work is the preparation, storage and distribution of World Health Organization International Standards and Reference Materials, to provide benchmarks for product quality. This is a vital contribution, but as biotech medicines become more complex, the analytical scientists will have to work hard to keep up with the demand for references.  

Meanwhile, the biotech industry could make characterization of its products easier by paying more attention to downstream processing and purification issues, creating a cleaner product that is easier to identify. Advances in affinity chromatography, as described by Professor Chris Lowe of the Institute of Biotechnology at Cambridge University at the recent BioProcess International conference, look promising in this respect. This innovative approach involves the application of molecular modelling to design and optimize ligands that are carefully matched to a particular biopharmaceutical product. When they are attached to a column, they can capture the product with a very high specificity so that when it is eluted it should be much easier to characterize.  

If the characterization issue is hard for small molecules and proteins, then it is even more difficult for more advanced therapies, for example, stem cells. Companies, such as Dynal/Invitrogen, are developing technologies for flagging up marker proteins on the surfaces of stem cells, and sorting them into purified populations. This is a world away from passing a small molecule drug down a column, but as medicines become increasingly complex, advanced analytical technologies are needed to characterize them.  

Biopharmaceuticals

... the biotech industry could make characterization of its products easier by paying more attention to downstream processing and purification issues, creating a cleaner product that is easier to identify.

Pharmaceutical Technology Europe-07-01-2007

Nanotechnology: the next silver bullet?

Pure water technology

Rapid progress in pharma RFID

Coenzyme Q10-loaded NLCs: preparation, occlusive properties and penetration enhancement

Fostering France's pharmaceutical recovery

Profiling biopharma medicines

FDA's new guidance for industry

Pharmaceutical LIMS — finding your way to the best solution

The extrusion and spheronization of chitosan