Manufacturers do not need reminding that in today's litigious and safety conscious climate, a solid metal detection process is crucial. As they strive for greater automation and uptime, compliance with legislation and good manufacturing practice (GMP), manufacturers want a metal detector that does more than just prevent contamination. Proactive suppliers have responded by conceiving metal detectors capable of performing multiple functions. Enabling efficient cleaning and changeover, data control and regulatory compliance, this new breed of intelligent inspectors offers a range of added-value benefits in addition to sensitive detection. 

This article looks at the ways in which changing customer demands have impacted on inspection technology, confronting issues such as washing-in-place (WIP), 21 CFR Part 11 compliance and the relentless push for heightened sensitivity. 

Traditionally, product changeovers for highly active pharmaceutical ingredients (APIs) involve a time-consuming cleaning process. A machine operator in climatized, ventilated clothing enters the cell room and rids the tablet press of any visible powder residue. All components in contact with APIs such as the tablet press rotor and metal detector reject are then removed, dismantled, cleaned and replaced. This accrues costly downtime, compromises the flexibility of the production process and incurs high personnel costs for adverse working conditions.        

In a drive for higher quality from the Medicines Control Agency (MCA) and employee protection from health and safety legislation, cleaning-in-place (CIP) and WIP systems are now becoming commonplace. But although technology for WIP tablet presses is fairly advanced, until very recently, metal detectors still had to be dismantled for cleaning as their aluminium construction meant they could not withstand the rigours of cleaning in situ. Fully sealed stainless steel metal detectors with reject systems that can be connected to a tablet press or deduster are now available to allow all contact areas to be WIP. Furthermore, integrated WIP systems containing a tablet press, deduster and metal detector can also be built. 

These integrated WIP systems operate by pumping water at pressure through the tabletting system to remove, in place, traces of dangerous ingredients from the press and metal detector. An operator in normal pharmaceutical clothing can then strip the machines and take the rotor and other removable components outside the press for cleaning. In the meantime, production can continue as the rotor can be exchanged immediately. This approach eliminates the need for bulky 'space suits,' reduces cleaning and inaccessible time, and assists companies in production planning. It also ensures dust-free connections. Although dedusters rid tablets of most dust, they are not capable of removing 100%. Sealed connections between the deduster and the detector prevent dust from escaping at these points, creating a dust-free production environment.  

Line space is an important consideration for pharmaceutical manufacturers. Historically, machinery suppliers have faced problems producing machinery that is compact enough to fit into the limited cell room space available. Forward-looking suppliers are developing combination systems that overcome space constraints and perform multiple functions.        

However, co-ordinating the interfaces of different machines requires detailed electronic and mechanical engineering. A wide variety of metal detector configurations is needed to enable compatibility with the various types of tablet presses and dedusters on the market. For example, metal detectors can be fitted with a height/angle adjustment facility for integration with different tablet presses. 

Metal detection equipment suppliers can work with pharmaceutical manufacturers to integrate the metal detector, deduster and press, reducing the overall footprint and saving valuable line space in the non-sterile manufacturing area. By deploying a combination metal detector and deduster at this point, companies gain the dual benefits of alleviating excess dust and checking for metallic contamination before the final stage of blister packaging or bottling. It is also possible to configure the metal detector to transmit feedback signals to the tablet press. So, in the event of a metal detector fault, the press stops producing tablets and an alarm alerts the operator to the problem. This prevents product wastage and blockage, and guards against contaminated product passing through undetected.  

The industry standard for validating and calibrating metal detection equipment is to pass spherical balls of varying sizes and metal types through the detector. However, in reality, contamination is more likely to be in the form of metal slivers or short lengths of wire or swarf. These will produce differing signals in the metal detector, depending on their alignment to the detector's aperture. This is known as the 'orientation effect.' Leading metal detector suppliers now run performance tests using real life contaminants, such as stainless steel sieve wire rather than spheres, so that customers are confident that the detector can handle any type or shape of metal.                

Pure, high resistance non-magnetic, stainless steels such as 304 and 316 still cause problems for metal detectors, as they go undetected at anything other than extremely high frequencies. It is difficult to design high frequency machines for a pharmaceutical plant because of interference from the external environment and the detector hardware. Metal detector manufacturers have responded to this issue in two different ways:				

Developing detectors with smaller apertures. This improves sensitivity, but reduces product throughput rates.

Reducing frequency to 800 kHz. This eliminates interference, but reduces sensitivity. 

Removing electronics from the head of the detector can achieve 1MHz frequency and stability. The use of a larger aperture maintains a high rate of product flow while the high frequency ensures unparalleled sensitivity levels - even for the most elusive stainless steel contaminants.  

Pharmaceutical companies are facing mounting pressure to comply with 21 CFR Part 11, which was introduced by the US Food and Drug Administration (FDA) in 1997 for controlling electronic records and electronic signatures in validation and GMP. Metal detection is now subject to risk assessment to determine whether it falls within Part 11 compliance - a decision that lies with each individual.        

Leading metal detection manufacturers have developed software according to GMP guidelines that allows equipment to be Part 11-compliant. The software implements all security access controls, user identification, audit trails, electronic records and electronic signatures, so in the event of contamination, batches can be fully traced and accounted for.  

The metal detector has come a long way since the balanced coil principle was registered as a patent in the 19th century. The transition from analogue to digital, the advent of information technology and the upgrade to powerful microprocessors have been among the technological milestones to date in its evolution. Now, as detector performance reaches a peak, limitations are imposed by the boundaries of physics. Technology has entered a new era, with customer requirements determining the direction of the latest generation of intelligent inspectors.  

Articles

Feature article

Customers are placing high demands on pharmaceutical manufacturers to produce sensitive, cost-effective and regulatory compliant inspection technology. This article examines how metal detection equipment suppliers can combine forces with manufacturers to provide state-of-the-art inspection systems, giving particular consideration to cleaning processes and regulatory issues.

Intelligent Inspectors

Changes are afoot in the life science sector; the pressure is on to retain full regulatory compliance, provide faultless customer service and to reduce costs (by using leaner processes and dramatically reducing cycle times). Nowhere in the organization is this beginning to be felt more keenly than in quality control (QC) and research and development (R&D) operations. In many organizations it also necessitates a major cultural shift.  			

The hub of QC and R&D operations are the laboratories, and the challenge is to maximize the testing activities of the analysts who are often highly qualified, difficult to recruit, difficult to retain and essential to the process. Maximizing this resource is the key to breakthrough performance, and the solutions to achieving this lie within the people themselves and their management and support systems. Many companies also have to deal with rapid expansion, variable and unpredictable peaks in workload and constraining registered testing procedures, as well as persistent pressure to reduce costs.  

Visitors to a lab will usually notice how little actual testing appears to go on, despite the operations being under apparently heavy workload (often with a growing backlog of batches to test). Understanding the operational aspects of QC can be complex; there is little product to actually see; the volumes are low; the bill-of-testing is often complex; the opportunities for campaigning are complex; and there are numerous systems (compliance, deviations, retesting and paperwork flow) involved in the release of results. 			

At the beginning of 2002, Tefen launched a benchmarking survey of QC labs across the biopharm sector using a range of detailed operational metrics. During the last few years, Tefen has used this database along with the benchmarking process as an integral part of its QC labs diagnostic studies and lean labs implementation programmes. The process has highlighted the value and power of benchmarking, and demonstrated that labs that have very different testing regimes (active pharmaceutical ingredient [API], micro, biotech and packaging) suffer from the same operational issues and can be compared directly as long as there is careful normalization of the indices used. Tefen has continued to develop and add to the database further world-class companies and is in the position to be able to answer the question of what a best-in-class lab actually looks like. This article reports on the main findings from this benchmarking process, the lessons learnt and where to go next. 

Figure 2 QC & QA cycle time breakdown.						

Initially, 15 QC labs joined the survey, from API, biotech and pharma formulation sites (including packaging and distribution). Three were based in the US, 11 in Europe and one in the Middle East. All were US Food and Drug Administration (FDA) registered good manufacturing practice (GMP) labs. During subsequent years, a further five companies were added to the database. For companies that performed a lean labs improvement programme in partnership with Tefen, data exists prior to and after the improvements were made. 						

A range of operational metrics for QC labs was established in six key areas:  									

A questionnaire detailing all the required data for the various indicators was sent to the participants and the data validated via face-to-face interviews. After the report had been published, management presented the results and the recommendations for improvement.

Full details of the results are restricted, however, the following provides a summary. 			

 The average management:analyst ratio was 0.3, and the average direct:indirect labour ratio was 3 (with the highest score of 15). Lab assistants were used at 46% of sites to perform lower-skilled daily tasks (for example, glassware cleaning, sample management and stock replenishment [Figure 1]). 

 The quality operation cycle time was calculated from the sample receipt in the lab until the quality assurance (QA) release (Figure 2). The different cycle time performance of the various types of samples (for example, raw materials intermediates and finished product) were weighted according their volume in the lab. The overall quality operations cycle varies from 5-34 calendar days. 

The highest analyst availability across the survey was for the non-European Union (EU) participants; and the average was approximately 1700 hours per year per analyst. Analyst activities are split into two main categories, routine testing and other activities. Detailed studies show that with little or no support staff, 45-60% of analysts' time is spent on routine testing. For labs with support staff this is in the 70-85% range. 						

Indicators of productivity include direct and indirect hours per test; tests and samples per head (Figure 3); and percentage of planned hours performing routine testing (Figure 4). The direct labour hours per test varied from 0.5-3.8 h and the tests per head were in the range of 50-250. There is usually a trade-off between analyst utilization and cycle time performance. The utilization is affected by several factors, which include backlog and samples undergoing testing, lab flexibility (in terms of training), analyst availability for testing and layout effectiveness. The cycle time is the counterbalancing indicator affected by the lab capacity and the planning and scheduling processes in the lab.  

Figure 4 Percentage of planned hours performing routine testing.						

Quality is measured primarily by lab yield (first time valid rate for the tests). This is measured by considering the total number of tests that failed per year because of QC lab error. The average was very high at more than 99.7%. 							

Most of the labs had LIMS systems. Two sites had no LIMS system, but managed all their samples on the site-wide production and inventory control system, or on an in-house database. Half the sites were considered to have a need for an automated scheduling system to manage prioritizing and allocating work.  

Figure 5 Finished products cycle time breakdown.						

Benchmarking survey results can be very sensitive within an organization, both at local and corporate level. They have to be handled with some care. The relative positions on the charts are of great interest to everyone involved and yet, the participants invariably feel that their operations are somehow different and more complex. The real value in the survey results is to highlight areas for improvement.  						

The benchmarking survey was used in all cases as the basis for recommendations for operational improvements. The sites used this data to prioritize their improvement initiatives, identify opportunities for improvement and confirm areas of operational weakness. An added benefit was the ability to track performance against best-in-class before and after an improvement programme. 

Figure 6 Proportion of QC 1 micro staff versus all staff on site.

The main lesson, however, is that the real benefits are only truly realized when a properly designed improvement programme is implemented. Companies involved in the QC benchmarking survey have gone on to realize great jumps in operational performance through improvement programmes. Examples of such programmes (and typical results achieved) include 					

cycle time reduction (30% reduction in receipt to release cycle times)

productivity improvement (20% reduction in costs or increase in testing volumes)

layout changes (20% reduction in testing cycle times)

system improvements — such as key performance indicators (KPIs) system implementation achieving better integration into the supply chain.

The benchmarking process is a cycle of data collection and feedback with a number of obstacles and potential roadblocks. The metrics must be detailed enough to be of use to individual companies, but able to be normalized across all companies and not be too complex.  

Figure 7 Example performance indicator system.			

The data collection process is also potentially controversial and sensitive because different interpretations of the definitions can easily cause argument. One conclusion from the first round of the survey was that independent analysts must perform site visits, interviews, observations and analysis of data systems to establish what the real values are (Figures 5 and 6). Definitions must also be very clear (for example, what constitutes a "sample" and "direct" labour). 

A number of measures need to be extracted at a higher level for corporate and senior executive functions, such as: 					

Percentage of resource performing routine testing (budget that is actually doing value added work).

Yield and retests (failures and deviations that are because of QC lab error).

Cycle time performance (and on time delivery to customer).

Overall lab effectiveness (hybrid measure of efficiency and yield).

More qualitative measures can be included that outline what constitutes a world-class lab, an analysis of the management structure and effectiveness of meetings, mapping of deviations, out-of-specification (OOS) process, and corrective-action-preventive-action (CAPA) systems. Also, the survey should be expanded to include all QC support functions, the speed of equipment validation and effectiveness of QA. 

Figure 8 Visual lab (example testing workstation).

 Although detailed analysis is required to determine the operational effectiveness of a lab, there are some clues that can be used to tell at a glance if the lab is world-class. Good lab operations always include the effective use of KPIs (Figure 7) that are highly visible, widely understood, relevant to the weekly operations in the lab, easy to measure and have achievable but challenging targets. Other factors include the use of lab stewards, the close proximity of QC support functions, the close proximity of documentation areas and frequent presence of management in the lab. 			

Truly world-class labs also have aggressive reduced testing programmes, particularly in raw materials labs, an active programme of continuous improvement, efforts to create a "visual lab," (Figure 8) and planning and scheduling systems. Finally, world-class labs are constantly trying to achieve the balance between compliance, cost effectiveness and customer service, and recognizing that this is an ongoing issue that must be constantly readdressed. 

This article investigates what defines a best-in-class QC lab based on experience of implementing operational improvement projects in world-class labs. It includes an assessment of a benchmarking process, a case study of improvements made as a result at one company and findings on what constitutes best-in-class for QC labs.

Is There Such a Thing as a Best-in-Class Lab? Benchmarking of QC Operations

Mystics would have us believe that "you can never step into the same river twice." The onward rush of the water imposes change even where no change is apparent. But had mystics contemplated the European approach to pharma politics, they may have altered their perceptions dramatically.  

For here, in Europe, it could reasonably be maintained that the onward rush of time has imposed no change at all during the last 25 years. Anyone could step back in at any point, at any moment, and find the same depressingly familiar debates, interminably failing to reach any real conclusions. 

This reflection is prompted in part by the premature departure of Erkki Liikanen, the genial Finn who has been largely responsible for EU pharma policy during the last 5 years in his role as Commissioner for Enterprise. In what was more or less his swansong, he chaired a forum on the European pharmaceutical sector in high summer in Brussels. The meeting was the final fling of the so-called G10 process of pharma policy planning — a 4 year high-level review of options that has in reality achieved practically nothing. 

Liikanen is going not because he has been fired — that hardly happens in the comfortable circles of senior EU policy making — but because he has been summoned back home to take over as chairman of his country's central bank. He only had 6 months to go anyway as Commissioner: all these senior jobs are up for grabs again, since a new Commission is due to take over from 1 November. 

But like water down the stream bed, the Commissioners come and go, and leave so little behind. The Liikanen-inspired G10 was intended to, in his own words, "establish consensus between key stakeholders on ways to improve the competitiveness of the pharmaceutical sector in Europe in a manner that was compatible with achieving our public health objectives." More simply put, it was a mechanism to bring pharma industry economics centre-stage in EU policy making, and to help make drug-pricing and reimbursement systems more realistic. 

This is where Liikanen's departure sets up resonances that echo down the long reaches of past decades. There have been some legendary predecessors in his post — a roll-call that includes the untiringly loquacious Martin Bangemann ("I always dreamed of being able to make speeches like Fidel Castro," he used to joke, and then go on to make speeches like Fidel Castro), or the somewhat waspish figure of Karl-Heinz Narjes (who never forgave the European pharma industry for jilting him after he offered support for its economic arguments, and the industry then declined to provide him with the supporting data). 

Each of them, in their own way, fought the same battle, to help keep the European pharmaceutical industry vigorous and vibrant, without precipitating violent reactions from the national governments that have always held the purse strings for health care. Each of them, in their own way, set up mechanisms to bridge the gulf between industrial and social security imperatives. And each of them, in their own way, failed to make any real headway. 

The industry still exists, of course. And it still makes money and provides jobs and new medicines. But it is hardly any longer a European pharma industry. Even the European Federation of Pharmaceutical Associations and Industries (EFPIA), the sector's principal lobby group, has long since abandoned its mission of defending a European pharmaceutical industry. In the face of the inevitable, it now seeks merely to promote pharmaceutical industry activity in Europe, irrespective of ultimate ownership. 

And even the level of activity, whatever the ownership, has consistently declined as a proportion of world pharmaceutical activity. The economic and regulatory constraints in Europe, and the perennial failure to establish a strongly entrepreneurial climate, have driven manufacturing and research away to more conducive locations. 

In 2002, EU-based pharma companies had an output of some 160 billion, 20 billion in R&D spend, and employment near 0.6 million, of which 90000 were engaged in R&D. But between 1990-2002, R&D investment in the US rose more than fivefold while in Europe it only grew by 2.5 times. In the 10 years from 1990, the major European research-based companies cut back the share of their worldwide R&D expenditure within EU territory from 73% to 59%. 

The US is now the leading inventor of new medicines, generating eight of the top ten worldwide products in 2002, compared with just two from Europe. And 70% of the sales of new medicines launched on the world market in 1998-2000 were made in the US compared with only 18% in Europe.  

The EU fiction about fixing the situation continues, however. The much-lamented decline in European pharmaceutical innovation is compensated for by the apparently limitless innovative capacity of bureaucrats to invent new forms of camouflage for their inability to intervene effectively in this protracted decline. 

The G10 is only the most recent example, after years of round tables, seminars and conferences, and task forces that also proved inadequate to the challenge. And what a miserable example it is. Even Liikanen himself, the progenitor of the process, could not find much to say about it when he summed up its achievements during its epilogue this summer. He claimed there had been "some national initiatives in the spirit of G10," offering the fact that "national medicines agencies have all agreed to participate in a benchmarking exercise on their regulatory activities." 			

For those who do not inhabit this strange world of invented terminology, and may not be aware what benchmarking is, or why it should amount to a breakthrough, it may be helpful to set out just what Liikanen said about it. "We set out a first set of competitiveness performance indicators. The objective of these indicators is to establish an EU-wide tool for measuring the impact of EU and national G10-related measures. The process has started and we are currently updating the indicators." Stirring stuff, indeed. 

And on the key question of pricing — "one of the most controversial areas in our G10 communication" — all he could claim was that "our objective is to reflect first on the necessary conditions and second on possible pricing mechanisms that would allow faster, wider and better secured access to medicines for all European patients without sacrificing any national control over health care budgets." How far has the reflection advanced? Wait for it: "Work has also begun in this area. A working group of stakeholders had its first meeting on 24 May. We will need to see what comes out of this process, but it is clear that, with many member states examining their own pricing procedures, this is a good time to examine this issue." 			

And this is the sum total of the years of high-level thinking — despite the fact that, on Liikanen's own admission, "the wide variety of national schemes is having a significant impact at the European level." Similarly, its extended review of the question of relative effectiveness of medicines, G10, and Liikanen, can report little more than broad agreement that there are benefits in examining, along with national governments, existing national relative effectiveness systems. "Last year, we established a working group that is currently analysing these systems to see what approaches there are," the outgoing Commissioner boasted. But the objectives are limited. "The aim is not to develop a European system of relative effectiveness and, indeed, we firmly believe that this must not become part of the authorization process. However, it must be in everyone's interest to ensure that, whatever systems member states choose to use, there is greater transparency, speed and consistency." 

				And this despite the fact that systems for measuring the effectiveness of medicines "have become an increasing feature of national systems," and that "these various national systems are having an important impact on competitiveness at a European level."				It is a disappointing outcome in light of the unambiguous conviction — with which "everyone agrees" — that the European-based pharmaceutical sector "plays a vital role in the life of the EU ... not just an economic contribution, although this is substantial, but also in social terms with the provision of high quality employment, support for our science base and, of course, to our public health objectives."				It is disgraceful in light of the rallying cry of the Commissioner that "our key objective is to tackle the relative decline in competitiveness of the European-based pharmaceutical industry when compared with its American-based competitors." The undisputed evidence is already on the table, and has been growing for years, that "as a whole, Europe is lagging behind in its ability to generate, organize, and sustain innovation processes that are increasingly expensive and organizationally complex" (as a key commission study concluded 3 years ago). And it is bordering on the dishonest alongside the Commissioner's clear statement that "For an area  that used to lead the world in pharmaceutical innovation this is unacceptable," and his recognition that "without investing in innovation now we will undermine the long-term future of the industry."				

Liikanen is not personally to blame for the failure — other, perhaps, than for the failure in honestly acknowledging that efforts so far have been a failure. The G10 deficiencies are just another stage in a continuum of conspiracy to pretend that effective action is being taken. As the Commissioner himself conceded, "Many of you will know that, given the history of unproductive  discussions in this area, this was a very challenging objective." 			

The problem lies in the divided responsibilities within the EU — with member states retaining most of the power for the price of medicines, which inevitably subverts or even vitiates the discussion at EU level of industrial policy. So little serious improvement can be expected no matter how often Liikanen (or his predecessors, or his successors) repeat mantras about a new future, such as Liikanen's assertion that "our long-held objective is to create a 'Standort Europa' where Europe, once again, becomes the favoured location for pharmaceutical research and innovation. We want to do this in a way that meets the specific challenges facing this sector while also tackling the risks of deindustrialization and delocalization." 

The Deputy Prime Minister of Ireland (which has chaired EU business in the first half of 2004) maintained the same fiction at the same meeting. Mary Harney, who is also Irish Minister for Enterprise, Trade and Employment, ritually intoned her "firm belief" in "the need to regularly reiterate and highlight the importance of the pharmaceutical sector to the European economy." She too noted that "the productivity gap  vis-Ã -vis the US is widening in the high tech areas," because of "Europe's comparatively poor performance in R&D and innovation." And she was under no illusions as to the principal cause: "The constraints that stifle economic growth and innovation do not come from outside, but rather from inside the EU economies themselves." 

But the recognition of the problem — and the identification of the solution — remained at a theoretical level. "Investment decisions of firms operating in a global market place are influenced by the economic climate that exists in the EU and in the member states," she said. So "Europe is not at the mercy of competition from lower-cost locations; it is very much the master of its own destiny." Her recipe, for which she claimed the backing of EU ministers responsible for industry, was clear and direct. "What is required is lighter regulation of industry and business, particularly for those sectors operating in a global market place where competition is intense, and we must be more supportive of innovation. Better regulation is crucially important for competitiveness." There are, she insisted, "compelling economic reasons for undertaking regulatory reform." 

Which is all very well. But if all the EU is able to do is to talk endlessly about the problem, rather than act, then the problem remains. And the G10 exercise demonstrates again that talk is the maximum output, obfuscating rather than clarifying what needs to be done. 

The new European Commission that will take up the reins of EU business in November faces many challenges. Prominent among them will be the urgent need to boost EU competitive capacity. It will be a step forward if the new chiefs of EU policy making abandon the pretence that benchmarking, innumerable working groups and long paragraphs of meaningless bureaucratese constitute a solution to the dilemma facing the pharmaceutical sector. For the pharmaceutical industry still being swept along in Europe's turbulent stream, it could be a matter of sink or swim. 

Column

In Europe ... the onward rush of time has imposed no change at all during the last 25 years. Anyone could step back in at any point, at any moment, and find the same depressingly familiar debates, interminably failing to reach any real conclusions.

Stepping Back into the River

Oral absorption efficiency can be influenced by several factors, acting independently or in concert. These include the physicochemical properties of the administered agent, human physiology, pathology (including disease state), the way the drug is presented (formulated) and possibly the amount that is administered (dose). Other influences include time of administration, whether the patient is resting or active and body position, for example, recumbent or standing. Optimizing absorption requires knowledge of how these variables affect the drug or formulation. However, it may take many years before such comprehensive knowledge can be gleaned on compound-specific behaviours. 

In the absence of such detailed insight it may necessary, particularly with novel therapeutic agents being dosed to humans for the first time, to design a formulation based on generic considerations of factors affecting absorption, the physicochemical properties of the agent being administered and 

 findings in animals or animal tissue. Such a strategy can help identify the optimum form of the drug and clarify possibilities and limitations for manipulating its properties to optimize delivery.  

Hence, good understanding of the physicochemical properties of the drug, and of the anatomy and physiology of the gastrointestinal (GI) tract provides valuable insight on the possibilities and constraints for optimizing oral absorption. 			

Some materials are absorbed by active transport across the intestinal barrier, but absorption by passive diffusion is probably far more prevalent.

  Regardless of the mode of transport, however, it is reasonable to conclude that, in the vast majority of cases the drug must be in the solvated state to diffuse into and across the enterocytes lining the intestinal lumen. Thus, solubility and rate of dissolution of the drug are of major importance and many approaches to absorption enhancement concern the optimization of these properties. 

Table I Aqueous solubilities of tetracycline and erythromycin derivatives. 			

Poorly soluble drugs present a major challenge in dosage form development. In simple terms, a material must be in solution if it is to pass from the intestine to the systemic system. At the same time, lipophilicity is frequently associated with higher activity, or receptor specificity and is invariably incorporated in molecular structures by the medicinal chemist. Low aqueous solubility (which is usually associated with high lipophilicity) and poor bioavailability are often a consequence of such molecular design. Improving absorption in such cases may mean using a form of the drug with optimum solubility, or employing a vehicle in which the compound is soluble. Optimizing solubility may entail using a more soluble salt or polymorph (if one exists), or even the amorphous form of a compound. Each approach has advantages and complications, and such options may not always be available, depending on the molecular composition and physical behaviours of the material under consideration. 			

 Agharkar found that the solubility of the free base form of the antimalarial, Î±-(2-piperidyl)-Î²-3, 6-bis(trifluoromethyl)-9-phenanthrenemethanol was 7 Î¼g/mL.

  The hydrochloride salt in contrast had solubility of approximately 30 Î¼g/mL whereas a value of 1800 Î¼g/mL was attained for the dl-lactate salt. Tetracycline and erythromycin salts also exhibit differing solubilities (Table I). Bastin 

 also found that some salts of the cardiovascular compound RPR127963 afforded significantly improved solubilites compared with the free base (Table II).

Enhanced solubility does not necessarily translate to better 

 absorption. There are several reports of salts with differing solubilities behaving no differently in bioavailability studies.

  Better solubility may simply be a pH effect that is neutralized in the gastric or intestinal milieu, with solubility changing to reflect local environmental pH. Conversely, it is also feasible that the pH engendered by a salt in its micro-environment facilitates dissolution. The salt acts as its own buffer so to speak. Once in the solvated state, the dynamics of transport or reprecipitation may be such that there is a net enhancement of amount dissolved and absorbed. 

Table II Aqueous solubilities of salts of RPR127963.			

The counter ion can be important for other reasons. Many drug substances are organic bases, and hydrochlorides are usually the first (sometimes only) salts considered when seeking a more soluble form. However, the presence of chloride ions in gastric acid may well depress solubility 

  Consequently, absorption may not be improved.  

  The hydrochloride and mesylate salts of two novel protein kinase inhibitors were more soluble than other salts, but when bioavailability in beagle dogs was evaluated the mesylate salts of both compounds had better bioavailabilities than the hydrochlorides (Figure 1). 			

This may have been because of better solubility of the mesylate salts (five times more soluble than hydrochloride), but a common ion effect with the hydrochloride salts cannot be ruled out. Interestingly, these authors established (from a review of recently approved compounds) that mesylate salts are now being more widely used. It would be of interest if such increasing popularity was a result of better 

Table III Bioavailability of tolbutamide polymorphs in dogs.*

The potential for absorption enhancement by salts could be usefully explored in small animal 

 studies, particularly in cases where human studies are not possible or appropriate; for example, at the compound selection stage in drug discovery programmes. Animal studies, while not necessarily predicting absorption efficiency in humans may provide useful rank order ratings on the effects of different salts. 			

 Medicinal compounds may exist in a variety of crystal forms that can have differing aqueous solubilities. Riboflavin has three polymorphs with solubilities varying from 0.06-1.2 mg/mL

  Bioavailability of various morphic forms of cimetidine was shown to correlate with dissolution rates suggesting that solubility might be important for oral absorption.

 obtained differing plasma levels in dogs when dosed with different polymorphs of the poorly soluble hypoglycaemic agent tolbutamide (Table III).

 differences in dissolution rates and solubilities between the forms. 			

Polymorphs with the lowest free energy (lowest solubility) are usually most stable in thermodynamic terms; more soluble forms tend to transform to the low energy state. Such transformation can occur during storage, processing or even during dissolution.

  This makes polymorph selection for solubility enhancement an uncertain process. The more soluble form might become less soluble with time because of reversion to the more thermodynamically stable form, with absorption being compromised as a consequence. It is important, therefore, that any promising crystal form is thoroughly assessed to confirm that: 					

It can be prepared consistently by a realistic and reliable process.

The preferred form can be readily identified by a technique suitable for routine quality control.

It does not transform to a less useful form on storage, during processing or after incorporation in the dosage form.

It does not transform to the less soluble state after ingestion but prior to absorption; that is, in the GI tract environment. 

Figure 1 Mean plasma concentrations of LY333531 and LY338522 in male beagle dogs orally administered with LY333531ÃÂ·HCl and LY333531 mesylate (20 mg LY333531/kg).*						

Modest improvements in solubility or dissolution rate may be of little benefit 

 claimed that slight differences in solubility and dissolution rate of the anhydrous and trihydrate forms of the antibacterial ampicillin lead to differences in oral bioavailability in dogs and humans.

  However, a later study using unformulated drug showed that both forms were bioequivalent, suggesting that the results from the Poole study might be ascribable to formulation differences.

  The work by Aguiar and Zelmer provides further elucidation on solubility differences. They showed, using polymorphs of mefenamic acid and chloramphenicol, that when free energy differences (reflecting solubility values across a range of temperatures) were modest, bioavailability differences would not be expected. When differences are large they can affect absorption.

Amorphous materials can be more soluble and have faster dissolution rates than crystalline forms because of lower solvation energy. Amorphous novobiocin dissolves rapidly and is well absorbed in humans. The crystalline form, by contrast, is less soluble, has slower dissolution rates, and exhibits poor and erratic bioavailability.

Amorphous materials have the same potential disadvantages as polymorphs or pseudopolymorphs in that they may transform to the less soluble crystalline state. The molecular mobility (and associated tendency to transform) of an a morphous solid is a function of the differential between storage temperature and its glass transition temperature (T

). It has been claimed that storage at temperatures of 50 Â°C below T

 for most amorphous solids should be greater than 75-80 Â°C if they are to remain stable in the morphic sense at ambient storage. Excipients with a much higher T

 can sometimes be added to stabilize a drug in the amorphous state. For instance, polyvinylpyrrolidone (PVP) (T

 of 280 Â°C) inhibits the crystallization of  indomethacin.

Table IV Organic solvents used in parenteral formulations.*			

Crystallization is the preferred technique of the organic chemist for isolation in a pure state, and provides a consistent physical form. Isolation may be more difficult if an amorphous form is preferred. "Upstream" purification, or reprecipitation following original isolation in the crystalline state may be necessary. This will add to cost and complexity.  			

Whereas it may be advantageous from an absorption perspective to select a particular salt, polymorph or material in some other physical state, other selection criteria must not be ignored. With respect to counter ions in salts, the potassium ion can be a GI irritant unless the dose is low. Other cations, such as magnesium or calcium, can influence GI tract motility and affect absorption where GI tract residence time is important. However, the dose of counter ions may be too low in most cases to evince undesirable effects.  

Different salts might also contain different residual impurities because of solubility, partitioning or crystallization effects during isolation, or different impurities in the reagent providing the desired counter ion. A preferred salt may not be stable or optimal for processing to product because of moisture sorption, flow or compaction properties, or other such pharmaceutical behaviours. In the examples given in Table II, the sulfate salt was chosen because solubility was adequate and the physical characteristics were better than for the more soluble mesylate salt. The selection of a preferred form has to be a multidisciplinary exercise, ensuring that advantages for one facet of the programme are not negatived by introducing other problems. 

Figure 2 Dissolution profiles of itraconazole forms in 0.1N HCl at 25ÃÂ°C. *			

Use of the crystalline form of a drug can be advantageous from purity, stability and processing perspectives. Thus, methods of retaining crystallinity whilst enhancing solubility and bioavailability may be worth considering. The recent upsurge of interest in cocrystal formation reflects this. Properties such as solubility can be influenced by crystal packing and this in turn can be influenced by the crystalline alignment of drug molecules with structurally complementary structures.  

Hydrogen bond donors can, therefore, be aligned with hydrogen acceptors. In this context it appears that drug molecules with appropriate amide groups can align, in the crystallographic sense, with 1,4-dicarboxylic acids such as citric and tartaric acids, which are suitable materials, from a safety perspective.

  The poorly soluble/poorly bioavailable antifungal itraconazole had comparable dissolution profiles with the amorphous, optimally bioenhanced commercial product when presented in cocrystal forms with the L forms of malic and tartaric acids (Figure 2).

  Such crystal engineering technology is potentially very promising for poorly soluble drugs.  

 If a compound is ionizable it may be possible to increase solubility by adjusting pH. Compounds with pKa/b values between 3-11, namely weak acids and bases, may have solubility enhanced  in this way.

  If a drug is poorly soluble at low pH, it is conceivable that co-administration or coformulation with an acid-neutralizing material provides a gastric environment more conducive to better solubility and dissolution rate. Elevation of gastric pH could also reduce presystemic degradation of acid labile compounds, leaving more available for absorption.

Table V Bioavailability of SCH 56952 (azole antifungal).*

Magnesium and calcium carbonate can be used as compression aids in tablet formulations. It is feasible that their acid-neutralizing effects could be capitalized on to enhance absorption of acid labile compounds or those with poor solubility at normal gastric pH. Some antacids have also been shown to increase the rate of passage from the stomach to the small intestine, consequent to elevating gastric pH.

  This can have theoretical benefit, not only for acid-unstable drugs or acid-insoluble drugs, but also where increased rate of absorption can have therapeutic benefit.  

Such possibilities must be carefully considered, however. Any effect is likely to be related to the amount of material utilized. Inadequate quantities may lead to marginal or no benefit; conversely, excessive amounts might stimulate acid rebound. Physiological effects may also play a part. Magnesium carbonate has laxative properties; by contrast calcium carbonate is a known constipating agent. Such effects on GI tract motility could complicate absorption processes. Antacids may also act as adsorbents, making less drug available for dissolution and adsorption.

Absorption enhancement approaches based on altering pH may be difficult to study preclinically in animal models. Differences in gastric volumes, acidity and physiology are likely to complicate responses. There may be no alternative but to explore possibilities in human Phase I studies.  

The least complex way to present a material to the GI tract for absorption is to administer in solution, thereby removing any dissolution stage. Occasionally, non-aqueous (organic) solvents are used to solubilize drugs for parenteral use. Use in oral products is constrained and complicated by many factors. They may not exert sufficient solubilizing action to be of practical value unless the dose of drug is low. Otherwise the volume of vehicle required cannot be readily contained in a convenient dose unit. Liquid-filled gelatin capsules offer possibilities for compounds when the drug dose is approximately 40-60 mg, but only a limited number of non-aqueous solvents can be employed for such presentations.  

Some synthetic aluminosilicates or silicates can absorb significant amounts (up to and exceeding an equal mass) of certain organic solvents whilst retaining the properties of a solid. Drug dissolved in the organic solvent and then absorbed on the silica provides a form that can be filled into capsules and even compressed to tablets.

  The drug is thus "in solution," but can be formulated as a solid dosage form. This approach requires that the drug has high solubility (and good stability) in the chosen organic solvent, and that the silicate in turn has high absorption capability for the solvent. These requirements restrict the applicability to potent medicinal agents (dose not greater than 10-20 mg) that have high solubility suitable of organic solvents. 

Organic solvents can have long-term effects on GI mucosa if the medication is for chronic use, even if levels employed comply with International Conference on Harmonization (ICH) guidelines. It is also possible that precipitation of drug from solution may follow administration, when the material encounters the aqueous environments in the GI tract. Thus, there may be little or no absorption enhancement. Table IV outlines solvents used in commercial parenteral formulations, which with the above caveats might also be considered for oral delivery.

Table VI Pharmacokinetics of unmilled and nanoparticle naproxen in rats.*

Cyclodextrins can provide a novel way to get small-molecule drugs in a molecular dispersion. These cyclic glucose polymers have hydrophilic "outer surfaces" and hydrophobic interior cavities that can accommodate molecules of mass between 400-500 (Figure 3). 

If interactions between drug and the pendant groups within the cavity are strong, a stable molar complex is formed. The compound "hides" in the cavity and the complex assumes the solubility of the cyclodextrin. Dissociation of the complex "releases" the drug in the molecular state.  

Table V summarizes bioavailability data, expressed as "area under curve" (AUC) for an azole antifungal drug dosed to animals, either parenterally or orally, as a hydroxypropyl cyclodextrin complex or as a dispersion in aqueous methylcellulose.

  The cyclodextrin complex afforded better absorption than the conventional suspension in all cases, but the differentials varied with animal species. Data from mice and monkeys suggest that absorption is significantly enhanced whereas improvement was more modest in the dog and rat. Such findings exemplify the uncertainties of accurately predicting absorption in humans using animal models. 

The original (alpha, beta and gamma) cyclodextrins have limited application for solubility enhancement because they themselves are not particularly soluble, thereby limiting the overall dose that can be contained in a conventional unit such as a tablet or capsule. Derivatized cyclodextrins such as the hydroxypropyl or sulfobutyl ether forms are much more soluble. Some have been subjected to comprehensive safety screening and do not seem to have undesirable features such as nephrotoxicity or propensity to cause erythrocyte hemolysis that were associated with earlier cyclodextrins. The sulfobutyl form in particular has excellent solubility; (ca 50 g/100 mL), so can "carry" a lot of drug.

Figure 4 The effects of different solubility and dissolution rate enhancement approaches on absorption.

For a particular cyclodextrin to be suitable for absorption enhancement it must not only accommodate the drug in "molecular dispersion" form to enhance solubility, but must also "release" the drug by complex dissociation in the GI tract. Too stable a complex can be problematical. Trapani showed that when cyclodextrin complexes of the hypnotic zolpidem were dosed to rats the induction period for ataxia was prolonged compared with controls. The effect was ascribed to complex dissociation being rate limiting to absorption.

  Complex formation can, therefore, possibly affect pharmacokinetics and compromise absorption if the complex is too stable. In effect, cyclodextrins, like all other approaches do not always solve solubility-related problems. 

In summary, a number of strategies can be considered for solubility enhancement where this is necessary. The conundrum for the pharmaceutical technologist concerns whether such approaches are warranted. There is fairly general agreement that when aqueous solubility at physiologically relevant pH is less than 1-5 mg/mL at 37 Â°C there is potential for solubility and dissolution-related absorption problems.

  By inference, steps to improve solubility might seem warranted when solubility is lower than this. However, factors such as site-specific absorption, elimination half-life and even dose may also be important. Additionally, it is likely that modest solubility increases may effect little or no improvement, particularly where solubility is very low. Each case must be judged on its merits and studied accordingly.  

This article reviews various physicochemical approaches that may be employed to enhance absorption following oral administration of solid dosage forms in humans. This article also examines strategies based on capitalizing or neutralizing physiological processes.

Physicochemical Approaches to Enhancing Oral Absorption

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.

Pharmaceutical Technology Europe-09-01-2004

Intelligent Inspectors

Is There Such a Thing as a Best-in-Class Lab? Benchmarking of QC Operations

Stepping Back into the River

Physicochemical Approaches to Enhancing Oral Absorption

Smart Skin Patches