The pharmaceutical industry faces increasingly intense economic pressure. Not only are new chemical entity (NCE) submissions to regulatory bodies at a 20-year low, but the demands for yet more stringent regulation — alongside the continuing squeeze on revenues as patents expire and generic formulations appear on the market — present significant challenges. 

Manufacturers are responding in a number of ways with two clear objectives emerging: the need to reduce production costs and the time it takes to get the product to market. In the past, pharmaceutical manufacturers have to some extent escaped the strong pressure on variable costs faced by other industries, such as bulk chemical producers. As a result there has not been the need to focus on process efficiency to the same degree. 

Patent protection coupled with the rigours of process validation, which has made the introduction of new technologies during scale-up unattractive, has resulted in processes that generate the required material, but not necessarily in the most cost-effective way. The need to change this situation is now being recognized. One clear sign is FDA's process analytical technology (PAT) initiative, which is designed to encourage pharmaceutical manufacturers to embrace new analytical technologies to monitor and control their processes more closely. It is hoped that this approach will reduce risk and enhance process efficiency. 

Development and optimization of a product and its manufacturing process are iterative rather than linear procedures. An approach in which the product and process are developed in tandem will lead to optimized production much more rapidly. 

However, this type of development relies on gathering process-relevant information at a relatively early stage. There is, therefore, a need for analytical systems that can deliver this data in a cost-effective manner using only small amounts of material. In this article we discuss the use of powder rheometers in this context.  

Powder behaviour is complex and not fully rationalized in terms of basic particle properties. It is tempting to think of powder systems as being single phase, but two-phase is a more accurate description because air content is such a significant variable. A stable tablet after all is simply a free-flowing powder mixture that has been pressed to exclude air and encourage cohesion.  

Powder properties are related to physical properties such as particle size and shape, but other factors are also significant. Aeration or consolidation, the uptake of moisture, segregation and attrition, can all occur during processing, transforming the way that the powder behaves. 

 The powder processor's expertise lies in manipulating variables to achieve the required result, but this can be a trial and error process in the absence of analytical data that can accurately reflect processing performance. 

Traditionally, process development has relied heavily on the experience of key personnel. In addition, processes have been run under manual control with operators developing a 'feel' for the material and plant — pragmatic solutions based on pulling certain levers to solve certain problems. 

To move away from this approach to one more firmly rooted in technical understanding, intuition and experience must be translated into measurable variables that can be correlated with process performance. If this can be achieved, then the efficiency of both process development and operation can be improved substantially.  

In almost all pharmaceutical products either the active pharmaceutical ingredient (API) or excipients will be handled in solid form at some point, and, therefore, effective powder processing lies at the heart of optimized pharmaceutical production. 

In terms of unit operations, core activities include reaction, homogenization/micronization, blending, drying, granulation, pressing and coating. Batch production is the norm, primarily because of the need for stringent quality control (QC). 

"When designing new processes or deciding whether a new product will process well in existing equipment, what powder property information will be valuable?" 

With blending, the aim is to efficiently produce a fully homogeneous mix. Demands on blending processes are increasing as the trend towards lower doses of more active APIs continues. A commonly encountered problem is that blending equipment that works well for a certain set of powders may not perform adequately for others. 

In this case assessing the way that materials flow and the sensitivity of flow behaviour to different variables can help developers to match material characteristics with processing equipment capability. 

If the characteristics of powders that blend well can be quantified then materials with very similar flow properties can be developed, and confidence that they will process relatively easily will be high. 

Drying is also a common unit operation, but it is often relatively poorly controlled. Knowing the sensitivity of a material to moisture will allow assessment of the likely impact of varying water content on downstream processes, such as tabletting; here excessive moisture can exacerbate the problem of picking, whereby material adheres to the machine resulting in an imperfect tablet.

  The effect of water content on sample rheology is also relevant in the development of successful wet granulation processes. Granulation is often used to improve the flow properties of a material, for handling and/or downstream processing reasons. If the properties of a granulate can be correlated with water content and blend time on the one hand, and subsequent processability on the other, then optimization of the granulation process, successful end-point detection and scale-up become much more straight forward.  

The properties of all powders are extremely sensitive to air content and materials differ significantly in terms of the way in which they both entrain and release air. Quantification of the impact of air on the properties of a given sample is, therefore, valuable for powder processors, particularly for specific unit operations. For example, in a tabletting mix air facilitates free flow of the material into the die, but if this air is not released quickly then it will be compressed along with the powder. 

If this happens the resulting tablet may laminate or split as the trapped air is released upon removal of the compression pressure. Measuring the ability of a material to deaerate allows prediction of this important aspect of tabletting performance. Aeration effects are also responsible for other widely observed processing phenomena, such as flooding of a feeder.  

It is easy to recognize that some unit operations, for example, those using fluidized beds, clearly involve aeration. The critical point that is less well-understood is that even when aeration is not a specified part of the process it can occur all too easily.  

Powders mix with air as they are discharged from hoppers or during pneumatic conveying and tend to deaerate whenever they are stationary. The dependence of powder properties on air content is, therefore, an aspect of powder behaviour that must be considered carefully by all powder processors. 

These simple examples underscore the link between the properties of a proposed formulation and aspects of process design and operation. It is clear that data collected at an early stage, which provide understanding of the basic properties of the material, can help formulators steer away from a poor product, and guide process engineers to focus on their design efforts.  

Angle of repose, flow through a funnel or aperture and bulk density measurement methods, such as Carr and Hausner, are all established techniques for assessing the properties of powders.  

Each provides some insight into a certain aspect of powder behaviour. The percentage compressibility function developed by Carr, for example, which is based upon measurement of the change in volume induced by repeated tapping, differentiates well between cohesive and free-flowing powders.  

Shear testing, as initially developed in the 1960s by Jenike, is also used widely for the characterization of various aspects of, primarily, cohesive powders, such as cohesion and compression strength. There is a well-developed design methodology based on these parameters for hoppers and bins, and the information gained using this technique continues to expand with the development of modern instruments that allow determination of the shear strength of unconsolidated powders as well as preconsolidated powders. 

Powder rheometers are a much more recent development designed to quantify how powders flow in ways that more closely relate to their behaviour in real processes. They describe the dynamic flow properties of powders in terms of the energy needed to cause flow. 

Powders are tested dynamically by measuring the force and torque required to rotate a blade through the sample in a specific manner. Rotating the blade downwards through the sample produces a bulldozing action along the blade length, whereas upward movement induces shear with minimum consolidation. 

These regimes deliver different, complementary sets of rheological data. In the absence of a unit of dynamic flowability the behaviour observed is described in terms of the energy needed to maintain the prescribed flow pattern, which is calculated from the force and torque measurements.  

A key feature of powder rheometers is that a sample can be conditioned prior to measurement and gently moved to ensure that the sample bed is laid down for testing in a repeatable way. This conditioning step eliminates a significant source of variability associated with other measurement techniques and ensures high repeatability. 

Differences in measurements made using a powder rheometer are a function of real powder properties not powder history. Furthermore, the dynamic measurement methodology involved is highly differentiating. These two properties combine to make powder rheometers particularly sensitive to small differences in flow properties. 

Universal powder testers that can measure the bulk, shear and dynamic flow properties of powders for a full range of packing conditions have evolved from the first powder rheometers. The original concept of measuring the energy needed to cause powder flow has been extended to include automated assessments for all flow regimes — consolidated, conditioned (unstressed) and aerated or fluidized powders as well as bulk density, compressibility and permeability measurement, and shear cell modules to determine shear strength properties.  

To illustrate the relevance of powder property testing, samples of four different types of lactose, a commonly used excipient, were investigated using a universal powder tester (as described before) to determine bulk and flow properties using both the dynamic and shear methodologies.  

The bulk powder properties of compressibility and permeability were measured and the adhesive properties of the materials were assessed, by measuring the amount of material adhering to the blade following dynamic tests. Four types of lactose were used: spray-dried, sieved, coarsely and finely milled. Particle size and shape data for the samples are shown in Table 1.  

The much higher compressibility of the finely milled lactose is a clear indication of its higher cohesivity and this is reinforced by the adhesion data, which show that this powder is, by a significant margin, the most adhesive of the materials tested. Both characteristics are important and in the case of finely milled lactose, the high values indicate that difficulties should be expected during processing 

Figure 1 shows yield locus data, measured in the shear tests, for each of the samples. The finely milled lactose exhibits higher shear strength than the other materials, which have larger particles and tend to flow more freely. The spray-dried lactose has the lowest value of all, probably as a result of its spherical shaped particles.  

Figure 1 Yield strength loci for varying normal stress levels for powders previously preconsolidated to 9 kPa stress.			

For the finely milled lactose it was possible to extrapolate the yield loci and use a Mohr's circle analysis to derive the unconfined yield strength, maximum principal stress and flowability. This analysis was not possible with any accuracy for the less cohesive materials as their extrapolated yield loci were close to passing through zero.  

Flow energy measurements for the different lactose samples determined using dynamic tests are presented in Figure 2.  

Figure 2 Dynamic flow energy measurements for seven identical tests followed by four tests at reducing blade speed.			

Repeatability is good, highlighting the stable rheology of the samples. A wide range of flow energies is measured reflecting the rheological differences between the types of lactose; marked differentiation between materials is evident. 

Any method of comparing flow properties would show differences between the cohesive, finely milled lactose and the other three coarse grained powders. However, this specific ability to differentiate between very similar powders is most important to the powder processor, especially when faced with issues of batch-to-batch variability. 

Interestingly, the finely milled lactose is associated with the lowest flow energy even though it has the highest shear strength. The compressibility, permeability and adhesion data for the samples shown in Table 1 helps interpretation of the flow energy measurements. Cohesive powders such as the finely milled lactose tend to contain relatively large amounts of air and are far more easily compressed. As a result the flow zone of material — the numbers of particles moving at any instant as the blade rotates and, therefore, the energy required to maintain flow — tends to be relatively small. In contrast, for noncohesive materials relatively large amounts of the sample are moved simultaneously as the blade is rotated and a higher flow energy is seen. These results highlight the dependency of flow energy measurements on a range of factors, not only shear strength, but also cohesion, compressibility and physical properties.  

Table 1 Properties of lactose samples.			

Changes in flow energy induced by aeration are evident from Figure 3. It is clear that aeration has a much more significant impact on the flowability of the coarser lactose samples than on the finely milled material. The coarsely milled and sieved lactose in particular show a rapid rate of flow energy reduction even at relatively low air flow rates because of separation of their large, angular particles.  

Articles

Formulation

The trend towards developing pharmaceutical products and their manufacturing processes in tandem supports optimized production. Such developments rely on gathering process-relevant information at an early stage and being able to draw on past and current processing experience. Here, we discuss how powder rheometers can make a real difference in building a database of powder properties and removing subjectivity.

Understanding powder behaviour by measurig bulk, flow and shear properties

Clean rooms are critical areas in bio/pharma facilities, and it is essential that users are responsible for their care and upkeep, and familiarize themselves with the relevant regulations. 

Clean rooms make aseptic processing possible. FDA prefers parenterals to be terminally sterilized, but when that is not possible without affecting the product, the agency allows aseptic processing 

 of terminal sterilization. When a medical product is ingested, any live organisms in the drug may die before reaching the bloodstream because of the body's defence mechanisms, such as saliva and stomach acid. 

Parenterals, however, bypass some of these mechanisms and must, therefore, be manufactured under cleaner conditions. Airborne particles need to be controlled to reduce the possibility of contaminant particles entering the medicinal product and ultimately, the patient. Reducing the number of airborne particles in a clean room decreases the possibility of larger particles carrying bacteria and viruses. 

ISO 14644–1 (which defines clean rooms) and ISO 14644–2 (which specifies requirements to prove compliance with ISO 14644–1) have been in force for many years.

  European countries have incorporated these standards, whilst in the US, ISO 14644–1 and ISO 14644–2 replaced Federal Standard 209.

Section 2.1.1 of ISO 14644–1 defines a clean room as "a room in which the concentration of airborne particles is controlled, and which is constructed and used in a manner to minimize the introduction, generation and retention of particles inside the room, and in which other relevant parameters, for example, temperature, humidity, and pressure, are controlled as necessary". Table 1 shows the relationship between ISO 14644–1 definitions of a clean room, and FDA and European Commission (EC) requirements for facilities that use aseptic processing. Before ISO 14644–1 was adopted, clean rooms were defined in the US in simple terms such as a class 100 clean room. 

Section 3.3 of ISO 14644–1 states that the clean room designation should be based on three parameters:			

classification number expressed as an ISO class 

 particle sizes and their related concentration. 

For example, the proper definition of what was once a class 100 clean room is now ISO class 5; operational state; particle size 0.5 μm; 3520 particles/m

Although ISO 14644–1 defines clean rooms for various particle sizes ranging from 0.1–5.0 μm, in bio/pharma facilities, we are mostly concerned with particles greater than 0.5 μm. Bacteria are not usually found in the air as unicellular organisms, they are normally carried on materials such as skin particles, with an average size in the air of 10–15 μm. Small inanimate particles have a low deposition rate and little chance of entering containers from the air in sufficient numbers to be a problem.

  Standard ISO 14644–1 classifies  clean rooms only in terms of "particles per cubic meter" without differentiating between viable and non-viable particle count. US and EC GMPs is where the acceptable number of viable particles per cubic meter may be found. 

Guideline on Sterile Drug Products Produced by Aseptic Processing

 was the original document that defined clean rooms.

  It defined only two types of clean rooms — critical (class 100) areas where sterilized items are handled and controlled (class 100000) areas where unsterilized items are handled. 

 Table 1 Environmental requirements for sterile medicinal products.			

This guide was replaced in September 2004, with the new guideline containing some notable additions:

 Sterile drugs should be manufactured using aseptic processing only when terminal sterilization is not feasible.

 The classification rates clean rooms in particles/m

  and states their ISO class number. It also adds viable particle counts using microbiological settling plates in addition to the original air sampling method. 

 "Controlled" classification has been replaced by "supporting clean areas" for areas handling unsterilized items. Under this definition, class 1000 and class 10000 as well as the previously mentioned class 100000 areas have been added. 

 An air flow rate of 20 air changes per hour (AC/h) is still expected for class 100000 (ISO 8) clean rooms, but the rate is not specified for class 1000 or class 100000 clean rooms. 

 Poly-alpha-olefin (PAO) was used as an alternate aerosol to dioctylphthalate (DOP) for filter integrity testing of high-efficiency absorbency (HEPA) filters. 

 Filter scanning for HEPA filter leak testing should be conducted at a position about 2 in. (50 mm) from the face of the filter. 

 For HEPA filters in the critical (sterile) area, the air velocity is measured 6 in. (150 mm) from the filter face or at a defined distance close to the work surface. 

 The particle count during filling/closing operations is still taken no more than 305 mm away from the worksite, within the air flow. 

 Written standard operating procedures (SOPs) for microbiological environmental monitoring should address elements such as alert and action levels. 

 Blow-fill-seal applications should be performed in class 100000 (ISO 8) rooms or cleaner, and that the critical zone should meet class 100 (ISO 5) particulate and microbiological standards. 

 Procedures for aseptic connections, which expose a product or product contact surfaces, should be performed under unidirectional airflow in a class 100 (ISO 5) environment, in a class 10000 (ISO 7) or better room. 

 States that drains are considered inappropriate for classified areas of the aseptic processing facility, other than Class 100000 (ISO 8) areas. 

 Pressure differential between rooms of different classes should be 10–15 Pa, and 12.5 Pa between a classified and nonclassified room.  

Annex 1 of the EC good manufacturing practice (GMP) guide

 defines clean rooms in terms of grades (namely grades A–D). Annex 1 also addresses two particle sizes (0.5 and 5.0 μm) and two occupancy states (operational and 'at-rest') and says: "The particulate conditions for the 'at rest' state should be achieved in the unmanned state after a short clean-up period of 15–20 minutes". A room may have two ISO class numbers depending on the room's occupancy state. 

Figure 1 The main components of an air handing unit (AHU).			

For example, a grade B room is equivalent to ISO class 7 (352000 particles, size 0.5 μm/m

 ) in its operational state and ISO class 5 (3520 particles, size 0.5 μm/m

Annex 1 was updated in 2003, which contains some additions worth noting:

The 'in operation' and 'at rest' states should be defined for each clean room or suite of clean rooms. 

  or larger for grade A zones, both 'at-rest' and in operation, as well as for a grade B zone 'at-rest'. 

 The air velocity for a grade A area from 0.45 m/s ± 20% was replaced by a range of 0.36–0.54 m/s at the working position in open clean room applications. 

 References to the old US Federal Standard 209 were removed. 

 Terminal (ceiling) HEPAs should be provided for Grades A, B and C. This is very important because before this EC Guideline update, HEPAs for Grade C could have been located inside the AHU, but not any more. This now makes Grade C rooms more expensive to build.  

Classifying an entire facility class A (ISO 5) would ensure product purity, but doing so is unnecessary and too expensive. Table 2, which shows recent trends in the biotech industry, relate clean room classifications to various manufacturing operations, based on an operational state (when the product is actually being manufactured). 

Some of these classifications are fixed (e.g., for ISO class 5, grade A is required where sterilized items are exposed to room air), while others may vary depending on the contamination risk assessment by manufacturers. For example, downstream purification is sometimes performed in grade B clean rooms while at other times grade C suffices. The potential of product contamination is reduced by minimizing the number of particles in the clean room. 

Table 2 Air classification for various bio/pharma aseptic manufacturing steps and rooms.			

This reduction is the first step in cleaning the supply air. However, outside air is required to satisfy personnel ventilation, room exhaust-air requirements and for positive air pressurization. A cubic foot of untreated outside air in an average industrial area could contain as many as 1200000 particles of size 0.5 μm and larger. 

The maximum allowable particle counts in clean rooms varies from 100–100000 particles/ft

 though clean rooms have a number of systems (including air handling units [AHUs] and HEPA filters) to ensure the air supplied will be cleaner than required.

Another potential external source of contamination is the AHU and the ductwork distributing the conditioned air (Figure 1). Typical AHU construction includes aluminium interior panels with welded joints at the floor; cooling coils with stainless steel coil frames (that prevent rust); easy-to-clean direct-drive plenum fans (to eliminate the possibility of particles from fan belts entering the air stream); an access section between each AHU component (filter, fans, coils); and a covered floor drain at each access section. 

Clean Rooms

Clean rooms are critical areas in bio/pharma facilities, and it is essential that users are responsible for their care and upkeep, and familiarize themselves with the relevant regulations.

Keeping clean rooms compliant

Firms using biotechnology to manufacture medicines are embracing process analytical technology (PAT) at an ever-quickening pace as part of their quality by design (QBD) initiatives. 

They are often faced with complex and fragile processes lasting many hours or days, and are looking towards PAT as a means of not only understanding the fundamentals of their processes, but also to offer more incisive process monitoring technologies, control and optimization strategies.  

Commercial payback comes from both R&D — from being able to get more robust processes to market quicker — and from manufacturing — by being able to mitigate process risk, batch-on-batch, as well as through process optimization, which improves subprocess and final product yields. 

This article will describe how aspects of PAT are applied to a fundamental process stream in biotechnology manufacturing — fermentation. 

Biological processes often have high variation levels, making the development of a robust and reliable process inherently difficult. Couple this with the high intrinsic value of the end product, and a biotech firm has to bear a degree of risk during its manufacturing process that is unseen in other parts of pharmaceutical manufacturing. Mitigating this manufacturing risk has been a biotech goal for many years, and current approaches correlate with the principles QBD and PAT: 					

To identify critical quality attributes (CQAs) of the product and their acceptability limits.

To identify the sources that lead to the variability in the CQAs.

To identify the factors within the process that can be adjusted to control the variation in the CQAs.

To determine a control strategy to ensure that the CQAs are held within predetermined limits during the manufacture and lifetime of the product.

A typical fermentation-based biotech process flow is shown in Figure 1. From an economic and quality risk perspective, the critical parts of this process are the production of the active agent through the fermentation step, the recovery of the active agent in the purification step, and the stabilizing of the finished product prior to shipment during the freeze drying/lyophilization step.  

Figure 1 A typical fermentation-based biotech process flow.			

QBD and PAT efforts are being put into this process, not only to aid understanding, but to control the critical steps and go on to optimize the subprocess yields from the fermentation, purification and lyophilization steps. 

Understanding and monitoring what is happening during the fermentation process is vital to ensure the healthy progression of the culture, as its health determines the conversion rate of nutrients to product, the formation of unwanted by-products, and in extreme cases, the onset of poisoning. Growth kinetics and substrate consumption are key indicators of the progress. 

Process mass spectrometers (MS) and process FT-NIR spectrometers are widely used as the measurement technology components in these monitoring, control and optimization systems.  

Figure 2 illustrates a biotech fermentor with a process MS and process FT-NIR attached. Each technique monitors different aspects of the process as it progresses.  

Figure 2 A biotech fermentor with a process MS and process FT-NIR attached. Each technique can be used to monitor different aspects of the process as it progresses.			

The MS allows for highly sensitive and precise measurements of the components of the gas streams into and out of the fermentor. Analysis of the respiratory gases being fed to and removed from the fermentor is an ideal means of characterizing the fermentation state. A key indicator of the fermentation progression is the respiratory quotient (RQ). Respiration is the process by which an organism oxidizes food to produce energy. The RQ is the ratio of the carbon dioxide evolution rate (CER) to the oxygen uptake rate (OUR).  

Many fermentations are characterized by small changes in oxygen and carbon dioxide concentrations at critical phases of the fermentation. Therefore, the process MS (with ability to simultaneously measure multiple gas components, and use other components such as nitrogen and argon in the gas stream as reference gases) can very rapidly calculate this rate and feed it into a process control strategy to intervene, keeping the fermentation on track.  

When equipped with a sample stream multiplexer, a single process MS can be attached to multiple fermentation vessels, offering a high degree of operating and economic efficiency. 

Figure 3 shows the process MS generated trace of RQ versus fermentation time. Here, the RQ value falling below a predetermined level is used to trigger the addition of nutrients into the fermentor to keep the fermentation at an optimum state.  

Figure 3 Fermentation control: nutrient addition triggered from process MS data.			

Making direct measurements of fermentation components within the fermentor itself allows additional information to be obtained on the progress and state of the fermentation.  

Here, FT-NIR using a fibre optic probe immersed in the bulk of the fermentor liquor is used. The components measured by the FT-NIR vary by fermentation type, but can include: 					

Making measurements directly in a fermentation liquor can be inherently difficult because of the changing chemical and physical properties of the medium during the process. For example, as biomass is produced during a process, the liquor may go from being a relatively clear liquid to a turbid liquid with a high degree of suspended solids; this can confound the measurements of the critical components.  

Where transmission spectroscopy would work well at the beginning of this process, it is likely that reflectance spectroscopy would be the best technique to use as the medium turbidity increases.  

The latest generation of multipurpose fibre optic probes with both transmission and reflectance optics can be linked to a spectrometer with multiplexed measurement channels. This allows the system to be controlled through adaptive software work flows and can easily track these physical changes automatically. This enables the system to work at the optimum sampling regime for the most accurate and precise component concentration; ideal for automated process measurement and linking to a process control system. 

Figure 4 shows the data from using an FT-NIR to determine the concentration of a product during the fermentation process cycle.  

Figure 4 Monitoring fermentation product concentration using a process FT-NIR spectrometer.			

A fermentation stage with process MS and FT-NIR capturing large quantities of chemical component data coupled with classical process parameters such as temperature, pH, stir speed and gas rates being logged elsewhere, is ideal for investigating with multivariate data analysis tools. Currently, work is being conducted on this rich data pool and process fingerprints, multiplicative statistical process control, 'biological time' and model predictive control approaches are developing for use in control and optimization strategies.  

Although the processes involved in biotechnology manufacturing differ significantly from those of small molecule medicines, the underlying principles of QBD and PAT are being applied enthusiastically.  

The nature of biotechnology subprocesses allows control strategies to be extended into optimization strategies, and create sound economic value for firms.  

We can expect to see more of this pragmatic application of PAT in this part of the pharma industry, as measurement and control technologies develop, and are applied to other sections of the process, especially those downstream of the fermentation step that carry a high degree of residual risk.  

is director, PAT at Thermo Electron Corporation, Madison (WI, USA).			

Quality by design and PAT approaches are increasingly being used for the biotech manufacturing of medicines. Complex manufacturing processes can not only be controlled using PAT principles, but optimized with respect to both product quality and economic value. This column describes how the fermentation process is often the first to benefit from this type of implementation.

The development of PAT in biotech manufacturing

My job has many good points and just the occasional bad one. Overall though, the best part has to be the networking. I'm appreciative that as an Editor I get the opportunity to meet so many different people in all areas of the pharmaceutical industry, including lab technicians, product managers, senior scientists, CEOs and politicians — not to mention all the press and PR agencies.  

Now, while it's easier to maintain these relationships by e-mail (and like most people I do this every day), I prefer getting out and meeting people in person — for me, that's the key to building successful networks and friendships. But, it has to be done in the right way; for example, during my first CPhI 4 years ago in Paris, I would try to blitz my way through the exhibition, walking onto as many stands as possible, thrusting business cards into strangers' faces and thinking that everybody would send me an e-mail the minute they got back into the office. How wrong I was and how quickly I learned. 

   This year's CPhI expo (ironically back in Paris) was a much better experience as I once more blitzed through the halls, but this time it was all about renewing acquaintances, catching up with people I hadn't seen since the last CPhI, meetings over a coffee and croissant, and catching up on all the 'off the record' industry gossip. I still met my fair share of new contacts, but unlike previous years, I now understand that the process of developing a meaningful business relationship from that initial meeting will take time. Of course, there's no upper or lower limit as to how long it will take, but what I do know is that the foundation will be one of trust and understanding, which will only develop from meeting in person. 

Personally, I find that while e-mail is quick and convenient, it's too easy to hide behind (particularly when you're too scared to say something in person) and, ultimately, faceless. Speaking from experience, I believe it's simply a very lazy way to do business. My advice? Be constructive and get out there, network at industry events and be seen; but most of all, just make the effort to meet new and existing contacts in person — it's much more rewarding.  

While e-mail is quick and convenient, it's too easy to hide behind and, ultimately, faceless.

Faceless meetings

People with a visual impairment often experience problems in differentiating packets with the increased standardization of packaging sizes and shapes. They can also have problems with reading the instructions as they are often printed in a small typeface with poor visual quality.  

To alleviate these problems, the European Commission (EC) has issued a directive requiring suppliers to incorporate braille labels and produce information leaflets in alternative formats. However, the associated standard has yet to be published, which leaves uncertainty about the detailed implementation of the directive.  

Packaging poses significant problems for many older people. This is often because of an inability to read the label, understand its meaning or open the package without damaging the contents. Failure to take medicine correctly has been estimated to cost the US economy $100 billion per year.

About 1.5% of the UK population has vision that can be registered a 'blind' or 'partially sighted' and about 0.4% of these have to rely on nonvisual methods to access information.

  Within these groups there are considerable variations from one individual to the next. For instance, people with low vision includes those with: 

 Macular degeneration accounts for about half of all registerable blindness in the UK; it is particularly common among the elderly. Typically, it results in the loss of central vision. This group often benefits from larger-than-normal print. 

A cataract is an opaqueness of the lens at the front of the eye. It has similarities to driving a car with a dirty windscreen; if the sun is in your eyes, it is difficult to see anything, but with the sun behind you there are relatively few problems. Fortunately, cataracts can usually be operated on successfully, with the lens being replaced by a plastic lens. 

. Haemorrhages occur on the retina at the back of the eye. This is the single most common eye disease among the 16–64 age group. One effect of diabetes tends to be a very poor sense of touch; therefore, few people with diabetic retinopathy can read braille. 

 Tunnel vision can be associated with some forms of 

 is the name for a group of conditions that are genetic and result in night blindness. Glaucoma is from increased pressure in the eye; if detected early enough, it can be treated by taking pills. People with tunnel vision can find it easier to read small print rather than large print. 

Additionally, total colour blindness affects about 0.0025% of the UK population. However, about 8% of males and 0.5% of females have problems distinguishing red and green 

The ageing process also affects vision. In a 60 year old person, only about one third of the light reaches their retina compared to when they were 20. There is also a decline in visual accommodation (the ability of the eye to change focal distance), coupled with a deterioration in the speed of adapting to changes in illumination.  

Many older people also have a combination of impairments. More than half of people with a visual disability have a significant additional impairment. This number is increasing because more people are living to an older age. However, it is difficult to predict the effect of multiple impairments as two individuals who appear to have the same combination of impairments may function very differently.  

For partially sighted people it is essential to design labelling to maximize legibility. It is recommended that designers should

use a solid background colour with good contrasting lettering

 upper and lower case letters — lower case words are easier to read 

print on a flat surface (i.e., no embossing).

The choice of typeface is particularly significant because misreading the dosage quantity could have serious consequences. It is important to use a font with 'open' numerals (such as Tiresias) and avoid those such as Arial with 'closed' numerals. 

Various types of information must be included on the packaging: primary (product name, dosage); secondary (do not take if ...) and tertiary (advertising).  

The size of the print for the primary information on packaging should be at least 14 point. Ideally, secondary information should be in 12 point because most older users would benefit from a large print size, but there is finite space on the packaging and increasing regulation requiring more and more information to be included. 

A European directive (2004/27/EC) requires braille labelling for medicinal products introduced after 30 October 2005.

  The braille should be on the outer, or secondary, packaging and must include 					

whether it is intended for babies, children or adults

international nonproprietary name or common name

multilingual packaging; the braille should be in all the different languages.

Braille characters consist of one to six embossed dots, which can have 64 different configurations (Figure 1).  

Figure 1 Examples of braille characters.			

One problem with braille is the lack of redundancy — a damaged or missing dot can completely change the meaning of the text (Figure 2). Therefore, it is very important that the braille dots do not become damaged between the time they are embossed and the time the package reaches the patient. This will require some changes in how the packages are handled in the supply chain.  

Figure 2 Only one dot differentiates ÃÂ´Â£75ÃÂ´ from ÃÂ´largeÃÂ´			

Another problem with braille is the relatively small number of people who can read it. Out of about one million people in the UK whose vision is such that they could be registered as blind or partially sighted, between 10000–20000 can read braille.

There are various methods for adding braille to packaging including embossing the card or plastic packaging, depositing dots (also known as 'solid dot'), using a stick-on label, or incorporating in the mould. 

Whichever method is used there is a problem of space on smaller packets, such as those used for eye drops. The dimensions for braille (Figure 3) cannot be scaled up or down. Therefore, to include even a short name such as 'Ibuprofen 200' in braille requires a space of over 500 mm

, but the guidance notes to the directive specify that the underlying printed text has to be easily legible. This implies that the underlying text has to be in a large bold typeface otherwise the embossed braille dots will significantly erode the legibility of the text.  

The practicalities of finding space for the braille will probably require manufacturers to use larger packaging. An alternative would be a fold-out label, but this is likely to be difficult to integrate into the production process. 

However, the dimension which is likely to be the most problematic is the dot height. In a braille book this is normally between 0.45 and 0.5 mm

. On packaging it could be significantly less, subject to the constraint that an appropriate dot profile is used. With lower dot heights the radius of curvature at the top of the dot (r in Figure 4) should decrease.  

However, the radius of curvature at the bottom of the dot (R in Figure 4) determines the strength of the dot; if R is too large then the dot can easily be squashed, but if it is too small then the material becomes too thin and will burst. Using long fibre card and high humidity can improve the embossing characteristics of the material. It is possible to spray a reinforcing agent on the back of the card to improve the durability of the dots. 

			The directive also requires patient information leaflets to be available in alternative formats which could include									

However, there will be a problem with the timely delivery of this information. When a patient collects their medication from a chemist, they do not want to wait a few days to receive the patient information leaflet in a form they can read. 

Therefore, there must be a system for delivering this information within hours, but it will not be viable for the chemist to stock the whole range of leaflets in all the alternative formats. 

Therefore, it is likely that patients will opt for the audio information over the telephone because it will be the only format they can have immediately. The problem will be to design an easy-to-use service. It may not be practicable to have a different telephone number for each pharmaceutical product, but many older patients will decline to use an interactive voice response system. 

If all information leaflets are produced in alternative formats, the cost to the pharmaceutical industry is likely to be considerable, while take up of the service could be modest. 

Packaging & Labelling

A European Commission directive requires suppliers to incorporate information on medicines in formats suitable for blind and partially sighted people, although the associated standard has not been introduced yet. This article looks at some of the issues that will need to be addressed when the standard is adopted.

Pharmaceutical packaging and labelling for blind and partially sighted people

			Since it emerged in the late 1970s, biotechnology has transformed the pharmaceutical industry. Biotechnology has become a core part of the pharmaceutical industry's R&D strategy, and biopharmaceutical products are a major part of its pipeline. Pharmaceutical companies rely on innovation, which biotechnology undoubtedly offers, and biotech companies nearly always require the financial and marketing power of Big pharma to turn innovation into a successful product. Nowhere is this more evident than in the area of therapeutic antibodies. 

From the late 1970s to the early 1990s, most pharmaceutical companies regarded biotechnology with scepticism. There was a widespread belief among scientists and managers in big pharma, that proteins would never make commercially successful drugs. There were exceptions: one of the earliest successful partnerships was between Eli Lilly and Genentech, who, in 1982, launched the first commercially available recombinant human insulin. Other significant relationships between pharma and biotech were the result of crisis on the biotech side, examples being the acquisition of a majority stake in Genentech by Hoffmann La Roche in 1990, and the 1992 marketing relationship between Lilly and Centocor. The Genentec–Roche deal has been enormously productive, and has helped provide Roche with the strongest oncology franchise in the pharmaceutical industry — heavily based on biotech drugs developed at Genentech. 

By the mid-1990s, the biotechnology sector had demonstrated that it could generate commercially successful products while the productivity of chemistry-based pharmaceutical R&D was in decline. Pharmaceutical companies recognized the need to retool and, in the race to discover and market new drugs, turned increasingly to biotech for technology and products. 

The reliance of pharma on biotech is best exemplified in the field of antibodies. After a slow start, and several major setbacks relating to new potential sepsis treatments in the early 1990s, (for example, Centocor's Centoxin and Xoma's E5), therapeutic monoclonal antibodies are now providing a very rich pay-off for those companies with the courage to pursue them. The €9.5 billion ($12 billion) therapeutic antibody market comprises over a dozen antibodies that have been generated using recombinant genetic methods developed over the last 20 years. 

Clear evidence of the commercial potential of therapeutic antibodies came in the late 1990s, with the success of drugs such as Rituxan, Remicade and Herceptin. This success triggered wide-scale interest in recombinant antibody technology, and created a surge of partnering activity between pharmaceutical firms and those biotech companies that had developed proprietary antibody technologies: PDLI, Abgenix, Medarex, Cambridge Antibody Technology (CAT), MorphoSys and others. Most of the deals were based on technology licenses, involving varying amounts of technology internalization by the pharma company. In most cases, the antibody specialist performed all of the 'front-end' generation of the lead molecule, before handing over to the pharma company for formal development. This represented the fastest and most convenient way for pharma to use modern antibody technology in their drug discovery programmes. 

Recently, signs have emerged to suggest that big pharma's flirtation with therapeutic antibodies is turning into a serious affair. In 2005, Hoffmann La Roche surprised many in the industry by acquiring the private Swiss company GlycArt Biotechnology AG for €150 million ($190 million). This was a technology-based deal as Roche saw substantial value in integrating the GlycArt technology into its therapeutic antibody R&D. In August 2005, Pfizer acquired the privately held Bioren Inc. The most significant antibody deal occurred in December 2005, when Amgen acquired Abgenix for almost €1.73  billion ($2.2 billion). This deal was clearly about products — Amgen is highlighting full ownership of the previously shared cancer drug panitumumab, as well as eliminating a royalty obligation on denosumab (an antibody in clinical development for a range of inflammatory and musculoskeletal conditions). Since January 2006, drive has been constant as Merck & Co. purchased antibody technology companies Abmaxis and GlycoFi, and AstraZeneca has made an offer for CAT. 

Only time will tell to what extent the increasing commitment by pharma to therapeutic antibodies will pay off. However, the events of the last few years in the field of therapeutic antibodies may well foreshadow the development of other segments of the biotech industry: the progression by big pharma from scepticism, through partnership, to the full embrace of acquisition.  

Biopharmaceuticals

The ¤9.5 billion therapeutic antibody market comprises over a dozen antibodies that have been generated using recombinant genetic methods developed over the last 20 years.

The fall and rise of biopharma

Since initial research on terahertz radiation began to gain momentum nearly 20 years ago, this technology has evolved from being a pure research tool to one that is used for pharmaceutical applications. More specifically, techniques using pulsed terahertz radiation such as terahertz pulsed spectroscopy (TPS) and terahertz pulsed imaging (TPI) are now increasingly employed to analyse solid dosage forms. So far, TPS has been predominantly used to acquire physical information of solid-state properties of active pharmaceutical ingredients (APIs), particularly in the field of polymorph recognition, characterization and quantification. 

TPI can be used to nondestructively analyse tablet matrix physicochemical composition, coatings and buried interface properties in solid oral dosage forms because of its pulsed and coherent nature of the radiation together with its frequency-dependent unique penetration characteristics. In addition, both two- and three-dimensional (2D, 3D) imaging techniques are currently being developed.

The term 'terahertz radiation' corresponds to the far-infrared region of the electromagnetic spectrum (3–333 cm

This article investigates pharmaceutical applications of terahertz technology, specifically using techniques for solid dosage form analysis such as pulsed spectroscopy (to generate physical information and detect API changes) and pulsed imaging (to locate formulation impurities, and regulate tablet coating quality and thickness).