Press Releases

2002

• Xcelodose^® breaks with tradition to lead the way in micro-filling
  
• Meridica and Sartorius announce co-marketing agreement for Xcelodose^® - 29 July 2002
  
• The automation of preparation of test articles and clinical trial supplies - April 2002
  
• Evaluation of a solid dose delivery technology for filling capsules and other small containment systems with a broad range of drug substance and carriers - 8-11 April 2002

Xcelodose^® breaks with tradition to lead the way in micro-filling

Traditional route of bulk blending is eliminated in revolutionary new system utilising skills of Sartorius

Preparation of drug candidates for clinical and pre-clinical trials often means working with only very small amounts of drug. This presents a number of difficulties, particularly in maintaining consistency and accuracy when handling the drug, which can be a slow, laborious and inaccurate operation.

The traditional response has been to blend these very small amounts of drug substances with excipients such as lactose, and then to work with the drug in the form of a bulk blend. This necessitates constant testing of the blend to ensure adequate homogeneity and stability over a period of time. The pharmaceutical work involved will add considerable time and expense to the development of the process as well as increasing the risk of failure.

Now, thanks to a revolutionary new micro-filling system developed by Hertfordshire-based Meridica, the drug delivery company formed by PA Consulting Group, the need to follow this traditional processing route has been eliminated.

The ground-breaking system, branded Xcelodose^®, utilises advanced Sartorius weighing technology to enable pharmaceutical companies and Contract Research Organisations (CROs) to fill capsules or other solid-dose containers with weights in the range of 100 micrograms to 100 milligrams with drug alone, giving an accuracy of 1.5-4% RSD, a figure not previously achievable. The current Xcelodose^® system with its sophisticated software controlling the filling process and the degree of precision required, automatically weighs and records the exact amount of drug required into each capsule. The ability to perform this operation reliably and consistently can result in significant savings in pharmaceutical development resource, cost and time, while providing enhanced quality control over the drug content of the capsules.

Tom Richardson, Managing Director of Sartorius Limited, said:

" As a market leader in weighing technology we have long since been associated with companies like Meridica that specialise in hi-tech original equipment manufacturing where the process requires precision weighing equipment and hi-tech performance. Sartorius has successfully supplied balances and scales to PA Consulting, Meridica's parent Company, and we are excited at the prospect of supplying microbalances for the Xcelodose^® project. The success of this co-operation was first seen at the recent PPMA Exhibition in London when two Xcelodose^® capsule filling systems were exhibited. The Xcelodose^® system is not only important for Meridica but key to successful growth in current and future OEM business for Sartorius."

So what has been Sartorius' role in this exciting new development? Meridica's Director of Strategic Marketing, David Edwards, explains: "In this application we initially tested a 5-figure balance produced by one of Sartorius' competitors, but it failed to deliver sufficient resolution for very low dose weights in addition to a number of other performance shortcomings.

"We then tested the Sartorius MC5 and SC2 microbalance against a number of alternative systems, and it simply outperformed them all. We have found that Sartorius provided a consistently high level of support, which is critical when your business is dependant on the development and ownership of new processes and technologies."

Two versions of the system were launched in late 2001 at a series of major exhibitions in the UK and USA. The Xcelodose^® 600 is fully automated and is designed for the manufacture of supplies for early stage clinical trials. Xcelodose^® 120 is a semi-automatic system designed for the preparation of materials for pre-clinical safety studies.

David Edwards added:

"The direction we are taking for our advanced Xcelodose^® systems means that they should be capable of filling in excess of 5,000 capsules per hour. We are hoping that this system will also be based around Sartorius weighing technology.

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Meridica and Sartorius announce co-marketing agreement for Xcelodose^® - 29 July 2002

Meridica Ltd., a leading drug delivery technology company, today announced a co-marketing agreement with the UK division of Sartorius, one of the world's premier manufacturers and suppliers of precision balances and weighing systems. The agreement will take the form of a number of joint promotional activities throughout 2002 and beyond.

The agreement covers Xcelodose^®, Meridica's new precision micro-dosing system for filling capsules. The system, which was launched recently, utilises a novel gravimetric technology that enables pharmaceutical companies to weigh very small amounts of drug powder (100µg-100mg) into capsules or other solid dose containers as part of pre-clinical or early stage clinical trials within the pharmaceutical drug development process.

Xcelodose^® incorporates a novel dispensing technology in conjunction with a software system, which controls the dosing from a dispensing head. Capsules may be filled at a rate of 600 capsules per hour with an accuracy of typically less than 2% Relative Standard Deviation. The combination of such speed and accuracy was previously thought to be impossible.

A key component of the Xcelodose^® technology is a Sartorius precision microbalance that records the weight of each capsule to six decimal places, and checks the weight of each capsule constantly during the filling process. The precision required is programmed prior to the filling process. A predictive control algorithm has been developed that reduces fill cycle time to previously unobtainable levels. The predictive algorithm also enables the system to allow for material characteristics, and even compensates for variability in the flow characteristic of the drug powder in real time.

The Xcelodose^® system eliminates the need to fill capsules manually. Also, through its ability to dispense precisely such small amounts of pure drug powder, it removes the need to blend the drug with excipients traditionally used to facilitate dispensing of the drug. The need to test such blends for stability and homogeneity is eliminated. The resulting advantage to pharmaceutical companies is significant in terms of savings in both resource and time. This reduction in development time delivers potentially faster time to market and increased sales revenues via extended time and opportunity following product launch. A typical increase in revenue may be as much as $1million per day for a major drug product.

In addition to being available for demonstration at Meridica's laboratories near Cambridge, the Xcelodose^® system is currently being 'showcased' by Quintiles, one of the world's leading Contract Research Organisations, operating under GMP conditions at their Edinburgh, UK site.

Both Meridica and Sartorius UK Ltd see synergies arising from their co-operation. David Edwards, Meridica's Director of Strategic Marketing said

"Sartorius is well known and widely respected for the quality of their balances and the service and support they provide to the pharmaceutical industry. Meridica is proud to use Sartorius' balances within its Xcelodose^® system."

Tom Richardson, UK Managing Director at Sartorius UK Ltd said

"At Sartorius we are keen to develop working partnerships especially with high tech development companies like Meridica that provide innovative automated solutions in the pharmaceutical market sector. Emerging technologies such as Xcelodose^® form an increasingly important part of the market for micro-balances".

Editor's Notes:

1. Meridica is a PA Group company. Its vision is to become a leading source of creative drug delivery systems and drug products for the pharmaceutical industry, based on the excellence and quality of its products. Meridica's technologies will enable the full exploitation of the "biotechnological" advances made in the last decade, and build a position as a leading industry provider of cutting-edge solutions to drug delivery systems.

2. Sartorius is a clear market leader both in developing and manufacturing weighing technology, and headquartered in Goettingen, Germany. Originally established in 1870 the company has grown to its present size and now employs some 3700 people worldwide. The Sartorius Group is divided into three divisions, Mechatronics, Biotechnology and Environmental technology and is therefore represented in three of the most important technologies for the future. Mechatronics describes the Sartorius core competence as an innovative combination of high tech mechanical weighing systems with state of the art electronics.

3. PA Consulting Group is a leading management, systems and technology consulting firm, with a unique combination of these capabilities. Established almost 60 years ago, and operating worldwide from over 40 offices in more than 20 countries, PA draws on the knowledge and experience of around 4,000 people, whose skills span the initial generation of ideas and insights all the way through to detailed implementation.

PA builds strategies for the creation and capture of shareholder and customer value, and helps clients accelerate business growth through innovation and the application of technology. PA works with clients to improve performance, mobilise human resources and deliver change effectively, including managing major projects, and designing and implementing enterprise-wide systems and full e-business solutions.

PA focuses on creating benefits for clients rather than merely proposing them, and this focus is supported by an outstanding implementation track record in every major industry and for governments around the world. PA also develops leading-edge technology both for its clients and within its own portfolio of venture companies in areas ranging from software to wireless technology to life sciences.

PA distinguishes itself from its competitors through the range and quality of its people, the depth of its industry insight, its development and use of technology, and also its independence and culture of respect, collaboration and flexibility in working with clients. We are proud that our clients say "PA makes it happen". See www.paconsulting.com for details.

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The automation of preparation of test articles and clinical trial supplies - April 2002

Imogen Gill, David Edwards, Bruce Macmichael, Meridica Limited

The pharmaceutical development director of today is under enormous pressure to progress new molecules through early phase development as rapidly as possible and at reasonable cost. In research, great progress has been made to reap the benefits of combinatorial chemistry and to provide potential new chemical entities (NCEs) for the company pipeline. For all leading pharmaceutical companies investment in research is high, but costs escalate when the molecule enters the full development phase. Recent estimates indicate that a delay of a single day can cost a pharmaceutical company between US$1 million and US$13 million in lost sales, and that the development process itself costs US$30,000 per day and is rising by 10-12% per annum¹.

It is crucial that strong NCE contenders for commercialisation are identified early on and receive full development support. Conversely, it is important that molecules with less promising or even no therapeutic potential at all are removed from the pipeline early to free up development resources for better drug candidates. For these reasons the decision by a company to move an NCE from the research phase to the development phase is vital for managing the success of the company. Preclinical and early clinical trials provide pivotal data for this decision process. The sooner these trials can be completed, and the higher the integrity of the trial results, the sooner the company can make this decision with conviction. One method of facilitating this process that is generating much interest in the pharmaceutical industry, is the automation of the preparation of test articles and early clinical trial supplies, and the focus on preclinical studies on the drug substance alone. Newly available automation technology can achieve these aims and bring significant benefits.

Preparation of test articles for preclinical supplies
Preparation of test article for preclinical supplies is typically labour-intensive, tedious and often inaccurate. Often, qualified scientists spend many hours hand-filling test substances into individually weighed capsules or other containers. Typically, the weight of each dose is pre-calculated and the technician must prepare these on a regular basis, perhaps weekly, throughout the trial. If the trial is a dose ranging study, then this will add further complications.

The scheduling of the trial is influenced by the availability of skilled staff and laboratory equipment to prepare the test article. Although this is certainly true of the smaller preclinical units, even the largest contract houses report that only a limited number of such trials can be scheduled at any one time due to the lack of availability of skilled staff. The time to complete such trials can be lengthy and staff costs are high.

Additionally, in early stages of the development process, the amount of drug material available may be a limiting factor, particularly in the case of biologically active materials or high cost compounds. Quantities as low as a few hundred milligrams may be all that the research technician has available for the required studies and therefore minimum wastage is paramount.

Preparation of early stage clinical trials materials
There are additional problems for early stage clinical trial supplies. The task of filling hundreds (or even thousands) of capsules by hand with minute quantities of drug within defined levels of precision has rightly been described as 'the job from hell' as it is highly monotonous. The task is also something of a double-edged sword; because of the need for accuracy and reliability, it is a job that requires the skilled input of a trained technician but one which offers little in the way of job satisfaction.

Furthermore, there are important quality issues that need to be addressed. When trials require many thousands of these individually weighed supplies, the human error rate may become significant as even the best-trained staff struggle to remain attentive to detail for such prolonged periods of repetitive work.

Blending with Excipients
When preclinical and clinical trial supplies are filled manually, large dose weights of drug substance are usually weighed directly into the containment system, but smaller dose weights (below about 20mg) of drug substance are often blended with a bulking agent. This, however, adds a time and risk factor to the studies because drug compatibility with the excipient must be predicted and then verified through stability studies. The blending of the drug substance with an excipient may more than double the overall time to complete the trial. The formulation and stability-indicating analytical methods must be developed, and the blend must be manufactured and tested for homogeneity. Furthermore, the stability study must be completed to ensure the test article is representative of the original drug substance. Homogeneity testing may need to be repeated on several occasions to ensure that the blend consistency remains constant.

Blending adds complexity to the clinical trial process. The blending process itself may be difficult to achieve with the degree of reproducibility required. Other typical problems might include analytical errors leading to results that are not representative of the sample collected for analysis due to poor sample splitting, dilution errors, improperly prepared standards, weighing errors, and container tare or vial-cap errors².

Another disadvantage of blending is that the excipient may mask the effect of the drug substance in the trial, leading to erroneous or misleading results. Although rare, such instances can be very costly. Occasionally, the use of an excipient has caused a trial to fail, as the test substrate has become unstable. Removing the need for bulking agent therefore has significant advantages when conducting preclinical and early clinical trials.

Preparation of preclinical and early stage clinical trials supplies should be automated.The automation of the filling process for these supplies has many advantages. For example:

• The study can be more easily scheduled in accordance with the study director or clinician's needs
• Resource requirements are reduced
• Risk is reduced by removing human error from the process
• Automation can also reduce the problems of material inconsistency and environmental effects on the filling process
• Automating can reduce the time for supply of clinical trial material and hence the critical data for decision making is available sooner

The advantages of automatic filling are even greater when pure drug substance rather than blended material is used. The problems outlined above regarding blending may be eliminated if a drug-only formulation is employed. In order to do this a technique must be adopted that will enable the technician or research scientist to handle small quantities of drug with confidence and precision. The advantages of eliminating the need to handle drug-excipient blends are potentially enormous, in that weeks or even months of stability and validation work can be avoided.

This will have a positive impact at all levels of the organisation:

• Laboratory Staff - The technicians' work is made easier by not only removing the monotony of manual filling, but also by considerably speeding up the process, which allows more value-adding work to be carried out. The reduction in technician time and resources in carrying out stability work and its subsequent validation is even more significant. The possibility of technician error may be greatly reduced which in turn reduces the risk of trial failure.
• Middle Managers - A reduction in the time taken to produce clinical trial supplies enables greater throughput. Automation also offers the chance of improved resource management, with valuable technician time being freed for other tasks.
• Senior Management - Better optimisation of asset and resources. Most importantly, for a pharmaceutical company, a reduction in preclinical and clinical trial timelines can mean increased speed to market, facilitating competitive advantage or increased sales. In the case of clinical research organisations, the ability to offer better service in terms of accuracy, reliability and greater throughput provides market advantages.

Review of automated system methodologies
The case for automation in the handling of clinical trial supply manufacture is a strong one, but begs the question, what is currently available on the market? The answer is surprisingly little, for two main reasons.

Firstly, most equipment suppliers that cater for this market sector have not been able to combine the fill speeds offered with the precision required. The precluding factor has been the ability to handle very small quantities (for example, sub-milligram quantities) of drug powder required, accurately and consistently enough to offer any real advantage to the pharmaceutical development process.

Secondly, most manufacturing equipment suppliers have tended to cater for the high volume sector of the market for production purposes post-launch. The clinical trial supplies market is small and therefore unattractive to the larger manufacturers of equipment.

Technologies for filling small dose weights
To date, all methods for the metering of drug and drug formulations for filling capsules, for tableting, or for dispensing into other containment systems have used a "volumetric" approach using dosator, auger and other feeding systems. Other technologies with the potential for dispensing small dose weights of drug have been investigated. Some of these include the use ultrasonic and electrostatic methods (Delsys and Phoqus) for dose dispensing. Although the latter technologies have the potential for very accurate dispensing, they only perform satisfactorily with well-conditioned powders of known and well-controlled physical properties; they are quite unsuitable for the range of NCEs that are routinely evaluated in preclinical and clinical trials. Where particle size distributions of the material are known with reasonable accuracy, particle-counting techniques could theoretically be used although to date, it is not believed that this approach has been developed.

Gravimetric dispensing has been used, but in the past this has been a very slow process. It does, however, have the advantage of providing a very simple validation route for dose uniformity, since each dose is individually weighed.

Gravimetric filling may be the only satisfactory solution that will give drug development and formulation scientists the control and precision required to meet their needs with accurately and reliably. The number of such systems on the market is limited. The systems available vary considerably in their features and benefits; the main factors are:

• Type of receiving dosage container (capsule, vial, tube and so on)
• Dose container throughput; filling rate, usually expressed as units / hour
• Automated or manual dose container handling
• Ability to handle different container sizes
• Weight range bandwidth
• Precision and accuracy
• Ability to deal with a range of powder characteristics
• Control systems; the recording of dose weights
• Level of validation for regulatory needs (CFR 11)

The main differences between the systems available are the form of the dosage container offered (capsules, vials, tubes and microtitre plates) and the range of weights that the systems are capable of handling, but usually with a trade-off between precision and speed of fill.

One new system also allows a programmable level of precision whereby greater precision can be achieved with slightly slower fill speeds even at fill weights as low as 100 micrograms. A predictive control algorithm is used that reduces fill cycle times. The system stores all relevant information on batch characteristics and sample/product identity and individual fill weights are recorded with GMP-compliant software.

The continuing development of such systems very much falls in line with software-controlled laboratory equipment, and the prospective buyer can expect to see further automation and sophistication in the control systems, which should offer increasing precision and fill speeds. This may develop to the point where such technologies may begin to have applications in manufacturing as well as laboratory use.

The pharmaceutical development director of today has a major opportunity. Automated dosing systems can offer the pharmaceutical company or CRO real advantages both in terms of resource savings (time, money and human), and reduction of risk - resulting in faster time-to-market. In the eyes of the pharmaceutical technician, eliminating the 'job from hell' allows for greater job satisfaction and the opportunity to carry out more value-adding work.

From the perspective of the pharmaceutical company, automation of preclinical and clinical trial supplies can provide one step towards increasing speed to market.

¹ Inqui J. Achieving Process Intelligence in Clinical Trials. European Pharmaceutical Contractor. pp 56-60. Autumn 2001.

² Prescott JK and Garcia TR. A solid dosage and blend content uniformity troubleshooting diagram. Pharmaceutical Technology, March 2001

Reprinted from European Pharmaceutical Contractor Copyright: Samedan Ltd. 2001
Samedan Ltd, 16 Hampden Gurney Street, London W1H 5AL Tel: +44 (0)20 7724 5444 Fax: +44 (0)20 7724 2632

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Evaluation of a solid dose delivery technology for filling capsules and other small containment systems with a broad range of drug substance and carriers - 8-11 April 2002

B Macmichael, S Bryant, I Gill*

Purpose
The purpose of this study was to investigate the opportunity to fill very small quantities of drug substance directly into capsules and other small containment systems.

Introduction
Oral administration is the most desirable and convenient route for drug administration. It is frequently applied for screening compounds in phase 1 trials and is the route of choice for phase 2 for most therapeutic areas. The time and cost of preparing trial samples is dominated by the amount of work necessary to formulate the drug with multiple excipients and analytical work for dose uniformity and stability studies at different dose weights and concentrations.¹

An innovative technology has been developed in our laboratories that is able to accurately fill solid dosage units with precise quantities of drug. This technology can be used for the preparation of clinical trial samples and dramatically reduce the requirement for supporting analytical and formulation work.

Method
Design of the delivery system: The Xcelodose technology provides accurate filling of pure drug in dry powder form directly into capsules and other small containment systems, at speeds and accuracies previously thought to be impossible. The core component is a gravimetric system with programmable levels of precision. The system uses a microbalance to provide assurance of filled dose weights. A predictive control algorithm is used that reduces fill cycle times to previously unobtainable levels. The predictive algorithm also enables the system to allow for material characteristics, and even compensates for variability in the flow characteristic of the material in real time. The system has been evaluated using a wide range of typical pharmaceutical materials and drug substance.

Results and discussion
Data will be presented which show the ability of Xcelodose to fill rapidly a wide range of drugs and other materials at very low dose weights, with accuracy, and with precision which is well inside USP and tight production control limits. For example, 1mg weights can be filled with a batch RSD of 1-1.5%. The data will demonstrate robust operation with materials of variable physical properties over a range of dose weights. The physical properties of these materials and the impact on filling performance will be described. Parameters explored include, for example, particle size mean and distribution, material cohesiveness, flowability. The data include conventional small molecules, and also protein and peptides, and conventional and more novel carriers for drug delivery.

The use of a specially designed dispensing head with innovative powder handling features has enabled the use of the solid dose delivery technology with pure materials with widely differing flow characteristics.

Conclusions
Conventionally, it is not possible to fill pure drug into capsules or device cassettes at weights of less than about 5mg. At these low weights, careful drug powder preparation is required to ensure consistent powder flow behaviour. Xcelodose technology allows the user to fill pure drug product at very low dose weights (0.1 mg upwards). Furthermore, novel drug delivery systems designed for delivery of peptides and proteins may also be accurately and conveniently filled using this technology.

This technology means that it is no longer necessary to formulate the drug with bulking agents or lubricants to make filling more easy and the associated stability work becomes unnecessary. This has promising implications for phase 1 and phase 2 studies of both conventional and biotechnology products.

Because each dose is individually weighed, there is no analytical process for dose uniformity and consequently analytical work is substantially reduced.

References
1. Automating the preparation of test articles and clinical trial supplies. Gill I, Edwards D, Macmichael B, Smith IJ. European Pharmaceutical Contractor, pp 36-40, Winter 2001.

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