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Journal of Commercial Biotechnology

, Volume 17, Issue 4, pp 319–329 | Cite as

Some considerations for the implementation of disposable technology and single-use systems in biopharmaceuticals

  • Tim SandleEmail author
  • Madhu Raju Saghee
Original Article

Abstract

This article, written from an industry perspective, examines the current trend towards the implementation of single-use disposable technologies in the biopharmaceutical and biotechnology sectors. Single-use technologies are generally sterile, plastic disposable items implemented to replace traditional pharmaceutical processing items that require recycling, cleaning and in-house sterilisation. The forces driving the technological change are a mix of process efficiencies (including cost reduction) and sterility assurance. This article examines the advantages of some single-use systems used for aseptic processing, although in doing so a cautionary approach is adopted, particularly with regard to the validation requirements and practical considerations when such technologies are implemented.

Keywords

single-use sterile disposable technology sterility assurance aseptic processing contamination control irradiation microbiology 

INTRODUCTION

Pharmaceutical drug products are produced to be efficacious; however, the presence of microorganisms or microbial by-products in these products may have adverse effects on their efficacy. Contamination of aseptically filled biotechnological products is costly and it can pose serious harm to the patient. 1 The permutations and complexity of variables in manufacturing of sterile products demand high-quality operating clean rooms with trained staff, and the use of sterilised clean-room items and technologies, to reduce the risk posed to the product. Until the 2000s, the development of clean-room items and supporting technologies was relatively slow. In the past 3–5 years, however, there have been a number of advances in new clean-room technologies, which have helped to both reduce the risk of contamination and to streamline process operations. According to Langer, for example, over half of biotechnology manufacturers are considering adopting single-use technologies. 2 The majority of these technological developments were oriented towards the manufacturing of sterile products, particularly aseptically filled products.

Arguably the most significant advances with clean-room technology have been with single-use disposable technologies. 3 Such technologies include tubing, capsule filters, single-use ion exchange membrane chromatography devices, single-use mixers and bioreactors, product holding sterile bags in place of stainless steel vessels (sterile fluid containment bags), connection devices and sampling receptacles. To an extent, the biopharmaceutical and biotechnology sector has been behind the medical device sector and hospitals in the introduction of disposable technologies (applications such as artificial cardiac valves, stents and other implants, balloon catheters, as wells as gloves and other clothing have been in place for several decades).4, 5 The first wave of single-use systems for biotechnological applications was with large-scale bioprocessing for sterile cell culture media and process buffer storage applications. 6 In the past 5 years, however, considerable investment has been undertaken into the implementation of other single-use technologies for biotechnology products and biopharmaceutical manufacturing. For example, the use of disposable mixing systems has increased by over 50 per cent in the past 5 years. 7

There are three primary reasons for research and investment into such single-use technologies. These are to reduce processing time (which is linked to economic pressure to improve time-to-market), to reduce manufacturing costs, to go for manufacturing systems that are more reliable, flexible, cost effective and to seek improved sterility assurance. 8 The time and cost savings arise through the removal of the need to clean and recycle equipment (such as stainless steel processing vessels). The investment into a higher level of sterility assurance, by improvements to controls while the product is being manufactured and filled, is to reduce batch rejection. Stronger controls during processing partly address the concern that by the time a product is assessed for batch release using the final product sterility test there is nothing that can be done to correct a sterility problem associated with the manufacturing of the batch should the sterility test fail. 9 The single-use technologies have reduced these risks by allowing pharmaceutical organisations to move away from equipment that needs to be sterilised or consumables that are recycled or pose a risk with their transfer into clean rooms, to disposable and single-use sterile items.

The advantages of single-use technology can be surmised as eliminating the need for cleaning; removing the requirements for the pharmaceutical company to perform in-house sterilisation (typically by autoclaving) for all components; reducing the use of cleaning chemicals; assisting with storage requirements; lowering process downtime; and increasing process flexibility and reducing risks of cross-contamination. 10 However, single-use technology is still in its infancy and there are a number of validation steps that need to be undertaken before such technology is adopted by a pharmaceutical manufacturer. These include assessing any leachables or extractables that might arise when the product comes into contact with the single-use technology. The presence of extractables could lead to adulterated product or to the inhibition of any microbial contamination (leading to a false negative result). Other disadvantages are in the availability of the technology (in that not all sizes or types required by pharmaceutical manufacturers are available) and development costs. This article examines some of the types of single-use technology available and addresses some of the steps required by pharmaceutical manufacturers to bring the technology online.

PHARMACEUTICAL MANUFACTURING

The pharmaceutical manufacturing environment is based around a series of rooms with specially controlled environments. These are termed as ‘clean rooms’, where ‘clean’ is defined by a maximum permitted concentration of airborne particles according to an assigned class. The key aspect is that the level of cleanliness is controlled. The regulatory requirements for clean rooms are detailed by EU GMP 11 or the FDA guidelines. 12

Clean rooms have been used for the preparation of pharmaceutical preparations since the 1960s. The genesis of clean rooms was after World War II when advances in HEPA (high-efficiency particle air) filters were applied by NASA to advance the space programme. Therefore, the basic clean-room design, with control of airflow, air filtration, air velocity, air change rates and so on, has been a stable part of the preparation of pharmaceuticals for the past 50 years and clean-room technology did not advance greatly until the late 1990s.

The pace of transformation has accelerated more quickly in recent years. In the twenty-first century, there have been a number of advances in novel clean-room technologies, which have helped to reduce the risk of contamination as well as to streamline process operations. The majority of these technological developments have been oriented towards the manufacturing of sterile products, particularly aseptically filled products. These technological developments have included barrier isolator systems and RABS (restricted access barrier systems) to protect the aseptic filling of medicines; methods to protect the product from personnel contamination, such as particle reducing air showers; sanitisation and sterilisation methods to decontaminate clean rooms; and single-use, sterile disposable technologies. 13 It is with the latter innovation that this article is concerned.

SINGLE-USE, STERILE DISPOSABLE TECHNOLOGIES

Single-use, sterile disposable technologies (sometimes referred to as biodisposable technologies) are available in many different formats and confer various advantages for pharmaceutical manufacturers. Single-use disposable technologies are generally manufactured from plastic polymers involving processes of injection moulding, extruding and blow moulding. The assembly of components should be undertaken in an ISO 14644 Class 5 clean room. Once assembled, the plastic items are sterilised using gamma irradiation.

Single-use items are typically sterilised using gamma rays (electromagnetic irradiation) 14 (ethylene oxide gas remains an alternative sterilisation process, although not one adopted by the majority of the manufacturers of single-use systems). Gamma irradiation kills bacteria, where there is sufficient energy, at the molecular level by breaking down bacterial DNA and inhibiting bacterial division. 15 The sterilisation cycles are designed to achieve a Sterility Assurance Level 10−6. Gamma irradiation is adopted because it safeguards the material from which the single-use device is constructed, primarily plastic, from degradation (that is the change in the properties of a polymer, such as tensile strength, colour, shape or molecular weight). The important aspects of the use of gamma irradiation are the selection of the appropriate irradiation dose (expressed in KiloGrays) and the checking of the sterilised item (through out its shelf life), for signs of degradation.

There are several types of single-use systems. This article examines some examples that are applicable to biotechnological aseptic processing: aseptic connections, disposable product holding systems and biocontainer bags.

ADVANTAGES OF SINGLE-USE TECHNOLOGIES

There have been a number of influencing factors driving the adoption of single-use technologies. These can be divided into improving or eliminating cross-contamination, sterility assurance, process efficiencies, operator protection and cost savings. The greater flexibility with the design and construction of single-use systems fits with the current regulatory drive, as with the FDA current good manufacturing practice guidelines, towards the adoption of quality by design (QbD) precepts (the theoretical approach that quality can be planned, and that most quality crises and problems relate to the way in which quality was planned initially). 16

Cross-contamination

Cross-contamination in pharmaceutical processing can be a sterility assurance issue (as discussed below) or a matter of product adulteration (whereby chemical residues of one batch are transferred to another). Cross-contamination can arise through the recycling of equipment where product residues are not adequately removed. Disposable components are single use only and therefore not used for subsequent operations, eliminating the chance of cross-contamination or product carry-over between process runs.

Sterility assurance

Single-use technologies improve the level of sterility assurance within the manufacturing process. This is achieved by a reduction in the possibility of cross-transference of microorganisms; minimising the risk of environmental microbial contamination; and by a reduction with the risk that contamination could be introduced into the process through a failed or inadequate sterilisation cycle. In terms of cross-contamination risk, sterility assurance is tightened through an elimination of the way that connections are undertaken and often with the number of connections that are required to be performed. Furthermore, single-use equipment allows the pharmaceutical organisation to move away from equipment that needs to be sterilised or consumables that are recycled or pose a risk with their transfer into clean rooms. Cross-contamination is also avoided through the removal of the need to clean components (where the process of cleaning, particularly manual cleaning, poses a contamination risk as a result of the variable nature of this human-centric activity). 17

Process efficiencies

Single-use technologies present an opportunity for processes efficiencies, several significant advantages over standard reusable stainless steel systems, particularly in reducing process downtime and by removing the need to clean and sterilise items. This eliminates the need to turnaround equipment thereby presenting opportunities to save on such factors as energy, waste disposal, the quantities of detergents and other cleaning chemicals used, and labour costs. 18 Energy savings arise primarily from the elimination of cleaning that leads to less pharmaceutical grade water (like water for injections) being generated. Associated savings can additionally occur with a reduction in heating costs (which would arise when recycled equipment is cleaned). A further energy saving relates to clean room heating ventilation and air conditioning systems, where the manufacturer could elect certain operations involving single-use items, such as connections, within environments that do not require unidirectional airflow cabinets (such devices utilise a considerable energy demand).

Arguably the most important benefit to the manufacturer is faster turnaround times. Such rapid deployment in turn helps to increase process flexibility particularly in reducing the time taken to obtain the next batch ready for processing. Single-use systems can also be adopted to suit the process through companies developing products to synergise with the existing biomechanical layouts of different production operations. Thus single-use systems can provide ergonomic advantages to manufacturers. Where single-use systems are supplied readily assembled, the complexity of the manufacturing operation reduces. When combined with QbD approaches, engineering and device integration analysis can allow processes to be streamlined. 19 When developing new processes, the introduction of single-use systems for new processes can also lead to savings in that fewer items of large-scale capital equipment are required to be purchased.

Other benefits arise from simplifying the changeover of equipment between processing different types of products. This reduces the amount of cleaning required in order to minimise cross-contamination. A further process benefit arises in reducing the space required to hold vessels before cleaning and sterilisation and post-sterilisation as many single-use technologies have a smaller footprint.

Cost savings

Cost savings are bound into process efficiencies. Although the initial cost of purchasing single-use disposable clean-room technologies is generally greater than the recycling of stainless steel components, the benefits of a faster turnaround, which potentially allows an organisation to produce faster and move between different product streams more quickly, deliver longer-term cost savings. Perhaps the greatest cost saving of all, depending on the value of the product, is the elimination of contamination events, which will lead to batch rejection and process downtime.

Cost savings also arise from process validation. Although there are a number of important validation steps to address (as with the risk of extractables and leachables), the adoption of single-use technologies arguably lowers validation costs in the longer term. This is because there are fewer reusable components, fewer items that need to be tracked, and there is no requirement for validation studies for sterilisation and cleaning.

Operator protection

In applications, where hazardous materials are being processed, such as cytotoxic drugs or potent biological materials, closed single-use systems offer additional protection to operators who are isolated from these hazards. 20

DISADVANTAGES OF SINGLE-USE TECHNOLOGIES

The disadvantages with single-use technologies rest with the time required to implement the systems and the availability or adaptability of a technology, still relatively infant, for particular biotechnological processes (especially the extent that a generic single-use system can be adapted to niche processing). The time taken to implement a single-use system is bound up with the validation requirements. The validation required depends on the type of technology. This article later explores the division in the validation requirements between microbiological studies (principally challenge studies and tests for inhibition) and physicochemical tests. Conducting these tests takes time and resources to prepare, which is expensive. The cost of conducting validation rises further if there are a range of different products that require testing (different products and the plastic material of a single-use system will react in variable ways).

An additional concern with the implementation of single-use systems is the requirement for the biopharmaceutical company to audit the sterilisation process of the single-use technologies and be satisfied that the materials supplied are suitable and are delivered sterile.

APPLICATIONS OF SINGLE-USE DISPOSABLE TECHNOLOGY FOR BIOTECHNOLOGICAL ASEPTIC PROCESSING AND REVIEW OF THEIR MICROBIOLOGICAL VALIDATION REQUIREMENTS

Aseptic connections

A critical clean-room step is the aseptic connection, especially for aseptically filled products. An aseptic connection allows fluid to be passed from one vessel to another in a way that does not introduce microbial contamination. For aseptic filling, the most important connection is the connection of a vessel to a filter for the transfer of product to a filling machine manifold. Conventional methods of connection involve steps such as clamping or heat welding of tubing. The major risks arising from this step are microbial: from the external environment and from any microbial contamination that could be transferred from the operator's hand. Although glove sanitisation is regularly undertaken before aseptic connection operations, a risk exists when conventional connections are undertaken, that bacteria transient or residential to human skin can be transferred from the hand of the operator onto the connector and potentially into the product. Companies who manufacture such devices include Pall (Kleenpack), Millipore (Lynx) and Bioquate (DAC) (Figure 1). Single-use connectors can be used with single-use sterilised manifolds.
Figure 1

Disposable aseptic connectors (courtesy: BioQuate Inc.).

Innovations in aseptic connection technology have led to the development of single-use connector systems to allow for a totally enclosed and automated process. These are based on the so-termed αβ (or ‘male–female’) principle that allows the connection to be performed, by the joining of two components together, in an environment this does not require unidirectional airflow cabinets or other capital equipment to maintain sterility. 21 This principle allows liquid sterile products to be transferred simply and safely, towards or from contained areas, via a small-scale rapid transfer ports. These devices shorten the time required for the connection and could, depending on the risk-based position adopted by the pharmaceutical manufacturer, remove the requirement to undertake the connection under ISO Class 5 air (that is, air provided by a unidirectional airflow cabinet). The design of the connectors also facilitates a fast and safe disconnection through the αβ sections being disconnected through the pushing of an internal plunger that allows the two parts to become separated. The rapid disconnection means that any backflow of fluid is avoided.

Before single-use connectors are adopted by a pharmaceutical organization, it is important that they are assessed through a bacterial challenge test. This is designed to determine if bacteria can breach the connector seal and thereby contaminate any product passing through the connector. A suitable test would involve producing a high-concentration broth culture of a diminutive microorganism, such as Brevundimonas diminuta (a gram-negative rod, biohazard safety level 1 with a typical cell size of 1.0 μm length and 0.5 μm width, 22 ). This microorganism is used in filter validation studies (strain reference ATCC 19146) and is suitable where leakage or transfer is being examined as the cellular size of the bacterium is relatively smaller than many other bacteria (and it thereby acts as a worst-case challenge). A suitable concentration of bacterial cells would be >10 million in a broth medium such as soyabean casein digest medium.

To conduct the challenge test, a sterile connector should be immersed in the broth culture for a period of up to 5 min. Sterile culture media should then be transferred through the connector and into a sterile container. The collected media should then be incubated for 7 days at 20–25°C followed by 7 days at 30–35°C in order to allow for any B. diminuta cells, which might have penetrated the connector to grow. The incubation regime is one commonly used to assess media simulation trials for aseptic filling operations. In addition to B. diminuta, a manufacturer may elect to use a representative microbial isolate from the manufacturing facility in order to demonstrate the integrity of the connection join against the actual types of common bacteria found in the processing areas.

An alternative to the immersion test is an aerosol test. This test involves placing the unjoined connector within a bioaerosol chamber and spraying an aerosol containing a high concentration of bacteria (an approach similar to that used for the evaluation of microbiological active air samplers). Following the aerosol challenge, the connectors are joined and microbiological culture media is passed through and collected into a sterile container. The container would then be subjected to similar incubation conditions as with the immersion test above. Again, the use of a diminutive microorganism like B. diminuta would be the most appropriate bacterium to select for the study. This test is seemingly more variable than the immersion test as it relies on the rate of sedimentation onto the connector joint to be sufficiently high in bacterial cells (which is difficult to quantify). Furthermore, a bioaerosol test chamber is a specialised and expensive item of equipment and not one readily available to many pharmaceutical manufacturers. It provides a useful adjunct to the immersion test but is not a reliable alternative to it.

Disposable product holding systems

In-line with advances in aseptic connections, there is a drive towards the adoption of disposable bag technologies in biopharmaceutical production and away from fixed, stainless steel equipment (which requires more complex engineering configuration and far more components in terms of separative valves and piping). 23 The single-use technology takes the form of plastic bags or packs used to process or store product. This change has arisen because such technologies can reduce validation and clean-in-place requirements; single-use technologies use less energy, lowering the requirements for pure water (connected to clean-in-place systems), clean steam (produced from steam generators) and water for injection (WFI). There are other economic savings, such as from reduced equipment setup times. 24 For example, the cleaning and sterilisation downtimes for stainless steel vessels, transfer lines or filter housings might require 8–10 hours and copious amounts of cleaning solutions and WFI. With single-use holding bags, none of this is required.

The first disposable units were probably filter capsule devices, which could filter small volumes without the need of filter housing and associated cleaning. The next development was single-use sterile bags to replace glass bottles, plastic carboys or stainless steel containers for small-volume storage, transport of biological solutions and growth media. A later development has been with disposable mixing systems, which can be connected to capsule membrane filters and a hold bag. These interconnected disposable systems have a considerable advantage in that they are supplied ready to use as sterilised components.

The common configuration of product holding bags is as single-use assemblies consisting of either two- or three-dimensional bags connected to a manifold of tubing, connectors and filters. The design should be so that no part of the equipment will have direct contact with the product unless the component or part of the equipment is also sterile, single use, and maintains the sterile liquid pathway of the closed system assembly. For the future, rapidly developing connectivity will enhance the development of connected, integral systems and potentially total disposable processes. The validation considerations with product holding bags include microbial inhibition studies, which are similar to those performed on biocontainer sampling bags with the proviso that the validated holding times reflect the maximum hold times of product. These studies are discussed below.

Biocontainer sampling bags

For sterile products, there is a regulatory requirement that sample is taken off the bulk product before the final filtration (through a 0.2 μm filter) of the bulk product. This filtration is either into a vessel that is then connected to a filling machine, or before the transfer of the product along a transfer line that directly supplies the filling machine. The sample is taken for bioburden testing using the total viable aerobic count technique. The commonly adopted requirement, and the one recommended by the European Committee for Proprietary Medicinal Products, is that the bioburden must not be >10 colony forming units (CFU) per millilitre of product. 25 CFU is a unit of measurement for the assessment of viable microorganisms on microbiological culture media.

The conventional way to sample the bulk product for bioburden is to withdraw a quantity of the material from a holding vessel, using a valve or syringe and to transfer this to a sterile sampling container. This process, which is operator dependent and involves multiple steps, poses a risk of adventitious contamination and thus of a false positive result being reported which, at a sufficiently high bioburden, could lead to product rejection. Owing to the integral nature, the use of single-use, sterile biocontainer bags allows the sample to be taken in a way which eliminates the possibility of external or operator contamination triggering a false positive result.

Before the use of biocontainer bags for product sampling, it must be verified that the product solution is fully compatible with the plastic material of the bag. This is to assess whether any leachables or extractables (compounds that can migrate into the product from the plastic material) can cause inhibition of microbial growth. Inhibition of microbial growth is of great concern because any inhibited microorganisms, within the product, could move from a state of dormancy and begin to grow once the product is no longer in contact with the single-use item. This is overcome by running a microbial challenge study whereby product held in the bag is challenged with a low level (<100 CFU) of a microorganism. The challenged product is held for a period of time that approximates the filtration time, after which samples are taken and the level of microorganisms assessed. The absence of inhibition is confirmed by the suitable recovery of the challenge microorganism at a level close to the initial challenge (such as between 50 and 200 per cent). This study should be repeated for different types of microorganisms that are representative of the typical clean-room environmental flora (such as gram-positive coccus like a Staphylococcus spp., a gram-positive rod such as a Bacillus spp., a gram-negative rod such as a Pseudomonas spp. and a fungus, such as an Aspergillus spp.).

COMPATIBILITY OF SINGLE-USE SYSTEMS: PHYSICOCHEMICAL ISSUES

In addition to the microbiological considerations examined above, certain physicochemical factors must also be taken into account in the transfer of single-use technologies into a biotechnological process. Before single-use technologies are adopted for processing, tests must be undertaken to ensure that the technology is compatible with the product. 26 The optimal condition is that the plastic is chemically inert and several manufacturers are developing plastic materials, which will not react with a range of different chemicals and formulations.

Examination of physicochemical properties involves an assessment of chemical and physical factors, based on USP Physicochemical Testing (<661> ‘Containers – physicochemical tests – plastic’) guidelines. With the European Pharmacopoeia, there are specific tests applicable to silicone (Ph. Eur. 3.1.9). These assessments are dependent on both the plastic material and the product with which the plastic comes into contact with and involve running a formal study. It is recommended that studies are conducted in conjunction with the vendor. The vendor should have data relating to the chemical composition of each material family.

Physicochemical testing consists of measuring the properties of impurities extracted from plastics when leached with a suitable extraction medium (such as isopropanol alcohol or purified water) over a specified period and at a set temperature. The impurities measured include heavy metals (detection of the presence of metals such as lead, tin, zinc and so forth), buffer capacity (a measurement of the alkalinity or acidity of the extract) and non-volatile residues (a measurement of organic and inorganic residues soluble in extraction media). Other changes can occur such as discoloration or loss of material strength. Testing should be undertaken for material after it has been gamma irradiated, for irradiation can cause a significant deterioration in mechanical properties of materials. Physicochemical testing should capture the storage times of the product and include the storage conditions (such as holding temperatures). 27

The test methods for physicochemical testing range from macroscopic examinations for signs of damage to the determine absorbance solutions. In order to assess volatile materials, the common techniques include solid phase micro-extraction and gas chromatography systems equipped with a flame ionisation detector. 28

Validation in support of chemical compatibility is of importance because most disposable products are manufactured from organic polymers. A chemical reaction could cause the product to react with the plastic. The possibility of a reaction will increase in relation to the length of time that the product is in contact with plastic for. This varies with the pH of the product and its chemical nature.

With physical compatibility, the single-use disposables may be affected by the manufacturing process. This will depend on the type of single-use consumables and the process itself. Aspects of the manufacturing process that could affect the disposable items include pressure, mechanical force and temperature.

CONCLUSION

Single-use technologies arguably represent the most significant developments with biopharmaceutical manufacturing during the last 5 years. There are a range of different applications of single-use technology (of which this article has examined a selection). Table 1 lists the more common types of single-use systems in the biopharmaceutical industry.
Table 1

List of the common types of single-use technologies prevalent within the biopharmaceutical industry

Single-use technologies available to the biopharmaceutical industry

Tubing

Capsule filters

Single-use ion exchange

Single-use mixers

Bioreactors

Capsule filters

Single dose filtration systems

Product containing sterile bags

Aseptic connection devices

Sampling receptacles for aseptic sampling

Biocontainer sampling bags

This article has examined the advantages of the adoption of single-use, disposable technologies within the biopharmaceutical and biotechnology industries in terms of both improving sterility assurance and delivering process efficiencies. These are summarised in Table 2.
Table 2

Summary of the advantages and disadvantages of single-use technologies

Advantages

Disadvantages

Reduces the need for cleaning

Considerable validation required to assess risk of leachables or extractables; to determine of microbial inhibition is a concern; and to demonstrate that opportunities for microbial contamination do not arise

Lowers the use of cleaning chemicals

Technology remains in its infancy, it may not be adaptable for all types of processing

Lower energy requirements

Development costs

Reduces the need for equipment recycling

Time required for implementation

Removes the need top conduct in-house sterilisation

 

Improves manufacturing storage capacity

 

Reduces process downtime

 

Increases process flexibility

 

Reduces risk of product or chemical cross contamination

 

Improves sterility assurance by reducing microbial contamination risks

 

The article has also considered some of the validation steps that need to be implemented before introducing single-use systems into a pharmaceutical manufacturing environment. The importance of validation cannot be undersold. Although single-use systems confer many advantages in terms of sterility assurance and in terms of manufacturing costs over the longer term, they must be proven to be compatible with the product. Furthermore, the single-use systems must be rigorously tested in order to show that they do not rupture or are damaged in a way that makes them inoperable during processing. It is also incumbent on the pharmaceutical manufacturer to audit the supplier for evaluating both the manufacturing process and the sterilisation of the single-use systems.

By following best validation practices, single-use systems confer more advantages than disadvantages for the biopharmaceutical sector and represent the future direction that the industry is taking.

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Copyright information

© Palgrave Macmillan, a division of Macmillan Publishers Ltd 2011

Authors and Affiliations

  1. 1.Microbiology DepartmentBio Products Laboratory Ltd.HertfordshireUK

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