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Inside the Box


The second instalment of a two part article brings out developments in cleanroom activity, including personnel gowning and behaviour.

The first part of this article (PMPS May 2012, p38), outlined cleanrooms and clean air devices, and discussed recent developments, including the latest in isolator design. But while the ‘clean’ environment is undoubtedly of importance, what goes on within the cleanroom, from the way personnel gown and behave, to the way in which aseptic manipulations are conducted, is also of great importance to safeguard the product or medical device from contamination. Here in the second part, key items of cleanroom technology are examined, from the clothing designed to minimise personnel-generated particles, through to single-use disposable technology – an innovation which arguably represents the most significant boost to cleanroom operations in the past five years.

Clothing

Personnel pose the biggest contamination risk to cleanrooms. However, in most cases, the presence of personnel cannot be avoided other than through the use of restrictive barriers (as with the clean air devices discussed above). With most cleanroom operations, the control of personnel is achieved through restrictions on numbers, appropriate training and through the use of suitable cleanroom clothing. With cleanroom clothing, the primary objective of cleanroom garments is to form a particulate barrier to prevent contaminants carried by personnel from entering into the controlled environment and making contact with equipment or product. In terms of general design, the full-piece cleanroom suit, mask and gloves has not altered significantly since the 1960s. However, there have been recent advances with laundry technologies and the manufacture of state-of-theart fabrics applicable for cleanroom wear. Traditionally, polyester has been considered the most practical fabric for reusable cleanroom wear due to its non-lint generating filaments. However, the fabric fibres which constitute polyester can break down through gamma irradiation, especially after repeat applications. This has led to advances with new synthetic blends, some of which have anti-microbial finishes, while others are electrostatic, which helps to prevent some particles from being attracted towards the person wearing the gown.

But it is not only the actual material and its properties that are important. The filtration efficiency of the fabric, together with the level of comfort experienced, must be considered very thoroughly. Filtration and comfort are inversely correlated; in other words, the better the filtration efficiency, the poorer the comfort experienced by the user, especially from a thermal point of view. This antagonistic situation is dependent on the way the textile fabric is woven: the tighter the weave, the poorer the breathing capacity of the material, the less comfortable it is to use, and vice versa.

In relation to gowning, some changing areas which lead into cleanrooms have utilised air-shower technology as a means of reducing the particulate contamination on operators generated from the lower cleanliness levels common to cleanrooms. Air-showers are specialised antechambers which personnel pass through before entering a cleanroom, in order to blow off excess dust particles.

Disposable Technology and Single-Use Systems

Arguably the most significant advances in cleanroom technology in the past two to three years, have been related to single-use disposable technologies. Such technologies have reduced risks by allowing pharma organisations to move away from equipment that needs to be sterilised or consumables that are recycled or pose a risk with their transfer into cleanrooms, to disposable and single-use sterile items. This technology eliminates the need for cleaning, as well as the need for the pharma company to perform in-house sterilisation, reduces the use of chemicals, storage requirements, and process downtime, increases process flexibility, and avoids cross contamination. Single-use items are typically sterilised using gamma rays (electromagnetic irradiation), which kill microorganisms by destroying cellular nucleic acid.

Aseptic Connections

A critical cleanroom step is the aseptic connection, especially for aseptically filled products. Types of aseptic connection include the connection of a vessel or filter to another item of equipment for the transfer of fluids. The major risks arising from this stem from the external environment and from any microbial contamination which could be transferred from the operator’s hand.

Innovations in aseptic connection technology have led to the development of single-use connector systems. These are based on the so-called alpha-beta principle, which allows the connection to be performed in an environment that does not require laminar flow hoods or other capital equipment to maintain sterility. This principle allows sterile liquid 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. Companies who manufacture such devices include Pall (Kleenpack), Millipore (Lynx) and Bioquate (DAC).

Disposable Product Holding Systems

In line with advances in aseptic connections, there is a drive towards the adoption of disposable bag technologies in biopharma production, and away from fixed, stainless-steel equipment. This change has arisen because such technologies can reduce validation and clean-in-place requirements, lower the requirements for pure water, clean steam and water for injection (WFI), and cut costs by reducing set-up times. For example, the cleaning and sterilisation down-times for stainless steel vessels, transfer lines, or filter housings might require eight to 10 hours and copious amounts of cleaning solutions and water-for-injection (WFI), none of which is required with single-use approaches. The single-use technology takes the form of plastic bags or packs used to process or store products.

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 was 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 gamma sterilised and ready to use. For the future, rapidly developing connectivity will enhance the development of connected, integral systems and potentially total disposable processes.

Consumables

The transfer of materials into and out of a cleanroom or clean air device is, as noted in EU GMP, one of the greatest contamination risks. Most items which are untreated by sterilisation or disinfection are contaminated with microorganisms. This phenomenon creates a problem as many items, particularly plastics, cannot be sterilised. Although such items can be disinfected, where contamination originates from spore bearing microorganisms the contamination cannot be removed by many of the standard cleanroom disinfectants. This risk has helped to trigger the recent advance in disposable, plastic irradiated consumables for cleanrooms. These are typically presented in sterile multipacks. These are bags, often constructed from polythene or other low particulate material, which contain consumables such as connectors and syringes. These packs are normally double or triple bagged so that any contamination on the outside is removed prior to transfer into a critical area.

Filling Machines

The technology related to product filling machines in cleanrooms continues to advance, with systems designed to increase throughput and to decrease the big risk of operator intervention. The most robust machines combine in-line filling and stoppering with continuous motion positive in-line transport systems, which are particularly suitable for filling cylindrical vials with liquid solutions and for rubber stopper insertion. The construction of modern filling machines means that they can be exposed to the vaporised hydrogen peroxide (VHP) sterilisation gas agent required for isolators, while the flexible nature of contemporary design allows machines to be positioned under restricted access barrier systems (RABS) or isolators. Many of the current technologies utilise lasers to measure fill sizes, headspace gaps and closure seals.

Furthermore, in keeping with the earlier discussion on single-use disposable technologies, many filling machines use peristaltic pumps with single-use tubing or tubing sets, as well as disposable filling needles and manifolds. The advantage of peristaltic pumps is that the piston pumps associated with older models of filling machines have many moving parts, which can not only break down, but are also a common source of airborne particle counts. With these technologies, careful calibration is required to ensure accurate and consistent fill volumes. Nevertheless, providing that these difficulties of measurement are overcome, the many advantages of sterile disposable design can be successfully applied to filling lines.

Cleanroom Decontamination

There are different techniques used to decontaminate cleanrooms. Traditionally, this has involved either manual cleaning or disinfection by operators using mops and buckets, or decontamination with fumigation units and chemicals like

formaldehyde (which, in the gaseous form, creates significant health and safety concerns). More advanced means for cleanroom decontamination involve the use of VHP. VHP is created by liquid hydrogen peroxide being placed into special generators which, when operated, create a gas. VHP is an oxidising agent and readily kills most microorganisms, including spore forming bacteria such as Bacillus.

Gas generators can be placed into cleanrooms at known locations. It takes some time and effort to map the cleanroom (which additionally requires some form of validation using chemical and biological indicators). More advanced applications of VHP generators position the generator in the HVAC system so that the gas vapour can be evenly distributed into all areas of the cleanroom. Comprehensive validation studies are required to develop the appropriate cycles (which move from dehumidification, through conditioning, to decontamination and finally aeration); however, once the validation studies have been completed, the time savings are considerable and the effectiveness of decontamination is greater than comparable manual cleaning methods.

Cleanroom Surfaces and Flooring

Various items of equipment and surfaces are now manufactured with antimicrobial coatings. This is more commonplace in the US than in Europe, although the number of available items is increasing. One example is the incorporation of silver, which is effective

against a range of micro-organisms. An advantage of silver ions is that, although they have antimicrobial properties, the element is rarely toxic to human cells. Examples of the application of silver include implements such as forceps. Also in relation to surfaces, the incorporation of wipeable surfaces onto equipment allows for the easier cleaning and disinfection. Some of these innovations include polythene covered computer keyboards.

One of the risks to cleanrooms arises from personnel transferring contamination into the area via footwear or through equipment transfer (such as trolley wheels). One way to minimise contamination is to use special mats which are designed to remove dirt, particles and micro-organisms. Where such mats are used they have traditionally been sticky-mats. Although these are fairly effective, more efficient contamination control can be achieved from polymeric flooring. Polymeric flooring is a specially designed ‘plastic’, which works by electromagnetic forces causing particles to be attracted from surfaces such as footwear, and retained on the surface of the mat. This mechanism ensures that any contamination residing on the mat is not passed back onto the personnel who walk across it.

Energy Efficiency

Cleanroom technologies are not only directed towards contamination control. The energy efficiency of cleanrooms is currently of great importance for companies who wish to save costs and to reduce the amount of carbon generated. To address this, International Standard ISO 14001, which describes environmental management and practices, and BS EN 16001, a new European energy standard, are increasingly used (both standards are likely to be amalgamated into international energy standard ISO 5001). Care must be taken when adopting such standards in relation to contamination control, as the enthusiasm towards altering the operation of heating ventilation and air conditioning (HVAC) parameters can have an impact upon the level of non-viable particles and viable counts.

Environmental Control

Arguably the most important aspect of environmental control in a cleanroom is the control of airborne particulates, as this is a direct indicator of cleanroom contamination. Particles in the air are measured through particle counters. The most efficient means of monitoring particles is by linking particle counters to a facility monitoring system (FMS). In the 1980s and 1990s, FMS technology connected particle counters to a manifold system. Such a system meant that particle counters were only operated intermittently and that there was a risk, given the need to locate vacuum pumps centrally, that particles could be lost as they were drawn from the counter down lengths of tubing. Today’s FMS systems consist of discrete particle counters, each with individual pumps, and the data is sent using wireless ethernet to a central data capture system. Modern particle counters have an advantage in that they meet the more rigorous demands of the new international standard for particle counter calibration (ISO 21501). In the event of a counter breakdown, a spare counter can quickly replace the malfunctioning counter due to ‘plugand- play’ features, and the particle counting software will record the serial number for audit purposes. This feature is important for aseptic filling where continuous particle counting is a GMP requirement.

Other recent developments in environmental control are real-time microbiological air-samplers (so-called instantaneous microbial detection counters). These systems are capable of instantaneously detecting the presence of extremely small particles using optical technology and determine, on a particle-by- particle basis, the size of each particle, the total quantity of each size of particle, and if each particle is biological or inert. The advantage of such systems is that they can alert cleanroom operators to the start of a microbiological contamination problem so that action can be taken and the potential loss of a product batch avoided.

Conclusion

Cleanroom technologies have evolved impressively over the past 20 years. They offer a greater range of options and easier means of achieving those options, along with better productivity and cost-effectiveness. The two articles in this series have introduced several of these technologies and have shown how these are being implemented in modern cleanroom settings. While such technologies are of great value for modern pharmaceuticals and medical devices, such advanced technology requires careful planning, validation and investment prior to implementation, so that the technologies can satisfy the demands of external regulators and senior management.

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Tim Sandle is Head of Microbiology at the UK Bio Products Laboratory. In addition, Tim is an honorary consultant with the School of Pharmacy and Pharmaceutical Sciences at the University of Manchester and is a tutor for the university’s Pharmaceutical Microbiology MSc programme. Tim serves on several national and international committees relating to pharmaceutical microbiology and cleanroom contamination control, and runs an online microbiology blog (www.pharmig.blogspot.com).


Madhu Raju Saghee is a Corporate Quality Assurance Executive at Gland Pharma, India. Madhu holds a BSc and a Master’s in Microbiology. Madhu specialises in GMP, sterility assurance and cleanrooms and, together with Tim Sandle, is the editor of the forthcoming book Cleanroom Management in the Pharmaceutical and Health Care Sectors.

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Tim Sandle
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Madhu Raju Saghee
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