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Setting the Scene

 

The rise of cleanrooms as an essential part of pharma production has rendered plenty of related technological innovations. In the first of a two-part article, the setup of the room itself is explored, along with the implementation of air control. The pharmaceutical manufacturing environment is based around a series of rooms with specially controlled environments – cleanrooms. A cleanroom or zone, rather than simply being a room that is clean, has a more specialised meaning defined by the International Organization for Standardization (ISO) in the international cleanroom standard ISO14644, 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 cleanrooms are detailed by EU GMP or FDA guidelines.

Cleanrooms have been used for pharma preparations since the 1960s. Cleanrooms came into use in the 1940s when advances in high efficiency particle air (HEPA) filters were applied by NASA to further the space programme. The technology was later adopted by the electronics industry and then by healthcare. The basic cleanroom 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.

Cleanroom technology did not advance greatly until the late 1990s, but the pace of transformation has accelerated in recent years. The 21st century has seen a number of advances in new cleanroom technologies, which have helped both to reduce the risk of contamination and to streamline process operations. The majority of these technological developments have been orientated towards the manufacturing of sterile products, particularly aseptically filled products.

Given that most new drug development is centred on biopharmaceuticals rather than chemicals, technological innovations have been primarily geared towards drugs produced as injectable liquids rather than solid compounds. This technological drive has arisen through pharma organisations facing incessant pressures to enhance efficiency, reduce costs and minimise risks, including crosscontamination between batches. In light of these infl uencing factors, this article reviews some of the more significant advances in cleanroom technology being embraced by pharma organisations.

This two-part article assesses the latest developments in cleanroom technology. In the first part, the focus is upon cleanrooms and clean air devices. In the second part, the emphasis shifts towards cleanroom equipment, clothing and innovations including single-use disposable technology.

Cleanroom Design

In recent years there have been considerable advances in cleanroom design – these are aimed at ensuring that the cleanroom is designed in a way that ensures it meets both the requirements of the user and of contamination control. It is important to dedicate time to designing cleanrooms and the equipment located in cleanrooms, as a design fault in one part will affect equipment, and if there is a fault at the conception stage, it will be expensive and time-consuming to rectify.

Modern approaches to cleanroom design utilise computer aided engineering, such as building information modelling (BIM) software. BIM covers geometry, spatial relationships, light analysis, geographic information, quantities and properties of building components (for example manufacturers’ details). BIM can be used to demonstrate the entire building life cycle, including the processes of construction and facility operation. Quantities and shared properties of materials can be extracted easily. Systems, assemblies and sequences can be shown on a relative scale with the entire facility or group of facilities. When designing modern cleanrooms, the following approach should be adopted.

Function

The type and function of the cleanroom should be established. This should include the required cleanroom grades or classes, and how cleanrooms of different grades will interact (including requirements for air-locks and pressure cascades).

The most important aspect is drawing up the process flow. Here the cleanroom management team, together with engineers and quality assurance personnel, should map the path that equipment, product and operators will take within the cleanroom. Established quality risk management tools such as hazard analysis and critical control points (HACCP) or failure modes and effects analysis (FMEA) can be used for this purpose. Areas which pose a contamination control risk should be noted, and attempts should be made to remove these risk areas from the design (the principle of quality by design). Other considerations can also be factored in at this stage, including whether there is adequate clearance under door frames for equipment to pass through.

Engineering must be involved at the early design stage in order to ensure that the conceptual design for the cleanroom can be built as intended and within the required timeframe. The design should include sufficient space for equipment and connections. The cleanroom should be constructed from a material which is compatible with different cleaning and disinfection solutions. A mock-up of the cleanroom should also be constructed; this is particularly important for testing the process, product and personnel workflow. In terms of understanding contamination control, it is essential to understand what objects are passed from one class of cleanroom to another.

With regard to cleanroom construction, there have been some recent advances in ensuring that cleanrooms are built to a higher standard, which further reduces contamination risks. For example, plasma welding can be used for potentially weaker areas, like ventilation ducting, to ensure improved leak tightness (a leak of air from a less clean area into the cleanroom is a major contamination risk). Another development is the use of ‘double skin’ constructions around air-handling units as another means of minimising air leakage.

Modular Cleanrooms

There have been a number of changes to the way in which cleanrooms are designed and constructed, with a wider use of modular cleanrooms. The traditional cleanroom design is sometimes described as ‘hard walled’ or ‘hard lidded’ to distinguish these cleanrooms from the softer walled modular designs.

The relative advantages of hard-walled and modular cleanrooms depend upon the required durability and the application. Hard-walled cleanrooms are often easier to clean and sanitise as there are fewer joints and seams, which may be an important factor for contamination control. A second advantage is that the materials for construction and the various coatings (such as epoxy or vinyl sheeting with heat welded seams) are well known within the industry and have an established history of reliability.

Nevertheless, modular cleanrooms are becoming more common and offer the advantages of fast construction, normally at a lower cost, and allow users of cleanrooms to expand their clean area footprint relatively easily. Modular cleanrooms also offer flexibility, and flexible designs are important for small-scale or emerging technologies such as biotech. A modular cleanroom is sometimes described as a ‘soft wall’ cleanroom, and tends to be free-standing. A modular cleanroom is a series of pre-engineered and prefabricated components. These components are prefabricated at a factory, which allows for greater flexibility and minimises on-site installation time. Also, modular cleanrooms are often steel structures that require no external ceiling supports. So in general, modular cleanroom systems carry lower costs compared with a traditional cleanroom build.

Companies that manufacture modular cleanrooms provide services whereby a cleanroom can be constructed easily, including the cleanroom itself, a changing room, transfer hatches, air showers and air locks. The main benefits of the modular cleanroom approach are that during construction, contamination of surrounding areas is minimised through the use of non shedding materials and prefabrication. A second advantage is that modular cleanrooms can be easily modified, upgraded or expanded with minimal interruption to the existing cleanroom operation, or if the need arises, even relocated to a new facility. Furthermore, with appropriate cleanroom design, upgrading a cleanroom from one ISO class to another can be achieved with minimal interruption of the environment.

Clean Air Devices

There have been several innovations within clean air devices situated inside cleanrooms. The most technologically advanced of the clean air devices are isolators. Other applications include restricted access barrier systems (RABS) and weighing stations. Each of these clean air devices are grouped under the category of ‘barrier technology’. Barriers range from simple screens or demarcated zones, through RABS to full physical barriers in the form of isolators. The industry acknowledges that people are the primary sources of contamination; most of the contemporary cleanroom technologies are centred on separating the operator from the process.

Isolation Technology

Isolators, or microenvironments, are increasingly being used in place of conventional cleanrooms for aseptically filled products. An isolator is “a containment device which utilises barrier technology for the enclosure of a controlled work space”. Thus, isolators provide a separated environment in order to avoid contamination during processing. Isolators are less prone to contamination than conventional cleanrooms by their design. However, although isolators reduce the chance of contamination, they do not entirely eliminate risk; as the FDA notes: “barrier isolators cannot prevent contamination caused by GMP deficiencies such as poor aseptic procedures and inadequate training of…operators.”

Most isolators consist of a either a solid wall envelope or a flexible wall which serves to separate the inside of the isolator from the surrounding environment. Most pharma isolators, when operative, are at a positive pressure level relative to the room and have a HEPA filtered air-flow (there are some examples of hermetically-sealed negative pressure isolators for applications where the drug poses a risk to the operators; an example would be a cytotoxic drug manufactured in a hospital pharmacy unit). The pressure level of the isolators is demonstrated by pressure alarms and readings. The internal environment inside most isolators is sanitised using hydrogen peroxide vapour (a surface disinfectant), although some isolators are sanitised using other chemicals like peracetic acid. Isolators are said to ‘disinfect’ or ‘sanitise’ because absolute sterility cannot be demonstrated (sanitisation, in this context, is the reduction of a number of micro-organisms within the clean environment as demonstrated through the use of biological indicators in validation studies. The biological indicators are a preparation of microorganisms in the endospores state).

Isolator systems function to achieve:

  • Isolation between the operator and the process
  • A non-corrosive, drainable and easily cleaned enclosure
  • Doors to provide access to the equipment inside the isolator
  • Glove ports to allow access to machinery and product during testing
  • Rapid gassing ports to introduce materials, product and equipment to the environment
  • Infeed opening to introduce testing materials and product to the system
  • Exit opening to allow finished product and test materials to exit the system

In achieving these functions, a greater level of contamination control is achieved than would be possible in a conventional cleanroom.

Restricted Access Barrier System

Restricted access barrier systems (RABS) are similar in basic design to isolators. Nevertheless, there is a fundamental issue that separates RABS from isolators. RABS provide product protection and contamination control by the combination of a ‘physical and aerodynamic barrier’ over the critical process zone and operate in cleanroom environments of EU Grade B (ISO Class 7). This is the same grade of cleanroom that is used to house the older style uni-directional airflow (UDAF) cabinets common in conventional cleanrooms. In contrast, due to the complete separation of the environment, isolators can be housed in lower trade cleanrooms. Other important differences between RABS and an isolator relate to the degree of closure (RABS are not necessarily fully separative devices) and with disinfection (with RABS this is typically manual, but with an isolator it is automated and can be rated using biological indicators of a known population and D-value). These differences aside, the restricted access barriers provide further zoning, by screened barriers and HEPA clean-air filtration above, so that an EU GMP Grade A (ISO Class 5) critical zone can be established.

The RABS is superior to a conventional UDAF because the system provides a high level of protection against contamination from operator intervention, under validated conditions, due to the operator accessing the internal environment through glove ports. The construction of an efficient RABS minimises the number of process operations including ‘open door’ access and manual intervention, which would occur, for instance, with a UDAF covering a filling line.

Cleanroom Weighing Stations

Another type of separative device is the cleanroom weighing station. These weighing stations are portable devices with controlled environments that prevent contamination of the sample or product, but are also sufficiently stable to prevent the air from disrupting the calibrated balance. The construction of such devices, in stainless steel, makes them easy to clean.

Conclusion

The use of isolators and equivalent devices is a growing trend, as the pharmaceutical and medical device industries seek greater protection of products from contamination. While the construction of a cleanroom is of great importance, understanding the activities that take place within the cleanroom is also necessary for maximum effectiveness. It is towards these technological developments that the second part of this article will turn in the next issue.


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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 (http://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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