Pharmaceutical manufacturing takes place within a series of specially controlled environments – cleanrooms. On one level, a cleanroom or clean zone is simply an area that is clean in terms of both particle counts (as defined in the international cleanroom standard ISO14644) and microbial counts (as defined in a second cleanroom standard for bio contamination control, ISO14698.) In addition, regulatory requirements for cleanrooms are detailed by EU, GMP or the FDA guidelines. One important step towards achieving microbial control within a cleanroom is the use of defined cleaning techniques, together with the application of detergents and disinfectants. The detergents and disinfectants used in pharmaceutical grade cleanrooms need to be of a high quality and effective at killing micro-organisms. Both correct product selection and cleaning techniques are important, particularly, in relation to some of the newer cleanroom technologies.
Cleaning Agent Selection
The types of detergents and disinfectants used represent an important decision for the pharmaceutical manufacturer. There are various different types of disinfectant with different spectrums of activity and modes of action. Disinfectants have differing efficacies. Some are bacteriostatic, where the ability of the bacterial population to grow is halted. Here, the disinfectant can cause selective and reversible changes to cells by interacting with nucleic acids, inhibiting enzymes or permeating into the cell wall. Once the disinfectant is removed from contact with bacteria cells, the surviving bacterial population could potentially grow.
Other disinfectants are bactericidal in that they destroy bacterial cells through different mechanisms, including causing structural damage to the cell; autolysis; cell lysis and the leakage or coagulation of cytoplasm. Within these groupings the spectrum of activity varies, with some disinfectants being effective against vegetative Gram positive and Gram negative micro-organisms only, while others are effective against fungi. Some disinfectants are sporicidal in that they can cause the destruction of endospore forming bacteria.
Suitable disinfectants, such as this sterile spray, must be manufactured under clean conditions, with the quality assessed through appropriate manufacturing techniques and held in appropriate packaging
Pharmaceutical manufacturers are expected to use at least two disinfectants of different modes of activity in order to conform with current good manufacturing practices. The use of a sporicidal disinfectant is recommended for sterile areas on an occasional basis, even where such a disinfectant does not form part of the standard set. When selecting disinfectants, it is prudent to opt for manufacturers who offer a range of disinfectants of different modes of activity (which target and kill microbial cells in different ways).
For a disinfectant to work effectively, soil (such as grease and dust particles) must be removed first using a suitable cleanroom grade detergent. Detergents are, typically, either sterile, neutral solutions or have added cleaning chemicals, such as premium sterile non-ionic surfactants. When selecting a detergent a check should be made to determine that it is compatible with the disinfectant because some detergents, where there are residues, can neutralise the active ingredient in certain disinfectants. This can be overcome where detergents are purchased from the same manufacturer as the disinfectant.
It is important to understand the manufacturer of the disinfectant and to be assured that the cleaning agents purchased are of an appropriate quality. High quality disinfectants and detergents are manufactured under clean conditions with the quality assessed through appropriate manufacturing techniques and for the product to be held in appropriate packaging. With disinfectants, it is also important that the chemicals have been tested to the appropriate European standards.
Disinfectant should ideally be sprayed onto the surface rather than the wipe and left for the required contact time before wiping
Cleaning Techniques for Cleanrooms
The cleaning technique used for cleanrooms should be defined and standardised. It does not matter how effective the cleaning agents selected are if the cleaning technique practised by cleanroom operators is poor.
This relates partly to the techniques used and partly to the quality of the cleaning materials. With the techniques for the cleaning and disinfection of cleanroom floors, either the ‘two-bucket’ or the ‘three-bucket’ technique is recommended. Both of these techniques involve using a bucket of disinfectant and a bucket of water.
In the ‘two-bucket’ technique, there is a ‘wringer’ (for the mop) over the bucket of water. In the ‘three-bucket’ technique, there is a third bucket, empty except for having a wringer mounted over it. To illustrate this, the three-bucket technique involves:
- Dipping the mop in disinfectant
2. Mopping the floor
3. Dipping the mop in the bucket of water
4. Rinsing the excess water off the mop head into the third (empty) bucket
5. Dipping the mop in disinfectant
6. Repeating
Such techniques do not achieve is the removal of disinfectant residue from the floors. To overcome this, the final stage in floor cleaning and disinfection is typically a rinse with sterile Water for Injection. For Grade A and B areas, careful consideration is required as any water used will need to be sterile.
Disinfectants can have different spectrums of activity and suitability: microbial filtered concentrated liquid, for example, is suitable for cleanroom surface disinfection
Use of Cleaning Products with New Cleanroom Technologies
In recent times there have been a number of advances in cleanroom technologies that have helped to reduce the risk of contamination and to streamline process operations. This includes the wider use of isolators and restricted access barrier systems (RABS), orientated towards the manufacturing of sterile products, particularly, aseptically filled products.
These ‘clean air devices’ are categorised as barrier technology and are situated inside cleanrooms. Isolators, by their design, are less prone to contamination than conventional cleanrooms. This protection is maintained by a barrier between the inside environment of the isolator (at Grade A) and the outside environment.
Some of the key criteria for the cleaning of cleanrooms and the appropriate use of disinfectants, detergents and cleaning apparatus in the pharmaceutical industry are elaborated. While selection of the right type of cleaning agent and materials is of utmost importance, controlled and careful cleaning techniques must be applied. This philosophy applies to both conventional cleanrooms and to the application of the more recent advanced cleanroom technologies.
The ultimate assessment of cleaning products and cleaning techniques is revealed through environmental monitoring programmes in terms of the numbers and types of micro-organisms recovered. Therefore, the construction of a cleanroom cleaning regime needs to be carefully planned and fit into an organisation’s quality systems. To aid such decisions, important technical advice is provided by many of the leading manufacturers of cleaning products.
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