By Rebecca Smith – Connect 2 Cleanrooms
Why do I need to clean my cleanroom, it is already clean? What is rotational cleaning and do I really need to go that far? Why are there so many chemicals and how do they all work? What chemicals should I use? As a Business Development Coordinator for a cleanroom consumables provider, I get asked questions like this every day.
"a room in which the concentration of airborne particles is controlled, and which is constructed and used in a manner to minimise the introduction, generation, and retention of particles inside the room and in which other relevant parameters, e.g. temperature, humidity, and pressure, are controlled as necessary”.
To control the bioburden in your cleanroom you will need to use disinfectants; these are chemicals that have properties that can kill micro-organisms. You will probably need to use two or more disinfectants in rotation, and this is why the process of killing micro-organisms in your cleanroom is called rotational cleaning.
Annex 1 – Manufacture of sterile medicinal products - Volume 4 EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary use, point 61, states the following:
"The sanitation of clean areas is particularly important. They should be cleaned thoroughly in accordance with a written programme. Where disinfectants are used, more than one type should be employed. Monitoring should be undertaken regularly in order to detect the development of resistant strains.” 
Over time, bacteria that were once controlled by alcohols for example would develop a genetic resistance to that disinfectant, meaning it would no longer be an effective agent. For this reason it has seemed advisable to use different disinfectants to try and prevent this from happening. Although there does not seem to be any evidence to show this happening or even show the potential for this to happen, we still need to take precautions.
There are differences between the environment where MRSA developed and a cleanroom environment. In simple terms, for resistance to develop, a few bacteria will just about survive a dose of whatever agent has been employed to kill that type of bacteria. These bacteria then have the chance to multiply, and whatever advantage they had over other strains that allowed them to survive will be passed on, and you are left with a surviving strain which grows and thrives.
Again, a few of these bacteria will just about survive a dose of agent, multiply, and the advantage that allowed them to survive is passed on again and gets stronger. This happens over and over with continued use of that same agent. The advantage grows and grows, until you are left with a strain that it totally resistant to that agent. In the cleanroom environment, because we tend to overdo the quantity and frequency of disinfectant use, very few microbes actually do survive. This means that it is unlikely that selection for resistant strains will occur. Also, antibiotics have a very specific and targeted action which makes selection more likely. Disinfectants have a very broad action which means it will be less likely that selection can take place.
Quaternary Ammonium Compounds (QACs or Quats) work by causing disorganisation of the cell membrane and the cell’s insides leak out and degrade. They are effective against bacteria, enveloped viruses and fungi, but have little activity on non-enveloped viruses or endospores.
Biguanides alter the permeability of the cell membrane. They can damage the outer layers and attack the inner layers and this will also cause leakage. They have similar effects to the Quats.
Chlorine is a highly active oxidising agent. It oxidises DNA and cell proteins destroying their activity. Disinfectants containing chlorine kill most things including endospores at higher concentrations.
Hydrogen Peroxide is highly reactive and acts as an oxidant, producing free hydroxyl radicals. These free radicals can then attack the essential cell components. Hydrogen Peroxide based disinfectants tend to kill everything including endospores, but this kind of disinfectant is very harsh on the surfaces it cleans.
So because a biguanide kills by affecting the cell wall and cell membrane, it may not be very effective against a micro-organism with a very strong cell wall. That kind of micro-organism will be naturally resistant to the effects of a biguanide.
This strong coat means that in this state the endospore can be very difficult to kill, as it will resist the effects of gamma irradiation and many disinfectants. Chlorines and Hydrogen Peroxide are two disinfectants that do have an effect on endospores, and are often referred to as sporicidal. Chlorines can increase the permeability of the endospore coat and Hydrogen Peroxide can remove proteins from the coat.
We also must consider that if we only use a disinfectant that kills bacteria but not viruses, we are creating the conditions for viruses to thrive. We are creating an environment where viruses will flourish, and the disinfectant we have chosen to try and prevent this from happening will be unable to make an impact.
EU-GMP guidelines recommend that you clean thoroughly, have a written cleaning programme and, if using disinfectants, use more than one. The reason you need to go that far is to prevent resistance. This means naturally occurring resistance, where microbes are just not affected by a particular disinfectant and also selection for resistant strains where microbes that were once controlled by a disinfectant, have developed resistant strains that are no longer controlled by the same disinfectant.
We use different types of disinfectant with different active chemicals because they have different modes of action. This means that they are effective against different types of microbe, and using more than 1 allows you to maximise your kill spectrum. There are many factors which will affect the type and frequency of disinfectant you choose to use including your process and cleanroom class, residues, what format it is available in, how easy it is to use and the environmental impact, amongst others. So, as a guide it seems sensible to rotate 3 agents - an alcohol, another general disinfectant and a sporicide.
1. Sandle, T. (2012) A guide to cleaning & disinfecting cleanrooms, Surrey: Grosvenor House Publishing.
2. Whyte, W. (2010) Cleanroom Technology, Fundamentals of design, testing and operation, West Sussex: John Wiley & Sons Ltd.
3. Araújo, P. Lemos, M. Mergulhão. Melo, L. Simões, M. (2011) Antimicrobial resistance to disinfectants in bio-films, Science against microbial pathogens: communicating current research and technological advances, p826.
4. Sartain, E. (2005) Disinfectant Rotation, Available: www.cemag.us/print/articles/2005/03/disinfectant-rotation.
5. Martinez, J.E. (2009) The rotation of disinfectants principle: true or false? Available: http://www.pharmtech.com/pharmtech/Article/The-Rotation-of-Disinfectants-Principle-True-or-Fa/ArticleStandard/Article/detail/580032
6. "Annex 1: Manufacture of Sterile Medicinal Products," Good Manufacturing Practice (GMP) Guidelines (Brussels, Nov, 2008), Available: http://ec.europa.eu/health/files/eudralex/vol-4/2008_11_25_gmp-an1_en.pdf
7. McDonnell, G. Denver Russell, A. (1999) Antiseptics and disinfectants: activity, action and resistance, Clinical Microbiology Reviews, Jan 1999, vol 12. No 1 147-179.
8. Critical Cleaning Bulletin (2007) contact Weitzel, S. Critical Process Cleaning, CANI, Inc, Available: http://cdn.shopify.com/s/files/1/0186/2832/files/BULLETIN_selection_and_rotation_of_disinfectants.pdf?380
9. Guideline for disinfectant and sterilization in healthcare facilities, 2008, Centers for Disease Control and Prevention, Available: http://www.cdc.gov/hicpac/disinfection_sterilization/6_0disinfection.html
10. "Part 1: Classification of air cleanliness” Cleanrooms and associated controlled environments, The European Standard EN ISO 14644-1:1999.
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