Monday, July 21, 2014

Contamination control and preparation of anticancer drugs

Tim Sandle MA PhD CBiol MSBiol MIScT
Cleanrooms play an important role in hospitals, from special environments for the preparation of medicines in pharmacies to providing clean air zones for operations. Cleanrooms are designed with special air filters (high efficiency particulate air) to provide 'clean air', have positive pressure differentials to prevent the ingress of less clean air, and have strict entry and clothing requirements for personnel. Nevertheless, cleanroom surfaces can become contaminated with microorganisms, transported in from consumables and equipment or shed from personnel. Surfaces pose a risk if they harbour high numbers of bacteria and fungi because these microorganisms can be readily transferred. Thus, an important part of contamination control within a cleanroom requires the use of cleaning and disinfection agents. Hand contamination poses an additional risk. Hands, whether gloved or ungloved, are one of the main ways of spreading infection or for transferring microbial contamination and the use of hand disinfectants and appropriate hand hygiene is also part of the process of good contamination control.(1) 
Disinfectants used on cleanroom surfaces and for hand sanitisation need to be of a high quality and be effective at killing microorganisms. However, there are a multitude of disinfectants in the marketplace. This range and choice of disinfectants can make the selection process difficult. This article sets out to provide a practical approach for the selection of disinfectants for use in cleanrooms.
Disinfectants vary in their spectrum of activity, modes of action and efficacy. 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. 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.(2) Within these groupings, the spectrum of activity varies, with some disinfectants being effective against vegetative Gram-positive and Gram-negative microorganisms only whereas others are effective against fungi. Some disinfectants are sporicidal in that they can cause the destruction of endospore-forming bacteria (these are the most difficult forms of microorganisms to eliminate from cleanroom surfaces). However, a chemical agent does not have to be sporicidal in order to be classed as a 'disinfectant' or as a 'biocide'.(3)
Ensuring that surfaces are regularly disinfected and that the numbers of bacteria present are kept to a minimum is of great importance. However, disinfectants are only effective when used in conjunction with a detergent. This is because most disinfectants have poor cleaning ability and will not easily penetrate 'soil' (dust, grease and dirt). Surfaces must be rinsed frequently with a detergent and then disinfected at frequent intervals.
Hand sanitisation is also paramount. Personnel carry many types of microorganisms on their hands and such microorganism can be readily transferred from person to person or from person to equipment or critical surfaces. Microorganisms (including Staphylococcus, Micrococcus and Propionibacterium) are either present on the skin not multiplying (transient flora) or are multiplying microorganisms released from the skin (residential flora). For critical operations, some protection is afforded by wearing gloves. However, gloves are not suitable for all activities and, if they are not regularly sanitised or are of an unsuitable design, will pick up and transfer contamination.
Selection of disinfectants
There are many different types of disinfectant for use within cleanrooms.(4) The range of disinfectants presents a somewhat bewildering choice for the cleanroom user. Disinfectants have different spectra of activity and modes of action. A range of different factors needs to be considered as part of the process of selection, including the mechanism of action, and also efficacy, compatibility, cost and with reference to current health and safety standards.(5) For this, the cleanroom manager should have a rationale or policy in place for selection. 
The key factors: 15 points for success
There are 15 key factors for disinfectant selection. 
Type of disinfectant
Disinfectants can be divided into two groups: non-oxidising and oxidising. Non-oxidising disinfectants include: alcohols (which disrupt the bacterial cell membranes); aldehydes (which denature bacterial cell proteins and can cause coagulation of cellular protein); amphoterics (which have both anionic and cationic character and possess a relative wide spectrum of activity); phenolics (some phenols cause bacterial cell damage through disruption of proton motive force); and quaternary ammonium compounds (QACs) (which cause cytoplasm leakage and cytoplasm coagulation through interaction with phospholipids). QACs are among the most commonly used disinfectants. Oxidising agents have a wider spectrum of activity than non-oxidising disinfectants and can damage endospores. However, they pose greater risks to human health. This group includes halogens (for example, iodine), peracetic acid and chlorine dioxide.(6)
Wide spectrum of activity
A disinfectant must have a wide spectrum of activity. This refers to the ability of the disinfectant to kill different types of microorganisms and microorganisms that are in different physiological states.
Sporicidal activity
Many disinfectants are capable of killing vegetative microorganisms only and will not work against bacterial or fungal spores. Periodically, for disinfecting surfaces, a sporidical disinfectant should be used (for example, on a monthly or quarterly basis). Many sporidical disinfectants are oxidising agents. This requirement influences the type of disinfectant purchased. However, sporicidial disinfectants tend to have greater health and safety considerations and some, particularly chlorine-based disinfectants, are aggressive to certain types of surface (especially stainless steel) and will cause discoloration and abrasion. To avoid this, the residue of the disinfectant should be removed by wiping with sterile water or alcohol.
Rapid action
The disinfectant must have a rapid action, with an ideal contact time of less than ten minutes. The contact time is the time taken for the disinfectant to bind to the microorganism, traverse the cell wall and membrane and to reach its specific target site. The longer the contact time, then the longer the surface needs to be left before use. For the contact time, the surface needs to remain 'wet'.
Rotating use of products
Often, two disinfectants are used for regular disinfection, and are often used in rotation (for premises that are inspected by the European Medicines Agency, this is a Good Manufacturing Practice requirement). When two disinfectants are used, the disinfectants selected must have different modes of action. The argument for rotating two disinfectants is to reduce the possibility of resistant strains of microorganisms developing. Although the phenomenon of microbial resistance is an issue of major concern for antibiotics, there are few data to support development of resistance to disinfectants.(7)
Correct temperature and pH for activity
Some disinfectants require certain temperature and pH ranges in order to function correctly. One type of disinfectant, for example, may not be effective in a cleanroom that requires a cold temperature (below 10oC) and many disinfectants have not been validated by the vendor to show that they work at temperatures below 20oC.
Compatibility between detergent and disinfectant
For effective disinfection, surfaces must be cleaned with detergents first. Some disinfectants are not compatible with certain detergents. In such circumstances detergent residues could neutralise the active ingredient in the disinfectant. Before selection, a check should be made that the disinfectant is compatible with the detergent used. This is normally overcome by the use of neutral, non-foaming detergents. 
No residues
Some disinfectants leave residues on surfaces. Whilst this can mean a continuation of an antimicrobial activity, residues can also lead to sticky surfaces and/or the inactivation of other disinfectants.
Surface compatibility
Different disinfectants are not compatible with all types of surface. The disinfectants must not damage the material to which they are applied and can cause corrosion and discolouration. For more aggressive disinfectants, a wipe down using water or a less aggressive disinfectant, such as an alcohol, is sometimes necessary to remove the residues.(8) 
Manufacturer validation
The disinfectants used should have been validated by the manufacturer. There are a series of European Standards for disinfectant validation for bactericidal, fungicidal and, if appropriate, sporicidal and viriucidal activity.(9) 
The presentation of the disinfectant is an important choice, whether as a pre-diluted preparation in a trigger spray, a ready-to-use concentrate or an impregnated wipe. 
Safe to use
The disinfectants selected must be relatively safe to use, in terms of health and safety standards. Here the main concern is with operator welfare. A related concern is the impact upon the environment, especially in the way that waste disinfectant solutions are disposed.
The cost of the disinfectant is also a factor to consider, especially it is to be used over a large surface area.
Sterility of disinfectant
Certain high-grade cleanroom activities require disinfectants to be sterile (for example, aseptic preparation areas). For these purposes, disinfectants that have been sterile filtered (through a 0.2μm filter) and are provided in gamma irradiated containers with outer wrapping are available.
Hand sanitisers
Hand sanitisers fall into two groups: alcohol-based, which are more common, and non-alcohol-based. The most commonly used alcohol-based hand sanitisers are isopropyl alcohol or a form of denatured ethanol (such as industrial methylated spirits), normally at a 70% concentration. The more common non-alcohol-based sanitisers contain either chlorhexidine or hexachlorophene. Hand sanitisers must not cause excessive drying and must be non-irritating.(10)
Carrying out such a review, based on the above factors, prior to purchasing a disinfectant does not guard against the incorrect use of the disinfectant within the cleanroom. Any disinfectant will only be effective if it is used at the correct concentration and by wiping the disinfectant into the surface. 
Disinfectants are of great importance for controlling the microbial population in cleanrooms. However, the selection of the most appropriate disinfectants is not straightforward. This article has examined some of the key criteria for the selection of disinfectants. Whilst selection is important, disinfectants must be applied and used appropriately. Given that the objective of the disinfectant are to kill microorganisms and reduce the surface bioburden, the real test of whether a disinfectant is efficacious is the numbers of microorganisms present after use. This can be assessed by periodic viable microbiological environmental monitoring using surface techniques such a contact plates and swabs.  Further evidence as to how effective a disinfectant is can be shown by the types of microorganism recovered (the 'microflora'). Finally, the selection of disinfectants should not be thought of as a one-off decision; it must remain part of the ongoing quality reviews undertaken by the cleanroom manager.
Key points
  • Disinfectants are of great importance for controlling the microbial population of cleanrooms but selection of the most appropriate products to use is not straightforward.
  • Disinfectants vary widely in their spectrum of activity, modes of action and efficacy.
  • Different factors need to be considered including mechanism of action, efficacy, compatibility, cost and current health and safety standards, and the cleanroom manager should have a policy in place for selection.
  • There are 15 key factors for disinfectant selection.
  • The selection of disinfectants should not be thought of as a one-off decision; it should remain part of the ongoing quality reviews undertaken by the cleanroom manager. 
  1. Larson E. A causal link between handwashing and risk of infection? Examination of the evidence. Control Hosp Epidemiol 1988;9:28–36.
  2. Sandle T. Selection and use of cleaning and disinfection agents in pharmaceutical manufacturing. In Hodges N, Hanlon G (eds) Industrial Pharmaceutical Microbiology Standards and Controls. Euromed Communications, England;2003.
  3. Denyer SP, Stewart GSAB. Mechanisms of action of disinfectants. International Biodeterioration Biodegradation 1998;41:261–8.
  4. Block S. Disinfection, Sterilisation and Preservation, Third Edition. Lea and Febiger, Philadelphia;1977.
  5. Sandle T. Selection of laboratory disinfectants. J Inst Sci Technol;Summer 2006:16–18.
  6. McDonnell G, Russell A. Antiseptics and disinfectants: Activity, action and resistance. Clin Microbiol Rev 1999;Jan:147–79.
  7. Huovinen P. Bacteriotherapy: the time has come. BMJ 2001;323:353–4.
  8. Pharmig. A guide to disinfectants and their use in the pharmaceutical industry. Pharmaceutical Microbiology Interest Group;2006.
  9. Vina P, Rubio S, Sandle T. Selection and validation of disinfectants. In Saghee MR, Sandle T, Tidswell EC (eds) Microbiology and Sterility Assurance in Pharmaceuticals and Medical Devices. New Delhi: Business Horizons;2011:219–36.
  10. Kramer A et al. Limited efficacy of alcohol-based hand gels. Lancet 2002;359:1489–90

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