Decontamination procedures for medical equipment

Introduction Decontamination of medical equipment involves the destruction or removal of any organisms present in order to prevent them infecting other patients or hospital staff. Microbes (bacteria & viruses) can be carried from one person to another on the surface of any equipment that is shared between them unless it is decontaminated between use. They can also be carried on the skin surface which is why handwashing between examining patients is important. Microbes gain access to the body, through open wounds, inhalation of infected secretions or by close contact with mucous membranes. The process by which microbes are passed from one infected person, to cause infection in another, is known as 'cross-infection'. Cleaning, disinfection and sterilisation are all procedures that are used in the decontamination process. Decontamination reduces the risks of cross infection and helps to maintain the useful life of equipment. It is important in the overall control of hospital acquired infection. Definitions Cleaning is the process that removes contaminants including dust, soil, large numbers of micro -organisms and organic matter (e.g. blood, vomit). It is an essential prerequisite to disinfection and sterilisation. It also removes the organic matter on which micro-organisms might subsequently thrive. Disinfection is a process used to reduce the number of micro-organisms but not usually bacterial spores. The process does not necessarily kill or remove all micro-organisms, but reduces their number to a level which is not harmful to health. Sterilisation removes or destroys all forms of microbial life including bacterial spores. Each instrument or piece of medical equipment which comes into contact with a patient is a potential source of infection. These are divided into 3 groups of risk: high risk intermediate risk low risk High risk items come into close contact with a break in the skin or mucous membranes or are introduced into a normally sterile body area. e.g. surgical instruments, needles, urinary and other catheters. Sterilisation is required for this group. Intermediate risk items come into close contact with mucous membrane or are items contaminated with particularly virulent or readily transmissible organisms. e.g. Items of respiratory equipment including laryngoscope blades, endotracheal and tracheostomy tubes, oropharyngeal and nasal airways. Disinfection is required for this group. Low risk items only come into contact with normal intact skin. e.g. stethoscopes or washing bowls. Cleaning and drying is usually adequate for this group. Techniques of disinfection and sterilisation
		Before equipment is to be disinfected or sterilised, it should be thoroughly cleaned to remove any visible dirt or secretions. This involves washing with water and detergent (soap). Protective clothing (an apron, gloves and a facemask) should be worn. Disinfection is best achieved by moist heat such as boiling in water (100°C for 10 minutes at sea level) which kills all organisms except for a few bacterial spores. It is important to remember that the temperature at which water boils decreases with altitude and a longer boiling time will be required. e.g. at 4000m above sea level where boiling occurs at 86°C a minimum of 20 minutes is required for disinfection. It is important to note that boiling equipment items in water will not achieve sterilisation. Disinfection can also be achieved by using chemicals which however may themselves be toxic when allowed contact with skin or are inhaled. They can also be corrosive and flammable so that protective clothing (gloves, apron and a facemask) should be worn. Chemical disinfectants may be supplied ready to use or may need accurate dilution to provide an appropriate solution. It must be remembered that disinfectants can decay and lose activity. Decay is more rapid at high temperatures and can be accelerated by the presence of impurities. All disinfectants take time to work. Range of activity of disinfectants Gram positive bacteria e.g. Staphylococci, are more sensitive than gram negative bacteria e.g. Pseudomonas. Mycobacteria and spores are relatively resistant. Enveloped viruses e.g. HIV are killed by most disinfectants but non-enveloped viruses e.g. Coxsackie tend to be more resistant. Spores. Fungal spores are easily killed by disinfectants. Other bacterial spores e.g. Clostridia are resistant to most disinfectants in common use. Tubercle bacteria are more resistant to chemical disinfectants than other bacteria. They can be killed by exposure to 2% alkaline Glutaraldehyde solution (Cidex) for 60 minutes. Viruses. Hepatitis B virus (HBV) and Human Immunodeficiency Virus (HIV) are inactivated by Cidex in 1 - 2 minutes, although to ensure adequate penetration, soiled items should be placed in a 2% glutaraldehyde solution for 30 minutes. Exposure to 70% alcohol solution for 10 minutes is also effective. Viruses causing Rabies, Lassa fever and other haemorrhagic fevers are also killed by Cidex. Chemical disinfectant solutions Clear Soluble Phenolics (e.g. Stercol & Hycolin) are good for killing most bacteria including TB. They have limitied activity against viruses. Hypochlorites (e.g. Presept & Milton) have a wide range of activity against bacteria, fungi, viruses and bacterial spores. They may be used for decontaminating any area with blood spillage. They are corrosive to metals and must be applied at the correct concentration. They are inactivated by organic matter and decay on storage. Alcohols (eg methanol, ethanol & isopropanolol) have good activity against bacteria & viruses. They should only be used after all the visible surface dirt has been removed from the area to be disinfected. Aldehydes (e.g. glutaraldehyde & formaldehyde) are active against bacteria, viruses and fungi. They have a slow action against tubercle bacilli and are irritant to skin and eyes. Sterilisation This can be achieved by steam, steam & formaldehyde, hot air, ethylene oxide or irradiation. Autoclaving is the commonest method. It uses steam under pressure and is the most reliable way to sterilise instruments. A temperature of 134°C for 3 minutes or 121°C for 15 minutes is recommended. Formaldehyde is irritant to the eyes, respiratory tract and skin. It can also be absorbed by some materials and subsequently slowly released with potentially hazardous results. Hot air sterilisation takes a long time and items must be able to withstand temperatures of at least 160°C for periods of 2 hours or more. Ethylene oxide is a colourless gas which is toxic to inhale. It is effective against all organisms and does not damage equipment. The operating cycle ranges from 2 - 24 hours so the turnaround time is prolonged and it is a relatively expensive process. Sterilisation by irradiation is an industrial process and particularly suited to the sterilisation of large batches of products. Irradiation can cause serious deterioration of materials and is therefore not a suitable method for the resterilisation of equipment items. Summary of Decontamination Procedures Respiratory equipment Sterilisation is unnecessary since spore-bearing organisms are not a cause of respiratory infection. Infection hazards can be reduced by lowering the amount of condensation in a circuit by means of heat-moisture exchangers, moisture traps and by the regular cleaning and drying of valves and circuits. Many hospitals do not have access to disposable ventilator circuits and therefore with mechanical ventilators the internal circuit can often be autoclaved. The external (or patient) circuit and humidifiers may be disinfected in a washing machine at a temperature of at least 71°C for 3 minutes. The external circuit should be changed every 48hr or between patients. Heated water humidifiers should be cleaned, dried and refilled with sterile water every 48-72hr. If nebulisers are used they should be rinsed in alcohol after cleaning every 48 hours. Anaesthetic face masks should be washed and cleaned after each use. Laryngoscope blades should be washed after use and disinfected either chemically by soaking in 70% alcohol for 10 minutes, or by thermal means such as boiling in water at 100°C for 5 mins. Endotracheal tubes intended for single use can be re-used if they are cleaned and disinfected. Thermal methods are likely to cause material damage but following cleaning, chemical disinfection can be provided by immersing tubes in a solution of 70% alcohol for 10min. The tubes should then be allowed to dry before use. 2% glutaraldehyde is not suitable as it may be absorbed by the plastic and is too irritant. Suction catheters are not easy to clean but provided they are free of visible soiling they may be disinfected using 70% alcohol as descibed earlier and allowed to dry before use. Instruments Needles and cannulae (including spinal and epidural needles). After thorough cleaning these must be sterilised. In many situations autoclaving is the most practical technique

New Tools, Old Concerns in Inhalation Therapies

Neil Canavan

The development pathway for inhaled drugs may not be straightforward, but recent advances are making it an easier way to go

Everyone wants to breathe a little easier, have more room to breathe, maybe get a breath of fresh air. Given those truths, it’s a bit surprising that the central importance of the lungs, recognized in metaphor, doesn’t carry over to drug development.
“There’s a general fear of putting something in your lungs that’s not normally there,” said John Patton, PhD, founder and CEO of Dance Pharmaceuticals in San Francisco. “Nobody thinks twice about putting something in the GI tract that’s never been there before.” But put a foreign substance in the lung?
Yet the lungs have evolved numerous mechanisms to clear particulates or prevent their admission. In general this is good, but for drug development, this self-protection presents challenges. The obstacles are:

• getting the drug where you want it to go (the deep lung);
• making sure the formulation is appropriate for the lung (the right excipients);
• attaining the desired efficacy (which may require sustained activity); and
• getting a rat to take a deep breath (see case study).

Lessons Learned

Before considering the inhalation pathway, take a look at two fair warnings: Pfizer’s Exubera, and Mannkind’s AFREZZA, both inhalable insulins. Dr. Patton was the co-founder of Inhale Therapeutics (later called Nektar), Pfizer’s partner on Exubera. Long story short: The drug formulation worked, the inhalation device was a marketing disaster. “Pfizer got a heap of abuse about the so-called ‘bong,’ ” recalls Dr. Patton of the inhaler’s size and shape.
Marketing blunder aside, Dr. Patton remains impressed by the inroads made by the program, including therapeutic proof of concept. “We achieved identical glycemic control as you get with variable dose injections,” proving that insulin can be effectively administered via the lung; the formulation worked, and the device did, too. Second, insulin, a protein, was successfully formulated with novel excipients (amnnitol, sodium citrate, and glycine) in a combination that created a powder of high glass transition temperature, so it didn’t have to be refrigerated. A further innovation of Exubera’s development was the spray-drying methods, which are becoming industry standards.^1,2
As for Mannkind’s AFREZZA, “They used a new excipient, too,” said Dr. Patton, “but an unusual one, and a whole lot of it.” The excipient itself required additional safety tests, which were subsequently passed.³ “If you’re going to use an excipient,” Dr. Patton advised, “use ones that are endogenous, or have already been in other drug products.” Mannitol has long been in use. “And though both glycine and sodium citrate were new, both are endogenous.” He also suggested that, whatever the excipient, use as little as possible. (For a review of endogenous excipients, see Minne, et al. Eur J Pharm Biopharm. 2008.)⁴
The primary driver for the development of inhaled insulin is patient compliance—no needles, better compliance. Other systemic diseases may also be suitable for this approach; the most compelling reasons to develop inhaled formulations are the diseases of the lung, which can be treated much more effectively, and with less toxicity, using local administration. “There’s a bunch of killer diseases out there,” said Dr. Patton. “Lung cancer, sarcoidosis, pneumonia, pulmonary fibrosis ... the opportunities are broad and significant.”

New Dissolution Method

In the formulation of a drug for pulmonary delivery, a big part of the solution is dissolution. “There is quite a strong, established in vitro/in vivo correlation for orally administered drugs,” said Jason McConville, PhD, assistant professor of pharmaceuticals at the University of Texas, Austin. “Dissolution is performed, and knowing a drug’s solubility and how that effects its rate of uptake is quite well known. But for the lung there isn’t any such dissolution test currently employed for existing therapies.” Dr. McConville, whose research foci include advanced formulation design, set out to change that.
The challenge was significant. “The method I’m proposing is not the perfect answer—it’s impossible to mimic the lung,” he said. “One of the biggest issues is a gigantic surface area of essentially unknown composition—it’s even difficult to know exactly how much water is present.”
For his dissolution method, Dr. McConville adapted a commercially available dissolution device by the incorporation of a membrane-containing cassette. “The cassette was designed to enclose previously air-classified formulations, so that they could be uniformly tested in the dissolution apparatus.” His initial investigation looked at the utility of a composition of a simulated lung fluid dissolution media, the influence of particle size, and the amount of drug loading for a known standard, micronized hydrocortisone.⁵
“We created a bit of an obstacle for ourselves because we really wanted to simulate the lung, including a recipe for a simulated lung fluid.” The initial concoction, derived from the literature, exhibited an upward drift in pH over time, proving unworkable. Adjustments had to be made.⁶ “We worried about matching physiological conditions, which in the end proved futile. The best approach we took was just to treat the device as an in vitro comparison test for formulations.” He believes this technique will inform us about future controlled-release inhalable formulations to a degree not previously known.
One application Dr. McConville looks forward to is addressing the issues of drug loading—the subject of a recent paper of his on inhaled chemotherapy—and the potential of proposed sustained-release formulations.⁷
continued below...

Activaero’s AKITA Jet and AKITA APIXNEB pulmonary drug-delivery devices.

CASE STUDY: A Reliable Ventilator for Human Testing

You’ve got your inhalable formulation in hand and you’re ready for in vivo studies, but there’s a problem. “There are no animals on earth which you can train to breathe in a way that you can optimize drug deposition in the lung,” said Gerhard Scheuch, PhD, founder and CEO of Activaero GmbH.
As soon as it is ethically safe to do so, you need to test in humans. But there’s a problem: Not everyone breathes the same way. “You can imagine if someone is breathing very shallow, then the air is not getting deep and neither is the particle,” Dr. Scheuch said. A healthy subject could be instructed to take a deeper breath (though this is still subject to variation). When testing efficacy in an actual patient, diminished lung capacity may be a defining symptom of their disease.
Because variables of any kind are anathema to the experimentalist, Dr. Scheuch, a physicist and engineer by training, set out to create a type of ventilator that could reliably deliver a controlled inspiration flow and volume of aerosolized particles. The result is the AKITA APIXNEB system that not only controls flow but also, through the use of a vibrating mesh technology, can generate particles from most types of liquid formulations.¹
“This is a good technology for early clinical development because you can be assured that you can get the drug into the lungs, and that observed efficacy (and side effects) are not dependent on how the patient is breathing or manipulating an inhaler.”² It might also be cheaper. The device was initially conceived by Dr. Scheuch while he worked in collaboration with Bayer, to carefully dose a limited, and very expensive, supply of alpha 1 antitrypsin. “Using such a sophisticated inhalation system, you really get pulmonary drug delivery in the order of 80-85%.” And that helps everyone breathe easier. —NC

References

1. Watts AB, McConville JT, Williams RO III. Current therapies and technological advances in aqueous aerosol drug delivery. Drug Dev Ind Pharm. 2008;34(9):913-922.
2. Kirsten A, Watz H, Kretschmar G, et al. Efficacy of the pan-selectin antagonist Bimosiamose on ozone-induced airway inflammation in healthy subjects—A double blind, randomized, placebo-controlled, cross-over clinical trial. Pulm Pharmacol Ther. 2011;24(5):555-558.

Stay on Target

Regardless of the utility of Dr. McConville’s new assay, the true pharmacokinetics of any type of formulation must be established using human testing. For budding inhalation drug developers, this requirement adds an extra high hurdle because of the dearth of related human-derived data in the literature.
“There’s a lot of in vitro data out there for sustained release formulations, but only limited information for in vivo,” said Aliyah Sheth, Pharm D, Department of Pharmacy Practice and Science at the University of Arizona, Tucson, who recently completed a survey on the subject. “Unfortunately, the animal models for inhalation are poor, and much of the work doesn’t translate because of the inability to determine long-term effects.”
That said, there are promising sustained-release formulations, generally of a polymer of liposomal design, being investigated. A few with recent data include:

• DOTAP-modified PLGA: Inhalable dry powder nanoparticles were loaded with siRNA;⁸
• PEG(5000)-DSPE micelles: Polyethylene bubbles containing the chemo-therapeutic paclitaxel exhibited a sustained-­­­­release behavior;⁹ and
• Liposomes: A formula for sustained-release budesonide using freeze-dried liposomes is proposed.¹⁰

For her part, Sheth suggests investigators stick with phospholipid excipients because they’re endogenous, and polymers for their ease of being aerosolized. “Development of sustained-release formulations may take more time, but in terms of clinical need, the extra effort (and innovation) will be more than worth it.”

References

1. White S, Bennett DB, Cheu S, et al. EXUBERA: pharmaceutical development of a novel product for pulmonary delivery of insulin. Diabetes Technol Ther. 2005;7(6):896-906.
2. Depreter F, Amighi K. Formulation and in vitro evaluation of highly dispersive insulin dry powder formulations for lung administration. Eur J Pharm Biopharm. 2010;76(3):454-463.
3. Potocka E, Cassidy JP, Haworth P, Heuman D, van Marle S, Baughman RA II. Pharmacokinetic characterization of the novel pulmonary delivery excipient fumaryl diketopiperazine. J Diabetes Sci Technol. 2010;4(5):1164-1173.
4. Minne A, Boireau H, Horta MJ, Vanbever R. Optimization of the aerosolization properties of an inhalation dry powder based on selection of excipients. Eur J Pharm Biopharm. 2008;70(3):839-844.
5. Son YJ, McConville JT. Development of a standardized dissolution test method for inhaled pharmaceutical formulations. Int J Pharm. 2009;382(1-2):15-22.
6. Davies NM, Feddah MR. A novel method for assessing dissolution of aerosol inhaler products. Int J Pharm. 2003;255(1-2):175-187.
7. Carvalho TC, Carvalho SR, McConville JT. Formulations for pulmonary administration of anticancer agents to treat lung malignancies. J Aerosol Med Pulm Drug Deliv. 2011;24(2):61-80.
8. Jensen DK, Jensen LB, Koocheki S, et al. Design of an inhalable dry powder formulation of DOTAP-modified PLGA nanoparticles loaded with siRNA [published online ahead of print Aug. 12, 2011.]. J Control Release.
9. Gill KK, Nazzal S, Kaddoumi A. Paclitaxel loaded PEG(5000)-DSPE micelles as pulmonary delivery platform: Formulation characterization, tissue distribution, plasma pharmacokinetics, and toxicological evaluation. Eur J Pharm Biopharm. 2011;79(2):276-284.
10. Parmar JJ, Singh DJ, Hegde DD, et al. Development and evaluation of inhalational liposomal system of budesonide for better management of asthma. Indian J Pharm Sci. 2010;72(4):442-448.