Infection Control Today - 02/2004: BUILDING THE PERFECT GERMICIDE

From idea to finished product, the birth of germicidal products is a lengthy process

By John Roark

It starts with an idea, says Pat Braden, chief chemist and vice president of research and development for Medical Chemical Corporation. Someone says, I think this is going to work better than whats out there, or, Something out there works, and lets do that too. You start with an idea, and then you do the background studies is it going to work? How can it be optimized? Once you get something that you think is workable, thats when you start looking at clinical studies.

Obviously, each company would like to be first on the block, says Jeanne Medvick, clinical studies group manager for STERIS Corporation. We hold brainstorming sessions with the scientists, with the marketing personnel and anybody else who has an idea. You can sometimes get an idea about something thats already on the market, and you think, Thats a good product, could we make it better? How can we distinguish ourselves from it? and also events in the world start you thinking about new ideas or new applications of what you already have.

Medvick cites recent incidents involving anthrax distributed through letters. We asked: do we have anything to combat that? Do we already have it, or can we develop something? Things like that can also stimulate creativity. Youre always trying to think ahead you would like to be ready to meet the needs, rather than be reacting once it hits. Whoever would have thought that the coronavirus that causes SARS would be a problem? Coronaviruses have been around for a very long time. What were the factors that made them so virulent in 2003?

I have been around microbiology for more than 30 years, Medvick continues. Back in the 1980s I thought, nothing new will ever be needed; well always have a chemical for every organism either an antibiotic to kill it in humans, or one of the chemicals to wipe it off surfaces. Im so very humbled now I almost get this feeling that were back in the pre-antibiotic era. Humans have evolved stronger we live longer, we look younger than our ancestors and thats because weve adapted. Unfortunately the harmful microorganisms have adapted too.

I think all industries that have anything to do with healthcare take their customer seriously, whether they manufacture hand sanitizers, germicides or sterilizers, says Medvick. They recognize that they have to have input from their customers in order to bring something to market thats going to be helpful in controlling hospital-acquired infections, and to be able to develop a viable product that customers need. Its kind of difficult because some customers have really grand ideas they are very, very good. But sometimes its hard to put all the good ideas into one package right away.

Customer input can reach manufacturers in a variety of ways. Information relayed back via the sales force, focus groups, surveys and attendance at healthcare conferences. We seek out customers on an individual basis and through professional organizations, and also keep updated with the regulations and guidelines from the CDC, the FDA, and the EPA theyre our customers also, says Medvick.

When evaluating germicides from a clinical perspective, Nancy Bjerke, RN, MPH, CIC, an infection control consultant in Texas, asks a lot of questions. Youve got to decide what it is you want it to work for and basically list the characteristics that you want a basic product to have, she says. Is it effective against the environment? Is it multi-purpose can you use it on the floors, the walls, the furniture? Is it fast-acting? What is its spectrum of microbial activity? Does it get all the viruses, all the bacteria? Is it EPA or FDA approved, depending on what its uses are going to be? Is it safe and effective in actual use? Does it destroy any of the building materials or instrument surfaces? Does it come full-strength or is it concentrated? What are the human factor requirements in point of use do you have to wear personal protective attire? Does it have to be a well-ventilated room? Does the label claim meet the requirements of proper use, instruction on use of the product, counter-indications, and cautions if there is an exposure that occurs? It should also have a contact number on the label, as well as the EPA registration number so that you can go to a website and actually check that yes, it is effective. You can also call into any of the EPA sites and see if there have been any adverse reports on it.

What would be on the ICPs wish list for the perfect germicide? You would have an active agent, either a germicide or a sterilant that you knew would kill absolutely everything in sight: bacteria, viruses, fungi, micobacterium tuberculosi, says Medvick. Yet it would be compatible with all the substrates (the material components and surfaces of instruments and devices), even those used for very delicate operations. For example, instruments used for eye surgery are made of titanium or brass and copper; metals flexible enough to be used in tiny areas, but softer, which means they can be adversely affected by chemicals that are relatively strong. You want a germicide with broad spectrum activity, and you want something thats compatible with whatever is being disinfected or sterilized. Because lets face it those instruments are very expensive to replace, and you want them to last.

A clinician would look for something thats a super-killer of microorganisms, yet can be handled safely by humans on a day-to-day basis, says Medvick. Not only the humans who are using it, but whoevers going to come into contact with it afterwards, such as the patient lying in bed. You want to clean and disinfect their room, but you dont want to overwhelm them with anything that has such a potent fragrance or odor that it would make them uncomfortable, or irritate membranes or skin.

I would venture to say that most of us would like something that is totally biodegradable, says Bjerke. Its not going to harm us when we get it on us, whether we use PPE or not, and that we can dispose of it safely down our normal sewer system. If it comes in a concentrated form that we can dilute, thats better. The ideal product would be something that is not causing occupational exposure and damaging materials.

Truly, anything that will not corrode or be flammable or dangerous, destroying or deteriorating any of the surfaces that the agent is going to come into contact with would be the ideal, continues Bjerke. Plus, it takes care of the full spectrum of known and unknown microbes that were dealing with in a healthcare facility. From the vendors perspective, can we use it in the acute care facility, but also in private practice? What I find when I consult and go into doctors offices or clinics whether theyre dental or radiology, surgical or endoscopic, their cleaning procedures leave a lot to be desired. And in many cases there is none behind the reception room. So if you could get something that would be applicable in all of those areas where bioburden is truly a risk factor, that would be very advantageous.

The Process

The road is not a short one, with many products taking as long as five years to be granted approval. The EPA and the FDA have jurisdiction over product approval. That is a real pain in the neck, says Braden. Low-level disinfectant sterilants are EPA registered and high level are FDA registered. Deciding between the two can be an issue, and its not really straightforward. When they split up the jurisdictions, they basically claimed that it wouldnt be a problem. Its a problem.

Lets say that we have a product thats used as a high-level disinfectant/ sterilant, continues Braden. We know that it also could work well for low-level stuff people would just as soon use that. You can not mention low level on your lable anywhere. You cannot even explain what low level disinfectants are. We originally included information about how to decide if you need a low-level or a high-level disinfectant in our insert. The FDA made us take out all references to low-level, period. We couldnt even use the word. They said that would be an EPA claim, just using the word. They seem to be jealously guarding their territory.

Theres a lot of toxicity testing thats involved not only toxicity relative to humans, but toxicity relative to the environment, says Martin Favero, PhD, director of clinical and scientific affairs, Advanced Sterilization Products. A lot of the constraints and standards that are extant today werent in existence 12 to15 years ago. There was a time when we literally didnt have an EPA. No one really worried if you put a product down the drain if it was going to kill some fish.

The way that the process goes is we submit whats called a 510(k), continues Favero. These types of germicides are referred to as whats called a Class 2 device. The FDA says to be classified as a high-level, a disinfectant it needs to do A, B, C, D. We perform tests, and submit those data to the FDA for review. Quite often we meet with them before we submit, just so that we can introduce them to our protocols and so forth, and see if they have suggestions.

You can get guidance from the FDA, says Medvick. They wont tell you how to develop a product, but you can always ask generic questions to see if youre on the right track. You have to be pretty sophisticated to develop a product. Its not something that someone can do in a quick snap.

Once you have the idea of what you want to attack, you have to look at what are considered active ingredients that the EPA and the FDA accept as antimicrobial or antiseptic ingredients. Theyve got certain ingredients that they know are germicidal. Youre going to use an ingredient that has been identified as antimicrobial by either one of those two regulatory bodies. Then you have to make sure through feasibility studies, that when you come up with a formula, youre going to test it for efficacy. Youre also going to also do stability tests. Theres no point in bringing a product out thats only going to be stable for 24 hours. Youre also going to have to do some safety testing even, for example, inhalation testing to make sure its not harmful. So, theres a whole process even before you get out there with the final formula. Plus, once youve done all of these studies, youve got to present them to the EPA for registration.

It was decided about 10 years ago was that the FDA would regulate sterilants, continues Medvick. A sterilant is something that will kill absolutely everything that we know of today. For example, bacterial spores such as anthrax that is the hardest thing to kill. Then you go to Micobacterium tuberculosis. Then you have some viruses. Then you have fungi, then Staphylococcus aureus. The FDA regulates those sterilants used for surgical instruments that are going to cut into a body. You want absolutely nothing on them.

The EPA regulates what we call disinfectants that we use from a concentrate, diluted with water, will kill Micobacterium tuberculosis, fungi, viruses, and Staphylococcus pseudomonas. Most disinfectants are not sporicidal because they will not kill 100 percent of spores. Thats why you wouldnt use them for surgical instruments.

For products being reviewed by either the EPA or the FDA, criteria must be met, says Medvick. For example, lets discuss disinfectants and the EPA. If you say you have broad-spectrum activity, youve got to show them test results done on bacteria, fungi, and viruses. The testing methods have to be recognized by the EPA as standard testing methods. If you dont, how can you compare one companys product to another companys product? You show them the methods and the results. Also you have to show them any safety studies you have done to prove that your new product is nontoxic to humans. And stability testing is important, too. You have to go in front of the EPA and defend your product: show that you knew exactly how it was tested. Its a very rigorous process.

Not only are the testing methods important, but the microbiology laboratories where you tested whether internal or external must be in compliance with Good Laboratory Practices (GLP). They will question you on calibration of your scales and your temperature controls, says Medvick. Everything is scrutinized. After all, neither a manufacturer nor the EPA wants to bring out a product thats going to put anybody at risk, because they are assuring the user of that product that if its used correctly, according to the directions, the user will have a decontaminated or disinfected surface.

As part of the development process, certain technical items must be written and published. If you ever took a look at the label of a disinfectant, youll be there for two days you have to list everything, says Medvick. The EPA has strict regulations as to what should appear on a label: the name and the registration number should be front and center so its not missed; all the activity against the different microorganisms, how you store it safely, how you dispose of it safely, and also during the use of the disinfectant, using personal protective equipment (PPE). Thats because youre around potentially contaminated organic soils, but also, if its a concentrate, some companies may have you wear protective equipment when you dilute it to protect your eyes. A concentrate can be very powerful, and you dont want any splashing to occur.

Anything you need to know about a disinfectant can be found on the label, especially the directions for use.

Thats what a lot of people have a hard time understanding: if a company says one ounce per gallon, thats exactly what you should use says Medvick. Im sure you know people who say, If one ounce is OK, then two ounces will be better. Thats so dangerous.

Every product must have a material safety data sheet (MSDS). This is required to list all hazardous ingredients contained in the final formulation, says Medvick. The EPA has certain chemical levels that they define as hazardous. The MSDS is also used to define anything that may be carcinogenic. And obviously, most companies stay away from any of those ingredients. But you may find that its necessary for a complete formula.

What Happens Tomorrow?

Is there a brand new germicide on the horizon, a new entity which will surpass the products of today? A lot of products come on the market, but when you look at them theyre just reformulations, says Favero. Usually the only thing new about them is the marketing hyperbole that goes along with it.

Bjerke agrees. When vendors come in with new and improved, we want to know, really, is it? They cant release the formulation or the recipe as we say, because thats patented. What we have experienced is that some of the manufacturers just slap on a new label that says New and Improved, and they have not changed formulations. If you look closely, the EPA number may not have changed, but the label did. The label may be new and improved, but the contents are not. And then they can charge more for it. You have to be pretty astute when youre evaluating your products from that perspective.

Probably the biggest need is to come up with standards, says Favero. Everyone agrees that cleaning is a very important step, but how do you know that? We have biological indicators and chemical indicators, but we dont have any clean indicators. There are some companies that are approaching that, but basically what it comes down to with practice is visual inspection. Does it look clean? If the answer is yes, then they assume its clean. But relatively little is published in the literature on this. People are working on this. Theres a committee for the Association for the Advancement of Medical Instrumentation (AAMI) thats working on five or six methods. Some are easy to do, some are hard to do. None of them have caught on yet.

Im a strong advocate of objective product standardization in the facility, no matter how big or how small you are says Bjerke. And this is an area that is not really touted a whole lot by any of the professional groups. When I see CDC mention subjective criteria, for selecting product, I have some real concerns about that. But thats all opinionated, and somebody ultimately has to make the decision, so what do they make the decision on? The most yea votes, or the most reasonable? Many times it comes down to financial decisions which is the cheaper that we can get, whether its the best investment for the dollar or not.

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