Pre-clinical Antimicrobial Test Method Development

Hospitals and physicians are under pressure to prevent Healthcare Associated Conditions, commonly known as HACs, from occurring. This fairly recent focus on HACs, which are considered preventable, is due to  the changes in CMS reimbursement  for certain HACs, the continued focus by the government to further control Healthcare spending, and the recent public reporting of Medicare HAC rates. Infection is one of the major areas within the identified conditions. Three of the ten listed HACs are infections; specifically they are catheter-associated urinary tract infections, vascular catheter-associated infections and surgical site infections.  Healthcare providers are looking to the medical device industry to deliver novel products that not only continue to serve their primary function as devices but that include additional features to reduce microbial adhesion and colonization at the device surface, and ultimately prevent infections.

Antimicrobial technologies are often evaluated as potential options to give devices these additional features of microbial control and prevention.  However, there can be significant challenges and risks associated with the development of an antimicrobial device if the development team does not have prior knowledge and experience in the area of antimicrobials.  A common misconception with these projects is that it should take minimal effort and time to incorporate an antimicrobial because, in most cases, the technology is being applied to a device that is currently on the market.  This assumption usually leads to underestimating the testing and development work that needs to be performed to prove safety and efficacy of the antimicrobial device.

One of the biggest technical risks in developing an antimicrobial device is predicting clinical efficacy during pre-clinical testing. Ensuring that the in vitro testing is a good indicator of the performance of the device in vivo so that there are no surprises at the end of the project or once the product is on the market is a challenging requirement. It requires proper planning and design early on in the project to develop robust and clinically relevant in vitro efficacy models to evaluate the device. One challenge is that historically, the project team’s focus has tended to be on the design of the device and less on the development of test methods needed for evaluating the device. Particularly with a new feature such as an antimicrobial, it’s often not until the team is going through the Design Failure Mode Effects Analysis (DFMEA) process that they even identify the complete battery of testing that needs to be conducted. Significant time and resources are spent on the design of the product, but if the test method has not been properly designed and is not relevant to the end-use environment or challenging enough to adequately evaluate the effectiveness then, in spite of diligent design efforts, the product could fail to meet clinical requirements.

Developing in vitro microbiology test methods that are used to evaluate antimicrobial efficacy is a critical component in successfully launching effective antimicrobial medical devices.  In vitro efficacy testing is used at almost every stage of research and development to assess the effectiveness of the antimicrobial technology and the method to incorporate it onto the device.  Each phase in the product development process may require different efficacy methods depending on the goal of the testing.

There are quite a few antimicrobial efficacy test methods that have been published from different organizations, such as ASTM, ISO, AATCC, and JIS, in an attempt to standardize antimicrobial microbiology testing. It would be ideal to have one test method that could be used for all devices and every technology but, as with most standardized test method, this is not presently the case.  The best use of a standardized method is to provide the basic framework for the development of a customized test method for a specific end use and with a particular technology or set of technologies in mind. The level of evaluation and debate among the experts that are behind these standardized methods lend credibility to the customized method that is being developed.

Several factors should be considered when choosing a standard method and while making modifications to that method.

The first thing to take into consideration when designing a test method is the purpose of the desired testing and the stage of the project when the method will be used. While in the research stage, a high-throughput screening method is ideal to quickly and efficiently compare and rank several the technologies. Once a specific technology has been chosen and the project moves into characterization and optimization, it is important to use an in vitro method that is more tailored to replicate the end-use environment that the device will be in, and to start to simulate the desired duration of use. During verification and validation testing, it is a best practice to validate the test method prior to initiating the testing protocol.  

The second thing to keep in mind while developing an antimicrobial test method is the chemistry and mode of action of the technology. This can be a difficult task while evaluating several different technologies to create a true one to one comparison. Some test methods or certain inoculation media can favor a particular technology over another. For example, if the goal is to compare two eluting technologies and one operates on the principle of simple hydrolysis to release the active component, while the other works by exchanging ions to release the active, then testing these two technologies in deionized water would favor the technology that simply dissolves over the other which would not have sufficient ions with which to exchange. This would potentially eliminate an effective technology due to poor test method design.The chemistry must also be considered when choosing a neutralizing agent for the method. The neutralizing agent inactivates the antimicrobial after the desired contact time with the microorganisms so it cannot continue to have an effect. This agent must either be broad enough to neutralize all the different technologies being evaluated or different neutralizers must be used to ensure proper neutralization of all antimicrobials during testing.

A third area to consider is the clinical end use environment of the device. It is important to make sure that the antimicrobial technology is thoroughly challenged in a clinically relevant environment.  For example, an antimicrobial wound dressing that is intended to be used for three days should be exposed to a simulated formulation of wound exudate that would be similar in chemistry to the actual fluid found in a wound to account for any potential interaction between the active agent and the proteins and ions that are present in the wound bed. The device should also be exposed to this fluid for the intended duration of use to evaluate the sustainability of the technology.  This pre-conditioning of the antimicrobial device in a chemically relevant simulated fluid, such as wound exudate, blood, urine or mucus, for an appropriate amount of time is vital to successfully predicting efficacy in the clinical environment.

The task of developing pre-clinical efficacy test methods is not an easy one. And it shouldn’t be taken lightly or left to the last minute. The engineer or scientist assigned the job of creating a test method to evaluate efficacy must have considerable knowledge in several diverse areas. She must understand the clinical use environment, the chemistry and mode of action of the antimicrobial technology, and the intricacies of microbiology. This task is often outsourced to the third party laboratory that will perform the microbiology testing with the assumption that this is an area of expertise for the laboratory. But typically these testing laboratories lack the understanding of the antimicrobial technology, either because the device manufacturer has blinded them to it or simply because they are not familiar with it.  If the method development is taken on in-house, by the design team, they commonly also lack a deep understanding of the antimicrobial technology and often are inexperienced in microbiology test methods.

It is fundamental to the success of the project to objectively assess the capabilities of the project team at the start to address these areas that are critical to proper antimicrobial test method development. Early on in the research stage while choosing a technology, a factor not to be overlooked (but often is)is the experience and knowledge of the organization behind the technology.  Ideally the antimicrobial technology provider should be an active member of the project team. Typically, the source company of the AM technology possesses the combination of expertise in the technology and microbiology test method development that is critical to the project. Choosing an antimicrobial company that also offers a partnership to develop the device as a part of the team, taking ownership of critical tasks, will position the project for success.  Assembling a knowledgeable and experienced project team is the single most important step towards successfully developing pre-clinical methods that can reasonably predict clinical efficacy. Once the test methods are in place, the team can focus on the other challenging aspects of developing an antimicrobial device, such as product design, antimicrobial characterization and regulatory submission.

Jeffrey A. Trogolo, PhD., Chief Technology Officer, Sciessent LLC
Dr. Trogolo directs Sciessent’s technology operations and product development, and was an original member of the team that founded Agion Technologies. This work has earned him the 2006 Technology Pioneers Award from the World Economic Forum.  He joined Agion in 1998, after serving as Staff Scientist and Research Director for orthopedic device applications at Spire Corporation, a medical device surface engineering company. While at Spire, Dr. Trogolo developed silver antimicrobial applications using ion beam assisted deposition onto metal and polymer substrates and surface modification processes for improving artificial joint performance. Prior to Spire Corporation, Dr. Trogolo operated Niche Microstructural Corporation, a materials characterization and consulting firm serving clients such as General Electric Company, Knolls Atomic Power Laboratory and the United States Army Research Laboratory. Dr. Trogolo has published papers in various journals including the Journal of Materials Science, Journal of Electronic Materials and proceedings of the Society for Biomaterials and the Materials Research Society. Dr. Trogolo earned his B.S. and Ph.D. in Materials Science and Engineering from Rensselaer Polytechnic Institute.  Dr. Trogolo is an inventor on 11 issued and eight pending U.S. Patents. Dr. Trogolo is on the board of directors of Solutions Benefiting Life (SBL), a non-profit organization with a mission to bring cleaner, safer water to the developing world.