Bringing a High-Level Disinfectant and Automated Endoscope Reprocessor to Market

By Terry Mistalski and Brent Geiger

The intent of this article is to answer some questions regarding which government agency or department regulates different classes of antimicrobials (disinfectants, sterilants), as well what is required to develop a 510(k) submission package for Food and Drug Administration (FDA) review, comment and ultimate clearance related to new high-level disinfectants (HLDs) and automated endoscope reprocessor (AERs).

Since the subject has been covered many times before, this author will not re-cap the Spaulding Classification of appropriate levels of antimicrobial efficacy based on intended use of the device. This article will focus on high level disinfectants for Class II medical devices, specifically flexible endoscopes, and related accessories or ancillary devices.

The FDA definition of medical device originates in section 201(h) of the Federal Food, Drug & Cosmetic Act.  The formal FDA statutory definition is: "A device is an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:
recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them,
intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or
intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes."

Thats quite a definition! It is the same or very similar to definitions used by regulatory agencies around the world. AERs and associated high level disinfectants are considered accessories to endoscopes, which are used in the diagnosis and treatment of disease.   

So what are some other Class II medical devices? There are a huge number of class II devices, probably several thousand. Classification is dictated by the FDA classification database where each type of device is associated with a classification regulation number and a classification product code. The classification scheme is based on risk, i.e., class I is low risk and class III is high risk. The most relevant device classification regulation for flexible endoscopy is 876.1500 which covers all endoscopes and accessories. Classification regulation 876.1500 contains 110 different associated device product codes and includes endoscopes, AERs and disinfectants. The large majority of endoscopes and accessory devices under 876.1500 are class II devices cleared for market via the 510(k) process.

Why are some disinfectants regulated by the Environmental Protection Agency (EPA) and others by FDA? In general the difference lies in what is intended to be disinfected. Since 1996, FDA regulates them as medical devices products that are intended to be used to disinfect medical devices, while the EPA regulates disinfectants intended for general medical surfaces but not necessarily specific medical devices. Both types of products may have similar performance, but the FDA has dictated a specific set of strict performance criteria for high-level disinfectants intended for semi-critical medical devices that differs from EPA requirements. EPA covers hard surface sterilants for non-medical applications, hospital-grade disinfectants, broad-spectrum disinfectants, hard surface sanitizers, germicidal spray disinfectants for hard surfaces, and cleaner/sanitizers for surface. The EPA does not use the terms high-, middle- and low-level to refer to disinfectants, as does the FDA based on the Spaulding classification.

What is a predicate device, and why is it important? For practical purposes it means any device with existing 510(k) clearance. Predicates are important because as part of the 510(k) submission process the safety and performance of new products must be directly compared and substantially equivalent to existing predicates. It is challenging to achieve FDA clearance of new claims or new performances beyond what is already cleared as a predicate because in those cases the FDA requires specific testing/data to clearly and irrefutably show that any risks arising from differences from predicate devices are acceptable. Typically one or two predicate devices are references in each 510(k) submission. In the case of AERs and disinfectants, there are FDA guidelines available that dictate the specific types of testing required, so direct comparative testing to predicates is not typically submitted. But in instances where no specific FDA guidance is available, then direct comparative testing to existing predicates is used.

What changes to a device would qualify as a new submission (versus letter to file) for a device (significant changes, etc.)? The criteria for determining when to submit a new 510(k) versus just documentation of the change in your quality system for a device change is outlined in FDA guidance documents. The guidance currently in effect was issued in 1997 and outlines the criteria for determining when there is a significant change to a device.  FDA has issued updated draft guidance in July 2011 and the final version is still pending. Any device changes are evaluated against the criteria in the applicable guidelines and implemented accordingly. The fundamental basics of testing required for AER 510(k) submissions are outlined in the FDA guidance for premarket submissions of washer/disinfectors issued in August 1993.  ISO 15883-4 is a more recent document and is also a good reference, but it is not officially recognized by the FDA. This standard is recognized and accepted by many countries outside of North America.

The 510(k) submission package for a new AER will typically include these data packages:
- Simulated-use disinfection efficacy: Representative endoscopes (typically bronchoscope, gastroscope, colonoscope from several manufacturers) are inoculated with specified levels and types of microorganisms, and reprocessed. Effective kill rates are measured; target minimum reduction in the number of viable organisms is log 6.
- Clinical in-use disinfection efficacy: Representative endoscopes (typically bronchoscope, gastroscope, colonoscope from local hospitals) are taken post-procedure and after manual cleaning and reprocessed. Effective kill rates are measured.  Criteria for acceptance is no survivors
- Temperature, time, cycle function verification: To confirm and verify that the AER is capable of reliably running reprocessing cycles that deliver the HLD at the indicated time, temperature and concentrations.  
- Software validation: To validate that the software that controls the AER performs consistently and reliably as intended. 
- Hookup/endoscope connection validation: To validate that the means used to connect the AER to the endoscope performs consistently and reliably as intended for the delivery of HLD to all endoscope channels, and typically involved microbiological efficacy validation.     
- Rinse residual and biocompatibility: Toxic level threshold of the HLD are determined, and the endoscope is tested for the efficacy of the post-HLD rinse in the AER by determining the level of residual HLD on and in the endoscope.  Testing typically involves evaluation of post rinse residues after 100 or more consecutive cycles to confirm that HLD residues are reduced to safe levels after cumulative exposure. 
- Material compatibility testing: General materials used in the construction of endoscopes and similar/related medical devices or accessories, and all materials in the AER that are exposed to HLD are tested for compatibility with a range of HLD solution.
- Electrical safety and electromagnetic compatibility testing: Testing to recognized standards to assess the electrical safety and EMC of devices to ensure safe use in the laboratory environment.
- Risk analysis: Comprehensive evaluation and analysis of the acceptability of risks and hazardous situations that could occur during use of the AER.  Typically involves an analysis of failure modes and the resultant impact on the user/patient.  Situations that present a high risk are mitigated through design and/or labeling updates.   
- Human factors/usability evaluation: Testing or evaluation of human factors considerations to ensure/verify that usability of the AER is acceptable. 
In a similar fashion to AERs, the basic requirements for testing for high-level disinfectant 510(k) submissions are outlined in the FDA guidance for premarket submissions of liquid chemical high level disinfectants and sterilants issued in January 2000.

The 510(k) submission package for a new HLD will typically include: 
Complete and detailed description of formulation, stability, microbicidal mechanism, safety factors, buffering, MRC, etc This is typically just a written, whitepaper description of germicide properties and characteristics.
In-vitro efficacy tests: Laboratory testing of the microbiocidal properties of the HLD The HLD is tested under worst case conditions (at MRC and stressed with the addition of biological soil).

In addition to the data packages (for AERs), verification of the sensitivity and specificity of the chemical indicator (test strip) is required for HLDs. Antimicrobial testing against numerous current pathogens of concern such as Clostridium difficile, VRE (vancomycin resistant enterococcus) and MRSA (methicillin resistant Staphylococcous aureus) is not required. These organisms are all known to have lower resistance to disinfectants than the ones listed above. All of the above items are still required for 510(k) submissions of an AER and HLD together. If submitted together, then both products are required to be used together and therefore the HLD becomes AER specific, which can be viewed as both an advantage or disadvantage.

The FDA requires testing of representative models of all types of scopes, including those with architecture that is considered worst case.  510(k) submissions of new AERs or HLDs will typically include testing with representative bronchoscopes, colonoscopes, gastroscopes and duodenoscopes from various endoscope manufacturers. The important thing is to design your testing to represent a worst case scenario, and then clearly present to FDA your rationale for why your test set-up represents a worst case scenario.

For a new AER or HLD the 510(k) submission package is typically quite large (300-plus pages). For 510(k) submissions for a specific additional claim (i.e., cleaning claim) or a more simple change to an existing device, the submission package is typically smaller. The size of the submission is not really important, rather the important thing is that the submission contains all the required info and testing to support your device and its intended performance/claims.

The length of the 510(k) review process varies greatly depending on the nature of the submission. For new AERs and HLDs the entire process takes six to nine months. Experience indicates that FDA will respond with questions within 90 days of the initial submission, and then the submitting organization has up to 180 days to respond. There are typically at least two rounds of questions and correspondence back and forth.

Terry Mistalski is vice president of marketing and Brent Geiger is international regulatory affairs manager, both with Medivators.