Document ID: EPA-HQ-OPP-2016-0467-0011
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2016-08-10T04:00Z

Panel Members:
Matthew J. Arduino, M.S., Dr.P.H., FSHEA, RM(NRCM), M(ASCP)cm
Chief, Clinical and Environmental Microbiology Branch
Centers for Disease Control and Prevention

Joel Bozue, Ph.D.
Bacteriology Division
USAMRIID

Christina Egan, Ph.D.
Chief, Biodefense Laboratory, Wadsworth Center
New York State Department of Health

Lynne M. Sehulster, Ph.D., M (ACSP)
Prevention and Response Branch, Division of Healthcare Quality Promotion
Centers for Disease Control and Prevention

The panel was provided with Industry comments from the industry groups/individuals below:
 Copper Development Association (CDA)
 CuPron
 ASTM
 Antimicrobial Test Labs
 Olin Brass
 Rhonda Jones
Panel members were asked to respond to the comments from the various groups.
Arduino
General Comment: I don't think I'll be changing my responses.  There is a common theme among some of the industry regarding lengthening contact time back to the 2hr in the original protocol and to have a way to show continual activity whether this is done by multiple repeat inoculations or an additional reinoculation at some time point.  I do not have a problem with this.
My main concern with extending the time post inoculation is that the registrants would also account for loss because of the drying of inocula  (remember stainless steel has different surface properties that could influence persistence/survival).
Also I know the copper industry likes to influence others with the DoD clinical trial.  This is one small study (not well controlled and with potential bias).  One small study is not a body of evidence that copper surfaces prevent HAI.  We also believe much to industries dismay that not everything in a patient room would have to be clad in antimicrobial surfaces.
Our thoughts on what would be needed is in the attached editorial [McDonald & Arduino. 2012]
Specific Comments:
 CDA
 Topic- Continuous reduction claim
 Response- I understand why they would want reinoculation of surfaces to show that product continuously works; Would require reinoculation after x period of time from the first experiment;  Would they propose a cleaning step between serial trials?
 Topic- Contact time
 Response- I think contact time might be discted by the controls we know that organisms deposited onto a surface and allowed to dry may have significant loss in viability and the longer the contact time the harder it may be to demonstrate activity based on Cu alone.
 Response- With regards to the DoD study cited (Salgado et al, 2013), while it is a start the study did not address other confounding factors and does not reach the level of evidence needed see McDonald LC, Arduino M.  Editorial commentary: climbing the evidentiary hierarchy for environmental infection control.  Clin Infect Dis. 2013;56(1):36-9 (available from http://cid.oxfordjournals.org/content/56/1/36.long)
 Topic- Concerns regarding 1 hour contact time
 Response- I think other factors begin to play a role when extending out contact time of these is the impact of drying on the survival of the challenge organisms.  There is always some die - off;  other factors also play a role.  These factors include surface characteristics roughness, contact angle, surface charge, hydrophobicity, and relative humidity.
 Topic- DoD Clinical Studies
 Response- There are a number of scientific issues with these studies (including the surface sampling methods; not accounting for confounders, eg. Changes in hand hygiene,; bias etc); one study is not a body of evidence:  the three peer reviewed citations are the same study
 Topic- Testing does not mimic cleaning in hospitals
 Response- It is true that most cleaning in hospitals is daily; with exceptions being for special situations; spills (visible contamination of surfaces with blood or other potentially infectious material).
 Topic- Copper based products and contact time
 Response- Label claims are specified by the manufacturer depending on established contact times for their product; the problem with a two contact time is other factors may influence results.
 Topic- Test antimicrobial resistant strains associated with HAIs
 Response-This is not necessary, AR is not in a traditional sense associated with increased resistance to disinfection.  Tolerance may be seen but this is usually detected with disinfectants below the use-dilution of product.
 Topic- Humidity (RH or AH)
 Shouldn't product be tested under use conditions?  If this is the case the product will be used in "conditioned space" (US hospitals) so humidity levels should reflect at a minimum this RH or AH range.
 ASTM (Mary Bruch)
 Topic- General comment
 Response- Comments are editorial in nature
 Topic- Exposed/unexposed
 Response-Is it possible to use treated and untreated surfaces?
 Topic- 70% alcohol (perhaps better choice is 95-98%)
 Response- Well either way alcohol is not effective against bacterial spores and the optimum antimicrobial activity is between 60 and 80% (it's a bell curve with 70% being the most effective).
 Antimicrobial Test Labs (Diego Ugarte)
 Topic- Abrasion and Chemical Exposure
 Response- Use of a scouring pad may be a way to simulate aging.   Though traditionally these surfaces would not be cleaned with scouring pads but with the wipers that Diego says.
 Topic- Disinfectants
 Response- Some of the products EPA has proposed are commonly encountered in the healthcare setting, having the registrant specify (though they could choose a product based on capability with their product) may not reflect actual use in a healthcare facility where they may choose a single cleaning product for all surfaces.
 Topic- Test Protocol Prior to Finalizing
 Response- This may be a good idea and several people have mentioned this.
 Olin Brass- No additional comments. 
 Cupron
 Topic- Remove EDTA\Phosphoric acid as cleaning agents; stick to commonly used products
 Response- Yes these chemicals are not routinely used in healthcare for cleaning purposes;  These have been used in industry for cleaning metal parts (stainless steel, tiles, aluminum, concrete, etc), cleaning of RO membrane.
 Topic- Substitute > for at least
 Response- Agree
 Topic- Remove requests relating to visual appearance of the carrier post-treatment regimen
 Response- Main concern this is not the endpoint, however this may show surface damage.
 Rhonda Jones
 Topic- Intent of protocol
 Response- More of the question as to why non-food contact and whether protocol would be different for food contact surfaces
 Topic- Abrasion cycle time is intensive and costly
 Response- Several people have commented on cost and time of the procedure. Is it possible to reduce to one scrub cycle (1080 passes) and one long chemical exposure?
         
Bozue: I have read through the various responses and do not feel it necessary to revise my previously submitted answers to the charge questions.
         
Egan: After careful review of the comments received for review, I do not have the need to change my comments submitted in February.
         
Sehulster: 
General Comment- I read the comments documents provided and determined whether or not they were a match to the main points I raised about the EPA draft lab protocol for assessing antimicrobial potency of copper- and copper-alloy surfaces.  Briefly, I and some of these commenters focused on the issue of needing a lab method to measure continuous potency (the current method revision does not address this).  With regards to the abrasive testing part of the protocol, I can agree with the substitution of a quaternary ammonium compound for the EDTA-phosphoric acid, but I do question the labor-intensive and time-intensive aspects of this part of the protocol.  Two of the reviewers conducted the highly detailed critique of the protocol, raising good questions.  From the information and directives provided to me, I didn't apply that level of scrutiny but rather focused on addressing the general questions posed to us.
Basically, I'll stick with the vast majority of my original comments with the departures noted above and in the attached document.
Specific comments- I will address the comments made by other entities in chronological order from earliest to most recent.  
Re: Comments from Ms. Rhonda Jones (no date of submission)
Ms. Jones is commenting on the version of the potency test method released on 09/19/14.  Her first major point of concern is the duration and details (or lack thereof) of the method to evaluate the effects of abrasive action and chemicals.  She raised good questions, asking for clarification and background information.  The revised EPA test protocol of 02/03/15 addresses these questions.  The majority of Ms. Jones' comments are questions about specific details of the method in which she asks for explanations and additional steps to better eliminate process variations among labs.
 Her level of scrutiny is typical for a person who has extensive experience reviewing lab methods for microbial inactivation for registration purposes, and her questions are reasonable.  As for the task presented to me as part of the Letter Review of the revised lab method dated 02/03/15, my sense was that EPA wanted me to respond to general questions about the revision.  Had the agency's instructions for the Letter Review indicated that EPA wanted a step-by-step critique of the revised method, I would have done that.  My comments and questions would have aligned with those of Ms. Jones on the details.  However, I made a mental note that the agency appeared to be moving away from exquisitely detailed protocols, thereby allowing some room for process variation.  The lab technician, however, would have to make note of all the details done in some of the steps for EPA review and documentation.
Re: Comments from Dr. Mary Bruch (no date of submission)
Dr. Bruch is commenting on the version of the potency test method released on 09/19/14.  Her comments to the agency are similar to those of Ms. Jones, concentrating on detailed information needed for various steps in the protocol, with some editorial comments.  Dr. Bruch also has extensive experience in providing method reviews that are highly detailed and specific.  She raises an interesting point of discussion about "surface products" or "product surfaces."  The EPA revised method of 02/03/15 does not appear to comment on this question.
My statement that the 02/06/15 method appears to be reasonable is made with the awareness that several of the steps in the revised method could be more detailed, but my sense is that the agency is allowing some lab variation on some of the steps so long as the lab provides the agency with the details about said variations.  If my assumption is wrong, then yes  -  the method details as pointed out by these two reviewers should be addressed by the agency.
Re: Comments from Mr. Alastair Monk
Mr. Monk discusses a few major items in his comments.  The first point is the number and identity of the challenge microorganisms (he recommends only two, these being Staphylococcus aureus and Pseudomonas aeruginosa).  In my opinion, I view the agency's recommended challenge microorganisms of S. aureus, P. aeruginosa, and Enterobacter aerogenes to be appropriate selections for this reason  -  these bacteria are representative of bacteria commonly found on skin (S. aureus), bacteria found in water (P. aeruginosa), and bacteria found in fecal matter (E. aerogenes).  This selection covers the three main sources of contaminated reservoirs we would most likely encounter in settings where copper- and copper alloy fixtures and surfaces would be used for infection prevention.  Mr. Monk does make two good points about the abrasive test, saying that there should be a dry version and a wet version of the test, and a representative quaternary ammonium compound should be used in place of EDTA-phosphoric acid as one of the chemicals.  In concept, I would support these suggestions, but other reviewers have commented that in their opinion the abrasive testing phase of the overall test protocol is both labor- and time-burdensome.  With regards to contact time, Mr. Monk supports the two-hour exposure period, so he doesn't appear to comment on the notion of continuous potency.          
 Re: Comments from Mr. Andrew Kireta (CDA)
Mr. Kireta's two major points of discussion are the following: 1) the need to demonstrate continuous inactivation of microbes by copper and copper alloys; and 2) the need for the agency to gear up for validation testing of the protocol via intra-lab studies and inter-lab comparative studies.  My previous submission of comments to EPA centered on these two points as well.  Knowing the EPA laboratory professionals, I'm confident that the agency will pursue validation studies on this or any testing method they promote for regulatory purposes.  With regards to the issue of continuous potency, I have not seen any earlier version of the protocol in which this topic may have been considered, but a test does need to be developed to support any claim for continuous potency.  
Re: Comments from Mr. Diego Ugarte
Mr. Ugarte joins the other commenters in his questions about the abrasive test.  He basically asks about the rationale for the agency's selection of chemicals and experimental design points, and what happens from a registration viewpoint when a test lab misses the requisite number of test runs.  If EPA produces another revision to this method, responses to Mr. Ugarte's questions would be very helpful not only to him but to all the laboratorians who will be thinking of offering this testing to their clients for product registration.
Re: Comments from Mr. Kon John (Olin Brass)
Mr. John basically wants to keep the status quo.
Re: Comments from Mr. Joseph Green (CDA)
Mr. Green corroborates the earlier comment from his colleague Mr. Kireta regarding the issue of demonstrating continuous potency.  As I mentioned in my comments on the protocol and repeated elsewhere in this document, a validated lab method must be developed (if one doesn't already exist) in order to generate those data in support of a continual inactivation claim.  The lab test protocol dated 02/03/15 does not achieve this objective, as it clearly indicates a contact of two hours.