SGDEPARTMENT OF HEALTH AND HUMAN SERVICES

 

FOOD AND DRUG ADMINISTRATION

 

CENTER FOR FOOD SAFETY AND APPLIED NUTRITION

 

 

 

 

 

 

 

 

 

CONTAMINANTS AND NATURAL TOXICANTS SUBCOMMITTEE

 

OF THE FOOD ADVISORY COMMITTEE

 

 

 

VOLUME II

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Wednesday, March 19, 2003

 

8:39 a.m.

 

 

 

 

4700 River Road

Riverdale, Maryland

 

PARTICIPANTS

 

Francis Fredrick Busta, Ph.D., Chair

James E. Heubi, M.D., Co-Chair

 

MEMBERS

 

     Alex D.W. Acholonu, Ph.D.

     Lawrence J. Fischer, Ph.D.

     Marion H. Fuller, D.V.M.

     Lawrence N. Kuzminski, Ph.D.

     Ken Lee, Ph.D.

 

ACTING INDUSTRY REPRESENTATIVE (NON-VOTING)

 

     R. Bruce Tompkin, Ph.D.

 

TEMPORARY VOTING MEMBERS

 

     James Anderson, Ph.D.

     Robert D. Baker, M.D., Ph.D.

     Larry R. Beuchat, Ph.D.

     Henry M. Blumberg, M.D., Ph.D.

     Margaret E. Briley, Ph.D., R.D., L.D.

     Laurie J. Moyer-Mileur, Ph.D., R.D., C.D.

     Marguerite A. Neill, M.D.

          Virginia A. Stallings, M.D.

     Phillip Tarr, M.D.

     Patti Thureen, M.D.

 

 

 

 

 

 

 

 

 

 

 

C O N T E N T S

 

Page

 

Opening Remarks                                              4

 

Questions from the Committee                                 7

 

Subcommittee Discussion of Issues,                          47

Recommendations, and Response to Charges

P R O C E E D I N G S

Opening Remarks

     DR. BUSTA:  Good morning.  It looks like we are all here on time and ready to go, bushy-tailed and no snowstorm, here in College Park.

     If we could convene the committee meeting at this point.  A few announcements.  First of all, microphone style.  It's the switch closest to the mouthpiece into which you speak, that is the off-on switch, the one that is closest to the end of the microphone.  The bottom one, you just don't bother with.  Just work with the top one, that is the on-off, and it has to be turned off when we are not using it because we get a lot of feedback if we don't.

     The second important announcement.  On the sheet that we got yesterday called Charge and Questions, the most recent draft, if you would strike "Draft," because those are our final questions that we are addressing today, so it is really not a draft.  That is the set of questions that we are addressing.

     That is the one that, if you recall, the third line in Charge 1, No. 1, is factors, not facts.  That is how you differentiate that final draft, last draft, but it is no longer a draft, it is, in fact, the Charge and Questions.

     A number of committee members have indicated that there are some questions they would like to ask for clarification and explanation this morning before we continue on with our discussion of the charges and our committee responses, so arbitrarily, we are going to take 30 minutes.  We will limit it to 30 minutes of asking questions of the presenters from yesterday.

     We really need to limit it to 30 minutes, so we will try to be succinct in our questions because otherwise, we could spend I imagine the whole day grilling various people for details, so I think just key questions, we will take 30 minutes and try to get some of those clarifications made this morning.

     If the individual isn't here that needs to answer the questions, then, we will just have to go on.

     Are there any other items that anyone on the committee would like to bring up?

     The approach to the questions that we are contemplating, not necessarily final depending on your committee, for example, after the first 30 minutes, again discuss Charge 1 as we were doing just before 6 o'clock yesterday, discuss that as best we can, and the Chairs will do their best to summarize what that discussion was and what we think is a consensus and see if everyone agrees with that consensus.

     If there are dissenting comments, then, obviously, those can be put in the record, as well.  If that doesn't work well, we can go around with each individual making a statement, but we will try that approach first.

     Is that all right with everyone?  We will give that a try.

     I see Dr. Tompkin with a microphone in his hand, poised and pointed, so I assume that you wish to start.

     DR. TOMPKIN:  I would just like to make a comment. As we progress with the discussion and as we try to reach a consensus, there will be some issues where we don't have all the data we need, and are we capturing the data gaps separately, because we can only take a discussion only so far in the absence of more data.

     So, can we somehow create a parking lot for those kind of things as we move through, and then come back and discuss them further?

     DR. BUSTA:  I think that is an excellent comment, as always.  We will do our best to capture those here, and I would think that Charge 2, No. 4, Critical Knowledge Gaps, would be the place to accumulate those, and that is toward the end.

     The other thing is that you all should have gotten four handouts from the public comment group that are the slides that they used in the last presentations.

     Questions for clarification.

Questions from the Committee

     DR. FULLER:  Two questions.  One is if we can have anyone from the industry that spoke yesterday, one of the questions we had asked early on had to do with what were the steps taken in, I believe it was the Norwegian plant, that resulted in their not having problems further.

     Then, the second question, totally unrelated, has to do with the temperature of mixing the powdered formula, and we heard that boiling water created problems with protein coagulation.  I am curious, because we also heard that 70 seconds at just a few seconds resulted in significant kill, you know, what happens at 75 degrees C or 80 degrees C, do you still have that problem.

     DR. BUSTA:  Do we have an industry representative to respond to that?

     DR. SMOOT:  I will try to respond to the first question regarding the Netherlands plant.  After the situation that occurred and the data that was used yesterday to demonstrate microbiologically improvements in the process and the environment, the primary actions that took place were in the hygienic design of the process equipment itself where there was an elimination of water used.

     Part of the spray dry process is a water scrubber, so we found in the environment, there were pockets in areas that were designed into the process that brought more water into this dry processing environment.

     So, there was considerable engineering redesign efforts to improve the process and eliminate the water that was currently in that type of process stream and to improve the management and use of water in and around that area, as well as the knowledge to further investigate breakdown equipment, design equipment that is easily accessible, you know, designing in the cleanability of the equipment.

     These were the types of things that were the primary, as well as then enhancing our surveillance in terms of the efficacy of good hygienic practices that were being taken in the factory at that time, you know, a continuous improvement.

     These are the types of things that, in that particular factory, as well as learning some best practices there, have been continually being spread throughout that particular organization.  I am sure the learnings there have found their way throughout the infant industry, as well.

     DR. FULLER:  So, did you end up having to replace equipment or were they able just to make changes to existing equipment and water, and I understand you did say water use, as well?

     DR. SMOOT:  Both, there was both.  I mean there was redesign of unit operations, as well as replacement of equipment.

     DR. FULLER:  Thank you.

     DR. SMOOT:  I don't believe I would be qualified to approach the second question.

     There is a point of information from Bruce.

     DR. TOMPKIN:  The data that you provided were data on product.

     DR. SMOOT:  Correct.

     DR. TOMPKIN:  In addition to that, there was a lot of samples collected, I would assume, from the environment, and those data are not included, so whereas, in each year, you had 700 to 900 and some samples analyzed of product, that was supplemented with some additional environmental samples.

     DR. SMOOT:  Correct.  The data that you I believe now have a copy of, in that one table, that was a focused study that ran concurrent to the normal process monitoring for finished product, which you have seen again cited in the Codex risk profile, and many of you have made reference to where there is a more stringent norm for coliforms, less than 0.3 npn/gram.  That was the normal operating monitoring for finished product.

     This dataset that you have access to was a concurrent focus study to look deeper into that, and then as Dr. Tompkin pointed out, as a supplement to that enhanced environmental monitoring, was also taking place at the same time, yes, and that data has not been shared.

     DR. HEUBI:  Just a quick question also about that data.  Is that product that was actually stored in like a bag and then checked, or was it tested during the process of drying?

     DR. SMOOT:  I would say that I don't have intimate detail, but knowing the nature of the process monitoring, it would have been minimally into the big bag tote stage of the process.

     DR. BUSTA:  Dr. Kuzminski.

     DR. KUZMINSKI:  This is for Dr. Smoot, a question. On your slide yesterday, it's on page 4 of the handouts which were provided this morning, and thank you for that, the slide yesterday on current manufacturing intervention strategies, and you outlined there programs and practices, such as HACCP, supplier QA, et cetera, all the way from the raw materials to the finished product steps of the manufacturing process.

     My question is related to this.  If we consider the Tennessee incident in 01 as an event, were all of these practices in place at that point in time?  I am not saying that your organization is linked to the Tennessee event, I just don't know--

     DR. SMOOT:  I would have to defer specific comment to that particular event to people more knowledgeable of the quality and safety procedures in place.  I could not speak for that particular event.

     DR. KUZMINSKI:  Is there someone here, others from the industry, that could answer that question?

     DR. SMOOT:  Yes, I believe so.

     DR. MARCH:  My name is Dan March.  I am with Mead Johnson.  Yes, I can say that the HACCP programs were in place at the time.  We looked at the quality of that product at release.  It was probably one of our best batches microbiologically that we had produced under the standards that currently existed at that time.

     DR. KUZMINSKI:  Thank you.  If these processes or programs were in place at that time, what different has industry done since the event in 01?

     DR. MARCH:  HACCP is an evolving process, and it is always open to improvement, so we have instituted improvement in our HACCP programs in the plants to take account for some things that we had not noticed in the past, such as use of water and minimization of water in certain processing.

     We have gone to a higher level of HACCP, looking at different control points or controlling what we thought were critical control points to a higher level, so it is an evolving process.

     DR. KUZMINSKI:  And the sampling plant that was described on finished product yesterday, the 5 grams in 5 for the Enterobacteriaceae.  That would be something new in terms of the evolving HACCP, to verify HACCP.

     DR. MARCH:  Yes, it would, exactly.

     DR. KUZMINSKI:  Thank you very much.

     DR. BUSTA:  We had a second half of a question on the lower temperature, 70 to 80 degrees C causing coagulation or clumping in the product.  I know the statement was that very hot water caused clumping yesterday. Does that occur at 70 or 80?

     DR. MARCH:  I can speak to that.  We had done studies with the boiling water and had shown that there is an immediate, as Dr. Buchanan's graph showed, there was an immediate loss of temperature when you add boiling water to product that is tempered at room temperature.

     So, you have to take into account there is immediate loss of temperature, so therefore, in order to get the temperatures of what we would say pasteurization around 70 degrees where the kill is most effective, you do need to heat it up somewhat, 85, or something like that.

     We do know that somewhere in that range between that temperature and boiling, there is going to be some effect on the protein, potential coagulation.  Again,  vitamin C losses will still be substantial in the presence of oxygen and heat.

     Also, we do need to consider the potential burn hazard even at 75, 80 degrees to the preparer and also to the infant.  Does that help?

     DR. BUSTA:  Dr. Stallings.

     DR. STALLINGS:  To clarify that, then, if we were talking about preparation in the home, we could ask people to boil water and add it to room temperature formula or in a nursery setting.

     What would be the temperature that we would achieve in that sort of setting, are we going to be at the 70 degree killing temperature, or are you suggesting that if you did that--part of what we are trying to figure out is, is that effective in killing bacteria that would be in the product at the point of preparation.

     DR. MARCH:  Was that to boil the water, cool it, and then prepare products with it?  I am sorry.

     DR. STALLINGS:  I thought the question may be a misunderstanding, it was about preparation of a dry powder, so if I were doing that at home, I would be boiling water, adding it, and you reminded us that you have an immediate temperature drop, and what is the temperature of a mixed formula, and it cools.

     The question is are we going to get any killing if we use that.

     DR. MARCH:  Yes, there would be an immediate kill. If you used boiling water, there would be an immediate, once mixed, immediately, but the graph that Dr. Buchanan showed, showed that there was an immediate loss of temperature down to somewhere around 80, 85 degrees.

     That is still too hot, and it showed by leaving that out over a period of time, the cooling curve did flatten out, so it took much longer then to drop down once it reached equilibrium with the product, it remained at a temperature that is still capable of causing burns.

     DR. STALLINGS:  What is an acceptable serving temperature just so we have an idea of what that number would be?

     DR. MARCH:  An acceptable serving temperature is probably going to be around body temperature, you know, 98 degrees or something like that--37 C.

     DR. STALLINGS:  Let's stay in one unit or the other.  So, we are starting out with boiling water at 100.  We mix it, we are at 80 something.  We have got to let it, in an equilibration, come down to 30.

     DR. MARCH:  That is correct.

     DR. LEE:  On the same subject, you know, I bottle fed three of my own at home.  One of the first things I do is I pour some of the formula on my hand to make sure it is not too hot.

     Are we saying that these healthcare professionals are not capable of observing the temperature of what is being fed to the neonate?  I am kind of missing--there seems to be some significance given to the potential burn hazard to the healthcare worker and to the baby, but I think most parents do this at home all the time, so I am just wondering what is different, because to me, it's a tradeoff to kill these bacteria.

     DR. MOYER-MILEUR:  I think in a NICU situation what you would have is this formula is being prepared in a formula room.  They would have to be held I guess at a certain temperature and then cooled, and then taken to the unit and then rewarmed to room temperature in a Level 3 NICU.

     Now, whether or not you are going to have people who are trying to mix it just prior to a feeding or not in a smaller nursery, I don't know.

     DR. BUSTA:  Dr. Fuller.

     DR. FULLER:  Thanks.  I guess what I am trying to get at is--and I don't have the experience here--but I was thinking more along the lines of if we have identified a population that is very highly at risk, and yet we have also heard there is a very real need for some of these products, my question is can you not heat the water to, say, 85 degrees, yes, you will have a rapid dropoff, do you then have enough to mix with formula, you know, mix for one minute, let cool a minute, mix with formula a minute and then rapidly cool to the temperature either for storage or to serving temperature.

     That is where I was going with that, and does that take care of the protein coagulation problem.

     DR. BUSTA:  I see no volunteers.

     DR. THUREEN:  I would like to just add this, because it is the same question.

     How significant is the clumping issue, would it be enough to clog up a tube or clog up a bottle, or is it just an inconvenience, it might not be digested as well, and is the remaining protein of the same nutritive value, which is really the important question, because boiling, I mean it seems like a good way to get rid of the bacteria, but are we really going to be destroying the product, so that it is not effective for nutrition.

     DR. MARCH:  I don't believe that I can respond to the clumping and the degree of clumping, however, when we get into--going back to the previous comment--there was a thought of doing an incremental heating and cooling.

     I guess what we are looking at there is some very complicated hospital protocols that could possibly become very confusing.  I don't mean very complicated, but at least more complicated than it is now.  I guess that is the danger of that.  If not properly heated and cooled, you could be getting yourself into an incubation situation if you are not warm enough then.

     That would be my fear of a microbiologist warming the product up 10 degrees doubles or I guess shortens the growth of bacteria.  I guess I would discourage that in that it does complicate the matter.

     DR. BUSTA:  Dr. Heubi.

     DR. HEUBI:  I have a manufacturing question.  Yesterday, Dr. Zink told us that there was not any major advantage to one of the other drying methods for formula, and now both Dr. Smoot and Dr. March have told us that in response to some of the issues that were raised, they reduced the amount of water used in this process.

     Is it your opinion as industry that, generally speaking, the less water that is utilized, the safer the procedure is, and are you moving in the direction to minimize water in this process?

     DR. SMOOT:  Very succinct, yes.  The issue of use of water, parts of the process, whether you are using steam heat or water cooling of some type, there is water somewhere throughout the system, so engineering designed to minimize that exposure to the process stream is one aspect.

     The other, as we talk about spray dried runs, I believe Dr. Zink had mentioned yesterday his preference to run longer and dryer, I think even Dr. Tompkin had pointed out is very true.  However, due to formula changes and allergen issues and cleaning, you have to address allergen issues with wet cleaning, so depending upon production schedules and changeover, you have to do some type of wet clean sanitation.

     But again, working with our partners in sanitation practices, we are trying to even improve how we do wet cleaning in a controlled wet clean scenario.  So, yes, by all means, it is something that we are working very hard with in industry.

     DR. BUSTA:  Dr. Thureen.

     DR. THUREEN:  Thank you.  So, if we assume that you can't eradicate all E. sak contamination at the plant level, and that you could potentially eliminate it at the nursery level, I think most nurseries would be willing, with boiling, to go ahead and take that step particularly since most Level 3 nurseries have milk labs with fairly well trained people.

     So, it seems like if you don't know, that there could clearly be steps outlined that would show effective means of heating and cooling, might require special equipment, but you could develop that, that nurseries, with all their costs, would clearly be willing to invest in something like that, so that there should be able to be research done that would identify the proper process for that, and if you get a good kill, then rewarming shouldn't be a huge issue for bacterial contamination, at least to E. sak, or not.  I mean that may not be true.

     There are clearly other bacteria in the process and you are going to introduce them during the process, but if you could have a good heating and cooling procedure, and then rewarming procedure, and then do studies to see if the protein is denatured or not, then, you could at least say this is an intact product, maybe we need to add some extra vitamin C after we finish the product or give the baby vitamin C supplementation, but it seems like if we can't clear up the problem at the manufacturing level, we could at least go a long way at the preparation level.

     Clearly, there is going to be a lot of education involved in that, but it seems to me that that would be a part of the solution.

     DR. BUSTA:  That was not a question.

     DR. THUREEN:  It is a question in that there was a lot of no head shaking from that little group over there that this is not a realistic solution.

     DR. BUSTA:  Let the record note that she was pointing to the previous respondent.

     DR. THUREEN:  Several of them.  There are some yes's and no's over there.  Do you not think that is a realistic solution?

     DR. GEHRIG:  Good morning.  This is Tom Gehrig with Wyeth Nutrition.  My background is mostly in food technology, in that area.  I have done some work in denaturing of milk proteins, soy proteins, and I guess if you look at the milk proteins, your wheys particularly, they start to denature about 60 degrees C, and as you go up the time-temperature relationship, they continue to denature.

     The soy proteins are even a little bit more susceptible and my quandary would be that you are going to have to make it so precise on the mixing that, you know, we design these, we do a lot of protein efficiency studies to ensure that the protein is intact, that I think you would start to see, especially through the nasogastric feeding tubes, especially when the diemers go down, that you would have some problems with plugging of those tubes.

     We know we have plugging in the nipples of the baby bottles, and I think it would be a big issue if we start taking these things up to 80 degrees and holding them for any amount of time.

     I think it works, but, you know, from the industry standpoint, we spend a lot of time on our processes, especially on the evaporation, on the drying, to try and minimize the changes to the proteins, and I fear that if we take and reconstitute with 80 or 90 degree water, and hold it for any amount of time, we are going to be in some trouble.

     DR. THUREEN:  Thank you.  That really lays the issue to rest for me, and I didn't think I had had a good answer before, so thank you for that.

     DR. BUSTA:  Dr. Lee.

     DR. LEE:  I appreciate that observation.  If one were to anticipate reformulating with hot water, say, even as high as 100 degrees centigrade, one could design the proteins appropriately, so they are soluble, perhaps hydrolyze them somewhat, maintain your protein availability.

     It is really a process design question, is it not?  I mean the protein is not adversely--correct me if I am wrong--the protein is not destroyed nutritionally by this boiling water syndrome.  I mean you can solubilize protein in hot water.

     DR. WALLINGFORD:  John Wallingford, Wyeth.

     I think this is an area that we need to work together on.  We don't have all the information we need, so if I could recommend this be one of the parking lot items where we actually go out and get the data at what happens to the physical properties with formula after different temperatures of mixing and actually after subsequent mixing different temperatures of holding prior to feeding, I think this is an area where there is a potential for some improvement in the ultimate bacterial safety of the product.

     DR. BUSTA:  Dr. Tarr.

     DR. TARR:  I have two questions.

     First, yesterday, you talked about microbial sampling.  I forget what the exact numbers were, but I know the numerator was expressed in grams and the denominator was expressed in tons.

     How validated are these sampling techniques, can we be confident there, in this part of the HACCP protocol,  you are getting reliable data from your production line? That is my first question.  I can wait for the answer.

     DR. BUSTA:  Dr. Smoot, it looks like he is being nominated.

     DR. SMOOT:  Referring to the validation of this type of sampling plan, currently, the sampling plans for coliforms in our finished product monitoring now is at the level of N equal 5, and the sample size equal 1 gram.

     The proposal, continuing with a N equal 5, in other words, number of samples, is consistent with an ICMSF Class VI sampling plan for fecal coliforms.  That would give you a certain level, and has through time been validated as an acceptable sampling plan for a bacterium of moderate risk.

     So, what we have proposed from industry is to cast a broader net on our process control monitoring going from coliforms to the family of Enterobacteriaceae first, and then secondly, increasing the sample size from 5 grams to 25 grams.

     So far we have found at least working with the N equal 5 one gram for coliform has been reasonably successful in monitoring and assuring the process control, and what we were proposing yesterday was a step moving into the more stringent with both the target of the sampling, as well as the sampling size.

     DR. TARR:  A follow-up to that then, and this might have been answered yesterday, the incriminated product in Tennessee, did that meet, exceed, or was under the cut points for what you would consider acceptable for your process?

     DR. MARCH:  Yes, it did meet the specifications at that time for coliform organisms according to the plan that Dr. Smoot just laid out.

     DR. TARR:  To meet the future protocols or the proposed?

     DR. MARCH:  Retrospectively, that would be a difficult question to answer because it would be hard to make the equation--there would be some challenges, but I have a feeling, and it is only speculation, that it would meet that.

     DR. TARR:  And then my second question unrelated, it looks like the breast milk substitute is an important priority for both medicine and industry, and we would like to keep that available, and it might have to remain in powder form for the near future.

     How close, though, is industry towards coming up with a liquified higher caloric concentrated form that could be sterilized and administered safely?  We heard yesterday that it was technically difficult, but how active is the scenario developing?

     DR. BUSTA:  It doesn't appear that we have anybody on that.  For clarification, Dr. Zink said that the breast milk supplement was tested.

     DR. ZINK:  Going back into our little database of samples, two human milk fortifier products were tested and classified as transitional formula, so in the survey we did two human milk fortifier products were tested.

     DR. TARR:  What were the results?

     DR. ZINK:  They were negative.

     DR. BUSTA:  In regard to the plant that you showed the data on that were reducing the count, and the last data for 2002, the fourth one, there were 6 positives and all 6 were E. sak positive, and that appeared to me that as the plant was improving all of their cleaning processes and design, et cetera, it ended up selecting for E. sak.

     Am I reading that wrong?

     DR. SMOOT:  Clarification.  The data that was presented was on a percentage basis, so it was 0.6, not 6 positives, individual positives.

     But, yes, as our experience with that particular factory, and across the 70, 80 that we have around the world, as we improve our hygienic practices and reducing water and driving down and monitoring the environment, the comment made yesterday, and I think it was borne out as well by Dr. Buchanan's data, is that this particular organism adapts well to warm, dry environments.

     So, as we continually monitor the environment for the Enterobacteriaceae family, which is basically a biologic indicator for the presence of water, hence, we use it to assure we are keeping the environment as dry as possible, because they need water to grow.

     High levels of EB indicate that you had water somewhere in the system at an unacceptable level.  But with refining with this particular organism, E. sakazakii, is that out of this group of the Enterobacteriaceae family, it does appear to possess the adaptation to warm, dry environments, so as we are driving that number low, yes, we are starting to see exactly what you observed.

     DR. BUSTA:  So, in fact, another placeholder for research would be trying to determine why ecologically we are selecting for that type of organism and how we can modify the ecology to eliminate that kind of organism.

     DR. SMOOT:  I would say yes, that is a correct assumption.

     DR. BUSTA:  Peggy.

     DR. NEILL:  I think my question is somewhat headed in your direction, Les, but it combines some of the information that Don Zink gave us yesterday with his illustration of the process, as well as the implications of the most recent data that you were just explaining.

     Don painted a fairly powerful portrait that by the time the product is coming through the dry sifter spray dryer, it has undergone several kill steps, and the subsequent suspicion, obviously not proven, is that this is a contamination of product post that step.

     My question relates to the following.  What are the technical obstacles for creating a sterile product post the spray dryer including conceptualizing that it would not have to be the entire product lot, production run, et cetera?

     In other words, if we are steering our way towards identifying that there is only a subpopulation of recipients of formula that are at risk for this infection, then, one could conceptualize that you only need some of this formula to be sterile and directed towards that particular patient population.

     DR. SMOOT:  First of all, you know, we have been successful in industry in terms of environmental control at assuring the eradication for the most part from the process environment, other pathogens of concern, such as Salmonella and Listeria.

     As we look at the Enterobacter sakazakii and its place as a member of the Enterobacteriaceae family, though maybe not totally convinced, but we are finding data on a weekly basis that it is a little bit more ubiquitous than what we maybe thought to begin with.

     So, this organism has been able to eliminate it from the environment post-heating steps of these either wet mix, dry mix technology streams.  The proposal as I understand it then, can we divert or can we provide some type of unit operation for a small production portion to go into almost a Class I00 sterile room type environment.

     I would say on the scale of the industrial process, the total process, yes, that would be very difficult, is that something that we could again maybe work in partner, is this technologically feasible, is something like this possible, I wouldn't say no, it is not possible, but this is something the industry would have to study in terms of a risk-benefit there.

     But you are basically talking about going to a Class 100 room type environment for post-drying process stream, and you saw the magnitude and size of the equipment to do that even after the cooler, after dryer, which is the first unit operation post-star valve on the bottom of the cone.  To even put that in the frame of a sterile environment would be very difficult because what we are finding, that is a part of the areas that we need to improve anyway in terms of hygienic design.

     There would have to be a considerable learning to go to that level of process control to this sterile environment.

     DR. NEILL:  I think my comment is that in the hospitals, we do this all the time in terms of having a triage of medical products and foods that are adjusted to the perceived risk of the recipient population.

     I mean it's pasteurized egg product now in most hospitals, so that is where I am coming from in terms of a conceptual approach.  I think what I am trying to ask is really much more at the level of the technologies.

     I am intuiting that an ultra-high temperature step is likely to cause difficulties with the protein denaturation, so that you may end up with an insoluble product, and I don't think we heard a clear answer yesterday to irradiation, and all irradiation is not created equal because there is certainly different types.

     What are the perceived obstacles in the physical-chemical nature of the formula that would prevent creation of a commercially sterile product?  I think maybe that is a better way for me to articulate the question.

     DR. SMOOT:  I might have to defer to people more intimately involved, maybe Tom, to someone more involved in the actual process or in technology.  Would you want to speak to this?  I defer to Tom Gehrig, Wyeth.

     DR. GEHRIG:  I was responsible for design of our new factory largely, in part, in Singapore, which we started about a year and a half ago.  We took a good look at this, and, you know, speaking to what Les said, the volume of the air that moves through one of these dryers or in the conveying systems is tremendous, you know, in the volume of like 270,000 cubic feet per minute.

     What we do is try and install Hepa filters on the inlets to these dryers, but where it gets difficult is, you know, we can control on basically the transfer of the powder into the packaging operations, and we take a lot of care to ensure that that air is filtered especially going into the packaging hauls.

     We set up basically a hospital room environment where employees that move into that area have to do full gowning.  They have got masks, they have got gloves, full head gear, so in the particular zones where the powder can be exposed to the environment or to the employees, we actually zone kind of on a concept of 1 through 5, 5 being the most stringent zone.

     The only people allowed in that area are the people working in that area.  Where you get into some difficulties is when you have a breakdown in the line and you have to have an intervention, and the employees have to be very well educated when they go into this equipment, especially a mechanic or something, that those tools basically have to be sterilized or sanitized before they go into the system.

     I think, on the industry's part, it is requiring us to really go back and look at our processes, kind of what Les was saying, that whenever there is an intervention, we write it down, we mark down what has been done, who goes in, that the equipment has been sanitized and cleaned.

     But to create a clean room environment basically from the spray dryer south, so to speak, into the packaging line, I am sure it could be done, but it is going to be extremely difficult to do.

     It has been our experience that these powders for the E. sak, we can get down to counts that are actually less than 100 CFU per gram, and we still have E. sak in there, so as far as the drying