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]{.underline}
>
> [Page]{.underline}
>
> Opening Remarks 4
>
> Questions from the Committee 7
>
> Subcommittee Discussion of Issues, 47
>
> Recommendations, and Response to Charges
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **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 process goes,
> it is essentially sterile as far as the powder operation goes.
>
> So, the bug is selective, and we could take controls, but I guess my
> concern is when you are operating a plant, we can\'t really operate to
> two different standards. I can\'t say this product is going to be
> diverted off and it\'s going to go through sterile product, and this
> other product is\--we really have to operate to one standard, and
> especially if you are taking term infant formula, and it is being
> added in, we know this is being done for low birth weight, to
> supplement the formula, so we would have to produce really the term
> formulas also to that standard.
>
> DR. BUSTA: Dr. Baker.
>
> DR. BAKER: I would like to take that one step further. It seems that
> one possibility or a good way to get around this whole problem is to
> develop a sterile product. We have sort of beaten this sterile
> powdered formula into the ground.
>
> Is there a way of providing everything that the sterile powdered
> formula can do in a liquid form that could be sterilized, so we just
> completely move away from powdered formula in the NICU setting, is
> that a possibility for the industry to come up with high-concentration
> formulas that could be added without adding a lot of volume is what it
> comes down to.
>
> DR. VANDERHOOF: Jon Vanderhoof. I guess the question is could we as an
> industry convert our entire manufacturing process to providing nothing
> but liquid formulas worldwide, and I think the answer to that is no.
>
> Could we provide selective products for the NICU as liquids, and I
> think the answer to that is most, and we are doing that.
>
> Thirdly, there are probably some products that are going to have to be
> continued to be used as powders at least for the time being until we
> come up with better solutions for that.
>
> We have heard a lot of interesting ideas with both some good and some
> bad in them, but I think we are all moving in the right direction. I
> think the likelihood going down the line is that most of the products
> that will be needed in NICUs will be available as liquids, but there
> are probably going to be some small numbers that will be needed as
> powders that we will probably just have to take extra precautions
> with.
>
> DR. BAKER: I was only talking about NICUs, not about your whole
> worldwide production of powdered formula, and I guess the problem with
> the milk fortifier, human milk fortifier, which I guess now is not
> produced as liquid, but, for instance, the amino acid formulas, they
> presumably could be produced as liquid, is that not true?
>
> DR. VANDERHOOF: Well, I guess I am the only physician here, and we
> don\'t have an amino acid formula, so I can\'t really tell you except
> that most of the ones that are available are powders, and the ones
> that I have had experience with using are powders, and you are seeing
> more and more use of these formulas in high-risk children.
>
> Certainly, in my prior experience, up until six months ago, as a
> pediatric gastroenterologist in a transplant center, we used an awful
> lot of amino acid formulas in powder, and I don\'t see that practice
> changing very much, so your concerns are right on.
>
> Whether that can be made as a liquid or not, I don\'t know. I think
> there are some problems making amino acid formulas in liquid. I can\'t
> really tell you what they are. The hydrolysates you can make as
> liquids, and we do that.
>
> DR. BUSTA: I am doing a terrible job of chairing because we are
> already 15 minutes past the maximum, but Dr. Stallings, and after Dr.
> Stallings, just one more, so whoever thinks they have got the greatest
> urgency will have to signal me.
>
> Dr. Stallings.
>
> DR. STALLINGS: I just wanted some clarification. I am still
> struggling, and I am sure it is because my microbiology isn\'t that
> good, but the issues of sampling. When we were hearing the information
> early in the day, there seemed to be an important point to get to our
> bug of interest, that we needed to be sampling like at 100 grams for
> this particular organism to be able to say if it\'s there or not with
> some reasonable assurance.
>
> Now, we are at a sampling of an N of 5 times 5 grams, which gave us a
> 25-gram per lot, and we know that we don\'t understand exactly what a
> lot is in the sense that probably varies from each production site.
>
> But I still am not sure that what is proposed is an adequate sampling
> for the organism that we are interested in, and I understand we have
> gone from fecal, the most general term of fecal coliforms to the
> family, but we haven\'t gone to the bacterium that we are really
> talking about.
>
> So, I would appreciate a little more understanding of why that
> response is most appropriate for addressing this issue.
>
> DR. SMOOT: One of the questions I think the committee is here to look
> at, and we from industry, as well as other presenters, are trying to
> provide information to come to what is, if there is, a safe allowable
> level for this organism in a powdered infant product as it is
> delivered to be reconstituted.
>
> The proposal by industry again would provide, not going over the
> enhanced more stringent from where we are at today, but what we are
> looking at is an absence of 25 grams type of sampling plan.
>
> Based on information that industry has relative to our understanding
> of the relative risks involved with the delivery of a powder at a
> certain microbial level of this particular organism, we feel, in terms
> of a process monitoring control, if we can assure that the process of
> delivery product of absence in 25 grams in terms of a dose or a
> feeding provided to an infant, that you would provide yourself with a
> safe allowable level. I mean in a sense, that is what we are
> proposing.
>
> Yes, it open for question and debate, but we are proposing that this
> is a starting point for this broad group of Enterobacteriaceae absence
> in 25 grams is an acceptable level.
>
> DR. BUSTA: One last urgent. Dr. Lee.
>
> DR. LEE: I actually am going to change the subject a little bit and
> ask the industry formula guys to think of the whole product line. I
> would like to know, particularly in these particular days of the
> global conflict, Tom Ridge has asked us in the food processing
> industry to place particular vigilance on the quality and
> wholesomeness and safety of our food supply.
>
> I would like to know, without giving away any specific details, is our
> formula manufacturer and distribution network doing its best as far as
> security and homeland security can go particularly in terms of
> minimizing counterfeiting and diversion of these products, because,
> you know, feeding the babies is critically important to us in America,
> and it is a point of intervention that I think I would like to hear
> somebody tell me what is being done.
>
> DR. COULTER: Julia Coulter, Mead Johnson.
>
> I am responsible for our efforts around food security at Mead Johnson,
> and I can tell you that shortly after the 9/11 crisis, all of the
> industry was invited to come to Washington and talk to the FDA about a
> risk assessment process.
>
> They rolled out an excellent methodology, which they asked us to
> apply, and I know that we have gone back and we have done risk
> assessments in our firms and identified gaps where there might have
> been an opportunity for an unwanted act to occur and have invested
> significant amounts of money in bringing ourselves closer to where we
> need to be as far as food security.
>
> DR. LEE: Do you feel good about the trace-back, if I should happen to
> walk into WalMart and find something that I question whether or not it
> came out of your plant, do you think you can do that?
>
> DR. COULTER: We all are regulated to have product traceability, so
> yes, we have that in place and would be able to identify back to point
> of manufacture if something occurred.
>
> DR. BUSTA: Dr. Lee has this incredible capability of bringing us back
> to reality, what the threat is.
>
> **Subcommittee Discussion of Issues, Recommendations,**
>
> **and Response to Charges**
>
> DR. BUSTA: Let us, if it\'s all right with everyone, return to
> Charge 1. We were discussing this as we closed yesterday, and I am
> asking if there are individuals who would like to comment or discuss,
> in a preliminary fashion, characterizing the infants at risk.
>
> What I recall hearing yesterday, let me say it in the negative, I
> don\'t recall anyone saying that there is not a risk from E. sakazakii
> in powdered infant formula. I heard people say there is a risk
> existing, and then went on to go on to the next sentence there and
> basically identifying specific populations that were at risk,
> specifically, in the compromised infants of one way or another
> identifying those and some of the factors, wouldn\'t you like to have
> additional discussion.
>
> Let me restate that. Have we adequately identified the infants at risk
> and the factors that make them at risk to this infection?
>
> DR. HEUBI: I am going to make my prerogative as the Co-Chair.
>
> As I gathered from what we talked about yesterday, it was the sense
> that pre-term infants who are less than 36 weeks gestation, up to the
> age of about 4 to 6 weeks of age, were an at-risk population, and that
> individuals, infants and children of any age who were
> immunocompromised were potential at-risk population. Not considered at
> risk were term infants greater than 36 weeks gestation.
>
> The question I still was sort of left with yesterday was if there was
> concern about term infants who were in the NICU environment, and
> whether that was a consideration.
>
> DR. STALLINGS: I think that is one of the important points. When I was
> jotting down my notes last night, it was we have incomplete
> information. We know, though, that, if infected, it is often a fatal
> infection or one that results in brain damage.
>
> So, I think given that we don\'t know how to describe the immune
> status of newborns very well, certainly not in a clinical setting,
> that my advice at this point would be to say, if you are sick enough
> to be in a Level 3 nursery, which many people would include many term
> infants, particularly term infants with surgical diagnoses, that I
> would say that that, for a starting point, should be anybody that is
> sick enough to be in a Level 3 nursery, I would put at risk.
>
> It also has some practical advantages that that is a nursing unit,
> it\'s a formula delivery unit, it\'s an organization that we
> understand.
>
> My question then would arise, given the nature of healthcare in the
> U.S., and referral patterns and all the other things, is are we sure
> of who the babies are at Level 2 nurseries because in the past, many
> of those babies, we would have expected to be in Level 3 nurseries,
> but there is a lot of pressure to deliver some care particularly more
> standard neonatal respiratory care at a Level 2 setting.
>
> So, that is the place that I don\'t have as much confidence in, but I
> am pretty comfortable that Level 3 nurseries should be a site of
> interest.
>
> DR. BUSTA: Dr. Thureen.
>
> DR. THUREEN: I think that extending the same guidelines to Level 2
> nurseries is probably a reasonable thing to do, because it sets a
> standard since most of those are manned by Level 3 physicians.
>
> Also, most of those babies in Level 2 nurseries are probably not going
> to be getting on any of these powdered formulas, near-term infants,
> and that the same kind of concocting is not going on in that
> population in the Level 2 nurseries and the Level 3, but just setting
> that standard and gearing the education to both Level 2 and Level 3
> nurseries makes a lot of sense because if just simplifies the process
> and makes the issue less confusing.
>
> DR. BUSTA: Dr. Moyer-Mileur.
>
> DR. MOYER-MILEUR: My only comment would be on the age limit. I think
> when we are saying 4 to 6 weeks, we need to be careful because I think
> we need to say 4 to 6 weeks post-term, because I think it makes a big
> difference to a baby who is born at 23, 24, or 25 weeks.
>
> DR. HEUBI: I have a comment. Does the FDA understand what this
> designation of Level 2, Level 3 is, so that we don\'t need to clarify
> that?
>
> Patti, do you want to clarify?
>
> DR. BUSTA: The request was to clarify it.
>
> DR. THUREEN: Level 3 designation is for the most intensive care and
> generally, also includes the ability to do surgery and cardiovascular
> surgery.
>
> So, some of the Level 2 units, it varies around the country, and what
> is considered Level 2 unit in different places is very different,
> because some units will vary and take care of small babies with
> intensive respiratory needs, but because they aren\'t able to provide
> surgical services, are considered a Level 2, so people were refer to
> those as 2 1/2.
>
> That is not an official designation, but some Level 2 nurseries only
> take care of nearly well babies, so a Level 2 nursery is hugely
> variable, and that is why applying it to Level 2 and Level 3
> nurseries, the same standard of Level 2 and Level 3 nurseries would
> cover the entire gamut of different types of Level 2 nurseries that
> are in this country.
>
> Did that answer the question?
>
> DR. BUSTA: Is that clear? Okay.
>
> Any further comments? As a Chair who has only learned all about this,
> this week, it really sounds quite complete.
>
> Co-Chair?
>
> DR. HEUBI: The question is now do we want to go around and get each
> person\'s consensus, attitude about this, so we can have it for the
> record before we go to the next charge, I guess that is the next
> question.
>
> DR. BUSTA: Finalize this one.
>
> DR. HEUBI: Yes, we could get away from this one, I think.
>
> DR. BUSTA: A real vote.
>
> DR. HEUBI: A real vote, we could do a real vote.
>
> DR. BUSTA: The industry people, of course, do not vote. You will
> recall from yesterday that Dr. Beuchat had a special event that he had
> to go to this morning, so he will not be voting.
>
> I see Dr. Fischer with a microphone in his hand.
>
> DR. FISCHER: Before I vote on this, I want to make sure that I
> understand, that there is no risk to immunocompromised full-term
> babies.
>
> DR. HEUBI: I don\'t think that was what my comment was. When we
> actually started this, I actually included that in the criteria that
> was included, yes, immunocompromised of any age.
>
> DR. THUREEN: Would you restate that?
>
> DR. HEUBI: What I stated was that for infants who are pre-term infants
> less than 36 weeks gestation, up to the age of 4 to 6 weeks post-term
> are at risk, also, immunocompromised infants and children of any age.
>
> We also entered that infants of any gestational age up to 4 to 6 weeks
> post-term age in Level 2 or 3 nurseries.
>
> DR. THUREEN: But I think your comment is, is there no risk to the
> healthy term infant. No, I don\'t think we can say that. We believe
> that there is minimal or very low risk, but that we can\'t absolutely
> say there is no risk.
>
> DR. BUSTA: Dr. Neill.
>
> DR. NEILL: An amendment somewhat to what Patti was just saying might
> be to include the phrasing \"an even lower risk.\" In other words, we
> have said there is a risk to the subgroups, but we can\'t peg it
> exactly, but whatever it is, it is even lower for the term healthy
> child.
>
> DR. HEUBI: I would accept that as an amendment.
>
> DR. BUSTA: If there is a risk for a full-term infant, it would be
> lower than the group that we are describing.
>
> DR. HEUBI: Right, and I think the other point that has been raised,
> the information that we have been provided actually doesn\'t allow us
> to actually assess the risk of either one of these currently because
> most everything that has been described to us has been case series
> that doesn\'t really give you any kind of denominator, it\'s all sort
> of like the numerator without a denominator.
>
> DR. BUSTA: Dr. Thureen.
>
> DR. THUREEN: We could say there is a low but as yet unquantified risk
> for all these groups, but in this order, or then we categorize them by
> what we think is relative risk.
>
> DR. BUSTA: Did you take that as an amendment, too?
>
> DR. HEUBI: Absolutely.
>
> DR. BUSTA: Dr. Tarr.
>
> DR. TARR: Do we need to go down the route of qualifying the risk as
> low, medium, or high, all we have to state is there is a risk, yes or
> no, and are we asking for trouble by putting a modifier on the risk?
>
> DR. BUSTA: Are there other opinions on that?
>
> DR. HEUBI: I am a little reluctant to quantify the risk because we
> just don\'t have a good answer.
>
> DR. TARR: And \"low\" has a connotation to it, so does \"medium\" and
> \"high.\"
>
> DR. BUSTA: Dr. Thureen.
>
> DR. THUREEN: As a clinician and knowing pediatricians in the community
> and interacting with these people, I think that pediatricians need to
> know that for their practices, we believe that this is not completely
> risk-free, but really a safe product by most general standards, and
> that this really is referring to high-risk populations. Our
> deliberations on prohibitions or recommendations against minimizing
> use or how to use these formulas really refers to just the high-risk
> populations.
>
> So, a statement about well term infants, I got calls about this all
> the time when it first came out, but does it apply to babies in my
> office practice, and this would answer that question, and I think that
> is what people out there want to know, I think we have to make some
> comment about relative risks in different populations for the
> practicing physician.
>
> DR. HEUBI: The answer may be that term infants are at lower risk.
>
> DR. THUREEN: That\'s right.
>
> DR. HEUBI: That\'s all, because we don\'t exactly know what the risk
> is to the pre-term infant for sure.
>
> DR. BUSTA: We had some nodding by several of the committee as to
> lower, what Dr. Heubi related.
>
> Other comments? Okay. Are we ready?
>
> All in favor of the description of our response to Charge No. 1, raise
> your hand.
>
> \[Show of hands.\]
>
> DR. BUSTA: It appears unanimous.
>
> Charge No. 2. Dr. Heubi says we are now halfway there. No, that one
> has four parts.
>
> If there is a meaningful risk, and we have established or indicated we
> have a meaningful risk for selected populations, how can this risk be
> addressed?
>
> No. 1. What intervention strategies can be used in infant formula
> manufacturing processes and plants? Discussion. Dr. Kuzminski.
>
> DR. KUZMINSKI: Thank you, Frank.
>
> We have heard a lot from industry on the programs and practices that
> they do in the manufacturing environment, and taking HACCP to a higher
> level, as they have described, is the new activity since a point in
> time in 01.
>
> I fully agree that HACCP, as a practice, is an evolutionary practice
> based on learning, and you keep taking it to higher levels. I
> understand the complexity in the manufacturing process and in a
> manufacturing facility.
>
> I firmly believe that there is no silver bullet here in terms of if we
> do this, this problem will now be solved, but I do believe that very
> serious effort\--and I don\'t doubt the effort, I believe these plants
> have been taken apart and put back together again in the last couple
> of years in order to find out more knowledge as to where this bug
> comes from\--but I do believe also, knowing the size of some of these
> units processes, unit operations in these, that there is room for
> process development research in terms of food safety and hygienic
> design especially with these humongous pieces of equipment that these
> processes employ.
>
> So, is there a specific intervention that can be recommended? I guess
> I must say I don\'t think so, but I think a coordinated full court
> press needs to be continued and maintained in concert with the agency
> as to how HACCP continues to be taken to a higher level on the
> manufacturing floor by the industry.
>
> So, in terms of a specific recommendation for an intervention, I
> can\'t make one, but in terms of a blanket recommendation of taking
> HACCP to a higher level, I think there can be more collaboration with
> the agency by the industry as to here is what we are doing.
>
> I can recall five or six years ago that the agency put out a call to
> the food industry looking for volunteers actually, volunteer companies
> that might come forward and put HACCP into their food plants.
>
> That is a model that perhaps could be used with this specific industry
> as to how this industry is taking HACCP to a higher level on a
> collaborative level.
>
> DR. BUSTA: Other comments? Dr. Fuller.
>
> DR. FULLER: My thoughts are sort of fuzzy, but let me throw them out
> for discussion anyway. I am wondering if some recommendations to
> develop, I don\'t know, an industry guidance document that would speak
> more specifically to whatever the specific measures might be, but
> something that could be developed in concert with industry. I think
> they have the experts there.
>
> We have heard some discussion about design, engineering designs, as
> well as process designs, that can help in this area. The use of
> hygienic zones apparently has stepped up since at least the Tennessee
> event, if I understood that correctly.
>
> I think yesterday we heard, as well, something along the lines of
> product or ingredient specifications coming into the plant, you know,
> some of those things. Again, I mean I am just trying to recall some of
> that.
>
> The other thing that one of my questions, another question I wanted to
> ask, I think FDA mentioned that there were some GMPs that were going
> to be reopened for comment. It was not clear to me whether those GMPs
> addressed the powdered infant formula as well.
>
> I think we heard yesterday in one of our opening comments that it did
> not or the existing GMPs did not, I wasn\'t clear on that, but that
> might be another avenue for addressing some of these things, as well,
> in a longer term.
>
> DR. BUSTA: Requests for comment.
>
> DR. TAYLOR: We, as an agency, apologize for the microphone situation.
> As soon as we get funding from Congress, we will buy more microphones.
>
> In terms of reopening the comment period, in fairness, we will reopen
> on the entire rule. Obviously, we are looking to refresh the data and
> get better input for anything that might have happened since 1996.
>
> So, we will not just be taking comments on one particular area, the
> full rule is open, but clearly, we will be asking questions
> specifically targeted in areas that we think have become increasingly
> problematic.
>
> In 1996\--if you would like copies, we can certainly get it for
> you\--we proposed GMPs, as well as the definition for quality factors.
> This was in response to the statute that does allow separate GMPs for
> infant formula.
>
> It is broad reaching, it goes across the entire terrain of GMPs. It is
> a very long, extensive rule.
>
> DR. FULLER: And it does cover the powder formula.
>
> DR. TAYLOR: It covers all.
>
> DR. FULLER: Great. Thank you.
>
> DR. BUSTA: Comments? Dr. Fischer.
>
> DR. FISCHER: Under Charge 2, No. 1, we must talk I think about the
> monitoring procedure again. The industry has proposed this monitoring
> scheme and sampling scheme, and basically, the scheme starts out with
> a change from a quantitative analysis to a presence or absence test.
>
> I don\'t think we have heard why they want a change from a
> quantitative test to one that is just yes or no, they are there or not
> there, and I guess I am not experienced enough in sampling to know
> what is the best thing to do, but my gut feeling is that I would
> rather know how much is there, if it is there, and work from that
> aspect rather than work in a presence or absence mode.
>
> I guess I am not very keen about the switch that is proposed by the
> industry here, and I would much rather think about, if we are going to
> go to a presence or absence, I would say there should be an absence of
> all of the offending organism there.
>
> The trouble with going to presence or absence, I think, is simply what
> is the sensitivity of the test. If you made a test of inadequate
> sensitivity or used a test of inadequate sensitivity, you could have
> almost anything there.
>
> So, I think the first thing we ought to do is decide whether, in fact,
> we want to recommend that the change in the type of test from
> quantitative to non-quantitative, if you will, the presence or
> absence, my recommendation was not to accept, I think, this presence
> of absence test.
>
> DR. BUSTA: Response? Dr. Tompkin.
>
> DR. TOMPKIN: Well, actually switching from a quantitative to a
> qualitative does increase the sensitivity, and actually analyzing the
> full 25 grams for presence/absence is a more sensitive approach to it.
>
> I don\'t think, as a panel here, that we can define a sampling plan
> that is or is not appropriate, and I think that that should be the
> responsibility of FDA really working with the industry, but I think we
> could indicate that there is a need for review of the sampling plan as
> it existed and as has been proposed for the agency to consider that
> and arrive at a proper sampling program.
>
> The sampling program that was proposed by the industry does fall in
> line actually with history in terms of Codex and International
> Standards for this class of product. Moving to a presence/absence does
> increase the stringency of the sampling plan, so it is a step forward
> in that sense, but this alone is not the true indicator.
>
> It is only an indicator of the conditions under which the product was
> produced. That is all it is doing, it is not providing a specific
> level of confidence that a pathogen is or is not present.
>
> You have to consider that this sampling plan that has been proposed
> and that has been used historically as part of a total food safety
> management system, and that is really to follow on an earlier comment
> that the HACCP is being enhanced, but really what the industry is
> doing\--and this is not just the only industry moving in this
> direction, other food industries are moving in the same
> direction\--you have to consider that it\'s the supporting
> documentation that occurs whether it is HACCP and the GMPs.
>
> But in this case and in other cases in the food industry, it is the
> environmental sampling that really provides an additional supplemental
> level of confidence, whether it is, in my case, my past, sampling for
> Listeria and the environment was tremendously important in our ability
> to produce lowest risk possible, ready-to-eat meat and poultry
> products.
>
> That worked very effectively for us as a company, and the industry has
> moved in that direction. This is similar in that sense, in that
> controlling the environment is critical to managing the food safety
> risk and that by having an effective sampling program in place to
> measure that level of control is an important aspect.
>
> I posed that question to the industry, and certainly FDA has access to
> the procedures, how those procedures are applied, and so on, so it is
> not a secret thing. I would say that you have to consider the whole
> package rather than putting your reliance on an indicator test on the
> finished product.
>
> DR. BUSTA: Dr. Fuller?
>
> DR. FULLER: No.
>
> DR. BUSTA: Dr. Blumberg.
>
> DR. BLUMBERG: I think it gets back to the risk again because the
> sampling, the procedures they are using now, 1 gram or this 5 gram, in
> the outbreaks, they took 100 grams to be able to detect E. sakazakii,
> so for healthy babies, there is low levels there, it probably doesn\'t
> make a difference, but for the high-risk infants, the current sampling
> probably isn\'t good enough, so I think it just gets back to the
> population at risk and whether you want to use this product or switch
> to another product in the neonatal ICU, like a liquid product that is
> sterilized.
>
> I think that gets back to the issue, because I think saying, well, we
> have sampled at 1 gram or 5 grams, it is not sensitive enough, it
> sounds like, to detect E. sakazakii using those sample methods. For
> most people, it probably doesn\'t matter, but for the high-risk
> infants in the neonatal ICU, it may make a difference.
>
> DR. BUSTA: Dr. Fuller.
>
> DR. FULLER: Thanks. I will make my comment.
>
> We have I think heard that the powdered formula cannot, at least for
> the moment, be manufactured to produce a sterile product at this
> point, so we know that there is going to be risk, and absolutely we
> have identified the population we think at risk.
>
> The sampling done, if I am understanding correctly, the in-plant
> sampling, be it finished product or environmental sampling, is done as
> process verification, that is, to ensure that whatever manufacturing
> processes are in place, they are minimizing the points at which there
> is exposure to the product and the amount of bacteria, the bacterial
> content or load, or what have you.
>
> So, I think\--and this is where I don\'t have the expertise\--I don\'t
> know if that 25 gram plus or minus is an adequate process verification
> or not. I think maybe that is probably what is giving all of us some
> difficulty because the sampling that we were hearing about in the
> infant formula, I believe is for a different purpose.
>
> I mean the sampling that we have been hearing about with the 25 gram
> is to determine whether the procedures in that production line are
> adequately controlling exposure. We don\'t know what those infective
> doses are or anything like that. It just is that process working to
> minimize that risk.
>
> I don\'t know how to get to, and I don\'t think we have the expertise
> here, to determine if that is adequate for that purpose or not, but I
> think that is the point of discussion for both of those issues, and
> whether you release product that contains, I think is another issue
> all together and I am not sure how to answer that.
>
> DR. BUSTA: Dr. Stallings.
>
> DR. STALLINGS: Thank you, Dr. Fuller, I think that is very helpful. I
> was sitting here thinking if those of us who really do clinical
> practice or a group of neonatologists in nutrition support people, if
> we told them the story, I think that is one of the critical issues.
>
> That is why I am not reassured by the industry appropriate sampling
> for product leaving the door when I know that we have a fatal bug
> that, at least as I understand the data that were presented yesterday,
> the only way that we have some reassurance as to whether it was there
> or not is the 100 gram sampling.
>
> I think that is where I have a real quandary, and I think we are going
> to be, or the agency is certainly, and industry going to be facing a
> period of time where we don\'t have enough information, we don\'t know
> if we can change more manufacturing processes, we don\'t know if we
> can quickly get the sterile products through things that are just good
> practice and not regulatory.
>
> But what are we going to do for the year or two while we know this
> exists, and if somebody said, look, you know, is it safe to feed this
> product to this baby in the NICU, assuming that it is not going to
> clog the tubes and all of that, how do we reassure them.
>
> If I were presenting this as a seminar to my colleagues, I would say,
> well, it sounds like from my infectious disease colleagues, the way to
> be reassured is a sample that is significantly greater, and we don\'t
> know any denominators. That has come up again and again, we really
> don\'t know the exposure rates, we don\'t have enough information to
> do risk assessment, so what do we do in the meantime.
>
> So, really, I see this as sort of the crucial next issue is, is there
> something we can do even if it\'s in an interim stage while more
> information in the animal studies and the infectivity and the dose,
> and all of the things will probably will come up out of the No. 4
> section, is there something that we can be doing now that would give
> reasonable reassurance for clinical care for the high risk group. You
> know, that is where I think from an infectious disease point of view,
> what can we do now, is there anything.
>
> DR. BUSTA: Dr. Thureen.
>
> DR. THUREEN: This doesn\'t answer this question directly, but I still
> think the most important thing we are going to come away with is
> educating physicians, nurses, et cetera, that these are not what these
> products were intended for, and if you choose to use them in a
> different way that they are not intended for, these powdered formulas
> as additives, that you are running a risk of potentially putting this
> patient at risk for an infection. It is a low risk, but it\'s there,
> and that there is so much more that we have to learn, that you just
> have to realize the risk and you are taking that risk until we get
> more information that can be more definitive.
>
> DR. STALLINGS: As a follow-up, the only thing that I see as the
> exception would be the breast milk fortifiers, and right now there is
> a sterile liquid product available and some of the others are powder,
> if I understand the product lines correctly now.
>
> Then, like you said, everything else, there is sort of an alternative,
> but as was presented yesterday, and most of my life has been spent
> trying to argue for good growth velocity, you know, in children with
> chronic diseases, so I think it will be a hard balance if we are
> trying to take off products that people have learned to use
> effectively to get good growth. So, it will be a challenge.
>
> But what about the breast milk fortifiers?
>
> DR. THUREEN: I think the people feel they are going to have to use
> powdered breast milk fortifiers because the liquid concentrate is
> good, but it just dilutes the breast milk and adds too much volume, so
> I think that they are still going to be there no matter what
> recommendations we make, people are still going to use fortifiers, but
> in terms of all the other concoctions that come up, I think it could
> change practice.
>
> There will be units that even with all the education and knowing all
> the facts, will choose to continue their current practices of making
> up their own formulations, but it has got to be an educated decision,
> I think, and I don\'t think the education is completely out there.
>
> DR. BUSTA: Dr. Tarr.
>
> DR. TARR: Assuming we are staying focused on the high-risk,
> hospitalized infant, is it possible to filter sterilized fortified
> breast milk, pass it through a millipore filter? Will there be too
> much retention once it is solubilized?
>
> DR. BUSTA: From my experience, it is hard to filter more than about 10
> milliliters of milk through a given small membrane filter, so that
> would seem difficult.
>
> DR. HEUBI: In response to that, we have done not things with milk, but
> with other volumes, and you are right, I think it would add another
> technical aspect to this that would make it very difficult for staff
> to do it timewise, because I think Frank\'s point is a good one.
>
> It takes a good while to push things through a millipore filter that
> is the size that you are going to trap bacteria, because breast milk
> formulas, the breast milk additives are still a black box, we have no
> idea how microbiologically safe they are. There is no data yet.
>
> DR. MOYER-MILEUR: I think we need to remember when we are using
> powdered human milk fortifier, we are adding it to mother\'s milk,
> which does have immunologic properties, and that maybe some research
> needs to be done to see what bacterial counts are after this product
> is added to mother\'s milk.
>
> Now, it needs to be done in a number of ways, because mother\'s milk
> is stored in a number of ways. Sometimes it is given in a fresh state,
> while other times it has been frozen and then thawed, but I think we
> really need to keep in mind that mother\'s milk does offer some
> protection to the infant.
>
> DR. BUSTA: Dr. Neill.
>
> DR. NEILL: I think I have been sitting here finding myself like
> everyone else, sliding into Question 2, under Charge 2, which I think
> most of us saw yesterday as being the central conundrum to this
> meeting.
>
> I suspect our discussions so far have gotten us to a point
> that\--throw it back at the Chair\--we should struggle to articulate
> the responses for 1, and that is something along the lines of there is
> intervention strategies you can do, but we really cannot say that we
> could HACCP our way or test our way to safety for this at-risk
> population, because I think that is what we just said.
>
> We can go back and add some supplemental sentences that talk about the
> need to do it nonetheless, but even so, we all just heard through much
> of yesterday that it can\'t get us to a point by which we would say
> the albeit low risk has been now made quantitatively lower to a
> fashion that it is acceptable to feed the product to the at-risk
> population.
>
> But in terms of I think trying to keep our eyes on the horizon, I
> think I am seeing that we have made the statements that we could make
> at this point for Question 1 under Charge 2.
>
> DR. BUSTA: Dr. Fuller.
>
> DR. FULLER: Okay, let me throw something out and really get us going.
> I think, to follow along what you are saying, we certainly can\'t
> HACCP our way to a sterile product, and I don\'t think anybody is
> attempting to do that.
>
> We have talked about a number or heard about a number of intervention
> strategies that industry has talked about. They have told us that here
> are some things we can do.
>
> I guess, for me, the place that I am still having the hardest problem
> gets back down onto that one issue of if you are sampling your
> finished product and understanding that you are sampling that for
> process verification, and I don\'t know how to do that sampling in a
> perfectly meaningful way, but I think that the bottom line is if you
> find something, do you release the product, and I wasn\'t clear in
> yesterday\'s presentation. I think what I heard was that in some
> cases, even with the sampling regimen, whether it is more or less
> sensitive, that you would release product with a positive finding.
>
> If that is the case, you know, I question that. I would like to hear
> some discussion on that. Otherwise, I think we are saying, yes, we
> heard the industry present, here are the intervention strategies, we
> talked about some of them, and then I think this, that get to me
> anyway, is the one place that I am not sure we have addressed, and my
> question is do we need to address it.
>
> DR. BUSTA: Dr. Kuzminski.
>
> DR. KUZMINSKI: I sense that there is some frustration here on the
> committee\'s part in coming to a finished statement for Question 1
> under Charge 2.
>
> Perhaps a way to address it is to build on what Dr. Fuller has said,
> that perhaps there should be more transparency at least to the agency
> as to what industry is doing to heighten the level of taking their
> internal intervention programs to a higher level.
>
> An ability to communicate to the agency that a sampling plan has,
> whatever the sampling plan is, they proposed one, a common methodology
> to be followed by the industry, but whatever it is that we, as an
> industry, have X level of confidence that this sampling plan indeed
> represents a lot, and if we find this, this, and this, that we have X
> level of confidence that the product either meets or does not meet
> specifications down that decision tree.
>
> That is what I haven\'t heard here in the presentations, and for me,
> in a simple way of looking at it, it would help me understand the
> goodness or badness, if you will, of the thoroughness of the program.
>
> DR. BUSTA: Comments? Dr. Thureen.
>
> DR. THUREEN: I think your points, both previously and now, combined
> with Marion\'s, are excellent and really get to the heart of the
> matter, and that our trying to figure out a sampling plan that would
> reflect a lot\'s purity or risk is not part of this committee\'s
> assessment, but should be done between the agency and the industry
> with statisticians who can clearly, I would think, come up with a
> sampling plan that would reflect a lot, I mean that\'s got to clearly
> be out there, and that we should just stick with general guidelines
> and that particular point be addressed in a combined agency-industry
> effort.
>
> DR. BUSTA: To reiterate the question, No. 1, what intervention
> strategies can be used in infant formula manufacturing processes and
> plants.
>
> Dr. Acholonu.
>
> DR. ACHOLONU: I seem to be getting the feeling that we are talking
> about methods rather than answering the question, what intervention
> strategies can be used. Industry has helped, they have responded
> enhanced environmental monitoring and controls using HACCP principles.
>
> I feel that does the job, and then they have another statement here,
> complementary final product testing for Enterobacteriaceae. We are
> looking for method, not the actual practice what to do.
>
> A general statement what intervention methods can be used, and there
> are 1, 2, 3, 4. That is what I feel we should be doing, and I am of
> the opinion that industry has done a good job of suggesting those
> kinds of responses.
>
> Thank you.
>
> DR. BUSTA: Dr. Neill.
>
> DR. NEILL: Well, I think Bruce is going to kill me for doing this,
> but, Bruce, could you speak a little bit about the difference,
> intellectually, not statistically or methodologically, for testing for
> process control and finished product testing, since I think your
> comments in many other venues have been enormously instructive to many
> of us, myself included, and it might be helpful if you could try to
> speak to that now.
>
> DR. BUSTA: Dr. Tompkin.
>
> DR. TOMPKIN: There is historically in the past, microbiological
> sampling of individual lots was the approach that was used to
> determine whether or not individual lots were acceptable, and
> therefore, whether or not a food operation was in compliance.
>
> There has been a movement toward a more holistic approach, and
> essentially that involves sampling, for example, from the environment
> as one source of data, and to collect the data, but then track it and
> plot it in a manner that you can follow trends and with the idea that
> we indicate, the data would indicate that there are some positives in
> the environment.
>
> I think we have to accept that, but the question is what is the
> number, what is the prevalence rate, and how low can you go in any
> given operation and track it at that level, and if you do see a trend
> showing an indication of a higher prevalence rate in this case, then,
> you determine why.
>
> It can reach a point where the data indicate that you should shut the
> operation down and essentially reclean and restart. So, you are
> controlling the process and using the data to track it.
>
> That can be done over time in terms of months, and you have to look at
> the data, don\'t just collect the data and put it in a file, it has to
> be used in a meaningful way.
>
> In a similar manner, the testing of finished product, those data also
> should be tracked, so we are talking about 25 grams total being
> analyzed with 5 subunits. If you are up one this week and another one
> the next week, that indicates that there is an intermittent level of
> control and your goal is all zeros.
>
> So, by tracking those values, you can again get a measure of trends
> and whether or not your process is in control. Those can also be
> supplemented by, as we heard yesterday, that a production run may
> involve 20,000 pounds over, let\'s say, five days just as an example.
>
> To understand the process, that means that you probably should, well,
> would be prudent to collect samples at the beginning of the run and at
> various intervals throughout the production.
>
> That allows you to know whether or not you have a problem at the
> beginning as a result of cleaning, as we mentioned yesterday, or if
> something is occurring in the process that, over time, leads to
> additional contamination.
>
> That information allows you to determine whether or not a five-day run
> is acceptable or not in terms of control. So, that is another means of
> collecting information. You wouldn\'t need to do that on a continuing
> basis, but it could be done on an intermittent basis, whatever is
> appropriate to the specific facility.
>
> Also, in the event you do have an intervention, mechanical breakdown,
> and you have to go in and do some work on an operation, that would be
> a time where additional sampling would be a prudent thing to do,
> don\'t just rely on what you have been doing, do some additional
> investigational sampling of the environment and/or the product.
>
> So, all these kinds of information then can be used to come up with a
> comprehensive understanding of whether the process is in control, and
> there are different approaches from a statistical standpoint, then,
> that can be used to use the data from a statistical standpoint and
> arrive at some level of confidence of control.
>
> Is that helpful at all?
>
> DR. BUSTA: Dr. Baker. We are way past a break. Does your question need
> to be or can you wait until after the break?
>
> DR. BAKER: I think this is quick.
>
> DR. BUSTA: Okay. Go ahead.
>
> DR. BAKER: I have two questions actually. One of them is I understand
> that the sampling is a process sampling, it is not meant to assure
> that the formula that is produced is safe, and I understand that a
> negative test does not mean necessarily that every can in that batch
> is free of E. sakazakii.
>
> So, that is one thing, but then if you get a positive and then you are
> planning to send this out to nurseries where you know there may be a
> risk, that seems to me that is a kind of a different world than the
> question what you are doing. With your eyes closed, it may be all
> right, with our eyes open, is it okay. That is one thing.
>
> The second part of the same question is, is there a way that you could
> do the 100-gram test in a sub-lot and supply that to Level 1 and 2
> nurseries as opposed to the rest of the world?
>
> DR. BUSTA: First of all, I think that sampling plan did not imply that
> if you found E. sakazakii, that you still would ship it. I think the
> response was in regard to the Enterobacteriaceae and whether that was
> positive, and then whether it was a high temperature organism implying
> fecal coliforms, and the decisions would be being made on that, not on
> classifying E. sakazakii, if I recall that sampling plan that was
> proposed.
>
> DR. TOMPKIN: The point at which any testing for E. sakazakii was not
> defined in that sampling program, and I think the group is having some
> difficulty with the idea that you are coming up with a positive sample
> for Enterobacteriaceae in the lot, in one of the five subsamples.
>
> That is still a more stringent, much more stringent sampling test than
> has been used in the past. When it comes to a sampling plan, the
> sampling plan is internationally recognized with the five subsample
> units, and so on, as an indicator test.
>
> So, there is a statistical and international recognition for that
> program. The decision as to whether you ship with a C equals 1 or a C
> equals 2, the C equals 1 is accepted, it has been accepted in the past
> even with the older procedure, analytical procedure.
>
> When it comes to the C equals 2, it is debatable, and I agree it\'s
> fuzzy, what does all this testing, what does all this evaluation going
> to consist of, and I think this is an area where FDA is going to have
> to have some input into that.
>
> This is a proposal, and it has to be considered also that what we are
> undergoing is a process of reaching some level of testing, some level
> of control, and so on. What we are going to propose or recommend today
> is not what is going to happen hereon, because as new information
> comes along, there may be other needs for testing.
>
> So, I think that the C equals 2, if that is a problem for you, I think
> that that is where FDA, in fact, FDA will have input into this
> proposal. That is all it is, is a proposal.
>
> With that, I just should say that all the testing in the environment
> does include testing for E. sakazakii, as well as for Salmonella, and
> those are larger samples.
>
> DR. BUSTA: We will take a 15-minute break and we will come back. Thank
> you very much.
>
> \[Recess.\]
>
> DR. BUSTA: Dr. Heubi.
>
> DR. HEUBI: I was asked at the break to help to clarify our response to
> Charge 1 in terms of what we, as a group, perceive the risk to the
> normal healthy term infant, and we qualified it as being lower, but I
> think if it would be agreeable to the committee, we would probably
> place it at the level of minimal, but we don\'t know specifically what
> the risk level is.
>
> DR. STALLINGS: As I remember the discussion, part of what we were
> trying to stay away from were words that had a lot of value judgment
> to them, because we have no data, so that is where I think we came up
> with, you know, there is we recognize a real risk here, and the other
> one is lower, but I guess I would react to calling it minimal makes it
> sound like we have had information to evaluate.
>
> Now, from what we know, I would bet that it is minimal, so I think it
> is just an issue of how the committee wants to deal with that language
> in the absence of data.
>
> DR. HEUBI: Alex. I am not going to try your last name even though you
> went through all that.
>
> DR. ACHOLONU: Acholonu.
>
> DR. HEUBI: Acholonu.
>
> DR. ACHOLONU: Please forgive me. I need some clarification here. I
> would like industry, maybe Dr. Zink is here, to tell us what is meant
> by final product testing. Do you do this test when you have put the
> baby foods in containers, or you have in a big container and you just
> come and take about 5 grams or so, and if you do, do you take it from
> the top, do you take it from the bottom, what is going on, what do you
> mean by a lot, testing of lot? Can you explain that to me?
>
> DR. HEUBI: Can we hold that for just one moment? We want to finish
> Charge 1.
>
> DR. ACHOLONU: All right.
>
> DR. HEUBI: We will not forget it.
>
> DR. BUSTA: Dr. Thureen.
>
> DR. THUREEN: Well, I would still go back to saying there is a risk,
> but as yet unquantified, and it just says we don\'t know what the risk
> is, and then put them in the relative order and just say upfront we
> don\'t know what it is and admit it, and not try to get too detailed
> in the definitions of what minimal and moderate meant.
>
> DR. STALLINGS: To keep our dialogue, if I heard the Co-Chair\'s
> question, was could we change that rank order to minimal.
>
> DR. HEUBI: Actually, I just was suggesting that. I think it is more
> from the standpoint of relative to the question of the mother of the
> healthy term infant who calls and says is it safe to feed my baby
> powdered formula, and I guess that is sort of where I would come down
> to say is this risk material enough that we should be presenting it as
> a significant risk.
>
> DR. STALLINGS: Are you saying like on the label, because this is a
> discussion that is going on to help the agency continue discussions
> with industry versus on a label, and if we were talking a label, my
> personal opinion is the labels need to clearly state that these
> aren\'t sterile products, but I wouldn\'t put anything on a powdered
> formula intended for use for normal infants that would discuss these
> risks.
>
> I thought we were talking about educating primarily health providers
> for the high risk group, so I don\'t want to cause undue alarm either.
>
> DR. BUSTA: Dr. Tarr.
>
> DR. TARR: I am uneasy as a health professional stating what the public
> needs to know and wants to know. I am differentiating between those
> two. I would have no qualms about feeding my children powdered
> reconstituted formula being able to put in perspective all the
> possible risks that are out there.
>
> Yes, if we have to label food as being irradiated, which is still
> presumably quite safe, I would say that irradiated food poses
> considerably less risk to the public, very low risk compared to the
> low presence of a potential bacterial pathogen within powdered
> formula.
>
> If you then ask the public which would you rather know, and in putting
> it on that scale, I think that they would probably both say that they
> would like to be informed, but as a health professional, I feel a
> little bit imperialistic in stating that.
>
> Would this be an appropriate question to ask Dr. Briley as the
> consumer representative or to open this up to a wider, we need more
> data about public desire to be informed of this small risk?
>
> DR. HEUBI: Margaret, did you want to comment?
>
> DR. BRILEY: I don\'t believe I have ever had any data that would tell
> me exactly how the consumer would respond to this, but knowing the
> consumers in our part of the world, they make an awful lot of impact
> in asking a lot more questions than the normal group would be in the
> boonies, for example.
>
> They are very informed consumers and they go to their physician or
> their care provider with questions and written down, and I feel like
> that, as a consumer, I would want to know. I would want to know
> exactly, and I would find out.
>
> I would call the industry if I did not feel like I had gotten complete
> answers, and that is not an uncommon thing, that happens in our part
> of the country.
>
> DR. HEUBI: Patti.
>
> DR. THUREEN: May I ask a question? What will be done with the
> recommendations that we come up with today, will they be put on food
> labels, is it just going to be general recommendation?
>
> DR. TAYLOR: If I can just go back to Charge 1, which I think feeds
> into your question about the recommendations. Obviously, we are asking
> for scientific input to help us make some decisions, and clearly the
> industry is here, and there is a role for dialogue there, as well.
>
> I think the important thing to realize is that when there is an
> advisory given to the agency, we then take it and move it into a
> regulatory mode, and there is a step in there that considers that.
>
> I think the question in Charge 1 is not what you tell consumers, but
> can you characterize the public health issue around this. I am sure
> you all know we get press questions basically saying we have a lot of
> mothers out there with full-term infants, what does FDA say about
> issues related to powdered infant formula.
>
> So, I think the short answer is I don\'t think at all the intent in
> the charge was to go down the direction of labeling risk on infant
> formula, so I think that would personally be a very bad idea,
> regulatorily a very bad idea, and that was not the question on the
> table.
>
> Perhaps the question is if you are focusing on immunocompromised
> children, don\'t forget there is a large population out there that is
> interested in knowing about full-term healthy.
>
> DR. HEUBI: If there is no additional comment, I guess I will re-read
> my proposal for Charge 1, and that was that for populations at risk
> for potential with exposure to powdered formulas for E. sakazakii
> include pre-term infants who are less than 36 weeks gestation up until
> they are 4 to 6 weeks post-term, infants of any gestational age in
> NICUs Levels 2 or 3, and then immunocompromised infants of any age,
> and for term infants, the risk is considered to be less than it is for
> pre-term infants, but not zero. I was going to say not non-existent,
> but that is a double negative, less than pre-term infants.
>
> DR. BUSTA: Yesterday, I said something to the effect of and if the
> risk exists, it would be less, because we don\'t know if that risk
> does exist, we do not have that in a quantitative fashion at all.
>
> Dr. Thureen.
>
> DR. THUREEN: I like that, just what you said.
>
> DR. HEUBI: Me, too, I like that, too.
>
> DR. THUREEN: I think we should add that.
>
> DR. BUSTA: So, for full-term healthy infants, if the risks exist, it
> would be less.
>
> DR. HEUBI: That is correct.
>
> Can we call for a vote again?
>
> DR. BUSTA: Dr. Tarr.
>
> DR. TARR: \"Would be\" sounds authoritative, and in the absence of
> data, I am not sure we can absolutely say would be less.
>
> DR. BUSTA: Maybe or appears to be less.
>
> DR. HEUBI: We will use the Tarr-Busta amendment.
>
> DR. BUSTA: It appears that it would be less. Is that what you are
> saying? Okay.
>
> DR. HEUBI: We had better quickly vote before we are done here.
>
> DR. BUSTA: As I said, two hours to get to yes, and we all agreed.
>
> DR. HEUBI: Can I call for a show of hands with my proposal with the
> amendment, the famous Tarr-Busta amendment or Busta-Tarr? Thank you.
>
> DR. BUSTA: We are back on No. 1. I understand that one of our
> colleagues has a proposed statement\--I am sorry Alex\'s question.
>
> DR. ACHOLONU: Just to become surer of what we are trying to articulate
> here, as I said before, we have industry talking about this question
> of complementary final product testing, and I heard the word \"lot\"
> used, and what I want to know is from the industry, this complementary
> final product testing, is it when you have put all the stuff in
> containers or when you have the very big container and you have taken
> some sample from there, put it into containers that would be shipped
> out for the public, if when that is answered, when you take samples to
> do final testing, if it is a big lot, do you take it from the top, do
> you take it from the bottom, and is the sample random, or is there any
> special method you use for taking samples that you test?
>
> DR. BUSTA: Do we have a respondent?
>
> DR. ZINK: I will just give you a brief discourse on finished product
> testing. Once a powder is manufactured and it comes out of the final,
> comes through the sifter and it is in its final form, it is, in fact,
> at that point finished, but, of course, there is opportunity for
> further contamination until it is sealed in a can.
>
> These terms aren\'t precisely defined by microbiologists. Certainly,
> once a product is hermetically sealed in a can, all would agree it is
> finished product at that point. Some might even refer to testing it
> before it goes into that can as finished product.
>
> Other terms of art used are line samples and things like that, but the
> truth is in practice, manufacturers are often doing testing all along
> the way.
>
> For example, in terms of microbiological testing, if a manufacturer is
> going to store this in large sacks or totes or drums for a period of
> time, they likely will do some testing on it at that point, again to
> see if there is a problem, then, they avoid the added cost of putting
> it in can and then finding out there is a problem.
>
> Also, another reason for doing that is if they test it and find that
> it\'s okay, and then they go ahead and fill it into cans and test it
> again, and this time find a problem, that helps them narrow it down
> where such a problem might have occurred, but all manufacturers test
> finished product after it\'s in the can.
>
> Sampling schemes for this vary, but generally, they will fall into two
> categories. I think most manufacturers pull cans from the can-filling
> line at predetermined intervals. In other words, they might say to
> their staff to pull one can every 15 minutes or pull two cans every
> hour, some scheme like that.
>
> Those cans go into the laboratory. They are hermetically sealed,
> labeled cans usually. They go into the laboratory, and then the
> laboratory will take those cans into some kind of a biological cabinet
> or contamination-controlled area, and they will aseptically open those
> cans, they will take their samples for chemical and microbiological
> testing, and perform those tests.
>
> Now, those cans, at that point they are destroyed, they don\'t go back
> to the line, and any remaining powder is destroyed. It goes to animal
> feed or something like that, so this is destructive testing. It is not
> unusual for a manufacturer to pull, oh, my, more than 100 cans perhaps
> from a lot that they are testing.
>
> Now, you asked about the definition of lot. This varies somewhat, but
> generally, a lot of product is an amount of product that is produced
> under substantially identical conditions, and this often means a
> calendar day\'s production.
>
> A lot may be composed of many batches, and a batch is something truly
> is a homogeneous blending unit, if you will, and very often in the
> coding on product cans, they actually identify the batches that go
> into a specific lot, and all of this is traceable back to specific
> lots of raw materials, if you will.
>
> Does that answer your question?
>
> DR. ACHOLONU: If you happen to find some contamination, what do you do
> then?
>
> DR. ZINK: Well, it depends. Let\'s take a situation where you are a
> manufacturer using a dry blended situation, in other words, you have
> produced some of the product, maybe the fat and protein component, you
> have wet blended it and spray dried it, and now you are going to blend
> it with a carbohydrate function, carbohydrate, such as maltodextrin,
> and you have tested that maltodextrin, and you have audited the
> supplier of that maltodextrin, you have visited their plant, you have
> a great deal of confidence in them, and everything looks fine. You
> have tested your protein and your fat component before you blend them
> together, and you blend them all together and now, all of a sudden you
> have found, let\'s say, E. coli in the finished product. Where did it
> come from?
>
> Well, I think most manufacturers would put that product on hold and
> then they would launch an investigation, and that investigation would
> probably go back and look at much larger sample sizes of all the
> components.
>
> It would probably involve some environmental testing of the equipment
> that touched those since then. What they would be trying to do is find
> the smoking gun, if you will, and figure out what caused that to
> happen.
>
> The fate of the product could very well be sealed if it exceeds a
> regulatory or a manufacturer\'s internal requirements, they likely
> would destroy it, but nonetheless, the investigation would proceed.
>
> DR. ACHOLONU: Thank you.
>
> DR. BUSTA: You have a proposed statement for 2, Section 1?
>
> DR. FISCHER: I am working on it.
>
> DR. BUSTA: Do you want to try it?
>
> DR. FISCHER: It\'s a general statement, so hopefully, that will do the
> trick.
>
> It would start out by saying something like this. Industry should
> continue to improve the manufacturing process with an ultimate goal to
> produce a powdered formula product containing essentially no
> pathogenic organisms.
>
> So, what we are doing is setting an ultimate goal, striving for doing
> better all the time, not to say that it has to happen, but we ought to
> be going in that direction, and I think probably from the sound of it,
> they are.
>
> As part of the manufacturing process, a product monitoring scheme that
> accurately detects for each lot the quantitative level of offending
> pathogenic organisms, including E. sakazakii.
>
> This information would be provided to the agency prior to release of
> the product. So, what I am saying is that for each lot, they would
> have an idea of the number of colony-forming units per 100 grams of
> the product, which would be provided to the agency.
>
> Now, I am thinking about E. sakazakii, but it might be other organisms
> if that comes up, that is a problem. Further on, the industry has
> already suggested a level which they consider a safe level, if you
> will, and we could talk about that when we get to that part, No. 3, I
> think.
>
> Then, there are these other things, other parts of the process that
> can be improved, have already been discussed, that is, monitoring of
> the environment and improvement of the environment, and so on. We
> could put language in there for those kinds of things, as well, or we
> could leave it out, I don\'t know.
>
> But basically, what I am trying to do is saying that the goal should
> be to produce the best product possible, which I know they want to do,
> and that for the purposes of regulation, if you will, that they
> provide a quantitative level of the bacterial content of selected
> organisms to the agency, and the agency, of course, will have some
> number in mind that is acceptable or not acceptable.
>
> DR. BUSTA: Other comments? Dr. Thureen.
>
> DR. THUREEN: I agree with the first statement, but I think the very
> first sentence you said, that the goal would be to strive to set a
> process to having no contamination, we may or may not get there, but
> that would be the goal that you would work towards.
>
> The whole second part, I don\'t think we should go into any specific
> numbers, and also make a general statement that the means to get to
> this point would be commonly decided upon by industry and the FDA with
> experts that the FDA would choose to involve in manufacturing
> processes to set up a plan that would be general.
>
> It could apply to all the members of industry that they would use, and
> just leave it very general, in that order, that FDA and industry would
> come up with a plan. We would not make any specific recommendations
> because we don\'t have the expertise on this committee.
>
> DR. BUSTA: Other comments? Dr. Fischer.
>
> DR. FISCHER: You mean not provide them with a number?
>
> DR. THUREEN: No, industry, I mean industry and the FDA and the experts
> that the FDA have at hand, like Dr. Tompkin, would help come up with a
> reasonable plan, and not leave it up to this committee, who still have
> a lot of questions about the whole process, but really get several
> experts in to help with that plan.
>
> DR. FISCHER: So, what would be bad about saying that the level of
> bacterial content or pathogenic organisms in a particular lot ought to
> be determined as part of the plan?
>
> DR. THUREEN: Right. Well, I presume that that is what they put in
> their plan, that they would determine levels, monitors, that there
> would be ongoing assessments of is this an acceptable level, that
> it\'s a moving target, a moving plan, and part of that would be
> included in it, but I think that is sort of a given with everything
> that we have heard, that that would be part of the plan, I presume it
> would be a given, that that information would be included in whatever
> plan combined industry and the agency came up with.
>
> DR. BUSTA: To my knowledge, if one detects a pathogen in a product
> like this, it is considered adulterated and unacceptable for sale.
>
> Am I correct on that? So, consequently, quantitatively, all you can do
> is say less than 1 in a given amount of product, because that is all
> you can measure. So, I am having trouble with saying report the
> numbers of pathogens when I don\'t think if you have got pathogens
> there, the product doesn\'t move.
>
> Dr. Kuzminski.
>
> DR. KUZMINSKI: In regard to Dr. Fischer\'s statement as amended by Dr.
> Thureen, I would agree with that basically. I think we need to keep
> the recommendation at a fairly high level, more general level, and
> trust that the technical capabilities of both the agency and those
> that they can draw on, and the industry, which are enormous in this
> case with the companies represented, will come to the technical
> capability and plan that we are talking about here.
>
> I think also the recommendation, the verbiage, recognizes that, in my
> own personal opinion, recognizes that industry is on the right track
> here, but I think also, again my own opinion, that there needs to be
> some, because of the seriousness, may be a rare event, but when it
> happens, it is really serious in terms of fatality.
>
> There needs to be some accountability, and I put it earlier in terms
> of transparency, collaborative with the agency, as to what the
> continuous improvement program is within the industry.
>
> DR. BUSTA: Dr. Blumberg.
>
> DR. BLUMBERG: I was wondering if there could be clarification about
> this issue about contamination because clearly, this product is not
> sterile, and it is just a level of detection you are getting into.
>
> I was wondering in the statement that if you detected an organism that
> had to be\--
>
> DR. BUSTA: Pathogen.
>
> DR. BLUMBERG: A pathogen.
>
> DR. BUSTA: If you detect a pathogen, it is adulterated.
>
> DR. BLUMBERG: Clearly, this is not sterile, there is pathogens there.
>
> DR. BUSTA: Just saprophytic organisms, they are not pathogens.
>
> DR. BLUMBERG: I guess in the right host, it\'s a pathogen.
>
> DR. BUSTA: Dr. Neill.
>
> DR. NEILL: I think we have a lot of confusion on the medical side of
> the table, and probably over there, because what is a pathogen for one
> person may not be a pathogen for another, but they are both a microbe.
>
> Don, can you help us with what is the current assessment of the
> agency\'s\--maybe it is not correct to say the agency\'s\--what we are
> not asking is what is current practice, I don\'t think, on the part of
> the industry, but if a microbe is present in powdered formula on
> microbiological testing done for whatever purpose, process control, et
> cetera, but it is in product, what is the current meaning and
> significance of this?
>
> DR. BUSTA: Do we have anybody in conformance here?
>
> DR. ZINK: I just love these questions. I told you that your capacity
> to cause mayhem was increased in this job. We used to have a term in
> clinical microbiology called \"frank\" pathogen, and that was an
> organism that everybody agreed was likely to cause illness in man,
> things like Salmonella, Shigella. The list of frank pathogens only
> gets longer, it never gets shorter. I don\'t recall anyone ever saying
> that, okay, we were wrong, this Salmonella isn\'t a pathogen anymore.
> That has never happened.
>
> So, we are continually faced with new organisms that may not be all
> that new, they predate us, but we find organisms that seem to have a
> potentiality to cause disease that was not previously recognized.
>
> This is, in fact, the situation we are in with Enterobacter sakazakii.
> In this specific case within the agency, a Health Hazard Evaluation
> Board met and determined, in fact, that this organism constitutes a
> health hazard.
>
> Does that mean it constitutes a health hazard to every individual? No,
> but it means that it has risen to a level where the agency feels that
> its presence in a food could constitute a hazard that is going to
> affect at least some portion of the intended population and that they
> need protection from that.
>
> That is not to say that everyone who might consume this product will
> become ill. That doesn\'t even happen with the frank pathogens like
> Salmonella and Shigella, but it becomes difficult.
>
> You could carry this argument on out and cite cases of almost every
> member of the Enterobacteriaceae has caused illness in some host or
> another, in some reported time, and I think it becomes a difficult
> judgment at some point for a group of experts to say this organism has
> now risen to the level of what we would call a pathogen.
>
> I am sorry if that sounds a bit nebulous, but the topic is a bit
> nebulous.
>
> DR. STALLINGS: In follow-up to that, did you really answer the
> question, what organisms today, if they show up, would constitute that
> they are adulterated and the product would be discarded?
>
> DR. ZINK: Certainly, if we find Salmonella in infant formula, I think
> we are going to consider that to be adulterated. If we find Listeria
> monocytogenes in there or any other of the more widely recognized
> pathogens, we would consider that to be adulterated.
>
> Now, put into a difficult situation, we have been taking that view for
> Enterobacter sakazakii, and I think we are looking to this group to
> comment on that.
>
> DR. STALLINGS: My sense from the committee over this day and a half is
> we believe that organism has risen to that level, that if it were
> there, that if it were there, then, it represents a significant risk.
>
> I guess that is one of the things we need to be sure of, because from
> that flows the whole concept of what is adequate surveillance from the
> public protection point of view, which is different from the
> well-developed surveillance from a manufacturing point of view, and it
> seems like that is exactly what we are struggling with.
>
> DR. ZINK: We struggle with this, too. If it becomes clear to the
> scientific community that Enterobacter sakazakii is a pathogen, then
> finding that in a ready-to-eat food like this, I believe we would
> regard that as an adulterated product.
>
> DR. STALLINGS: So, just to continue that, I mean if we were here
> talking about another dried food product that was not going to a group
> we have defined as high risk, then, this organism wouldn\'t go there,
> whereas, you might say Salmonella found in\--I don\'t know if this is
> true or not\--dried powdered milk for general consumption in baking,
> and all of that, but in infant formula, this organism has risen to the
> status of a pathogen, and thus, we are looking for a different
> surveillance, not just a manufacturing surveillance.
>
> DR. BUSTA: Dr. Lee.
>
> DR. LEE: I agree with everything that has been said about food, but I
> also think that the formulas we are talking about have a special
> niche, maybe a step above food. Somebody I think the other day said we
> are halfway between plasma and food because of the way it is being
> used, and that the neonate really doesn\'t have the same ways of
> handling this material as somebody with a normal digestive system
> would or fully developed digestive system would.
>
> So, I think we are applying a higher standard here. I certainly would
> include E. sak on that list of deleterious incidental ingredients that
> would flag an adulterated status if present.
>
> DR. BUSTA: Dr. Tarr.
>
> DR. TARR: I am doing a little bit of Poisson distribution in my head.
> With 0.6 percent of 100-gram samples have E. sak in it, from The
> Netherlands, that means 100 percent of each ton has E. sakazakii in
> it, does it not? When we look at small quantity testing as it goes out
> the door, does absence of proof mean proof of absence? No.
>
> Then, we have to assume that everything could potentially have E.
> sakazakii in it and should undergo a sterilizing step before it is
> given to\--rather than relying on recalls, which are high publicity,
> debatable interventions and to preserve public health, should we not
> rely\--I am not saying that something shouldn\'t be recalled\--but
> should we not use as the mainstay a reliable sterilizing step prior to
> consumption rather that use recall as a safety net, as an assurance of
> safety?
>
> DR. BUSTA: Would someone like to respond to that before I get to Alex?
> Dr. Kuzminski.
>
> DR. KUZMINSKI: You had a key phrase there, a reliable step prior to
> consumption, and I think the charge in Item 2 under Charge 2, in terms
> of recommendations to feeding institutions where the formula gets
> prepared in a finished step for the infant, that, to me, encompasses
> the phrase that you used prior to consumption.
>
> DR. TARR: It would seem to be an alternative to reliance on recalls
> and declarations of adulteration.
>
> DR. KUZMINSKI: I don\'t think it\'s an alternative. I think it\'s a
> continuous step in the manufacture and consumption of the product, of
> a dried infant formula.
>
> It\'s a personal viewpoint, a step that starts at a raw material
> supplier, and the process continues through the manufacturing and
> distribution system to the hospital, where it is prepared in a
> finished form for consumption by the infant. I view that as a
> continuous process in the life of the product.
>
> DR. TARR: I agree.
>
> DR. KUZMINSKI: It\'s not preparing it with hot water, and we are going
> to debate instructions in a while. I don\'t believe that is an
> alternative at all to a recall situation as you have described.
>
> DR. BUSTA: We have had a hard time staying on No. 1. We have talked a
> lot about No. 2, we have talked a lot about No. 3, and we have got one
> proposed on No. 1, and we keep looping back or downward, so what I
> would like to do is just hold on the proposed No. 1 and go on to No. 2
> and get some of that off of our respective chests and go on. We can\'t
> seem to hang in there, and we keep hanging really down on No. 3, as
> well.
>
> Alex.
>
> DR. ACHOLONU: I was just going to comment on your statement.
> Microbiologically, a pathogen or pathogenic substance is one that is
> detrimental to health. There is not a way you can consider it
> microbiologically. If it is not, we call it a commensal \[ph\], one
> that gets into you, but doesn\'t do any harm. It is either a commensal
> or it is a pathogenic or parasitological or microbial organism that is
> detrimental to health.
>
> Having said that, when Dr. Busta talked about the discarding of
> contaminated specimens or substances, if it is contaminated, you
> cannot go ahead and distribute it to the public.
>
> We must understand that we are dealing with bacteria here. When you
> talk about parasites, it takes time for them to complete their life
> cycle, but when you are dealing with something like bacteria, they
> multiply in a short time.
>
> You can have one bacterium in a sample, and it will stay there under
> propitious conditions, under optimal conditions, will multiply and
> become plated, so I feel that when we have established the fact that
> E. sak is a pathogenic organism, we have spent time discussing what it
> does to human beings, it is pathogenic, and if we find one that is
> contaminated, my feeling is that it should be discarded.
>
> Thank you.
>
> DR. BUSTA: Dr. Fischer.
>
> DR. FISCHER: So, we are on No. 2, right?
>
> DR. BUSTA: Let\'s give No. 2 a try.
>
> DR. FISCHER: I just want to make sure. I think another intervention is
> labeling, labeling the product. I noticed that industry recommends
> that we eliminate the use of powdered products for feeding the at-risk
> population. I don\'t think anything is wrong with that, I think
> that\'s a good idea.
>
> We also discussed the possibility of labeling the powdered product to
> indicate that it is not sterile, and I don\'t think that\'s a bad idea
> unless labeling it as such will reduce the care with which the product
> is prepared.
>
> I mean if you label it that it\'s unsterile, will people begin to just
> feel that they don\'t have to take extra precautions in preparing the
> product for use. I don\'t know whether that would happen or not, other
> people may know, but I think that it wouldn\'t be a bad idea to label
> it as a non-sterile product unless there is a real down side. So,
> that\'s the labeling issue.
>
> DR. BUSTA: Dr. Heubi.
>
> DR. HEUBI: If we make that recommendation, we should also recommend
> that there be some caveat saying that every effort is being made from
> a manufacturer\'s standpoint to reduce the amount of bacteria in the
> product.
>
> If we make the statement that it is non-sterile, then, we should make
> some comment also, so the public doesn\'t say, oh, this is full of bad
> stuff, that the comment is made that every effort is made by
> manufacturers to reduce the presence of bacteria in the product.
>
> DR. BUSTA: I have a question for those of you that work with a product
> like this. If it is stated on there that the manufacturer is making
> every effort to minimize the microorganisms in the product, but it is
> not sterile, would that mean something to the handlers, would that
> register, would it be like the label on liquor or cigarettes?
>
> DR. MOYER-MILEUR: Cigarettes, yes.
>
> When you say handlers, a lot of times these are technicians that have
> been trained in formula preparation, so the fact that there is a label
> warning on there really may not make much difference to them, and a
> physician may never see that label warning, so I don\'t think that
> saying this product is not sterile, that\'s fine to put there, but the
> however, we are doing everything we can to make it more sterile, I
> don\'t think would be helpful.
>
> My other comment is that the thing to realize, that we can train
> technicians to have good practice and good skill in making these
> preparations, but I think you need to go further up the food chain to
> the person who is ordering the product, and they are the ones who
> require the education piece.
>
> I think that if you work within a nursery situation, you realize that
> there is a lot of independence in the decisionmaking on what infants
> are fed, and that if there is not\--and at times even within specific
> nurseries, not agreement on how best to feed these infants, so I
> think, and I would put this to the industry to help with the education
> of the healthcare providers, that when they are making these
> decisions, they need to make thoughtful decisions and realize that
> when they are opting to use a powdered product, that it is not sterile
> and that they are opting to use a product that may not be in the best
> interests of a high-risk infant, and that there are safer products
> available for use. But I really think that the education piece needs
> to come at a much higher level than the technician preparing the
> product.
>
> DR. BUSTA: Dr. Stallings.
>
> DR. STALLINGS: Commenting on that and what Dr. Lee said, I think the
> reason that you would change the label is because you are going to
> change institutional policy. It is going to have nothing to do with
> the resident ordering the formula, it is going to have nothing to do
> with the technician.
>
> If we create a label and a set of knowledge and working forward that
> says this shouldn\'t be done for these reasons except under
> extraordinary circumstances, then, in essence, Hospital Nutrition
> Committees and hospital lawyers, and if we can get to that level, and
> say this is what we need to be doing now, then, we will get
> compliance, because the policy and procedure that the technician is
> going to inherit\--and I agree with you, I think the facilities are
> good and the people are well trained, and they are trying to do a good
> job\--that is what we are really talking about.
>
> If we are going to change practice, we are changing practice at the
> level, and this kind of product is right between a food and a drug,
> and in this setting, it is much more like a drug than it is a food, we
> don\'t have any trouble in this environment treating this just the way
> we would in many ways an I.V. product.
>
> I mean these are very high risk infants, this is an essential compound
> for them to get to survive, it is what gets them off of I.V. feeding
> and all of those inherent risks, but we just need to recognize this
> isn\'t about technicians.
>
> If we put things on the label and we educate the nurseries, it will be
> a policy decision and the trickle-down will be that residents may or
> may not learn at this point in their careers that this may not\--we
> are still trying to figure out this organism\--but they will learn the
> process of prescribing the least risky product they can to take care
> of the baby.
>
> That is why the labeling is important. If I try to get my committee
> and my lawyers to do something, this is how we change it from it\'s my
> personal opinion as a pediatrician taking care of babies in a nursery,
> to this isn\'t in the best interests of children as a group or the
> hospital, and we are working with industry to find the right place.
> So, I think the label stuff is very important. I don\'t know what the
> language is, but that\'s the only way we are going to change care.
>
> DR. BUSTA: Dr. Fuller.
>
> DR. FULLER: Thanks. I think I would sort of try to throw a couple
> things out. First of all, we are talking about an educational or an
> outreach to various user groups, specialty groups, the neonatologists,
> the NICU nurses, and whatever other specialty populations, so we have
> got that piece, and along with that piece would go the things that
> might include how often you change the tube, you know, the hang time
> of the tubes, and all that great stuff.
>
> So, you have got that piece. I think that another potential
> intervention strategy we might want to ask ourselves, and that is
> looking at the current label. There are two pieces I would look at on
> that, and one of those is the instructions for preparation, are they
> adequate as they are now, can they be more uniform, do we want to make
> any enhancements or changes or recommend anything there.
>
> Then, a correction I think to what Larry said earlier, I don\'t
> believe industry said eliminate the use, I think they said minimize
> the use in the at-risk populations, so a piece of that educational
> would be to identify that these products should be used only when
> there is no other product available yada-yada, and then the last thing
> is whether or not to add the piece on the label, is there benefit to
> saying that the product is not sterile, or is that better addressed
> through this educational outreach, does putting that on the product
> raise a red flag to the consumer and say, ooh, I shouldn\'t use this.
>
> I would say if we are going to\--well, I will stop here.
>
> DR. BUSTA: Dr. Baker.
>
> DR. BAKER: I would say about Question 2, all of these things are
> really covered in the recommendations that were put out by the CDC and
> the FDA, and now the new revised ADA guidelines for institutional use
> of non-human milk. I think the ADA included human milk, so all of
> these things are already set out. I think all we need to do is
> reinforce them and say that we go along with those guidelines.
>
> That does not include the labeling, and I do think the labeling should
> include a statement that this is a non-sterile product if no other
> reason than just for transparency, but also for education, and that is
> the other piece of the recommendations. Somehow we have got to get to
> the people who are actually ordering these formulas and reinforce what
> has already been said, that you ought to find alternatives whenever
> possible to let them know the risks.
>
> DR. BUSTA: Dr. Tompkin.
>
> DR. TOMPKIN: There are some issues with regard to labeling, whether it
> is labeling the intact container or labeling the carton or the inserts
> that may be placed in a carton, and there are different approaches to
> that.
>
> But what we are talking about, I believe, is the labeling or
> communicating information to those who are healthcare givers of the
> higher risk population. The CDC did, of course, as you just mentioned,
> provide some guidance, but it does not state in here that\--this is
> the Morbidity and Mortality Weekly Report statement anyway\--it does
> not say anything that this product is not sterile, and, in fact, it
> communicates a confusing message, \"Trained personnel should prepare
> powdered formula under aseptic technique,\" which assumes you are
> dealing with a sterile product, and that is not the case, so I think
> the message is not clear, and it should be improved upon.
>
> So, this was, in fact, the summary interim recommendations, and they
> should be further enhanced based on what is occurring here.
>
> DR. BUSTA: Dr. Kuzminski.
>
> DR. KUZMINSKI: I think if we are on Charge 2, Question 2 on the page,
> I am addressing that one. I think there are two areas that are
> important in my view for other intervention strategies.
>
> One is on preparation instructions on the label to encompass the most
> current information on temperature of water, on mix, on holding time,
> on cooling it down to a certain time, hang time, whatever. There is
> newer information that we have heard today and yesterday. That is
> perhaps not reflected on the labels of products that are out there in
> today\'s marketplace. So, that is one area.
>
> The other area for an intervention strategy, I believe builds upon a
> couple of recommendations that we have had in the material given to
> us. One is the elimination of powdered formula to at-risk populations.
>
> Industry has proposed a definition of what they think at-risk is. It
> is different from what this committee thinks, and I think this
> committee could build upon the industry recommendation of eliminating
> powdered formula and fold in its definition of at-risk.
>
> I think where the fuzzy area is, is in terms of\--and I have learned
> more about pediatric nutrition in the last two meetings of this
> committee than I think I had ever dreamed of knowing\--but where the
> fuzzy area in my layman\'s way of looking at it is in healthy
> full-term infants as to yes, there is a risk, it\'s lower, but do we
> restrict that large population from use of powdered infant formula.
>
> DR. BUSTA: Dr. Thureen.
>
> DR. THUREEN: Addressing that question, I don\'t think it\'s practical
> or reasonable to eliminate from the healthy term population from a
> cost standpoint, that much of the population that use powdered milk
> could not afford a more expensive product, and I think we would be
> jeopardizing healthy infants by taking that off the market.
>
> DR. BUSTA: Dr. Stallings.
>
> DR. STALLINGS: Just as a point of clarification because we found that
> the three of us were disagreeing, the response to the charge that was
> mailed out before we came, it actually used the term eliminate the use
> of powdered products in response to this charge to Question 2.
>
> When Dr. Merritt presented yesterday, and the slides we got this
> morning, it uses \"minimize,\" so just for the future, we need
> industry to know, there may be a response if the Chair would
> recognize, so that I think would be helpful because sometimes these
> documents do come back to haunt us, and we want to be sure we are on
> the same page.
>
> DR. BUSTA: Yes.
>
> DR. GHILARDI: Ron Ghilardi \[ph\] with IFC.
>
> The wording is a continuation of the same sentence, and I think that
> may be the confusion. In the Response to the Charge, industry
> identified as a Charge 2 response, \"Eliminate the use of powdered
> products for feeding the at-risk population (hospitalized, premature,
> low birth weight, and immunocompromised individuals to the extent
> possible, as FDA already recommended).\"
>
> So, in other words, it is either eliminate to the extent possible or
> minimize, and the clarification relates to that population, and I
> think we were very close to what the committee was identifying as the
> at-risk population.
>
> I think you further specified it when we referred to both low birth
> weight and immunocompromised, I think you further identified what that
> means, but I didn\'t see any difference in that.
>
> DR. STALLINGS: So, for follow-up then, do you see that this language
> is any different from the current practice, because I saw this as a
> move to be more firm in our commitment to get powdered product, and
> that is where the issue of eliminate used in this very narrow setting
> versus minimize, but I see it in the context.
>
> But is industry proposing anything different from what it was from the
> interim proposals from CDC and others that we have been working with
> the last year or so?
>
> DR. GHILARDI: I think we are emphasizing that that has a need for
> further communication. I don\'t think that that is in practice
> everywhere, and we are saying that that should be something that is in
> practice everywhere.
>
> DR. BUSTA: Other comments on No. 2? Dr. Baker.
>
> DR. BAKER: I just wanted to answer that comment about aseptic
> technique. Aseptic technique, to me, does not mean that the product
> you are dealing with is sterile, it means that you are dealing with it
> in a certain way, but it doesn\'t mean necessarily that it is sterile,
> and I don\'t think that was the intent of the statement, that they
> were claiming that it was a sterile product.
>
> Do you want to comment on that?
>
> DR. BUSTA: Dr. Tompkin.
>
> DR. TOMPKIN: Well, as a microbiologist, I wouldn\'t imagine using
> aseptic technique for something that is not sterile. It just doesn\'t
> seem like something that I would do. I would use caution, care, but I
> wouldn\'t take it into a hood or do anything like that.
>
> DR. BAKER: The ADA, the new ADA recommendations are going to be
> aseptic technique, I believe, and they do recommend a hood when
> possible.
>
> DR. BUSTA: Dr. Beuchat.
>
> DR. BEUCHAT: To that issue, it means perhaps obviously, two different
> things. It might mean handle the product in a way that you don\'t
> contaminate it, that is, handle it aseptically, but it may also mean
> to the reader, a microbiologist, that it is already sterile and you
> need to keep it that way.
>
> DR. BUSTA: I think this has been a very interesting meeting.
>
> \[Laughter.\]
>
> DR. BUSTA: The only time I have had experience like this as a food
> microbiologist is working with engineers. They are sort of off the
> other end.
>
> It is really astonishing that identical terms conjure up different
> concepts in practitioners\' minds depending upon what your background
> is and where you are practicing it, and that is a perfect example of
> some of the experiences we have had.
>
> I think that we have worked on No. 2 quite well and actually stayed on
> it, which was better than we did on No. 1, and No. 3, I think is of
> greater depth and we can handle without some additional energy.
>
> I am recommending\--oh, my Co-Chair says do you want to get consensus
> on No. 2 before we move on.
>
> Dr. Kuzminski.
>
> DR. KUZMINSKI: I thought we agreed that our Chair would synthesize as
> the discussion went along, and I would be happy to repeat what I
> repeated, but I will take a shot at it if I can recall with all the
> other discussion going on.
>
> There are two opportunities or two areas of opportunity for
> intervention strategies. One area is in the area of labeling and
> labeling instruction to reflect current knowledge on precautions in
> preparation, the need for certain water temperature, the need for
> certain holding times, cooling temperature, et cetera.
>
> But the point there is that the label should reflect current
> knowledge.
>
> The second area of intervention strategy is to build upon two pieces
> of information that we, as a committee, one we have generated, and the
> other, the industry has brought forward: one, to eliminate powdered
> infant formula from populations at risk, and that definition of
> populations at risk would be the one that this committee has generated
> with the precaution as raised on the healthy term availability of
> powdered formula to that population, as Dr. Thureen has raised.
>
> DR. BUSTA: May I add that when you say eliminate, \"wherever
> possible?\"
>
> DR. KUZMINSKI: Sure.
>
> DR. BUSTA: So that we don\'t flush that. And may I add to the first
> aspect, there seemed to be a great deal of emphasis on not only
> labeling of the product appropriately, but transmitting the
> information on that preparation procedure to the entire, I think food
> chain was a very appropriate word, all the way up, educational
> material all the way up the administrative system all the way
> throughout the hospital, so that everybody acts appropriately on that
> information, if that is an appropriate addition to that, because I
> heard a lot of that.
>
> Dr. Fischer.
>
> DR. FISCHER: Let me see. I want to make sure we get some agreement or
> not on labeling it as a sterile, as a non-sterile product. Do we want
> that label on it?
>
> DR. BUSTA: I heard a lot of people say be sure to have non-sterile on
> that or this product is not sterile, whichever is the appropriate
> wording, indicate that it is not sterile.
>
> DR. FISCHER: It is being honest to do that.
>
> DR. BUSTA: Yes. It emphasizes that.
>
> Other comments on that summary? Dr. Blumberg.
>
> DR. BLUMBERG: I think it\'s important to include that term you
> mentioned, \"wherever possible,\" because it sounds like for breast
> milk, that is a real issue with fortifier, because right now it
> doesn\'t sound like we have any fortifiers that are sterile.
>
> DR. BUSTA: Right, and I think we have to say \"wherever possible,\"
> and it could be at the end of the phrase or at the beginning of the
> phrase, but I think it has to be \"wherever possible,\" otherwise you
> are proposing an activity that may not be able to be carried out.
>
> Other comments? Dr. Beuchat.
>
> DR. BEUCHAT: I apologize to the committee for not being here earlier,
> but I pick up now on the meaning of the word \"eliminate\" versus\--
>
> DR. BUSTA: It\'s too late.
>
> DR. BEUCHAT: Eliminate all viable cells through techniques that are
> available. You can detect dead cells. I think that we probably are
> thinking in terms of, if it\'s the word \"eliminate,\" we are talking
> about viable cells.
>
> DR. BUSTA: It\'s eliminate powdered infant formula wherever possible,
> and you can get back to that other theme on Question No. 1.
>
> Dr. Thureen.
>
> DR. THUREEN: I just have a question. Do you think that it would be
> useful or advisable to put on the label, like the web site, the
> ADA/FDA web site, so that people could go to reference for any
> materials that get updated as time goes on, or would you say if you
> have questions about this, call the manufacturer, or that gets
> outdated that it is not worth putting on a label?
>
> DR. BUSTA: Personally, I would hesitate to get into the details of the
> label because I don\'t know what can be or cannot be, and there is a
> lot of designation of size, all that.
>
> DR. THUREEN: That\'s fine.
>
> DR. BUSTA: Any other comments?
>
> DR. KUZMINSKI: Just a comment. I just would be interested to learn
> what the practitioners feel that the preparers of the formula, from
> preparers of the bottle of food for the baby from the infant formula
> mix, powdered infant formula mix, do they now think that the powdered
> infant formula is a sterile product?
>
> DR. THUREEN: I would say yes, I think there is a huge misconception,
> and I think that people just don\'t know, and it\'s just a presumption
> that if it is for babies, and it comes in a container, it is going to
> be given to babies, it\'s a sterile product, anything that you pop
> open like that is a sterile product. It is just an assumption. There
> is no education\--I mean they just don\'t know.
>
> I took a poll and I asked people if it was sterile or not, and the
> majority of people presumed it was sterile. I mean at all levels, from
> the technicians to the physicians, they presumed it was sterile, the
> majority of them. It just never occurred to them to even ask that
> question.
>
> DR. BUSTA: Dr. Tarr.
>
> DR. TARR: I agree with Dr. Thureen, and even if they would defer on
> the question of sterility versus non-sterility, if you asked them is
> there a possibility that there is a germ in there that could harm a
> child the answer would be \"no\" almost uniformly, whether or not they
> understood the technicality of sterilization.
>
> DR. KUZMINSKI: You see, the difficulty I have, and I agree with truth
> in labeling, the difficulty I have with putting the statement of
> whatever the wordage turns out to be, this is not a sterile product,
> is may imply that this is a defective product.
>
> If the wide preconception, as you have described, is that it has been
> a sterile product, and if that is now on the label, is this something
> different, has the process changed that makes a product less good than
> it used to be, because I thought it was sterile, and now they are
> telling me on the label it is not sterile.
>
> DR. BUSTA: Dr. Tarr.
>
> DR. TARR: What about a more inclusive, but still accurate term,
> powdered formulas are not subject to sterilizing conditions as a
> statement. In that way, it doesn\'t say this product is not sterile
> inferring that there could be a product out there that is dry and
> powder and is sterile.
>
> DR. STALLINGS: To continue the discussion, I think we have all
> committed that this has to have an educational component to it, so we
> are going to raise a level of awareness that will naturally, you know,
> well, what is the big deal.
>
> This will have to come across that this class of products has gone
> through a different understanding that it potentially has risk, that
> had been there all along, and where it is now telling you that we are
> clear of them, there is a plan to minimize the risks both industrially
> and clinical care.
>
> So, I mean this isn\'t going to be stealth. If we go ahead with this,
> and the few people that need to know this, which again are a select
> number of people in a healthcare organization, are going to hear it
> and going to make the policy changes and educate the people.
>
> There will be an element of concern that is natural for people who
> think that, well, people who have been doing their very best to
> understand, but it\'s the nature of new knowledge.
>
> I mean we just have to capture it within that, but I am sure we are
> going to cause some concerns, and I am sure if there is anybody in the
> country whose baby was diagnosed with this unusual bug, you know, they
> may think about it, but there is no avoiding that just by nature of
> having this panel and these alerts that have come out over the last
> couple of years, this is a different topic.
>
> So, I think we have to say, I mean we have to state the facts. I think
> there will be the perception as Larry was talking about, that
> something that we did trust, you are going to be uncomfortable about
> and that our job is to move it quickly back into trust and select
> products that you need.
>
> DR. BUSTA: Dr. Baker.
>
> DR. BAKER: I feel like one of Larry\'s problems with this is that it
> is somehow labeling one product as being inferior. If the statement
> were something like powdered infant formulas, all of them are not
> sterile products, powdered infant formulas are not sterile products,
> then, it wouldn\'t single out that particular brand as being not
> sterile, it is just all powdered formulas, and I believe that is what
> we heard the last few days.
>
> DR. BUSTA: No, am I correct in that we are addressing this specific
> group of products for this group of at-risk population? This would be
> not on all powdered infant formula. Are you proposing for all powdered
> infant formula?
>
> DR. BAKER: I would say all powdered formula.
>
> DR. BUSTA: Okay. Co-Chair, are you going to get us to consensus, so we
> can go to lunch?
>
> DR. HEUBI: We need to go to lunch, but I tend to now agree with the
> concept of this issue of putting a label that all powdered formulas
> are non-sterile, and I think that takes care of my question about
> manufacturers making every effort to make them as clean as they can
> be, because that actually defuses this concept that everyone is the
> same in terms of how they are handled.
>
> DR. BUSTA: Dr. Tarr.
>
> DR. TARR: Maybe time for one more clarification. Pasteurization may be
> a better term than sterilization because of the differences\--let me
> back up. A pasteurized product is not sterile, so we would have to
> extend that to all pasteurized products is this is not sterile. So,
> perhaps we should state this subject has not been subject to
> pasteurizing conditions using pasteurization as the noun rather than
> the sterilization.
>
> DR. HEUBI: I am a little concerned about whether that nuance will be
> lost on the public totally.
>
> DR. TARR: But technically, well, I would like to throw that open for
> discussion because we are inaccurate. There is a disconnect between
> saying this product is not sterile, but a pasteurized product is also
> not sterile, so perhaps it is equal to pasteurization, yet it is not,
> going up to the level of pasteurization.
>
> DR. HEUBI: In contrast, though, I guess what we are contrasting is
> with liquid concentrates and rate of feed are all sterile.
>
> DR. TARR: Are they sterile or are they pasteurized?
>
> DR. HEUBI: Commercially sterile.
>
> DR. BUSTA: We have got a wonderful conversation going. Dr. Lee.
>
> DR. LEE: I think we just made a jump, and I want to just point out
> that we are consciously doing that. Someone said that we are going to
> label all powder formula as not sterile or containing microorganisms
> or whatever.
>
> I am not quite so sure that is in the best interests of public
> information and knowledge or the industry or the science, because if
> you look at foods, most foods are not sterile, we are not labeling
> them in such a way.
>
> I really think that this communication has to occur to the at-risk
> groups and the care providers to that at-risk group, but to globalize
> it and say all formula has to be labeled in this way is a bit of a
> leap to me that is not justified at this time.
>
> DR. MOYER-MILEUR: The exception would be that some of these powdered
> term products are being used as additives to breast milk for pre-term
> infants in some nurseries, so it makes it very difficult to single out
> which products would be found.
>
> DR. BUSTA: Dr. Tompkin.
>
> DR. TOMPKIN: Since all this material is coming off one stream in some
> cases, not in all, but in some cases, it is one product stream, and
> the question is some of it is being used in a hospital setting.
>
> Inserts into the carton is one way of dealing with that. Providing the
> information, you can place an insert into it. It is not an uncommon
> practice even with foods to put an insert into a carton as
> instructions for preparing the food prior to serving.
>
> That way, you could target the information for the intended user in
> that specific setting, and you can build as much information into that
> as possible, and it should, of course, be complementary and in
> agreement with the American Dietetics Association, and so on, so it is
> a complete message.
>
> DR. BUSTA: Do you want to get consensus or do you want to ruminate on
> it?
>
> DR. FULLER: My sense was we were pretty much in agreement on the first
> two issues, and the issue of label, what should be on the label is the
> sticking point.
>
> I think we have heard some differences of opinion. We have heard some
> people state that labeling should include a statement that powdered
> infant products are not sterile or have not been pasteurized or
> something along that line, and then we have heard a differing opinion
> that says no, that information is better placed in an educational
> program or outreach or perhaps, although in an insert, but I thought
> that was labeling also, so I am not sure of the fine points there.
>
> One point maybe Ken could explain because I am having a little bit of
> difficulty. I heard that the liquid products are sterile or
> commercially sterile or pasteurized. Can somebody help me with the
> differences between those terms?
>
> DR. LEE: If you take a commercially sterile can of, you know, I don\'t
> care, but beef stew, and subject it to high temperatures in a
> warehouse, it is going to grow, because it does have microorganisms in
> it that are not pathogenic. Did I get that right, Frank?
>
> DR. BUSTA: Has anybody got a chalk board?
>
> DR. FULLER: I only raise the point because we had the discussion about
> if we put something on the powdered product as not being sterile or
> something of that nature, should you also extend that same to the
> liquid formula, which is also not sterile, but may be commercially
> sterile, and that was why I was raising that issue.
>
> DR. BUSTA: To my knowledge, I.V. fluids and things of that type in a
> hospital are sterile. Thermophiles, high temperature organisms, or
> whatever, theoretically, I mean essentially, they don\'t exist. They
> have been superheated to eliminate all of that.
>
> In commercially sterile food products, it indicates that anything at
> ambient temperature, that can grow at ambient temperature is not in
> that product, and it could be a variety of ways.
>
> If the product has a lot of sugar or a lot of salt, it is commercially
> sterile and could have a lot of organisms in it. It is free of
> pathogens, and it may have viable organisms that can grow at these
> high temperatures, as Ken indicated, so that in some cases, a food
> product like that would not be usable if you wanted to do I.V. because
> there may be saprophytic organisms that could not grow in that
> product. If you put it into a vein, you might get just an unusual
> growth that you wouldn\'t want to do.
>
> Pasteurized is to eliminate generally for something like milk, is to
> eliminate any pathogens in that milk, and pasteurized is sometimes
> used merely to reduce the population of spoilage organisms.
>
> DR. FULLER: Okay. My last comment would be if we are going to put
> anything on the label, let\'s be accurate with whatever it is in terms
> of what terminology we use.
>
> DR. BUSTA: So, in synthesis, I heard that when we are asked the
> question are there other intervention strategies, I heard that it was
> essential to label in some way, either by insert or directly on the
> container, depending on the message that you intend to deliver, that
> the specific handling instructions for these individual products and
> their exceptional needs for the populations that are at risk, I heard
> that this included the handling practices, as well as the instructions
> on the product not being sterile.
>
> The insert or additional educational materials are required and an
> additional education program is required for the staff all the way
> through to the upper administration and the facilities to understand
> what these labeling systems mean and what the important parts of the
> preparation procedures are, so that they are carried out
> appropriately, not just by the individual workers, but being
> instigated and enforced by the entire administration.
>
> Dr. Kuzminski.
>
> DR. KUZMINSKI: I think you have captured the first area of
> intervention.
>
> DR. BUSTA: No. 1? Okay.
>
> Dr. Blumberg.
>
> DR. BLUMBERG: I know we don\'t want to get into the exact wording, but
> that is probably important because if it\'s said it is not
> pasteurized, I think people are going to think, well, this is like\--
>
> DR. BUSTA: It is not sterilized.
>
> DR. BLUMBERG: Right, but if somebody used that word, I think there
> could be a lot of confusion depending on how the wording ends up, so I
> am not exactly sure what we are agreeing to.
>
> DR. BUSTA: I was hoping to leave it loose enough, so that the people
> who are in communications and understand what the public understands
> would select whether this product is not sterilized, this is not
> sterile, this product contains bacteria, whatever words would
> appropriately get the message across to the clients would be the term.
>
> I am not sure I am in a situation or we are in a situation where we
> know the best way to send that message that this is not a sterile
> product.
>
> Dr. Stallings.
>
> DR. STALLINGS: I would agree with that, because I think there really
> is an art to deciding on label and educational materials, and I think
> it is probably beyond both the time and the talents that we have.
>
> So, I think the big question for the committee is have we captured the
> idea, and the agency can work with communications and space and proper
> place with that experience.
>
> DR. BUSTA: Dr. Tompkin.
>
> DR. TOMPKIN: This communication, it\'s for those healthcare givers who
> are preparing and handling these products in high-risk populations,
> this is not for the general population at large. I want to make sure
> that we understand who is being communicated the concept of
> non-sterility.
>
> We are really communicating this to a special health group.
>
> DR. BUSTA: And that is what I heard, that it would be accompanied with
> educational materials, so that one does not get a backlash from the
> handlers or the workers or the medical staff, or whoever.
>
> Not unlike the aseptic technique, if aseptic technique meant don\'t
> contaminate it, and you remove that terminology, some people might get
> quite cavalier. So, I am assuming this comes with an educational
> program to make sure that the staff all the way through realizes that
> care needs to be at a higher level than it was.
>
> Dr. Blumberg.
>
> DR. BLUMBERG: Just to clarify, are you saying to label all products or
> just products that are going to be used in the neonatal intensive care
> unit?
>
> DR. BUSTA: My understanding, the last that I heard is for products for
> the at-risk populations, so if it was infant formula, straight infant
> formula going to hospitals, that it would have inserts or labels, but
> for anybody dealing with an at-risk population.
>
> DR. HEUBI: I think the problem is, is that you can\'t separate out
> products that just go to the hospital versus those that go to the
> public because we know, as Laurie pointed out, that there is
> supplementation of products with powder that is intended for term
> infants, that is given to pre-term infants.
>
> So, it sort of like we are going to have to either go all the way or
> not is sort of what it boils down to, and I am now thinking in my own
> mind, after I have heard all this conversation, about whether we
> should just ignore this and not include anything about sterility at
> all, because I think it has now gotten to the point where I now know
> facts that I didn\'t know before.
>
> In fact, Ken has pointed out that even products that are liquid
> products are not sterile, which then are you going to put something on
> them saying that they are not sterile?
>
> So, then, I get into the situation where maybe we have opened a
> Pandora\'s Box here that I don\'t want to let the little genies and
> folks run out of because you are going to be dealing with cleaning
> this up for years after we make recommendations about this.
>
> So, in part, although I thought this was a great idea to begin with, I
> am willing to admit that my mind has been changed somewhat. I am not
> sure that I think it is now appropriate to include something about
> sterility.
>
> DR. BUSTA: Dr. Fuller.
>
> DR. FULLER: I agree with you. I think that I agree with what we had
> come to with that one piece of label change. I think that the issues
> that Dr. Kuzminski first stated about using what we know about
> preparation of the product that we have learned over time, that the
> current label instructions might be enhanced.
>
> I don\'t have any problems with changing those labels. We have to keep
> in mind the product is going to more than one user group, and the
> product has to be an appropriate label for all.
>
> I think the stress has to be on the outreach and education to the
> medical community that are involved with the use under these very
> specific conditions where the risks are, and I don\'t think there is a
> problem with inserts that address those risks and those instructions.
> I think that is fine, but I am not convinced that putting something
> about sterile or non-sterile is where we need to be.
>
> DR. FISCHER: Dr. Stallings.
>
> DR. STALLINGS: Not to belabor the point, but I think one of the things
> that I have learned throughout this is something from a healthcare
> point of view about something I perceived as sterile, and, you know,
> the definition of commercially sterile versus naively thought to be
> sterile is new understanding.
>
> But the formula that is liquid, we think of in a healthcare setting as
> sterile, and if that were to be punctured we wouldn\'t use it, if
> something inappropriately were to be put in it, we wouldn\'t let
> somebody stir it or mix it without it being a sterile instrument, or
> the blenders are cleaned, and all of that.
>
> So, I know we are dealing a little bit with semantics, but if we go
> back to our job, it is really to protect the public\--in this case the
> public are these little, tiny babies\--what is it that we can do to
> really meet that.
>
> I think I do believe that without it being in big red letters and
> alarming, the fact that these aren\'t sterile is an important new
> fact. Now, could we get that same information across if we had an
> educational program? Probably. And then the question is can we sustain
> that change in practice or we sustain it long enough until the product
> is changed, and all of this really goes away.
>
> But the only reason I like the labels is it is part of how we learn
> when you are unfamiliar as a healthcare provider with something, part
> of how you learn about it is you glance at the label and it puts it in
> a place.
>
> So, I am not looking to alarm people, but I agree that all of the
> powdered products have a real potential to be used in the nursery, at
> least for the foreseeable future, so I sort of favor whatever the most
> straightforward bland, you know, non-sterile product is something that
> I am accustomed to seeing with everything I use in an intensive care
> unit, it is either sterile and I put on gloves, and it goes into that
> range, or it is not sterile, and I am still careful.
>
> So, I am still voting for non-sterile statement.
>
> DR. BUSTA: Well, we had a synthesis, but it dissolved on sterile
> versus non-sterile, or non-sterile versus no indication of
> non-sterile. That is what I think we had.
>
> Some people want to state this is a non-sterile product in some
> fashion. Others say it probably shouldn\'t, that may cause more
> problems than not putting the information on the product.
>
> Dr. Tarr.
>
> DR. TARR: I would like to ask a question. Are the liquid formulas
> pasteurized, do they meet the definition?
>
> DR. BUSTA: Oh, absolutely.
>
> DR. TARR: Then, why don\'t we state that the difference is these
> products or this group of products are not pasteurized.
>
> DR. BUSTA: They are pasteurized.
>
> DR. TARR: But the powder.
>
> DR. BUSTA: The powder is pasteurized.
>
> DR. TARR: That counts as pasteurization? If something is pasteurized,
> but then is subject to contamination or association with something
> that is not pasteurized, does that render it non-pasteurized?
>
> DR. BUSTA: No, otherwise you wouldn\'t have pasteurized milk. Milk is
> pasteurized, then packaged.
>
> DR. FULLER: Getting to that point, are they currently labeled as
> pasteurized, the powdered? No, I am talking about the powdered
> product, is that labeled as pasteurized? I didn\'t think so. And the
> liquid is labeled as sterile. I am seeing nodding heads out there.
>
> DR. BUSTA: It is not labeled.
>
> DR. FULLER: Okay.
>
> DR. BUSTA: Those words are not used, to my knowledge.
>
> DR. FULLER: So, we have got neither of these products currently have
> any labeling to address the issue of sterility or non-sterility, and
> we are suggesting that we identify the powdered as being non-sterile,
> and we just ignore or leave alone the liquid product, and let it go
> with perception.
>
> I want to do the right thing here, believe me, I want to do the right
> thing, and I am just wondering if labeling is the way to do it.
>
> DR. BUSTA: I am going to hold this to no more than five minutes,
> because as a good food microbiologist we have product incubating next
> door.
>
> \[Laughter.\]
>
> DR. BUSTA: At low concentrates, the dose makes the poison, as you all
> know.
>
> Dr. Tarr.
>
> DR. TARR: May I ask you to consider asking us, in a two-tier question,
> should there be some public declaration on the product that there is a
> categorical microbial difference between powdered versus liquid
> substance, and then, secondly, if the vote is yes, that we then defer
> to the FDA to work on the appropriate wording?
>
> DR. BUSTA: All right. That is a question you are asking me. Let\'s
> see, I am Chair, I am Co-Chair.
>
> DR. LEE: I will second that motion that we basically introduce the
> concept that there ought to be a communication that the liquid is
> different, perhaps cleaner, all right, and leave it to the healthcare
> professionals how to communicate that in whatever words are necessary.
>
> DR. BUSTA: He just made the point that we may not be able to choose
> the right words.
>
> Dr. Neill.
>
> DR. NEILL: A point of clarification perhaps from one of our FDA
> colleagues in the audience. In full recognition of the fact that the
> road to hell is usually paved with those good intentions, are there
> different recognitions of the definition of the term pasteurization as
> applied to a food label versus the legal and regulatory interpretation
> of the term pasteurization.
>
> I ask in the concept that it was my understanding from a long time ago
> that the only legal definition of pasteurization was for a particular
> time and temperature combination as applied to fluidized milk.
>
> DR. ZINK: You know, it just gets better. Within the processed milk
> ordinance, there is a definition for pasteurized. I don\'t profess to
> be an expert in food law here, but I am not aware of any other
> definition of pasteurization anywhere.
>
> Now, certainly the agency is confronted under the new farm bill of
> considering more broadly other processes, and that has to be done kind
> of on a case-by-case basis. You know, there is a process where we can
> be petitioned to decide whether or not something is pasteurized by the
> process, but right now the processed milk ordinance is the only one
> that defines the term pasteurized.
>
> DR. BUSTA: And that is by a state-by-state decision, right?
>
> DR. ZINK: Well, the states enforce it, but the ordinance defines it.
>
> DR. BUSTA: Dr. Tompkin raised his hand, Dr. Beuchat has the phone, so
> whichever one.
>
> DR. TOMPKIN: We might be about to say the same thing, but in the case
> of citrus juices, if they have not been subjected to a 5D reduction
> process, they must be labeled non-pasteurized, so as you go through,
> you can come up with some other examples.
>
> DR. BUSTA: I believe there is a pasteurized for eggs.
>
> DR. ZINK: There is a process for eggs, for milk or dairy products. Any
> other product, we would have to define it.
>
> Dr. Beuchat.
>
> DR. BEUCHAT: Just to add to that, to communicate that there is
> confusion outside this committee or at least concern about the
> definition of pasteurization, the National Advisory Committee for
> Microbiological Criteria for Foods has been charged by subcommittees
> with an issue entitled Redefining Pasteurization. That is a presently
> ongoing activity.
>
> DR. BUSTA: We have 30 seconds. Dr. Tarr, would you like to restate
> what you said?
>
> DR. TARR: Yes. We should vote yes or no. Are we in favor of stating
> that the powdered formulas are categorically different from a
> microbiologic standpoint than the liquid formulas?
>
> DR. BUSTA: All who want to vote\--
>
> DR. TARR: And publicizing this.
>
> DR. BUSTA: Those who want to say yes to that statement, raise your
> hand.
>
> DR. TARR: The proposal, that there be a statement on or in the package
> to the effect of this powdered substance is categorically different
> from a microbiologic standpoint than the liquid substance.
>
> DR. BUSTA: The first time was even better, but what you are indicating
> is that, with the appropriate wording, it is to indicate to people
> that powdered product has a different treatment that makes it less
> microbiologically hazardous, or whatever, than the liquid formula.
>
> DR. TARR: And hazardous is a buzz word.
>
> DR. BUSTA: Dr. Lee.
>
> DR. LEE: I like it.
>
> DR. TARR: Different rather than hazardous.
>
> DR. BUSTA: All those in agreement with his statement, who want to say
> yes to his statement, raise your hand.
>
> \[Show of hands.\]
>
> DR. BUSTA: Eight.
>
> All who want to say no, raise your hand.
>
> \[Show of hands.\]
>
> DR. BUSTA: Five.
>
> Lunch is served. I was six.
>
> \[Whereupon, at 12:30 p.m., the proceedings were recessed, to be
> resumed at 1:15 p.m.\]
>
> AFTERNOON PROCEEDINGS
>
> \[1:15 p.m.\]
>
> DR. BUSTA: We have one hour and a half, and we are going to try to do
> our very best.
>
> In No. 2, I am going to give an option and ask for your indulgence in
> listening to this option which I have heard comments about one way or
> the other, and see if you can jump at that, and if not, we may just
> have to put it onto a shelf and hold it for a while.
>
> There was an 8-7 vote on that one option, and in the interim, I am
> learning a lot about what is involved in trying to come up with a
> labeling issue, and that labeling is another world that we have not
> addressed here, and if communications between clinicians and food
> microbiologists use terms differently, labeling is even really off in
> another sense.
>
> So, I would like to propose the following synthesis on No. 2 - are
> there other intervention strategies: that we suggest to FDA that they
> prepare educational documents that can be used in attaching to the
> appropriate infant formula materials, especially for those for the
> children at risk, and when used for the specific children at risk,
> that would alert all individuals whether it be mothers or hospital
> personnel at any level, to the absence of sterility of those products
> or the special handling needs of those products, stated in a way that
> they will understand it and in a way that will deliver the message
> that it requires special handling without causing a panic or a loss of
> use of those essential products, that reflects the handling
> procedures, it reflects all the recent handling procedures that are
> recommended, and it gives a system that can be updated regularly to
> any new understanding and information that comes out.
>
> With that, I am not specifically saying that it is labeling, but I am
> emphasizing that it should indicate in those materials, in educational
> materials, that these are not sterile products and have to be handled
> specifically.
>
> Dr. Baker.
>
> DR. BAKER: Just to clarify, this would be addressed to hospital
> personnel, as well as lay mothers, parents, who are making up formula.
>
> DR. BUSTA: It is people that would use it as indicated where they
> would be supplementing mother\'s milk with formula, places in those
> situations.
>
> DR. BAKER: So, some formula would have this, and some would not?
>
> DR. BUSTA: Or the message would get to individuals that would be using
> formula for potentially risky children, children at risk.
>
> Dr. Tarr.
>
> DR. TARR: I think that that is close or at where we should be for the
> healthcare professional. I think it doesn\'t address the issue of the
> general public and the purchase of an item that we are now agreeing is
> not sterile.
>
> Will you have a second proposal for that population or is this one
> notice fits all?
>
> DR. BUSTA: You have a proposal for one notice fits all? This is big
> enough for me right now, this section.
>
> Dr. Fuller.
>
> DR. FULLER: I would like to suggest, and everybody shake your head if
> I have gone in the wrong direction, an alternate. What I would suggest
> is I think we were in agreement where we were on 2(2) with the
> exception of the labeling, which we took this vote and we had a very
> close vote. The committee did not agree on whether the product label
> should address sterility.
>
> I would suggest that we agree to everything else and on that issue, we
> just note that we, as a committee, were not able to reach agreement,
> and recommend that FDA look at that issue and, if appropriate\--I mean
> they are the ones that know what should and shouldn\'t be on labels
> and making that decision\--obviously, some people feel very strongly
> that it is worthwhile, and if it is appropriate and appropriate
> terminology is out there, but to look at that issue and address it as
> they feel it should be.
>
> I mean the committee has said this is something important, we have
> noted that to FDA, I think in our deliberations, and I think we just
> best move on.
>
> DR. BUSTA: Dr. Stallings.
>
> DR. STALLINGS: I think when we were earlier talking about labeling,
> the idea at the FDA, I mean the food label is such a precise, highly
> regulated space, that I think the idea was that people using the
> product would have this information.
>
> I don\'t know enough, it\'s like the product insert, packaging, there
> are a lot of different places that you could put this information, and
> if that is captured in what everybody is saying, I think we, at least
> I, had moved a little bit towards the idea that this was something I
> didn\'t understand, and if I didn\'t understand it, a lot of people
> probably didn\'t, and if we use the principle of transparency as fact,
> but not to institute fear.
>
> I mean it is the idea that now that we have gone through this process,
> it should be made publicly available in some way, labeling may not be
> the right term to talk about what we are doing.
>
> DR. FULLER: I think that is the point, that\'s exactly, and I think if
> we could just agree with that, and move on.
>
> DR. BUSTA: Dr. Blumberg.
>
> DR. BLUMBERG: I would like to go back to the point that you brought
> up, about the steps that FDA should take as far as education, and
> maybe split it into two components.
>
> Maybe that is for consensus reasons, and maybe there is other reasons,
> but one is that FDA should provide outreach to physicians to make them
> aware that powdered formulas are not sterile, and these are not
> generally the preferred agents in the neonatal ICU setting. Some kind
> of very strong statement that would follow up what is in the MMWR, and
> that be modified perhaps, the guidelines that were in the MMWR.
>
> DR. BUSTA: That would be fine to add onto what I said. Do you want to
> vote? All in favor of what I said?
>
> DR. FULLER: Yes, with those add-ons.
>
> DR. BUSTA: With those additions.
>
> \[Vote taken.\]
>
> DR. BUSTA: Thank you. No. 2 is gone.
>
> No. 1, we have two individuals that said they had some items to put
> forward.
>
> Dr. Neill.
>
> DR. NEILL: I have written what are four separate statements that could
> be deleted in part or in whole, in which I have attempted to capture
> the spirit of the scientific content as we discussed the Question 1
> under Charge 2.
>
> That question was what intervention strategies could be used in the
> plants.
>
> Intervention strategies which reduce bacterial presence in powdered
> infant formula should be used in manufacturing processes and plants.
> These include, but are not limited to, prerequisite programs to assure
> the microbial quality of raw materials, hygienic design and
> maintenance of equipment, hygienic zoning in plant design, and
> continuous use and improvement of HACCP programs and their
> verification.
>
> The committee encourages the development of a microbiological sampling
> and testing program through joint efforts by industry and the FDA, the
> purpose of which is to assure great clinical safety of this product.
> It would be highly desirable to formally assess the contribution of
> such a microbiologic testing program when added to the intervention
> measures described above.
>
> The committee recognizes that with currently available processing
> technologies for powdered infant formula, the risk for illness due to
> E. sakazakii cannot be completely eliminated for the at-risk
> populations specified above (as in Question 1). Whether the additional
> interventional strategies described herein can achieve this result is
> not clear.
>
> Recognizing the important clinical purposes for which powdered infant
> formula is used among the very populations most at risk for E.
> sakazakii infections, the committee strongly encourages and enjoins
> the powdered infant formula manufacturers to develop product
> formulations which combine the attributes of maximal growth promotion
> and microbiologic sterility for use in these at-risk populations noted
> above.
>
> DR. BUSTA: Dr. Fischer.
>
> DR. FISCHER: I like that one.
>
> DR. BUSTA: Okay.
>
> Dr. Fuller.
>
> DR. FULLER: I think we just need that the maximum growth was of the
> infant, not the E. sak.
>
> DR. BUSTA: Dr. Beuchat.
>
> DR. BEUCHAT: The very last point that you made, the last sentence,
> microbiologic sterility?
>
> DR. NEILL: I chose the words I chose for their specific meaning and
> offer them to you, then, for your consideration and debate.
>
> DR. BUSTA: Could I expand on that? I think that you are referring to
> your earlier comment, or at least I interpreted that earlier comment,
> that in the right situation, nearly any microorganism can be a problem
> for this at-risk population that we are dealing with.
>
> DR. NEILL: I would also be making the point of trying to be forward
> thinkers for the committee, and that E. sakazakii is a currently
> identified problem, and we really at this point don\'t know if there
> are other microbes for which we do not yet have knowledge that they
> pose a problem and, in fact, have a specific association with infant
> formula. So, there was a method to the madness in terms of trying to
> choose the words I did for that purpose.
>
> DR. BUSTA: Dr. Lee.
>
> DR. LEE: On that point, I would agree with the use of the word
> \"microbiological safety\" because we may someday indeed find out that
> there are desirable microorganisms to have in this product.
>
> DR. BUSTA: Dr. Tompkin.
>
> DR. TOMPKIN: I like it, too. I think it was well considered and it is
> broad enough and yet addresses in a specific manner the real intent. I
> think it is very well done.
>
> DR. BUSTA: Are we willing to go with microbiological sterility?
>
> DR. NEILL: Yes.
>
> DR. BUSTA: Will you accept the modification to microbiological safety?
> Okay.
>
> DR. BAKER: Can I just point out one thing?
>
> DR. BUSTA: Yes.
>
> DR. BAKER: Safety is a judgment, sterility is not.
>
> DR. BUSTA: Dr. Kuzminski. Two minutes on this and then we are done.
>
> DR. KUZMINSKI: If we hinge it on microbiological sterility versus
> safety, I really question the ability of the technology to deliver in
> a powdered infant formula product at this point in time that kind of
> product.
>
> I didn\'t hear a time frame in your statement, which is good, because
> I think when we were talking about it earlier, we set an ultimate goal
> of zero content of problematic microorganisms, so I think your
> statement is a good one, and I like it.
>
> I am a little discomforted by it, I am just trying to put my finger on
> why I am discomforted by it.
>
> DR. BUSTA: It is late in the afternoon.
>
> I would like to speak for safety in that sterility may not consider
> toxins that came through the product, that it could be sterile but
> still have microbial toxins in it, and it would be sterile, but not
> safe.
>
> So, I would like to\--as well as the viable wanted organisms\--so, I
> would like to speak for microbial safety, microbiological safety.
>
> All in favor of that very well constructed set of four comments, raise
> your hand.
>
> \[Show of hands.
>
> DR. BUSTA: Unanimous unless there is somebody against. Thank you.
>
> No. 3. Is it possible, based on available information, to specify
> allowable lower levels of microbial detection of E. sakazakii in
> powdered infant formula, and do allowable levels vary by risk
> characteristics of the infant?
>
> Open for comment. Dr. Baker.
>
> DR. BAKER: I would say no and yes.
>
> DR. BUSTA: And as I read the question, those are contradictory, but
> outside of that, it\'s a paradox.
>
> DR. BAKER: Given the present information that we have, there is no way
> that we can set lower allowable limits. I don\'t think there is enough
> information to do that. So, no to the first.
>
> Do the allowable levels, if there are any, do they vary in infants?
> Well, we have sort of already said that they do, said that there are
> at-risk groups and not at-risk groups, so we can assume that they
> would vary group to group.
>
> DR. BUSTA: What I am hearing is that with the information that we
> have, we really can\'t make a judgment on No. 1, and there is no
> question in your mind, as a commission, that No. 2 would vary, because
> we have identified groups. Okay.
>
> Dr. Beuchat.
>
> DR. BEUCHAT: This may be nit-picking, but I need clarification of the
> meaning of this question. Could it mean\--I don\'t think it does\--are
> we talking about methodology here, \"to specify allowable lower levels
> of microbial detection,\" I don\'t think it means lower levels of
> sensitivity in terms of detecting the organism, but rather the number
> of the organism per unit product.
>
> DR. BUSTA: I am seeing head shaking in the back that says this is not
> related to methodology, but is related to number of organisms in a
> food product that would be allowable.
>
> Dr. Kuzminski.
>
> DR. KUZMINSKI: I think an underlying point to this question is do we
> consider E. sak a pathogen, and if the answer to that question is yes,
> can you allow any level of a pathogen in the product.
>
> DR. BUSTA: One of the greatest tricks is to answer a question with
> another question, and I don\'t know.
>
> Dr. Stallings.
>
> DR. STALLINGS: To continue the discussion, I think over the course of
> time, we have decided it\'s a pathogen in the high-risk group we are
> discussing. So, I would agree with the information we have at hand,
> that there is no way for us to recommend a lower allowable level, and
> if we can\'t do that, I don\'t see that there really is a second.
> Until we have the kind of information that would allow you to do a
> real risk analysis, I mean that is sort of where that one ends.
>
> DR. BUSTA: Dr. Tarr.
>
> DR. TARR: As far as I can tell at this point in our knowledge, all we
> know is it\'s a genus and a species, we have no idea about subtypes.
> So, until we gather more information, we have to assume that all are
> potentially pathogenic. Perhaps we can refine that in the future.
>
> DR. BUSTA: We had some information yesterday, but that was in mice.
>
> DR. TARR: Right now I would have to propose that unless and until
> further data emerge that there are clearly pathogenic subtypes that
> could then be subject to a second tier of screening or testing we
> should be safe with E. sakazakii.
>
> DR. BUSTA: So, you are consistent with the earlier comments that we
> really are not in a position, we don\'t have enough information to
> respond to the first one, and the second one, therefore, is a moot
> point.
>
> All in favor say aye.
>
> \[Ayes.\]
>
> DR. BUSTA: Opposed?
>
> I am sorry I cut you off.
>
> DR. BEUCHAT: That\'s fine. We do have, I think, pathogens in infant
> formula. Bacillus cereus, for example, isn\'t a zero tolerance, so it
> wouldn\'t be setting precedent. I am not arguing for or in favor of a
> limit, but I think Bacillus cereus can be present at a certain level,
> and not be considered adulterant. Am I wrong?
>
> DR. ZINK: I feel better about this one. Oftentimes you hear people
> talk about zero tolerance. There really isn\'t any such thing. We test
> for pathogens using a sampling plan. The sampling plan, if it\'s well
> designed, is based on what we feel we need to be able to assure
> ourselves in order to manage the risk.
>
> I mean when you do microbiological testing in the context of a quality
> control procedure or a regulatory agency, it is a form of risk
> management. So, if there is something that is very, very risky, it
> often has a very stringent sampling plan.
>
> If there is something that has relatively low risk, it has a much less
> stringent sampling plan, and when someone is talking about zero
> tolerance, what they really mean is that according to whatever
> sampling plan you apply, if the result is negative, it\'s okay; if the
> result is positive, it\'s not okay, and it would be adulterated.
>
> There is no way that you can look at a 40,000-pound lot of infant
> formula and say I am 100 percent certain that there is not a single
> cell of any given pathogen in there without actually testing all of it
> for the pathogen thus rendering the status of the lot moot because you
> have grown it all up.
>
> So, I think, you know, one of the central questions we face is what
> sort, given our perception of risk here, what sort of sampling plan,
> if you will, is appropriate for risk management of this type of
> organism.
>
> There is sampling plans that a regulatory agency might use, there is
> sampling plans that are manufacturer might use for quality assurance.
> I mean some of you on this committee know this better than I.
>
> Even a broader question, is microbiological testing for this organism
> a risk management strategy that you would recommend.
>
> DR. BUSTA: If you find Bacillus cereus in this product, is it
> considered adulterated?
>
> DR. ZINK: I believe in the 1996 ANPR, we proposed a limit of 1,000 per
> gram\--what is it\--of 100. So, anything more than that, we would be
> likely to consider it adulterated, anything less than that, we would
> be likely not to.
>
> DR. BUSTA: We voted on No. 3. Now we are on No. 4, right?
>
> PARTICIPANT: We said that we did not have the\--
>
> DR. BUSTA: As I recall from two and a half minutes ago, we said that
> at the present time, we don\'t have sufficient information to make any
> kind of decision as to whether there is an allowable lower level of
> microbial detection or number of microorganisms, E. sakazakii in
> powdered infant formula.
>
> We don\'t have information to know if there is some allowable level,
> and that consequently, do allowable levels vary by risk
> characteristics of infants, we said, well, being that we identified a
> risk group that was different from the general infant population, it
> is probably yes, but it is dependent on the first question and
> therefore it is moot.
>
> That is what I just called for a voice vote, but if we need to raise
> hands, that is why I thought how we dispensed with that No. 3. Is that
> all right? All right.
>
> No. 4. Dr. Blumberg.
>
> DR. BLUMBERG: I think one thing that has come out is we really need
> better data on rates of E. sakazakii infections, and as has been
> pointed out, all we really have is numerator data from reported cases
> in the literature, and obviously, not all cases are reported.
>
> What I would encourage FDA to do, and perhaps the group would agree,
> is that there are currently available population-based surveillance
> activities that CDC has called FoodNet, which I think is part of the
> Emerging Infections Program, and I would encourage that FDA work with
> CDC for these groups to do population-based surveillance to establish
> what are the rates, because I think if they did this for a year in the
> surveillance\--they have six or seven surveillance areas,
> population-based surveillance areas scattered around the
> country\--that they could come up with some data for us on what are
> the rates of infection with this organism.
>
> DR. BUSTA: That\'s the first item on No. 4, right, critical knowledge
> gaps.
>
> I am proposing that we make No. 4 a shopping list, and we just go on,
> and I calculated that if we had one hour to do this, which is exactly
> that, we would have approximately four minutes per person.
>
> Dr. Stallings.
>
> DR. STALLINGS: I will do my shopping list and then let everybody else
> talk.
>
> So, the understanding of the level of occurrence of the organism in
> the powdered products with acceptable sampling, so this isn\'t for
> assurance of the product line, but as a separate study. Some
> understanding of the dose required for infection in the best animal
> model that we could get.
>
> A review of current clinical practices for diagnosing an infection
> with this organism, and I am concerned about two things, one, that
> there could be partially treated meningitis because of the way we
> practice in a high-risk infant, you often give antibiotics before you
> know the organism.
>
> The issue of clinical microbiology labs with the new automated
> systems, are those fully capable of doing everything that we want them
> to do.
>
> DR. BUSTA: Dr. Heubi.
>
> DR. HEUBI: I just wanted to amplify what Henry said, that is, we need
> to make sure that those include the at-risk populations that we are
> looking at, and also that the microbiological techniques actually
> allow us to be able to identify E. sakazakii, because that is another
> issue, as well.
>
> DR. BUSTA: Do you have other ones on the list?
>
> DR. HEUBI: Not immediately. I will think about it.
>
> DR. BUSTA: Next volunteer. Dr. Briley.
>
> DR. BRILEY: I don\'t believe we have enough data on the breast milk
> formula with the mother\'s milk combined in terms of the organism, as
> well as use, and that is where the consumer might be using it more.
>
> DR. ACHOLONU: Alex Acholonu. In light of we were told that we don\'t
> have any knowledge of the reservoir hosts, I am suggesting that we
> conduct some experimental studies, may use some laboratory animals,
> and find out the reservoir hosts.
>
> The next thing that I feel we should go into is the question of
> effective control, what would be the effective control measures.
>
> Thank you.
>
> DR. BUSTA: Dr. Fuller.
>
> DR. FULLER: I will add my two cents. I think additional work on
> identification of pathogenicity factors, some of the host
> susceptibility factors that lead to disease, the issue of colonization
> versus disease I should say.
>
> Then, an area that we talked about earlier, as well, was the potential
> for use of other microbes for competitive inhibition within the
> product, as well.
>
> DR. BUSTA: That would include probiotics?
>
> DR. FULLER: Right.
>
> DR. BUSTA: Dr. Tarr.
>
> DR. TARR: I have four elements I would like to propose. First, a needs
> assessment pertaining to consumer and provider knowledge base
> regarding microbial safety of these products.
>
> No. 2. Optimal therapy for the infected child. I am concerned when I
> see brain abscesses and don\'t quite know the best way to address
> that.
>
> No. 3. What is the spectrum of disease in the human host, does it
> include gastrointestinal disease in particular.
>
> I just want to clarify Dr. Briley\'s comment. What exactly is the
> safety of breast milk supplements? Is that what you are asking? That
> seems to be a void in what we have heard in the past couple days.
>
> DR. BUSTA: Dr. Lee.
>
> DR. LEE: I put a short-term and long-term spin on this, just two
> items. One would be I think in the relatively short term, we can
> determine whether or not reconstitution with hot water is advantageous
> or not. That is just something that could be done technologically, so
> I will defer to the research community whether or not that is
> something that is advantageous. I think that can be done in a short
> period of time.
>
> More on the long term is the issue of competing flora and what is the
> impact of having other bacteria present in inhibition of pathogens.
>
> DR. BUSTA: Dr. Tompkin.
>
> DR. TOMPKIN: With regard to doing a risk assessment, information is
> needed in terms of exposure, what is the potential exposure in
> hospital settings, as well as other mother foods, and in the
> environment. I don\'t think we have a real good feeling for that.
>
> In a brief survey that was done in The Netherlands, for example,
> analyzing 16 sweeper bags, vacuum sweeper bags from households, just
> analyzing a 10-gram sample, they found 5 of those to be positive, so
> it is present in our home setting, as well as in hospital settings.
>
> The other thing that is necessary for a risk assessment is the
> infectious dose, has been conducted in Canada, and that should be
> pursued, so that we can better understand that aspect of this ailment.
>
> DR. BUSTA: Dr. Thureen.
>
> DR. THUREEN: I would suggest that we have more information and actual
> preparation, things like the rate of colony increase, such as we got
> from the CDC that is not published, that type of data to help better
> guide preparation in hospital, cooling time, heating time, minimal
> cooling and heating times, things like that, so we can have very
> specific recommendations for preparation.
>
> DR. BUSTA: Dr. Beuchat.
>
> DR. BEUCHAT: Two questions or two areas that need I think research
> attention, both of which would provide I think information, better
> allow us to discuss levels, numbers in the formula, one is to
> determine from the isolates of commercially produced or processed
> formula, whether or not they are pathogenic or not, what is the level
> of the virulence, the possibility being that some are avirulent,
> others are highly virulent.
>
> Secondly, under all ranges and combination of conditions to which the
> dehydrated formula would be exposed in the hospital or in the home,
> temperature release times, this kind of information on growth,
> survival, death behavior, I think would be of value in any discussions
> that would lead toward a recommendation for levels in the product.
>
> DR. BUSTA: Dr. Fischer.
>
> DR. FISCHER: I would like to add to that, if it hasn\'t been added
> before, an investigation into the inactivation of the organism be done
> particularly I would like to see the irradiation work done to see how
> effective that might be in others.
>
> DR. BUSTA: Do you mind if a piggyback on that and add pulsed electric
> field and high pressure processing, and some of those non-destructive,
> low thermal treatments.
>
> Dr. Acholonu.
>
> DR. ACHOLONU: You are almost right.
>
> I think it may be necessary to go into differences in susceptibility
> between the pre-term and the term infants, find out if there are some
> differences in susceptibility.
>
> Next, I did make a reference to the possibility of prenatal infection.
> It may be good to go into checking mothers to see, since we have
> neonates being the group that is infected most, to find out if all of
> the infections come from the environment or from the powdered milk, or
> if some are coming from the mothers.
>
> We have established the fact that this organism has no respect for
> age, that it affects both the young and the old. If that is the case,
> there is a possibility that mothers may have the infection, but it may
> be asymptomatic in them. So, I am suggesting that we look into the
> possibility of having prenatal infection.
>
> DR. BUSTA: Dr. Kuzminski.
>
> DR. KUZMINSKI: Just linked to the comments on hyperbaric and
> pulsed-field radiation, just in more general terms, in terms of
> process development research, looking at ways especially in the
> existing technology, process flow that employs spray drying to
> research methods of inactivation post-spray dryer.
>
> Secondly, I am not that close to the microbiological detection
> methodology, but just in conversation here, it is not a real-time yes
> or no answer. It takes time, 72 hours, and that time kind of time
> frame, perhaps research into detection methodology to give more rapid
> knowledge of presence or absence.
>
> DR. BUSTA: Dr. Tompkin.
>
> DR. TOMPKIN: I think it would be advantageous to clarify whether or
> not a positive stool sample does, in fact, reflect colonization.
>
> DR. BUSTA: Dr. Neill.
>
> DR. NEILL: I would be interested to know whether E. sakazakii can
> exist in a viable but non-culturable state and for which detection
> methodologies then would need substantial revision.
>
> I would also be interested in the enhanced recovery methods that might
> be necessary for detecting thermally injured E. sakazakii.
>
> DR. BUSTA: Could I piggyback on that and also look at dehydration
> injured and other type of injury.
>
> Dr. Beuchat.
>
> DR. BEUCHAT: Asking again for definition of colonization. To me,
> discovery or detection of the organism in the stool doesn\'t mean
> colonization necessarily. In some of the comments in discussion that I
> have heard, the impression is that to some, it means the mere presence
> of the organism. To me, it means the actual establishment within the
> infant of a colony that is not easily removed or sloughed or gotten
> rid of through normal processes.
>
> So, I am asking for a definition, is colonization that I have
> described, is it the same way that you would describe it as a person
> looking at the clinical area.
>
> DR. BUSTA: This is for information, I am assuming.
>
> Dr. Blumberg.
>
> DR. BLUMBERG: I would say if you recover it from the stool of a
> patient, they are colonized with it. I mean you are not going to be
> doing invasive procedures to find out if somebody is colonized.
>
> So, if you can recover it from a patient from a clinical sample, and
> the patient is not infected with the organism, then, the assumption is
> they are colonized with that organism.
>
> DR. BUSTA: Dr. Tarr.
>
> DR. TARR: I would like to ask how you differentiate innocuous
> passthrough, if it\'s in the formula, versus actual replication and
> some residual staying power that the word colonization would define.
>
> Furthermore, I would even say that there is a chance that it could be
> not recoverable from the stool, get in the mucous layer of the
> gastrointestinal tract and colonized.
>
> DR. BLUMBERG: I would agree with that. I mean the absence of the
> organism there doesn\'t mean it could not be colonized, it just means
> you couldn\'t recover it.
>
> DR. TARR: I am not certain how to handle, though, passthrough in a
> stool, you know, a temporal wave coming through.
>
> DR. BUSTA: Dr. Tompkin.
>
> DR. TOMPKIN: In order to obtain maximum information in terms of the
> prevalence of organisms like E. sakazakii and processing environments,
> there has to be an atmosphere in which industry is encouraged to
> aggressively detect it.
>
> A finding of a positive for this organism, and others perhaps,
> suggests by one interpretation of regulations, is that the products
> then are being produced under conditions whereby contamination of the
> product may occur.
>
> So, in order to get the maximum amount of information in terms of
> control and information on prevalence, some flexibility in the
> interpretation of the regulation for that specific organism would be
> desirable in order to gather as much information from across the
> industry in a manner in which it can be shared and made available for
> review and use in developing policy.
>
> That is almost not a question, but I tried to make it a question.
>
> DR. BUSTA: I have a couple to add. I think we need to study the full
> ecological aspects of this organism in nature, in the plant, and in
> the human, and what unique characteristic permitted to do the things
> it is doing, becoming dominant in a dry situation, what results in its
> capabilities there, whether it has some unique aspects of coming in,
> in certain dry ingredients, and why it might exist under those
> conditions, the possibility of growing at low water activities.
>
> Some of the information indicated that it resisted dehydration, but
> there is a great amount of information in its ecological relationships
> that does not exist even its competitive nature against other
> organisms in similar situations.
>
> I would also like to see that relationship between these ecological
> characteristics related to its pathogenicity in that some of its
> characteristics may make it uniquely suited to establish itself in the
> feeding system, and I don\'t necessarily mean in the infant itself,
> but maybe it has a great deal of ability to form biofilms.
>
> If you recall some of the information about a sediment or precipitate,
> which to me says if cells are falling out, it means a lot of
> extracellular material are being produced, and that may permit it to
> be an excellent biofilm producer, and it may be colonizing, in fact, a
> feeding tube, not the infant, and then sloughing off toxins.
>
> So, there is a tremendous amount of opportunity there that I think I
> can see researched. It, in turn, relates to hygienic design. I am not
> sure about the hygienic design of the feeding systems, the tubes, et
> cetera, or if that is even considered very much, if it\'s
> self-cleaning or what it does.
>
> Maybe the food industry that is trying to find all the hygienic
> designs of the dehydration systems might be able to contribute to
> hygienic design of feeding tubes and vice versa.
>
> I think someone else has pretty well covered the others.
>
> Alex.
>
> DR. ACHOLONU: I was having a chat with Dr. Tompkin and we were talking
> about the question of allowable levels of the organism in the can or
> any container, and he left me with the impression that the organism
> doesn\'t increase, it stays there.
>
> The thing is it is in a dry condition, it is in an inimicable
> environment, it is not able to grow because the condition is not
> conducive for replication, but then how long does each stay that way,
> is it one month, is it three months, is it six months?
>
> Let\'s say you have a baby food can that was bought today. If it stays
> for six months, will the organism still be viable? In short, we may
> need to study the longevity of the organism. That is one thing I
> wanted to suggest.
>
> Another is we talked about Enterobacteriaceae. Is it possible to have
> multiple infection, different species occurring in only one person or
> one baby? If this occurs, does it exacerbate the pathological
> conditions?
>
> Those who are interested in pathology may want to look into this, what
> happens when you have E. sak and E. cloacae?
>
> Thank you.
>
> DR. BUSTA: Dr. Fischer.
>
> DR. FISCHER: I would like to propose, if it hasn\'t been proposed
> already, that the microbial ecology of the organism in relation to the
> developing flora in the GI tract be understood. Certainly, the other
> flora might inhibit or enhance the growth of this organism or perhaps
> the unit\'s virulence.
>
> So, I think this microbial ecology of development needs to be done.
>
> DR. BUSTA: Dr. Tompkin.
>
> DR. TOMPKIN: I think it would be helpful to do a survey of the
> literature including patents with regard to technologies for reducing
> populations of gram-negatives such as this in dry products.
>
> For example, in the 1970s, we actually built a small batch process or
> system for pasteurizing gums and stabilizers in a plant we had in
> Kearny, New Jersey, and it essentially involved controlled humidity, I
> forget what the level was, and then heating at 160 without leading to
> denaturation or product degradation.
>
> That was intended specifically to kill Salmonella, so killing enteric
> organisms in dry powders is a difficult task to retain the
> functionality and other features, but there may be other opportunities
> that have not been explored.
>
> DR. BUSTA: Have we exhausted the research? Critical knowledge gaps and
> research priorities relative to the need to address issues about the
> presence in powdered infant formula?
>
> DR. FULLER: That\'s it.
>
> DR. BUSTA: Well, we could have spent another 15 minutes discussing to
> get to the same end.
>
> I, Frank Busta, the only reason I know how to pronounce my last name
> is there is a rock star who uses it as his first name, apologize to
> most of you for mispronouncing your name at one time or another.
>
> Thank you all very, very much for a really highly engaged committee
> meeting. Each and every one of you was highly engaged in the entire
> process and very involved.
>
> I would like to thank on behalf of my Co-Chair, all the FDA staff and
> especially Don Zink, the industrial representatives who stayed on and
> responded to a lot of our questions, and all the help and assistance
> from everyone who is here.
>
> It was I think an excellent committee meeting and we look forward to
> seeing you again.
>
> Thank you all.
>
> \[Whereupon, at 2:13 p.m. the meeting concluded.\]

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