SGDEPARTMENT
OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR FOOD SAFETY AND
APPLIED NUTRITION
CONTAMINANTS AND NATURAL TOXICANTS SUBCOMMITTEE
OF THE FOOD ADVISORY COMMITTEE
VOLUME II
Wednesday, March 19, 2003
8:39 a.m.
4700 River Road
Riverdale, Maryland
PARTICIPANTS
Francis
Fredrick Busta, Ph.D., Chair
James E.
Heubi, M.D., Co-Chair
MEMBERS
Alex D.W. Acholonu, Ph.D.
Lawrence J. Fischer, Ph.D.
Marion H. Fuller, D.V.M.
Lawrence N. Kuzminski, Ph.D.
Ken Lee, Ph.D.
ACTING
INDUSTRY REPRESENTATIVE (NON-VOTING)
R. Bruce Tompkin, Ph.D.
TEMPORARY
VOTING MEMBERS
James Anderson, Ph.D.
Robert D. Baker, M.D., Ph.D.
Larry R. Beuchat, Ph.D.
Henry M. Blumberg, M.D., Ph.D.
Margaret E. Briley, Ph.D., R.D., L.D.
Laurie J. Moyer-Mileur, Ph.D., R.D., C.D.
Marguerite A. Neill, M.D.
Virginia A. Stallings, M.D.
Phillip Tarr, M.D.
Patti Thureen, M.D.
C O N T E N T S
Page
Opening
Remarks
4
Questions
from the Committee
7
Subcommittee
Discussion of Issues, 47
Recommendations,
and Response to Charges
P R
O C E E D I N G S
Opening Remarks
DR.
BUSTA: Good morning. It looks like we are all here on time and
ready to go, bushy-tailed and no snowstorm, here in College Park.
If we
could convene the committee meeting at this point. A few announcements.
First of all, microphone style.
It's the switch closest to the mouthpiece into which you speak, that is
the off-on switch, the one that is closest to the end of the microphone. The bottom one, you just don't bother
with. Just work with the top one, that
is the on-off, and it has to be turned off when we are not using it because we
get a lot of feedback if we don't.
The
second important announcement. On the
sheet that we got yesterday called Charge and Questions, the most recent draft,
if you would strike "Draft," because those are our final questions
that we are addressing today, so it is really not a draft. That is the set of questions that we are
addressing.
That is
the one that, if you recall, the third line in Charge 1, No. 1, is factors, not
facts. That is how you differentiate
that final draft, last draft, but it is no longer a draft, it is, in fact, the
Charge and Questions.
A number
of committee members have indicated that there are some questions they would
like to ask for clarification and explanation this morning before we continue
on with our discussion of the charges and our committee responses, so
arbitrarily, we are going to take 30 minutes.
We will limit it to 30 minutes of asking questions of the presenters
from yesterday.
We really
need to limit it to 30 minutes, so we will try to be succinct in our questions
because otherwise, we could spend I imagine the whole day grilling various
people for details, so I think just key questions, we will take 30 minutes and
try to get some of those clarifications made this morning.
If the
individual isn't here that needs to answer the questions, then, we will just
have to go on.
Are there
any other items that anyone on the committee would like to bring up?
The
approach to the questions that we are contemplating, not necessarily final
depending on your committee, for example, after the first 30 minutes, again
discuss Charge 1 as we were doing just before 6 o'clock yesterday, discuss that
as best we can, and the Chairs will do their best to summarize what that
discussion was and what we think is a consensus and see if everyone agrees with
that consensus.
If there
are dissenting comments, then, obviously, those can be put in the record, as
well. If that doesn't work well, we can
go around with each individual making a statement, but we will try that
approach first.
Is that
all right with everyone? We will give
that a try.
I see Dr.
Tompkin with a microphone in his hand, poised and pointed, so I assume that you
wish to start.
DR.
TOMPKIN: I would just like to make a
comment. As we progress with the discussion and as we try to reach a consensus,
there will be some issues where we don't have all the data we need, and are we
capturing the data gaps separately, because we can only take a discussion only
so far in the absence of more data.
So, can
we somehow create a parking lot for those kind of things as we move through,
and then come back and discuss them further?
DR.
BUSTA: I think that is an excellent
comment, as always. We will do our best
to capture those here, and I would think that Charge 2, No. 4, Critical
Knowledge Gaps, would be the place to accumulate those, and that is toward the
end.
The other
thing is that you all should have gotten four handouts from the public comment
group that are the slides that they used in the last presentations.
Questions
for clarification.
Questions from the Committee
DR.
FULLER: Two questions. One is if we can have anyone from the
industry that spoke yesterday, one of the questions we had asked early on had
to do with what were the steps taken in, I believe it was the Norwegian plant,
that resulted in their not having problems further.
Then, the
second question, totally unrelated, has to do with the temperature of mixing
the powdered formula, and we heard that boiling water created problems with
protein coagulation. I am curious,
because we also heard that 70 seconds at just a few seconds resulted in
significant kill, you know, what happens at 75 degrees C or 80 degrees C, do
you still have that problem.
DR.
BUSTA: Do we have an industry
representative to respond to that?
DR.
SMOOT: I will try to respond to the
first question regarding the Netherlands plant. After the situation that occurred and the data that was used
yesterday to demonstrate microbiologically improvements in the process and the
environment, the primary actions that took place were in the hygienic design of
the process equipment itself where there was an elimination of water used.
Part of
the spray dry process is a water scrubber, so we found in the environment,
there were pockets in areas that were designed into the process that brought
more water into this dry processing environment.
So, there
was considerable engineering redesign efforts to improve the process and
eliminate the water that was currently in that type of process stream and to
improve the management and use of water in and around that area, as well as the
knowledge to further investigate breakdown equipment, design equipment that is
easily accessible, you know, designing in the cleanability of the equipment.
These
were the types of things that were the primary, as well as then enhancing our
surveillance in terms of the efficacy of good hygienic practices that were
being taken in the factory at that time, you know, a continuous improvement.
These are
the types of things that, in that particular factory, as well as learning some
best practices there, have been continually being spread throughout that
particular organization. I am sure the
learnings there have found their way throughout the infant industry, as well.
DR.
FULLER: So, did you end up having to replace
equipment or were they able just to make changes to existing equipment and
water, and I understand you did say water use, as well?
DR.
SMOOT: Both, there was both. I mean there was redesign of unit
operations, as well as replacement of equipment.
DR.
FULLER: Thank you.
DR.
SMOOT: I don't believe I would be
qualified to approach the second question.
There is
a point of information from Bruce.
DR.
TOMPKIN: The data that you provided
were data on product.
DR.
SMOOT: Correct.
DR.
TOMPKIN: In addition to that, there was
a lot of samples collected, I would assume, from the environment, and those
data are not included, so whereas, in each year, you had 700 to 900 and some
samples analyzed of product, that was supplemented with some additional environmental
samples.
DR.
SMOOT: Correct. The data that you I believe now have a copy
of, in that one table, that was a focused study that ran concurrent to the
normal process monitoring for finished product, which you have seen again cited
in the Codex risk profile, and many of you have made reference to where there
is a more stringent norm for coliforms, less than 0.3 npn/gram. That was the normal operating monitoring for
finished product.
This
dataset that you have access to was a concurrent focus study to look deeper
into that, and then as Dr. Tompkin pointed out, as a supplement to that
enhanced environmental monitoring, was also taking place at the same time, yes,
and that data has not been shared.
DR.
HEUBI: Just a quick question also about
that data. Is that product that was
actually stored in like a bag and then checked, or was it tested during the
process of drying?
DR.
SMOOT: I would say that I don't have
intimate detail, but knowing the nature of the process monitoring, it would
have been minimally into the big bag tote stage of the process.
DR.
BUSTA: Dr. Kuzminski.
DR.
KUZMINSKI: This is for Dr. Smoot, a
question. On your slide yesterday, it's on page 4 of the handouts which were
provided this morning, and thank you for that, the slide yesterday on current
manufacturing intervention strategies, and you outlined there programs and
practices, such as HACCP, supplier QA, et cetera, all the way from the raw
materials to the finished product steps of the manufacturing process.
My
question is related to this. If we
consider the Tennessee incident in 01 as an event, were all of these practices
in place at that point in time? I am
not saying that your organization is linked to the Tennessee event, I just
don't know--
DR.
SMOOT: I would have to defer specific
comment to that particular event to people more knowledgeable of the quality
and safety procedures in place. I could
not speak for that particular event.
DR.
KUZMINSKI: Is there someone here,
others from the industry, that could answer that question?
DR.
SMOOT: Yes, I believe so.
DR.
MARCH: My name is Dan March. I am with Mead Johnson. Yes, I can say that the HACCP programs were
in place at the time. We looked at the
quality of that product at release. It
was probably one of our best batches microbiologically that we had produced
under the standards that currently existed at that time.
DR.
KUZMINSKI: Thank you. If these processes or programs were in place
at that time, what different has industry done since the event in 01?
DR.
MARCH: HACCP is an evolving process,
and it is always open to improvement, so we have instituted improvement in our
HACCP programs in the plants to take account for some things that we had not
noticed in the past, such as use of water and minimization of water in certain
processing.
We have
gone to a higher level of HACCP, looking at different control points or
controlling what we thought were critical control points to a higher level, so
it is an evolving process.
DR.
KUZMINSKI: And the sampling plant that
was described on finished product yesterday, the 5 grams in 5 for the
Enterobacteriaceae. That would be
something new in terms of the evolving HACCP, to verify HACCP.
DR.
MARCH: Yes, it would, exactly.
DR.
KUZMINSKI: Thank you very much.
DR.
BUSTA: We had a second half of a
question on the lower temperature, 70 to 80 degrees C causing coagulation or
clumping in the product. I know the
statement was that very hot water caused clumping yesterday. Does that occur at
70 or 80?
DR.
MARCH: I can speak to that. We had done studies with the boiling water
and had shown that there is an immediate, as Dr. Buchanan's graph showed, there
was an immediate loss of temperature when you add boiling water to product that
is tempered at room temperature.
So, you
have to take into account there is immediate loss of temperature, so therefore,
in order to get the temperatures of what we would say pasteurization around 70
degrees where the kill is most effective, you do need to heat it up somewhat,
85, or something like that.
We do
know that somewhere in that range between that temperature and boiling, there
is going to be some effect on the protein, potential coagulation. Again,
vitamin C losses will still be substantial in the presence of oxygen and
heat.
Also, we
do need to consider the potential burn hazard even at 75, 80 degrees to the
preparer and also to the infant. Does
that help?
DR.
BUSTA: Dr. Stallings.
DR.
STALLINGS: To clarify that, then, if we
were talking about preparation in the home, we could ask people to boil water
and add it to room temperature formula or in a nursery setting.
What
would be the temperature that we would achieve in that sort of setting, are we
going to be at the 70 degree killing temperature, or are you suggesting that if
you did that--part of what we are trying to figure out is, is that effective in
killing bacteria that would be in the product at the point of preparation.
DR.
MARCH: Was that to boil the water, cool
it, and then prepare products with it?
I am sorry.
DR.
STALLINGS: I thought the question may
be a misunderstanding, it was about preparation of a dry powder, so if I were
doing that at home, I would be boiling water, adding it, and you reminded us
that you have an immediate temperature drop, and what is the temperature of a
mixed formula, and it cools.
The
question is are we going to get any killing if we use that.
DR.
MARCH: Yes, there would be an immediate
kill. If you used boiling water, there would be an immediate, once mixed,
immediately, but the graph that Dr. Buchanan showed, showed that there was an
immediate loss of temperature down to somewhere around 80, 85 degrees.
That is
still too hot, and it showed by leaving that out over a period of time, the
cooling curve did flatten out, so it took much longer then to drop down once it
reached equilibrium with the product, it remained at a temperature that is
still capable of causing burns.
DR.
STALLINGS: What is an acceptable
serving temperature just so we have an idea of what that number would be?
DR.
MARCH: An acceptable serving
temperature is probably going to be around body temperature, you know, 98
degrees or something like that--37 C.
DR.
STALLINGS: Let's stay in one unit or
the other. So, we are starting out with
boiling water at 100. We mix it, we are
at 80 something. We have got to let it,
in an equilibration, come down to 30.
DR.
MARCH: That is correct.
DR.
LEE: On the same subject, you know, I
bottle fed three of my own at home. One
of the first things I do is I pour some of the formula on my hand to make sure
it is not too hot.
Are we
saying that these healthcare professionals are not capable of observing the
temperature of what is being fed to the neonate? I am kind of missing--there seems to be some significance given
to the potential burn hazard to the healthcare worker and to the baby, but I
think most parents do this at home all the time, so I am just wondering what is
different, because to me, it's a tradeoff to kill these bacteria.
DR.
MOYER-MILEUR: I think in a NICU
situation what you would have is this formula is being prepared in a formula
room. They would have to be held I
guess at a certain temperature and then cooled, and then taken to the unit and
then rewarmed to room temperature in a Level 3 NICU.
Now, whether
or not you are going to have people who are trying to mix it just prior to a
feeding or not in a smaller nursery, I don't know.
DR.
BUSTA: Dr. Fuller.
DR.
FULLER: Thanks. I guess what I am trying to get at is--and I
don't have the experience here--but I was thinking more along the lines of if
we have identified a population that is very highly at risk, and yet we have
also heard there is a very real need for some of these products, my question is
can you not heat the water to, say, 85 degrees, yes, you will have a rapid
dropoff, do you then have enough to mix with formula, you know, mix for one
minute, let cool a minute, mix with formula a minute and then rapidly cool to
the temperature either for storage or to serving temperature.
That is
where I was going with that, and does that take care of the protein coagulation
problem.
DR.
BUSTA: I see no volunteers.
DR.
THUREEN: I would like to just add this,
because it is the same question.
How
significant is the clumping issue, would it be enough to clog up a tube or clog
up a bottle, or is it just an inconvenience, it might not be digested as well,
and is the remaining protein of the same nutritive value, which is really the
important question, because boiling, I mean it seems like a good way to get rid
of the bacteria, but are we really going to be destroying the product, so that
it is not effective for nutrition.
DR.
MARCH: I don't believe that I can
respond to the clumping and the degree of clumping, however, when we get
into--going back to the previous comment--there was a thought of doing an
incremental heating and cooling.
I guess
what we are looking at there is some very complicated hospital protocols that
could possibly become very confusing. I
don't mean very complicated, but at least more complicated than it is now. I guess that is the danger of that. If not properly heated and cooled, you could
be getting yourself into an incubation situation if you are not warm enough
then.
That
would be my fear of a microbiologist warming the product up 10 degrees doubles
or I guess shortens the growth of bacteria.
I guess I would discourage that in that it does complicate the matter.
DR.
BUSTA: Dr. Heubi.
DR.
HEUBI: I have a manufacturing
question. Yesterday, Dr. Zink told us
that there was not any major advantage to one of the other drying methods for
formula, and now both Dr. Smoot and Dr. March have told us that in response to
some of the issues that were raised, they reduced the amount of water used in
this process.
Is it
your opinion as industry that, generally speaking, the less water that is
utilized, the safer the procedure is, and are you moving in the direction to
minimize water in this process?
DR.
SMOOT: Very succinct, yes. The issue of use of water, parts of the
process, whether you are using steam heat or water cooling of some type, there
is water somewhere throughout the system, so engineering designed to minimize
that exposure to the process stream is one aspect.
The
other, as we talk about spray dried runs, I believe Dr. Zink had mentioned
yesterday his preference to run longer and dryer, I think even Dr. Tompkin had
pointed out is very true. However, due
to formula changes and allergen issues and cleaning, you have to address allergen
issues with wet cleaning, so depending upon production schedules and
changeover, you have to do some type of wet clean sanitation.
But
again, working with our partners in sanitation practices, we are trying to even
improve how we do wet cleaning in a controlled wet clean scenario. So, yes, by all means, it is something that
we are working very hard with in industry.
DR.
BUSTA: Dr. Thureen.
DR.
THUREEN: Thank you. So, if we assume that you can't eradicate
all E. sak contamination at the plant level, and that you could potentially
eliminate it at the nursery level, I think most nurseries would be willing,
with boiling, to go ahead and take that step particularly since most Level 3
nurseries have milk labs with fairly well trained people.
So, it
seems like if you don't know, that there could clearly be steps outlined that
would show effective means of heating and cooling, might require special
equipment, but you could develop that, that nurseries, with all their costs,
would clearly be willing to invest in something like that, so that there should
be able to be research done that would identify the proper process for that,
and if you get a good kill, then rewarming shouldn't be a huge issue for
bacterial contamination, at least to E. sak, or not. I mean that may not be true.
There are
clearly other bacteria in the process and you are going to introduce them
during the process, but if you could have a good heating and cooling procedure,
and then rewarming procedure, and then do studies to see if the protein is
denatured or not, then, you could at least say this is an intact product, maybe
we need to add some extra vitamin C after we finish the product or give the
baby vitamin C supplementation, but it seems like if we can't clear up the
problem at the manufacturing level, we could at least go a long way at the
preparation level.
Clearly,
there is going to be a lot of education involved in that, but it seems to me
that that would be a part of the solution.
DR.
BUSTA: That was not a question.
DR.
THUREEN: It is a question in that there
was a lot of no head shaking from that little group over there that this is not
a realistic solution.
DR.
BUSTA: Let the record note that she was
pointing to the previous respondent.
DR.
THUREEN: Several of them. There are some yes's and no's over
there. Do you not think that is a
realistic solution?
DR.
GEHRIG: Good morning. This is Tom Gehrig with Wyeth
Nutrition. My background is mostly in
food technology, in that area. I have
done some work in denaturing of milk proteins, soy proteins, and I guess if you
look at the milk proteins, your wheys particularly, they start to denature
about 60 degrees C, and as you go up the time-temperature relationship, they
continue to denature.
The soy
proteins are even a little bit more susceptible and my quandary would be that
you are going to have to make it so precise on the mixing that, you know, we
design these, we do a lot of protein efficiency studies to ensure that the
protein is intact, that I think you would start to see, especially through the
nasogastric feeding tubes, especially when the diemers go down, that you would
have some problems with plugging of those tubes.
We know
we have plugging in the nipples of the baby bottles, and I think it would be a
big issue if we start taking these things up to 80 degrees and holding them for
any amount of time.
I think
it works, but, you know, from the industry standpoint, we spend a lot of time
on our processes, especially on the evaporation, on the drying, to try and
minimize the changes to the proteins, and I fear that if we take and
reconstitute with 80 or 90 degree water, and hold it for any amount of time, we
are going to be in some trouble.
DR.
THUREEN: Thank you. That really lays the issue to rest for me,
and I didn't think I had had a good answer before, so thank you for that.
DR.
BUSTA: Dr. Lee.
DR.
LEE: I appreciate that
observation. If one were to anticipate
reformulating with hot water, say, even as high as 100 degrees centigrade, one
could design the proteins appropriately, so they are soluble, perhaps hydrolyze
them somewhat, maintain your protein availability.
It is
really a process design question, is it not?
I mean the protein is not adversely--correct me if I am wrong--the
protein is not destroyed nutritionally by this boiling water syndrome. I mean you can solubilize protein in hot
water.
DR.
WALLINGFORD: John Wallingford, Wyeth.
I think
this is an area that we need to work together on. We don't have all the information we need, so if I could
recommend this be one of the parking lot items where we actually go out and get
the data at what happens to the physical properties with formula after
different temperatures of mixing and actually after subsequent mixing different
temperatures of holding prior to feeding, I think this is an area where there
is a potential for some improvement in the ultimate bacterial safety of the
product.
DR.
BUSTA: Dr. Tarr.
DR.
TARR: I have two questions.
First,
yesterday, you talked about microbial sampling. I forget what the exact numbers were, but I know the numerator
was expressed in grams and the denominator was expressed in tons.
How
validated are these sampling techniques, can we be confident there, in this
part of the HACCP protocol, you are
getting reliable data from your production line? That is my first
question. I can wait for the answer.
DR.
BUSTA: Dr. Smoot, it looks like he is
being nominated.
DR.
SMOOT: Referring to the validation of
this type of sampling plan, currently, the sampling plans for coliforms in our
finished product monitoring now is at the level of N equal 5, and the sample
size equal 1 gram.
The
proposal, continuing with a N equal 5, in other words, number of samples, is
consistent with an ICMSF Class VI sampling plan for fecal coliforms. That would give you a certain level, and has
through time been validated as an acceptable sampling plan for a bacterium of
moderate risk.
So, what
we have proposed from industry is to cast a broader net on our process control
monitoring going from coliforms to the family of Enterobacteriaceae first, and
then secondly, increasing the sample size from 5 grams to 25 grams.
So far we
have found at least working with the N equal 5 one gram for coliform has been
reasonably successful in monitoring and assuring the process control, and what
we were proposing yesterday was a step moving into the more stringent with both
the target of the sampling, as well as the sampling size.
DR.
TARR: A follow-up to that then, and
this might have been answered yesterday, the incriminated product in Tennessee,
did that meet, exceed, or was under the cut points for what you would consider
acceptable for your process?
DR.
MARCH: Yes, it did meet the
specifications at that time for coliform organisms according to the plan that
Dr. Smoot just laid out.
DR. TARR: To meet the future protocols or the
proposed?
DR.
MARCH: Retrospectively, that would be a
difficult question to answer because it would be hard to make the
equation--there would be some challenges, but I have a feeling, and it is only
speculation, that it would meet that.
DR.
TARR: And then my second question
unrelated, it looks like the breast milk substitute is an important priority
for both medicine and industry, and we would like to keep that available, and
it might have to remain in powder form for the near future.
How
close, though, is industry towards coming up with a liquified higher caloric
concentrated form that could be sterilized and administered safely? We heard yesterday that it was technically
difficult, but how active is the scenario developing?
DR.
BUSTA: It doesn't appear that we have
anybody on that. For clarification, Dr.
Zink said that the breast milk supplement was tested.
DR.
ZINK: Going back into our little
database of samples, two human milk fortifier products were tested and
classified as transitional formula, so in the survey we did two human milk
fortifier products were tested.
DR.
TARR: What were the results?
DR.
ZINK: They were negative.
DR.
BUSTA: In regard to the plant that you
showed the data on that were reducing the count, and the last data for 2002,
the fourth one, there were 6 positives and all 6 were E. sak positive, and that
appeared to me that as the plant was improving all of their cleaning processes
and design, et cetera, it ended up selecting for E. sak.
Am I
reading that wrong?
DR.
SMOOT: Clarification. The data that was presented was on a
percentage basis, so it was 0.6, not 6 positives, individual positives.
But, yes,
as our experience with that particular factory, and across the 70, 80 that we
have around the world, as we improve our hygienic practices and reducing water
and driving down and monitoring the environment, the comment made yesterday,
and I think it was borne out as well by Dr. Buchanan's data, is that this
particular organism adapts well to warm, dry environments.
So, as we
continually monitor the environment for the Enterobacteriaceae family, which is
basically a biologic indicator for the presence of water, hence, we use it to
assure we are keeping the environment as dry as possible, because they need
water to grow.
High
levels of EB indicate that you had water somewhere in the system at an
unacceptable level. But with refining
with this particular organism, E. sakazakii, is that out of this group of the
Enterobacteriaceae family, it does appear to possess the adaptation to warm,
dry environments, so as we are driving that number low, yes, we are starting to
see exactly what you observed.
DR.
BUSTA: So, in fact, another placeholder
for research would be trying to determine why ecologically we are selecting for
that type of organism and how we can modify the ecology to eliminate that kind
of organism.
DR.
SMOOT: I would say yes, that is a
correct assumption.
DR.
BUSTA: Peggy.
DR.
NEILL: I think my question is somewhat
headed in your direction, Les, but it combines some of the information that Don
Zink gave us yesterday with his illustration of the process, as well as the
implications of the most recent data that you were just explaining.
Don
painted a fairly powerful portrait that by the time the product is coming
through the dry sifter spray dryer, it has undergone several kill steps, and
the subsequent suspicion, obviously not proven, is that this is a contamination
of product post that step.
My
question relates to the following. What
are the technical obstacles for creating a sterile product post the spray dryer
including conceptualizing that it would not have to be the entire product lot,
production run, et cetera?
In other
words, if we are steering our way towards identifying that there is only a
subpopulation of recipients of formula that are at risk for this infection,
then, one could conceptualize that you only need some of this formula to be
sterile and directed towards that particular patient population.
DR. SMOOT: First of all, you know, we have been
successful in industry in terms of environmental control at assuring the
eradication for the most part from the process environment, other pathogens of
concern, such as Salmonella and Listeria.
As we
look at the Enterobacter sakazakii and its place as a member of the
Enterobacteriaceae family, though maybe not totally convinced, but we are
finding data on a weekly basis that it is a little bit more ubiquitous than
what we maybe thought to begin with.
So, this
organism has been able to eliminate it from the environment post-heating steps
of these either wet mix, dry mix technology streams. The proposal as I understand it then, can we divert or can we
provide some type of unit operation for a small production portion to go into
almost a Class I00 sterile room type environment.
I would
say on the scale of the industrial process, the total process, yes, that would
be very difficult, is that something that we could again maybe work in partner,
is this technologically feasible, is something like this possible, I wouldn't
say no, it is not possible, but this is something the industry would have to
study in terms of a risk-benefit there.
But you
are basically talking about going to a Class 100 room type environment for post-drying
process stream, and you saw the magnitude and size of the equipment to do that
even after the cooler, after dryer, which is the first unit operation post-star
valve on the bottom of the cone. To
even put that in the frame of a sterile environment would be very difficult
because what we are finding, that is a part of the areas that we need to
improve anyway in terms of hygienic design.
There
would have to be a considerable learning to go to that level of process control
to this sterile environment.
DR.
NEILL: I think my comment is that in
the hospitals, we do this all the time in terms of having a triage of medical
products and foods that are adjusted to the perceived risk of the recipient
population.
I mean
it's pasteurized egg product now in most hospitals, so that is where I am
coming from in terms of a conceptual approach.
I think what I am trying to ask is really much more at the level of the
technologies.
I am
intuiting that an ultra-high temperature step is likely to cause difficulties
with the protein denaturation, so that you may end up with an insoluble
product, and I don't think we heard a clear answer yesterday to irradiation,
and all irradiation is not created equal because there is certainly different
types.
What are
the perceived obstacles in the physical-chemical nature of the formula that
would prevent creation of a commercially sterile product? I think maybe that is a better way for me to
articulate the question.
DR.
SMOOT: I might have to defer to people
more intimately involved, maybe Tom, to someone more involved in the actual
process or in technology. Would you
want to speak to this? I defer to Tom
Gehrig, Wyeth.
DR.
GEHRIG: I was responsible for design of
our new factory largely, in part, in Singapore, which we started about a year
and a half ago. We took a good look at
this, and, you know, speaking to what Les said, the volume of the air that
moves through one of these dryers or in the conveying systems is tremendous,
you know, in the volume of like 270,000 cubic feet per minute.
What we
do is try and install Hepa filters on the inlets to these dryers, but where it
gets difficult is, you know, we can control on basically the transfer of the
powder into the packaging operations, and we take a lot of care to ensure that
that air is filtered especially going into the packaging hauls.
We set up
basically a hospital room environment where employees that move into that area
have to do full gowning. They have got
masks, they have got gloves, full head gear, so in the particular zones where
the powder can be exposed to the environment or to the employees, we actually
zone kind of on a concept of 1 through 5, 5 being the most stringent zone.
The only
people allowed in that area are the people working in that area. Where you get into some difficulties is when
you have a breakdown in the line and you have to have an intervention, and the
employees have to be very well educated when they go into this equipment,
especially a mechanic or something, that those tools basically have to be
sterilized or sanitized before they go into the system.
I think,
on the industry's part, it is requiring us to really go back and look at our
processes, kind of what Les was saying, that whenever there is an intervention,
we write it down, we mark down what has been done, who goes in, that the
equipment has been sanitized and cleaned.
But to
create a clean room environment basically from the spray dryer south, so to
speak, into the packaging line, I am sure it could be done, but it is going to be
extremely difficult to do.
It has
been our experience that these powders for the E. sak, we can get down to
counts that are actually less than 100 CFU per gram, and we still have E. sak
in there, so as far as the drying 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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