P-R-O-C-E-E-D-I-N-G-S

8:03 a.m.

SECRETARY FREAS: Dr. Priola, members of the public, invited guests and public participants, I would like to welcome all of you to this our 14^th meeting of the Transmissible Spongiform Encephalopathies Advisory Committee. I am Bill Freas. I am the executive secretary for this Committee. At this time, I would like to go around and introduce to you the members at the head table, starting on the right hand side of the room.

The first chair will soon be occupied very shortly by Dr. Pierluigi Gambetti. He is a professor and director Division of Neuropathology Case, Western Reserve University. Okay. Then the second chair will soon be occupied by Dr. Richard Johnson, professor of neurology at Johns Hopkins University. And then going around the table, the people who are here, Dr. Arthur Bracey, associate chief Department of Pathology, Saint Lukes Episcopal Hospital. Next is Dr. Lisa Ferguson, a senior staff veterinarian, U.S. Department of Agriculture.

Next is Dr. Nick Hogan, associate professor of ophthalmology, University of Texas, Southwestern Medical School. Next is Dr. Rima Khabbaz, associate director for Epidemiologic Science, National Center for Infectious Diseases, Atlanta, Georgia. Around the corner of the table is a gentleman, whom I'm going to ask to join us at lunch time, if that is okay, Dr. Nelson. Could I ask you to join us at lunch time instead of in the morning?

DR. NELSON: Certainly.

SECRETARY FREAS: This is my mistake. I apologize. Dr. Nelson will be a temporary voting member, and he will join us right at lunch time, and if you could just sit over in the FDA section up until Topic 1 is over. And when I read the Conflict of Interest statement, hopefully, that will be explained. My apologies for not checking before I started. Okay.

Next is our Chair, Dr. Suzette Priola. She is an investigator of Laboratory of Persistent and Viral Diseases of the Rocky Mountain Laboratories. Next is our consumer representative, Ms. Shirley Walker, vice president of the Health and Human Services, Urban League of Greater Dallas in north central Texas. Next is Dr. Sidney Wolfe, director of Public Citizen Health Research Group, Washington, D.C.

Next is Dr. John Bailar, professor in America's University of Chicago. Next is our non-voting industry representative, Dr. Stephen Petteway, director of Pathogen Safety and Research, Bayer Corporation. Three Committee members in addition to the two that are joining us shortly could not be with us at all for this meeting. They are Mr. Val Bias, consumer representative, Lynn Creekmore, staff veterinarian and Dr. Stephen DeArmond from the University of California.

I would now like to read into the public record the Conflict of Interest statement for this meeting. "The following announcement is made part of the public record to preclude even the appearance of a Conflict of Interest at this meeting. Pursuant to the authority granted under the Committee Charter, the Director Center for Biologics Evaluation and Research has appointed Mr. Terry Rice and Drs. Kenrad Nelson, who I just asked to leave the table, and David Stroncek as temporary voting members for Topics 2, 3 and 4 of this meeting.

In addition, the associate commissioner of External Relations of FDA has appointed Dr. Charles Edmiston as a temporary voting member for Topics 2, 3 and 4 of this meeting. Based on the agenda, it has been determined that the Committee will not be providing advice on specific firms or products at this meeting. The topics deemed discussed by the Committee in open session are considered general matters issues.

To determine if Conflicts of Interest exist, the Agency reviewed the agenda and all relevant reported financial interests from meeting participants. The Food and Drug Administration prepared general matters waivers for special Government employees, who required a waiver under 18 U.S. Code 208. Because general matters topics impact on so many entities, it is not prudent to recite all potential Conflicts of Interest as they apply to each member.

FDA acknowledges that there may be potential Conflicts of Interest, but because of the general nature of the discussion before the Committee, these potential conflicts are mitigated. We would like to note for the record that Dr. Stephen Petteway is serving as a non-voting industry representative member for this Committee. He is employed by Bayer and thus has interests in his employer and other similar firms.

Listed on the agenda are speakers making industry presentations and/or updates. These speakers have financial interests associated with their employer and with other regulated firms. These speakers were not screened for these Conflicts of Interests. With regard to FDA's invited guest speakers, that's all other speakers, except those from industry, the Agency has determined that the services of these speakers are essential.

The following interests are being made public to allow the meeting participants to objectively evaluate their presentations and comments that they may make. Dr. Robert Rohwer has disclosed he has financial interest with various firms that could be affected by the Committee discussions. Dr. William Rutala receives consultant fees from several firms that could be affected by the Committee discussions. Dr. Robert Somerville has research supported by the Gelatin Manufacturers of Europe. His expenses to this meeting were also paid by the Gelatin Manufacturers of Europe. Dr. Charles Weissmann holds patents related to Prion Disease work.

Members and consultants are aware of the need to exclude themselves from the discussions involving specific products or firms which they have not been screened for the Conflict of Interest. Their exclusion will be noted in the public record. With respect to all other meeting participants, we ask, in the interest of fairness, that they address any current or previous financial involvement with any firm whose product they may wish to comment upon. Waivers may be available by written request to the Freedom of Information Office."

That's the end of the Conflict of Interest statement. I do ask that throughout this meeting before it starts if you would check your cell phone or your pager and, please, put it in the silent mode, so it won't disrupt those people sitting next to you.

Next, the FDA is continually trying to improve its Advisory Committee Program and to reduce any perceived Conflicts of Interest. It has asked Dr. Katherine McComas from the University of Maryland to conduct a survey of this program, and I would like to give her the opportunity to tell us how we can help her with this survey and how the survey is being conducted. Dr. McComas, either place. Keep talking and they'll turn the mike volume up.

DR. MCCOMAS: Okay. Good morning and thank you. I'm Katherine McComas and I'm a faculty member at the University of Maryland, and I'm here today to conduct a study of what people know and understand about the Conflict of Interest procedures that the FDA uses to monitor real or potential Conflicts of Interest of its Advisory Committee members. This is a study that is being conducted across multiple meetings. This is the 11^th meeting I have attended across the centers at FDA, including CBER.

For those of you in the audience, I've distributed a questionnaire on your chair and I have also distributed a different questionnaire to the Advisory Committee members. If you have an opportunity today to complete this questionnaire or tomorrow, there is a box on the registration desk where you can drop it. Otherwise, there is a business reply envelope that you can just drop it in the mail as soon as you can. Your participation is voluntary, but it is important. The more responses we get, the better we are to provide feedback to the FDA about what people know and understand about the Conflict of Interest procedures, and what may be done to improve satisfaction, if necessary, with the Advisory Committee process.

Again, I appreciate your participation and if you have any questions, my contact information is included in the letter, in the questionnaire and I would be happy to provide any answers. Also, when the study is done, the responses will be available in summary form to everyone who is interested. So thank you very much for your time and have a great day.

SECRETARY FREAS: So if you got here early and did not receive a questionnaire, the questionnaires are on the table outside and, please, everybody on the FDA staff will be more than glad to help you if you have any questions with this questionnaire.

Dr. Priola, I turn the microphone over to you to start the meeting. Thank you.

DR. PRIOLA: So since we have a very full agenda today, we will just get started with the first speaker, who is Dr. Potter, who will give us background on Topic 1.

DR. POTTER: Good morning. FDA has been considering the safety of gelatin with regard to BSE for a number of years, and has come to this Committee on a number of occasions to get its recommendations on FDA's guidance to gelatin manufacturers and users. The safety of gelatin is determined as you've told us before by the safety, the source materials in the degree to which the gelatin manufacturing process destroys prions that enter the system.

Questions to the Committee have dealt with these two factors and how well knowledge about TSE's was reflected in FDA guidance for assuring the safety of gelatin for food and cosmetic use. Before 1996, FDA did not include gelatin within its recommended restrictions concerning bovine ingredients in FDA regulated products. In 1996, FDA began to review its position on gelatin in light of new information that associated BSE exposure with Variant CJD in humans and new data from a study on the effect on infectivity of gelatin processing that suggested only partial effectiveness.

In 1997, this Committee met to consider the safety of gelatin and to provide an assessment on the overall risk to humans associated with imported gelatin. This Committee made the following observations: First, that the scientific information available no longer justified excepting gelatin from restrictions recommended by FDA for other bovine derived materials from BSE countries. Second, that bovine gelatin injected or implanted forms posed a higher risk of transmitting BSE to humans than gelatin that is ingested. Third, that brains and spinal cords from cattle from BSE countries should be excluded from raw materials used to produce gelatin for human consumption. Fourth, alkaline or acid processing in gelatin manufacturer may only reduce rather than eliminate BSE infectivity, and the Committee called for better validation studies, particularly to investigate the other steps of gelatin manufacture. And finally, that porcine gelatins appear to pose no known risk of transmitting TSEs to humans.

After the 1997 TSEAC meeting, FDA issued its gelatin guidance document which remains the current FDA position in policy on the production of gelatin. In this guidance, FDA proposed the following recommendations concerning the acceptability of gelatin in FDA regulated products intended for human use. First, that importers, manufacturers and suppliers should determine the tissue, species and country source of all materials used in processing gelatin for human use.

Second, that bone and hides from cattle from any source country that show signs of neurologic disease should not be used as raw materials. Third, gelatin production from bones and hides obtained from cattle that reside in BSE countries or countries that do not meet the latest BSE related OIE standards should not be used in injectable, ophthalmic or implanted FDA regulated products or in their manufacture, but may be used in FDA regulated products for oral consumption and cosmetic use by humans if the cattle come from BSE-free herds and if the slaughter house removes heads, spines and spinal cords directly after slaughter.

Fourth, gelatin produced from bovine hides from any source country may be used in FDA regulated products for oral consumption and cosmetic use by humans if processors insure that the hides have not been contaminated with brain, spinal cord or ocular tissues of cattle residing in or originating from BSE countries. Fifth, gelatin produced from bovine hides and bones may be used in FDA regulated products for human use if the gelatin is produced from raw materials from countries like the United States that observe OIE standards and have not diagnosed BSE in their national cattle herd, that is RBSE-free. And finally, gelatin produced from porcine skins from any source country may be used in FDA regulated products for human use.

In 1998, this Committee met again to discuss gelatin among other issues. FDA's guidance, based on the 1997 TSEAC recommendations, was presented to the Committee to consider several new pieces of relevant information. For example, the infectivity of dorsal root ganglia and low level infectivity in bone marrow and the growing number of BSE cases being discovered in Europe. The Committee considered this new information and decided gelatin could be safely sourced from bones and hides of cattle in BSE countries as long as the recommendations in the guidance were met. That is that the cattle came from BSE-free herds and the high-risk materials were removed after slaughter.

And this is at present the status of the safe source factor for gelatin. Continuing on with the other key factor, that of validated effectiveness in the manufacturing process, in June 2001, the Committee was given an update from the Gelatin Manufacturers of Europe on the interim validation study results on the inactivation of BSE through the gelatin manufacturing process. This was an information sharing meeting only and no questions were posed to the Committee.

The Committee reviewed the study design and the preliminary data and requested a presentation of the final results as soon as they were available. The Committee is now about to get its wish as GME will present their completed studies, and we will hear other marketing and manufacturing information on gelatin in North America and Europe. After you have heard this new information, we would like you to comment on the studies and to consider the current gelatin guidance in light of these completed studies and other relevant information.

And I think, according to my schedule, Yuan-Yuan will now charge up the Committee. Thank you.

CHAIR PRIOLA: Thank you, Dr. Potter. Dr. Chiu will now present the questions for Committee.

DR. CHIU: Good morning. First, I would like to thank Dr. Priola and the Committee members to take the time to come out and also we have sent you a huge package, gelatin studies protocols and procedures and the results. We appreciate how much time you need to really review those studies. In the early days, in the 1998 year, when the Agency and the Committee together made a decision for the Agency's recommendation on gelatin was based on previous study which the Committee thought was somewhat flawed.

So generally, this reason follows the advice of the Committee to then redesign the studies and then today, you know, we have the new study results. You did not review the interim results, but today we have the final results off of five studies. We're hoping, you know, with the presentation today and the background information you have you will be able to help the Agency to answer two questions.

Next slide, the first question is "Do those results of these new studies demonstrate a reduction in infectivity that is sufficient to protect human health?" And we are only limited to hear the question to bovine bone gelatin is consumed by humans through oral or topical administration. The question is not for gelatin of other administrations, such as the injection, you know, implantable. We would like the Committee to focus on oral and topical administration.

Next slide, now, the first question, you know, the answer could be yes or no or in between regardless, you know, the answer we also would like you to answer the second question. There are two parts. The first part is "Do the scientific data and the information available support the current FDA recommendations on bovine bone gelatin for oral and topical administration?"

The current recommendations, next slide, is on this slide. The general policy of FDA is for FDA regulated products, the bovine derived material should come from cattle not bone residing as slaughtered in BSE countries, but the Agency also provides some exemptions. The exemption could be a total exemption unconditional, such as milk, dairy products and the milk derived product. But some of the substances, you know, the Agency provide conditional exemptions, and the gelatin for oral and topical use are giving conditional exemptions.

So if the cattle actually is coming from BSE countries, then that condition is the cattle must be from a BSE-free herd and also at the slaughter house the head, the spine and spinal cord should be removed. And this is from BSE countries. Now, some countries may not have BSE cases, but there is consider of high-risk of BSE. Then the recommendation is the heads, the spine and the spinal cord should be removed as the first step in the slaughter house. So the first question is whether this current recommendation still is valid, based on the scientific information we have today.

Next slide, if the answer is yes, then that's the end of it. If the answer is no, then we would like to know what changes the Committee would like to recommend to our current policy. The changes can be in all different directions. You may consider we can actually grant a total exemption to the gelatin for oral and topical use or you may consider to modify the current recommendation the FDA has, either by strengthening or by relaxing the conditions. So we are anxious and grateful you will give Agency your deliberation. Thank you.

CHAIR PRIOLA: Okay. Thank you, Dr. Chiu. Our next speaker is Mr. Masson, who will discuss market trends in the U.S.

DR. MASSON: Yes, good morning everybody. Madam Chairman, I would just like to thank the Committee and the FDA, in particular, about the opportunity to address the Committee. As we have heard from Drs. Potter and Chiu, it has been a long and winding road, the saga of gelatin, and we hope today that we can reach a satisfactory conclusion and see gelatin taken off the file, so to speak, having reassured you of its safety.

My first slide, please. Can I have the first slide, please? Okay. Thank you. Well, just an introduction of I'm currently the president of our industry association, the GMIA, and also president and CEO of one of its members at Russelot. The next slide? A bit of history as to GMIA and credentials, so to speak. Our association was formed in 1956. We have six members, all NAFTA based, four from the U.S., one in Mexico and one in Canada. And we've listed here the typical working committees by which we run the institute. There is no particular order of precedence, but the technical and regulation committees as you can imagine, indeed, are the primary focus of most of our work, I guess.

Next, in terms of what we represent, we, as you see, represent roughly 22 percent of the global gelatin production, and almost 100 percent of all the gelatin made in North America. And, indeed, three of our members are also affiliates of the Gelatin Manufacturers of Europe. And I should have added actually that one of the other members is an affiliate of the Japanese Gelatin Manufacturing Group.

Next, please. This lists our objectives. As you see, we try to monitor and inform our members of any and all regulations which can impact gelatin. We are the liaison with FDA, USDA and other regulatory authorities, and we gather and distribute technical information to our members, endeavor to promote a broader knowledge of gelatin and encourage its wider consumption. And we provided the forum as you've seen from our committee information on all of the major aspects concerning technical, environmental and safety issues.

And as time has gone by and as other industry associations have been formed around the world in Japan, South America and so on, a major function which has emerged has been to liaise with them to ensure that technical information and regulation information, etcetera, is shared with the other associations around the world. And I just participated, for instance, in the Japanese meeting or the Asia Pacific meeting, which was held in Japan, just last month, as an example of the increasing international corporation among the industry associations.

Next, please. This slide lists the primary uses of the concentrated, obviously for today's purposes, bovine bone gelatin and, as you see here, this is a list of the major uses for bovine bone gelatin in the United States. It is listed in the standing order of use with photographic still being the largest consumer going on down to food. There's less and less bovine bone gelatin used in food products, by food we mean confectionery and marshmallows or whatever else.

It is being, I guess, more replaced there by pigskin porcine gelatins. But anyway, those are the primary uses and, as you see, no matter what the end use, all the gelatins are produced through the same manufacturing processes and my colleagues will be describing those in some detail in a few minutes.

Next, please. To give you an idea of the scale of the gelatin business globally, and in particular the bovine part of that production, we have listed here the various theaters, so to speak. Europe is still the biggest gelatin producer. Significantly so with 117,000 tons out of a total of some 270,000 tons around the world. Above that, I would have to say, over 25 percent or so is actually bone gelatin. The U.S. in total we make something like 60,000 tons. And again, these are all gelatins, whether bovine or porcine or bovine hide or bovine bone, porcine skin.

And as you see, of the 60,000, about 17,000 tons is actually bone gelatin. Other covers is Asia Pacific, the Asia Pacific regions and South America, and you see about a third of their gelatin is of bovine bone origin. So totally, bovine bone represents almost 80,000 out of the total of 270,000 tons. And to give you an idea again of this international value industry total globally is not that big. It's 1.5 billion dollars equivalent.

Next, please. What we tried to do here is to put to ourselves a few questions, the elimination of which, I think, will be helpful to the committee in looking at bovine bone gelatin, in particular, in the U.S. The first question, as you can see is, "Can the U.S. gelatin industry supply total U.S. capsule industry's needs?" The answer is no. And this illustrates how that is the case.

As you saw earlier, the U.S. bovine bone gelatin production totals some 17,000 tons, but of that 11,500 are needed for photographic and other non-capsule uses. So you see that that remains, there remains only about 5,500 tons which can be used by the capsule industry, but the total needs, in fact, are 10,000 tons, and this means that the shortfall roughly 4,500 tons of bovine bone gelatin has to be imported and they come primarily from Europe, also from Japan and India, and immediately derived nevertheless from U.S. bones or from bones from other countries.

Next, just continuing that theme, of those 4,500 tons of which we need to import, "Can they be derived solely from U.S. bones, even if it's not actually manufactured in the U.S.?" Again, the answer is no. As you see here, the total amount of U.S. bones which are made available to the gelatin business is roughly 130,000 tons and because of its use in photographic production, whether in Europe or in the U.S., and also for manufacturing bovine bone gelatin by other companies outside of the U.S., the amount remaining available for pharmaceutical gelatin production here is only 28,000 tons.

The next line which is in bold print illustrates that we need roughly 6 tons of bones to make a ton of gelatin. So that the 10,000 tons of gelatin, which the capsule industry needs, is actually equivalent to 60,000 tons of bovine bones and, consequently, you see the shortfall here is roughly 32,000 tons, so to speak, to be able to make all of the capsule industry requirements strictly from U.S. bones. So in other words, the deficit has to be sourced from bone suppliers outside of the United States.

Next, so then I apologize, this is a little bit of a busy slide, but the bottom line is that there are, indeed, other sources outside of the United States, but even though the quantity is maybe available for various reasons in terms of surveillance, the inspection procedures and so on, it's not so obvious that the quantities, the tonnages, which are listed in the second line or the second section are, indeed, available and because of the various restrictions and so on, you see, in fact, that the bone and that those numbers diminished to rather smaller numbers.

And this really drives to the heart of the matter. This is the crux really of what we want to get at today and my colleagues will be addressing this individually and then in the public comment session later, the question of how we can determine the BSE status adherents and also the question as Dr. Chiu referred to of just when they have to be removed in the gelatin bone process. Again, we'll be traveling to that in some much more detail in later presentations.

Next, please. I guess that concludes my presentation, unless there are any questions.

CHAIR PRIOLA: Yes, are there any questions for Mr. Masson?

DR. MASSON: Thank you.

CHAIR PRIOLA: Oh, Dr. Hogan?

BOARD MEMBER HOGAN: I have one question.

CHAIR PRIOLA: Just a second, Mr. Masson, there's a question.

BOARD MEMBER HOGAN: Sorry. I had one question, perhaps it is contained in this information you provided us, which is quite huge. In terms of the amount of gelatin that is derived from Europe, could you tell us something about the country breakdown, that is it's most from the UK, France, Switzerland, etcetera?

DR. MASSON: Yes, I think you'll find in the information packet there is a detailed breakdown of the various imports. The consumption in the U.S., actually the total marketing, is closer to 80,000 tons. And as you saw, we make 60,000. There is a net import/export situation. The U.S. does export gelatin, but basically to get to the 80,000 that we need, we need effectively a net import of 20,000 tons.

Those 20,000 tons come from quite a variety of countries and, indeed, they are listed in the information packet. We didn't go into the detail of it here, because it's somewhat difficult to differentiate, certainly differentiate country by country. It's a little bit more difficult to differentiate within certain countries whether it is bovine gelatin or porcine gelatin, which is actually being imported. But basically the primary countries who do export into the States would be France, Germany, not so much any more from UK, for obvious reasons, Brazil, Argentina, Japan, India. Those would represent the large majority of the total import picture.

And again, the variety of gelatins some of that is bovine bone, for sure, but also a lot of bovine hide gelatin comes, for instance, from South America, and bovine bone also from India. It's quite a variety of types from those principle countries.

CHAIR PRIOLA: Dr. Khabbaz?

BOARD MEMBER KHABBAZ: Yes, I didn't hear you well and I apologize. When you said in foods increasingly, there's less bovine gelatin and an increased used of porcine gelatin. Was that porcine skin?

DR. MASSON: Yes, one can make and, indeed, one does use porcine bones, but the large majority of porcine gelatin made around the world is from porcine skins. And again just to elaborate on that point, the food industry, the present manufacturing process of bone gelatin, which we'll hear much more about in a few minutes, is a very long process. It's a very costly process. Whereas porcine gelatin and hide gelatin, certain portions, is a much sorter process. And economically, therefore, it's much more viable to utilize porcine gelatin, in particular, in the food industry compared to bone, you know.

CHAIR PRIOLA: Dr. Bailar?

BOARD MEMBER BAILAR: The numbers went by pretty rapidly, but it looked to me like the proportionate shortfall from U.S. production is about the same as the proportionate shortfall when you add production from U.S. bones processed elsewhere. Is that correct? I'm looking at the second and third from the last slides.

DR. MASSON: And again, could you just repeat that?

BOARD MEMBER BAILAR: Well, in the answer here to question 1, the third from last slide.

DR. MASSON: Yes.

BOARD MEMBER BAILAR: There was a shortfall of 4,500 tons and a need of 10,000. And in the next one, it was a shortfall of 32,000 tons and a total need of, was it, 60,000, maybe I have misread this. Yes, 60,000. It's about the same proportions, but I understand why these includes other production and the other does not.

DR. MASSON: The shortfall with the U.S., as you see, makes 17,000 tons, that is equivalent to over 100,000 tons of bones, and as we said, basically the cattle industry needs 10,000 tons of gelatin and only half of that effectively is made here in the States. The other half, because of lack of availability of bones and lack of capacity in the States for bovine bone production, has to come from outside of the States, and that's, as you mention, roughly the same proportion. It's almost 50/50. Does that help?

BOARD MEMBER BAILAR: If I understand correctly then, adding the U.S. bone processed elsewhere doesn't help much at present?

DR. MASSON: Excuse me, adding?

BOARD MEMBER BAILAR: Adding gelatin from U.S. bones processed elsewhere does not, at present, help very much.

DR. MASSON: No, because again the total demand for U.S. bones, because of the other applications, particularly for photographic and other European and other countries utilization of U.S. bones, they don't always end up as pharmaceutical gelatin. The end up more often as photographic gelatin, so there's just not the amount of U.S. bones going overseas which can come back to the U.S. as pharmaceutical gelatin for capsule production.

BOARD MEMBER BAILAR: At what point is the distinction made regarding the ultimate use of the gelatin?

DR. MASSON: Regarding what, sir?

BOARD MEMBER BAILAR: Regarding the ultimate use of the gelatin. Is it all processed? I thought it was all processed in the same way.

DR. MASSON: Well, my colleagues will describe that in a great deal of detail, and it is more or less, yes.

CHAIR PRIOLA: And Dr. Wolfe?

BOARD MEMBER WOLFE: This is sort of a follow-up on John's question. You mentioned two factors that are rate limited, so to speak, in terms of the use of U.S. bones. One was the capacity, presumably, to convert U.S. bones into gelatin, and secondly, was the unavailability or the shortage of U.S. bones. I can't believe that the second one is really a problem. It is likely that only a small fraction of U.S. bones are currently being exported to other countries for reprocessing. I mean, is that correct or not? I mean, it must be a limitation on production, not a limitation on U.S. bones, and that gets to the issue of why there couldn't be an increase. If the capacity is the problem, why there couldn't be an increased export of U.S. bones to European countries to use them, preferentially, in favor of bones from BSE countries.

DR. MASSON: Yeah, your point is well- taken. The problem, however, is that the largest consumer of bovine bone, as you see, is the photographic industry. Out of the 130,000 tons, which is produced in the states, over 100,000 or approximately 100,000 goes to the photographic industry. And by definition, therefore, the remainder simply isn't satisfactory, and we can't drive -- the gelatin industry is at the bottom of the totem pole, so to speak, in terms of creating greater availability of bones. The different industries sell so much bone that's made available to us basically, and there is only so much.

BOARD MEMBER WOLFE: Are you saying that the bone either goes to photographic industry or elsewhere and that there isn't, at the present time, bone from U.S. beef that is not being converted into gelatin? I mean, what percentage of the, theoretically, available bone from U.S. beef is, in fact, being converted to some kind of gelatin? Because my question is sort of getting to the issue of whether or not it is possible to divert or not to divert, but just to increase the use of bone from U.S. beef, even though you want to -- you said there's a tug between photographic gelatin and other gelatins if the total amount of bone was available, you could satisfy both of them. So just, specifically, how much of U.S. bone is, in fact, getting converted into some kind of gelatin? Half of it, two thirds of it, all of it? What?

DR. MASSON: Well, the bone that is available is being converted. Again, there are only a few bone producers of the major beef players, but only a few of them actually make gelatin bone at some of their facilities. And again, it's supply and demand. We can't. Basically, there's not enough demand from our side that would force them or encourage them, let's say, to produce still more bone. It's that simple.

BOARD MEMBER WOLFE: Okay.

CHAIR PRIOLA: Dr. Johnson?

BOARD MEMBER JOHNSON: Yeah, I may understand the way this is processed. But it seems to me that the ready solution would be that U.S. bone would be used for all consumables, whether they be dietary supplements and then you could use the foreign bone for photographic materials. It's about even.

DR. MASSON: On paper that's true, but that's --

BOARD MEMBER JOHNSON: That's what I'm looking at.

DR. MASSON: Yes. But it's rather simplistic, because again we can't make that determination. It's those industries who make that determination. The photographic industry has determined that they will use bovine bone, and that's their prerogative that we can't influence it.

BOARD MEMBER JOHNSON: So a solution would be if we deregulated photographic bovine bone, and that would be a possibility. Does FDA regulate photographic gelatin?

DR. MASSON: No.

BOARD MEMBER BAILAR: No, they can use whatever they want.

DR. MASSON: Yes.

BOARD MEMBER JOHNSON: So you could split it up.

DR. MASSON: I'm sorry?

BOARD MEMBER JOHNSON: If there's no regulation on photographic gelatin, you're subtracting it out to produce all this shortfall, why not make the photographic gelatin from British bones?

DR. MASSON: I'm sure some is, but again, we as an industry can't make that determination. It's the photographic people who make that determination.

CHAIR PRIOLA: Dr. Bracey?

BOARD MEMBER BRACEY: Yes, in the information that you present, the majority of the gelatin is used for photographic purposes. It seems to me that there has been a major move away from film based photography towards digital. Have you seen a reduction in the demand and, in essence, your picture is a static picture, but what does it look like really as far as the demand for photographic gelatin in the future?

DR. MASSON: That's a very good question. As you rightly observed, digital photography is here in a big way and will continue to grow. But there is some complimentality between silver halide, the traditional silver halide process, which does utilize photographic gelatin and the digital business. So that the two things, digital is growing certainly at a much more rapid rate, but photographic traditional silver halide photography is still very much en vogue and, indeed, you know, the last photographic companies, Kodak, Fuji and so on still continue to invest quite significantly in the traditional side of the business as well. So the two things, I'm not sure of --

BOARD MEMBER BRACEY: Well, I guess, what I'm wondering is over the years the data in terms of total demand has been static or has it been actually declining?

DR. MASSON: I would say it is fairly static. There has been a diminution for sure in some sectors of the traditional silver halide, photographic side of the graphic arts, for instance, probably uses any photographic gels any more. That has gone totally, more or less totally, to the digital side. But the traditional film that you or I shoot, the amateur film, medical x-ray and other types of cinema, film photography for movies, those are still the traditional situation, and that demand is still very much there.

CHAIR PRIOLA: Yes, is there a question from this side or answer?

MR. SCHRIEBER: Thank you, Madam Chairman. I would like to make -- Reinhard Schrieber.

CHAIR PRIOLA: Could you identify yourself?

MR. SCHRIEBER: From GME, and I would like to make a remark about potential replacement for the photographic industry of domestic bones and imported bones. The following situation is the biggest manufacturer of photographic gelatin is Eastman-Kodak sitting here in the United States. They are forced to use domestic bones, because as a ban on import of bones from out of the U.S. into U.S., because the risk of bringing in bones from maybe BSE risk countries is tremendously high to bring in just in case by the bones BSE into the United States.

So gelatin is safe to be imported, but importing bones from other countries, I think, is of high-risk for this community here, so therefore it would really replace and most probably negligible risk with gelatin by a big risk by importing bones, degreased bones from other countries, who therefore is a replacement in this way, I think, is not a good idea for the U.S. On the other hand, I think it is really impossible to force Eastman-Kodak just out of using bones from the U.S. I don't know how their reply would be in this case.

And maybe one more question, answer to your question about from which European countries is sourced in Europe has no bone at all coming for the last 20 years from UK, so the European gelatin industry did not source bone from UK. We do not source bone from Ireland. We do not source bone from Switzerland, Portugal, the so-called higher risk countries in Europe. All the bones, proven bones used by the European industry are coming from either Germany, France, Belgium, Netherlands or Austria. These are the source countries. Thank you.

SECRETARY FREAS: Because our meetings are being transcribed, we're asking everybody who uses a microphone other than at the table to identify themselves. That was Mr. Schrieber, the chief manufacturing officer of the Gelatin Group.

CHAIR PRIOLA: Okay. I think we'll move on to our next speaker. Thank you, Mr. Masson.

DR. MASSON: Thank you.

CHAIR PRIOLA: Our next speaker is Dr. Dunn, who is going to explain some of the manufacturing processes for gelatin in the U.S. and that might address some of the questions that have arisen.

DR. DUNN: I also would like to thank the FDA and the Committee for the opportunity to come in and speak with you today about the practices of the U.S. gelatin manufacturers. My name is again Michael Dunn. I'm currently vice president of Gelita North America, and I also serve as the chairman of the Regulatory Committee for GMIA. As you can tell on this slide, there are two current manufacturers of bone gelatin here in the United States, Eastman Gelatin, who provides to Kodak, they are primarily producing photographic gelatin, and GELITA USA, who is primarily a pharmaceutical producer.

When we put those together, though, the majority of this gelatin goes to the photographic applications, although there is a substantial quantity that does go to the pharmaceutical sector as well. The limed share of the gelatin that we produce is limed bone gelatin. We do, however, produce a small amount of what we call Type A or acid bone gelatin, but this is a very small quantity.

I also wanted to note that the practices that I'm going to be talking about today, as well as the processes, apply to both GELITA USA as well as Eastman Gelatin. Could I have the next slide? So just to set the overall objectives, they basically are two-fold today. I want to adequately describe for you today what our current sourcing practices are, as well as the processing conditions that we use to manufacture bone gelatin in the United States.

I also want to clearly confirm that the bone gelatin processing conditions that we employ here are virtually the same that are currently used in Europe. And more importantly, they meet or exceed the minimum processing requirements that were spelled out in the GME TSE Inactivation Study Protocol. This I want to make clear, because we want to make sure that any of the results, we want to make sure that they are applicable to what we are producing here in the United States, as well as what is being produced in Europe.

Could I have the next slide? So when we get to sourcing, in the U.S. degreased gelatin bone is sourced exclusively from USDA inspected beef processing facilities in the United States, and this raw material is derived solely from healthy cattle that have been deemed fit for human consumption based upon both anti and postmortem inspections.

Could I have the next slide, please? When it comes to SRMs, the U.S. gelatin bone suppliers have been removing SRMs with the exception of vertebrae since as early as 1998. And right now, limited quantities of vertebrae-free gelatin bone have been available from as early as fall of 2002. Currently, there are no FDA or USDA requirements for the removal of SRMs in the United States. We primarily do the two above bullet points primarily because of EU regulations and we supply a large number of customers that have business in Europe that must comply with those kinds of regulations.

Could I have the next slide, please? So let's go on to the process. What I have outlined here is an overview of what happens in a daily gelatin production. The major input, of course, to this is the degreased gel bone. We're on the order of about 100,000 pounds of gel bone per a production day. And we have an equivalent amount of hydrochloric acid, so another 100,000 pounds of hydrochloric acid would go into this next. We use at least a half a million gallons of water in the production and, of course, there is a lot of labor and energy that goes into this as well.

What I'll be talking about primarily today is what goes on in this blue box here, in terms of the DTL processing conditions. The output we're looking for, of course, is gelatin. On a base of 100,000, you get out about 25,000 pounds of gelatin, and then about 50,000 pounds of dicalcium phosphate, which is the primary byproduct of this process.

Could I have the next slide? So overall, what we're trying to achieve here, we're starting with the protein we call collagen, which is an extremely fibrous insoluble protein and we're going to transform that into a protein that is fragmented and soluble, but has a variety of very interesting functionalities, which makes gelatin such an interesting business. So there are three major things we are trying to achieve here.

Initially, we need to hydrolyze the collagen. We do this by breaking, there is intra and inter molecular cross links between the adjacent chains. We start to break up peptide bonds, so that we're able to water extract this material from the ossein that we're producing. Subsequent to that, we spend a lot of time purifying and concentrating the gelatin. When we do that initial extraction, it's a very dilute solution about 5 percent, so we have to take a lot of water back out of that and then we purify the material from both a chemical, physical and micrological point of view.

If I could take the next slide, please? So the incoming gel bone comes to us. It's delivered by a truck or rail car and these are just simply typical characteristics of that material, and we would use the same material to make either the Type B or the Type A gelatin. So the fat content ranges from 1 to 2.5 percent. The size of these chips is an 1/8^th inch to 5/8^th inch. The mineral protein ratio is about 2 to 1. And the moisture content is about 6 to 9 percent. And in contrast, it's worth mentioning in the EU all of the producers there have their own degreasing facilities, which is different than the way things are done here in the United States. The big meat producers have their own gel bone processing facilities, and they supply us with this finished bone chip.

Next slide, please. The first pretreatment step is what we call acidulation. But what is happening here is the demineralization of the bone. This is where all that hydrochloric acid comes into place. What we're trying to achieve here is the production of what we call ossein, which is this demineralized bone material. There's a number of washings, hydrochloric acid washings during this process. We also remove a lot of non-collagen impurities that come in with the raw bone.

The concentrations that we're looking at here, maximum, 4 to 6 percent. The way this works is it's a counter-current distribution process. We start out with a dilute hydrochloric acid concentration, that's what the initial bone is exposed to, and it's gradually raised up over this 4 to 5 days. It's a very exothermic reaction, and this is why it takes to long to carry this out to dissolve out all of this material. The typical ambient range as far as temperature after this process is done, the residual acid, is washed out for about a 24 hour period before we go on to the next step, which is on the alkaloid side of things.

Could I have the next slide? So if we choose to lime, at this point, this is the breaking point we choose to make either lime bone or acid bone, at this point. In the case of liming, this is a lime pit that you're seeing up there in the picture. Again, we being, this is where we continue to hydrolyze the collagen molecules and there's a lot of washing that goes on here with the refreshing of the lime solution, so we're moving impurities.

There is also something important that happens here chemically that is different than porcine gelatin. You hydrolyze away the asparagine and glutamine. You deanimate those and form their respective acids which drops the iso-electric point of that molecule from about 9 down to about 5. So electrically, the porcine and the bovine gelatins are quite different. We use a saturated lime slurry to do this. The pH is approximately 12.5. The liming time is 25 to 70 days that we're tying up this material in production for a long period of time before we can make gelatin out of it. Again, and the temperatures, these lime pits are agitated on a daily basis. We're there to make sure we're getting proper exposure to the alkaline material to the bone chips that are in the pit. And these lime slurries are completely refreshed on a weekly basis.

Next slide, please. After that, there is a washing and acidification step. We want to neutralize the excess lime, again remove, wash out additional non-collagen impurities, and we want to adjust the pH of the ossein slurry, so we can prepare it for extraction. So this wash out period under alkaline conditions is 24 to 48 hours under vigorous agitation, temperatures from 45 to 70 degrees. The neutralizing or souring of acids in this case are either hydrochloric or sulfuric acid, and our target pH for this part of the process range between 5 to 7.

Could I have the next slide? In lieu of liming or alkaline which is what we do most of the time, we're only talking a few percent of the time we do this process. We can do an acid treatment and produce Type A or acid bone gelatin. So the purpose of this process here is to condition and ready the ossein material for an extraction at a very low pH. In the traditional process, we use a sulfuric acid and we expose the ossein to a pH of about in the range of 1 to 2 for about 6 hours, and then we rinse that back to a pH ranging from 2.8 to 3.2. And this is where we will extract the gelatin. This is, I mean, usually pH to extract gelatin. Most gelatin is extracted at much higher, more neutral pH.

We also have an alkaline pretreatment option that we're looking at, that some of our customers are looking at, because of all the discussion around sodium hydroxide pretreatment. In this situation, you would do this alkaline pretreatment prior to the ossein treatment. And in this case, you are able to maintain the pH at 13 or greater with sodium hydroxide for a period of three hours.

Next slide, please. Okay. Now, we've finished with the pretreatment, whether it be for acid bone gelatin or lime bone gelatin and the rest of this will be common to both of these types of gelatins. Now, we extract the gelatin. This is where we've wetted the gelatin, we've hydrolyzed it, now we're going to actually pull this, extract this out of that ossein particle to produce the gelatin.

We use demineralized water. What you're seeing up there is a typical gelatin extractor. We do a series of extractions. I said 4 to 6 depending on the plant and the company, the way they do that. But the initial extracts are done at a lower temperature, and what you will get out is a material that typically has a higher molecular weight, a higher viscosity, a higher bloom strength.

As you go to subsequent extracts, that material will become more degraded. It will have a longer profile of treatment with time and temperature. And those ending extracts will conversely have higher collagens, lower molecular rates, lower viscosities and so on and so forth. So the temperature range is from about 120 to 200 as you go through that series of separate gelatin extracts that you are pulling out. The conditioning time for each extraction ranges from 1 to 6 hours and it's 4 to 6 extracts.

Next slide, please. When that extract comes off, it's a typical, very dilute solution somewhere in the range of about 4 to 6 percent. So you're saying to get to a dry product, we got to pull a lot of water out of here as well. So we have initial filtration, this is a U.S. type filter, vertical leaf type filter. It's precoated with diatomaceous earth and cellulose. And that basically is to give us initial and improvement in the clarity. The solution will also go on to ion exchange. We want to protect these ion exchange collagens.

Could I have the next slide, please? So you're looking here at an ion exchange battery. You see three columns in the forefront and three in the background. Those are batteries of cation in that exchange columns. Of course, the objective here is to deionize this material, depending on whether it is pharmaceutical or photographic. It gets more exposure to those columns depending on what is needed.

Primarily, the cations we're removing are calcium magnesium and iron. On the anion side, it would depend on the acid that we were souring the material with before we extracted it. And sometimes we use hydrochloric and sometimes sulfuric. So those would be the primary anions that would be removed under those conditions. And the finished product from an ash standpoint would be somewhere between .1 and 1 percent, depending on the product that we're making.

Could I have the next slide, please? Now, we begin to remove water, and we do this by using evaporative means initially. So we have this 5 percent solution that we're going to drive up to a 15 to 25 percent concentration. The evaporator you see there in the picture is a triple effect plate and frame type evaporator. The output temperature is not too high. It usually runs about 125 to 130 degrees on the average. Basically, a temperature that will just make sure the gelatin doesn't gel up in the production plant.

Could I have the next slide? Then we have another filtration. We heat it again. We've concentrated that material, so there is more particulate becoming apparent, in certain cases, and then there is a chance that you may get some coagulated protein, so we have another clarification step here. The medium we use are exactly the same in the prior filtration cellulose and diatomaceous earth, but we use a plate and frame pressure filter. The viscosity of this solution is increasing now as we move along in the process, and this is what requires a completely different configuration for filtration.

Could I have the next slide, please? Then we take the opportunity to adjust the pH, at this point. The final pH targets of the finished product are usually in the range of 5 to 7. At this point, it's usually just a fine adjustment and most typically it's done with sodium hydroxide.

Could I have the next slide? Then we do our final concentration with evaporative means. Again, this solution is becoming quite viscus, so we're concentrating our thick, what we call at this point, our thick gelatin liquor. This is an example of a double effect plate and frame type evaporator as well. And the concentration here will be a fairly broad range here from 25 to 50 percent, and this is because, I talked earlier about your initial extracts are much higher viscosity, so you only will be able to drive those up to about a 25 percent. However, the latter extracts, which have a much lower viscosity, you're able to drive those up to a much higher concentration level, and that's what is done.

Next slide, please. Then we go through a sterilization step at the end of the liquid phase. After this, we're going to be going into a more solid mode with the gelatin production, so this is our last opportunity to do something with the liquid phase. So we use direct steam injection. We use a temperature that ranges anywhere from 138 to 149 C for 8 to 16 seconds, and this is primarily to ensure the product, hygiene of the product.

Next slide, please. Then we're taking another tack here in terms of drying the gelatin. We're beyond evaporative means, so what we do is to increase the surface area, then able to dry this material, we cool it down from about 120 down to about 70 degrees where the gelatin actually sets, starts to set, and this is down with a glycol cooled heat exchanger. Then it is extruded out through these perforated heads to form these noodles, which will range in size from under 2 feet long and about an 1/8^th inch thick, and they are deposited on the front end of a dryer, which is in the next slide.

These dryers are typically about 12 feet wide and about 150 feet long. The air quality we use is heated, dehumidified and filtered air. The object is to produce a stable product. It has very low water activity. Typically, it has 10 to 12 discrete zones with different temperatures. There's a gradient that ranges from about 80 to 160 degrees fahrenheit that goes across that entire dryer. It takes about like 2 to 3 hours to get through this system, and the final moisture content of the gelatin product is about 10 to 12 percent.

It's a very touchy process. It's very easy to melt the gelatin. If you try to dry it too fast, you know, with too much water, the melting point is lower and it is going to melt down or you can get case hardening. It's a very delicate process drying this gelatin effectively.

Next slide, please. Then we do a milling after the drying and our size is typically 8 mesh. That's our kind of working mesh size. We can do a variety of mesh sizes in the finished product, but most of our intermediate products we're producing these intermediate extracts that we use to do our final finished blending, and it's typically about 8 mesh.

Next slide, please. So as these individual extracts, whether it be 4 or 6, come off there, they are separated on the dryer as discrete extracts. Those individual extracts from daily production are individually blended to make sure that there is no lack of homogeneity as that material is processed across that dryer. So we blend those with homogeneity. We sample those materials, as intermediate product, and those that go in the dryers are weighed and go into storage as intermediate product for future blending and mixing.

Next slide, please. So there is our inventory that we're building up with our daily production, and then based on the specifications of our customers, we build mixes and we formulate mixes with these individual extracts that we have been producing. These are much larger blends. Some of these are 10, 20, 40,000 pound mixes, so now we have a high capacity blender that allows us to put those together.

Many times we'll make a much smaller small scale mix to make sure that we can blend it properly, particularly if it's a new product. We can hit the specification before we go to the large scale blend. So sometimes there is a series of analysis that we've done it two or three times before we finish off the finished product.

Next slide, please. And then we provide that product once we are ensured that it meets the specifications of customers. We'll package that up using drums, FIBCs or small bags and then it is off to the customer.

I hope that has given you a quick -- I had to go through that rapidly. There is a lot of information to cover there, but you've got that in your handouts there. So I hope that was useful and I would be glad to entertain any questions you have. And I also would like to invite you to come out to see our facility in Sioux City, Iowa if you would like to see first hand how we make gelatin.

CHAIR PRIOLA: Yes, Dr. Bracey?

BOARD MEMBER BRACEY: Yes, I have one question. You said in the cation exchange process that you treat the product in a different manner depending upon the end use, i.e., photographic versus other. So, in essence, that suggests that there is the potential for control.

DR. DUNN: That's right. That's right. I mean, there are certain types of food products where you may not go through the columns at all. I mean, it depends on the ash content. Typically, the ash if it was unprocessed, it could be as high as 2 percent, okay. In some cases, there would be no need. And it would get very sophisticated with the photographic realm whether you are interested in anions and cations, you go through a cation and bypass an anion or you may go through a secondary column.

You know, we have a battery with three columns of each type. Usually, one is a lead column, lag column and then there is a regenerate one under regeneration. So there is a variety of ways to go through that ion exchange system, depending on what the specifications of the customer are. You might have a food customer who says well, ash is less than 2 or you might have a photo customer and it has got to be between .1 and 2.5 or .1 and .25 or something like this. There is all kinds of variations on the thing in terms of exposure to ion exchange.

CHAIR PRIOLA: Dr. Bailar?

BOARD MEMBER BAILAR: I understand from Dr. Chiu that it is the processors who are responsible for the safety of supplies. How is that monitored or enforced here and abroad?

DR. DUNN: You're talking about the supply of our gel bone?

BOARD MEMBER BAILAR: Right.

DR. DUNN: Okay. We audit our suppliers. One of the things that makes it a little bit easier here in the States is we only have a few. We basically have -- it depends on the company. Between the two companies, I think, we have five or at most six different suppliers. So it's not an unmanageable deal to go in and audit these customers on a regular basis. We also know that USDA is in these plants. They help us with this. As a partnership, they are in there auditing all the time.

For example, when we worked with the USDA because of these European regulations to start taking our SRMs, back in 1998, they worked with us to do that, to go in and validate those procedures and so on. So we have an ongoing program in that respect and we work with the USDA sometimes to do various things as well.

BOARD MEMBER BAILAR: What about foreign supplies?

DR. DUNN: All of our suppliers here in the United States, everything we source is here in the United States right now.

CHAIR PRIOLA: Can you remind me, you said there were Type B and Type A --

DR. DUNN: That's right.

CHAIR PRIOLA: -- process and the Type A is acid?

DR. DUNN: Type A is the acid. Type B means base.

CHAIR PRIOLA: Right. And why do you choose one of those others?

DR. DUNN: Like I said, we do very little Type A. I mean, very little. We're talking probably less than a couple percent, something like 2 to 3 percent, and that's all directed to the pharmaceutical capsule industry, and there are reasons for that. Because of the way we process this material, the ratio of viscosity bloom and the ratio of viscosity to concentration is very different. We can acquire a very low viscosity concentration ratio with this process for acid bone.

And sometimes those customers who make the capsules require that they have a higher concentration. And the limit usually is viscosity. So if they can get a gelatin that has a lower viscosity to concentration ratio, that allows them to bring more gelatin into that capsule, and sometimes in the soft gel, it depends on the drug fill and what is going on there, that can be very important. So it's very important for a number of applications in the soft gel area.

CHAIR PRIOLA: All right. So even though it's a small percent of the time you do this process, most of it goes to the pharmaceutical industry?

DR. DUNN: That's right.

CHAIR PRIOLA: Then the sodium hydroxide option, the base treatment, you said that's under review. Is that to see how that might effect --

DR. DUNN: That's right. That's under review for acid bone. The most important thing it's under review by our customers, and they are currently evaluating that to see if there is not any other shortcomings of the fact that the sodium is there as opposed to the calcium from the lime.

CHAIR PRIOLA: Does it seem to change the end product at all?

DR. DUNN: From our prospective, it doesn't, but that's why we're relying on the capsule manufacturers to do their full evaluation and that's what we're looking for. Okay. So we can do it. It's easy for us to do. It's not a problem for us to do that.

CHAIR PRIOLA: Dr. Khabbaz?

BOARD MEMBER KHABBAZ: Yeah, I have a question regarding the bovine bone sourcing practices. You said since 1998, you have been removing the specified risk materials, except for vertebrae.

DR. DUNN: Yes.

BOARD MEMBER KHABBAZ: Why that exception and is it still practiced?

DR. DUNN: That's a very difficult thing to do, and there is really up until recent times there has been no requirement. There are EU regulations now developing and that's why there is concern there that that may be a requirement coming into place as early as the end of this year. We're not sure how this is going to roll out, so we're looking at this strategically. Right now, there is not a requirement, but there is a big hurdle there in terms of industry's ability to do this.

This will cost us more money. It will reduce the amount of bone available. Right now, if you take the vertebrae and take it somewhere else, you reduce the quantity right there by 25 to 50 percent. And then there will be certain facilities that will just not be able to do this with the equipment they have. They won't be able to make this change without investing new capital. But anyway, the prices we are seeing now, you can get this material, small masses of this material now, but it is going to cost you 50 to 100 percent more than the traditional. So, I mean, nobody wants to go there unless we have to. It's going to be very costly for us, our suppliers and our customers.

CHAIR PRIOLA: Okay. Thank you very much, Dr. Dunn.

DR. DUNN: Thank you.

CHAIR PRIOLA: I think we'll move on to the next speaker. It will be Mr. Schrieber, who will describe the European manufacturing processes for gelatin.

MR. SCHRIEBER: First slide, please. I would like to thank you, Dr. Priola, this Committee and the FDA for the opportunity of presenting on behalf of the Gelatin Manufacturers Association, GME. Again, details about raw materials sourcing and the bone gelatin manufacturing practices in Europe. My name is Reinhard Schrieber. I'm the chief manufacturing officer operating GELITA Gelatin Group. I'm 36 years in the gelatin business, and I have served at European Gelatin Association for many years as president, chairman of the regulatory committee and the chairman of our BSE Steering Committee.

After my American colleague, Mr. Dunn, has already substantially presented the details of the bone gelatin manufacturing process, I would like to go only relatively shortly into this issue. The manufacturing processes in general and although the bone gelatin manufacturing processes in particular are very similar to each other, not only in the U.S. and Europe but all over the world. The main differences which can be noticed between the continents are related to the safety status of the raw material and the sourcing systems in place.

This is why I like to focus more on these topics, whereas I would like to try as well to connect the connections and the conditions of our study to those existing in reality.

Next slide, please. GME members have taken several voluntary steps to ensure the safety of the raw materials. Long before the emergence of BSE, the European gelatin industry has decided to use, and this applies for all types of raw materials, only raw material coming from healthy slaughtered animals and released for human consumption, regardless of whether this was mandatory or not in different member states. So we don't use any materials from fallen or sick animals.

So traditionally, no material from fallen animals have been used by European manufacturers. The three bones gelatin manufactures in Europe have never used UK bones, but when BSE in the UK became evident, they confirmed immediately in writing not to use UK bones. After the condition of BSE to humans was detected, the GME members committed themselves to stop the use of skull bones, the target which was reached in 1997. This was further followed by the complete removal of spinal cord by European meat packers only on request of the European gelatin industry.

In parallel, our industry started to replace European bones to a certain extent by imported bone chips, mainly from the United States, but also from other countries outside Europe. In 1999, the European gelatin industry was able to convince its suppliers to remove vertebrae from bovine bones of all ages, which again was more than European law required.

Next slide, please. As I stated before, on top of our European sourcing of our demand for bovine bones can only be covered with additional imports from different countries. So we always force our suppliers in GBR II countries to voluntarily take measures in order to increase the safety of our raw materials. GBR II country means that there are so far no BSE case detected and the European has assessed that it is unlikely that there will be a case, but it cannot be excluded.

The U.S. is and Canada has been until recently GBR II countries. Together with our American colleagues, we implemented the removal of spinal cord, also in the U.S., and one year before we succeeded in doing so in Europe, we had forced our suppliers in India, Pakistan, Nigeria to remove the vertebrae as a precautionary measure.

Next slide, please. Most of the measures which we had already implemented became mandatory by regulation in Europe some years later. On top came the postmortem rapid testing of all cattle older than 30 months. Furthermore, the removal of vertebrae as requested now by law only for animals older than 12 months, but again in the bones we use in Europe, there are no vertebrae in at all. So in practice, the vertebrae is removed from all cattle in the European Union if the bones are intended to be supplied to the gelatin industry.

I assume that you are aware of all those regulations presented to you, I think, by Dr. David Asher in February of this year. With gelatin regulations, the EU fixed raw material sourcing conditions and certain safety relevant procedures to all kinds of food grade gelatin. This has been presented to this Committee two years ago by my colleague, Dr. Scheigas. Those requirements are in line with the new study conditions, and our regular intervals controlled by public veterinarians responsible for the supervision of our plants, although the FDA has made audits to the gelatin bone manufacturers in Europe two years ago, they went to all plants.

Next slide, please. Because of the steps taken by the industry, there was always only a very little chance that BSE infectivity could be present in the raw materials used to produce bovine-origin. To date, due to additional more recently implemented controls like the postmortem BSE testing and the careful removal of all SRM, it is almost impossible for highly infected material to enter our supply chain.

Next slide, please. As with any process and systems, there is a certain possibility of error. What could happen, for example, animals with very low infectivity might not be detected by the rapid BSE test. But they are considered today as to posting no risk to human health. The surveillance systems in place might not be adequate in all countries. The removal of SRM may not be done perfectly. The infectivity of bone marrow has not been finally clarified. Based on our experience, we believe that those risks are low, but they are not negligible. They will be quantified by the Scientific Steering Committee of the European Union and then used in the coagulation of the quantitative risk assessment, which is currently under development.

Next slide, please. Last year, more than 9 million normal slaughtered animals were tested on BSE within the whole European Union, including the UK. And 287 positive cases were found, which gives a ratio of 1 to 50,000. But our tests which had been done and our study has assumed that all animals used were clinically infective. Supposing that the removal of SRM is not effected perfectly and that those impurities may not be detected by the gelatin industry when inspecting the incoming fresh bones, some might enter the process. Again, our tests and our study have assumed that the bones from all animals contained the food quantity of infective spinal cord and dorsal root ganglia. Well, this gives a huge safety margin between the study conditions and reality.

Next slide, please. Here again, the major production steps applied during the commercial and the study manufacturing processes, most of them have already been described by Dr. Dunn. All plants in Europe are ISO 9000 certified for the quality management and they apply the HACCP principles. The combination of those is about equivalent to GMP. FDA audits have been successfully conducted in all European bone gelatin operations two years ago. And a further round of audits is scheduled for the end of August and early September this year.

It has to be noted that SGS and independent institute specialized in quality certification carried out a validation audit. And each of the bone gelatin plants of GME in Europe and there are no known GME bone gelatin plants in Europe, and by these inspections all processed parameters of our study design have been validated against minimum production conditions in place in those plants.

Just to clarify what this means, minimum conditions. In certain plants, for example, a higher concentration of the hydrochloric acid or a longer liming time might be applied by one or the other manufacturer compared to the conditions of this study. But we used in our study the minimum conditions applied at least by all manufacturers.

Next slide, please. One of the differences in Europe compared with the rest of the world is the fact that in Europe bone gelatin manufacturers have their own bone degreasing plants. In other countries, like the U.S., degreasing is part of the meat packers work. In the Far East, for example, it is effected by independent specialized companies. As mentioned before, only bones from healthy slaughtered animals released for human consumption following audit and postmortem inspection are collected from the meat processors, who do then later the deboning of the carcasses.

In the U.S., slaughtering and deboning is done normally at the same premises. In Europe, we have very often different locations. So this means that the carcasses of the animals are transported to a sausage manufacturer, to a meat packer at a different place and during this transport, the bones are still with the carcass. Only the SRM, the spinal cord, the heads are gone, spinal cord is out, but the bones are still with the meat.

The incoming uncrushed bones are then inspected by the gelatin industry on sorting belts for extraneous materials, including potential SRM contamination. Then the bones are crushed to small chips of about 5/8^ths of an inch, this fingernail size. Then the bones -- this means after crushing that we have a big surface. And for example, with the hollow long bones the inside would as well become an outside.

These small bone particles are then degreased by hot water in a continuous flow process at approximately 185 degree fahrenheit of an average period of about 20 minutes in equipment with high education. This mix of water, temperature and movement separates fat and soft tissue from the solid bone particles. The little ones are then separated by sieves and cyclones, dried with hot air, but the surface temperature of the bone particles will stay below 150 degrees fahrenheit to avoid degradation. Then they are sieved to remove fine particles and stored in silos.

Next slide, please. Demineralization to remove the phosphates from the bones is carried out at the same conditions like in the U.S. in a conduct current system. The total treatment is about 4 days with hydrochloric acid of 4 percent. The remaining protein matrix of the bones is called ossein.

Next slide, please. To cut the cross veins of the collagen acid or alkaline can be applied. This was addressed just before. For a small portion of the total bovine bone gelatin production, it is about 2 to 3 percent for special pharmaceutical soft gel capsules. The ossein is treated again for 24 hours with sulfuric acid at the low pH and after some washes, the gelatin can be extracted at a pH between 2 and 3.

So standard bovine bone gelatin is normally extracted at a pH between 6 and 7. And the ossein is treated before the saturated or over saturated lime solution for at least 20 days. As you have heard, the pH of this lime solution, which is replaced several times during the process, is around pH 12.5.

Next slide, please. To make sure that acid bone will be as safe as lime bone, our industry looked into an alternative process which would include an alkaline pretreatment, but without working the special physical and chemical properties of this pharmaceutical as in bone gelatin. Based on the knowledge that after the bones are crushed potential infectivity would sit on the surface of the bones and not inside the bone matrix, we assumed that a short time treatment of about 2 hours with .3 molar sodium hydroxide solution should be enough to inactivate infectivity if this pH is kept at 13 for this time.

Our study results have shown that this treatment is very effective. But our study has also shown that gelatin made by the traditional acid bone process did not show any detectable remaining infectivity, which means there is a demand for this type of gelatin is still very rare. You've heard that we are depending, of course, on our suppliers to do it or not to do it.

Next slide, please. During extraction of the pretreated raw material, several single extracts are collected, each with different physical properties due to an ongoing hydrolysis during the extraction. It has to be stated that due to the different requirements of the gelatin using industry, quite often photographic, pharmaceutical and food grade gelatins manufactured from the same raw material batch in sequence. Also, Eastman-Kodak is manufacturing some pharmaceutical and some food grade gelatin.

This means that all gelatin of one production day, including the photographic gelatin, have to comply with the regulatory requirements for food and pharma. When talking about food and pharma, one has to keep in mind, as well, that the same capsules might be filled today with nutritional products, being food, and tomorrow with Rx drugs.

Next slide, please. For further clarification, the diluted gelatin solution is filtered by different types of equipment and filter media in the ossein and ion-exchange columns and concentrated in the apparatus.

Next slide, please. So final concentrated gelatin solution is sterilized by direct steam injection. The temperature is at 4 bar. The pressure in the liquid phase, which is very important, is a minimum of 280 degree fahrenheit and the temperature stays for at least 4 seconds.

Next slide, please. Finally, the sterilized gelatin solution is chilled to set and then dried with purified and conditioned air on belt dryers. Each production batch, which is a single extract, is then tested on physical, chemical and bacteriological properties. According to customer specification, different production batches are then dry blended. The final blends are again tested under compliance with regulatory and customer requirements and then released for shipment. These are the common processes applied by the European industry.

Next slide, please. There is one special process which is done by only one company in Europe to manufacture gelatin with low gelling strength for limited applications. The degreasing is done of the bones in the common way, but then the bone chips are autoclaved for at least 20 minutes under 3 bar pressure and 270 degree fahrenheit. After the autoclaving, bone chips are rinsed with salt water. A certain quantity of gelatin goes into solution.

After this gelatin solution is taken out, autoclaving at lower temperature and shorter time is repeated several times. Then these different extracts are collected, flocculated, ion-exchanged and evaporated, drying, testing, blending, retesting and shipping is effected, like with all other gelatins. Low gelling strengths, the gelatin is used only for certain applications, and the Committee members might remember that two years ago at this meeting, we already explained that the main application is a confectionery licorice, although this process has been successfully simulated during our study.

Next slide, please. What are the conclusions which we have drawn from this review presented here? So commercial mineral manufacturing conditions are reflected by the GME study conditions. The GME plants and process parameters have been validated for conformity against the study design. The inactivation results of the study, which will be presented next, are therefore fully applicable to the practical gelatin manufacturing processes. The study demonstrates the ability of the gelatin manufacturing process to remove and inactivate infectivity even under conditions in which raw material contain unrealistically high infectivity levels.

Last slide, please. So safety of European bone bovine gelatin is established on two principles. The safety of the raw material as required by GME practices and EU law and the safety of our manufacturing processes as demonstrated by the GME study. The Scientific Steering Committee of the European Union has concluded based on all these principles, in it's opinion, on the safety of gelatin that the risk is close to zero.

Madam Chairman, Committee, that concludes my presentation. I would like to thank you and the Committee for your attention. Thank you.

CHAIR PRIOLA: Okay. Thank you, Mr. Schrieber. Are there any questions? Okay. Thank you very much. Our schedule says there is a break, I believe, after Mr. Schrieber, so we can adjourn and return at 10:00, so that's about 15 minutes from now. All right. Thank you.

(Whereupon, at 9:42 a.m. a recess until 10:03 a.m.)

SECRETARY FREAS: We're going to go ahead and resume the meeting.

CHAIR PRIOLA: Okay. I would like to go ahead and get started. Dr. Hogan had a question for our last speaker, Dr. Schrieber, that he would like the Committee to hear the answer to. So, Dr. Hogan, do you want to?

BOARD MEMBER HOGAN: Mr. Schrieber, I asked just after our last talk about how the meat processors were audited, in terms of providing safety of the raw materials to the gelatin manufacturers. Could you address that, Mr. Schrieber, please?

MR. SCHRIEBER: Surely. The standard procedure in Europe is that in every slaughter house, every meat packing operation there is a public vet present all time, every day as long as this operation works to supervise that regulation is followed, removal of SRM is done and so on. And besides this, the gelatin manufacturer are auditing their suppliers on a regular basis, normally once a month or every two months, again inspecting as well the commercial documents about where the animals have been sourced, because commercial document which is required as well by law. So there's a double-fold. But the main thing is that the public vet is present all day, all the time. Thank you.

CHAIR PRIOLA: Okay. Thank you, Mr. Schrieber. We'll go on to our first speaker for this later morning session. That's Dr. Robert Somerville, who is going to discuss the GME validation studies on bone gelatin.

DR. SOMERVILLE: Okay. Thank you, Madam Chairman. It's a pleasure to be back in the USA where I've spent quite a few happy years working a couple of decades ago. My task is to describe to you the actual validation studies that were performed in three labs actually over several years. There were several people involved and I want to mention them. First, Ad Grobben is perhaps the most important one of them all, because he, as an employee of gelatin, which was a member of GME, actually performed or was participating in all three studies in Edinburgh, in Holland and here in the USA in Baltimore.

Phil Steele, actually I should say that, I know a consultant to GME and is present in the audience and I hope will assist in any different questions you might ask me later on. Phil Steele is a technician in my group and he assisted at not only in the work he did in Edinburgh, but also in Holland to assist in the experiments there.

David Taylor was my predecessor in running the inactivation group, and he initiated the studies that we're about to describe and collaborated in setting up the whole thing. He again is here in the audience. I inherited the work from David and responsibility for the work when David retired in 2000, so it's my duty to report the results, but all the hard work was done before that.

The work I'm specifically going to concentrate is on the Neuropathogenesis Unit, which is part of the Institute for Animal Health in Edinburgh. It was funded by GME with further support from the European Union. I should also say that at the end of my presentation, I suggested that Bob Rohwer, who performed the Baltimore studies, spend a few minutes describing the work that was done in Baltimore.

The next slide, please. I thought it would be helpful to describe the basic mechanisms of TSE inactivation first, and there are three ways in which inactivation or removal can take place. The first is through some form of destruction through combustion, incineration, oxidation with hypochlorite, hydrolysis of extreme pHs or with very high concentrations of highly effected proteases and radiation can have an affect at very high doses.

Next section, please. What possibly concerns us mainly today is denaturation type of processes where materials hydrated, in particular, will have a degree of inactivation effect and exposure to chemicals, such as strong detergents or chaotropes, can also have an effect.

Next. And we have to look at treatment variables. There are several biological parameters that we must consider. The strain of the TSE agent is particularly important and I will illustrate that in a couple of slides time. The PrP genotype may well be important, and we have to consider that. The tissue and the state in which the tissue is presented in the experiment are also important. We have to consider physicochemical parameters such as heat temperature, pH and the kind of chemicals that one uses. And finally, the dynamics and kinetics of the reaction have to be considered, the time, concentration of any chemicals involved and the temperature are particularly critical.

Next. Okay. This shows a slide of some data that was originally published in 1983 by Kimberlin, et al, where TSE infectivity from two TSE strains was heated for various lengths of time shown on the axis. On the Y axis is the titre that was recovered after these treatments. Two strains were used, as I say the 22A strains and the 139A strain, and you can see that there is a lot of rapid reduction in the amount of infectivity present, first. Then a plateau. So the reaction is biphasic with respect to time, and there is little effect of time after initial exposure.

The second point to notice is that was a strain difference, so the 22A strain on this particular example is much more resistent to an activation than the 139A strain.

Next. Now, in this slide, we're looking at what happens when we heat at a constant time, 30 minutes, with a range of temperatures, and what we can see here is that there is little reduction in infectivity to start off with until we reach an inflection point, and then the amount of infectivity drops rather rapidly, and that happens for both the TSE strains that we're looking at here. But you can see that the inflection point for these two strains differs, so that for 22C, it's rather thermolabile, which might be a surprise to some. In fact, this temperature which starts to inactivate is only about 70 to 75 degrees centigrade.

With 22A it's higher, about 97 degrees. But we haven't specifically done experiments comparable to this BSE or BSE derived strains, although I'm hoping to do them in the near future. But from the data that we have available, we think that BSE derived strains are even more resistent to inactivation than the 22A strain here in red, which is the more thermostable of the ones we have seen. So we can say the inactivation process is biphasic with respect to temperature and dependent on temperature. TSE strain, and I mentioned the hydration state, and I'll come on to that in one moment.

Next slide. Okay. This slide shows the effect of hitting again at 126 degrees centigrade for 30 minutes autoclave, three strains of TSE, and you can see with the 22C strain that all infectivity shown in red has been destroyed. The blue shows the starting titres. The two different blue bands are indicative of two different PrP genotypes that the TSE strains were passaged in, and there is no effective PrP genotype in this experiment available.

With ME7, we cover both the types, a little infectivity, but with 301V, we cover a lot more. Now, 301V is important to the rest of this talk. 301V is the most thermostable TSE strain that has been derived from the passage of BSE through a particular strain of mice, the VM strain of mice. And it has certain advantages to these studies. Notably, it is very high thermostability, and that makes it a greater challenge to the studies that we are performing.

On the right hand side of the panel, you can see a different experiment where material was heated in a dry oven to 200 degrees centigrade for either 20 minutes or 60 minutes. And I think the contrast between what happened in the autoclave and the dry oven is really quite remarkable. We get much less reduction in infectivity and we've lost our strain differentiation. So there's no strain difference in the results. And also material survives the dry oven much better than it does in the autoclave. So that emphasized the point about hydration status. I think if we dry out infectivity, we make it much more resistent to inactivation.

Can I have the next one? Okay. This is an experiment where we have combined temperature treatments with a range of pHs. I don't suppose you can read this, but each line represents a different pH from pH 7 up to pH 12 with three strains of TSE again, 301V, ME7 and 22C. And the point is to say that with 301V, in particular, we got very little reduction in the amount of infectivity up to 100 degrees. Certainly up to pH of 11.

We didn't measure what happened at pHs greater than 11, whether we were getting any reduction infectivity at pH 12 up to 100 degrees, but at 60 and below there was very little reduction in the amount of infectivity recovered there. You do start to see, in effect, that pH 12 with the more thermolabile strains ME7 and 22C. So the suggestion is that high pH acts synergistically with temperature when TSEs are inactivated.

Can I have the next slide, please? So on the left you can see a list of the things that I have been showing on all previous, three or four slides, and results and conclusions. Thermostability is an intrinsic property of TSE agents developed to kinetic mother which I'm not going into today, and so forget about the rest. Thank you.

Next slide. Okay. I want to move on now to reduction of risk of TSE infectivity in gelatin. The challenges that we face, there is very high resistent to inactivation, and the resistance increases on drying up infectivity. There are several available approaches. We can remove by filtration, for example. We can denature with heat and high pH or we can use at very high pH, we can get hydrolysis of infectivity.

Looking specifically at the risk reduction steps that are available in gelatin manufacturing, the sourcing of bones, which Mr. Schrieber has just described, is important as practices in precleaning the raw materials. I'm not going to discuss this. The standard gelatin extraction methods are thought, were thought to be effective, and that is what the valid study of it we've been involved in is designed to test. And then the sterilization steps are steps which may specifically move TSE infectivity and, of course, other contaminants.

Next slide. Now, this slide shows the results from the very first studies that were performed in the gelatin manufacturing process. What was done by Inveresk was to take any 7 grain homogenate and look at two components of the process, either treating with hydrochloric acid, the liming step or the combination of the two. The reduction in titre after exposure to the hydrochloric acid was about 1 log, 1.2 was measured. So that's 10-fold roughly.

Exposure to lime for 20, 45 or 60 days resulted in a reduction in titre of about 2 to 2.3 logs. And you can see that even after 60 days, these values are very similar. So there was a small reduction of about 100-fold, but the time of exposure had new extra effects. And the combined treatment results in the reduction of nearly 3 logs, but you can see that adding these two values together does not come to 2.8. So there isn't complimentary effect, but the treatments are not completely out of it.

Can you give me that slide, please? So there is a reduction in infectivity titre measured by the acid and alkali in combined treatment of any 7 homogenate. The combined treatment is more effective than either single treatment, but they are not titre, and time of exposure to costs in hydroxide does not effect infectivity titre. And these processes were not representative of the actual process involved in the plant.

There is another study by Manske, et al, which showed that there was removal of proteins under industrial degreasing conditions. These initial studies led to the desire for more systematic studies to be performed.

Next slide, please. As I've already indicated, there was several experiments performed. In Edinburgh we performed four experiments, two alkaline treatments using two TSE strains, the 301V strain, which I have described, also the 263K strain, which is a hamster-facade strain, which we believe is reasonably thermostable, but may not be quite as thermostable as 301V.

We also looked at an acid process and we tested the addition of an NaOH treatment in the acid process. Mr. Schrieber has described the Dutch heat and pressure method and an experiment was performed in the Netherlands to look at that process. And as I say, Bob Rohwer will describe the sterilization filtration experiments later.

Next slide. Okay. The rational of the experimental design. The TSE source is a high titre BSE derived model. It's thermostable. It's readily assayed in experimental mice. We feel that the total titre is a likely BSE contamination event during industrial processing the gelatin, as Mr. Schrieber has already suggested. Short incubation periods, but we have to be aware that we occasionally see very extended incubation periods after heat treatments. And so we kept the mice under observation for up to 600 days.

The limits of detection depend on concentration of the sample and the toxicity of the sample. We cannot inject material that is toxic, obviously, to the mice. So sometimes dilution factors had to be included so that we could inject the mice and not limit the clearance levels that we can measure. However, we feel that near optimum demonstrate clearance levels are demonstrated from this model.

The scaled down to simulate typical gelatin manufacturing conditions was performed by Ad Grobben from earlier and that was reviewed by an international panel prior to initiation, and as already indicated, Ad Grobben is here to answer specific questions on that matter. And the quality of gelatin was checked as the experiments proceeded and again I can address those questions.

Next slide. Okay. So this is what was done. The raw materials were 1.5 kilograms of fresh crushed bones and 500 grams of intact calf backbone, spiked with approximately 10 grams of TSE infected grain homogenate. Half this back was injected into the spinal column and the remainder smeared onto bones and dried onto the surface, and the backbone was then sawed into pieces. There was a degreasing process where the bone chips were washing at 85 degrees centigrade to remove soft tissue and fat after the spike had been added, and then dried in the hot air at 120 degrees centigrade.

Then the demineralization step was performed. The bones were soaked in hydrochloric acids of increasing concentrations. The ossein, of course, remains as already described. Then the liming process, the ossein was exposed to saturated calcium hydroxide of pH 12.5 for the minimum of three weeks, and then neutralized. On the acid treatment left over night, also a pH 3 and then washed in water. The NaOH treatment, which is included in the acid experiment, one acid experiment, the ossein was exposed to .3 molars of sodium hydroxide pH 13 for two hours.

Then the extraction process ossein was stirred gently with water at temperatures from 60 to 90 degrees to a final gelatin concentration of 2.8 percent. And then purification steps were performed, depth filtration, ion-exchange, heat sterilization and drying, and all steps were designed to accurately represent the conditions of the industrial process.

And it should be pointed out that in the larger process we used indirect heating, but in the industrial skill process, of course, direct steam injection is used.

Could I have the next slide? Okay. The spike, as I've already indicated, we use the 301V strain in three of the four experiments, and we use it because it is the most thermostable TSE strain tested so far, and it also is BSE derived. We actually titrated the spike on three separate occasions. We actually had two spikes, Pool 1 and Pool 2, and you can see the values are very similar in all three titrations that we performed with a value of about 7.7 in each case.

And as I've already mentioned, all clinically negative animals were observed for at least 600 days, and then we examined the brains for any evidence of pathological lesions of TSE infection afterwards. And all positive clinical cases were confirmed by pathological examination.

Next slide. Okay. Some results. So this is the first experiment where the bone was spiked with 301V. The steps were performed degreasing, demineralization and DCP, the dicalcium phosphate, which is a byproduct of the gelatin manufacturing process, was also tested for residual infectivity and we find little. The extract sample after the liming initialization extraction had a little bit of infectivity here, and you can see the individual numbers on the left, and that calculates, according to the Carver Method, to titre of less than or equal to 10^1.8 ID₅₀ per mil.

I say less than or equal to, because if you use the Carver Method, you have to make it -- and you've got incomplete groups at either end of your dilution series, you have to make assumptions about what happened in that group. So we don't have a 10⁺¹ group, but we assume to get the number 1.8 that that value, all the mice would have gone down the 10⁺¹ dilution. So the number over here is the total recovery calculated against the 10 gram spike that was used. So we got from total infective load to 10^8.7 to total recovery of 10.5.

Then the sample was taken through the filtration ion-exchange in concentration steps and the sterilization steps, and a sample was then also measured for infectivity, and no infectivity at all was recovered. And in this case, what these data say is that we couldn't detect anything. We don't know what would have happened if we had been able to inject a more concentrated sample again. So again, we can only say this is the limit of the clearance that we have achieved. So the total recovery is less than 10^3.8 starting with the 10^8.7.

Okay, next slide, please. Okay. So this is the second experiment in the alkaline process where we used the other strain, 263K, and I will go through this a bit quicker. The total infective load is 10⁹. We recovered a little infectivity again and the DCP, the dicalcium phosphate, and we also recovered a little bit of infectivity in the extract sample totaling out to a total recovery of less than or equal to 10^4.3.

Next slide. The acid process here we again had a spike which had a total infectivity of 10^8.8 and following the steps of degreasing, demineralization, then the acid treatment and extraction we had a recovery of infectivity of 10^6.2. In this case, we got a clear end point to the experiment, because the neat fraction, all the animals came down to 10^-2, none did, so a nice, neat Carver calculation of 10^6.2.

After the filtration, ionization, concentration, sterilization steps no infectivity was recovered and we can say that is less than or equal to 10⁴ logs of infectivity were recovered.

Next slide. Okay. Now, this is the variation on the acid treatment where the sodium hydroxide step was included after the acid treatment had been performed. And when this was done, we find that no infectivity at all was recovered in the titration and we can calculate total recovery of less than or equal to the 10^3.3.

Next slide. Okay. Looking at the data across the way, that's the first alkaline process and you can see it went from 8.7 to less than 5 down to 3.8 with no positives.

Next. Next? Oh, there we go. Thank you. And this is the alkaline process with 263K, and now you can compare the numbers directly with each other. So we start off with slightly higher spiked titre and slightly lower recovery of infectivity at this point on the crude gelatin extract.

Next. And next again. And with the two acid process experiments, we start off with the spike of 8.8, 8.7. We recover a little bit more infectivity than in the alkaline process at the crude gelatin extract, but again when we look at the purified material, no infectivity is recovered and we can, as I already said, indicate the clearance values from that part of the process. And you can see now that the acid process with the included NaOH treatment in here resulted in no infectivity being recovered.

Next. So this summarizes the data and now I have included on the right hand side the clearance factors that have been obtained from the experiment. So we can say that the alkaline process, the crude gelatin extracts have a clearance of greater than 3.7, logs of infectivity and for the 263K experiment it was greater than or equal to 4.7. The finishing, the purification and sterilization steps have additional clearance factors that we have demonstrated of greater than 1.2 and that totals over the two parts of the process to greater than or equal to 4.9.

In the acid process, we got a clearance from the -- in the crude gelatin extract of 2.6. The sterilized gelatin after finishing has got an additional demonstrated clearance of greater than 2.2 and adding that together, we've demonstrated a clearance for greater than or equal to 4.8. And then in the acid process with the additional NaOH treatment, the overall clearance demonstrated is a value of greater than or equal to 5.4 logs of infectivity.

Next. Okay. So that summarizes what we have. From the acid bone process, we have got substantial infectivity measured before purification in the third experiment, but complete appearance after -- complete clearance after purification, including sterilization. Complete clearance, no infectivity detected before purification if an additional sodium hydroxide step is included.

With the alkaline process, there is greater removal of infectivity than after equivalent acid hydrolysis procedure and there was complete clearance. No infectivity detected after purification, including sterilization.

Next. So our conclusions are that the gelatin manufacturing procedure was successfully scaled down and normal bone gelatin was produced. Both degreasing and the standard acid and alkaline treatments alone remove most, but not all, of the implied infectivity before final purification of gelatin. The liming or alkaline procedure was more effective and the additional sodium hydroxide step in the acid procedure inactivates a residual detectable infectivity before purification. After purification, all samples do not show any detectable infectivity. And again, this was pointing out the removal of infectivity is cumulative, but not necessarily additive.

Okay. I want to move on to report the data obtained by the Dutch experiment where they applied pressure treatment to produce their gelatin. They started off with titre of their spike, total titre of 9.2. They went through the standard procedures of degreasing and preheating, then did the pressure treatment at 3 bar, 20 minutes, 130 degrees centigrade, then extracted the gelatin. In the crude gelatin extract, they showed that no infectivity could be recovered, and the volume that comes to is less than or equal to 0.2.

So they record a clearance factor of greater than or equal to 6.8 with this process. They did nothing -- well, they didn't follow this, the purification steps. They didn't test that, but there was no infectivity in the gelatin solution that would have come through this procedure anyway, so it would have been a waste of time.

Next. So risk reduction and gelatin. We've had several descriptions of this already in the earlier session about sourcing using only animals passed fit for human consumption, omission of head bones and vertebrae from source material in BSE infected countries, and we have shown the removal or inactivation steps or removal of TSE infectivity during the gelatin extraction and purification process.

It's also worth noting that the species barrier would reduce the effect of titre or BSE being -- if humans were exposed to BSE from the source. It is worth also noting that the acids were performed by injection intracerebrally, and this is by far the most efficient route of infection, other routes of infection are less efficient.

Next. I'll skip that. That's it. Okay. Thank you very much.

CHAIR PRIOLA: Are there any questions for Dr. Somerville? Dr. Bailar?

BOARD MEMBER BAILAR: I have a couple of related questions. First, I find the time deactivation curves somewhat troubling. They suggest that some of the infected agent is being protected somehow. What is your take on that?

MR. SOMERVILLE: Exactly that. That there is -- I didn't want to get too much into the fundamental thoughts that I'm having at the moment about that, but I think we're getting a dissociation reaction and a protective reaction occurring when inactivation, heat inactivation is attempted. And the protected species that is formed or the stabilized species is much more difficult to inactivate. It may be similar to the dried material that I was showing in some of the earlier slides, too, and that we know is much more difficult to inactivate.

BOARD MEMBER BAILAR: Well, there are at least a couple of other possible explanations.

MR. SOMERVILLE: Sure.

BOARD MEMBER BAILAR: One is that some of the agents being protected inside little particles. There many be subtle differences in the chemical structure of the ones that survive versus those that don't. Which leads me to my second question. In the intact animal, the infection occurs while the animal is alive. It gets circulated and I would presume gets distributed throughout all the tissues and whatever titre is appropriate for that. In the experiment, the infective agent was added to the bone chips, that is at a considerably later stage of things, where it might be more on the surface of any particles that remain or it might stay on particles and so forth. So I'm asking if you have looked into this, and if there is any reason for concern about this difference in the sequence of when the infection is added to the materials that you are processing.

MR. SOMERVILLE: Well, let me answer this, your question this way. I don't know if it actually addresses what you are saying. But the reason for doing the experiment the way we did it was to try and maximize the exposure in the experiment. So the thinking was that the greatest risk of BSE contaminating bones was that during the slaughter process, and that spinal cord, for example, would get spread down the vertebrae column included with it and dry onto it. So that was what was attempted to be mimicked in the experiment.

I'm not -- I suppose the other side of the question is how much infectivity in living animals associated with bone and bone related tissue? Our primary concerns in that respect again is to do with spinal cord in BSE infected cattle with spinal cord and ganglia and related nerves and, of course, the brain in the skull. These should be removed, and again we're asking the question what happens if they don't, and we've tried to include that kind of thought in the design of the spiking of the experiment.

BOARD MEMBER BAILAR: Have you tried to grow out the infective agent that survives the steps for 20, 40, 60 minutes to see if it remains highly resistent?

DR. SOMERVILLE: No, not formally. It's an experiment I want to do, obviously, but I haven't formed it. I don't think -- David Taylor whether he has actually done that experiment, either. My prediction is that it would not be in the protected form after passage through an animal, but we have to do the experiment. Thank you.

CHAIR PRIOLA: Dr. Petteway?

DR. PETTEWAY: Thanks. I just have a couple of questions about the process of doing the studies and setting them up. Just to make sure I understand, these were scaled down, coupled steps, so that the spike was at the initial step and then removal was monitored throughout the process without respiking it each additional step, correct?

DR. SOMERVILLE: That's right. Yes, that's correct.

DR. PETTEWAY: Okay.

DR. SOMERVILLE: I think the experiments that Dr. Rohwer will describe are looking at process of the final steps in the process with spiking at the beginning of those individual steps.

DR. PETTEWAY: Exactly. So that your final removal shows the cumulative effect of the process to remove the input spike.

DR. SOMERVILLE: Yes, yes.

DR. PETTEWAY: I have one other question and that's with the magnitude of the clearance numbers.

DR. SOMERVILLE: Yes.

DR. PETTEWAY: And the less than or equal to or greater than or equal to. The magnitude reflects the limit of detection of the assay.

DR. SOMERVILLE: Precisely.

DR. PETTEWAY: As opposed to what may actually be the magnitude of removal. The magnitude of removal is likely to be much greater than the numbers reflect, because of the limit of detection of the assay, right?

DR. SOMERVILLE: Basically, yes. We can only report what we observe.

DR. PETTEWAY: Right.

DR. SOMERVILLE: But we can also make some predictions about what we know from other parts of the process.

DR. PETTEWAY: Right.

DR. SOMERVILLE: And that is why, as you've said it before, it's important not only to look at the overall process, but to look at individual steps and evaluate what they may be contributing to the inactivation process or removal process. However, as the study illustrated, for example, we also have to be aware that individual steps will not be additive and that one part of the process may remove the same thing as a later part, later stage might also remove, so you have to be very careful when you're doing that.

DR. PETTEWAY: But we can be confident in the linking of these studies that based on the input spike that there was no detectable infectivity based on the limited detection of the assay at the end of the process?

DR. SOMERVILLE: Yes, yes.

DR. PETTEWAY: And then the last question I have is the additional step with the sodium hydroxide. That was evaluated independently?

DR. SOMERVILLE: What? It was a separate experiment, if that's what you mean.

DR. PETTEWAY: Yes, that was a separate experiment?

DR. SOMERVILLE: Yes.

DR. PETTEWAY: Evaluated independently. Okay.

DR. SOMERVILLE: Right.

DR. PETTEWAY: Thanks.

CHAIR PRIOLA: Dr. Hogan?

BOARD MEMBER HOGAN: Very nice studies, Bob. I had a question on when you are calculating the clearance factor here, you've listed an equation that says clearance factor is equal to gram spike times 10 the log titre spike divided by milliliters of gelatin times correct factor times 10 to the log titre reduction or gelatin. For somebody that can't balance their checkbook, what do you mean by correction factor in the denominator and why was that entered?

DR. SOMERVILLE: Okay. The correction factors are to account for the inherent losses in the process by taking a sample out for intermediate titration or other evaluations. So there is natural loss in the amounts going through the process. Does that deal with that?

BOARD MEMBER HOGAN: Yes, that's great and it makes good sense. The second question is did you look at any place in the process where titre might have accumulated or concentrated, such as inner vessels or on any of the columns or anything like that?

DR. SOMERVILLE: I think the short answer is no. Unless Dr. Grobben would like to comment on that. But as far as I'm aware, there was no specific attempt to evaluate that.

MR. GROBBEN: I do want to. I would like to comment to that, I think. No attempt was done to try to measure the infectivity which remains in the equipment, especially for filtration and ion-exchange, because of the problem to extract that infectivity from that equipment, so that was not done. We just measured what was left in the gelatin.

CHAIR PRIOLA: Go ahead.

BOARD MEMBER HOGAN: That's what I presumed. It's just very difficult to get that stuff off to measure it regardless. Now, am I to understand that in the gelatin processing process that these filters would be reused batch after batch or are new filters introduced in the manufacturing process either in Europe or the United States?

MR. SCHRIEBER: May I answer this. There is no reuse. It's a one time use. It may be the answer as well as with the ion-exchange columns. They are regenerated with either alkaline or assay to purify for the next round of ion-exchange. So there is a constant chemical treatment after the gelatin has passed those columns.

CHAIR PRIOLA: Okay. If there are no further questions, we'll move on. Thank you very much, Dr. Somerville, and Dr. Rohwer is going to present some data.

DR. ROHWER: Can we go to the next slide, the first slide here or do I control it? Are you controlling it or am I? Where is it here? Oh. Yes, please, go to the first slide. Thanks. The gelatin manufacturing process is a diverse one. It has many generic features like the contractionation for plasma, at least I see it that way having worked in both areas. So they needed a protocol representing as much of their collective production as possible. And the steps that we were asked to validate in our laboratory were on bone gelatin.

Next. And we used the process parameters that were selected by GME, their scale down and this took a lot of time setting this up. Ad Grobben deserves a lot of credit for this, as was mentioned. And from our end, our major concern was about hazard control, and we spent quite a bit of time on this as well. We did this study at a scale that was much larger than we typically use in the laboratory. We were using meters and liters instead of 100 mls at a time and some of these steps did not fit easily into the valid safety cabinets and that type of thing, so we had to figure out other ways to do them. But in the end, we were successful and it worked without a hitch when we finally got down to doing it.

Next. The filtrations, the way this was done is we tested several different types of filtrations that are used across the industry and then pulled the filtrates, and that's what was actually titred. I'll show you that in a moment. And getting them all done though it took quite a lot of time, because of the scale and the precautions we had to take to do it safely.

Also, all of the work that is done with gelatin has this complication that it is only liquid above 50 degrees centigrade, so you have to keep things warm. You have to keep them warm on a large scale, and so we developed a lot of technologies for doing that, which the tempering beaker turned out to be one of our best tools, but circulating baths and hot pads were also useful.

Next. Next, please. About hazard control, we used safety cabinets, bags to cover everything up during the actual processes. All joints between chromatography column unions and filtration things were -- transfers were covered with plastic sleeves in case they leaked, put things in large pots when we could. We poured nothing. Everything was done by pumping from one vessel to another in a safety cabinet.

Next. We are also concerned about cross-contamination simply because of the scale that we were doing this on and also because of the sensitivity of the results. And as a consequence, all new dedicated equipment was used for these steps. Everything was disposed -- most things were disposable. The only things that weren't were the stainless steel filtration vessels and a couple of other things which could be autoclaved under sodium hydroxide for reuse.

Next. Next, please. We had a question about -- some discussion about the spike earlier, and I think this was a very gratifying experiment for me. We've been trying to figure out whether our spikes are relevant in our plasma studies and that type of thing. But in the case of bone gelatin, the most likely source of infectivity is CNS tissue. And as a consequence, in this particular case, at least we can say that the brain derived spike is probably the most appropriate spike for testing removal from this type of study.

And personally, I think this is the relevant tissue and we can use it with confidence. There are issues about whether 263K or the less adapted BSE strain is more relevant. My feeling is that there are advantages to both. Actually, clinically, hamster 263K looks a lot more like BSE than the less adaptive 301V strain. On the other hand, this is a strain that was devised from BSE and so we use that as well. The important thing is when you do two different strains, is what you're looking for is the point of convergence between the two to give you some confidence that the result you are getting are generalized more.

Next. The continuous process was done at the Institute for Animal Health, and we are only working on the end stage process right here. Robert has discussed the rest of this. The continuity was maintained by Ad Grobben, who took copious notes, and we also have a lot of further documentation, which I'll share some of that with you in a moment.

Next. So here is the process we have been looking at. This is the part that Robert has been describing right here. Well, actually, they carried it through this stage as well, but the only part of this process that we're going to be dealing with is this part right here at the bottom. The so-called purification steps, the filtration, ion-exchange and UHT sterilization, and we're going to look at step wise removals.

Actually, we're going to gang these two together in one experiment. We're going to look at them independently as well, and we're going to compare the cumulative versus the serial with the individual testing of these two steps. This was done just individually.

Next. Here is the basic layout of these experiments. We have the infectivity spike. It goes into the crude gelatin, which is taken directly from production at the same stage of production. It's passed through the filtration device. And in the filtration experiments, on one arm, we took the filtrates and took it straight through the ion-exchange columns and then titrated it. On another arm, we took it over here and respiked it, figuring that we may have -- hopefully, we had removed something in the filtration.

This spike, at the most, would only double the titre that we started out with here by respiking. If we got any kind of removal here, we're just starting over at this point. And then testing the ion-exchange by itself. We wanted to use this so that we had filtrated material to test the ion-exchange process with.

Next. The filtration steps, in fact, involved five different protocols with various compositions of cellulose, sources of cellulose and formulations depending on different manufacturing setups across the industry. The filtrates from those were all pooled and then they were titrated by themselves before being passed to the ion-exchange column over here or respiked on this arm and passed through the ion-exchange columns here. The ion-exchange consisted of two columns, the cation exchange followed by an anion exchange, and what we assayed was the eluate from both, the final eluate from both.

Next. And then in terms of the UHT sterilization, the ultra high temperature sterilization, we again started with gelatin from production, infected that, spiked that with infectivity and then did the UHT test and titred that. So it's a much simpler pathway.

Next. Next, please. Here is a picture of Ad Grobben setting up the filtration experiments. This is the filter apparatus over here. We're transferring, I believe at this step, we're preheating the filter with hot water that has been heated over here, and I'm not sure that's what we're doing there, but that's what this is doing. This is the hot water. It had to be preheated so that it was warm enough to keep the gelatin melted once we put it in there. We've got another bath heating up the gelatin to dry through the filter.

Next. Here's the filter being assembled. It's quite a large apparatus, compared to what we're used to, but we were able to do all of this within the hood, though the transfers had to be through this pump on the outside. There's the filter A being added.

Next. Here is the filter A being stirred in the filter and then it's drained to form the filter cake in the bottom.

Next. Here is the filtration apparatus setup being done. Here is the vent in case, because you have to vent some air out of it in the early stages, and through HEPA filter here. And here is the assembly after the filtration is over.

Next. This was a keeper in that experiment, and this was a failure. We always inspected the filter cakes after the filtrations to make sure they were intact. There were no possibilities of leaks and that kind of thing before we would keep the filtration as a successful one. And so the only thing that goes into this study were successful filtrations.

Next. Here is a picture of the column apparatus, the ion-exchange apparatus. These were gigantic by our standards. We set them up on a mobile cart on a chromatography rack that we can roll, so that once we got everything setup and ready to go, we could roll the cart over a very large plastic bag and then cover the whole thing in this plastic bag and seal it up during the actual experiment in case there were leaks. Thank God there were none.

Next. And here is the apparatus that we used for the UHT Inactivation Experiment, and I can make that a little clearer in the next slide, which is diagrammatic.

Next. The principles that we are trying to employ in the UHT study that we were trying to mimic from the actual production environment is, from my prospective in studies that I'll talk about later this afternoon, infectivity is not intrinsically resistent. The problem is delivery of the inactivant and the inactivant finding sanctuaries to hide from the steam, and drying is -- drying into a film is one of the biggest problems.

And one of the nice features of the UHT process is the gelatin is being pumped through a pipe in which live steam is being injected. There is no head space. There are no sanctuaries. There is no place for this stuff to dry. There is no place for it to escape from the hydrolytic environment. We wanted to duplicate that as best as we could.

Next. Next, please. So we did that with this apparatus where we filled this stainless steel capillary and we used this capillary so that we could affect a very rapid heating and cooling, because the whole process, the UHT process, is a 4 second exposure to 140 degrees centigrade. So how do you do that in 4 seconds? Well, you have to get the heat to it in a hurry. We didn't try to do it dynamically. We did it statically. But we did it in this way.

So we have this chromatography capillary here. We have a thermocouple, which is embedded in the tube. The probe is right about here. We have another thermocouple on the outside to track what is happening in the bath. And then to relieve any over pressure in the device, we have a water column going here to a back pressure gauge, which ultimately if it were to leak, it would go into this tube right here. And this relieves the hydrostatic pressure that is developed by the fact that we're heating this gelatin up in here. But we've got within the gelatin column itself, we have no head space.

Next. We'll take that and the way we get our rapid heating is through trial and error. We set up a protocol where we can dip this thing, hooked to its various thermocouples, up to this recording device into our 160 degree oil bath and then as we see the temperature hit our target transfer temperature, which was about 80 degrees, we quickly dump it into the 140 degree bath and it comes to equilibrium in the successive period. We then take it from there after 4 seconds has elapsed and dump it into the other temperature. We're tracking this whole thing on the computer. We're watching it in real time as we're doing it.

Next. So we get curves like this. This is seconds down here. This is degrees over here. This is the outside of the capillary tube. So we're seeing the capillary dipped into the 160 degree bath, and here we're seeing the transfer into the 140 degree bath, and we're seeing it come to -- and this is the internal thermocouple and it is coming to temperature very quickly thereafter, and then at 4 seconds we plunge it into the water bath and that's the way there.

Now, what I showed you first was the hamster experiment. We have now advanced to the mouse experiment. And there is one important difference. As we got more and more experienced with this, we were able to get this ramp time down to shorter and shorter periods. We had about 4 seconds on the first one and about 1 second here. We did four or five trials, actually, three in the end we focused on once we got the method working. And then we picked the best of those trials. And what I have shown you is the temperature records for the two best trials for mouse and hamster and that's what got titrated.

Next. Next, please. This is the results of all these experiments. The pooled filtrates gave a very disappointing clearance. I was expecting much higher than that. The respiked column gave this, only about a half log removal, and remember for these types of input titrations, we got about a .3 log error associated with these numbers. The successive filtration and ion-exchange gave about 1.8, which very interestingly, but probably somewhat randomly, is exactly the same as the added values between these two.

But I think it gives us some confidence that putting these things together, even though the removal at each step is low, we are getting some significant removal here of about 1.5 to 2 logs. The UHT sterilization by comparison gave a much better result. Even that 4 second exposure is giving us about 4 logs of removal. Attached to this, we have about 6 logs cumulative. And I think it is legitimate to attach these, because these are quite different methods of removal versus inactivation.

Next. And this is just a comment on that, these things were showing independent removal to the extent that we could detect it with the lower levels that we saw there. But in terms of looking at the total, at what was actually going on there, the serial experiment is actually the best one to use, and that's the one I think we should focus on. But both of these steps were much less effective than I had expected. And I don't know whether it is because of the matrix, the apparatus, the gelatin itself, but in the next slide I'll show you some data.

Next, please. In our experience, this is about half these experiments were done by us. The other half were done by other folks, but they were compiled for a former presentation of the FDA and a TSE Advisory Committee meeting in October 7, 1997. And typically, and we've done more of these since then, especially these depth filtrations, and they are typically removing 3 logs or better.

So there's something different about gelatin. And it's either the way we did the experiment or it could be that the gelatin is so overwhelming in terms of a competitive binder for the matrix that we're not getting removal because of that. But anyway, it doesn't fall into expectation. There is a warning in this though, which says that you have to check these things. You can't extrapolate from this cumulative experience and presume that it's going to work in all cases.

Next. I've already dealt with this. Let's go on. Next, please. I just want to point out that this UHT result is the worst case result. We did it under static conditions. It is heated from the outside instead of the inside. 4 seconds is a minimum exposure that is seen in the industry. And we're using crude brain homogenate instead of material that has been already refined by the process. And my guess is that the stuff that has been through the process may be even more susceptible, but that's a guess.

Next. I want to make one final point and that is that the total exposure that these samples got really begins, at least for sure, with the 263K case, with the 80 degree exposure. I mean, somewhere between 80 and 100 degrees. We have a series of experiments which are actually on the next slide that I did in the '80s showing that we start to see affect around 100 degrees, and we get total killing in a few seconds at 121.

So this ramp temperature is also contributing to the inactivation here. And if we take these ramp temperatures and add it from 100, the ramp exposure plus the exposure temperature for the 263K case and the 301V case and plot them on the same curve, which I'm going to do next.

Next, please. This is just showing you that there is an effect at 100 degrees and above for the 263K case, at least.

Next. These are the ramp times for those former experiments.

Next. Let's go on. Next. I just want to show you this last slide. If you plot the data from the 301V case and the 263K case on the same time axis down here, including these earlier studies out here which were done at 121 versus 140, and plot it back to the origin, you get a straight line through these things. Well, I first draw the line through them. And what that is telling me is two things.

One, there isn't really any significant difference between the sensitivity of these two agents to this process. And two, it gives me some confidence in saying that if you are to extend this process to 10 or 12 minutes, you get another 4 logs or so removal. This is something that should be checked with actual kinetic experiment and kinetic measurements, but it seems to me that this being a minimum is a very -- this 4 seconds being a minimum exposure is a very encouraging feature of this experiment.

Next. In conclusion, the purification steps are removing 4 to 6 logs and the UHT step, in particular, provides a potentially very secure inactivation step. Thank you.

CHAIR PRIOLA: Dr. Bailar?

BOARD MEMBER BAILAR: The next to the last slide you showed the susceptibility to heat over time, and what you had you mentioned the straight line fit, but I didn't see any intermediate points there that could really detect curvature in the line.

DR. ROHWER: No, there isn't. What I'm saying is we're working with the data that I have. And I think I also said at the same time that it would be very nice to do a complete kinetic study on this.

BOARD MEMBER BAILAR: Yes, but I would not conclude from that that it's a straight line.

DR. ROHWER: Oh, I see what you're saying. It may not be. You're right. From here to here, well, from here to here, extrapolation, I don't know. I mean, it's hard. I guess, what would you say? You could have something like that, I guess.

BOARD MEMBER BAILAR: I would say you do not have the evidence on which to detect whether there is any curvature.

DR. ROHWER: Okay. Well, I'll grant you that. And all I'm saying is that this is -- let's put it this way, this data is consistent with a first order process here, with these two samples behaving very, very similarly.

BOARD MEMBER BAILAR: Okay. That's all.

CHAIR PRIOLA: Dr. Petteway?

DR. PETTEWAY: That's a very impressive set of experiments, Bob, especially dealing with the scale down, handling it all. That's an extremely difficult thing to do. But the 4.2 logs, was that the magnitude with some residual infectivity found?

DR. ROHWER: Oh, yes.

DR. PETTEWAY: Okay.

DR. ROHWER: Yes, I mean, we started with 7.5 logs.

DR. PETTEWAY: Yes.

DR. ROHWER: So there's still 3 or 4 logs left.

DR. PETTEWAY: And that was at 4 seconds which is worst case?

DR. ROHWER: Yes.

DR. PETTEWAY: And what you're saying, I mean, even given other points that would show a change in that curve, the likelihood is 8, 10, 12 seconds, there would be nothing left is the point?

DR. ROHWER: I was very interested this morning when Michael Dunn pointed out in his presentation that in North America anyway the typical time is 8 to 16 seconds, as opposed to 4 seconds, and apparently gelatin can tolerate that quite well. If you would like to say something about that? Well, that's up to Sue. Sorry.

CHAIR PRIOLA: Dr. Dunn, do you want to comment on that?

DR. DUNN: Could you say it again?

DR. ROHWER: Yes, if I could repeat that, what I just heard here is that there is apparently no problem extending that time for 8 to 16 seconds.

CHAIR PRIOLA: And Dr. Hogan?

BOARD MEMBER HOGAN: Well, the question is why does the European process use 4 seconds and is there a ramp up time to that or is it just the batch is brought in, zap 4 seconds and then it is taken out?

DR. ROHWER: I would like to defer to Mr. Schrieber, if I could.

CHAIR PRIOLA: Yes, Mr. Schrieber?

MR. SCHRIEBER: What I explained in my presentation already is that we used the softest condition we have found in one of the gelatin plants in Europe. So it's not uncommon to have like in the States a longer temperature or even a somewhat higher, longer time or even somewhat higher temperature, but we had to choose the minimum conditions founded in the three or four studies, and that's what it is. You are right if the time would be expanded to 6 seconds or the temperature would go up to 140 instead of 138, this would not really harm the quality of the gelatin.

CHAIR PRIOLA: All right. If there are no other questions, thank you very much, Bob.

(Applause)

CHAIR PRIOLA: I would just like to say having gone through the bulk of this, these infectivity studies in our rather thick handout, that it is very impressive the work that Drs. Taylor, Somerville, Rohwer, Ad Grobben and Schrieber have done studying inactivation of TSE infectivity through the gelatin processes. It's a lot of real nice work.

I would like now to ask Dr. Morris to come up and explain to us the USDA's gelatin policy.

DR. MORRIS: Okay. Good morning and thank you for the opportunity to speak with your Committee regarding APHIS's policies regarding the importation of gelatin.

COURT REPORTER: Dr. Morris, hit the volume button.

DR. MORRIS: Thank you.

CHAIR PRIOLA: I'm sorry. My apologies. It was supposed to be Dr. Rogers. I'm very sorry. That's my error. Can we just go with that?

DR. ROGERS: Yes.

CHAIR PRIOLA: Okay. My apologies. I'm sorry. You should have told me. I'm misaligned in the agenda. Okay. So, in fact, we're not going to hear from Dr. Morris yet. It's Dr. Rogers who is going to give us a risk analysis of infectivity.

DR. ROGERS: Well, I guess the slide has disappeared for a minute there, so don't start the thing until -- the timer until it shows up. Is the mike on? Okay. Thanks for inviting us down here today from Canada. I'm from Health Canada.

CHAIR PRIOLA: We can't hear.

DR. ROGERS: So is the mike on? Oh, it's on now? Oh, closer. Taller and closer. How's that? Okay. At Health Canada we have been doing a number of quantitative risk assessments and part of our topic today that we will be covering is what's on your agenda. But I did want to say that what we're really looking at is the varying-CJD risk to consumers eating foods containing small amounts of processed ruminant products. And I want to talk about some of our modeling functions.

Next slide, please. We have just completed a quantitative risk assessment for basically products that contain beef extracts and the beef extract industry certainly has a lot of similarities to the gelatin industry, so some of the information I'm going to provide today will certainly with some understanding of the overall picture. I do want to present today like the quantitative model parameters for the evaluation on pairing CJD risks. I want to focus on the front end parameters for risk analysis, and I want to provide some information on evaluating uncertainty in the parameters and provide information on variability that we're using in our models.

Next slide, please. The purpose of our risk assessments are really to provide information on two risk outcomes of the probability of individuals acquiring varying-CJD through the consumption of a product and the annual number of varying-CJD infections that could be predicted.

Next slide, please. The approach that we're using, basically, the first thing that we look at is the length from BSE agent to varying-CJD. To date, there is no direct evidence linking the acquiring of varying-CJD to particular products. And I want to emphasize that certainly the only information we had previously was the work of Simon Cozens of the UK for food products which had some implicated meat pies, sausages, these types of things in his work, but he has, in fact, recalculated his and reevaluated some of that publications and in Edinburgh last year he has, in fact, shown there has been no statistical significance to particular food products and varying-CJD. So that's an important picture.

The presence of the BSE agent in the product of concern are not measurable by our current techniques. The only thing that we can actually still seem to have some type of laboratory analysis for is the presence of CNS materials through IHCGFP and some neuro analyst techniques. The hazard identification basically has established that there is a route from BSE to consumption exists. And so that's the reason for the presentation of the modeling.

Next, please. In Canada, we are using the model that has basically been setup by the Kodak element. We have an issued statement. We do hazard identification, hazard characterization, exposure assessment and risk characterization, but nothing goes forward until you have hazard identification.

Next slide, please. Our structure in our risk characterization is depicted here. Basically, we are looking for these probability statements in the middle, which are outcomes, but we are looking at the infectivity consumed, which really comes through our exposure assessments and the consumption frequencies from the exposure assessment, and then the dose response models that we have been developing, which are in the hazard characterization.

Next slide, please. Our structure in hazard characterization, basically, the main things, variables that we would be looking at are the susceptibility in human population. We can say that certainly the we in our risk assessment are looking at worst case assumptions. In fact, with the human population, we are not looking at divergence, for instance, because of met type of codons, we say that all humans are susceptible. We're not looking at immuno-compromised or younger children. There's no infant instances of that, so like our population characteristics say that all populations are susceptible.

Infectivity accumulation is one of the things we are looking at particularly with dose response type of modeling. Our species barrier from bovines to humans, I guess, what I would say there again is that we are looking at the worst case. We're saying that there is no species barriers. It's a 1 to 1 ratio, but certainly when we're looking at the advice that we get from the Scientific Steering Committee over in Europe that they say that we should use the range of 1 to 10,000.

And, in fact, the latest publications do say for oral transmission to food products, you probably should be looking at 10,000. And we are looking at risk assessments to be tried and say, for instance, they do want things to be practical and realistic, but then we are going with due caution. And so some of these products that we're looking at to start with, we are emphasizing generally worst case assumptions and seeing what those numbers generated look like, and so that's what we have been doing.

Next slide, please. In particular, it's the dose response area for varying-CJD. And in our models we are using a threshold dose response as well as an accumulation dose response. I have a lot of slides here, so I'll have to hurry along with this. We'll talk about that a little further along.

Next slide, please. The structure and our exposure assessment just basically analyze the model that we use.

Next slide, please. And particularly, which is of interest to this particular audience is the fact that we are looking for the presence of BSE in cattle populations. Our models are setup in such a way that we do know that the disease status of a country changes and I think we have that from our own experience, but we have them working along the lines, for instance, that food products and gelatin products are produced over periods of time, so the BSE status and the amount of BSE possibly infected cattle in the country change, and so we really want to be able to adapt that to the different lots and processes.

The tissue infectivity information that we use, basically, a lot of it from the oral pathogenesis studies to start with from Dr. Wells group and that continues on in the UK. Our source of infectivity in the slaughtering areas, our sources of infectivity certainly depend on the tissues that are used in the products, and I think you've been discussing a lot of those today with specified risk materials, for instance.

And this area here I put the word gelatin for the commercial product of what we're looking at. In fact, this model was developed particularly for beef extracts, but it is the front end that I wanted to talk about today. Because what we've been doing as well as we do look at consumption, the actual final products, the amount of material that are in final products, and then the amount that go to consumers and consumer individual servings.

Next slide, please. So our quantitative model prevalence of BSE into -- the BSE infected bovines in populations in the screening procedures. The inference from the countries of BSE surveillance, first of all, I want to say one thing and that is that the products we were looking at were generally ones that were coming from the European Union or could have been coming from other places. But when we were looking at prevalence data itself, because of the wide enhanced surveillance targets that have been going on in the EU that we particular have some good observational data there to work backwards from.

And I must say that certainly the EU has also been doing a lot of missions out to their member states to go for audit and compliance, and they have been doing a number of good reports on that. That's why we get some excellent data to sort of give some parameters around to put in models. However, I'll tell you that particularly our concerns are detected diagnosed cases are removed from -- are diverted from food chains.

But the incubating cattle are a question in the amount of infectivity in incubating cattle, certainly one of the major things that we have been struggling with. But in our particular assessments, we're using 4 incubating cattle per adult cattle diagnosed and we've done that, basically, from talking to experts in Europe. And the other thing that we're doing, though, is that we're talking about the infectivity of tissues.

We started off with giving them exactly the same infectivity as the clinical animals to run through the worst case numbers, and then we scaled that backwards. But I'll explain a little bit later. But what we've done is basically we try to group countries into low, medium and high prevalence rates and so then I do have numbers on that, but again this presentation is going to be a little small for that, but we'll get to that.

As far as the abattoir screening itself it's concerned that certainly now there are rapid tests involved, and we've seen that they were talking about 100 percent sensitivity, 100 percent specificity. There's a number of rapid tests out there. We have done an evaluation of them and we've used the worst case sensitivity for one particular rapid test, because we cannot tell because there are varied tests that have been used in similar countries and so you don't necessarily have all that information.

But for modeling purposes, again, we're using the worst case. And for the ante-mortem, postmortem inspections only for diverting BSE infected cattle from the food chain, we're using a 2.5 percent removal from ante-mortem. And I think most people know how very difficult it is to diagnose TSE diseases and that they are very complicated.

However, they have gone back and it is a requirement in the European Union to, in fact, state where you are during your diagnoses, are they ante-mortem or are they rapid test. And so that the range of variability in ante-mortem depends on the country and in the awareness, the education and in a lot of infrastructure elements. However, I can tell you that for what we've done, I've only seen six reports so far from mission compliance audit states and the lowest amount of divergence is 3 percent out of Belgium from ante-mortem and up to in the high 30 percents in Germany. So there's a lot of variability in the amount of BSE infected animals that are removed postmortem. And this goes into the models as well.

Next, please. Next, please. Oh, sorry, I couldn't see it right. Okay. So now, I'm looking at tissue infectivity. I just want to give a brief run down here that we are using .1 gram of raw unprocessed brain tissue from a clinically infected bovine as the minimal or as the threshold dose in our models, at this time. I think that most of you are aware that that is the amount of unprocessed tissue now that has been orally given to a cow that has come down with BSE in the UK in the latest pathogenesis studies. That animal was 52 months. Again, like a very low dose, but it is our starting point.

However, we do put uncertainty around these things, again, up to, per program, 10¹ to 10³ infectious doses. And then the infectivity that we are assumingly using the same infectivity scaling standardization to the trigeminal root ganglia, the dorsal root ganglia, the spinal cord and emboli could possibly go into this slaughtering and stunning procedures. And I have mentioned already we are looking at the incubating bovine, and particularly the sensitivity issue around that, and so we have a scale at different levels in our final results.

Next, please. Our sources of infectivity, particularly, when we are looking at raw materials, it could be going into things like gelatin. Our CNS emboli in the blood, possibly spinal column cross-contaminations, blood itself, edible fat contaminations, bone marrow, spinal column, and trigeminal ganglia.

Next, please. And, in fact, this is the way that we have started in our beef extract risk assessment that we sort of look at in terms of tissue restrictions and no tissue restrictions, and particularly, although I guess this was the top line here that would be very much parallel to what could, in fact, be going on in the gelatin industry, because in beef extract, we do have some productions that only use muscles only.

Next, please. One of the things that we see are really the number of bovines that are, in fact, going into batches and lot production and silo storage in beef extract and this is very similar to some of the things you are seeing in the gelatin production. So that we do have, in fact, calculated the probability of a batch contamination, lot contaminations by the prevalence rates and by -- well, it's a little complicated here for me just to go over that quickly, but it's those calculations that we were looking for to say that there's a probability that the consumer product is made from a contaminated product at that end.

And so we are looking at the number of infected bovine tissues that go into the batch or lots based on those country prevalence ratios as well. We also are looking at the infectivity reductions, because in beef extract production, as well, you get a lot of heating, wet heat, filtering, decanting and denaturation and, in fact, we have tried to mix estimations on the log reductions there.

Next, please. In terms of defining our concerns and characteristics for these products, and I suppose this is one of the difficulties that we do have with food products that contain small amounts of a ruminant product ingredient, not always on the labels and not always necessarily going to the ingredients. In the beef extract production business, for instance, there is no GME type organization.

We, in fact, had to go to every country, major country, around the world that does have beef extract production and do our individual investigations by companies to find out the capacity of their equipment, the number of animals, for instance, that -- first of all, one animal contributes so much tissue per lot, and so there is a range of animals that go into lots or batches. And so the probabilities are all derived from that type of information.

And so like that's something I'm -- actually, I skipped over that a little bit, but it's very important for this type of estimation of, for instance, that even if you did have a BSE infected cow going to gelatin production, for instance, you have to know the capacities of the equipment and the type of equipment and the different processes and certainly that the gelatin industry have indicated that there basically are very similar processes, a little different in the other areas.

I see I'm at stop time already, but I just need to go to the next slide, please. Basically, these were the variabilities and the components that we've been looking at, and I'm probably way over time here. But can I just kind of continue on just real quick? Okay? Because certainly like our particular interests is really in the production methods themselves, the production practices, the sources of infectivity, all of these that we've quite clearly documented in our written reports, which we would be glad to share with this Committee at a later time.

And the consumer product characteristics themselves, because there is differences amongst the groups of products and within the groups of products. And so we have gone through actual analysis of the amounts of materials that go in there, and then the consumption characteristics themselves, because each product has a different consumption characteristic and so we've tried to work that through with a point estimate of the maximum values.

Next, please. And the uncertainty issues that we really weren't looking at in our reports and reporting them as sensitivity, you really have to do a tissue infectivity incubating bovines or species bearing the dose response.

Next, please. And if you want to -- next, please. Because this is basically the charts that we prepare, and we are providing like product groups within our report.

Next, please. The BSE prevalence is basically put into our charts.

Next. Our abattoir screening techniques.

Next. For divergence of BSE animals.

Next. Other production methods that we have been going through with all information we collect and we can provide that as a range.

Next. And then we've done production parameters which are a range of ranges depending on the type of processing, etcetera, and the types of tissues that are added.

Next, please. And I think I'll skip this one right now. Next, please. Next. And this basically is just giving us some information on if you're using rapid test and ante-mortem tests.

Next, please. Because it was this type of scatter diagram that we're trying to provide to sort of show or give the information on the probability of the consumer batches themselves. If you've got large batches, small batches, high prevalence, low prevalence, and so we tried to do some diagrammatic information in our reports to give some idea of the dilution of tissues with no infectivity or with infectivity.

Next, please. And the difficulties I have talked to, and next, please. Bottom line is that these are the individual outcomes that we have been trying to quantify in our risk assessments, and particularly, though that we -- you will find that you can have a lot of problems with surveys, nutrition surveys, etcetera, for the types of details that you would be looking for for trying to get estimates on consumption values.

I'm sorry to have gone over.

CHAIR PRIOLA: Okay. Well, thank you. Are there any questions for Dr. Rogers? Yes?

BOARD MEMBER WOLFE: You mentioned earlier on that your assumption of the ratio of incubating cows to infectiveness is 4 to 1. What is the basis for that?

DR. ROGERS: Excuse me, well, that's basically expert opinion from Europe, because like we had talked to people that had the experience with BSE for a number of years, and so that that is just strictly an expert opinion. There's no rationale for that except there is a range of incubating cattle that we do use, but I can tell you the reason why we're using 4, at this time, is because we have implied such harsh assumptions to the fact that there is, it has the same amount of infectivity as the clinical animal.

BOARD MEMBER WOLFE: Can you tell me what the range is that you said that you use it for? What is the range or ratio?

DR. ROGERS: 4 to 10.

BOARD MEMBER WOLFE: 4 to 10. Thank you.

CHAIR PRIOLA: Okay. Thank you again, Dr. Rogers. After carefully checking my agenda, now, we're going to hear from Dr. Morris from the USDA. I apologize again for putting you on the spot earlier.

DR. MORRIS: Good morning. Thank you again for the opportunity to share our Agency's policy on gelatin. Next slide, please.

I am Dr. Terry Morris with the National Center for Import/Export. I am representing the United States Department of Agriculture, Animal Implant Health Inspection Service, Veterinary Services.

Next slide, please. We are headquartered out of Riverdale, Maryland.

Next slide. And we are under the direction of Dr. Karen James-Preston.

Next slide, please. Title 9, Code of Federal Regulations, Part 94, 95, 121 and 122 gives APHIS the authority to regulate animal products. Part 94 gives us the authority to regulate gelatin.

Next slide, please. We regulate gelatin based on the presence or absence of BSE and the association with the BSE affected region, BSE being Bovine Spongiform Encephalopathy. We have lumped gelatin into one of three categories. One category would be gelatin that is derived from non-ruminant species. A second category would include ruminant gelatin that is derived from cattle that have no association with a BSE affected region. And the third category is ruminant gelatin that has been derived and has an association with a BSE affected region. For the gelatin that has an association with a BSE affected region, those regulations are found in Part 94, Section 18(c).

Next slide, please. And pretty much to summarize, 94.18(c), the gelatin that is derived from ruminants and the ruminants are from a BSE affected region, that gelatin is prohibited entry, unless the gelatin is imported for human food purposes, pharmaceutical products, photography or any other similar uses that would not result in the gelatin coming in contact with ruminants in the United States.

Next slide, please. 94.19 addresses gelatin derived from non-ruminant species. This would include your pig, horse, poultry and fish gelatin. On May 27, 2003, an interim rule was signed that modified the current verbiage in 94.19.

Currently, next slide, please, the gelatin that is imported that is derived from pigs, horses, birds and fish species must be accompanied by an original official certificate endorsed by the full-time salaried veterinarian responsible for animal health of the exporting country, and it must state the animal species of origin.

Next slide, please. 94.19 also deals with gelatin derived from ruminants, provided those ruminants have not been in a BSE affected region.

Next slide, please. This part of the regulation requires that each shipment should be accompanied by an official original certificate endorsed by the full-time salaried veterinarian responsible for animal health of the exporting government, and that certificate must state four things. The first thing it must state the animal species from which the material is derived. The second statement must include the region in which the facility where the material was processed is located. The third statement would include a statement that the material was derived only from ruminants that have never been in a BSE affected region. And the fourth statement must address dedicated facility conditions, meaning the facility cannot receive, store or process any ruminant material from any BSE affected region.

Next slide, please. The last category deals with ruminant gelatin that has been associated with a BSE affected region.

Next slide, please. Ruminant gelatin that has been associated with a BSE affected region must be accompanied by a veterinarian import permit. A permit is a legal document that authorizes the importation of controlled materials or organisms or vectors into the United States. For ruminant gelatin associated with a BSE affected region, the permit would address the country of origin. It would address the animal tissue species, meaning hide or bone. It would address the exporting and the processing country of origin. Again, we're looking at BSE-free versus BSE affected.

Next slide, please. The next few slides depict scenarios that address how APHIS would regulate the importation of ruminant material under certain circumstances. In this scenario, the ruminant material whether it be hide or bone is derived of ruminants from a BSE-free country, but it is processed and exported in a BSE affected country. In this case, we would issue a permit for this material.

The permit would require that the government certify the country of origin of the raw animal materials and the government would also have to certify specific conditions that exist within that facility and the BSE affected region. Again, that facility would have to be a dedicated facility, meaning it cannot store, receive or process any ruminant material from any BSE affected region, with the exception of milk and hides.

Next slide, please. In the second scenario, we address high derived gelatin only, sourced from ruminants. In this case, whether the hide is derived from ruminants from a BSE-free or a BSE affected region, the fact that it is processed in a BSE affected region requires the need for the permit. The permit, when issued, would require that the government certify that the gelatin is hide derived only, and again because the facility is in a BSE affected region, the facility would have to be dedicated.

Next slide, please. The last scenario addresses bone derived gelatin. For bone derived gelatin, and in this case, the ruminants are from a BSE affected region. This material is allowed entry, provided the individual obtains a permit. And when we issue the permit, the permit would require that the individual maintain affidavits that they obtained from individuals who they distribute this gelatin to. The affidavits would require that the individual certifies that the material will not be used as livestock feed ingredient.

The material cannot be incorporated into veterinary pharmaceutical uses or the material cannot be incorporated into veterinary biologic products. And this goes back to 94.18(c), which says that the material can be imported, provided it is imported for human food, pharmaceutical products and other uses, photography, and other uses that does not result in the material being introduced to U.S. ruminants.

Next slide, please. To complete the process for obtaining an import permit, you have to submit an application, which is VS form 16-3. It takes about 2 to 3 weeks between the time that we can process the application and turn around a permit to you. The application can be submitted electronically through our website. It can be submitted by fax or my mailing it into our office. The permit is good for one year, and the permit will only allow for the specific commodity requested from the specific exporters, and it would have to go to the importer that requested the permit.

Next slide, please. This is my contact information, in the event that you need to contact our office.

Next slide, please. And again, I wanted to thank the Committee for the opportunity to share APHIS policies regarding the importation of gelatin. I'm happy to answer any questions you may have.

CHAIR PRIOLA: Dr. Wolfe?

BOARD MEMBER WOLFE: This is not meant to put you on the spot, but as you know, the Department of Agriculture is seriously considering, we have heard from others, on the verge of, lifting the ban on importation of cattle, beef, from Canada to this country. You've outlined a thoughtful and, I think, careful permit process that affects gelatin, for instance, which would come from a BSE affected region, such as Canada.

Do you not think that there is somewhat of a contradiction between being so tight properly and restrictive about allowing gelatin to come in from there, but seriously considering lifting the ban on meat from what would be the first time the United States would ever have lifted a ban that previously existed from a BSE affected country?

DR. MORRIS: Yes, sir, the APHIS TSE working group has devised a list of low-risk commodities and a list of mitigation factors under which those low-risk commodities can be imported, the specific criteria under which we would consider accepting these low-risk commodities. That list has been presented through channels to the White House and it is our understanding that the White House has disseminated that list to the trading partners, so it is in negotiation to make sure that all of our trading partners are aware of what the potential actions would be.

BOARD MEMBER WOLFE: So you're saying that beef is presumably on a list as a low-risk commodity? Is that what I interpreter you're saying?

DR. MORRIS: And I would have to look at the list, but it's specific categories and it's specific ages. And, Lisa, if you want to help me out here? Thank you.

BOARD MEMBER FERGUSON: Yes, I'll try and help you out. Speaking for the Department, first of all, I would like to reiterate the point that you probably shouldn't necessarily believe all the rumors that are in the press and everything that you hear. There are lots of things under consideration, not only at USDA, but through the entire Administration, so all of the departments are contributing to these discussions.

And the discussions are centered around, you know, is there a science-based way to look at the situation? Are there things that we can do, that are based on known science to address the situation with Canada? And as Terry has described, at least, we, at APHIS, have provided some recommendations for certain products that perhaps could be considered low-risk and could initially be allowed for import under certain conditions.

I'm not at liberty necessarily to say what is on that list, what might not be on that list, but we have tried to address it. Okay. First of all, products that are accepted internationally not to present a risk of transmission, obviously, are not affected already. But we are looking at a range of things to say these could be considered lower risk than other things. And really it's a wide ranging list that goes over a lot of issues.

BOARD MEMBER WOLFE: Thank you.

DR. MORRIS: Thank you.

CHAIR PRIOLA: Okay. Thank you very much, Dr. Morris. We'll now move on to the open public hearing portion of the morning. So, Dr. Freas?

SECRETARY FREAS: As part of the Advisory Committee program, we hold open public hearings, so that members of the public may wish to make comments to the Advisory Committee will have the opportunity to do so. At this time, I have received two requests. One is a written request. This written request was run off for the Committee members, posted in the viewing notebook out on the table and some copies were provided for the public if you were here early.

The second request is from Mr. David Bieging and he is at the microphone right now. Welcome.

MR. DWYER: Actually, I'm Dan Dwyer. Dave Bieging made the request and I'm going to speak. I'm Dan Dwyer. I represent the Gelatin Manufacturers of Europe, and I'm also speaking today on behalf of the Gelatin Manufacturers Institute of America. You've already heard from representative of these two associations this morning. These associations represent virtually all of the gelatin produced in Europe and in the United States.

These two associations have been working for many years, as you know, to ensure that gelatin is safe and we've been pleased to be able to do so in cooperation with the FDA. As we've discussed with FDA previously, we would like, at this time, to comment on the questions that FDA has asked this Committee to address today.

Specifically, FDA's Question 1 currently reads "Do the results of these new studies demonstrate a reduction in infectivity that is sufficient to protect human health?" This question must be interpreted in light of the normal circumstances surrounding gelatin production. In particular, the question focuses only on the manufacturing processes that were studied, but in practice, as you've heard today, the safety of gelatin is based on two principles.

The first principle is the use of raw materials. As you know, in Europe this involves controls on raw materials imposed by the European Union and by GME members. The second principle is the use of manufacturing processes that can eliminate any potential infectivity that might theoretically be present in the raw materials. In Europe, this involves the use of the processes that you've already heard discussed today and that have been studied by GME.

These two principles of gelatin safety apply as well to all bone gelatin regardless of geographic origin. Therefore, we request that when the Committee considers FDA's Question 1 it take these two principles into consideration, that is we would recommend that the question be revised to read "Based on the use of raw material sources and gelatin manufacturing processes, as described in the information presented to the Committee today, do the results of these new studies demonstrate a reduction in infectivity that is sufficient to protect human health?"

FDA's Question 2 addresses the Agency's guidance on gelatin. As you have heard already today from Dr. Potter, in 1997, FDA issued a guidance document that established certain parameters for the sourcing and processing of gelatin in order to avoid BSE risk. At that time, the effect of the gelatin manufacturing process on in infectivity had not been proven. The data discussed with the Committee today, however, in our view, provides a basis for concluding that FDA's guidance is no longer necessary.

Indeed, as Dr. Chiu mentioned to you earlier, you may decide that gelatin should be exempt that gelatin should be exempt from any FDA restrictions. At a minimum, we believe that the guidance should be modified so as to improve the opportunity for European raw materials to be brought into compliance with the guidance while at the same time maintaining appropriate controls on the use of European raw materials and, as Mr. Masson expressed before, ensuring a continued adequate supply of gelatin for pharmaceutical use.

If the Committee takes the approach of modifying the guidance in this way, we request that the Committee consider two potential modifications to the guidance. The current text of the guidance has been provided already to you by FDA and, indeed, our recommended changes to the text have also already been provided to you for your consideration.

First, FDA's guidance currently requires that "cattle come from BSE-free herds." As a practical matter, the term BSE-free herd refers to a herd in which there has not been a single animal identified with BSE. In Europe, it is mandatory, as you've heard, that animals over 30 months of age be tested for BSE, whereas animals under that age are normally not tested, because they have not been defined, at this time, to pose a risk to human health.

Thus, in practice, a BSE-free herd is a herd in which BSE has not been detected in tested animals. FDA's guidance in this regard would be clearer if it were to include a brief explanation of the term BSE-free herd by stating "BSE-free herd as determined by generally accepted testing procedures."

The second modification to the guidance that we would ask the Committee to consider is one that this Committee has considered before. FDA's guidance currently requires that heads, spines and spinal cords be removed from gelatin raw materials "directly after slaughter." In 1998, this Committee recommended that the removal of spines may be done at any time during the deboning process. Indeed, the removal of heads and spinal cords is not an issue as you heard, because they are already removed before or at the time of slaughter.

Therefore, it continues to be appropriate for FDA's guidance to be modified to permit the removal of spines at any time during the deboning process. As the Committee considers FDA's Question 2B then, we request that these proposed modifications to the guidance be taken into consideration. A copy of our recommended changes to the guidance has been distributed to you already for your consideration, and it also has been made available to the public.

Thank you very much. We appreciate the opportunity to appear before you today.

SECRETARY FREAS: Thank you for your comments. Is there anyone else in the audience who would like to address the Committee, at this time? If not, Dr. Priola, I would like to state that we all have three more open public hearings throughout this meeting, and we do encourage the public participation. Thank you.

CHAIR PRIOLA: Okay. So the questions put to us by the FDA are now open for discussion and voting. Do we have the questions to put up? So the first question, while they're getting it up there, is simply, well, hopefully simply, do the results of these new studies demonstrate a reduction in infectivity that is sufficient to protect human health? Are there any comments or any discussion from the Committee? Yes, Dr. Hogan?

BOARD MEMBER HOGAN: Since nobody else is biting, let me take this opportunity to say that when I reviewed your article and when I started reading this voluminous amount of material, I sort of looked with the same sort of skeptical eye that I do when I accept papers for publication, and I initially had, when I started reading, several questions about processing and scale-down issues and residual infectivity, etcetera. But as I got deeper and deeper in this, we concur that those had been addressed.

So the initial questions that I have asked today, I am extremely personally pleased with the results of these studies. And while no study can be absolutely perfect, and I think that all the questions that the original Committee in 1997 had regarding the data, in my mind, have been answered.

CHAIR PRIOLA: Dr. Bailar?

BOARD MEMBER BAILAR: I agree that these are very important experiments. They were very well done. I read the reports also as somebody who has done a lot of reviewing. I do have one remaining question or set of questions. I'm not sure that we know enough about the time course of deactivation and why some of the infective agents seem to be so resistent.

CHAIR PRIOLA: Well, maybe Dr. Rohwer would like to address that more specifically, but, well, would you, Bob, would you like to, since this is your day. I don't want to speak for you.

DR. ROHWER: You're asking a fundamental question of TSE science, actually. And it's something that is going to get a lot of discussion this afternoon. And so I don't know, I mean, I have another talk that I'll be giving and it goes directly to that question, and Robert Somerville has given his perspective on it, and we're going to hear from David Taylor as well. And I think, is there anybody else? I honestly can't remember. Well, and David Asher has some new data on this area as well.

And you, yourself, put your finger, I think, on the central issues in your first question to the panel, I mean, to the speakers earlier this morning about the biphasic nature of these inactivations and what is behind them. And we don't know for sure. My own bias is quite different from Robert's. I mean, I don't think there is any intrinsic difference between these agents. What we're talking about is sanctuaries and an inability to actually reach all of the agent. But there are other interpretations.

You pointed at one which is a genetic one and there are different ways that you can look at these kinds of protections. We don't have the answers to that. And I think it is a residual question that haunts every single validation study, inactivation study that is done, is to know just how far you can extrapolate this data to zero.

I would like to point out that this is not a new issue. It's something that has bedeviled the vaccine industry, water purification, virtually any area in which you want to assure that something is sterile, but you have no way of measuring the entire production lot to find out whether it is or not. And we're kind of in the same boat here.

BOARD MEMBER BAILAR: Yes, but I'm not concerned about extrapolating down past the last data point. You have data showing that the curve flattens out, at least, to a considerable extent.

DR. ROHWER: Yes, and the point that I'll be making this afternoon is that the place where that flattening out occurs is very context dependent. And you can force it down or up depending on what kind of mixture you are inactivating, what the conditions are and that type of thing. And so the one thing I can say about these studies is that the knowledge that that occurs was part of the design of the study.

And your other question about intrinsic versus extrinsic infectivity, the idea that you have to introduce the spike into this spine preparation at the beginning, and you can't know for sure whether you have really mimicked the invito situation in which you would find the infectivity in a BSE infected cow is a very appropriate one. However, in this particular case, I feel more comfortable with it than practically any other study like this that I have done, because it is the spinal cord and the ganglia that we feel are the threat. They are extrinsic to the bone.

And what was done here is the stuff was actually injected into the spinal cord and smeared on the bone, actually given an opportunity to dry on the bone, which is something that probably actually happens, and is something that is very, in my opinion, probably very dangerous to do with TSE infectivity. And so the original for the total process experiment, which by the way I wasn't part of the experiment, but nevertheless, my perspective on that is that that was probably just about as good a spike as you could devise. And I mean, I can't think of anything better.

You could always argue with the downstream position of spiking homogenate into these things, but even there I think we're talking about a worst case spike in the sense that the homogenate is completely unrefined. And having taken this through the process, you're liable to have stripped away some of the fats and things like that that may be protective to these agents in pure brain type associations. But that's speculation on my part. I can't satisfy your basic underlying concern there, because we don't have data on that point.

BOARD MEMBER BAILAR: Well, I remain a little bit concerned, because I recall reading basically in the Daily Press that in the usual method of slaughter, bits of CNS material do get into the peripheral tissues. Is that correct?

DR. ROHWER: With penetrating concussive slaughter, I think, it is without a question that that happens. And that's -- I don't want to comment on that. There are people here from the USDA who can probably tell us just whether that practice still occurs there or not. I'm not sure.

BOARD MEMBER FERGUSON: I'll answer that. Actually, the issue is with air injected stunning, where you've got a captive bolt and then you've got holes drilled at the end of it, and you inject a bolt, a blast of air, and that type of nomadic air injected stunning is not used in the U.S. industry any more. Our colleagues at the Food Safety Inspection Service are actually in the process of promulgating regulations that officially prohibit that, but based on our understanding of slaughter practices, it is not used in the U.S. Is it used elsewhere?

BOARD MEMBER WOLFE: Well, like in the countries where we're talking about, the European countries?

BOARD MEMBER FERGUSON: In Europe it also prohibited by regulation within Europe.

BOARD MEMBER WOLFE: Within all of Europe?

BOARD MEMBER FERGUSON: Yes, yes. Actually, well, within the EU. EU regulations prohibit it. So within the community, I think, you can probably also then assume that any of those countries that are exceeding to the community, the same thing applies.

CHAIR PRIOLA: Dr. Somerville, I think, also wanted to address part of your question, Dr. Bailar. Thanks, Bob.

DR. SOMERVILLE: Can I just -- is this on? Okay. Just to add to what Bob was saying and to emphasize what I said at the beginning of my talk, was that in processes that were considering its denaturation reaction which is, I suggest, leading to the stabilization of the aging, past the drying processes that Barbara has just mentioned. There are other processes involved in the gelatin extraction procedure which may assist in its destruction or removal.

I suggest that possibly there is a degree of hydrolysis of infectivity which would not necessarily depend on the stability of the agent in terms of its denaturation properties, and also, of course, the filtration properties described are of importance in removing, in the totality of the removal of infectivity from the process.

CHAIR PRIOLA: Yes, I think it is also worth remembering that having sat through many of these Committee meetings and always asking for data, I now have before me 2 inches of data, all of which point to the same thing. That in the worst case scenario you can still inactivate these huge doses of infectivity. And then in the real world we're talking about starting material that doesn't even have, at least from the European point of view, as we've heard, since they are now removing the vertebrae, it doesn't even have that material there to start.

So whatever contamination may be present is going to be significantly lower than anything that has been discussed here today. So at every step of the process, precautions are being taken that should also be taken into consideration when you're thinking about these things about total inactivation and sequestering evasion.

Are we ready to vote, dare I ask? Does anyone else have anything they would like to say now? Shall we call for a vote then?

SECRETARY FREAS: There are currently nine voting members at the table. I will go around the table starting with Dr. Johnson over there. Dr. Johnson, how would you like to vote?

BOARD MEMBER JOHNSON: I vote yes.

SECRETARY FREAS: Dr. Bracey?

BOARD MEMBER BRACEY: I vote yes.

SECRETARY FREAS: Dr. Ferguson?

BOARD MEMBER FERGUSON: Yes.

SECRETARY FREAS: Dr. Hogan?

BOARD MEMBER HOGAN: Yes.

SECRETARY FREAS: Dr. Khabbaz?

BOARD MEMBER KHABBAZ: Yes.

SECRETARY FREAS: Dr. Priola?

CHAIR PRIOLA: Yes.

SECRETARY FREAS: Ms. Walker?

MS. WALKER: Yes.

SECRETARY FREAS: Dr. Wolfe?

BOARD MEMBER WOLFE: Abstain.

SECRETARY FREAS: Dr. Bailar?

BOARD MEMBER BAILAR: No.

SECRETARY FREAS: The tally is 7 yes votes, 1 abstain vote, and 1 no vote.

CHAIR PRIOLA: Okay. So we can move on to Part A of the second question, which is due to scientific data and information available support the following current FDA recommendation on bone gelatin. And we can keep in mind that we can modify as the FDA has said we can modify this question if we think it is necessary for this recommendation. So that's open for discussion. Dr. Bailar?

BOARD MEMBER BAILAR: Before we vote on this, could we have somebody from FDA say whether the modifications suggested are acceptable?

CHAIR PRIOLA: I'm sorry, the modifications suggested by the gelatin manufacturers?

BOARD MEMBER BAILAR: Yes.

CHAIR PRIOLA: Yes. Would someone from FDA, yes, Dr. Chiu.

DR. CHIU: I would put the question back to the Committee. If the Committee think, you know, the modification suggested by industry is acceptable, then we will take that recommendation back to the Agency and then have internal discussion.

CHAIR PRIOLA: Comments from the Committee? I would like to read through the gelatin manufacturers recommendations. Is there any overwriting reason that anyone can see here to alter what the FDA already has down, which seems to cover what it should in terms of removing risk materials? Dr. Hogan?

BOARD MEMBER HOGAN: No, I don't think it should ever go under non-exempt. I think that this is good. The question is from the industry, why is it important to -- when you say BSE-free herds, that covers it. I guess what you're not allowed to use then are herds which contain animals that are younger than 30 months, and you would like to be able to do that. Is that the sense of why you want the modification? Since animals that are less than 30 months are already assumed to be BSE-free.

CHAIR PRIOLA: Dr. Schrieber, Mr. Schrieber?

MR. SCHRIEBER: This request for modification is based of an opinion expressed by the USDA. USDA has stated to FDA we do not consider any herd in Europe being BSE-free. So this means the current text, the way this is written, would exclude altogether all European bones to be used for gelatin manufacturing and then exported into the U.S. So therefore we need the clarifications that under certain circumstances, and that's what we have described, that the animals are tested according to current procedures in Europe, that this would be, let's call it, equivalent to the BSE-free herds. So that's one point.

And the other request for the modification is what I said before. Due to the transport of the carcasses from a slaughter house to a meat packer to sausage companies, with bone in, if the request will stay, removal of spine, I'm not talking about spinal cord, this is directly removed after slaughter. But removal of spine has to be taking place directly after slaughter, this would as well totally exclude the use of European bones, because this is not the standard procedure.

So we need some time frame during the further processing, because deboning is done somewhere else and transport of carcasses without the bones is not possible. This is the ratio behind our request.

BOARD MEMBER HOGAN: Well, then I would ask Lisa, is that true the USDA considers no herds in Europe BSE-free, despite testing?

BOARD MEMBER FERGUSON: Well, I think what we're dealing here with is the way our regulations are written. And our regs prohibit the entry of ruminant from any country that is on the BSE restricted list. So, you know, since our regs are clearly prohibiting all these animals, we can't necessarily make an exemption and say yes, okay, something is free, something is not free.

CHAIR PRIOLA: I'm sorry. Dick, go ahead.

BOARD MEMBER JOHNSON: Yes. If this were modified by this Committee, that would not affect the FDA regulations, and then you would have two conflicting rules, right? Is that right?

CHAIR PRIOLA: Well, you're not necessarily going to have two conflicting rules. You know, the way our regs are written, we prohibit gelatin from entering, as Dr. Morris has described, unless it can be demonstrated that it is not going to go for animal use. Okay.

BOARD MEMBER FERGUSON: So we don't make this type of an exemption, you know, for stuff going for animal use, if that's clear.

BOARD MEMBER JOHNSON: I thought it was all products derived from cattle that were from BSE positive countries that you don't permit. But as long as we eat it, it's all right? As long as humans eat it.

BOARD MEMBER FERGUSON: APHIS' authority is related to animal health issues. APHIS' authority is not related to public health issues, so our regs are written based on that authority.

BOARD MEMBER JOHNSON: But doesn't your animal health issue say that products derived from, cattle products derived from BSE positive countries cannot be brought into the country?

BOARD MEMBER FERGUSON: Correct. Our regs in general prohibit not just bovine products, but most ruminant products.

BOARD MEMBER JOHNSON: Yes.

BOARD MEMBER FERGUSON: From countries on our BSE restricted list. However, I think, as Dr. Morris explained in her presentation, there are certain things in the regs that can be allowed entry and one of those things is gelatin under certain conditions that is not going for animal use.

BOARD MEMBER JOHNSON: That's in your exemptions at FDA?

BOARD MEMBER FERGUSON: Correct.

CHAIR PRIOLA: This is USDA, Dick, so, yes. They are USDA.

BOARD MEMBER JOHNSON: USDA, that's okay.

CHAIR PRIOLA: Yes, the FDA is strictly concerned with oral or topical applications in humans of gelatin, so the USDA regs aren't our concern. It's the FDA. It's this specific recommendation by the FDA.

BOARD MEMBER JOHNSON: Except it isn't -- wouldn't it be a regulation, for instance, that you couldn't bring in cattle hides from Europe under the safety of animals?

BOARD MEMBER FERGUSON: No, hides and skins are exempted from our regs.

BOARD MEMBER JOHNSON: They are exempted? Okay.

BOARD MEMBER FERGUSON: They are considered, yes, not to present a risk of transmission.

BOARD MEMBER JOHNSON: Okay.

CHAIR PRIOLA: Dr. Bailar?

BOARD MEMBER BAILAR: How is herd defined? Is that all the animals on a single farm or ranch?

BOARD MEMBER FERGUSON: I don't know why you guys are looking at me, because these aren't our regs. Actually, I have to admit, I mean, these are the types of things that you always run into when you put that type of a thing in a reg. It's very difficult to define that. When we look at it from an animal health point of view, it's a group of animals that is housed together. And if a premise has, you know, two separate groups of animals that never come into contact with each other and are managed completely differently, those could, technically, be considered two different herds. But essentially, it's a group of animals that are managed together and handled together.

BOARD MEMBER BAILAR: Okay.

CHAIR PRIOLA: Mr. Dwyer has been standing there for a couple of minutes. Would you like to make a comment?

MR. DWYER: Yes, thank you. As you've explained, there is a complete distinction between the FDA's guidance and the USDA's regulations. The USDA's regulations are intended only to protect animals and not to deal with anything that the FDA has going on here. If you go back and look at the early meetings and transcripts of this Advisory Committee when FDA was discussing with the Committee the formulation of this guidance, you'll see that the requirement for BSE-free herd restriction was put in as one of a series of restrictions in FDA's guidance that were intended to protect the safety of gelatin.

There wasn't much discussion, at that time, of what a BSE-free herd meant or how that would be defined. Because it is obviously possible to define it in many different ways, what the industry was looking for is a way of defining it in a logical, rational way that is consistent with current practice in Europe. And that's basically it.

BOARD MEMBER BRACEY: Although --

CHAIR PRIOLA: Go ahead.

BOARD MEMBER BRACEY: Although I think the safety of gelatin has been certainly demonstrated to be rather robust today, what bothers me is, in essence, a disconnect between two levels of animals. One is the human where we are considering saying that well, it's okay, based on the data that we see, to allow humans to ingest these materials. Whereas, on the other hand, another arm of the Government says that another animal, which some of us think would be on a lower level perhaps than the human, that it is not acceptable.

And, you know, I really feel that we need to have some sort of harmonization, because the message, I think, that -- if I were the public, I would be somewhat concerned about the message that we would be issuing.

BOARD MEMBER FERGUSON: Yeah, that's a valid point. I would ask everybody, however, to keep in mind that, you know, it's one thing to talk about an agent that is coming from cattle and going directly back into cattle versus an agent that is coming from cattle and is going into a different species. Granted, it has been demonstrated that there is that transmission, but you do still have somewhat of a species barrier there.

CHAIR PRIOLA: Dr. Khabbaz?

BOARD MEMBER KHABBAZ: Yeah, and actually, listening to the USDA presentation, I have that same reaction saying there is an apparent contradiction here between conditions for animals and humans. But in thinking about it, I mean, you have a potential amplification. I mean, these are some different issues that go into place with animals and that's why I didn't comment. But there is an apparent contradiction. I agree.

CHAIR PRIOLA: Yes, Lisa?

BOARD MEMBER FERGUSON: Can I go back to the term BSE-free herd? That's very difficult to define and I don't want to necessarily sound too harsh, but in some ways it is sort of meaningless. I know we have struggled with those types of definitions as we tried to setup our scrapie or CWD eradication programs. And, you know, specifically, as we're doing our CWD program, we don't necessarily define under the auspices of that program as herd as free until they have gone through a 5 year period with extensive surveillance and a lot of that. So it is a bit difficult to define.

I guess I'm not quite sure exactly what level of risk mitigation it's necessarily adding in this guidance. Probably more of the risk mitigation is coming from removing those tissues that are at highest risk and also just through the inactivation of the process itself. So perhaps what we should consider is that specific point even necessary in there or does it just cause more confusion than it is really worth?

CHAIR PRIOLA: Dr. Bailar?

BOARD MEMBER BAILAR: I feel like I just don't know enough about all this. And I am concerned about the definition of a herd. Does this include animals that come from the same source, prior to the time they are parceled out into different farms? Does it include any element of time? That is, you know, if all those animals there today are gone and you bring in new ones, is that part of the same herd? What about overlap in time, which I understand is common in the industry, that there is a continuing flow of young ones in and older ones out. I just don't know enough about it.

CHAIR PRIOLA: Dr. Chiu, do you want to comment on what the FDA means by BSE-free herd or is there something more specific you can tell us?

DR. CHIU: Well, I will try. If I didn't get the picture across right, then I will ask Dr. David Asher to add it. I think in our original discussion we were thinking a herd is a group of animals managed, you know, by the same people and also physically they are together, so they are sort of separated from another group of animals. And also we think when we say BSE-free means, you know, that group of animals in the past there was never, you know, a BSE case among that group. In addition, we were also thinking, you know, that group of animals were never fed with meat and bone marrow, so therefore they don't have that kind of risk to contact BSE.

CHAIR PRIOLA: Dr. Wolfe, did you want to say something?

BOARD MEMBER WOLFE: I just wanted to ask Lisa, just from your perspective, what do you think the difference is between this guidance or recommendation as it now exists and the way that the industry would like to redefine it? I mean, the reason I'm asking you is (a) you're from the USDA, but (b) you have just gotten done saying you don't think the phrase herd has any meaning at all. So if it doesn't have any meaning, then what is the difference between our current version and what they propose?

BOARD MEMBER FERGUSON: That's a good point, and actually I don't really see a whole lot of difference in true meaning between what the industry has proposed and what currently exists. My sense of what industry has proposed is trying to make it more realistic and to make it more meaningful in what fits with industry practices, which is a very valid point, especially this one about the removal of tissues and where.

BOARD MEMBER WOLFE: I'm specifically just talking about the herd definition.

BOARD MEMBER FERGUSON: Actually, I mean, after what Dr. Chiu has just said, you know, if those are the specific issues that FDA is intending to address with that point, then I guess my suggestion would be to put that in there as the guidance to say that these animals have not been fed meat and bone meal, those types of things. That is a more accurate definition of the risk mitigation measure and is more easily understandable and leads to less confusion.

CHAIR PRIOLA: Looking though this, I don't have any trouble. I think that's an excellent suggestion actually for the FDA to modify it according to what they mean by BSE-free herd. The other suggested modification by industry down there at the bottom, I'm somewhat uncomfortable with, but you had mentioned that you weren't as uncomfortable. Why exactly is that?

BOARD MEMBER FERGUSON: Well, I think that's probably just because of my understanding of slaughterhouse practices. And if this is saying, you know, as it currently says, let me find it, "and if the slaughterhouse removes the heads, spines and spinal cords directly after slaughter," that lends itself to a lot of interpretation.

First of all, talking about spine directly after slaughter, does that mean right after the animal is stunned and, you know, hung up on the rail and bled out? if so, that's not necessarily common practice. You need that vertebral column there to give some structure to the carcass that's moving through the plant. You know, and I think the point is that those tissues are removed at some point in time during the process. Although they are not going into the start of the gelatin manufacturing process. It's not as much a point as specifically when are they removed, it's that they are removed.

CHAIR PRIOLA: Which the current guidance says anyway. I mean, I don't see where the industry modification makes that much of a difference if, in fact, they take that out at the level of the slaughterhouse they take out that requirement. The way I read it.

BOARD MEMBER FERGUSON: Well, I guess from an interesting point of view and actually let me rephrase that. From a Government point of view, as a federally employed Government veterinarian that might be put in a position to certify to this, I probably couldn't. And it is just because of the way that that is worded, where this stuff is removed directly after slaughter.

CHAIR PRIOLA: Where does it say directly after slaughter?

BOARD MEMBER FERGUSON: Right in the text, yes. If the slaughterhouse removes the head, spines and spinal cords directly after slaughter.

CHAIR PRIOLA: I just have after slaughter. Do I have the wrong one?

BOARD MEMBER FERGUSON: Can we put it up?

CHAIR PRIOLA: Oh, I see. You're looking in the -- I see. It says directly after slaughter if it's from a BSE herd. Later in the recommendation it says if the slaughterhouse removes after slaughter. So there is two different ones.

BOARD MEMBER FERGUSON: Yes, but even, I mean, the later one remove head, spines and spinal cords as a first procedure following slaughter, that just leaves open a lot of ambiguity and, you know, there are some of our folks who are very literal, you know, when they would read that and say oh, no, they didn't, you know, stun this animal, bleed her out and then immediately remove things, therefore, I can't attest to that type of certification.

CHAIR PRIOLA: I guess again, could we ask FDA, is there -- since that's a USDA interpretation of this recommendation, does the FDA have the same sort of reservations or are they concerned about those same sort of reservations as to when exactly the tissue is taken after slaughter or is the discussion enough?

DR. ASHER: No, I think the discussion is very useful. My recollection of the intent of the FDA with both those issues was that the reason why BSE-free herds was specified but not defined was just to put the industry on notice that under no circumstances did we consider material from a herd recognized to have BSE as being an acceptable source for any kind of gelatin entering the United States. No effort at the time was made to define a BSE-free herd.

If one were to try to define an acceptable BSE-free source, I would certainly agree with Dr. Chiu that it would not simply be all tests of 30 month old animals going to slaughter are negative. The herd would have to have a certified history of never using food supplements containing prohibited proteins. There would have to be an adequate surveyance program, not just 30 months slaughter animals.

And my personal opinion would have to include a sufficient number of older sentinel animals and, of course, careful veterinary surveyance to make sure that all sick animals were recognized. My personal opinion also is that this Committee not entertain an assertion that an animal that tests negative at 30 months poses no threat to the public health. I say both those things without attempting to influence the discussions of the Committee. Thank you.

CHAIR PRIOLA: Would it be sufficient to say something like a BSE-free herd is defined by the FDA, if that is in fact defined somewhere, clearly?

DR. CHIU: No, we have not put in writing. And regarding the slaughter, you know, the first procedure are directly after slaughter, I remember our discussion in the past, was because if you remove spinal cord, it is not possible, you know, to make sure entire cord, everything is removed. You might have residual, you know, tissues. And if you carry that to somewhere else and then remove the spine, then create contamination of other tissues, in the bones of other tissues. So we thought, you know, it would be better to remove, you know, the spine, the vertebrae at the slaughterhouse. That was the thought at that time.

CHAIR PRIOLA: I guess the other thing to consider is, again, given all the data we have seen showing inactivation of infectivity following the gelatin extraction process, the issue of contamination, cross-contamination by a spinal cord being removed at a different part of the slaughter process may not be as major an issue given the fact that now there are these five individual studies, all of which saying that the gelatin process itself, as you get to the end, can remove extremely high levels of infectivity under worst case conditions. So it's possible that this discussion as to when things are removed and may not, given that data, be as critical as it might have been before we had access to this data. Dr. Bailar?

BOARD MEMBER BAILAR: Dr. Priola, we have had questions about some of the wording in this recommendation, this draft recommendation. I have a question about the last sentence that the processors are responsible for the safety of what comes into them. Without offering any guidance about that, would it be appropriate? I don't want to vote against this. On the other hand, I'm not very comfortable about voting for it.

Would it be appropriate to defer action until the next meeting with a request that FDA consider revising the wording? I think the intent is fine. I have no particular quarrel with the intent of the changes proposed by the industry, but I think it needs some tightening up.

CHAIR PRIOLA: Well, I think in a way that's what the FDA is actually asking us to discuss. Given what we have heard today and the current discussion, how can we modify this or should we modify it in a way that addresses the concerns of the Committee? So this, I would think would be an opportunity to make that known, how you would want to do that.

BOARD MEMBER BAILAR: I'm not sure we can modify it on the fly this way. That's why I would like to allow a little bit of time for people who know a lot more about the process, the problems, than some of us on the Committee, and time for some reflection about the implications of any changes.

BOARD MEMBER WOLFE: I would agree with John, because I think based on what Lisa has said, which, I think, amplifies the understanding of the process somewhat and what other people are saying, that the FDA has gotten some input from us, which is what Question 2B is, and it would make most sense for us to get at the next meeting the new version of the recommendation to vote on.

CHAIR PRIOLA: Do you have suggestions for changes that we can make? I mean, we still have to actually vote on Question 2A, but would you have suggested for recommendations?

BOARD MEMBER WOLFE: I mean, defining, as Lisa suggested, what a BSE-free herd is, sorting out the differences between directly after, immediately after, first process or just after. I mean, there are three different ways of describing in the current recommendation the timing between slaughter and removal of spine, spinal cord and so forth, so I think, I mean, those are, I think, two areas that need to be neatened or tightened up.

CHAIR PRIOLA: Yes. Dr. Khabbaz?

BOARD MEMBER KHABBAZ: Yes, it's a question to the FDA. Can we vote on this recommendation and then leave to the FDA to wordsmith the BSE-free herd and the timing of removal based on the discussion that they heard?

DR. CHIU: I think we definitely can go back to before BSE-free herd, you know. We have some id