U. S. Department of health and human services public health service food and drug administration



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I want to now get into how you make the fundamental basics for derivatives where you take the fatty acid that we've gone through the process of high temperature and pressure and time. Now you're going to go into some of the more downstream derivatives that are used in food applications and pharmaceuticals. This is ethylene glycol monostearate. This is a standard item that you quite extensively out there -- where you're going to react the glycol with the stearic acid. It's a batch operation. It takes about 16 hours. Your temperature is about 204 to 221 degrees C and you're operating at atmospheric pressure. You'll get ethylene glycol monostearate.

Now the way we quality control those operations is, you're running an acid number and you want your acid number to go basically below one. That tells you you have very little free fatty acid left in the product. The way you control some of the other operations, you're always running acid numbers and sap numbers. Between those values, you instantly know how complete your reactions are.

This is how we take stearic acid and react ethylene oxide to it. Most of our systems are built like this in direct food additives. This is where you take ethylene oxide and you're going to react it with stearic acid. Now, this, again, is a batch operation under a very closed system and under a nitrogen atmosphere. You can not react ethylene oxide in the presence of any oxygen you have -- explosion. So, the system is totally under an inert atmosphere the entire operation. It takes about nine hours, 132 to 138 degrees C, 55 to 60 psi which is about four bars. You wind up with stearic acid hytoxilate.

Now, the number of moles of ethylene oxide can vary from very few all the way up to very many, depending on whether you're trying to balance an emulsifier system to be water soluble or oil soluble. Again, these are used in baking goods and very extensively so.

This is where you take stearyl alcohol and you react it. We're going to take stearic acid and go to stearyl alcohol. Let's give you a set of conditions. This is a batch operation where your time is 2.5 hours. Your temperature is about 320 to 340 degrees C. Your pressure is very high at over 4,000 psi. You wind up with stearyl alcohol and a catalyst. Obviously, you're doing hydrogenation to get to here. It's a metallic catalyst and it's very expensive and very difficult to do. It takes very specialized equipment to take these kinds of pressures and to handle hydrogenation. All companies that do that are very, very cognizant of the fact that hydrogen will explode very easily. Therefore, when I was alluding to a company in Europe whose headquarters is there and has plants in the United States, it's quite common for them to do partial hydrogenation and bring that product into the United States before finalizing it into their intermediates. I think if you really looked, you'll see where your importation from Germany comes from.

This is where you take cetyl/stearyl alcohol which is used in quite a number of topical applications and pharmaceuticals and you're going to ethoxylate it, basically the same way you do fatty acids except the conditions are slightly different. Your time is about five hours. Your temperature is 135 to 140 C. Your pressure is about 56 to 60 psi. Again, this is about four bars. You'll get a cetyl/stearyl alcohol ethoxylate. These are used in cosmetics -- very extensively in cosmetic formulations. They're also used in pharmaceutical topical applications. Almost all types of things that are used in facial creams and what-have-you have cetyl/stearyl alcohol or cetyl/stearyl alcohol ethoxylates in them.

This is where you add propylene oxide to it and these are products that are going to pharmaceuticals. They have a moisturizing effect and the PO is reacted slightly different than ethylene oxide. Propylene oxide does not react as high a temperature. It takes much, much longer to react. It's a very slow reaction, 24 hours, about 112 to 114 C and about 34 to 36 pounds per square inch or about two bars. The reason you do this, propylene oxide if subjected to harsher conditions will form a propanol content which has a potential of creating side reactions that are adverse to what you want to produce. So, it's a much slower reaction. Again, your catalyst here is either sodium hydroxide or potassium hydroxide. You have it under a base condition. The entire thing is under nitrogen atmosphere pressure.

Now I want to talk about going to the nitriles. These are used in pharmaceuticals in small amount. Then we'll go from the nitriles to the amines. This is a very large market area. If you take hydrogenated tallow, fatty acid, ammonia and a catalyst, your time is about eight hours. Your temperature is about 271 C to 282 degrees C. Your pressure is 50 to 60 psi or about four bars. You wind up with a hydrogenated tallow nitrile. This is a first step going to an amine. The nitrile is actually used, to a very small extent, in certain pharmaceuticals.

You take the hydrogenated tallow nitrile, more ammonia, hydrogen and a catalyst, and about three hours at 138 to 143 degrees C, 340 to 550 psi and you will wind up with tallow amine. I do not have a slide, but then you take the tallow amine and you distill it just the same way you distilled the tallow fatty acid, and you get the separated different amines. You get the stearyl amine, oleo amine, and the C16 amines.

Now, this same identical process is used in inedible tallow when we want to go through this process and take the amine and further derivatize it all the way to a fabric softener. This is the exact process that's used. You take it -- if you're going to go to a quaternammonia compound, you would take the particular amine -- you can take tallow amine directly or you can take stearyl amine or allyl amine and you react it with methyl chloride. You take it to a tertiary mean and then you react it with either dimethyl sulphate if you want the sulphate quot, or you react it with methyl chloride again and you'll have the chloride quot. This is how your bactericidal quots are made. Again, the particular one on the methyl chloride reaction is at high temperature and pressure. I'm sorry. I do not have a slide for that, but that's also done under a closed inert atmosphere of nitrogen.

Typical tallow mean distillation is basically the same, about four hours, 274 to 320 degrees C, and you're doing it under vacuum. You do not have a color problem and color deterioration. Now, this morning, there were questions asked on colors and what about the users of tallow and higher temperatures. Color is very critical and renderers know that. We specify any material coming into our plant. We have contracts. We have specified no head material can come into our plant. That's in a contract with our suppliers. Since we buy the quantity of tallow that we buy, we can dictate how they're going to process it, and they have to certify it.

The safety measures along these lines are going to be covered by Dennis in a later presentation. But one of the measures that the manufacturers and processors of tallow all do is, we specify the conditions of what we want, what we'll buy. If we want certain things left out, that's put in the contract. I assure you that the people who sell to us have no problem complying with those requirements. We do not need the tallow to be discolored because the conditions we're going to operate under far exceed anything the renderer could possibly do. As you've seen here -- this is what I've already presented -- the temperatures and pressures and times and conditions we're operating under far exceed anything in the rendering industry.

You can not make the products unless you do the conditions that I have outlined. They just won't happen. Industry has far exceeded all the conditions, and those were minimum conditions that we're referencing to back to Dr. Taylor's work. What we want you to do is look at the conditions we operate under and the conditions that products are manufactured under and why they're manufactured that way.

Taking a look -- this is a comparison and it's just a summary average of Dr. Taylor's 20 minutes versus three to four hours, 133 degrees to 248 to 271 C and 48 or 3 bars to 710 to 730 psi. We're operating under much, much higher conditions. Now the question on something going up a distillation tower, what we actually do when we distill tallow, fatty acid, we take it to the gaseous state and recondense it. It actually goes from a liquid to a gas and condenses back to a liquid. You will not get a protein molecule to do that.

Well, I think I'm out of slides, so let me sum up this. I've tried to not give you all the different ways you can make derivatives and I tried to laboriously tell you all the different products. Witco makes -- between blends and actual products -- over 1,000 derivatives and products off of tallow. We're not the biggest in the world, but we're one of the largest. We do not do any rendering. We purchase our tallow and it is purchased under contract to our specifications. Those specifications, we go -- and Dennis will cover exactly how we maintain those specifications. There's a program set in place that substantiates industry's position, and what we do, and how we do this. Again, it's not uncommon for multinational companies to do partial processing in one plant and ship to another plant. That other plant can very well be in another country. It will very well show an importation in that country, but what really got shipped was not necessarily the way the tariff is set up on it.

I think that I again want to stress the importance. We showed you the time, temperature and pressure. We do our splitting in the temperature in there -- when I say we take the fatty acids to the vapor phase, that we use counter flowing steam to separate the fatty acid from the glycerine. That's high pressure steam and it's counter flowed. It's a continuous operation.

With that, I'm going to end my speech and I'll try to answer any questions someone might have.

(Applause.)

CHAIRMAN BROWN: Thank you, Dr. Green.

Committee questions?

Yes, Will?

DR. HUESTON: You just talked about hydrogenation. That takes you from a soft tallow to a hard tallow, correct?

DR. GREEN: Yes, yes.

DR. HUESTON: Now, does saponification begin with hard tallow, or do you start saponification with soft tallow?

DR. GREEN: You can do it either way.

DR. HUESTON: Okay. And transesterification, does that start with hard or soft tallow?

DR. GREEN: Again, you can do it either way there. But as a rule, most large true-put units do some partial hydrogenation. There's a reason for that. It aids in the way you get the processing to go. We do a partial hydrogenation on all tallow in our facilities where we run it through a unit.

DR. HUESTON: One other question, and you touched on it there at the end. All of the tallow that's coming to you has some level of impurities, in other words, some level of protein residual. Now, in this process, what happens to the protein residual? If you're cracking or splitting and you're vaporizing, then you say that proteins don't vaporize. So, the proteins --

DR. GREEN: You would wind up in a still bottom. You have still bottoms which go out as greases. I don't think I can say it. You can not get a still to go dry. If you do, you're going to have a detonation. You've always got a little bit of a still bottom.

CHAIRMAN BROWN: Leon?

MR. FAITEK: Dr., do you buy both edible and inedible tallow for your products?

DR. GREEN: We process both edible and inedible, but anything that goes into food or pharmaceuticals is strictly made from edible.

MR. FAITEK: Thank you.

CHAIRMAN BROWN: Other questions?

In the series of slides that you showed, Dr. Green, I got a bit lost in terms of the following question. There were a few processes in which -- I think there were perhaps one or two in which the temperature was under 100 degrees Centigrade.

DR. GREEN: Yes.

CHAIRMAN BROWN: I think you explained that input material for that had already been exposed to more rigorous conditions.

DR. GREEN: That's correct.

CHAIRMAN BROWN: There were a number of slides in which the pressure was either atmospheric or vacuum. In each of those instances, have the input material been subjected to a step in which higher pressure have been necessary?

DR. GREEN: Yes. One of the areas you're talking about is like in fused calcium stearate. The stearic acid was distilled out of tallow acid and the tallow acid was stilled out of the tallow. So, when you split the tallow, you've been through two high temperatures, high pressures. Under making calcium stearate -- you use calcium hydroxide -- you're under a very alkaline condition.

CHAIRMAN BROWN: Yes, that was my sense but I wanted to be sure that each of the ones that you showed, even when they didn't meet the combination of time, temperature and pressure --

DR. GREEN: Right.

CHAIRMAN BROWN: -- had at least at some point before that input material was processed, undergone a step in which those three criteria were met.

DR. GREEN: Yes, it is. For instance, the calcium stearate is not made in the same plant that we make the tallow fatty acid or the stearic acid. Actually, we manufacture those in one plant and do an interplant transfer. The calcium stearate is actually made in another plant.

CHAIRMAN BROWN: Ray?

DR. ROOS: How much of tallow doesn't go through these further processings and is used, I guess at the hard tallow stage?

DR. GREEN: All of our tallow goes through the processing. We do not make soaps. I gave you saponification, but Witco does not manufacture soaps. All of our hard tallow is processed. In the inedible tallow, most of it is processed into all derivatives. We never stop at a tallow that's sold as tallow. We do sell some inedible tallow fatty acids, but most of it is converted to a means.

CHAIRMAN BROWN: Other questions?

Yes, Dr. Green, you have, I think, pushed the conservatism of this Committee to its limits. About all we could require was that you added a bleach step somewhere along the line. But we'll do our best. Thank you very much, Dr. Green.

(Applause.)

CHAIRMAN BROWN: I think we can go right on to the next presentation, if that's agreeable to the Committee, without a break?

This will be a description of the manufacturing process for magnesium stearate by Philip Merrell of the Mallinckrodt Chemical Company.

DR. MERRELL: We have to set up the slide projector here, and aim it.

I'm Phil Merrell from Mallinckrodt where I do research and development on inorganic products. Magnesium stearate, being an inorganic product, is my topic today. I thank Dr. Chiu for recognizing the importance of magnesium stearate in the pharmaceutical industry. It's basically ubiquitous. Every solid dosage form -- virtually every, I don't know about every one -- virtually every size dosage form of product that goes in the pharmaceutical industry using magnesium stearate as a lubricant.

Magnesium stearate is used to the extent of about 1.5 to 2 million pounds a year in the United States for pharmaceutical application. There's other applications, but the ones we're concerned with here are pharmaceutical. It's use per tablet or per solid dosage form, which can be gel caps or gelatins or tablets, is between about a half a percent to two percent -- generally, between a half percent and one percent. Somebody told me that there were some up around two percent, but that kind of makes it a pretty slick product. They're used as lubrication agents and mould release agents. It's got the long chain fatty acid, so it's slick and it allows the tablets to release from the mould, or to lubricate them as they go through the system.

Mallinckrodt is the largest supplier and I guess that's why we were invited. I am speaking about the Mallinckrodt process in this discussion here.

I need to reiterate something before we start this. We went through this a minute ago. Dr. Green alluded to the fatty acid splitting process. The product we buy is really refined fatty acid which is a mixture of palmitic and stearic acid with certain specifications. The splitting process which Dr. Green already mentioned, takes 260 degrees C, 720 pounds per square inch, and about three hours to accomplish. That produces glycerin on the one end and the fatty acid on the other. That fatty acid is then further refined -- and this step is backwards here. We'll just leave it like that -- at 260 degrees, 700 pounds per square inch for one-and-a-half to two hours. I say it gives you refined tallow acid which has the correct palmitic to stearic ratio that we need to produce a product consistently the same. There's a USP standard requirement that the product has greater than 90 percent C16 plus C18 in the magnesium stearate. So, it has gone through these two steps prior to our getting the material. We get the material then from the manufacturer. We buy refined tallow acid and go into the magnesium stearate process.

As Dr. Green said, there are two processes. One is fusion which is just simple acid base. You add the tallow acid to the calcium hydroxide or magnesium hydroxide or the zinc hydroxide, or whatever salt you're making. Our process is quite different in that we add -- we saponify first with sodium hydroxide, making a sodium tallowate which is really a mixture of sodium stearate and palmitate. Then we add magnesium sulfate in the second step. Then it's further refined by we dry it, mill it and package it.

In the saponification step, I'm going to talk about time, temperature and pressures also but you'll see -- not pressure, because we're always at atmospheric pressure, but you'll see that these are not near the extent of what it's already gone through in Dr. Green's plant. We take sodium hydroxide, tallow acid, make the sodium tallowate which is the salt. The conditions are 88 degrees Centigrade, pH is 8.5 to 9.5, and it's stirred and cooked for about an hour. Then the temperature is lowered to 75 degrees C, again for about an hour. At that point, it is separated from the water, washed -- I'm sorry.

At that point we add the magnesium sulfate to the sodium tallow solution, raise the temperature up to 88 to 90 degrees for an hour. The pH at this time is neutral, essentially. The pH is adjusted up with sodium hydroxide. Then it is diluted with water and held at 170 for about two hours -- I'm sorry, 77 degrees C for about two hours. At this point, it is filtered out and washed. The drying and the milling steps which also see some temperatures but only for seconds, we flash dry it and then mill it all in one big step. Those temperatures are 121 to 160 and they're only at those temperatures for seconds. Then we just package it and that's really the extent to this process.

The tallow acid that we buy has been treated twice by very high temperatures and very high pressures and long times. The process itself does not have all those extreme temperatures. That's it. Thank you.

CHAIRMAN BROWN: Thank you very much.

(Applause.)

CHAIRMAN BROWN: Questions?

Then we'll proceed to the next presentation by Stan Gorak on the manufacturing processes for polysorbates.

MR. GORAK: Thank you and good afternoon. I'd like to thank Dr. Chiu for inviting me to the presentation and to the Committee for allowing me to present the processing conditions associated with the manufacturing of polysorbates.

I show here the structure of polysorbates. Polysorbates are polyoxyethylene sorbitan esters. This is the structure as shown in the USP/NF. The center of the molecule here is basically derived from sorbitol which is anhydrized. The sorbitol is then reacted with the fatty acid, hence my invitation to this meeting. It's then further reacted with ethylene oxide which reacts at active hydroxyl groups.

The polysorbates as listed in the USP/NF include polysorbates 20, 40, 60, and 80. All have 20 moles of ethylene oxide which is added into the molecule. The difference between them being the fatty acid which is used to start, lauric for polysorbate 20, palmitic for 40, stearic/palmitic listed for polysorbate 60, and oleic for polysorbate 80.

Polysorbates are used in a wide variety of applications. They're a pharmaceutical excipient. They're approved as direct and indirect food additives. They are used in cosmetics, industrial applications, as well as agricultural applications. To get to the polysorbate, there's multiple processing steps involved from tallow. We've heard discussions on tallow and fatty acid. What I'll address in this presentation is the processing for the sorbitan ester and the polysorbate. The sorbitan ester is an intermediate to polysorbate. It is also sold as a product of its own, and it's also listed in the USP/NF as well as food chemicals codex.

I won't go into the structure of the fatty acids that much. We've seen that addressed already. Lauric acid, predominantly a source from coconut, palm kernel and other vegetable kinds of sources to arrive with the fatty acid. Palmitic acid is primarily derived from tallow. There are also some vegetable sources. Stearic acid is also primarily derived from tallow as is oleic with some vegetable sources for both also available. Predominantly, the tallow is used though because of availability and economics. The vegetable sources are used primarily for kosher grade products.

I'll address the sorbitan esters, the structure and processing conditions of them. Sorbitan esters, the first step is the sorbitol undergoes the anhydration to ring closure with elimination of water. This compound is then stearified with the fatty acid to form the sorbitan ester. The reaction is done under atmospheric pressure. The reaction mass sees temperatures at or above 200 degrees Centigrade for a period of about nine to 13 hours, depending on the product that's being made. Of that nine to 13 hours, approximately one to five hours is at or above 250 degrees Centigrade.

Polysorbates, I'll address also the structure and process conditions. The polysorbates are formed by taking the sorbitan ester and reacting it with ethylene oxide. This 3-ring epoxide adding itself to the active hydroxyl groups and forming a polyoxyethylene chain at each of those. The processing conditions for the reaction mass, which also includes a basic catalyst, both reactions, the stearification as well as the oxyethethylation are basic catalyzed. The reaction mass sees a temperature of greater than or equal to 130 degrees Centigrade for six to eight hours. Of that time, it sees greater than or equal to 150 degrees Centigrade at 30 to 45 psig for a period of four to six hours. Again, it's dependent on the kind of product that's being made.

The materials as excipients are made in conformance to GMPs. One of the presentations earlier showed the big vat with the man stirring the vat to make soap. Obviously, all the processes we've been discussing today are carried out in closed systems and under good GMP and conditions and clean systems. The products themselves that are manufactured are tested, including testing conformance to USP/NF and/or food chemicals codex requirements. The materials we purchase in the fatty acids are all certified to us by the suppliers and we, to our customers, are required to supply certificates of analysis on the quality of our material. We're subject to internal and external audits. External audits, both by our customers which tend to be very critical and grueling, having their very specific requirements, and we're also subject to FDA audit.

So, to summarize, the fatty acids that we use as our starting material have already been processed at elevated temperatures and pressures that we've already seen earlier in the presentations. The intermediate sorbitan esters and the polysorbates are manufactured at temperatures which at times exceed 250 degrees Centigrade, or see pressures of 30 to 45 psig at elevated temperatures for extended periods. Also, we do use bleach in one of the steps. There was a comment earlier about had everything but bleach. We've thrown bleach in. Also, ethylene oxide is a key reactant to making the polysorbate molecule and it's a well recognized known sterilant.

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