Introduction to Pharmaceutical Excipients

- Speaker A introduces the general introduction of session one. Speaker A asks people to take a seat. Speaker B will introduce the three speakers and Speaker C will go into the morning break. - Speaker A introduces the three speakers as part of the general introduction this morning. Speaker A Chris Morton, Speaker B Stephanie Choi, and Speaker C Tony Tongue. Speaker B Chris asks Speaker C to refer to the package. - Katherine is giving a presentation on the views of the United States Pharmacopoeia Convention and their interests. She introduces the definition of excipients and introduces the learning objectives for today's presentation. - Speaker B describes the definition of pharmaceutical excipients in the USPNF and argues that the therapeutic revolution of the last approximately 100 years would not have occurred without it. - Speaker B tells the audience that pharmaceutical excipients are there to overcome the limitations of the active drug. They are a very diverse group of materials with many different types and applications. - Speaker B tells the audience about the list of excipients by functional category taken from the uspnf. Speaker A shows the number of categories and Speaker B shows more categories will be added.

Speaker A: So good morning everybody. Before I start off session one, may I ask for those standing up in the back? Please feel free to take a seat. There are still plenty of seats. In order to keep us on track, we have quite a few speakers lined up. So session one this morning, the general introduction which will ease us nicely into the whole discussion for the next two days. What I will do is I am going to introduce the three speakers right now and we will then go into our morning break which is 10:30 to 10:45. So our three speakers that we have as part of the general introduction this morning. We will begin with Dr. Chris Morton who is vice chair of the excipients expert committee monographs 1. He will give the true introduction to pharmaceutical excipients. Chris is followed then by Dr. Stephanie Choi, delighted that she can make it here. And her presentation will be on impact of excipient grade. She will explain to you the Q1 Q2 on the bioequivalence of generic drug products. And then third speaker Dr. Tony Tongue from GNW Laboratories will speak about impact of excipient quality attributes on the bioequivalence of complex drug products. So again I would ask that you refer to your package. All the speaker's bio abstract is there but in the interest of time I will now hand it over to Dr. Morton. Thank you.

Speaker B: Thank you very much Katherine. Good morning everybody and thank you for the opportunity to speak to you today. This is going to be very simple. Overview of Excipients Excipients101 if you think about it, some people may know most of it, some people may know all of it. But I suspect that quite a few people will still find out things they didn't really know about excipients. I've been working with them for 40 odd years. I still find out things that I didn't know about. So first a disclaimer. I'm here on behalf of usp. So these are the views of the United States Pharmacopoeia Convention and their interests. I have very similar views, but maybe they don't always coincide. But that's part of being a volunteer. So here are the learning objectives for today's presentation. At the end of this I hope you'll be able to demonstrate an understanding of what excipients are and what they're not. The kinds of materials that we use and the range, how complex excipients are. And even simple molecules can be complex. When it comes to excipients I will talk about General Chapter 1059 very briefly, excipient performance, which I think is a very useful general chapter, particularly for formulation scientists. And that's really what I am. I'll talk about excipient sources and composition, excipient variability, which has already been mentioned and also a very current hot topic, excipients in continuous pharmaceutical product manufacture. So this is my presentation, outline a little bit of background, address the inactive versus inert debate, excipient safety and USP monographs, excipient composition, why we use excipients and also excipients for biotechnology drugs, excipient performance, excipient variability and the use of excipients in continuous processing. And I'll finish with summary and conclusion. So let's start with excipients in general. And here's a couple of definitions. One is a lot older than the other one. Lou Blecker, sadly is no longer with us. He came up in 1991 with a definition with all other components of a drug formulation other than the active drug. And if you look At General Chapter 1078 in the USPNF, you will see a definition for excipients there. Excipients are substances other than the API that are intentionally included in a drug delivery system. And these are very similar in intent and meaning. The USP is a little bit more precise as is as it should be. But if we think about pharmaceutical excipients, they're kind of I've described in the past as the Cinderellas of formulation science. They don't get invited to the ball, but without them the ball doesn't occur. So they don't treat the disease or improve the patient's condition. But I would argue that the therapeutic revolution of the last approximately 100 years would not have occurred without excipients. And I'll discuss a little bit more of that going forward because excipients, they are there to overcome the limitations of the active drug. Pharmaceutical excipients are a very diverse group of materials. We have inorganic salts. We have carbohydrates. We have oils, fats and waxes, synthetic materials, semisynthetic materials, natural products. We have products that are mined. We have products that come from the vegetables, the plant side of things. We have excipients that come from animals. We have representatives of all the states of matter, gas, liquid, solid and semi solid. If you want to be persnickety, they're very often manufactured at very large scales, thousands of tons, tens of thousands of tons per annum. And we maybe use 10% of that or less. Where does the rest of it go? You don't want to know sometimes. But things like food, industrial products. Who knew that MCC microcrystalline cellulose, a major pharmaceutical excipient, has a use in the manufacture of welding rods? Now I didn't know that until I worked for an MCC company, but they do. Apparently there are many different types and applications. And if we contrast excipients and active drugs, excipients are used in many thousands of products. One excipient may be used in a thousand or more products. One particular API may be used in 10, 5, 20. That's about it. Like I said, there are many applications and many types of excipients. And this is taken from the uspnf. It's the list of excipients by functional category. And we have to date 48 different categories. And I can tell you that many excipients appear in more than one category. So we have excipients that can be fillers, they can be disintegrants, they can be buffers, they can actually be used to create the tonicity in an injection. Just because there's a category here doesn't mean to say that excipient is exclusive to one category. And I expect the number of categories will increase over the years as we get more into the biotechnology drugs and we understand how to formulate them. We think about excipient manufacturer sources of materials. Some are harvested like in agriculture. Some are extracts. So we take a plant or an animal and we extract something from it. Some are mined. Calcium carbonate is mined, talc is mined. Calcium phosphate can be mined, though I don't recommend it for pharmaceutical use because it comes from the guano deposits on southern Pacific islands. I'm not sure you want those microbes there. Some are synthetic polyvinyl pyrrolidone, totally synthetic. Some are semi synthetic. So we take cellulose and we modify it. Some are made using batch processing. The largest batch excipient I've come across is about 800 to 1,000 kilos. And that's small by industrial standards because the barges annual output material that I've ever worked with, 60,000 tons per year, of which about 3,000 tonnes went to pharmaceutical use and the rest went wherever. But now moving on briefly to the issue of inactive or simply inertiluence, because this is a debate that's been around since I've been in pharmacy, which is almost 50 years now, they are not just inert diluents if anybody says, well, it's just an inert diluent, they're living in the prehistoric era as regards formulation science. Pharmaceutical excipients can modify various aspects of formulations and I'll cover them under this and the next couple of slides. But here we know that they can modify drug absorption. We can improve bioavailability of poorly water soluble drugs. We can inhibit efflux in the gastrointestinal tract. We can also reduce bioavailability by the inappropriate choice of excipients. And we can also enhance transdermal delivery. We can also modify the pharmacokinetic profile through modified release. We have delayed release, we have controlled extended release. And now we're getting into the era of where we're looking at receptor targeting using the advantages of excipients after administration we can impact and pharmaceutical excipients can impact drug stability. We can inhibit drug degradation. We can use buffers for optimum ph control for stability of example EstoPro Dryx. We can use antioxidants to reduce oxidative degradation. We can use chelating agents to sequester oxidation inducing metal ions. But we can also promote degradation through an inappropriate choice of an excipient. The Maillard reaction between a primary and secondary amine can be catalyzed, if you will, by things like magnesium stearate. But pharmaceutical excipients can also have physiological effect as opposed to pharmacodynamic effects. So polyols can act as osmotic laxatives. At lower doses they can speed up the gastrointestinal transit. And there's a study out there from the FDA which shows the by or inequivalence of a syrup made with sugar and sorbitol. Big difference in the pharmacokinetics of that drug and the area under the curve. Hydrophilic colloids can also act as bulk forming laxatives. And oleaginous excipients can modify skin properties by occlusion. Let's just talk briefly about excipient safety and USP monographs because this is something that I find people sometimes don't realize or don't ask the right question. The focus of the excipient monograph is on identity and composition and grade differentiation. Now we don't have to worry about efficacy for a pharmaceutical excipient because it should not have pharmacologic efficacy. Some do. And we have this gray area called atypical actives calcium and vitamin D tablets. We have calcium, we have vitamin D. Those are the two actives. But calcium carbonate or calcium phosphate, whatever we're using is also the major excipient. The USPNF expert committees on excipients do not assess the safety of the excipient per se. The only links to safety are via the assay and impurities sections of the monograph and in the general notices through statements on good manufacturing practices and the like and degradation and impurities. So this brings us into the dilemma USP monographs for a new chemical excipient can only be included in the book after the excipient is included in a commercial product approved by the FDA and thus in the FDA's Inactive Ingredient Database. So that, as Robert just mentioned, that means they're going to go through the NDA route. And that's a difficult, difficult proposition. I wrote a paper more than 20 years ago now. Things haven't changed. It's still not a great economic proposition unless you have an absolute unmet technical need that cannot be addressed in any other way. The USPNF's new monograph development process is highly dependent on the IIB, the active ingredient database. Because we're tied, we cannot do anything. We can propose that people get everything set up so that when the product is approved we can get a monograph out quickly, but we can't publish it in the book. And there is another piece of misunderstanding that a lot of people think that a type 4 drug master file that can be filed for an excipient means that the excipient is approved. It is not. It is just accepted and filed. It's only reviewed when it's mentioned in an NDA application. So let's move on to excipient composition because this is something else that creates considerable debate. Many excipients are not simple pure chemicals in the API sense. In the drug we look at 95 to 105 or 98 to 102. We look at levels of impurities, degradation products. We have limits from ICH Q3A and B and we also have the general notices statement not more than 2% total impurities. If we did that for excipients. Half perhaps. No more than that. Well, more than that. Perhaps 90% of the excipients would be off the market tomorrow because excipients are not conveniently simple molecules, all kinds of things, and particularly when we get into the polymeric materials and the oleaginous materials. So what apart from the nominal material, what else are excipients comprise of? And it depends. Depends on the excipient how it's sourced, what processes are used, what's the composition of the raw materials, what gets carried through and the reagents, what's the weather like when it's being harvested or transported. This is from the IPEC America, sorry, IPEC Excipient Composition Guide. And this is just intended to demonstrate to you how the components in the finished excipient can arise. Now, I'm not going to ask you to memorize all this. And I've expanded it in this next slide. So we've got the nominal chemical. That's what's described in the definition. We might be lucky and have a polymer molecular weight distribution, but that's very rare. But we have other things, like concomitant components, which may be necessary for performance. I can make very pure calcium phosphate today, which doesn't work as well as slightly less pure calcium phosphate. I can make a very pure polymer with a very narrow molecular weight. But in actual fact, the spread of molecular weights is important for certain applications. It's actually better sometimes to combine two to make an average than to have one at the average. We have reaction by products. We can have starting materials and reagents carried through. We can have intermediates. We can have processing aids. There's a documented example out there where a processing aid, an antioxidant, was carried through into the final formulation and stabilized the whole formulation. And when the company tried to qualify an alternate supplier which did not use antioxidants, they used nitrogen, blanketing the stability of the formulation failed. Totally unexpected. This was an existing product. You have to understand what's going on. We can have undesirable components or impurities. Some are potentially toxic monomer residues, some elemental residues. We can have reactive residues. We can have residual solvents. Some of them may be undesirable. Some of them may be desirable. Water. Sometimes it's necessary for performance. Sometimes it's totally undesirable. And we can have additives. And this is something we don't get in active drugs. If you use hydroxypropyl cellulose, you have an additive there called silica, because otherwise you won't get it out of the silo, the hopper or the bag. It just cakes. Ethylcellulose contains propyl gallate to prevent oxidation. Without it, you wouldn't be able to use it. So excipient composition is not straightforward. So please don't think that we can apply the standards that we rightly apply to APIs to excipients. Let's just remind ourselves of why we use pharmaceutical excipients. Now I'm a formulation scientist. It's what I've been doing for a long time. As I mentioned earlier, excipients overcome the problems of the active drug. They help convert the bulk active drugs into medicines that we can use. They bring properties to the formulation. They bring functionality or performance to the formulation that overcomes the difficulties of the properties of the drug. We formulate drug molecules for convenience. Most active drugs, almost without exception on their own, are totally useless. Can't be used by the patient, can't be used by the caregiver. Who knows a formulation that doesn't contain any excipients? I know of two, but they have a very special delivery system. The manufacturing techniques that we use, whether it's filling liquid into bottles or into these little eye drop containers, making tablets, making capsules, filling creams into tubes, very accurate sampling devices. We can make 500,000 tablets an hour off one machine. But we better have a formulation that will do that. The patient expects to get the accurate amount of drug. Now I might get away with giving the patient a bag of acetaminophen and say take one or two level teaspoonfuls up to three or four times a day for the pain as necessary. I'm not sure they'd like the taste. It doesn't taste very good, but it's not the worst one. I taste it. I couldn't do that with digoxin, I couldn't do that with warfarin. Narrow therapeutic index drugs, very low dose. We can get much more accurate dosing this way and much better, much more reliable medicines and it's safer for the patient. We can improve bioavailability. Look at all the BCS class 2 drugs that are being formulated. Amorphous spray dry dispersions with polymers. Without that we don't have bioavailability. As I mentioned, drugs can taste nasty. I've never tasted a sweet tasting drug. I've tasted some that are so insoluble I can't taste them. But I've never tasted a sweet tasting drug. Very often there are palatability and taste problems which we can overcome with formulation. We can reduce side effects. If the drug is absorbed too quickly and we get too high blood levels, we can run into side effects and that takes us into the whole area of modified release and so forth. Now the formulation objective is a robust medicinal product which will deliver the drug to the patient. And I put up a definition here. But in order to get that robust medicinal product, we need to understand our excipients and the limitations of those excipients. Because it's very often the limitations that govern what we have to do. We think about the components of medicinal product. We have the excipients and we have the drug. But we also need the process that gives us a product. And I've included packaging now because with all these new poorly soluble drugs where we're using amorphous spray dry dispersions and other types of formulation techniques, packaging suddenly becomes much more important for controlling degradation, controlling stability, physical stability and chemical stability. Let's just mention briefly the use of excipients in biotechnology drug products, because as I put here, caveat emptor, let the buyer beware. Very few excipients are manufactured for parental use. You have to be careful. I worked on, one of the things I do from time to time is act as an expert witness. And I worked on a case where a food grade material was upgraded to USP grade with no restrictions. It was used in an injectable product and there were a few about 10% febrile reactions. Nobody died. But there was a lawsuit and I got involved. We won, but that's beside the point. My client was discharged from the case, so that was a good win. But the point was that nobody had done an adequate due diligence. Now, when we make excipients, if we're making them at the 10,000 or more tons per year, do we control the microbiological content? And the answer is no, we don't. But in certain instances, because we're using chemical synthesis, microbes will not grow in that environment. And if they're there, they get killed and they get removed by the subsequent processing. But that still means there might be endotoxins present. We may remove the bacteria, but if they're dead bacteria, they may have released endotoxins. We also have to consider the composition profile, not only the concomitant components, but any trace reactive components, because these may be important for allergic reactions or reactions at the injection site. We have super refined grains of some excipients now available, but at a price. We've been used to paying a couple of dollars a pound excipients for a long time. But if we've got to make 10 kilos and super refine it, it's not going to be $2 a pound. It's more likely between 100 and $1,000 a pound. And we've got to get used to that kind of price differential. But we do need to understand again I'll come back to this composition and limitations of the excipients because if we don't understand that, we're going to get ourselves into trouble. Just want to briefly touch on excipient performance because this is something that has become increasingly an important hot topic. The focus of the USP excipient monograph is identity safety via the composition. Efficacy is not required because they're supposed to be inactive. But performance or function is meeting the requirements of the USPNF and the general notices. The monograph and the general notices, the two components some people forget. People think if you can test it into compliance it's good enough. No, you have to actually go and do the due diligence to check that the GMP has been adequate. So meeting the USPNF monograph and the general notices is the absolute minimum acceptable quality fitness for purpose performance in the formulation, if you will, is also very necessary. And be aware that the critical material attributes for the excipient may not be covered by tests in the monograph. And I want to develop this a bit more because how do we incorporate performance assessment into a pharmacopoeia monograph? And there are two options. We can include it in the monograph in the uspnf that monograph is mandatory testing. But how do we incorporate the testing for all the different possible uses of the excipient into one monogram? The book would be probably five times as long as it is now. Now, the European Pharmacopoeia introduced non mandatory functionality related characteristics in some of their monographs. We don't have that option with USPNF. The monograph is mandatory. We've included General Information Chapter 1059 on excipient performance. If you're a formulation scientist, this is where you need to go because this will tell you a lot more about your excipients than the monograph will from a formulation perspective. I'm not talking about controlling the excipient, I'm talking about using the excipient. Now, 1059 is a series of subsections, if you will. It's linked to the categories in the table, the excipients by functional category, which I showed you earlier. The focus is on the application of the excipient rather than the excipient itself, and the format of each section is fairly standard. We have functional category description, functional mechanism, physical properties, chemical properties and general chapters which may be of use in further characterizing this excipient for use in your particular application. This has been very much a quick look at everything I just want to go on and consider excipient variability. Now it's there, we cannot avoid it. I'm also conscious of the time, so I'll move on. Here's the components of the product. Product variability does not just rely on the variability of the bulk active the excipients in the process. There's this interaction term and if you ignore that, it will come back and bite you somewhere. What I've done here is I've just expanded that a little bit and the interactions can be. Is the sum of all interactions powder power to powder liquid. I'm not saying that every one will have an important effect on your particular application, but some will and we need to understand which will and the risk associated with it. But let's take a look briefly at variability. Here's just some data and this would be the excipient characteristic measured in the user's laboratory. And if this was the data and the green lines were our acceptance limits, I think everybody would be happy. There's enough room for a little bit of process drift, but we're well within these are three sigma limits. And that's where the pharma industry is today. At best, people are trying to get to six Sigma and I hope they succeed. But mostly we're at three sigma or less. And if we had these limits, would it be acceptable? Well, in the old days, probably. Today I'm not so sure because it wouldn't take much process drift to move out and have failing material. And these are impossible limits. Here we have one sigma limits. Approximately 60% of the batches fail. And so people say, well, why don't we do lot selection? Don't. It's a disaster waiting to happen. If you look in those little ovals, I've highlighted areas where seven and nine consecutive batches would fail. Now people do not get deliveries of excipients once a week or once a month. They're usually once a quarter or once every six months. Could you accept that? Could you wait that long for acceptable material to come in? Could the patient wait that long for their medicine? Just briefly, continuous processing. Continuous processing requires that we understand our excipients and their limitations again, and perhaps more thoroughly in a different way than for batch manufacture. In batch manufacture we can sometimes compensate using, for example, endpoint determination for a granulation. Such adjustments most likely will not be possible in continuous processing. So we need to understand to a better level what we can do, what we can't do. So in summary, this has been a very brief introduction to several of the hot topics and some of the basics. Pharmaceutical excipients are a very broad class of materials. They cover all the states of matter. They're not active drugs or finished products. We need to understand excipient composition, particularly for use in biotech products. We cannot avoid variability. We've got to come to terms with it. And like I said, excipient lot selection is a disaster waiting to happen. Continuous processing of pharmaceutical finished products will also require better and possibly different understanding of our excipients. It's the composition, it's what they do, and it's the limitations which are important. Thank you. It.