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Freeze-drying, Formulation and the Future of Lyophilisation

Interview by Helen Winsor, Pharma IQ

Pharma IQ speaks to Michael Pikal, Professor of Pharmaceutics at the University of

Connecticut, who explains why lyophilisation is so difficult to get right and why the regulatory landscape is often misunderstood

Pharma IQ: To start could you give me a little bit of background, to introduce yourself to the audience? M Pikal: Going way back, I was formally trained as a physical chemist, spent a little time in academia, and then joined Eli Lilly & Company quite a number of years ago, in 1972; I started becoming involved in freeze-drying in the late 70s; I have been doing freeze-drying ever since. About 14 years ago, I left Eli Lilly and joined the Faculty here at the University of Connecticut. The research interests; our focus is on freeze-drying but because, when you freeze-dry you’re dealing with amorphous solids, that is, what you produce is commonly either totally amorphous in the glassy state or a mixture of crystal and amorphous materials. We’re also interested in characterisation of amorphous materials and keeping in mind, of course, that when you freeze-dry you’re really doing so to confer stability on the product, and so we’re interested in the relationship between, let’s say, physical properties and the chemical and physical stability. Pharma IQ: That was a great introduction Mike. So, firstly, what do you see to be the keys to a successful lyophilisation process? M Pikal: I sometimes say, when I’m lecturing on freeze-drying, that the first thing you do is to purchase a freeze-dryer, but before you turn on the switch you also purchase materials characterization equipment and determine the materials’ properties that are key to freeze-drying, and this is, in particular, collapse temperature or perhaps, say, Tg’ with a DSC. You need to have some idea of what the target product temperature must be, otherwise you are very much flying blind and can waste an enormous amount of time and even, indeed, if you succeed you’ll never know whether you’re at a threshold of a disaster or not. So, materials characterisation; secondly, the freeze-dryer that you purchase really needs to be, let’s say, adequate in terms of the controls and process analytical technology available. Certainly monitoring product temperature is important although, frankly, in the manufacturing environment that is very difficult to do using any kind of temperature sensors in the product. There are other technologies emerging but really what I’m talking about with PAT is things that are very simple which basically allow you to determine, for example, when primary drying is over, and this is rather generally, I think, understood but unfortunately frequently not utilised, at least not properly utilised. Finally, you need to know what to do with the materials’ properties you measure and with this freeze-dryer that is capable of performing well, so you have to read the literature. There aren’t too many institutions that I know of that give you a formal training in freeze-drying or anything close to it, and so to become somewhat expert in freeze-drying, at least sufficient to perform, you have to take it upon yourself to look through the literature and there are, unfortunately, not a lot of, let’s say, text books out there, but there is a rather extensive review literature and the original science literature. It’s been developing quite a lot over the past 20 years or so, and you go to conferences. Pharma IQ: Now the key question on everybody’s lips, and we’d appreciate your perspective - does lyophilisation have a future in the biopharmaceutical world?

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M Pikal: I don’t think there’s any question of that. The biopharmaceutical world is growing rapidly. There are those who will claim it will overtake the small molecule drugs – I don’t happen to believe that – but certainly it is, I believe, basically a valid statement at this point to say that the biotech products are growing. Many of them are relatively unstable and while you don’t want to freeze-dry if the solution formulation has sufficient stability for the use intended, the fact is that a little over half of the biotech products are freeze-dried and they’re freeze-dried for a reason. They’re freeze-dried because the stability is not adequate and there is, I think, increasing attention being focused on instability issues, particularly with regard to possible impact on the patient, that is, negative impact on the patient. In the past few years there have been several conferences organised around the theme of aggregation and the immune response to aggregates being produced, and so you certainly want to maximise purity, at least avoid the impurities, the aggregates, that basically have a toxicology effect. So, freeze-drying is the classic way of biopreservation. It’s probably generally the best way for a variety of reasons – it’s not the only way - but I think freeze-drying is certainly here to stay and I think it’s going to expand in importance along with the biotech field. Again, I don’t think everything’s going to be freeze-dried but many of the products will need to be. Pharma IQ: Obviously there are certain problems with lyophilisation. Why is it so difficult to get lyophilisation right, and also, why are there so few world experts like yourself in the field? M Pikal: That is kind of a complex question, although you put it simply. First of all, I think, as with many other, let’s say, processes or areas of study, if you approach the topic, assuming it’s going to be routine, and all you have to do is plug in your freeze-dryer, throw the switch, and arbitrarily set a programme, you’re probably going to be in trouble. The process involves a lot of physics, and engineering concepts; they’re not that difficult but you have to give the area some respect and, again, look at the literature. Don’t treat this as a routine operation. It is a science. And, I think one needs to... you probably don’t have to devote an enormous amount of time to being a true expert, but you do have to actually do some studying. You have to have some think time. Unfortunately in the industry, these days in particular, there is often little time for the people doing freeze-drying, whether it’s formulation, process or both, to actually take time to read the literature and to think, to go to conferences, and they’re expected to push product out the door without thinking, and I believe that’s a rather serious error in judgement on the part of their management and, well indeed, themselves. Really, the difficulty is industry seems to have moved, over the years, to having mostly generalists. There are many companies, of course, that do treasure having people with a high degree of expertise, but this is, I think, the exception rather than the rule, at least that’s what I see in the US; I have less familiarity with Europe. But, unless you have individuals around in the company who have devoted a fair amount of time to a particular technology, whether it’s material science or freeze-drying, or whatever it is, you’re not going to be able to do anything but address the most routine of situations, and any time you run into a difficulty that’s not solved by the standard procedure, then basically you’re in trouble. In academia we have very few academic institutions being involved in freeze-drying. There are several in the US, there are several more in Europe, but there are very few, and the reason for that, quite simply, is those of us in academia need to survive on grant money. The universities don’t put money into the research programme. At best they pay for our salaries or most of it, but if you’re going to do research in an area you have to have financial support and historically financial support for this kind of work, pharmaceutical technology in general, but certainly freeze-drying is one example, research support has been lacking. And what that really means is you’re not going to have a large number of academics pursuing this, and that’s a problem here in the US. It’s, I think, a problem probably also in Europe. I can list probably a half a dozen or so laboratories in the world that actually have a very, very high focus on freeze-drying, and that’s not very much. Pharma IQ: It’s great to get your perspective and it will be interesting to see how it goes, moving forward, as it’s such a key area. Now, to move on to the regulatory landscape, in the lyophilisation field, it’s often misunderstood and sometimes not understood at all. Why do you think this is and how can it be improved?

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M Pikal: Well, I think, again, it’s the lack of effective scientific dialogue between the scientists in industry, academia and the FDA here, and regulatory bodies, let’s say, across the world. Expertise in freeze-drying does exist to some extent in the regulatory bodies but not a whole lot. In fact, we’re working with the FDA ourselves here and there’s a group of universities over here that have formed a consortium called The National Institute for Pharmaceutical Technology and Education, so-called NIPTE, and we’re working with the FDA to try to educate the FDA in some key technologies and freeze-drying is one of them; it’s certainly not the only one. But I think there needs to be more discussion back and forth, more training of the folks at the regulatory agencies who are responsible for reviewing submissions, in particular, but also for inspections, and we’re in the process of doing that. We just started just a few months ago with a formal programme and I hope that sort of thing catches on around the world because I think that’s very much needed. The other thing that I have seen over the years that I find rather disturbing is that there is oftentimes very much an adversarial relationship between, for example, the FDA and the folks in industry. Again, not always certainly, but there is oftentimes the attitude on the part of industry that says, tell me what I must do to stay out of jail, rather than, let’s work out together what really should be done and know why. And so, again, it’s, I think, the lack of a scientific dialogue and more of a legalistic attitude like, what are the rules, tell me what I must do, what boxes I must check? With that kind of an attitude I think the regulatory situation is going to continue to be very poor, but I do have some hope that things are changing. Pharma IQ: Now, your life’s work has been dedicated to freeze-drying, do you feel that the younger generations will be able to carry on your work, and also do you see any current or future advances in the pipeline? M Pikal: Actually the answer to the first part of that goes back to what I said just a few minutes ago about reasons for there not being a lot of experts around, either in industry or academia. Again, industry because of the focus on generalists and not specialists, and in academia because of the issue with financial support for this kind of work which won’t get done otherwise, and so unless the situation changes I think the answer is no. Again, I have some hope that it will change. For one thing the area is important; it’s becoming more important. I think industry is recognising that and, at least, my hope is that much of industry will follow what, frankly, some of industry has done. There are companies out there that have very strong expertise in the core technologies that the company really must rely upon, including freeze-drying. However, there are a lot of organisations that need to play catch-up. There is also an awful lot of reliance on contract development these days, and again, the contract development organisations, I would argue, have lagged behind the best of the pharmaceutical companies in terms of their expertise in freeze-drying. Hopefully that will change; I don’t know whether it will or not. It may not be consistent with their business model to actually develop experts, and so it’s a little hard to predict. I think the younger generation certainly can carry on the work. There have been a number of young folks getting involved with freeze-drying and doing a very good job, both in academia and industry. Some of these are my former students and students of some of my colleagues, and that’s good to see. Well, hopefully that will continue and intensify. But, again, in order to really build and intensify we’re going to have to have a change in the... well basically in the grant support mechanism for universities and, I would argue again, a change in the attitude on the part of at least much of industry with regard to the desirability of establishing experts. Pharma IQ: Now to move on to the final topic of our interview today, areas like formulation and scale-up seem to be the perennial scourges to lyophilisation. How would you advise scientists to deal with these two factors? M Pikal: There are formulation guidelines that do exist as a result of some review publications. I’ve been a part of several of those. And, again, I think what you do is you start with some knowledge from the past and you try to build on that. Now, the generalisations are a very good starting point and, in fact, in many cases that’s really about all you need. However, particularly with proteins and, let’s say, biotech products in general, there are oftentimes specific characteristics that you need to be aware of. You have to know a little bit

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about the chemistry of the API because you may have, let’s say, specific things that are key for your protein but not for others. A simple example of that is that there are some proteins that require, for activity, presence of a divalent metal, and if you put in something that will complex all divalent metals that’s obviously not going to be a good thing. There are a number of cases of systems that undergo oxidations which are somewhat mysterious and can be catalysed by a variety of things, and so in that case maybe a divalent metal is not what you want. So, there are specific chemistry requirements, I would say, that need to be recognised, and then basically you use the general knowledge, along with the specific information for your particular compound, and that gets you into what would be a reasonably well-defined design space, and then you do a series of experiments. You can do statistically based experiments, design of experiments or not, depending on the situation, but you basically need to use the knowledge base that you have in order to reduce the number of experiments to a manageable number and then you do what amounts to some screening studies. Usually you can have success. Sometimes it comes easy and sometimes not. If you have three months to come up with a formulation and a process, that may or may not work. If not, hopefully your management will be sympathetic to the variation in difficulty that may come from, let’s say, the product line that you’re asked to serve. With regard to scale-up, some of the problem with scale-up I think is that there has not been all that much fundamental work done on process and scale-up, not nearly as much as on formulation. And so the available literature is not quite, let’s say, all inclusive and perhaps not quite as useful. We still probably don’t have, simple-to-use guidelines for scale-up. In fact, we’re working on some of that now, but it’s not really all that user friendly at this point. And so we need to work a little harder, I think, in that area. One thing I would say, though, is that scale-up would be far easier if, in fact, good process analytical technology were used on both the lab and manufacturing dryer. We have had some very simple PAT techniques around for a very long time. They are used in industry on occasion but, generally speaking, they’re not used. The process does not usually run the same in manufacturing as it does in the laboratory for a variety of reasons. The principal issue is usually the difference in the ice nucleation behaviour, because in the laboratory there is a lot of particulate matter around and you don’t get as much super cooling as you would in a manufacturing operation which is being run in a Class 100 area, and that induces a bias in the ice crystal structure between, let’s say, a lab run and a manufacturing run. That has implications for the mass transfer because, in fact, the ice structure is really what makes the pore structure in the drying cake, and that pore structure is what dictates how fast the water gets out and determines the mass transfer coefficient. So, the bottom line is in manufacturing you are actually freeze-drying something that you actually haven’t studied in the laboratory, and that gap is the scale-up issue. There are ways to deal with that but, again, typically people don’t take advantage of what is already known and then, as I said earlier, we actually do need to do a bit more work on trying to develop new concepts, new technologies, and people are working on that, so there is more coming. Pharma IQ: Thanks, Mike, for your insight, and some great tips there which I’m sure will be of note to scientists in this field. Thank you. Now, just to round off, looking at the conference programme for the event in January, what do you think will be the most important or valuable talking point, for industry and regulators, to come out of the programme? And also I’d like to know what you’re looking to gain, from your own participation. M Pikal: First of all what I hope to gain is I can preach on some of the things I believe in strongly and then try and persuade people to use good process control; for example, control of ice nucleation, is the topic that I’m going to address. It’s one of many topics but, as I just indicated in the answer to the previous question, it’s, I think, a very important one. And then there’s an opportunity to network with people who I know, in particular some people I know who I don’t see very often. You have a pretty good representation from Europe. Some of the folks I deal with a lot. Mansoor Khan, we work with all the time. He is at the FDA and he has been a participant in some of our joint projects, and certainly Charlie Tang, a former student, he’s just not very far from Connecticut. But some of the rest of these, for example, Professor Barresi, who I have met but I really don’t know very well, the conference will give me an opportunity to talk with him and network with him; he’s interested in some of the same things

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that we’re interested in, basically impact of variance in input characteristics on the variance in product quality. Not everything in the freeze-drying batch dries exactly the same way and it does pay to know what the spread is if you’re going to try to design a robust process. The topics range really from formulation to processing and I would think that all people who attend would get something out of each field. There is a fair amount in here on processing, more than you would typically find, and that’s probably a strength of the programme. But I think even if you’re interest is mostly in formulation you’re going to get a fair amount out of the programme, and I would, frankly, advise anyone doing freeze-drying that you really cannot separate formulation and process completely. The formation clearly impacts the design of the process but, in fact, how you run the process can change the material characteristics and therefore can change the behaviour of the formulation. So, these are all together and one really has to understand both process and formulation if you’re going to do freeze-drying. It’s, I think, a pretty good programme. It’s got a lot of balance. You’re into some things that are, let’s say, pure pharmaceutical technology nuts and bolts, into formulation issues, regulatory issues, and discussion of vaccines which is certainly timely, so that’s, I guess, my take on the programme and what people should be able to get out of it. And if you’re an attendee you do have the opportunity to talk with everybody; the experts, the non-experts and, frankly, you can learn from both. Pharma IQ: Thank you so much, Mike. We’re delighted to have you chairing this event and we look forward to seeing you in January and to hearing more on the subject. M Pikal: Thank you for the opportunity.

Michael Pikal will be chairing the forthcoming Lyophilisation for Biologics conference, from 24

th-25

th January 2011 at the NH Hotel du Grand Sablon, Brussels, Belgium, where you can

find out more about developing best practice approaches for optimising formulation, enhancing homogeneity, and improving your freeze-drying processes. For further details please visit: www.lyophlizationevent.com, email enquire@iqpc.co.uk or call +44 (0)20 7368 9300.

IQPC

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