Freeze-drying, Formulation and the Future of lyophilization


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Freeze-drying, Formulation and the Future of lyophilization – Interview with Michael Pikal,
Professor of Pharmaceutics at the University of Connecticut

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Freeze-drying, Formulation and the Future of lyophilization

  1. 1. 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 ofConnecticut, who explains why lyophilisation is so difficult to get right and why the regulatory landscape is often misunderstoodPharma IQ: To start could you give me a little bit of background, to introduce yourself to theaudience?M Pikal: Going way back, I was formally trained as a physical chemist, spent a little time inacademia, and then joined Eli Lilly & Company quite a number of years ago, in 1972; I startedbecoming involved in freeze-drying in the late 70s; I have been doing freeze-drying eversince. About 14 years ago, I left Eli Lilly and joined the Faculty here at the University ofConnecticut. The research interests; our focus is on freeze-drying but because, when youfreeze-dry you’re dealing with amorphous solids, that is, what you produce is commonly eithertotally amorphous in the glassy state or a mixture of crystal and amorphous materials. We’realso 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’reinterested in the relationship between, let’s say, physical properties and the chemical andphysical stability.Pharma IQ: That was a great introduction Mike. So, firstly, what do you see to be the keys toa successful lyophilisation process?M Pikal: I sometimes say, when I’m lecturing on freeze-drying, that the first thing you do is topurchase a freeze-dryer, but before you turn on the switch you also purchase materialscharacterization 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. Youneed to have some idea of what the target product temperature must be, otherwise you arevery much flying blind and can waste an enormous amount of time and even, indeed, if yousucceed you’ll never know whether you’re at a threshold of a disaster or not. So, materialscharacterisation; 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. Certainlymonitoring product temperature is important although, frankly, in the manufacturingenvironment 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 thingsthat are very simple which basically allow you to determine, for example, when primary dryingis over, and this is rather generally, I think, understood but unfortunately frequently notutilised, 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 youhave to read the literature. There aren’t too many institutions that I know of that give you aformal training in freeze-drying or anything close to it, and so to become somewhat expert infreeze-drying, at least sufficient to perform, you have to take it upon yourself to look throughthe literature and there are, unfortunately, not a lot of, let’s say, text books out there, but thereis a rather extensive review literature and the original science literature. It’s been developingquite 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? 1
  2. 2. M Pikal: I don’t think there’s any question of that. The biopharmaceutical world is growingrapidly. There are those who will claim it will overtake the small molecule drugs – I don’thappen to believe that – but certainly it is, I believe, basically a valid statement at this point tosay that the biotech products are growing. Many of them are relatively unstable and while youdon’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, Ithink, increasing attention being focused on instability issues, particularly with regard topossible impact on the patient, that is, negative impact on the patient. In the past few yearsthere have been several conferences organised around the theme of aggregation and theimmune response to aggregates being produced, and so you certainly want to maximisepurity, 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 avariety of reasons – it’s not the only way - but I think freeze-drying is certainly here to stay andI think it’s going to expand in importance along with the biotech field. Again, I don’t thinkeverything’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 toget 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, aswith many other, let’s say, processes or areas of study, if you approach the topic, assumingit’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 involvesa lot of physics, and engineering concepts; they’re not that difficult but you have to give thearea some respect and, again, look at the literature. Don’t treat this as a routine operation. Itis a science. And, I think one needs to... you probably don’t have to devote an enormousamount of time to being a true expert, but you do have to actually do some studying. Youhave to have some think time. Unfortunately in the industry, these days in particular, there isoften little time for the people doing freeze-drying, whether it’s formulation, process or both, toactually take time to read the literature and to think, to go to conferences, and they’reexpected to push product out the door without thinking, and I believe that’s a rather seriouserror in judgement on the part of their management and, well indeed, themselves. Really, thedifficulty is industry seems to have moved, over the years, to having mostly generalists. Thereare many companies, of course, that do treasure having people with a high degree ofexpertise, but this is, I think, the exception rather than the rule, at least that’s what I see in theUS; I have less familiarity with Europe. But, unless you have individuals around in thecompany who have devoted a fair amount of time to a particular technology, whether it’smaterial science or freeze-drying, or whatever it is, you’re not going to be able to do anythingbut address the most routine of situations, and any time you run into a difficulty that’s notsolved by the standard procedure, then basically you’re in trouble.In academia we have very few academic institutions being involved in freeze-drying. Thereare several in the US, there are several more in Europe, but there are very few, and thereason for that, quite simply, is those of us in academia need to survive on grant money. Theuniversities don’t put money into the research programme. At best they pay for our salaries ormost of it, but if you’re going to do research in an area you have to have financial support andhistorically financial support for this kind of work, pharmaceutical technology in general, butcertainly freeze-drying is one example, research support has been lacking. And what thatreally means is you’re not going to have a large number of academics pursuing this, andthat’s a problem here in the US. It’s, I think, a problem probably also in Europe. I can listprobably a half a dozen or so laboratories in the world that actually have a very, very highfocus 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 thelyophilisation field, it’s often misunderstood and sometimes not understood at all. Why do youthink this is and how can it be improved? 2
  3. 3. M Pikal: Well, I think, again, it’s the lack of effective scientific dialogue between the scientistsin 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 wholelot. In fact, we’re working with the FDA ourselves here and there’s a group of universities overhere that have formed a consortium called The National Institute for PharmaceuticalTechnology and Education, so-called NIPTE, and we’re working with the FDA to try toeducate the FDA in some key technologies and freeze-drying is one of them; it’s certainly notthe only one. But I think there needs to be more discussion back and forth, more training ofthe folks at the regulatory agencies who are responsible for reviewing submissions, inparticular, but also for inspections, and we’re in the process of doing that. We just started justa few months ago with a formal programme and I hope that sort of thing catches on aroundthe 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 isoftentimes very much an adversarial relationship between, for example, the FDA and the folksin industry. Again, not always certainly, but there is oftentimes the attitude on the part ofindustry that says, tell me what I must do to stay out of jail, rather than, let’s work out togetherwhat really should be done and know why. And so, again, it’s, I think, the lack of a scientificdialogue and more of a legalistic attitude like, what are the rules, tell me what I must do, whatboxes I must check? With that kind of an attitude I think the regulatory situation is going tocontinue 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 theyounger generations will be able to carry on your work, and also do you see any current orfuture advances in the pipeline?M Pikal: Actually the answer to the first part of that goes back to what I said just a fewminutes ago about reasons for there not being a lot of experts around, either in industry oracademia. Again, industry because of the focus on generalists and not specialists, and inacademia because of the issue with financial support for this kind of work which won’t getdone otherwise, and so unless the situation changes I think the answer is no. Again, I havesome hope that it will change. For one thing the area is important; it’s becoming moreimportant. I think industry is recognising that and, at least, my hope is that much of industrywill follow what, frankly, some of industry has done. There are companies out there that havevery 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, thecontract development organisations, I would argue, have lagged behind the best of thepharmaceutical companies in terms of their expertise in freeze-drying. Hopefully that willchange; I don’t know whether it will or not. It may not be consistent with their business modelto actually develop experts, and so it’s a little hard to predict. I think the younger generationcertainly can carry on the work. There have been a number of young folks getting involvedwith freeze-drying and doing a very good job, both in academia and industry. Some of theseare 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’regoing to have to have a change in the... well basically in the grant support mechanism foruniversities and, I would argue again, a change in the attitude on the part of at least much ofindustry with regard to the desirability of establishing experts.Pharma IQ: Now to move on to the final topic of our interview today, areas like formulationand scale-up seem to be the perennial scourges to lyophilisation. How would you advisescientists to deal with these two factors?M Pikal: There are formulation guidelines that do exist as a result of some reviewpublications. I’ve been a part of several of those. And, again, I think what you do is you startwith some knowledge from the past and you try to build on that. Now, the generalisations area 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 areoftentimes specific characteristics that you need to be aware of. You have to know a little bit 3
  4. 4. about the chemistry of the API because you may have, let’s say, specific things that are keyfor your protein but not for others. A simple example of that is that there are some proteinsthat require, for activity, presence of a divalent metal, and if you put in something that willcomplex all divalent metals that’s obviously not going to be a good thing. There are a numberof cases of systems that undergo oxidations which are somewhat mysterious and can becatalysed by a variety of things, and so in that case maybe a divalent metal is not what youwant. 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 yourparticular compound, and that gets you into what would be a reasonably well-defined designspace, 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 theknowledge base that you have in order to reduce the number of experiments to a manageablenumber and then you do what amounts to some screening studies. Usually you can havesuccess. Sometimes it comes easy and sometimes not. If you have three months to come upwith a formulation and a process, that may or may not work. If not, hopefully yourmanagement will be sympathetic to the variation in difficulty that may come from, let’s say, theproduct 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 beenall that much fundamental work done on process and scale-up, not nearly as much as onformulation. And so the available literature is not quite, let’s say, all inclusive and perhaps notquite 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 sowe need to work a little harder, I think, in that area. One thing I would say, though, is thatscale-up would be far easier if, in fact, good process analytical technology were used on boththe lab and manufacturing dryer. We have had some very simple PAT techniques around fora very long time. They are used in industry on occasion but, generally speaking, they’re notused. The process does not usually run the same in manufacturing as it does in the laboratoryfor a variety of reasons. The principal issue is usually the difference in the ice nucleationbehaviour, because in the laboratory there is a lot of particulate matter around and you don’tget as much super cooling as you would in a manufacturing operation which is being run in aClass 100 area, and that induces a bias in the ice crystal structure between, let’s say, a labrun and a manufacturing run. That has implications for the mass transfer because, in fact, theice structure is really what makes the pore structure in the drying cake, and that porestructure is what dictates how fast the water gets out and determines the mass transfercoefficient.So, the bottom line is in manufacturing you are actually freeze-drying something that youactually haven’t studied in the laboratory, and that gap is the scale-up issue. There are waysto deal with that but, again, typically people don’t take advantage of what is already knownand then, as I said earlier, we actually do need to do a bit more work on trying to develop newconcepts, 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 ofnote to scientists in this field. Thank you. Now, just to round off, looking at the conferenceprogramme for the event in January, what do you think will be the most important or valuabletalking point, for industry and regulators, to come out of the programme? And also I’d like toknow 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 instrongly and then try and persuade people to use good process control; for example, controlof ice nucleation, is the topic that I’m going to address. It’s one of many topics but, as I justindicated in the answer to the previous question, it’s, I think, a very important one. And thenthere’s an opportunity to network with people who I know, in particular some people I knowwho I don’t see very often. You have a pretty good representation from Europe. Some of thefolks I deal with a lot. Mansoor Khan, we work with all the time. He is at the FDA and he hasbeen 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, ProfessorBarresi, who I have met but I really don’t know very well, the conference will give me anopportunity to talk with him and network with him; he’s interested in some of the same things 4
  5. 5. that we’re interested in, basically impact of variance in input characteristics on the variance inproduct quality. Not everything in the freeze-drying batch dries exactly the same way and itdoes 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 whoattend 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 Ithink even if you’re interest is mostly in formulation you’re going to get a fair amount out of theprogramme, and I would, frankly, advise anyone doing freeze-drying that you really cannotseparate formulation and process completely. The formation clearly impacts the design of theprocess but, in fact, how you run the process can change the material characteristics andtherefore can change the behaviour of the formulation. So, these are all together and onereally 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, regulatoryissues, and discussion of vaccines which is certainly timely, so that’s, I guess, my take on theprogramme and what people should be able to get out of it. And if you’re an attendee you dohave the opportunity to talk with everybody; the experts, the non-experts and, frankly, you canlearn from both.Pharma IQ: Thank you so much, Mike. We’re delighted to have you chairing this event andwe 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, from24th-25th January 2011 at the NH Hotel du Grand Sablon, Brussels, Belgium, where you canfind out more about developing best practice approaches for optimising formulation,enhancing homogeneity, and improving your freeze-drying processes. For further detailsplease visit:, email or call +44 (0)20 73689300.IQPCPlease note that we do all we can to ensure accuracy within the translation to word of audio interviews but that errors may stillunderstandably occur in some cases. If you believe that a serious inaccuracy has been made within the text, please contact +44(0) 207 368 9425 or email 5