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

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 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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2. 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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3. 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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4. 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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5. 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
24th-25th 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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