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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 youre 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. Were
also interested in characterisation of amorphous materials and keeping in mind, of course,
that when you freeze-dry youre really doing so to confer stability on the product, and so were
interested in the relationship between, lets 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 Im 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, T
g
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 youll never know whether youre at a threshold of a disaster or not. So, materials
characterisation; secondly, the freeze-dryer that you purchase really needs to be, lets 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 Im 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 arent 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, lets say, text books out there, but there
is a rather extensive review literature and the original science literature. Its been developing
quite a lot over the past 20 years or so, and you go to conferences.

Pharma IQ: Now the key question on everybodys lips, and wed appreciate your perspective
- does lyophilisation have a future in the biopharmaceutical world?

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M Pikal: I dont think theres any question of that. The biopharmaceutical world is growing
rapidly. There are those who will claim it will overtake the small molecule drugs I dont
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
dont 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 theyre freeze-
dried for a reason. Theyre 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. Its probably generally the best way for a
variety of reasons its not the only way - but I think freeze-drying is certainly here to stay and
I think its going to expand in importance along with the biotech field. Again, I dont think
everythings 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, lets say, processes or areas of study, if you approach the topic, assuming
its going to be routine, and all you have to do is plug in your freeze-dryer, throw the switch,
and arbitrarily set a programme, youre probably going to be in trouble. The process involves
a lot of physics, and engineering concepts; theyre not that difficult but you have to give the
area some respect and, again, look at the literature. Dont treat this as a routine operation. It
is a science. And, I think one needs to... you probably dont 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 its formulation, process or both, to
actually take time to read the literature and to think, to go to conferences, and theyre
expected to push product out the door without thinking, and I believe thats 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 thats 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 its
material science or freeze-drying, or whatever it is, youre not going to be able to do anything
but address the most routine of situations, and any time you run into a difficulty thats not
solved by the standard procedure, then basically youre 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 dont put money into the research programme. At best they pay for our salaries or
most of it, but if youre 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 youre not going to have a large number of academics pursuing this, and
thats a problem here in the US. Its, 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 thats not very much.

Pharma IQ: Its great to get your perspective and it will be interesting to see how it goes,
moving forward, as its such a key area. Now, to move on to the regulatory landscape, in the
lyophilisation field, its 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, its the lack of effective scientific dialogue between the scientists
in industry, academia and the FDA here, and regulatory bodies, lets say, across the world.
Expertise in freeze-drying does exist to some extent in the regulatory bodies but not a whole
lot. In fact, were working with the FDA ourselves here and theres a group of universities over
here that have formed a consortium called The National Institute for Pharmaceutical
Technology and Education, so-called NIPTE, and were working with the FDA to try to
educate the FDA in some key technologies and freeze-drying is one of them; its 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 were 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 thats 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, lets work out together
what really should be done and know why. And so, again, its, 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 lifes 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 wont 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; its 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 dont know whether it will or not. It may not be consistent with their business model
to actually develop experts, and so its 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 thats good to see. Well,
hopefully that will continue and intensify. But, again, in order to really build and intensify were
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. Ive 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 thats really about all you need.
However, particularly with proteins and, lets 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, lets 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 thats 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, lets say, the
product line that youre 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, lets say, all inclusive and perhaps not
quite as useful. We still probably dont have, simple-to-use guidelines for scale-up. In fact,
were working on some of that now, but its 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, theyre 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 dont
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, lets 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 havent studied in the laboratory, and that gap is the scale-up issue. There are ways
to deal with that but, again, typically people dont 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 Im 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 Id like to
know what youre 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 Im going to address. Its one of many topics but, as I just
indicated in the answer to the previous question, its, I think, a very important one. And then
theres an opportunity to network with people who I know, in particular some people I know
who I dont 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,
hes just not very far from Connecticut. But some of the rest of these, for example, Professor
Barresi, who I have met but I really dont know very well, the conference will give me an
opportunity to talk with him and network with him; hes interested in some of the same things
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that were 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 youre 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 thats probably a strength of the programme. But I
think even if youre interest is mostly in formulation youre 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 youre going to do freeze-drying. Its,
I think, a pretty good programme. Its got a lot of balance. Youre into some things that are,
lets say, pure pharmaceutical technology nuts and bolts, into formulation issues, regulatory
issues, and discussion of vaccines which is certainly timely, so thats, I guess, my take on the
programme and what people should be able to get out of it. And if youre 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. Were 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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