An interview with Dr. Lutz Uharek
Charité – Universitätsmedizin Berlin is the largest university hospital in Europe, affiliated
with both Humboldt University and Freie Universität Berlin. Lutz Uharek, MD, Head
of the Stem Cell Facility at Charité – Universitätsmedizin Berlin, is leading development of a new stem cell facility, moving cell production from a clinical setting to a GMP
environment. He is also the Chair of this year’s PDA Europe Advanced Therapy Medicinal Products
conference in Amsterdam, June 5–6.
The Managing Editor of the PDA Letter interviewed Uharek about his experience moving
from a clinical operation to a GMP environment.
PDA Letter: What has been your
biggest challenge with moving from a
clinical operation to a GMP facility?
Uharek: The biggest challenge is that
our clinicians are going from more
flexible processes and routines;
classical GMP is based on more
robust and inflexible processes.
I think there is also a different
language. Although the topic is
the same, the language is more
about risk management and quality
control. In the hospital, you have
standards for quality assurance; however,
there is no common language between the
pharmaceutical world and the clinical world.
It is like speaking German or French. I think
this is a problem. Of course, we often have
no really robust processes and routines in the
clinic. The physicians and other personnel
have to deal with frequently changing situations. This is a different world compared to
classical pharmaceutical production where
things are usually running on a more standardized and routine basis.
PDA Letter: How are you addressing that
“language barrier,” so to speak?
Uharek: We currently have “quality
circles” consisting of people working in
both worlds. People coming from the GMP
field, from quality control, from quality
management and product manufacturing
and people coming from the clinical world
who would like to use these products, or are using these products mainly within
clinical trials, so they are most interested in
connecting production and clinical evaluation.
We are currently bringing these people
together to speak a common language.
PDA Letter: How has your institution
applied key engineering principles in its
migration to GMP?
Uharek: I am personally very interested
in lean management, especially considering I wrote my master’s thesis about it.
I believe that thinking in processes and
thinking modular is key to ending up
with robust and reproducible processes
and routines, even if you are dealing
with a very flexible role.
You have to split
things up into basic processes that can be
controlled and, then, you can pull these
together to move processes to the next
level. To think in this more process oriented and modular way is essential, in my
opinion, to ending up with reproducible
and controllable processes in upscaling,
beginning with the first small batch to
production to large-scale manufacturing.
Too Much Light a Problem?
PDA Letter: What has it been like working with regulators?
Uharek: They have been very supportive
mostly. One advantage, of course, is that
they often understand the clinical need
behind the problem, and it is relatively
easy from the hospital point of view to convince them there is a problem that has
to be solved in order to bring beneficial
therapies to the patient. In other words,
the general attitude is helpful.
The problem I see is that the regulatory
agencies, companies and clinics are working together in the new field of ATMP
development, and the danger is that we all
are looking for problems in areas we are
familiar with. I like to call this problem the
“streetlight effect.” There is a joke I heard
about a drunkard searching for something
under a streetlight. A police officer happens
upon him and asks “what are you doing?”
“I am looking for my keys, I lost them in
the park,” replies the drunkard.
“Then why are you looking under the
“Because this is where the light is.”
The problem is known from social sciences. Everyone is looking in the place
they are most familiar with. Everyone is
looking where the light is. Regulators are
looking intensively at problems of sterility,
management of the cleanrooms, and so
on. And on the other hand, clinicians
are looking mainly at things happening
on the hospital ward. But they are not
looking at the production stage where
something critical might have happened.
All sides should be aware of the “streetlight effect,” and should help each
other to bring light in the areas where
the problems are really located. The “key” technology helping regulators, ATMP
manufacturers and clinical personal to
identify dark areas containing a problem
will be risk management.
PDA Letter: How can academic institutions, regulatory agencies and manufacturers collaborate to address the challenges
of this new field?
Uharek: The most important point really is to work together. Coming together and discussing all these critical issues is the most important thing. The other essential point for me is working on a general understanding of risk management, risk evaluation, that involves all stakeholders, this is very important to focus on with all parties that are involved, kind of risk management circles.
Another important point is to work more
modular, to think in terms of processes to
allow approval of routine processes and
technologies instead of finalized product.
First, there should be more focus on risk
and, second, on processes that can be put
together for production lines.
PDA Letter: Based on your experience,
what do you see as the future design of
GMP-processing spaces for ATMPs?
Uharek: Again, I think the future design
of GMP processing will be modular. It
will be flexible. It will be process oriented.
I am convinced we will not have these
classical cleanroom, GMP facilities in ten
years, at least not for the field of ATMPs.
Medicine will become more personalized
and we will have more and more smaller
batches. We will have a very trial period
of product development, which will also
include manufacturing technologies and,
therefore, we will have to work with flexible, modular, closed-system production
We have to avoid more rigid buildings
that were perhaps appropriate for classical
pharmaceutical production which usually
was unchanged for ten years or longer. Instead we will often have production times
of only one year and very small batches, and for that reason, we will need other types of technologies.
PDA Letter: Naturally, all these changes mean partnering with suppliers. In the past, ATMP manufacturers have been limited due to the small pool of available suppliers. Do you see this changing?
Uharek: Yes, definitely.
We are in contact
now with companies coming from different fields that are realizing that this more-
personalized type of production—you
can call it “microfactories” or modular,
closed-production systems, and so on—is
something being asked for by a couple of
companies producing ATMPs in the field
of genetic engineering. And the field of
cell therapies is evolving dramatically, so
there is clearly a need for these cellular
production technologies, say for CAR-
T cells and genetically modified stem
cells. And a couple of suppliers already
have realized the solutions that have to
be developed for this different type of
We are working together—and I think
this is something very fruitful—we
are working very closely together with
technology providers in the development
of new manufacturing technologies for
ATMPs. One problem is that you have to
validate your processes with biological, often human, cells, so you need to be close
to the hospital, to the manufacturing site
and to human material in order to validate your manufacturing equipment and
processes, and also quality controls. For
that reason, I think it is very important
that cooperation exists between suppliers
and these organizations, such as GMP
units, that are located near the hospital, to
improve and to speed up the development
of new technologies.
New Purpose for Sterility Tests
PDA Letter: What does the short shelf life
of these products mean for sterility testing?
Uharek: We are very familiar with products with short shelf lives in the routine
use of stem cell products for the treatment
of mostly hematological disorders. Hundreds of thousands of these products have
been shipped all over the world to treat
patients with stem cell transplants. Then,
we have this problem of sterility assurance.
We cannot wait with a transplant or
treatment unless we have all the information together.
What we do is a kind of conditional release
for these products with what we have in
terms of sterility testing. Perhaps there is a
need to develop more effective tests for a quick testing procedure, but in the end, I think
it will always be the case that you have
situations where you have to release the
product without complete sterility testing.
In that case, I think it is still very important
to have this data available, not to protect
patient from a critical infection—which is
not possible in this case— but perhaps to
provide a prophylaxis if it is known that the
microbiological testing was positive.
The most important reason to perform
extensive sterility testing and contamination control is to improve your processes.
First, to realize where you have critical
problems and, second, coming back to
the streetlight effect, to bring light into
the dark, such as what it means to have a
particular contamination. It is often the
case that we put this product, harboring
bacteria, into immunodeficient patients.
Perhaps they have an infected central line.
These positive microbiological results are
something we have to learn and gather
data on. What it means if such a product
is contaminated, and what is associated
with the contamination? And how does
the particular microbe impact the clinical
This is a very important point to me. It
is necessary to combine GMP and GCP
and to learn the effects. Could this be
infectious? This could also be a problem
of liability or problems associated with
characterization of the product: how do
these quality parameters affect the outcome
on the clinical side? This is essential for
ATMP development, that we have a very
close [working relationship] between the
manufacturing and the clinical sides to
initiate such a learning process.
What we need is a learning system that
allows the regulators to look at the system,
and to allow risk-based adjustments.
Quality assurance could be less strict.
You need a better control in situations where
you have not so much knowledge about
your processes, and you do not need
[control] any longer if you have very well
established processes. This is something
that has to be built up—both from outside,
from the regulators, and from inside from
the people evaluating these ATMPs in the
clinic and those manufacturing the product.
PDA Letter: In that case, based on
your experience, does it make sense for
academic institutions to build their own
research facilities? Or would it be better to
collaborate with the industry?
Uharek: I see a need for different solutions.
It really depends on the products. On the
one hand, we have products that are used in
a very dynamic clinical situation where any
failure in logistics has dramatic implications
and where you have to be very flexible. For
such products, near hospital production
might be preferable. Or we have situations
where we have orphan indications, rare diseases, where you have to establish something
like a Center of Excellence. In such situations
it might be more appropriate to have centralized hub-based production.
We will also have products where time is
not a critical factor and where production
problems, logistics issues and manufacturing failures are not so critical for the patient.
In such situations or when you can repeat
the process because the product is not so
expensive, it is definitely better to be more
on the side of classical pharmaceutical
production with a centralized and very well
controlled production unit or manufacturing facility. I think there might also be a
place for something in between.
We have to look first at the need for the
patient, the characteristics of the product
and then to see how this can be brought
in the best way to the patient. Then we
have to ask the question, ‘how can that
be done in a lean way with the lowest
efforts and with minimum resources?’ I
think this is how the decision should be
made about where and how production of
ATMPs should take place.