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Speaking the Language of GMP

April 2018

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 streetlight?”

“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 technologies.

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 production.

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 outcome?

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.

About the Expert

Lutz UharekLutz Uharek, MD, is a hematooncologist and senior physician at Charité – Universitätsmedizin Berlin’s Center of Oncology.