GMP Cell and Gene Therapy

employee working in clean room
© Fraunhofer IZI

The Main Department of GMP Cell and Gene Therapy operates Fraunhofer IZI's three modern GMP facilities consisting of ten separate clean room suites (altogether 21 clean room grade B manufacturing rooms) which have been specially optimized for manufacturing of cell and gene therapy products, so called Advanced Therapy Medicinal Products – ATMP. The particular specialty of the about 130 highly qualified staff members is the GMP-compliant manufacturing and quality control of investigational medicinal products.

GMP-compliant process and quality control development as well as the creation of Standard Operating Procedures (SOPs) are intensively discussed with the project partner before being implemented. The leading staff in charge has many years of experience in designing GMP-processes in the cell therapy area.

Manufacture of investigational medicinal products for a gene therapy to treat HIV infections

As part of a clinical trial conducted by the University Medical Center Hamburg-Eppendorf (UKE) together with the Heinrich Pette Institute at the Leibniz Institute for Experimental Virology (HPI), investigational drugs to be used as part of an innovative gene therapy will be manufactured in the GMP clean room facility at Fraunhofer IZI in future.

The procedure was developed by researchers from the HPI and TU Dresden university. It uses molecular genetic scissors (dubbed Brec1) to cut the exact provirus out of the genome of hematopoietic stem cells by means of “genome editing”. This procedure is expected to permanently eradicate HIV from patients, with few adverse effects. [Link] After having clarified the majority of questions pertaining to the activity and toxicity of the procedure in preclinical experiments, the results now have to be corroborated in clinical trials on HIV patients.

The process transfer began at Fraunhofer IZI in February 2019, ensuring that the genetically modified hematopoietic stem cells can be manufactured under GMP conditions and pursuant to the regulatory requirements placed on pharmaceutical production. After obtaining manufacturing authorization in accordance with Section 13 of the German Medicinal Products Act (AMG), the first investigational drugs are expected to be released to the UKE in 2020.

Press releases

Manufacture of Kymriah®

CAR-T cell therapy is a new type of cancer immunotherapy that uses the patient’s own T cells to fight certain types of cancer. In order to do this, the cells are extracted in the clinic by leukapheresis and then genetically reprogrammed in vitro in such a way that they can use a chimeric antigen receptor (CAR) to recognize cancer cells and other cells that have a special antigen on their surface. Following lymphodepleting chemotherapy, the reprogrammed cells are administered to the patient though an infusion. They then proliferate and can trigger the immune response.

In August 2017, the first CAR-T cell therapy became available in the USA in the form of Kymriah® (CTL019 / tisagenlecleucel). Kymriah® was granted FDA approval for children and young adults aged up to 25 years old diagnosed with acute lymphocytic B-cell leukemia (ALL) who are not responding to the usual therapies or have already suffered relapses. In May 2018, approval was also granted for adult patients with diffuse large B-cell lymphoma (DLBCL) who had suffered relapses after two or more lines of systemic therapy or who have not responded to therapy at all. On August 27, 2018, Novartis announced that it had received approval from the European Commission for both these indications.

Fraunhofer IZI has long since been a key manufacturing and development site for this innovative CAR-T cell therapy for various clinical trials throughout Europe. Over the next few years, prescription-only, approved T-cell therapies will also be manufactured on an interim basis in the Main Department of GMP Cell and Gene Therapy at Fraunhofer IZI, alongside investigational medicinal products. Following a one-year technology transfer period from Novartis’ Morris Plains site in New Jersey, USA, and after obtaining manufacturing authorization in accordance with Section 13 of the German Medicinal Products Act (AMG), the first clinical batch was manufactured at Fraunhofer IZI in Leipzig in August 2016. The Main Department of GMP Cell and Gene Therapy has continuously produced CAR-T cell therapies for Novartis ever since.

Until the end of 2018, batches in the high double-digit range were delivered to patients, including many children, all across Europe. The extremely complex process involved in manufacturing a cell preparation takes several days and involves not only state-of-the-art instrument engineering, but also manual tasks. Before being cleared for human use, extensive analytical release tests are first conducted on the finished product (e.g. concerning identity, purity, in vitro efficacy, microbiological safety) and the batch documentation is reviewed in detail.

Press releases and further information

With "Sleeping Beauty" against cancer

The US American Food and Drug Administration FDA approved for the first time in 2017 a gene therapy with so-called CAR-T cell therapy. Clinical studies of cancer diseases show that impressive success has already been achieved in the treatment of cancer using this form of therapy. This revolutionary therapy is also the focus of a research project that the PoC initiative will be supporting with about 2.8 million euros. The chimeric antigen receptors (CAR) developed at the University Hospital of Würzburg detect a certain molecule (ROR1), which is barely present in healthy cells, but which occurs all the more on cancerous cells from leukemia, breast or lung cancer. In the case of the research project now being funded by the PoC initiative, the non-viral gene transfer takes place by means of the so-called "Sleeping Beauty" transposon system (SB100X). The funding is to be used to complete pre-clinical studies on the safety and efficacy of the ROR1 CAR-T cells and to achieve the clinical translation into a Phase I study (First-in-Man).

Thy project is funded by the Proof-of-Concept initiative. The initiative was instituted by the Helmholtz Association, the Fraunhofer-Gesellschaft and the German university medical departments, to promote translation of innovative, promising research projects into clinic.


Fraunhofer Institute for Cell Therapy and Immunology launches collaboration with Iovance Biotherapeutics,Inc.

The Main Department GMP Cell and Gene Therapy of Fraunhofer is collaborating with Iovance Biotherapeutics Inc. (San Carlos, CA, USA) on the technology transfer and subsequent continuous manufacturing of allogeneic feeder cells used in Iovances’ Tumor Infiltrating Lymphocyte manufacturing process. This collaboration supports Iovance’s upcoming European clinical trials for the treatment of solid tumors in metastatic melanoma and cervical carcinoma.

Iovance Biotherapeutics, Inc. is a clinical-stage biotechnology company focused on the development of cancer immunotherapy products for the treatment of various cancers. The Company's lead product candidate is an adoptive cell therapy using tumor-infiltrating lymphocyte (TIL) technology being investigated for the treatment of patients with metastatic melanoma, recurrent and/or metastatic squamous cell carcinoma of the head and neck and recurrent and metastatic or persistent cervical cancer. For more information, please visit 

Development of an additive production platform for biodegradable, patient-specific breast implants for natural breast tissue reconstruction

Breast cancer is one of the most common forms of cancer among women. A mastectomy, i.e. the removal of the breast, is often recommended as part of cancer treatment. Many women who opt for this procedure have to deal not only with the physical consequences of surgery but also, in the longer term, with a huge amount of psychological stress. In Germany, measures taken to restore the breast form part of one of the most common surgical reconstruction procedures. Traditional reconstruction measures, however, continue to be accompanied by countless complications and side effects, including severe fibrotic reactions to exogenous implants, the emergence of capsular contracture that gives the breast an unnatural appearance and also tissue loss. This results in more stress for the patient and the need for additional, costly corrective surgery.

The company BellaSeno GmbH is working with partners to develop an innovative procedure that avoids the above-listed drawbacks of breast reconstruction while restoring the breast tissue in a natural way. In order to do this, state-of-the-art 3D manufacturing processes are combined with established biocompatible materials and surgical techniques.

With the help of 3D laser scanning, the patient's breast area is first evaluated and measured. Software is then used to turn these measurements into a computer model which the treating physician can use to model the implant. Finally, a 3D bioprinter produces the implant using medical grade polycaprolactone (mPCL) – a biodegradable polymer already used in various kinds of surgical applications. These novel implants are placed in the body in exactly the same way as conventional products. The porous structure encourages the surrounding tissue to form blood vessels. This approach is complemented by an autologous fat transfer procedure (injecting the patient's own fat under the skin). Tissue regeneration is stimulated; firstly, as the implant's pores give the adipose cells plenty of space and dimensional stability and, secondly, because the vascularization gives cells a direct nutrient supply. The scaffold gradually degrades as the tissue regenerates, ultimately being replaced with natural breast tissue.

Various development stages are yet to be completed before this procedure can be applied to patients. BellaSeno GmbH is being supported here by the Fraunhofer Institute for Cell Therapy and Immunology. The institute is responsible for evaluating safety in accordance with ISO 10993 and for developing a clean-room based ISO 13485 compliant manufacturing process for the production of BellaSeno implants. Dresden-based company GeSim mbH will further develop the manufacturing technology with an eye to optimizing production rate and capacity. Leipzig University is also involved in the project, carrying out preclinical, long-term studies to review the toxicology and biocompatibility of the implants, while their mechanical properties are being simulated and validated by the company Leichtbau-Zentrum-Sachsen GmbH.

The project has received funding from the Sächsische Aufbaubank (Saxon Development Bank, SAB), using funds from the European Regional Development Fund (ERDF). The Saxon cooperation project aims to have obtained manufacturing authorization for the product by 2020. The project will then move into the clinical trial stage, where the first patients could receive the implants.

Obtaining of a manufacturing authorization for CardAP-Cells

The Department of GMP Cell and Gene Therapy performs together with the Charité-Universitätsmedizin Berlin (Tissue Engineering Lab) and the Berlin-Brandenburg Center for Regenerative Therapies the GMP-process development for manufacturing and quality control of autologous heart muscle derived CardAP-cells. It’s the intention to investigate safety and efficacy by performing clinical trials in the field of chronic myocardial failure. Obtaining a manufacturing authorization according to section 13 German Drug Law is the first project goal.

Cooperation partners

  • Charité-Universitätsmedizin Berlin, Tissue Engineering Laboratory
  • Berlin-Brandenburg Center for Regenerative Therapies

autoCard study

A member of staff examines the cells through the microscope
© Fraunhofer IZI

A member of staff examines the cells through the microscope.

Adherent CardAPcells in culture
© Fraunhofer IZI

Adherent CardAPcells in culture.

Cardiovascular diseases are still the main cause of death in Europe. In Germany, around 60 000 people die from myocardial insufficiency every year. The field of regenerative medicine is, however, showing a great deal of promise here.

The investigational medicinal product ”CardAPcells” (cardiac-derived adherent proliferating cells) will be manufactured at Fraunhofer IZI in future in cooperation with Charité - Universitätsmedizin Berlin. The therapeutic agent contains myocardial cells that are isolated from biopsy samples taken from the patient‘s own heart muscle and expanded over the course of a cultivation process lasting several weeks. Once the required cell concentrations have been reached (usually after four to six weeks), the cells will then be applied as a suspension in their final formulation – intravenously (IV) through a drip on the one hand and intramyocardially, i.e. directly into the heart muscle, using the MYOSTAR™NOGA system on the other. The aim here is to establish the ”CardAPcells” investigational product as part of routine patient treatment, giving patients the opportunity to enjoy a better quality of life. There is no risk of rejection as the product uses the patient‘s own heart cells. The random formation of scar tissue (fibrosis) is probably also reduced.

Test batches were first produced during the project’s technology transfer stage. These batches were used to optimize the process and the application of relevant materials and reagents with an eye to the stringent GMP production requirements. The process, which is planned to be conducted in Fraunhofer IZI’s clean room, was then validated. Using samples taken from the three validation batches produced, the analytical methods that form part of the safety parameters (checking for mycoplasma, sterility and bacterial endotoxins) were also successfully validated. At the same time, a manufacturing authorization pursuant to Section 13 of the German Medicinal Products Act (AMG) was requested from the responsible state authority, Landesdirektion Sachsen (Saxony Land authorities), which was also on site for the acceptance inspection in February 2018. The inspection went smoothly and Fraunhofer IZI was granted a manufacturing authorization in accordance with Section 13 of the AMG without any further conditions being imposed. The sponsor submitted the study documents to the Paul-Ehrlich-Institut for review in August 2018. Furthermore, authorization to procure tissue samples pursuant to Section 20b of the AMG was also requested from the Berlin State Office for Health and Social Affairs in November 2018.

The first ”CardAPcells” tissue procurement cannot be manufactured for patient treatment until this authorization has been granted, a favorable opinion has been issued by the competent ethics committee of the state of Berlin and the autoCard study has received official approval from the Paul-Ehrlich-Institut.

Finished Projects

  • Manufacturing DCVax®-L for the American biotech company Northwest Biotherapeutics, Inc.
  • Manufacturing and quality control of EpiDex (autologous epidermal equivalent tissue-engineered from follicular outer root sheath keratinocytes for treatment of chronic wounds) together with euroderm GmbH Leipzig / Germany
  • Manufacturing and quality control of autologous stem cell preparations from cord blood (InnovaCB) together with Innovastem GmbH Leipzig / InnovaStem S.r.l. Brescia / Italy
  • Process transfer and manufacturing of the Dendritic Cell-based investigational medicinal product Cvac™ for the Australian biotech company Prima BioMed Ltd.

  • Class A (100), B (100), C (10,000), and D (100,000) pharmaceutical clean rooms with a total area of about 1000 sqm, modular structure, divided into suites with separate air filtration. We offer altogether 21 class B manufacturing rooms within three separate clean room facilities for handling different kinds of manufacturing projects for cell and gene therapy products. If required the rooms can be operated according to gene technology safety level S2.
  • Qualified equipment for the production of cell-based medicinal products, e.g. particle-monitored class II laminar flow workbenches, CO2-incubators (some with oxygen regulation), refrigerated centrifuges, inverse microscopes, controlled rate freezers for the cryopreservation of cells, storage tanks for storing cells in the vapor phase of liquid nitrogen, CliniMACS®-cell separation system, CliniMACS Prodigy® with electroporation unit, MaxCyte GT® Scalable Transfection System, LOVO-Cell Processing System, Sepax S-100-cell separation system, ELUTRA® cell separation system, gentleMACS™ Dissociator for tissue dissociation, TSCD II Sterile Tubing Welder, CR6 Tube sealers, etc.)
  • Qualified equipment for the quality control of cell-based medicinal products (e.g. Cytomics™ FC500 MPL, FC500 Navios and MACSQuant® flow cytometer, LightCycler realtime-PCR-Cycler, Tecan Sunrise ELISA-Reader, Vi-CELL™ device for the automatic determination of cell count and viability, Sysmex XS-800i haematology system)
  • Qualified equipment for sterility testing (BacT/Alert® 3 D Dual T-microbial detection system, Equinox-pump, overpressure isolator within clean room class C) and testing for bacterial endotoxins (Endosafe®-PTS™)

  • Kuhn S, Splith K, Ballschuh C, Feldbrügge L, Krenzien F, Atanasov G, Benzing C, Hau HM, Engelmann C, Berg T, Schulte Am Esch J, Pratschke J, Robson SC, Schmelzle M. Mononuclear-cell-derived microparticles attenuate endothelial inflammation by transfer of miR-142-3p in a CD39 dependent manner. Purinergic Signalling 14 (2018), 4, S. 423-432.
  • Kebbel K. Technical challenges and requirements transferring an early ATMP from laboratory to authorized GMP manufacturing: A case study report. »The Product is the Process – Is it?« Qualitätsaspekte bei der Herstellung von ATMP, November 7, 2017, Berlin.
  • Wittke S, Baxmann S, Fahlenkamp D, Schmiedeknecht G, Kebbel K, Kießig ST. Rationales for a Multi-Epitope Approach in an Autologous Renal Cell Cancer Immunostimulant. J Vaccines Vaccin 2016, 7:4. DOI
  • Kebbel K. Obtaining a manufacturing license according to §13 AMG for an ATMP – How to get there? World Conference on Regenerative Medicine, Leipzig, Germany, October 21-23, 2015.
  • Schmiedeknecht G. Challenges of Manufacturing of ATMP’s for clinical trials. 2015 PDA Europe Conference Advanced Therapy Medicinal Products, Amsterdam, Netherlands, June 2–3, 2015.
  • Schmiedeknecht G. Challenges of Manufacturing of ATMP’s for clinical trials. World Conference on Regenerative Medicine, Leipzig, Germany, October 21-23, 2015.
  • Schmiedeknecht G. Besondere Herausforderungen bei der Herstellung von ATMP. »The Product is the Process – Is it?« Qualitätsaspekte bei der Herstellung von ATMP, November 4, 2014, Berlin.
  • Schmiedeknecht G. Translational research initiatives in Germany: Experiences on cell processing services. Clinical Evaluation, Vol. 42, No. 1, Jul. 2014, page 87-94.
  • Schmiedeknecht G, Kebbel K, Sonnabend C, Wagner M, Gryczka M, Stella M, Ganjei K, Bosch M, Powers LF. Process transfer of DCVax®-L to Europe and initiation of a phase III clinical trial in UK and Germany. ISCT (International Society for Cell Therapy) 2014 Annual Meeting, Paris, France, April 23–26, 2014.
  • Schmiedeknecht G, Kebbel K. Challenges of Manufacturing of ATMP’s for clinical trials. PACT (Platform for Advanced Cellular Therapies Austria) Foundation Symposium, Vienna, Austria, April 3–4, 2014.
  • Schmiedeknecht G. Translational Research Initiatives in Germany: Experiences on Cell Processing Services. Translational Research Center Workshop, organized by the Foundation for Biomedical Research and Innovation (FBRI) and Ministry of Education, Culture, Sports, Science and Technology (MEXT), Tokyo, Japan, February 27, 2014.
  • Haag M, Augst H, Kebbel K, Ringe J, Van Linthout S, Thielemann D, Kellert C, Schmiedeknecht G, Tschoepe C, Sittinger M. Human cardiac derived cells for the treatment of chronic heart failure - from bench to bedside. Kooperationsforum - Technologien für zellbasierte Therapien, Erlangen 2014, Tagungsband S. 118-19.
  • Buchholz M, Knauer J, Lehmann J, Haß M, Gargosky S. Qualification of the COSTIM assay to determine potency and use in clinical trials. ISCT (International Society for Cell Therapy) 2013 Annual Meeting, Auckland, New Zealand, April 22–25, 2013.
  • Polchow B, Kebbel K, Schmiedeknecht G, Reichardt A, Henrich W, Hetzer R, Lueders C. Cryopreservation of human vascular umbilical cord cells under good manufacturing practice conditions for future cell banks. J Transl Med. 2012; 10:98. doi: 10.1186/1479-5876-10-98.
  • Schmiedeknecht G. Clean rooms and technical equipment for the development of cell-based therapeutics. Contamination Control Report, 1, 2007, 44-47.