GMP Cell and Gene Therapy

employee working in clean room
© Photo Fraunhofer IZI

The 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 90 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.

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 www.iovance.com

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.

Technology transfer of an investigational chimeric antigen receptor therapy (CTL019)

The Department of GMP Cell and Gene Therapy is collaborating with Novartis Pharma AG on the technology transfer of an investigational chimeric antigen receptor therapy (CTL019). It aims to obtain the specific manufacturing authorization in accordance with Section 13 of the German Drug Act.

Subsequently the department will assist in clinical programs for patients in Europe using CTL019.

CTL019 is an investigational, personalized T-cell therapy. T cells are drawn from the patient's blood and reprogrammed to hunt and destroy cancer cells that express specific proteins, called CD19. This protein is associated with a number of B-cell malignancies including acute and chronic lymphoblastic leukemia.

Manufacturing DCVax®-L for the American biotech company Northwest Biotherapeutics, Inc.

The Department of GMP Cell and Gene Therapy has successfully performed the GMP process transfer for DCVax®-L and the corresponding Placebo from the US to Leipzig. DCVax®-L is an immune therapy based on autologous Dendritic Cells. The process specific manufacturing authorization according to Article 13 of the German Drug Law was granted by the competent authority. This is the precondition for manufacturing investigational medicinal products for the European arm of a phase III clinical trial performed by Northwest Biotherapeutics, Inc. in UK and Germany. The indication is Glioblastoma multiforme (GBM). The partner for the process transfer was the US company Cognate BioServices, Inc. Beside of the support of the ongoing clinical trial there is also a provision of individual DCVax®-L doses according to Article 4b German Drug Law (so called “hospital exemption” according to Regulation (EC) No 1394/2007).

Cooperation partners

  • Nowrthwest Biotherapeutics, Inc.
  • Cognate BioServices, Inc.

Press releases

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

Finished Projects

  • 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®, 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™)

  • 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 dx.doi.org/10.4172/2157-7560.1000327
  • 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.