GMP production

Fraunhofer Institute for Interfacial Engineering and Biotechnology

Manufacturing of tissue engineering products and transplants according to guidelines of good manufacturing practice (GMP)

With the expertise of scientific work on the project and the conversion of application-orientated research into the practice, we at Fraunhofer IGB focus on the role of a mediator between preclinical research and clinical application for the development of GMP-compliant manufacturing processes for tissue engineering and investigational medical products (IMPs). We develop manufacturing processes for autologous transplants in regenerative medicine and clinical trials, apply for the manufacturing authorization and manufacture cell-based therapeutics in our certified GMP manufacturing unit in a pilot scale (according to the German Drug Law).

Established processes

  • Production of collagen (investigational medical product)
  • Re-seeded vascular graft
  • Stem cells for bone regeneration
  • Bioartificial reconstruction tissue for trachea surgery

Autologous transplantation and cell therapy: process development for tissue-engineered products

The Fraunhofer IGB offers process development and production of cell structures that can restore the biological function of damaged tissues or organs. This includes the isolation of primary cells from biopsy material, the optimization of culture conditions, the structure of the organoid system, analyzing the biological function of a tissue construct and biocompatibility testing.

Process development for the manufacture of tissue engineering products

Good to know

  • Allogeneic: Donor and recipient of a transplant or cells are not the same person.
  • AMG: The Medicines Act regulates the proper supply of medicine for human and animal safety in the transport of medicine, particularly for the quality, efficacy and safety of drugs (AMG § 1).
  • ATMP: Advanced therapy medicinal product. Somatic cell therapy medicinal products and tissue products developed, for example, using the techniques of tissue engineering are among the so-called "advanced therapies".
  • AMWHV: Drug regulation and drug manufacturing. Regulation of the implementation of good manufacturing practice in the manufacture of medicine and drugs and the application of good agricultural practice in the manufacture of products of human origin.
  • Autologous: Donor and recipient of the transplant are the same person.
  • GMP: Good manufacturing practice guidelines for quality assurance in production processes and environment in the production of medicine and drugs.
  • Human cells: Cells that originate from the human body.
  • in vitro: (latin) Studies that are conducted using components of an organism that have been isolated from their usual biological surroundings.
  • in vivo: (latin) Studies involving a whole, living organism.
  • Investigational medicinal product (IMP): All forms of a drug being tested in clinical trials in humans.
  • QP: Qualified Person. The Qualified Person in accordance with § 15 AMG is responsible for the compliance with applicable laws and regulations regarding drug manufacturing, testing, and approval before marketing a drug as well as the complete documentation of compliance with statutory requirements.
  • Quality: Quality is the characterization of a drug that is intended for identity, strength, purity, other chemical, physical, or biological properties of the preparation process (§ 4 (15) AMG).
  • Vascularization: The process by which body tissue develops proliferating capillaries and blood vessels.
  • Xenogeneic medicines: Xenogeneic medicinal products that contain living animal tissue or cells that are intended for use in humans.

Process development for the manufacture of tissue engineering products

Projects

Vascular grafts for bypass operations

  • Coating of PTFE vascular grafts with autologous endothelial cells for minimizing the risk of thromboses is a proprietary technology of VasoTissue Technologies GmbH (VTT). In contract for VTT we manufacture these grafts for application in cardiovascular disorders.

Amedrix: Production of collagen

  • On behalf of the company Amedrix GmbH unit we have developed the process and manufacture a collagen matrix as investigational medicinal product (IMP).

EU FP7-HEALTH-2009-1.4-2: VascuBone

Within the VascuBone project funded by the EU we establish GMP-compliant processes for the production of human mesenchymal stem cells (MSC) as well as of human endothelial progenitor cells (EPC) for bone regeneration.

  • Link to project homepage

Tracheal Reconstruction Tissue (BioVaSc)

  • Within our GMP unit, we are currently developing a vascularized matrix-based graft, which is seeded with autologous cells of the patient. As part of pre-clinical studies, the ability of such a graft to close tracheal defects has already demonstrated. The manufacturing license pursuant to § 13 AMG is currently under review. 

Services

  • Contract manufacturing or proprietary manufacturing
  • Since 2003 Fraunhofer IGB is in the possession of a Manufacturing Authorization after §13 German Drug Law (Arzneimittelgesetz, AMG), for autologous chondrocyte transplants. We develop and validate manufacturing processes for our partners and produce investigational medicinal products (IMPs) for clinical trials as a contract manufacturer in accordance with AMG. Alternatively we can apply for a Manufacturing Authorization for your own products and operate as a manufacturing site in the Fraunhofer IGB. In this regard we have received three manufacturing authorizations in the past four years. Our customers are biotech and pharmaceutic companies as well as hospitals worldwide.

 

  • Quality assurance within all sectors 
  • Extensive controls (bulk materials, intermediate and end products, in-process controls), complete documentation in accordance with the European guidelines, process validation and monitoring with qualified equipment and last not but least regularly trained personnel and self inspections are guarantees for the quality and the safety of our products.

  • Qualified, trained personnel
  • Facilities and equipment of defined quality status
  • Documentation system based on specifications and standard operation procedures for manufacturing and packaging
  • Production:
  • in-process controls
  • prevention of cross contamination
  • Quality control of raw materials, packaging materials, intermediate, bulk and end products
  • Certified suppliers
  • Self inspection
  • Services at a glance
  • Process development of autologous transplants
  • Manufacturing of cell- and matrix-based transplants
  • Production and quality control of cell-based investigational medicinal products (IMPs) for phase I / II clinical studies
  • Regulatory affairs / documentation
  • Quality management

Equipment

  • GMP manufacturing unit

Fraunhofer IGB offers services in development and manufacturing of cell-based investigational medicinal products according to the EU guidelines of current "Good Manufacturing Practices“ (GMP). In the year 2008 the GMP unit of Fraunhofer IGB was reconstructed, completely new designed, extended from 150 to 215 square meter (sq m) and reaudited by the local authorities (Regierungspräsidium Tübingen). The areas for storage and quality control cover now 100 sq m , classified as class D (equivalent to US class 100,000), and are completely separated from the production unit. The production facilities of cleanrooms class C (equivalent to US class 10,000) and class B (equivalent to US class 1000) add up together to 110 sq m. The new flexible designed areas allow an additional extension of the B-area of 30 sq m from the C-area and v.v. The B-area is divided into chambers with totally separated ventilation, therefore different manufacturing processes can be run simultaneously without the danger of cross contamination.

  • Analysis
  • Quantitative analysis of cell surface and intracellular flow cytometry
  • Sterility testing according to Pharm Eur. 2.6.1
  • Cell characterization by ELISA
  • Histological and immunohistological characterization of cells
  • Protein analysis by western blot
  • Light and fluorescence microscopy to evaluate cell therapy
  • Substance identification and purity testing by refractometry and photometry
  • Rheological analysis of viscoelastic properties of collagen gels
  • Media testing by osmolarity

Depending on the requirements of the individual transplant, we continually establish new methods of characterization.

Publications

  • Dally, I., In vitro development of a vascularised tracheal patch to restore airway defects after resection in 4th Congress on Regenerative Biology and Medicine BioStar 2010, 2010, BioRegioStern: Stuttgart.
  • Kempf, A., Entwicklung eines Lebertumor-Modells in einer dynamischen Bioreaktor-Kultur unter Verwendung der Melanomzelllinie MEL270 des Aderhautmelanoms, 2010: Ulm.
  • Linke, K., GMP conform manufacturing process of an autologous melanocyte graft, in 4th Congress on Regenerative Biology and Medicine BioStar2010, 2010, BioRegio Stern: Stuttgart. p. 1.
  • Pusch, J., GMP conform manufacturing process of an autologous melanocyte graft, in Fraunhofer Life Science Symposium 2010, Fraunhofer IZI: Leipzig. p. 1.
  • Pusch, J., GMP konforme Herstellung eines Melanozytentransplantates, in 126. Versammlung der Gesellschaft Deutscher Naturforscher und Ärzte e.V. GDNÄ, 2010, GDNÄ: Dresden. p. 1.