TY  - JOUR
A1  - Haeusner, Sebastian
A1  - Herbst, Laura
A1  - Bittorf, Patrick
A1  - Schwarz, Thomas
A1  - Henze, Chris
A1  - Mauermann, Marc
A1  - Ochs, Jelena
A1  - Schmitt, Robert
A1  - Blache, Ulrich
A1  - Wixmerten, Anke
A1  - Miot, Sylvie
A1  - Martin, Ivan
A1  - Pullig, Oliver
T1  - From Single Batch to Mass Production–Automated Platform Design Concept for a Phase II Clinical Trial Tissue Engineered Cartilage Product
JF  - Frontiers in Medicine
N2  - Advanced Therapy Medicinal Products (ATMP) provide promising treatment options particularly for unmet clinical needs, such as progressive and chronic diseases where currently no satisfying treatment exists. Especially from the ATMP subclass of Tissue Engineered Products (TEPs), only a few have yet been translated from an academic setting to clinic and beyond. A reason for low numbers of TEPs in current clinical trials and one main key hurdle for TEPs is the cost and labor-intensive manufacturing process. Manual production steps require experienced personnel, are challenging to standardize and to scale up. Automated manufacturing has the potential to overcome these challenges, toward an increasing cost-effectiveness. One major obstacle for automation is the control and risk prevention of cross contaminations, especially when handling parallel production lines of different patient material. These critical steps necessitate validated effective and efficient cleaning procedures in an automated system. In this perspective, possible technologies, concepts and solutions to existing ATMP manufacturing hurdles are discussed on the example of a late clinical phase II trial TEP. In compliance to Good Manufacturing Practice (GMP) guidelines, we propose a dual arm robot based isolator approach. Our novel concept enables complete process automation for adherent cell culture, and the translation of all manual process steps with standard laboratory equipment. Moreover, we discuss novel solutions for automated cleaning, without the need for human intervention. Consequently, our automation concept offers the unique chance to scale up production while becoming more cost-effective, which will ultimately increase TEP availability to a broader number of patients.
KW  - ATMP
KW  - tissue engineering
KW  - GMP
KW  - manufacturing
KW  - autologous
KW  - cartilage regeneration
KW  - automation & robotics
KW  - automation
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-244631
SN  - 2296-858X
VL  - 8
ER  - 
TY  - JOUR
A1  - Bittorf, Patrick
A1  - Bergmann, Thorsten
A1  - Merlin, Simone
A1  - Olgasi, Chistina
A1  - Pullig, Oliver
A1  - Sanzenbacher, Ralf
A1  - Zierau, Martin
A1  - Walles, Heike
A1  - Follenzi, Antonia
A1  - Braspenning, Joris
T1  - Regulatory-Compliant Validation of a Highly Sensitive qPCR for Biodistribution Assessment of Hemophilia A Patient Cells
JF  - Molecular Therapy - Methods & Clinical Development
N2  - The investigation of the biodistribution profile of a cell-based medicinal product is a pivotal prerequisite to allow a factual benefit-risk assessment within the non-clinical to clinical translation in product development. Here, a qPCR-based method to determine the amount of human DNA in mouse DNA was validated according to the guidelines of the European Medicines Agency and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Furthermore, a preclinical worst-case scenario study was performed in which this method was applied to investigate the biodistribution of 2 x 10\(^6\) intravenously administered, genetically modified, blood outgrowth endothelial cells from hemophilia A patients after 24 h and 7 days. The validation of the qPCR method demonstrated high accuracy, precision, and linearity for the concentration interval of 1:1 x 10\(^3\) to 1:1 x 10\(^6\) human to mouse DNA. The application of this method in the biodistribution study resulted in the detection of human genomes in four out of the eight investigated organs after 24 h. After 7 days, no human DNA was detected in the eight organs analyzed. This biodistribution study provides mandatory data on the toxicokinetic safety profile of an actual candidate cell-based medicinal product. The extensive evaluation of the required validation parameters confirms the applicability of the qPCR method for non-clinical biodistribution studies.
KW  - outgrowth endothelial cells
KW  - real time PCR
KW  - in vivo
KW  - gene therapy
KW  - factor-VIII
KW  - murine
KW  - quantification
KW  - establishment
KW  - phenotype
KW  - xenotransplantation
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230284
VL  - 18
ER  -