FRAUNHOFER INSTITUTE FOR TOXICOLOGY AND EXPERIMENTAL MEDICINE ITEM PRE-CLINICAL PHARMACOLOGY > < TOXICOLOGY TESTING < MANUFACTURING OF BIOPHARMA- CEUTICALS FOR CLINICAL TRIALS < EARLY-PHASE CLINICAL TRIALS ENVIRONMENTAL, OCCUPATIONAL AND CONSUMER PROTECTION > REGISTRATION AND RISK ASSESSMENT > ANNUAL Report 2014 This Annual Report 2014 of the Fraunhofer ITEM gives an insight into the activities and service profiles of the institute’s six business units and provides examples of typical contract and pre-competitive research projects performed in each of these areas. The title page and also the opening pages of the different business units in this Annual Report show the business unit spokespersons, who represent, coordinate, and further develop the individual business units to meet market requirements. Business units of the Fraunhofer ITEM Pre-clinical Pharmacology Toxicology Testing Manufacturing of Biopharmaceuticals for Clinical Trials Early-Phase Clinical Trials Environmental, Occupational and Consumer Protection Registration and Risk Assessment FRAUNHOFER INSTITUTE FOR TOXICOLOGY AND EXPERIMental MEDICINE ITEM PERFORMANCE AND RESultS ANNUAL REPORT 2014 Contents Foreword to readers 4 Business units of the Fraunhofer ITEM 20 Profile of the institute 6 Organizational structure 9 Business Unit Pre-clinical Pharmacology Competencies 10 Focus of activities in 2014 22 GXP – quality assurance according to international Projects 26 standards 12 Biofilms for testing of antibiotics 26 Staff and institute budget performance 14 Pre-clinical efficacy testing in models of Advisory board 15 pulmonary fibrosis 26 Clinical Research Center Hannover – the new Sensory nervous system affects asthmatic proof-of-concept center is picking up speed 16 airway constriction 27 Project Group in Regensburg 18 Carbon nanotubes as anticancer drug carriers 27 Development of a novel 3D human tumor model 28 Transcriptome analyses in a PCLS-based viral infection model 28 Establishment of a translational model of asthma 29 Stem cells in regenerative medicine 29 Business Unit Toxicology Testing Focus of activities in 2014 30 Projects 34 Risks from inhaled graphene 34 Engineered carbon black nanoparticles: prediction of human toxicity 34 Carcinogenicity study with multi-walled carbon nanotubes 35 Improved safety for workers in the ceramics industry 35 Using in-vitro models to predict drug-mediated CYP induction 36 Alternative ex-vivo method to determine the activity of lung surfactant 36 Standardized in-vitro testing of aerosols using the P.R.I.T.® ExpoCube® 37 Cigarette smoke induces cytotoxicity and inflammatory signals in precision-cut lung slices 37 Business Unit Manufacturing of Biopharma- Business Unit Registration and Risk Assessment ceuticals for Clinical Trials Focus of activities in 2014 54 Focus of activities in 2014 38 Projects 58 Projects 42 From draft decision to final decision with International cooperation for GMP manufacturing Fraunhofer expertise 58 of a biosimilar 42 Refinement of the environmental emission Custom filling processes: aseptic fill and finish of scenario for metalworking fluids 58 small volumes 42 Sensitivity comparison of acute ecotoxicity data Cell line development for recombinantly produced under REACH 59 veterinary medicinal products 43 Using QSAR methods to minimize animal testing Customized protein expression 43 under REACH 59 Business Unit Early-Phase Clinical Trials Fraunhofer-Gesellschaft 60 Focus of activities in 2014 44 Fraunhofer Group for Life Sciences 61 Projects 48 Allergen challenge in the Fraunhofer ECC: central Names, dates, events examination method in multicenter studies 48 Publications 62 Exhaled breath analysis in COPD patients 48 Doctorates 67 Contrast imaging of the airways with Master’s theses 67 hyperpolarized xenon 49 Bachelor’s theses 68 Birch pollen challenge established in the Fraunhofer ECC 49 Invited lectures at congresses and conferences 68 Contributions to congresses and conferences 70 Business Unit Environmental, Occupational Active participation in committees 73 and Consumer Protection Research projects 75 Focus of activities in 2014 50 Cooperation with institutions and universities 76 Projects 52 Exhibitions, congresses and workshops 78 Verification of measures for safer use of solvents 52 Beryllium at European workplaces: comparison of Editorial notes 80 two measurement methods 52 E-cigarettes: online measurement of the emitted vapor 53 Biomonitoring to capture occupational exposure of livestock workers to antibiotics 53 FOREWORD TO READERS Dear Reader, the challenges consist in developing more validated in-vitro and ex-vivo methods to assess hazards and risks to human Like no other publicly funded research institution, the Fraunhofer- health during manufacturing, processing, application, disposal Gesellschaft and its research institutes have committed them- and recycling processes and in reducing animal experiments selves to translational research, i.e. the translation of research to a minimum. results and early prototypes into economically successful and socio-politically accepted innovations. In the context of pharmaceuticals and medical products in particular, research institutions often tend to underestimate For the past 15 years, the Fraunhofer ITEM has been very in- the extensive set of laws and regulations these products and tensely and consistently engaged in the application and further related processes have to comply with to receive regulatory development of a translational platform for the pharmaceutical approval for use in man, and the vast amount of time and and chemical products sectors; for medical products and money that needs to be spent until a new product candidate implants, corresponding activities so far have been part of can even be tested in a clinical proof-of-concept study. The the institute’s research and service portfolio only to a minor aim here is to reduce time and cost to the first-in-man trial – degree, but in response to increasing need and demand enabling at the same time a high probability of success in the these are now being considerably expanded. clinical proof-of-concept study. The translational platform of the Fraunhofer ITEM for pharma- The Fraunhofer ITEM has set up a large variety of technical, ceuticals, medical products and implants and for chemicals chemical analytical, biomedical, biotechnological, and clinical and chemical products on the one hand is characterized by laboratories, staffed with highly qualified scientists and clini- performance of the clearly defined guideline studies that are cians and supported by an internationally recognized quality required for certification, registration, and marketing authori- assurance team to help clients, in particular also publicly funded zation; on the other hand, this platform also strives to develop research institutions, spin-offs, biotechnological companies novel cost-effective, time-saving, and optimally predictive and pharmaceutical start-ups develop their product candidates test methods and validated models for bringing product candi- to market maturity. dates to market and to apply these in contract research and cooperation projects. Development and validation of product-specific biological and clinical test systems are focuses of research and activity at the The challenges are indeed huge, whether in the area of inno- Fraunhofer ITEM, as is the performance of studies required for vative therapies with recombinant human antibodies, in the registration in compliance with the GXP quality standards. field of cell and even stem-cell therapy in regenerative medi- cine, or in gene therapy as ultimate therapeutic approach A very important part of the planning process for a drug develop- tackling not only the symptoms, but the very cause of a par- ment project, besides a pharmacoeconomic evaluation, is ticular disease at its site of origin, namely the genes. This holds communication with the competent authorities at an early also true for new implant materials and for the testing of stage (scientific advice). The Fraunhofer ITEM experts contin- active implants and medical products with an active pharma- uously enhance their regulatory research expertise required cological principle. With regard to chemical industry products, to support this process. 4 I 5 With its translational research in the field of the life sciences, I am very pleased that we have been able to set up this trans- including also performance of early-phase clinical trials in the lational platform, which we will continue to develop further. facilities of the research institution, the Fraunhofer ITEM is Let me take this opportunity to thank the institute’s staff, unrivaled in the publicly funded German and also European whose commitment has allowed this progress to be made. research landscape. In particular, I would like to express my gratitude to our clients A facility deserving special mention is the Clinical Research and cooperation partners – we will be happy to continue Center Hannover with its imaging center, biobank, and a supporting them in their market-relevant research and develop- broad range of clinical diagnostic laboratories, through which ment projects. the Fraunhofer ITEM has substantially enhanced its clinical research and its possibilities to perform proof-of-concept studies in cooperation with the Hannover Medical School and the Helmholtz Center for Infection Research under the same roof. Prof. Dr. Dr. Uwe Heinrich Executive Director PROFILE OF THE INSTITUTE Research at the Fraunhofer ITEM is focused on human