ZW 09-11 GMP Lab for production of PET tracers for clinical and translational research

1. ZW 09-11GMP Lab for production of PET tracers for clinical and translational research Luc Mortelmans, Guy Bormans, Koen Van Laere, Christophe Deroose, Alfons Verbruggen, Johan Nuyts

2. Positron emission tomography (PET) • Tracks molecules in the body by external detection of gamma rays emitted during decay of short-livedpositron emittingradionuclides 3. Images representing tracer distribution are reconstructed 1. Tracer injection + distribution throughout the body 2. External detection of gamma rays (PET camera)

3. PET allowsin vivoquantification of molecularevents Modelling of kineticanalysis of PET data provides parametricmaps e.g. in vivo receptor occupancy Clinical research Patient Care Drug development Time-activity curves Kinetic modelling Binding potential Bmax/Kd Plasma input curve Radiometabolite quantification

4. PET tracer production: layout Radionuclide production Cyclotron irradiation (fluorine-18, carbon-11) Generator (gallium-68) Radiosynthesis incorporation of radionuclide in target molecule Purification and formulation Prepar. HPLC, sterile membrane filtration QC HPLC, GC, pH, sterility, pyrogens …

5. PET tracer production: a race against time Cyclotron production Purification & formulation Scanning & Sample processing radiosynthesis QC

6. WhycGMPfor PET tracers? Radiopharmaceuticalforhumanuse Intravenousadministration For clinical trials: cGMPrequired

7. PET tracers for clinical research and cGMP: legal issues Belgian Royal Decree May 7th 2004 experiments on the human person CHAPTER XIII. – § 3 a …in the case of investigational medicinal products manufactured in Belgium, that each batch of medicinal products has been manufactured and checked in accordance with the principles and guidelines for good manufacturing practice EC Directives 2003/94/EC principles and guidelines of good manufacturing practice of medicinal products and investigational medicinal products for human use

8. PET tracers for clinical research and cGMP: legal issues Eudralex volume 4: Good manufacturingpractice

9. Requestedinfrastructure Total budget : €2,733,840 personnel € 238,000 maintenance contracts € 115,000 quality controlequipment € 457,000 hot cells € 850,000 infrastructure/equipment € 2,380,000 Radiolabelling modules € 1,071,000

10. Proposedfinancing Total support from companies:€ 750,000 (27%) Siemens € 150,000 GE € 150,000 Johnson&Johnson € 200,000 Merck € 250,000 Hercules foundation € 1,984,000 (73%)

11. Project fits in the strategy of K.U. Leuven • Molecular Small Animal Imaging Centre • Radiopharmacy research lab • Building for GMP lab • State of the art clinical pharmacology lab • Medical Image Research Center (MIRC) • Flanders “PET net” network

12. The research engine Pharmaceutical Industry GMP Drug development Clinical research Patient Care Academic research groups

13. The research engine Pharmaceutical Industry GMP Academic research groups Drug development Clinical research Patient Care

14. Project management Pharmaceutical Industry Academic Partners • Staff members • Nuclear Medicine • Radiopharmacy • Medical imaging Strategy Priorities Cost-benefit Human-resources scientific board Daily management board

15. Research Group MIRACLE Molecular Imaging Research and Clinical application K.U.Leuven Radiopharmacy Alfons Verbruggen Guy Bormans Nuclear Medicine Luc Mortelmans Koen Van Laere Christophe Deroose Medical Imaging Johan Nuyts Staff Faculty: 6 Post-docs: 9 PhD students: 14 Technologists: 7

16. Research Group MIRACLE Molecular Imaging Research and Clinical application K.U.Leuven Research output parameters (2005-2009) # PhD theses : # publications: # citations: # patents: # grant money :

17. Research Group MIRACLE Molecular Imaging Research and Clinical application K.U.Leuven Research output parameters (2005-2009) # PhD theses : # publications: # citations: # patents: # grant money :

19. “MIRACLE” (Molecular Imaging Research & Application Center Leuven) From bench to bedside

20. Onco-imaging clinic & research Oncology Clinical research Medical Physics • A) Diagnosis • Lungtumours • GI tumours • Lymphoma • Sarcoma (GIST) • Breasttumours • Response evaluation • earlyclinical trials • B) Therapy Reconstruction Kinetic modelling Data-analysis Image registration PET microPET SPECT microSPECT Bioluminiscense MRI microMRI Neurology & psychiatry Radiology Gene expression Infection and inflammation Cardiology Radiopharmaceutical chemistry PET 18F labeling 11C labeling SPECT 99mTc labeling 123I labeling

21. Nuclear neuro-imaging research Medical Physics Clinical research NeuroImaging Oncology Reconstruction • Neurology & psychiatry • Movement disorders • Epilepsy • Dementia • Brain Tumours • Eating disorders • Anxiety and mood disorders Kinetic modelling Data-analysis Image registration PET microPET SPECT microSPECT Bioluminiscentie MRI microMRI Radiology Gene expression Infection and inflammation Cardiology Radiopharmaceutical chemistry PET 18F labeling 11C labeling SPECT 99mTc labeling 123I labeling

23. ExperimentalPET-CT Biograph16-HiRez (contract research 2005)

24. MIRACLE : multidisciplinary platform Radiology Clinical nuclear medicine Medical Physics • Clinical Pharmacology • Recruitment (esp. HV) • Screening • Drug admin • PK sampling • ... Oncology Neurology/psychiatry Reconstruction Image registration Cardiology Infection-inflammation Data-analysis Stem cell research Kinetic modelling Gene expression Clinical Divisions - Patient recruitment PET 18F 11C SPECT 99mTc 123I Radiopharmaceutical chemistry

25. Position & Role of MoSAIC Life sciences imaging clinical Improved diagnosis/ therapy preclinical development Omics clinical research ‘basic’ research drug review/ market MoSAIC Novel diagnostic & therapeutic strategies Improved insights & novel hypotheses IMAGING SOLUTIONS core partners peripheral partners

26. MoSAIC multimodality imaging facility (2007) Dedicated small animal imaging equipment CT US PET SPECT Clinical imaging equipment adapted to small animal scanning: BLI MRI

27. positron emission tomography (PET) • Translational molecular imaging technique microPET scanner clinical PET scanner imaging of dopamine transporter Rat model of Parkinson’s disease normal PatientwithPD

28. PET in drug development $ 800 MM - $1.6BN $$$ Regulatory Approval Laboratory Clinic Research Clinical Trials Accept or Reject a Candidate or Hypothesis Toxicology Refine Leads Find Leads Identify Targets Development 1 3 5 7 Time (Years) Slide courtesy of R Hargreaves, MSD

29. PET in drug development PET provides -early clinical target validation -early clinical target occupancy data as a funtion of dose as a function of time p.i. development of PET probes for new targets in parallel to drug development by all major pharmaceutical companies (MSD, Novartis, J&J, SKB, Roche,…)

30. Therapeutic drugs and PET tracers

31. PET tracers for clinical research and cGMP: legal issues Eudralex volume 4: Good Manufacturing Practices Aseptic activities Class “A“air Production cell class “C” air

32. ISO-certificationNuclearMedicine (2005)

33. Center for ClinicalPharmacologyClinical Research Unit (1) Facilities hotel accommodation: 20 beds for overnight stay sanitary facilities (3 showers) 2 recreational areas (internet access, TV, video, …) research laboratories (4 laboratories; 2 temperature controlled) laboratory for sample processing medication room secretary and offices meeting room / monitoring office archive

34. Center for ClinicalPharmacologyClinical Research Unit: study types 1998-2007

36. MoSAICMolecular SmallAnimal Imaging Center A: µPET B: µCT C: µUS D:µSPECT E: µMRI F: BLI C Animal modelsof human disease D 380 m² Imaging 320 m² Support

37. 3 synthesishotcells 1 dispensing hotcell for FDG Upgrade level 0: FDG (temporarily) + research 10 synthesishotcellsfor research 1 gloveboxfor dispensing 1 LAF-cabinet Sas

38. 6 synthesishotcells, 1 dispensinghotcellforcontract research New building level 01 FDG + Contract research 4 synthesishotcells, 1 dispensinghotcellforFDG

39. University Hospital Leuven Nuclear Medicine Nuclear Medicine Cyclotron MoSAIC Radiopharmacy Lab

40. University Hospital LeuvenNuclear Medicine Antwerpen, VUB, KUL, RUG, UCL, ULG, ULB (UNIV – 7) Hasselt, Charlerloi, Kortrijk, Bodet, Antwerpen, Mont-Godinne (NIET-UNIV – 6)