The use of radioactively labeled substrates began with Georg de Hevesy, who introduced the ‘tracer principle’ in the 1920s (for which he was awarded the Nobel Prize for Chemistry 1943). By introducing a radioactive label, a chemical compound (radiotracer) can be used to explore chemical or biochemical mechanisms by tracing the path of the underlying physiological processes.

Nuclear medicine is based on the tracer principle and is an important application of radioactivity in life sciences; in this field radiopharmaceuticals can be used for diagnostics and therapy. In nuclear medicine diagnostics, weakly radioactive and extremely small amounts of pharmaceuticals are applied. PET is an important method in modern molecular imaging. Molecules are labeled with positron-emitting radioactive atoms and are used to visualize biochemical and physiological processes in living organisms. PET diagnostics in oncology, immunology, cardiology or neurology are increasingly important tools on the path to personalized medicine.

Due to the very short half-lives of PET isotopes, radiopharmaceuticals for PET are regularly produced either on a daily basis or even for individual patient examinations. PET centers include a cyclotron (i.e., an accelerator to produce short-lived PET isotopes) and highly specialized laboratories to produce radiopharmaceuticals and are located in close proximity to tomograph(s) for PET diagnostics.

Infrastructure and Equipment

The PET center in Tübingen was established in 1995. The cyclotron (PETtrace 890, GE Healthcare, Sweden, 6 target positions, dual beam possible) can accelerate high energy protons (16.5 MeV) or deuterons (8.2 MeV) to produce 18F (110 min half-life), 11C (20 min), 13N (10 min) and 15O (2 min). In addition, the production of less commonly used isotopes, including 124I (4 days), 86Y (15 h) and especially 64Cu (13 h), has also been established. Recently, the cyclotron has been upgraded to state-of-the-art technology (e. g., beam current 160 μA, high efficiency targets) to meet our requirements of maximum reliability and highest output.

To guarantee radiation safety and protect personnel and the environment during the production of radiopharmaceuticals, so-called hot cells have been installed; these hot cells are large boxes with at least 75 mm of lead shielding to minimize radiation doses. Inside the boxes, computer-controlled synthesizer modules are installed for automated production.

In further dedicated hot cells built as closed system isolators, products are sterile filtered under sterile conditions again to ensure the highest quality of the radiopharmaceuticals. Finally, in the isolator, samples are collected for quality control. Depending on the individual product, the final product batch may be divided into portions for various end-users (dispensing) by means of an automated system inside the isolator. Each product batch undergoes comprehensive quality control, ensuring that quality meets the specifications for the maximum safety of the radiopharmaceutical for the patient. Quality control includes testing for pH value, identity, radionuclidic purity, chemical and radiochemical purity and microbial status, such as endotoxin content and sterility. The product is released for human administration by the Qualified Person (QP) in charge only when all the specifications are met.

Our Facility

Our facility is equipped with clean room laboratories (class C) for GMP production of radiopharmaceuticals with 10 synthesis hot cells containing various automated synthesizers and 2 isolators (class A). Storage of materials is provided in a class D clean room. For quality control we run laboratories where 5 high-performance liquid chromatography systems, 2 gas chromatography systems with mass spectrometer and flame ionization detector, a phosphor imager, a high-performance gamma spectrometer, an endotoxin test device, sterile filter integrity test, 2 pH meters and an osmometer are included.

For radiopharmaceutical development we have seperate laboratories with 4 hot cells.

Further, we have a technical compartment with two compressing systems for radioactive gas waste storage and a central gas supply station (for the gases nitrogen, argon, helium and hydrogen).

The 6 Steps of Radiopharmaceutical Production

1.) Radioactive isotopes for medical application are available either commercially (e.g., 131I) or from a generator system that delivers the isotope on demand (e.g., 99mTc). In the case of PET, isotopes are produced by a cyclotron.

2.) Radiolabeling, i.e., introduction of the radioactive isotope into a chemical substrate, is performed. After this radiolabeling, further reaction steps may be necessary, depending on the individual product.

3.) The radiolabeled product is purified.

4.) The product is formulated to achieve a solution normally for intravenous injection; in rare cases, oral administration may be possible.

5.) Quality control of the radiopharmaceutical is performed.

6.) The radiopharmaceutical is released for nuclear medicine application.

Good Manufacturing Practice (GMP) Production Site

The production of radiopharmaceuticals for human application under a marketing license, manufacturing authorization or in a clinical trial must follow international GMP guidelines (as with pharmaceuticals in general). The purpose of GMP is to confirm identity, strength and purity and to ensure the uniform quality and safety of a pharmaceutical product. GMP, based on quality assurance of the system, encompasses everything that impacts the quality of the (radio-)pharmaceutical product (i.e., premises, personnel, equipment, raw materials, hygiene and monitoring, quality control and documentation). Our GMP-based facility for radiopharmaceutical production, put into operation in 2016, meets the highest standards of the current GMP requirements in order to satisfy modern demands for products that meet the highest standards for availability, reliability and patient safety.

Regulatory Aspects for Human Application

In Germany, radiopharmaceuticals can be produced and applied in the context of four legal frameworks which fall under either the ‘Medicinal Products Act’ (Arzneimittelgesetz, AMG) or ‘regulation on radioactive or ionizing radiation treated medicinal products’ (AMRadV)

• Marketing license (AMG §21 ff)
• Clinical trial (AMG §40 ff)
• Clinical use of a compound known in the literature (AMRadV §2 Abs. 1)
• Production and use for dedicated patients under direct responsibility of a nuclear medicine physician (AMG §13 Abs. 2b).

For the first three regulations, a manufacturing authorization from the local authority is mandatory, and GMP rules have to be followed. A marketing license is granted by the federal institution (BfArM) and allows for commercial distribution of a product.

Our products and what they are used for

Our radiopharmacy produces tracers and radiolabeled drugs not only for diagnostics (PET) but also for therapy, utilizing all four of the above mentioned possibilities. Products are used in-house for PET/CT and PET/MRI and are also offered to external customers outside Tübingen and to scientific collaboration partners. Under AMG §13 2b, external physicians may also produce a nonlicensed product for their patients in our laboratory with support from our staff.

One main focus of our department is to bring newly developed PET radiopharmaceuticals to the patient. This translational research is intended to further provide clinics with highly specific and selective biomarkers, enabling the visualization of new relevant target structures and mechanisms, thereby reinforcing the applicability of PET diagnostics for the benefit of patients.