Los medios de comunicación como agentes de socialización

IV-.4.2.1. Legislation and regulatory authorities

In Turkey, hospitals can be divided into two general categories: state-owned and privately operated. Approximately 300 hospitals have nuclear medicine departments and 116 of them PET scan capability. There are ~205 gamma cameras and ~120 PET scanners over Turkey, and in total there are ~230,000 PET scans annually performed. The most common ‘classic’ nuclear medicine procedures are bone scintigraphy, lung ventilation/perfusion scans, and myocardial perfusion imaging. ^99mTc Radiopharmaceuticals are prepared within nuclear medicine

121 departments by specifically trained technicians, under the responsibility of the nuclear medicine doctors. There are two ‘Molly generator’ producers in Turkey: Eczacıbaşı Monrol and Kamrusepa. Eczacıbaşı Monrol is also producing freeze-dried ^99mTc labelled kits (MIBI, MDP, DMSA, DTPA, ECD). In addition, distributor companies must be licensed to import SPECT and therapeutic radiopharmaceuticals.

PET scans are most often (>95%) performed in the field of oncology with most of these utilising [¹⁸F]FDG and [¹⁸F]NaF. Majority of the cyclotrons (13 cyclotrons in total) are installed in Istanbul, Ankara, İzmir and south of Turkey and run by private companies. Most of [¹⁸F]FDG doses are supplied from commercial cyclotrons run by Eczacıbaşı Monrol, Moltek and Medicheck. Additionally, two state-owned university hospitals (Ankara University and Hacettepe University) are in the process of building PET drug (labelled with ¹¹C or ¹⁸F) production facilities. These radiopharmaceutical production facilities are expected to become operational in 2017. In the past six years, there also has been a significant and evident increase in the preparation and use of both in-house-produced of PET radiopharmaceuticals, as well as therapeutic radiopharmaceuticals. Currently, there are 25 state and private hospitals that offer

68Ga labelled and ¹⁷⁷Lu labelled radiopharmaceuticals for clinical use. Most of these radiopharmaceuticals are produced using cassette-based automated radiopharmaceutical synthesizers.

IV-.4.2.2. Legislation and regulatory authorities

The Turkish regulatory responsibilities in the preparation of radiopharmaceuticals are divided into the pharmaceutical aspects and the radiation protection aspects. Turkish Medicines and Medical Devices Agency (TITCK), a section of the Turkish Ministry of Health, regulates all pharmaceutical manufacturing in Turkey, including manufacturing of radiopharmaceuticals.

Pharmaceutical (radiopharmaceutical) licensing procedures are governed by the national

‘Regulation on Licensing of Human Medicinal Products’ adapted from the European Commission Directive 2001/83/EC for human medicinal products. Pharmaceutical (radiopharmaceutical) manufacturing procedures are governed by the national ‘Regulation on Manufacturing Plants of Medicinal Products for Human Use’ adapted from European Commission Directive 91/356/EEC and Directive 2001/83/EC. As such, pharmaceuticals (radiopharmaceuticals) must be manufactured under GMP and controlled for quality in compliance with the general and individual monographs of related preparations’ directives in the European Pharmacopeia.

The Turkish Atomic Energy Authority (TAEK) regulates radioisotope production, quality control, production scale up, and distribution. Licensure by TAEK serves as authorization for governmental or private bodies or persons who possess, use, import or export, transport, store, and trade both radioactive materials and radiation equipment. TAEK also provides oversight with regards to radiation protection.

Generally, radiopharmaceuticals in hospitals can be prepared by a special manufacturing (or preparing) licence but that allows only an in-house application. The manufacturing licence is issued and inspected by both TITCK and TAEK. Therefore, radiopharmaceutical manufacturers and radiopharmacy laboratories in hospitals have to comply with the regulatory requirements implemented by these agencies.

122

From a regulatory point of view, three types of radiopharmaceuticals are considered:

(a) Radiopharmaceuticals extemporaneously prepared, not for clinical trials

Very short half-life radiopharmaceuticals need to be prepared extemporaneously ‘in house’ i.e.

in the hospital where they are used shortly after preparation. A major difference to other pharmaceuticals prepared in hospital pharmacies lies in the specific environment, where radioactive drugs must be handled in hospitals where they are prepared under a special manufacturing licence. In addition to a range of ^99mTc labelled products this would include ⁶⁸Ga and ¹⁷⁷Lu labelled peptides or small molecules, and radiopharmaceuticals labelled with ¹⁸F.

(b) Radiopharmaceuticals to be used in clinical trials

In this case, the radiopharmaceutical is considered an Investigational Medicinal Product (IMP) and manufacturing must be performed under an IMP licence with release by a Qualified Person (QP); and the radiopharmaceutical and the trial protocol must be evaluated by the local Ethic Committees. Investigational Medicinal Product (IMP) are used in the hospitals without marketing authorization for clinical trials and non-officially approved indications.

(c) Radiopharmaceuticals with marketing authorization

In this case, the radiopharmaceutical has a Marketing Authorization issued by TİTCK and is manufactured by a radiopharmaceutical company (or PET cyclotron unit) under full GMP, including release by a Qualified Person (QP). During marketing authorization of the application process, the national authority (i.e. TİTCK) evaluates the product in terms of its quality, safety and efficacy. This category would include ⁹⁹Mo/^99mTc generators, kits for labelling with ^99mTc and ¹³¹I, and ¹¹¹In labelled products. PET agents include [¹⁸F]FDG, [¹⁸F]NaF.

IV-4.2.3. Quality control frequency, tests and the qualified person

Larger state-owned hospitals, especially university hospitals, are better equipped than the private hospitals, when it comes to nuclear medicine applications. Additionally, quality control of radiopharmaceuticals is better controlled in the state-owned hospitals. The manufacturing controls and the quality control testing used in preparation of radiopharmaceuticals are in compliance with both the general and individual monographs and published sources.

Radiopharmaceuticals prepared from licensed generators and kits by using closed procedures under aseptic conditions do not require full QC before use as long as this practice has been supported by a risk assessment.

Radiopharmaceuticals used in clinical trials, or extemporaneously prepared radiopharmaceuticals not for clinical trials, full QC is required. QC most often comprises pre- and post-release tests (radionuclide half-life dependent) and includes identification, pH measurement, visual inspection, chemical impurity test, radiochemical purity test, radionuclidic purity, residual impurity test, (especially residual solvent testing) as well as bacterial endotoxin content and sterility assessments. Specifications, limits and acceptance criteria should be set for each tested parameter. These radiopharmaceuticals must be released by a QP under responsibility of the medical doctor.

123