Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Legal and regulatory aspects of manufacturing, quality control and release of 2-[18F]Fluro-2-desoxyglucose ([18F]-FDG) as an example for short-lived radiopharmaceuticals in reflection of relevant regulations, directives and guidelines ***

Michael Riesenberger (Abschlußjahr: 2003)

In this thesis the legal environment with influence on manufacturing, quality control and release has been identified. The different levels of legislation in the means of the European Legislation (Regulation 2309/93/EEC and the Directives 2001/83/EC, 2003/63/EC and 91/356/EC) as well as the European Pharmacopoeia Monographs 0125 and 1325, the EC Guide to Good Manufacturing Practice and the respective Annexes 1, 3 and 18 have been discussed and interpreted. Besides the European legislation, German laws and ordinances have been identified, of which are relevant for radioactive drugs: The Operation Ordinance for Pharmaceutical Entrepreneurs, the Ordinance of Radioactive or with Ionising Radiation Treated Pharmaceuticals. The first supplying general rules concerning manufacturing, quality control and release of this type of drugs, the ordinance named second is not usable for the subject of this thesis but regulating to marketing authorisation purposes. The Atomic Act and the Radiation Protection Ordinance do not cover any subject concerning manufacturing, quality control and release of radioactive medicinal products.

There are special needs for the production of radioactive medicinal products due to their radioactive nature, which need to be taken into account. In the Pharmacopoeia Monographs a permission is included that allows for release prior to completion of the sterility testing of an aseptically produced drug. In this context the priority of the respective provisions has been discussed.

A lot of different and scattered information about radioactive drugs is available in very different laws, ordinances, the European Pharmacopoeia, the Guidelines of Good Manufacturing Practice for Pharmaceutical Products and the Annexes thereof, European Directives and European Regulations. As discussed in this thesis, parts of basic legal requirements for the manufacturing of radioactive pharmaceuticals are equivalent to those of non-radioactive medicinal products. If you go for details, the deeper you go the more you get confused which of the rules really apply to radiopharmaceuticals or not. The European Pharmacopoeia supplies a lot of information but also information which differs from the general methods. Additionally, the monograph ruling [18F]-FDG names different methods of generating the precursor within the monograph but not mentioning the detection equipement.

Unfortunately there is no legal compilation available furnishing concentrated and dedicated information on the provisions to follow for the manufacturing, quality control, release, and considering the special needs of radioactive pharmaceutical products.

The European Commission should make up their mind whether it would be a great advantage to draw up such a compilation and to revise Annex 3 of the EC-GMP-Guide to Good Manufacturing Practice as well as the European monographs in this respective field. The German Operating Ordinance for Pharmaceutical Entrepreneurs should be amended by a paragraph dealing with the special needs for the release of radioactive drugs. The Ordinance of Radioactive or with Ionising Radiation Treated Pharmaceuticals should be repealed, and the legally necessary regulations be transferred to the German Drug Law: E.g. §§1 and 2 of this ordinance could be transferred to § 7 Drug Law, § 3 could be regulated within §§ 10 and 11 Drug Law. As the German Drug Law is routinely revised, amended or changed on an almost yearly basis, also due to changes in the European Legislation, there is enough legal flexibility to revise this subject as well.