**4.1 Radiopharmaceuticals within a clinical trial**

On the other hand, the Radiopharmaceuticals can be used for research and development. All requirements to apply in Europe for a clinical trial are stated in *EudraLex - Volume 10 -* **Clinical trials guidelines** *Volume 10 of the publication "The rules governing medicinal products in the European Union"* [9]*.*

The following four circumstances are possible for the use of Radiopharmaceutical within a clinical trial:


### **4.2 Small scale preparations of radiopharmaceuticals**

Radiopharmaceuticals may be prepared at small scale in healthcare establishments, and they may also be prepared outside the marketing authorisation track.

There are various types of radiopharmaceuticals prepared in healthcare establishments as it is described in PIC/S (Pharmaceutical inspection convention, pharmaceutical inspection co-operation scheme) [10] among which can remark:


*Quality in Non-Licensed Radiopharmaceutical Products: Are We Achieving the Goal? DOI: http://dx.doi.org/10.5772/intechopen.99388*


## **5. Preparation or manufacturing of radiopharmaceuticals?**

The difference between radiopharmaceutical preparation and manufacture is a sensitive issue which calls for a consensus that, it seems not exist at present.

The following definitions for preparation and manufacturing can be found in the GMP Annex 3 [11]:

*"Preparation: handling and radiolabelling of kits with radionuclide eluted from generators or radioactive precursors within a hospital. Kits, generators and precursors should have a marketing authorisation or a national licence".*

*"Manufacturing: production, quality control and release and delivery of radiopharmaceuticals from the active substance and starting materials".*

As per the extract above, it becomes apparent that in a preparation, products with marketing authorisation should be used. Provided that the summary of product characteristics (SPC) instructions is followed, the ultimate responsibility for the radiopharmaceutical preparation with respect to its safety, quality, and efficacy, over its shelf live lies with the marketing authorisation holder (MAH). However, this requirement is not remarked in the case of manufacturing.

By contrast, if we regard the Pharmacopoeia European monograph (5.19) Extemporaneous preparation of radiopharmaceuticals [12], the following definition is stated:

*"The preparation of radiopharmaceuticals is considered as a process involving some or all of the following steps: purchase of materials and products, production of radionuclides for radiolabelling, radiolabelling, chemical modification and/or purification, formulation, dispensing of the pharmaceutical form, sterilisation, analytical control, packaging, labelling and release. Drawing patient doses for immediate application (e.g., from a multidose vial) is considered as part of clinical practice, and not part of the preparation of Radiopharmaceuticals."*

As can be seen in the pharmacopoeia definition, the use of authorised materials and products is not a requirement. From this perspective, preparation and manufacturing processes could seem fairly similar, since purification and sterilisation steps are also encompassed within them. However, as it is stated in Pharmacopoeia European monograph (5.19), the manufacture of radiopharmaceuticals and investigational medicinal products should be covered by existing regulation (authorisation of any competent authority) and a pharmaceutical preparation definition would include all the preparations with licensed and non-licensed products. Additionally, the European Pharmacopoeia monograph 2619 [13] differences two categories, extemporaneous and stock preparations as it can be seen in the following extracts:

*"Pharmaceutical preparations are medicinal products generally consisting of active substances that may be combined with excipients, formulated into a dosage form suitable for the intended use, where necessary after reconstitution, presented in a suitable and appropriately labelled container."*

*"Pharmaceutical preparations may be non-licensed by the competent authority, or unlicensed and made to the specific needs of patients according to legislation. There are 2 categories of unlicensed pharmaceutical preparations:*


On the other hand, we cannot overlook that most radiopharmaceutical preparations are used for parenteral administration, and therefore required to be sterile. Then, if we consider the *EMA guideline on the sterilisation of the medicinal product active substance, excipient, and primary container*, [14] it might seem that whenever a sterilisation procedure has to be applied, it will be considered as a manufacturing process according to the following extract:

*"Sterility is a critical quality that cannot be assured by testing, it needs to be assured by the use of a suitably designed, validated and controlled manufacturing process".*

Therefore, this consideration seems to contradict the previous pharmacopoeia extracts where the sterilisation process was included in the scope of the preparation definition.

Notwithstanding the difficulties to get an official consensus on the definitions of preparation and manufacturing, there should be an agreement on who bears the final responsibility in them:

