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Published on 20 September 2010

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Harmonising applicable radiopharmaceutical preparation guidelines across EU countries

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Guidance for the small-scale preparation of radiopharmaceuticals, an initiative of the Radiopharmacy Committee of the European Association of Nuclear Medicine (EANM)

Sergio Todde1,2

Clemens Decristoforo1,3

1The Radiopharmacy Committee of the European Association of Nuclear Medicine

2University of Milano-Bicocca
Centro di Bioimmagini Molecolari
Monza
Italy

3Clinical Department of Nuclear Medicine
Medical University Innsbruck
Innsbruck
Austria

Radiopharmaceuticals (RPs) are composed of two main parts: ‘radio’ reflects a radionuclide, which provides the required signal for the diagnostic equipment in a molecular imaging procedure and/or the energy source to destroy a pathological tissue in targeted molecular radiotherapy; and  ‘pharmaceuticals’ stands for a more or less complex molecular structure, that binds the radionuclide and serves only as the carrier to bring the radioactive part to the molecular biological target without having a pharmacological action itself  (tracer principle). RPs, predominantly intended for parenteral administration and prepared aseptically, possess some remarkable specificities that make them different from ‘normal’ pharmaceuticals.

  • The short or even ultra-short half-life of the radionuclides (eg, F-18 with T1/2 = 109min; C-11, with T1/2 = 20.3min; N-13 with T1/2 = 10min; O–15 with T1/2 = 2min), make the shelf-life of this class of compounds often in the ‘minutes to hours’ range (eg, typical shelf-life of the most popular positron emission tomography [PET] radiopharmaceutical, namely [18F]FDG, is in the range 8–10 hours, while for C-11 labelled RPs shelf-life may be in the range of 1 hour only).
  • For the same reason, such RPs cannot be produced in large quantities and distributed over great distances. They are often prepared locally ‘in-house’ and used in a hospital (academic or not) environment.
  • RPs are generally prepared in micro-dose amounts (µg or even ng of the active pharmaceutical ingredient without any pharmacological effect).
  • RPs are usually prepared on a small-scale basis. The final products are very often represented by a single vial, containing one or a few individual patient doses. Therefore, they are not comparable with normal pharmaceuticals with batches including up to thousands of individual doses.

RPs may fall into one of the two main classes – RPs for imaging purposes and RPs for targeted radiotherapy. To date, a majority of the diagnostic examination using RPs are dedicated to oncology but they are also used in neurology, cardiology and other fields, where they may provide significant functional information, complementary to other imaging modalities such as computed tomography or magnetic resonance imaging.
There is an enormous variety of chemical and radiochemical pathways through which they are prepared, covering most of the main organic and inorganic reaction pathways. The complexity of the radiolabelling procedures range between the so-called ‘kit’ preparations, that often simply consist of adding the radionuclide to a vial containing all the components (precursor, reducing agent, excipients) in a freeze-dried form, to complex radiosyntheses of some PET RPs which may include up to four synthetic steps with intermediate and end- purifications, which all require complex sophisticated instrumentation, with a large proportion of automation. Thus, despite the small scale, the laboratory setup may not be so straightforward, considering also that every RP batch, in some cases corresponding to an individual patient dose, has to be carefully tested in a quality control laboratory equipped with state-of-the-art instrumentation, including gas chromatography, high performance liquid chromatography and Gamma spectrometry.

Specific pharmaceutical group
It is clear that RPs represent a particular group of pharmaceuticals, and in Europe they have been recognised as such only in the late 1980s with Directive 89/343/EU, where a definition of terms such as ‘radiopharmaceutical’, ‘radionuclide generator’ and ‘kit’ were introduced. The above Directive was subsequently adapted in various ways into the national legislation of the EU member countries. It was replaced by Directive 2001/83 stating that all medicinal products have to comply with the current standards of Good Manufacturing Practice (GMP).[1] For RPs a dedicated Annex (Annex 3, recently revised) covers specific GMP regulations for this kind of production, including specific issues related to radiation safety and the short half-life, allowing, for example, the release of the final product before all tests are completed (eg, sterility testing). However, Annex 3 is still part of the framework of general GMP, which was originally intended for industrial, large-scale production. This poses great challenges for small-scale preparation in a hospital and/or academic setting. For instance, GMP requires the classification of production areas according to industrial standards and the separation of quality control from production facilities. For industrial RP manufacturing, GMP issues such as vendor qualification, high rate of sampling for quality control of starting materials and the involvement of a Qualified Person (QP) with special training in the quality control and preparation are implicit, regardless of the size of the facility and the number and the complexity of RP preparations, whereas small-scale RP production facilities in mostly academic and/or hospital institutions can barely cope with these requirements.
Can this problem be solved? As stated above, from the legislation point of view the situation may vary, sometimes significantly, from country to country. Considering that most RPs do not have a marketing authorisation, the so-called ‘magistral’ or ‘officinal’ preparation approaches, as defined in Directive 2001/83, have often been applied. In some countries the hospital small-scale preparation of RPs is based on the pharmacy status of the radiopharmacy unit. However, there are laboratories, especially those preparing PET RPs, which are located in university institutes or research laboratories without pharmacy status, and some countries have even excluded pharmacies from handling radioactivity. The preparation of short-lived RPs is then either based on a specific local regulation or, in many cases, directly under the responsibility of the medical doctor based on individual patient need. In the first case, specific individual authorisation is given and institutions are usually controlled by national pharmaceutical inspection schemes. In the second, no clear regulations for pharmaceutical inspections authorities often exist and authorisation is given based on radiation protection legislation only. In many European countries this is still the case for local, hospital-based preparation of RPs.
Moreover, there are countries where the concept of ‘centralised radiopharmacy’ has been applied (eg, Spain, UK, the Netherlands), where a large number of individual patient doses are prepared in medium-scale facilities, which then distribute them to hospitals located within a reasonable distance. Although it is claimed that this reduces costs and allows small nuclear medicine departments to survive, by eliminating their need to comply with GMP or other national rules, it does not solve the problem of the preparation of RPs labelled with very short half-life radionuclides or having a very short shelf life, for which the distribution is not applicable, or the preparation of investigational RPs.
Both national and European authorities are becoming increasingly aware of this situation and recent developments indicate that specific solutions allowing the routine use and application of small-scale preparations of RPs need to be found.

European level initiative
For all of the above reasons, the need for an initiative at the European level was identified, with the aim to provide to the European nuclear medicine community harmonised and pragmatic guidelines on the small-scale preparation of RPs. The Radiopharmacy Committee of the European Association of Nuclear Medicine (EANM) has released specific guidelines,[2] recently followed by a more specific Guidance dedicated to the small-scale preparation[3] of RPs. The need for an additional document especially arose because official guidelines, including GMP, are widely unspecific and many underlying details may not be clear, resulting in misinterpretations, especially when specific training in the field is lacking. The Guidance document includes most of the arguments and chapters outlined in the GMP, but covering in more detail the practical aspects. Further, the Guidance document is especially focused on the preparation of PET, therapeutic or other RPs that are not intended for commercial purposes or distribution. These RPs are often characterised by a higher degree of complexity in the preparation process, compared with the preparation using commercially available ‘kits’. Besides general statements on quality assurance and documentation, that are not significantly different from GMP, chapters indicate possible solutions to the critical aspects depicted above.

Identifying a competent, experienced professional
First, a proposal for the assignment of the responsibilities, alternative to the QP, has been given. The responsible person for the small-scale preparation of RPs (RPR) should be a person with an equivalent academic background compared with the QP, but the necessary experience in a radiopharmacy is considered important rather than in an industrial pharmaceutical environment. The main purpose of such a statement is to identify a professional with the required competence by evaluating her/his background, career and experience in the specific field of small-scale RP preparation. In addition to the typical skills of the QP, the RPR should indeed be highly trained in radiation protection and radioactivity handling, and in general in all the matters that make the preparation of RPs different from that of classic pharmaceuticals. Furthermore, considering that there are many small-size facilities with a relatively few number of operating personnel, an additional solution is suggested regarding those situations where only one or two persons in the unit cover all functions (preparation, quality control, quality assurance). In these cases, the RPR may perform most of the tasks, provided that an additional independent professional is involved and a rigorous documentation system is in place. This individual could be anyone trained to look at the appropriate results, understand their meaning and confirm their correctness.
The Guidance then provides an ‘in-depth’ look at the practical aspects related to the facility and equipment characteristics. A major difference with classic GMP once again focuses on the small size of many facilities, where it is often impossible to organise the rooms following GMP specifications. Therefore, it has been proposed that in small-scale radiopharmacies the same area or room can be used for multiple purposes, ‘but as the complexity increases (multiple preparations of multiple RPs), it is important to develop the appropriate level of control required to prevent mix-ups and contamination.’ Moreover, ‘the storage room could accommodate both components that are released for use and those that are under quarantine, taking care to store them on separate shelves and provided that each lot is properly labelled as to its status and contents.’
As for the classification of the clean areas, special attention is focused on the radiation protection requirements that do not have to be compromised by the need to work in a clean room regime. For example, working in aseptic conditions (eg, under a laminar flow) would require that a minimum of components (tools, instruments, starting materials) are to be placed through the laminar flow pathway, to ensure optimal conditions – handling radioactivity may alter the layout of the above components, with the aim of allowing the operators to work safely.
Indeed, the other major issue to be considered in the implementation of a QA system to the preparation of RPs is, as stated above, the peculiar nature of one of the ‘starting materials’, the radionuclide. It should be noted that the radioactivity levels involved may be very high, peaking up to 370GBq in the case of the radionuclide F-18 used in the preparation of [18F]FDG.
A few examples are given on how this factor may affect QA management in a radiopharmacy:

  • The safest method of sterilisation, that allows for complete removal of microbial contaminants, is performed using heat sterilisation by autoclaving. However, time needed for a full sterilisation cycle may not be compatible with the half-life of some radionuclides, such as O-15, (T1/2 = 2min), N-13 (T1/2 = 10min) or even C-11 (T1/2 = 20min): moreover, there are RPs whose molecular structures do not survive a thermal treatment at 121°C.
  • Thus, sterilisation by filtration is the most frequently used method. This requires testing of the filter integrity before the release of the product. Here once again radioactivity plays a role, causing an excessive radiation hazard to the operator, as the filter may retain significant amounts of radioactivity. One of the solutions proposed by the Guidance is the use of two sterile filters in series, on a risk analysis basis.
  • In-process controls are considered ‘keypoints’ in the preparation of industrial pharmaceuticals, while they may not be always applicable in the case of RPs, again mainly due to radiation safety considerations.
  • Labels affixed to the vial containing the final RP product, unless the labelling process is automated, do not include all the information required by the GMP. Essential data such as the radioactivity of the final product or the radioactive concentration, which are available only at the end of preparation, cannot be handwritten on the label and therefore should be included on a second label usually affixed to the secondary shielded container.

Finally, the concept of risk assessment (or risk analysis) plays an essential role in this field, therefore this is frequently recurrent in the Guidance, as it helps to make decisions concerning the many questions that arise during all the steps involved in the small-scale preparation of RPs. Just to cite a few examples, in addition to those previously described, appropriate levels of microbiological sampling or quality controls and the nature of the controls themselves may be established on a risk analysis basis, as well as the necessary actions that need to be undertaken in the case of significant ‘out of specification’ results. Again, the Guidance suggests a simplified pathway for process validation, applicable by those small-scale radiopharmacies that have a well-established history of preparations, ‘using historical batch records, provided that there are adequate accumulated data to support a conclusion that the current process yields batches meeting predetermined acceptance criteria. The accumulated data should confirm that the preparation process was consistent and should document all of the changes to and failures of the process, if any.’

[[HPE52.41]]

In conclusion, we hope that the cGRPP guidance may contribute to the two major issues currently affecting the world of RPs preparation: adapting the regulatory framework to their specific characteristics and harmonising the applicable guidelines in the EU countries.

References
1. EU guidelines to Good Manufacturing Practice – Medicinal products for human and veterinary use, Vol. 4.
2. Guidelines on current good Radiopharmacy Practice (cGRPP) in the Preparation of Radiopharmaceuticals. Available online at: www.eanm.org/scientific_info/guidelines/gl_radioph_ cgrpp.pdf
3. Elsinga P et al. Eur J Nucl Med Mol Imaging 2010;37:1049–62.



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