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Radiolabelling
The radiolabelled component is usually prepared
only once, on a very small scale (less than one
gramme) and in a single batch. It is also subject to
significant dilution with unlabelled material. The
preparation of the radiolabelled component, the
radiolabelled API, is thus not subject to full GMP
manufacture but to Section 19 of the GMP guid-
ance which states that the controls should be con-
sistent with the stage of development of the drug
product and that appropriate GMP concepts
should be applied.
The relevant guidance has been issued in Europe
as Eudralex volume 4 and recently in the USA by
the FDA under their Guidance for Industry CGMP
for Phase 1 Investigational Drugs.
This guidance places the emphasis on avoid-
ing cross contamination, on accurate record
keeping and ensuring that the material is well
characterised. Process validation is not appro-
priate for a single batch so less emphasis is
placed reproducibility or consistency and envi-
ronmental controls.
Figure 3 Radiolabelled API: GMP concepts Preparation of the radiolabelled API may
The objective of human ADME studies is to involve a new synthesis or repurification of
determine the mass balance of a drug and to eval- DMPK radiolabelled material (Figure 3) under
uate its metabolism. Such studies require admin- GMP concepts. It is preferable to carry out the
istration of a radiolabelled compound and are synthesis at high specific activity to provide cer-
subject to a number of regulations summarised in tainty on the position of the C-14 atom and to
Figure 1. The exact applicability depends on the ensure knowledge of C-14 impurities thereby min-
nature of the study, for example administration of imising any problems that might arise during the
microtracer quantities do not require ARSAC analysis of the clinical samples.
ethics approval. Once the radiolabelled API has been prepared
This process for preparation of radiolabelled and fully characterised, the clinical laboratory per-
material suitable for administration to humans is forming the study accepts the material and pre-
Figure 4 shown in Figure 2. pares the final dosage form using a GMP-licensed
manufacturing process under the control of a
Qualified Person (QP) immediately prior to admin-
istration. It is good practice to test the final prepa-
ration using LSC and to keep a parallel sample as
a check.
If a radiolabelled intravenous dosage form is
required (ie for absolute bioavailability studies)
then an additional step is needed. As terminal ster-
ilisation, using irradiation or heat treatment is not
suitable for sensitive C-14 compounds, a GMP val-
idated aseptic process involving filtration is
employed to prepare the sterile dosage form (the
investigational medicinal product (IMP)).
Examples of companies which are licensed by the
MHRA to perform this in the UK are SCM Pharma
and HMR.
Successful C-14 GMP concepts projects rely upon
a smooth exchange of documentation between the
sponsor, the clinical unit performing the clinical
study and the radiolabelled API contractor.
56 Drug Discovery World Winter 2009/10
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