CHAPTER 3
FDG as a
3.1 Radiopharmaceuticals as medicinal products
For quite a long time, radiopharmaceuticals have been exempted, together with other exclusive products -such as allergenes, vaccines and blood-derived products- from adopted pharmaceutical regulations. Applicabile rules were on radiation protection and compliance to Pharmacopoeial monographs. As of 1992, European Pharmacopoeia had more than 30 monographs covering the majority of routinely used radiopharmaceuticals. Directive 89/343/EC has extended the existing rules of medicinal products to radioactive compounds used as diagnostic or therapeutic agents (radiometabolic therapy).
In Italy, the reference legislation has been D.L.vo 178/1991 for almost fifteen years; recently D.L.vo 219/2006 has been enforced and covered the gap with EU concerning aknowledgement of Directive 2003/94/EU. As a matter of fact, radiopharmaceuticals are to comply with legislation and regulation applicable to medicinal products both when dealing with the process of approval of a commercial drug and when a new product or substance has to be used in humans.
The core legislation on the rules applying to studies on the development of new medicinal products (Investigational Medicinal Products, IMPs) and the conduct of clinical trials refers to Directive 2001/20/EC, concerning the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use, and Directive 2001/83/EC dictating the Community code relating to medicinal products for human use.
Directive 2001/83/EC has been amended by other Directives, such as 2002/98/EC for regulating medicines based on human blood and derivatives, and 2004/24/EC on special issues on Herbal Medicines. Directive 2003/63/EC directly dealt with radiopharmaceuticals and in particular introduced a revised version of the Annex I (Analytical, Pharmacotoxicological and Clinical and Protocols in respect of testing of
“Particular Medicinal Products” contains a chapter dedicated to “ Radiopharmaceuticals and Precursors”.
Quite a different situation is being faced by products lacking a MA. Directive 2001/20/EC defines in a strict way the necessity of applying GMP to the manufacturing of drugs used in clinical trials and IMPs. This last point has been addressed under practical principles and guidelines by Directive 2003/94/EC.
The revision of some annexes to the GMP EU Guide included also radiopharmaceuticals, under Annex 3, and even though applying to MA track, the statement existed that, due to the increasingly application of short-lived radionuclides for PET in investigational and clinical use, production of radiopharmaceuticals in PET Centres, Nuclear Centres, Institutes or industrial manufacture should be covered by above-mentioned Annex 3.
Directive 2005/28/EC [10] has then further covered this topic, by laying down the minimal requirements for and management of authorisations to manufacture or import investigational medicinal products, as well as for the granting and the content of the authorisations, in order to guarantee the quality of the investigational medicinal product used in the clinical trial. This situation is going beyond radiopharmaceuticals and in general affects small-scale preparations used for research such as spontaneous, academic, no-profit programs that, at least in principle, should be run under full GCP. As a consequence of actual legislation, the investigational product(s) should be prepared under official EU GMP standards and this would have an extreme impact on premises and organisation.
3.2 Quality Control of FDG
18F-FDG has a long-lasting history and many efforts have been made to
reach standard reference values and limits for defining the criteria of product acceptance.
This is a dynamic process merging the outcome of research with the control on safety and efficacy performed by the Regulatory Bodies (AIFA in Italy, EMEA in Europe) and the robustness of procedures, effectiveness of validation & verification moniotred by pharmaceutical inspectors of the National Authorities.
In general, the publication of a product monograph in a National or European Pharmacopea provide a major support to both industrial manufacturer and small-scale producers, such as hospital pharmacists. Infact, they can adopt the limits and the tests published in the monograph without the need to demostrate their applicability.
The quality requirements of 18F-FDG are set out in the European
Pharmacopoeia and cover: radiochemical and radionuclidic identity, pH, chemical purity, residual solvents, radionuclidic and radiochemical purity, sterility, bacterial endotoxins.
Fig.12: 18F-FDG sterile injectable solution
The radiochemical purity is checked by TLC and radio HPLC. In the TLC a spot of the produced 18F-FDG is applied onto a silica plate. The plate is
developed in a mobile phase (acetonitrile/water 95%-5%) and placed in a radio TLC scanner; the gamma counter measures the activity. The peak at Rf 0.4, which is 18F-FDG, should compromise more than 95% of the
carbopac is recommended with 0,1 NaOH as eluent. Retention time is 9 minutes min (1 ml/min). This peak should compromise more than 95% of the activity.
The radionuclidic identity can be confirmed by obtaining a gamma spectrum and measuring the half life of the product. The photon energy of 0.511 MeV and the sum peak at 1.022 MeV are common features to positron emitters, so measurement of the half-life must be done.
It can be carried out by measuring the same test solution in the same dose calibrator at 2 or more time points. The half-life is then calculated by
plugging the results into the radioactivity decay equation. As for chemical purity, the test protocol includes injecting and run the
HPLC of a reference standard TBA, FDG and ClDG solution and then run the HPLC of the 18F-FDG solution. The acceptance criteria is that the area
under the TBA, FDG and the ClDG peak of the 18F-FDG solution should be
less than that of the reference solution.
A GC is required to check the residual solvents such as ethanol, acetone, and acetonitrile.
The sterility test is carried out by an external laboratory. The bacterial endotoxins level is commonly tested by LAL test. You are
allowed to release of the 18F-FDG before completion of the bacterial
endotoxins test.
The pH value of an injectable should be as close to the physiological pH as possible. Although there is no specified test method, it is obvious that a visual inspection of the 18F-FDG is implied. The product should be
observed behind adequate shielding. A yellow colour may indicate the presence of impurities. An 18F-FDG product should only be clear and
3.3 Quality Assurance
Quality Control is just a part of the overall effort that is needed to demostrate the robustness of the production process and the safety and efficacy of the products. A multilevel approach exists that encopasses not only QC but a comprehensive view of all components that play a role into the “manufacturing”. In this perspective the process is a pool of the site, the equipments, the process and the personnel. All these are regulated by and managed under the Quality Assurance approach.
Quality Assurance is a wide ranging concept which covers all matters which individually or collectively influence the quality of a product. It is the total sum of the organised arrangements made with the object of ensuring that medicinal products are of the quality required for their intended use. Quality Assurance therefore incorporates Good Manufacturing Practice plus other factors outside the scope of this Guide.
The system of Quality Assurance appropriate for the manufacture of medicinal products
should ensure that:
(i) medicinal products are designed and developed in a way that takes account of the requirements of Good Manufacturing Practice and Good Laboratory Practice;
(ii) production and control operations are clearly specified and Good Manufacturing Practice adopted;
(iii) managerial responsibilities are clearly specified;
(iv) arrangements are made for the manufacture, supply and use of the correct starting and packaging materials;
(v) all necessary controls on intermediate products, and any other in-process controls and validations are carried out; the finished product is correctly processed and checked, according to the defined procedures;
(vii) medicinal products are not sold or supplied before a Qualified Person has certified that each production batch has been produced and controlled
any
other regulations relevant to the production, control and release of medicinal products;
(viii) satisfactory arrangements exist to ensure, as far as possible, that the medicinal products are stored, distributed and subsequently handled so that quality is maintained throughout their shelf life;
(ix) there is a procedure for Self-Inspection and/or quality audit which regularly appraises the effectiveness and applicability of the Quality Assurance system.
