Alternative to existing oversight committees

is limited exclusively to just one or a few major hospitals, local legislative rules and regulations specifically for radiopharmaceuticals may be non-existent. This is particularly true if the numbers of radiopharmaceuticals produced are

limited and are based on ‘kit’ processes. The methods and procedures used by the radiopharmacist would be according to the knowledge based training received by the personnel in their facility or elsewhere, their experience and the current compounding practice of the hospital where the radiopharmacy is located.

In such situations, a local Oversight Committee for Radiopharma-ceuticals (OCRP) (e.g., the Radio-Pharmaceutical Committee in India) may perform the role of the RDRC, IND and, to some extent, that of the NDA to scrutinize the SOPs, QC protocols, sterility/BET records, dispensing and various other responsibilities, as appropriate, and construct a system that will ensure that the manufacturing practice for radiopharmaceuticals are safe for their intended use. The SOPs can be constructed, taking into account the requirements established under good radiopharmacy practice, and the feasibility of adopting the prescribed guidance within Member States.

The PET radiopharmacy investment is major due to the cyclotron and radiochemistry synthesis modules, auxiliary equipment, skilled staff and space.

The PET radiopharmacy is complex to operate, as is apparent from the above discussion, even if only ¹⁸F-FDG is produced. Operational costs are high, because of the basic cost of ¹⁸O-water, certified precursors and reagents, and spares. The 110 min half-life of ¹⁸F requires that time schedules of production and supply have to be strictly maintained, the latter by ‘parametric release’.

Hence, the stakes are high: failures in production and QC add to the operational costs and to a loss of reputation.

All of this implies that the PET radiopharmacy operations are well planned and executed expeditiously. The SOP is the critical document that will ensure that the procedures adopted are such that a PET radiopharmaceutical is produced and delivered on time, and that the QC criteria will be consistently met. It is expected that hospital based PET radiopharmacy will use precursors and other critical reagents procured from established and reliable sources for PET radiopharmaceutical compounding. The staff will have requisite training and hands-on experience suitable for the purpose. With the ready availability of much of the equipment and consumables required for satisfactory radio-pharmacy practices, there is no need to look for local alternative equivalents for most of them.

The OCRP can oversee radiopharmaceutical manufacturing compliance standards through MS self-inspection in Member State establishments that lack their own oversight committees. The relevance of self-inspection is to monitor the implementation and compliance with good principles and practices of radiopharmacy, and to propose necessary corrective measures. These may include at least the following items:

(a) Personnel;

(b) Premises and utilities;

(c) Equipment;

(d) Production and in-process control;

(e) QC;

(f) Storage of raw materials and finished products;

(g) Documentation;

(h) Printed packaging materials control;

(i) Distribution of the products;

(j) Calibration of instruments or measurement system;

(k) Validation and revalidation;

(l) Maintenance system;

(m) Sanitation and hygiene;

(n) Complaints management;

(o) Recall procedures;

(p) Results of previous self-inspection and corrective steps taken.

The frequency at which self-inspections are carried out would depend on the size and scope of the facility and the number of products made by it. Self-inspection can be conducted partially (on production lines, facility, SOPs, etc.).

However, a complete self-inspection should be carried out once a year.

All self-inspections should be recorded. Reports should contain:

(a) Self-inspection results;

(b) Evaluation and conclusions;

(c) Recommended corrective action;

(d) Implementation and assessment of corrective action.

Finally, it may be stated that oversight committees for radiopharmaceu-ticals should periodically carry out a quality audit. Quality audits would consist of an examination and assessment of all or part of a quality system by an independent outside agency, with the specific purpose of improving the QA programme.

3.5.1. European Pharmacopoeia guidelines for PET radiopharmaceuticals Effective from 1 October 2005, the EP has provided guidelines on current Good Radiopharmacy Practice [18], emphasizing the need to adhere to regulations on radiation protection, as well as to appropriate rules of working under aseptic conditions while preparing radiopharmaceuticals for injection.

The good radiopharmacy practice guidelines for PET radiopharmaceu-tical cover:

(a) Personnel and resources;

(b) QA;

(c) Equipment and facilities;

(d) Documentation;

(e) Production and process controls;

(f) Laboratory controls;

(g) Finished radiopharmaceutical controls and acceptance criteria;

(h) Labelling and packaging;

(i) Distribution;

(j) Complaint handling;

(k) Self-inspection;

(l) Records.

As expected, the good radiopharmacy practice guidelines cover all aspects of PET radiopharmaceutical production, similar to the good radio-pharmacy practice of the FDA mentioned earlier. The criteria list of the good radiopharmacy practice appears to have four more points than the good radiopharmacy practice, perhaps owing to the fact that good radiopharmacy practice combined some criteria under one heading. For example, the EP good radiopharmacy practice considers labelling and packaging, distribution and complaint handling as separate criteria, while the FDA good radiopharmacy practice combines them under one document.

3.5.2. Regulations in Europe for PET radiopharmaceuticals

The role of the EMEA cannot be compared with that of the FDA, which is the equivalent authority in the USA. European Union (EU) directives need to be adopted (implemented) by single Member States, which usually takes place with the possibility of introducing changes and on different timeframes.

Although this situation can be avoided for marketing authorization (MA) applications, the situation is quite complex for clinical trials where researchers have to refer and apply to their national competent authority. The evolution of the regulations has introduced tighter rules; the latest directives have extended good radiopharmacy practice to R&D medicinal products, and to non-profit and academic research. As in the USA, several organizations, such as the Association of Imaging Producers and Equipment Suppliers (AIPES) and the European Association of Nuclear Medicine (EANM), are lobbying regulators

for a simplification of registration procedures for radiopharmaceuticals or, even better, for adoption of a separate regulation.

Some of the core legislation in Europe can be found in:

(a) Directive 2001/20/EC of the European Parliament and of the EU Council on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use;

(b) Directive 2001/83/EC on the European 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 blood components, and 2004/24/EC on special issues as regards traditional herbal medicinal products. Directive 2003/63/EC directly dealt with radiopharma-ceuticals and, in particular, introduced a revised version of analytical, pharmacotoxicological and clinical, together with protocols in respect of testing of medicinal products aiming at giving more precise indications and instruc-tions on the marketing applicainstruc-tions. In particular, Part III on particular medicinal products contains a chapter dedicated to radiopharmaceuticals and precursors.

Directive 2003/94/EC explicitly provides guidelines for good radio-pharmacy practice of investigational medicinal products (IMPs). More recently, Directive 2005/28/EC lays down the principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorization of the manufacturing or importation of such products. In Europe, as the Members States have authority on clinical trial approval, the methods for implementing this directive and translating it into national regulations will be very important. Although any clinical trial of an IMP has to receive approval by the ethical committee and the national competent agency, they might operate with different references and will thus translate this directive differently.

The EMEA has recently published a concept paper on the use of the microdosing concept in drug development. The relevant EMEA documents on radiopharmaceuticals and on diagnostic agents are to be revised soon, and some simplification due to the microdosing concept might be expected in these documents.