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Handling PET radiopharmaceuticals

Handling radioactive material when making medicines brings many challenges. By adopting the principles of good radiation protection it is possible to provide this important service to patients in a way that is safe to the operator.

Positron Emission Tomography or PET for short is a term that not all pharmacists will be all that familiar with. PET radiopharmaceuticals utilise positron emitters which produce a pair of high energy gamma rays. These are detectable using a PET imaging camera. The Positron emitter is incorporated into a biologically active molecule which, once injected, follows a biological pathway. In this way, functional imaging is possible, and many different tracers are being investigated. By far the most successful so far is F-18 Fluorodeoxyglucose (FDG), which is essentially ‘radioactive sugar’ which is taken up by cells but not metabolised and so shows up the more active cells thus is used as a marker for glucose metabolism. Its primary use is in the identification of tumours, and for this it is extremely sensitive, being able to show lesions as small as 1cm. Modern PET cameras are now coupled with CT to give accurate anatomical details, as well as enabling identification of tumours even smaller than 1cm by ‘tracking back’ from active lymph nodes.

As the technique develops, an awareness of how PET is used in practice is increasingly becoming a must for both clinical and technical pharmacists. The former must understand how the tests made possible by PET impact upon the patients treatment. The latter may, in addition, be required to advise on their use and handling in a practical sense. This article attempts to provide some basic information for this purpose.

The science bit

Positron emitting isotopes are short-lived-the most widely used being Fluorine-18 (110 minutes half-life), Carbon-11 (20 minutes), Oxygen-15 (2 minutes), Nitrogen-13 (10 minutes) and Copper-64 (12 hours). They are produced by bombarding suitable starting materials with highly energised protons or deuterons in a cyclotron-which accelerates the charged protons in a circular path before directing them at a suitable target which can contain liquid such as O-18 enriched water (for the production of F-18 Fluoride), gas such as 1% oxygen in nitrogen (for producing C-11 carbon dioxide or O-15 oxygen) or solid such as Nickel-64 plated on gold (for the production of Cu-64). Because of the short half-lives the materials have to be produced on the day of need and close to the scanner though nowadays F-18 compounds can be made in good enough yields that they can be transported over several halflives (hence the UK market for F-18 FDG can be supplied by several sites spread around the country).

Positron emitters decay by emitting a positively charged electron (the positron) which travels a short distance before encountering an electron and the two particles annihilate to produce two 511-keV gamma rays which are emitted at 180° to each other and easily pass through the body to the ring of detectors in a PET scanner which detect these 2 coincident rays. The computer then back-tracks to the position of the original annihilation in the body and builds up a 3D picture of the uptake of the radiopharmaceutical.

The high energy of the pair of gamma photons emitted results in good pictures, usually in less than 20 minutes for a whole body scan. This compares to 25-30 minutes for a whole body bone scan with traditional gamma emitting tracers. The emission energy of 511-keV, which is significantly higher than that of technetium-99m (140-keV), does, however, have a significant downside which brings it’s own practical challenges in terms of radiation protection for the operator.

What does this mean practically?
Some increase in operator radiation dose is unavoidable. However, by adopting good radiation protection, this increase can be minimised to acceptable levels. There are three important words to remember when considering radiation protection:

  • Time.
  • Distance.
  • Shielding.

Keep the handling time to the minimum required to carry out a process effectively and safely, maintain as much distance between yourself and the radioactive source as practically feasible (for example, by the use of tongs and layout of the facility) and utilise appropriate shielding equipment. The type of shielding equipment used include syringe shields, vial shields as well as lead shields, containing a lead glass viewing screen which stand on the bench behind which the material is handled. The material used as sheilding may be tungsten or lead shields on syringes and vials for medium-energy emitters such as technetium–99m, or Perspex for beta emitters. A 2–3 mm thickness of lead is sufficient to shield vials containing technetium gamma photons. However, for the high energy positron emitters used in PET, the thickness of lead required is much greater – a minimum of 25 mm is needed for vials and the dispensing area is usually shielded with a minimum of 5 mm lead to protect the operator.

Most people find learning how to manufacture or dispense radiopharmaceuticals using shielding challenging at first for a number of reasons:
1. There is the increased weight to consider when holding both the shielded syringe and the shielded vial, which makes the process of manufacture or dispensing feel more awkward.
2. When the equipment has been sprayed with IMS to transfer it into the workstation it may remain slightly slippery and care must be taken to ensure the IMS has dried out.
3. Most tungsten or lead vial shields do not have viewing windows, and it is difficult to see whether the needle is within the liquid or not. Withdrawing doses from small volumes can therefore be difficult.

When handling PET radiopharmaceuticals, all these difficulties are magnified. The thickness of the shielding means that it is not possible to withdraw doses manually without risking Repetitive Strain Injury (RSI). Various devices are available to hold the shielded vial whilst withdrawing the dose. These devices must be transferable into the clean environment and must be cleanable. If doses were to be withdrawn inside a workstation, the heavy vial must be also transferred inside – something which must be considered in light of Health and Safety legislation. A risk assessment for the manual handling of all equipment must therefore be completed, as well as the usual radiological risk assessment required before starting any new procedure involving radioactive material. There are automated devices now available for drawing up a dose in a syringe from a multi-dose vial and even a machine that claims to inject the patient as well after drawing up the dose.

Manufacture of the PET radiopharmaceutical is generally automated because of the high activities needed. Although the  production of F–18 FDG generally has a good radioactive conversion with radiochemical yields of 60–65% – because of the number of doses required and including transport time the commercial suppliers often make batches of over 100GBq and even making on site for a local PET/CT scanner can require a batch production of over 35GBq of final product. Other F–18 compounds have poorer radiochemical yields and for C–11 compounds the overall conversion from cyclotron activity to final product can be less than 10%. The rise of the automation in PET radiochemistry coincided with the rising demand for F–18 FDG in oncology scanning. Several manufacturers came up with automated synthesisers which meant the operator could load the starting materials, then deliver the activity from the cyclotron and follow the synthesis via a computer program and then collect the product from a dispensing cell. Manufacturers also produced automated dispensers which could deliver the product in single or multi-dose vials. The very high starting activities meant that the automated synthesisers had to be placed in lead-lined fume extracted boxes – commonly called “hot cells”. These hot cells usually have a minimum shielding of 60 and often 75 mm thicknesses of lead all round to shield the operators and colleagues. These hot cells are extracted to protect the operators from any gaseous releases – the inlets and outlets are protected by hepa filters and the hot cells are placed in a minimum of Grade D clean rooms. The dispensing cells have a Grade A internal environment with Grade B transfer hatches for the input and exit of the dispensing equipment and the product vials. When setting up a PET imaging service, the administration and dispensing areas are ideally colocated.  If this is not possible, transfer between areas once dispensed is another consideration: how to practically move the heavy weight must be resolved and how to do so without increasing operator radiation dose can be a challenge.

The conflict between requirements of Good Manufacturing Practice (GMP) and Radiation Safety
Radiopharmacies will have inspections to assess their compliance with both the requirements of Good Manufacturing Practice (set out by European Directive 2003/94/EC) and legislation which provides a framework for the safe handling of radioactive materials (set out in European Directive 96/29/Euratom, Basic Safety Standards), which are in place to protect the operator. The practical radiation protection measures described above are required in order to keep operator whole body and extremity radiation doses within the limits identified in this legislation.

One of the conflicts with GMP lies in ensuring that the facility is easily cleanable, and there are no areas which could accumulate microbial or particulate contamination. The amount of equipment required for handling PET radiopharmaceuticals makes this challenging. Where possible, GMP would require this to be movable and cleanable. However, the weight of some of the shielding makes this impractical. Hot cells are usually cleaned with 70% alcohol wipes but care must be taken with the synthesisers so that no aggressive sprays are used. The types of synthesisers with fixed tube connections usually have automated cleaning programs which are validated to ensure there is no residual solvents and no cross-contamination between batches. Other types of synthesiser use disposable “single-use” cassettes for the production which makes change over between batches much simpler.

PET radiopharmaceuticals are Prescription Only Medicines. Handling radioactive material in order to make medicines undoubtedly brings challenges. There are risks which have to be managed. By adopting the principles of good radiation protection and by considering how to do this without compromising GMP, it is possible to provide this important service to our patients in a way that is safe to the operator.


Jilly Croasdale
Radiopharmacy Department
City Hospital NHS Trust
Birmingham, UK

Dr Rob Smith
Manager Radiochemistry
Laboratory / RPS
Wolfson Brain Imaging Centre
University of Cambridge,
Addenbrooke’s Hospital
Cambridge, UK

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