EU good manufacturing practice (GMP) relates to the manufacture of medicines, and in radiopharmacy this can be a challenge in some ways. Because the products have to be used immediately, it is not possible to perform all the usual end product testing that you would with other types of products. For example, sterility testing is done retrospectively, and, because the batch size is often one, it is not possible to sterility test each batch produced (or there may be nothing left to administer to the patients).
However, wherever possible, manufacture will conform to the regulatory requirements, and because of the need to often use radiopharmaceuticals immediately, there is particular emphasis on quality assurance of the process, in order to ensure the products made are fit for patient use.
Once the radiopharmaceutical has been released for use, further manipulations of the product to enable administration do not come within the remit of GMP. However, it is important that their handling does not pose a risk to patients.
How does the guideline relate to kits?
The Safe Drawing Up Document1 relates to how radiopharmaceuticals presented as multi-dose vials are handled in the nuclear medicine department. Although GMP does not directly apply, it should be remembered that the purpose of GMP is to make sure medicines are safe for use in patients. The manufacture of these is just one aspect – obviously how they are stored and used also has a considerable impact.
The Safe Drawing Up document therefore describes measures, which, if followed, support the continued integrity of the vials prepared throughout the period of use. It also covers steps which should be taken to ensure that the administration is done correctly. This is important. Although the products the guidance relates to are all for diagnostic use and therefore are not in themselves harmful from a therapeutic point of view, if administered incorrectly they can lead to misdiagnosis, delays in diagnosis and unnecessary radiation exposure.
What are the current issues of using multidose vials?
Ideally parenteral products should be for single use.2 This is the ideal, because they can be discarded after the dose has been drawn up and there is much less risk of contamination of the vial. Some radiopharmaceuticals are presented as single-use vials. These tend to be newer products, where the patient numbers are low or where the amount of ligand is particularly important – say, for example, in the case of radiolabelled antibodies such as LeukoScan (a radiopharmaceutical used for imaging infection). Why then, are so many diagnostic radiopharmaceuticals presented as multidose vials? The answer, although to some extent historical, lies in their radioactive nature.
A certain amount of overage is required if making up a vial of product for a single patient. Each time a vial is made, the generator elution vial has to be handled. This accounts for a significant proportion of the operator’s radiation exposure. The more vials made, the more times the elution vial has to be handled.
If more overage has to be allowed overall, the total amount of radioactivity used from the vial will also be higher. Both these factors result in a Health and Safety risk to the operator making the products, which is reduced as follows through the use of multidose vials:
- Less total activity is handled as a result because there is less wastage
- The generator elution vial is handled less.
And unlike single-use products, vials licensed for multiple use contain preservatives, which reduce the risk of any contamination replicating, should it occur.
What are the risk factors associated with individual injectable medicines, their preparation and administration?
There are a number of risks that must be considered.
Radiation risk to operators
First of all, I would like to make it clear that if handled correctly, the radiation risks to patients and staff are extremely low. It is important to remember that there are risks in everything we do, and the extremely low risk of harm to patients as a result of their radiation exposure is very carefully assessed and offset against the overall benefit of their having the test in question.
Operator radiation doses are measured and assessed routinely in the Radiopharmacy – both the dose received to the entire body, as well as that received to the fingers. Most operators making up technetium-99m radiopharmaceuticals will have a low whole body dose. To put this in perspective, a typical dose may be in the region of 4mSv a year, compared with the average dose received in the UK of 2.7mSv, and a resident of Cornwall of just under 8mSv.3
However, nothing is totally devoid of risk, and the higher the radiation exposure to the radiopharmacy operator or patient, the higher the risk. Therefore keeping the exposure levels low for both groups is vital. The Safe Drawing Up document, therefore, incorporates radiation safety recommendations as well as advice for minimising risk of repeated radiation exposure, for example.
Risk of microbial contamination of the product
If manipulations are carried out at ward or clinic level and injections are not administered immediately, there is an increased risk of microbial contamination that can lead to infection.4–6 It is now generally accepted that such activities are best performed centrally within the pharmacy or radiopharmacy department, where appropriate aseptic dispensing facilities are usually found. This was one of the principal recommendations of the Breckenridge report7 (and subsequently reinforced for all parenteral medicines by the National Patient Safety Agency in Patient Safety Alert 20).8
Risk of miscalculation or misadministration of dose
In a busy clinic, there could be an increased risk of error when carrying out complex calculations, drawing up part of a vial, measuring the correct volumes, etc. This could all add to the pressure on the operator to get the injection done one time, possibly increasing the risks of extravasation as a result.
How can misadministration be avoided? How should it be dealt with?
It is recommended that the risk of misadministration be managed as follows:
- There should be an independent check of the dose by a second person at the time of drawing up
- The syringe (in its shielded container) should be transported to the patient and injected immediately. Therefore drawing up multiple doses in advance is not recommended. Not only does this increase the risk of maladministration, but it will also become a pharmaceutical activity rather than part of the administration process, and, as such, should be supervised by a pharmacist.
Any incident of misadministration involving the wrong patient should be reported both internally via the hospital incident reporting system and externally to the Care and Quality Commission (CQC), in accordance with the Ionising Radiation (Medical Exposure) Regulations (IRMER).9
Should the right patient receive a dose much greater than that intended, then the need to report to the IRMER coordinator via the CQC website is determined by reference to Regulation 4(5) of the IRMER, and will depend on the exposure level and whether it occurred as a result of procedural failure or equipment malfunction. In the case of the latter, the Health and Safety Executive (HSE) may need to be involved.
Further advice can be found at the Department of Health website10 or on the BNMS website (www.bnms.org.uk).
How can written IRMER processes help to minimise errors in drawing up?
It is the employer’s responsibility to ensure that written IRMER procedures are in place, and their purpose is to control patients’ exposure to radiation and ensure their safety.11 They include:
- Correct identification of the individual to be exposed to ionising radiation – this is obviously crucial in minimising risk of maladministration
- Entitlement to act as the IR(ME)R roles of referrer, practitioner and operator – so everyone’s role and responsibility is defined. Anyone who has a potential impact on the radiation dose the patient receives is considered an operator.
- Processes around medico-legal exposures
- Establishing whether females of childbearing age may be pregnant or breastfeeding
- Quality assurance programmes for equipment and processes
- Assessment of patient dose – again, this is important if maladministration is suspected
- Diagnostic reference levels – these relate to the amount of radiation which may be administered for various tests. Obviously this will feed into the assessment of whether a patient has received an excessive radiation exposure.
- Medical research programmes
- Information and written instructions – this supports a consistently high quality service and helps assure patient safety
- Evaluation for each medical exposure
- What to do in the event of accidental or unintended doses.
What is the significance of the ‘non-touch’ aseptic technique and where does this apply?
This is particularly important when drawing up doses in an area that is uncontrolled from a microbiological point of view. The product must remain sterile and therefore steps must be taken to reduce the risk of the operator introducing contamination. Because it is not being performed in a pharmaceutical aseptic area, full aseptic processing, whereby the operator is gowned up and the environment carefully controlled with filtered air, etc, is not possible.
As a result, there is a greater chance that the operator will transfer micro-organisms from themselves into the product. It is therefore important that the operator does not touch the rubber septum of the vial, in addition to employing other precautions such as sanitising the area in which the radiopharmaceutical is being manipulated using sterile alcoholic sprays and wipes.
Why is it important to measure the syringe patient dose in a radionuclide calibrator prior to injection?
Because of the radioactive nature of the products, they are constantly decaying. For this reason, the amount of radiation administered is not absolute – it is acceptable to inject an amount that falls within a range, as specified for the test in question.
Different tests will require different amounts of radioactivity to be injected. For example, a bone scan involves waiting for two to three hours while the radio-pharmaceutical is taken up into the skeleton and disperses from the bloodstream. During this time the radiation will be constantly decaying. The agent is also spread throughout the entire skeleton and, for both these reasons, the bone scan will require a larger amount of radiation than a lung scan, for example. In this case, the radioactive tracer is retained in a much smaller area and imaging can take place almost immediately, hence the smaller amount of radiation required.
In order to ensure the patient is to be injected with the correct amount of radioactive tracer for their examination, each dose must be measured before administration using a dose calibrator.
1 UK Radiopharmacy Group on behalf of the BNMS. Safe drawing up of radiopharmaceuticals in nuclear medicine departments. www.bnms.org.uk/images/stories/UKRG/UKRG_Drawing_up_Feb-12.pdf (accessed March 2017).
2 RQA Multiple Use of Injections.
3 Ionising Radiation Exposure of the UK Population: 2010. Review by Public Health England. www.phe-protectionservices.org.uk/cms/assets/gfx/content/resource_3595cs… (accessed March 2017).
4 Daily MK, Dickey JB, Packo KH. Endogenous Candida endophthalmitis after intravenous anaesthesia with propofol. Arch Ophthalmol 1991;109:1081–4
5 Bennett SN et al. Post operative infections traced to contamination of an intravenous anaesthetic, propofol. N Engl J Med 1995;333:147–54.
6 Kuehnert MJ et al. Staphylococcus aureus bloodstream infections among patients undergoing electroconvulsive therapy traced to breaks in infection control and possible extrinsic contamination by propofol. Anesth Analg 1997;85:420–5.
7 Breckenridge A. The Report of the Working Party on the Addition of Drugs to Intravenous Infusion Fluids (HC (76)9). (The Breckenridge Report) London. Department of Health and Social Security;1976.
8 National Patient Safety Agency. Patient safety Alert 20. Promoting safer use of injectable medicines. Ref NPSA/2007/20. March 2007. www.npsa.nhs.uk/health/alerts (accessed March 2017).
9 SI 2000 No.1059 The Ionising Radiation (Medical Exposure) Regulations 2000. London. The Stationery Office;2000. www.legislation.gov.uk/uksi/2000/1059/contents/made (accessed March 2017).
10 Department of Health. Reporting incidents of radiation. www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicy AndGuidance/DH_4007957.
11 Society of Radiographers. Guidance on IRMER procedures. www.sor.org/learning/document-library/irmer-2000-and-irme-amendment -regulations-2006/1-irmer-employer-s-procedures-schedule-1 (accessed March 2017).