Safe drawing up of radiopharmaceuticals in nuclear medicine

departments
UK Radiopharmacy Group on behalf of BNMS

Correspondence to [email protected]

Summary
Many Nuclear Medicine departments in the UK draw minimise the risks that arise from drawing up patient
up and administer individual patient doses from doses of radiopharmaceuticals in areas other than
stock vials of the chosen radiopharmaceutical in controlled pharmaceutical environments.
designated clinical injection areas. Although this has
Radiopharmaceuticals are medicinal products, and the
been the practice for many years, it does not conform
responsibility for their safe and effective use usually
to the quality standards required for pharmaceutical
rests ultimately with the Chief Pharmacist for the
preparation under European Community Good
Trust. The term which is used to describe the
Manufacturing Practice (EU GMP) [1].
processes of ensuring safe use of medicines is
This document is intended to provide guidance to ‘Medicines Management’. It is intended that
Nuclear Medicine Departments on the provision and following these guidelines will support compliance
design of clinical facilities, procedures, with this.
documentation, training and audit in order to

1. Introduction
Whilst some Nuclear Medicine departments are contamination is increased [3,4]. To minimise this risk,
supplied with individual patient doses contained it is now generally accepted that multiple withdrawals
within a syringe, many receive either single or are best performed centrally within the pharmacy or
multidose vials which require further manipulation in radiopharmacy department where appropriate aseptic
clinics. dispensing facilities are available. This was one of the
principal recommendations of the Breckenridge report
Compounded radiopharmaceuticals for parenteral use,
[5] (and subsequently reinforced for all parenteral
including those made from kits, must be manufactured
medicines by the NPSA in Patient Safety Alert 20 [4]).
aseptically in a clean room in compliance with Annex
III of EU GMP [1]. Where they are presented to Nuclear Drawing up the dose and labelling it in advance means
Medicine staff as multidose vials, procedures must be it becomes a separate pharmaceutical ‘dispensing’
in place to ensure that the doses are drawn up and used activity which must be undertaken in a controlled
safely, and that the integrity of the product is pharmaceutical environment and can only be
maintained. Drawing up patient doses immediately undertaken under the direct supervision of a
prior to administration however does not require a full pharmacist or in a unit with an MHRA ‘Specials’
clean room facility. Licence.

The maximum shelf life for sterile products for human Published data have shown that when injections are
use after first opening or following reconstitution was drawn up in wards or clinics and not administered
addressed in 1999 by the European Agency for the immediately, there is an increased risk of microbial
Evaluation of Medicinal Products (EMEA) [2]. contamination that can lead to infection [6-8]. To
Radiopharmaceuticals are specifically excluded from eliminate this risk, nursing policies and procedures
this advice because, as part of their marketing specify that injections are drawn up and administered
authorisation, the kits used in the preparation of Tc99m immediately. This normally entails a single dose vial
products are intended to provide doses for more than being reconstituted with a suitable diluent, followed by
one patient, and are marketed as multidose vials. immediate withdrawal of the required volume and
administration. The vial is used for one patient and any
residual solution is disposed of immediately.
2. The issues
2.1 Potential microbial contamination When a dose is drawn up from a vial immediately
before administration, the drawing up is considered to
2.1.1 Drawing up from a multidose vial be part of the administration process and can be
When more than one injection is withdrawn from a undertaken in the Nuclear Medicine Department.
multidose vial in an uncontrolled, non-pharmaceutical However, when the withdrawal is from a multidose
area over an extended period, the risk of microbial

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 Safe drawing up of radiopharmaceuticals in nuclear medicine departments 2

vial, the environment in which the procedure is administration of incorrect activity are the most likely
undertaken should be controlled. adverse events that may happen due to poor design of
facilities for drawing up, procedures, documentation,
2.1.2 The environment for drawing up training and lack of audit. Any incident of
misadministration involving the wrong patient will
Marketing Authorisations have been granted to the
necessarily be reportable internally via the hospital
manufacturers of kits by the Medicines and Healthcare
error/near miss system (clinical incident form) and
products Regulatory Agency (MHRA) on the basis that
externally to the Care and Quality Commission (CQC),
once reconstituted with a suitable activity and volume
in accordance with the Ionising Radiation (Medical
of sodium Tc-99m pertechnetate solution, the product
Exposure) Regulations (IRMER) [9]. The Service
may be used in a clinical area, using ‘non-touch’
Manager will also report unintended radiation doses to
technique, over the period of their working shelf life,
CQC for all cases where the wrong patient receives a
which may be up to 12 hours. This clinic-based activity
radiation dose. Should the right patient receive a dose
that involves the extended use of a preservative-free
much greater than that intended due to a procedural
sterile injection for a period of several hours is unique
failure then the need to report to the IRMER
in the UK in the context of the clinical setting for IV
coordinator via the CQC website is determined by
injectables.
reference to Regulation 4(5) of the IRMER [9]. Should
Although inadvertent microbial contamination of a the right patient receive a dose much greater than that
patient from a radiopharmaceutical administration as a intended due to equipment malfunction then the need
result of drawing up the dose in a clinic has not been to report to the HSE is determined by reference to
reported, the theoretical risk must be managed. The Regulation 32(6) of the Ionising Radiations Regulations
first choice for managing this risk is to eliminate it by 1999 [10]. Further advice can be found at the
drawing up all doses within the radiopharmacy. Department of Health website [11] or on the BNMS
However, this is not always possible and could also website (www.bnms.org.uk). Reporting arrangements
affect the ability of the department to be flexible should differ in the devolved administrations although the
patient appointments be delayed (resulting in radiation dose levels are the same.
radioactive decay to below the administered dose
This reported data can be requested by any interested
range) or when additional doses are urgently required.
third party under the Freedom of Information Act [12]
When multidose containers are supplied, it is and thus can be freely published.
recommended that the risk of microbial contamination
It is recommended that the risk of misadministration
be managed as follows:
be managed as follows:
• The patient dose is drawn up in an area of the
• There is an independent check of the dose by a
clinic supplied with Grade A air (see Facilities
second person at the time of drawing up.
section).
• The syringe (in its shielded container) is
• The area is subject to a regular cleaning regime
transported to the patient and injected
using sterile disinfectant and wipes. The area is
immediately.
cleaned immediately before use and all materials
entering the area are sprayed with sterile 70%
alcohol and wiped with a sterile wipe. 3. NPSA Risk Assessment of drawing up
from multidose vials in clinical areas
• ‘Non-touch’ aseptic technique is employed for
withdrawing a patient dose from a vial. One of the recommendations of the NPSA Patient
Safety Alert 20 ‘Promoting safer use of injectable
• The dose is administered immediately.
medicines’ is the completion of a risk assessment of
• A risk assessment is in place which takes account injectable medicines procedures and products in all
of the facility, equipment, processes, training, clinical areas to identify high risks and develop an
documentation and consequences if the patient action plan to minimise them.
were to be denied the dose.
The NPSA developed a risk assessment tool which
One of the aims of this document is to support the identified eight risk factors associated with individual
completion of that risk assessment. injectable medicines, their preparation and
administration [4]. Products are categorised as red,
2.2 Misadministration of a radiopharmaceutical amber or green, dependent on the number of risk
factors met, where red indicates the highest risk and
Whilst the process of administration of
green indicates the lowest risk, thus facilitating a
radiopharmaceuticals is to be addressed separately in a
method of risk stratification.
future BNMS document, it is appropriate to mention
here the sequence that should be undertaken in the When radiopharmaceuticals are drawn up in nuclear
event of misadministration of a radiopharmaceutical. medicine departments from multidose vials supplied
Administration of a dose to the wrong patient or

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 Safe drawing up of radiopharmaceuticals in nuclear medicine departments 3

by a radiopharmacy, two scenarios exist within current drawn up in the nuclear medicine department, the risk
practice: is lower when the multidose vial is supplied in a ready
to use form. This is therefore the preferred method.
1. A ready–to-use multidose vial is supplied and the
Where this is not possible, written procedures must be
patient dose is prepared by calculating the volume
in place to support the process and reduce risk
required and withdrawing the dose in one aseptic
associated with further dilution of vial contents.
manipulation. Using the NPSA risk assessment
tool, the scoring of this scenario is shown in table 1.
4. Responsibilities and practical
2. A multidose vial that requires further dilution
arrangements in hospitals
prior to injection into the patient i.e. the process
involves a more complex calculation and several In the hospital setting, managing the problems
aseptic manipulations. The scoring of this scenario elaborated above will mean that for a Nuclear Medicine
is shown in table 2. Department receiving multidose vials from a
radiopharmacy, the Trust Chief Pharmacist has
The main conclusion that can be drawn from the NPSA
work is that where radiopharmaceuticals are being

Table 1. NPSA risk assessment tool score for ready to use multidose vial

Risk Factor Description Met

1 Therapeutic risk Where there is a significant risk* of patient Yes

harm if the injectable medicine is not used as
intended

6 Use of a part vial or ampoule. Example: 0.5ml required from a 10ml vial Yes

Total number of risk factors 2

Risk category Green

NPSA recommendation Risk reduction

strategies should
be considered

*Patient management altered by incorrect interpretation of image

Table 2. NPSA risk assessment tool score for multidose vial that requires further manipulation

Risk Factor Description Met

1 Therapeutic risk Where there is a significant risk* of patient Yes

harm if the injectable medicine is not used as
intended

2 Use of a concentrate Where further dilution is required before use, Yes

i.e., initially calculated volume is too small

3 Complex calculation Any calculation with more than one step Yes
required for preparation and/or administration,
e.g., decay to correct time and volume

4 Complex method More than five non-touch manipulations Yes

involved or others including syringe-to second
vial transfer, preparation of a burette, use of a
filter

6 Use of a part vial or ampoule, or use of more Examples: 5ml required from a 10ml vial or Yes
than one vial or ampoule two x 5ml ampoules required for a single dose

Total number of risk factors 5

Risk category Amber

NPSA recommendation Risk reduction

strategies are
recommended

*Patient management altered by incorrect interpretation of image

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 Safe drawing up of radiopharmaceuticals in nuclear medicine departments 4

responsibility for the quality of the • Although the supply of Grade A air for drawing
radiopharmaceutical, and this cannot be devolved. up radiopharmaceuticals for immediate
However, the ultimate clinical responsibility remains administration does not require a full EU GMP
with the Administration of Radioactive Substances facility and associated environmental microbial
Advisory Committee (ARSAC) certificate holder [13]. monitoring programme (as required for the
Thus a written agreement should be in place between preparation of radiopharmaceuticals), any
Pharmacy and Nuclear Medicine and approved by the equipment used to supply the Grade A air must
Trust Board. This agreement should devolve the be subject to a regular maintenance programme.
management of the function and ensure compliance
• Radiation protection by using an L-shaped barrier
with the necessary requirements of guidance and
shield. The barrier must not interrupt the supply
regulations relating to both the pharmaceutical and
or passage of Grade A air over the working zone.
radiological nature of the radiopharmaceutical. In
It should offer eye protection.
addition, the Chief Pharmacist must be satisfied that
the Nuclear Medicine Department is carrying out the • Ease of cleaning of area supplied with Grade A
various processes of these agreed functions to the air, and surrounding room.
appropriate standard; ensuring the use of a product is
• Security of radioactive materials (see also section
in accordance with its Summary of Product
8. Storage and security) [17].
Characteristics (SPC). For example, that doses are
drawn up immediately prior to administration, not in • Construction of benching that is capable of
advance. Thus the drawing up of the doses can be supporting lead shielding and allowing
considered part of the administration process. decontamination and disinfection regimens.
Corion and Trespa are suitable materials for
benching.
5. Facilities
• Location of sharps bins, secure lead safe and
This section outlines the facilities required for drawing
calibrators such that they do not compromise air
up radiopharmaceutical doses from multidose vials in
flow patterns.
clinical areas. To avoid unnecessary repetition, further
information and greater detail may be found in the • Hand washing facilities/alcohol gel
Medical and Dental Guidance Notes 2002 [14]. dispensers/gloving station. Sinks should not be
sited near the grade A environment.
A dedicated room should be designated for this
purpose. It may be in or in close proximity to the • Storage for components to be used for drawing up
clinical administration area. It must be sited away from and subsequent administration e.g. syringes and
patient and staff thoroughfares, and potentially needles.
contaminated areas such as toilets and sluices. The
• Storage for protective garments and
following design characteristics should be
decontamination equipment.
incorporated:
• Computer or workstation to access patient
• Protection of products: Environment in which
information systems.
doses are drawn up to be supplied with Grade A
air [15]. This may be achieved by use of a laminar • Lockable refrigerator.
flow cabinet, benchtop isolator/laminar flow or
vertical fan filter modules. The latter can be retro-
6. Drawing up
fitted to existing walls and occupy an area over
the bench surface of approximately 650mm x There may be several different radiopharmaceutical
650mm. They cost in the region of £2500, not multidose vials stored within the vicinity of the area in
including fitting. In each case, an air velocity of which drawing up is performed. To minimise the
0.36 – 0.54m/s must be achieved at the working possibility of microbial contamination, errors during
position [16]. It is recommended that this be drawing up and potential misadministration, the
incorporated into all refurbishment projects and following practices are recommended:
new builds. Ideally it should be incorporated into
• A process is in place to ensure verification of the
existing facilities even if refurbishment is not
correct radiopharmaceutical to be drawn up. This
planned. If this is not possible, a detailed risk
means that either the patients referral card or list
assessment must in place, and must be approved
of patient names and the studies they are due to
by the Chief Pharmacist.
undergo must not only be available but must
• An indicator to show that the air flow is operating actively be checked against when drawing up the
correctly and the cabinet or work station should dose. If the list of patient names and procedures
remain switched on throughout the working day. has been transcribed by hand from elsewhere, it

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 Safe drawing up of radiopharmaceuticals in nuclear medicine departments 5

must have been checked, and that check must be must be fully covered by written procedures regardless
documented, for example, by initialling the list. of whether single or multidose vials are being used.

• All items introduced into the work area are As part of the documentation for these processes, there
subject to an appropriate disinfection regime – for must be a written IRMER procedure for assessment of
example ‘Spray and Wipe’. administered activity [9]. This procedure would
normally include the following:
• Only the correct product is present in the work
area during the drawing up of an individual • Steps to verify and double check that the correct
patient dose. product is being used.

• The area is clean, uncluttered and as free from • Details of how to calculate the volume of
interruption and distraction as possible (see radiopharmaceutical that needs to be drawn up
Facilities). from the stock vial in order to achieve the desired
administered activity.
• The volume that will have the required activity is
calculated for the patient dose. • Measurement of the syringe patient dose in a
radionuclide calibrator prior to injection.
• Where possible, ready-to-use vials are supplied
such that they do not require further dilution. If • Checking of the calibrator setting.
further dilution is required, appropriate
• A statement on how accurately the measured
procedures are in place (see Documentation).
activity should match the desired activity (e.g.
• A protective garment is worn. within ±10%).

• The vial septum is disinfected with a sterile swab • If a label is applied to the syringe after drawing
and allowed to dry for at least 30 seconds prior to up, matching of the syringe label details to the
puncture [4]. details on the request card and finally to the
patient through an agreed patient identification
• A fresh needle/syringe assembly is used for each
procedure. Where the person who draws up the
patient dose.
injection is not the person who injects into the
• A ‘non-touch’ aseptic technique is used to patient, then the handover from one person to
withdraw the dose i.e. surfaces from which another may require an additional step in the
microbial contamination may be introduced are identification chain, particularly if the handover is
not touched. not face-to-face. As both individuals will be
operators under IRMER, both should verify in
• A check is performed to demonstrate that the dose
writing they have undertaken their duties in
calibrator is reading correctly on the setting to be
accordance with procedures.
used [18].
There must also be a written procedure to cover the
• A documented independent check of activity is
process of withdrawing the dose from the vial using
performed on each dose prior to injection.
appropriate ‘non-touch’ aseptic technique and
• Individual doses prepared in a clinical area are equipment as described in the previous sections. This
drawn up immediately prior to injection to procedure must state the maximum time limit from
minimise the risk of microbial contamination see withdrawal to administration. It is not recommended
section 13.1.2 in ref [3]. that radiopharmaceuticals are diluted as part of the
drawing up process but if this practice is to be
• On withdrawing a dose from a
performed then it must be covered by this or an
radiopharmaceutical vial (particularly a
additional written procedure.
technetium-99m product), air is not deliberately
introduced into the vial to equalise the pressure as All equipment used during the process of drawing up
this can create impurities through oxidation of the and administration must be subjected to an appropriate
product and may result in reduced image quality. quality assurance regime supported via a set of quality
control procedures. This would normally be performed
• Appropriate secure storage is available for
by external contractors and described by means of
multidose vials (see also section 9. Storage and
service level agreements (SLAs) and technical
security [17]).
agreements. Such equipment includes laminar flow
cabinets, fan filter modules, isolators and dose
7. Documentation calibrators.
7.1 Written procedures
7.2 Record keeping
The acts of drawing up and administering
Sufficient records must be kept about each
radiopharmaceutical patient doses from a stock vial
administration to enable a full audit trail to be
established. This includes the following:

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 Safe drawing up of radiopharmaceuticals in nuclear medicine departments 6

• Documented evidence that all the relevant checks and chemical degradation. Both sealed and unsealed
have been performed. sources are likely to be kept in the clinical area in which
drawing up is performed. It is recommended that the
• A record of key information such as administered
storage area is located close to the work station in order
activity, volume, radiopharmaceutical etc. The
to minimise the risk of accidental breakage during
time that the dose was withdrawn from the vial
transfer between these areas. Storage in a locked area,
should be noted in the records as well as the time
cupboard or refrigerator is necessary.
of administration so that there is documented
evidence that the time difference is within The dedicated clinical area must itself be kept locked
acceptable limits. when not in use, and consideration must be given to
include receiving areas for lead containers and
• The staff members involved in all steps of the
packages being delivered, and empty containers
process must be identifiable in the records.
awaiting collection. It is likely that when plans for new
• A unique vial identifier that links the hospitals are being considered the local police counter
administration to the product. This identifier will terrorism officers will insist on being consulted on final
also be recorded in the patient administration room layouts. The consideration of CCTV at delivery
record and the radiopharmacy records to provide points should be part of this planning and consultation.
a full trail to all the ingredients used in the
manufacture of the product.
10. Conclusions
• Key information such as radiopharmaceutical,
Drawing up radiopharmaceuticals from multidose vials
volume, diluent (if used), administered activity
must be considered as a higher risk operation
and time.
compared to direct administration of single use
• Evidence that all relevant checks have been products. Ready prepared products, whether syringes
performed. This includes a record that equipment or unit dose vials should be sourced from the supplying
maintenance and QC checks have been Radiopharmacy in the first instance. Where it is
performed. deemed that multidose vials are necessary, the
following factors should be taken into account.
7.3 Audit
• The practice of drawing up doses followed by
A regular programme of audit is required to monitor immediate administration is undertaken.
compliance with the facilities and standards specified
• Existing nuclear medicine departments, if they
in this guideline.
have the space, should install a contained
workstation supplied with Grade A air. This could
8. Training also be achieved by the installation of a bench-top
Staff involved in any aspect of the drawing-up and laminar flow cabinet or a vertical fan filter
administration process must be fully trained health module.
professionals with documented evidence of their • Where insufficient space is available, nuclear
training. This includes training for those staff medicine departments should work towards
performing the equipment QC tests. Where there is no refurbishing their clinical administration facility,
national guidance on training from health professional in order to make space for a dedicated drawing up
bodies or statutory bodies, then training should be area or room.
locally agreed by senior staff with management
responsibilities (including the ARSAC holder(s)). • When planning a new nuclear medicine
Training should be competency based and should be department, the clinical administration area
reviewed on a regular basis (e.g. annually). should have an adjacent drawing up room and
include a contained workstation (such as benchtop
As the tasks are classed as operator tasks under IRMER, isolator/laminar flow or vertical fan filter module)
these members of staff need to be formally identified as supplied with grade A air dedicated for drawing
operators under the IRMER employer’s procedures. up radiopharmaceuticals. Note that this does not
Training records related to these IRMER operator tasks mean a full EU GMP Grade A facility, as this
should be held by the Trust and be available for would require a Grade B clean room support and
inspection. In addition, NPSA Alert 20 requires Trusts a full pharmaceutical environmental monitoring
to ensure the training and competency of clinical staff. programme.

• Written procedures are in place to ensure that the

9. Storage and security integrity of products is maintained and that
The correct storage of radiopharmaceuticals in clinical patients receive the correct injection.
areas is important to ensure their security and minimise • ‘Non-touch’ aseptic technique is used and all
the potential for inadvertent microbial contamination members of staff involved in drawing up

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 Safe drawing up of radiopharmaceuticals in nuclear medicine departments 7

injections have documented approved training Sector Information.

with competency assessment. http://www.opsi.gov.uk/acts/acts2000/ukpga_2000
0036_en_1
• Risk assessments exist to support and document
the provisions made to ensure that the safety of 13. SI 1978 No.1006. The Medicines (Administration of
the patient is protected. Radioactive Substances) Regulations 1978. HMSO.
1978
References 14. Institute of Physics and Engineering in Medicine.
Medical and Dental Guidance Notes. A good
1. Volume 4. EU Guidelines to Good Manufacturing
practice guide on all aspects of ionising radiation
Practice, Medicinal Products for Human and
protection in the clinical environment. York IPEM
Veterinary Use, Annex 3, Manufacture of
2002.
Radiopharmaceuticals.
http://ec.europa.eu/health/files/eudralex/vol- 15. Eudralex, The Rules Governing Medicinal
4/2008_09_annex3_en.pdf Products in the European Union, Volume 4, EU
Guidelines to Good Manufacturing Practice,
2. Note for Guidance on Maximum Shelf-life for
Medicinal Products for Human and Veterinary
Sterile Products for Human Use after first opening
Use. Annex 1 Manufacture of Sterile Medicinal
or following reconstitution. CPMP/QWP/158/96.
Products (corrected version) March 2009.
EMEA London 1999
http://ec.europa.eu/health/files/eudralex/vol-
3. Beaney A M (ed). Quality Assurance of Aseptic 4/2008_11_25_gmp-an1_en.pdf
Preparation Services. 2006. Fourth Edition,
16. Rules and Guidance for Pharmaceutical
Pharmaceutical Press London
Manufacturers and Distributors 2007.
4. National Patient Safety Agency. Patient safety Pharmaceutical Press. London 2007
Alert 20. Promoting safer use of injectable
17. Quality Assurance of Radiopharmaceuticals.
medicines. Ref NPSA/2007/20. March 2007.
Report of a Joint Working Party; the UK
www.npsa.nhs.uk/health/alerts
Radiopharmacy Group and the NHS
5. Breckenridge A. The Report of the Working Party Pharmaceutical Quality Control Committee. Nuc
on the Addition of Drugs to Intravenous Infusion Med Commun, 22, 909-916 (2001)
Fluids (HC(76)9). (The Breckenridge Report)
18. Measurement Good Practice Guide No. 93.
London. Department of Health and Social Security
Protocol for Establishing and Maintaining the
1976
Calibration of Medical Radionuclide Calibrators
6. Daily MK, Dickey JB, Packo KH. Endogenous and their Quality Control. National Physical
Candida endophthalmitis after intravenous Laboratory. Teddington 2006. ISSSN: 1368-6550
anaesthesia with propofol. Arch Ophthalmol, 1991;
109: 1081- 1084

7. Bennett SN, McNeill MM, Bland LA et al. Post

operative infections traced to contamination of an
intravenous anaesthetic, propofol. N Eng J Med
1995; 333 147 154

8. Kuehnert MJ, Webb RH, Jochinsen EM et al.

Staphyloccus aureus bloodsteam infections among
patients undergoing electroconvulsive therapy
traced to breaks in infection control and possible
extrinsic contamination by propofol. Anesth Analg
1997; 85: 420 - 425

9. SI 2000 No.1059 The Ionising Radiation (Medical

Exposure) Regulations 2000. London. The Stationery
Office. 2000

10. SI 1999 No.3232 The Ionising Radiations Regulations

1999. London. The Stationery Office. 1999

11. Reporting Incidents of radiation

http://www.dh.gov.uk/en/Publicationsandstatistics
/Publications/PublicationsPolicyAndGuidance/DH
_4007957

12. Freedom of Information Act 2000. Office of Public

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