Draft Guidelines for Radiopharmacy

In the nuclear medicine laboratories (radiopharmacies) for European purposes. A first version of these docu-
of nuclear medicine clinics in European hospitals, quali- ments was discussed at the business meeting of the Com-
ty assurance varies from non-existent to good manufac- mittee at the 11th European Symposium on Radiophar-
turing practice level. Thus at the business meeting of the macy and Radiopharmaceuticals in Innsbruck, 15–18
Committee on Radiopharmacy of the EANM in Vienna March 2003, and also in plenary session during the con-
2002 it was deemed of urgent interest to provide the nu- ference, where it was favourably commented upon by
clear medicine community in Europe with guidelines delegates from 32 countries (not all of them European).
which would ensure a necessary and sufficient level of After consultations with the Committee for Proprietary
safety and efficacy in the production, reconstitution and Medicinal Products of the European Agency for the Eval-
handling of radiopharmaceuticals in hospitals, both for uation of Medicinal Products (EMEA) and the radiophar-
classical radiopharmaceuticals and for PET products. It macy expert circle of the Pharmaceutical Inspection Con-
was anticipated that draft guidelines would be formulat- vention Scheme, we are now anticipating submission of
ed for classical nuclear medicine radiopharmacy and that these documents to EMEA to be considered by the rele-
special good manufacturing practice rules would be vant working parties (especially the Quality Working Par-
drawn up for PET products. ty) so that they might become the official quality assur-
After discussions within the radiopharmacy and ra- ance guidelines for these types of laboratories. Before do-
diopharmaceutical chemistry community, including at ing that, however, we would like to consult once more
the annual meeting of the Radiopharmacy Group of the with the nuclear medicine community (notably the radio-
German Society of Nuclear Medicine (DGN), the Com- pharmacy experts). For this purpose both draft guidelines
mittee has adopted the strategy of starting to develop have been annexed to this report and they are also to be
“Draft guidelines for radiopharmacy” for nuclear medi- found on the radiopharmacy pages of the EANM home
cine laboratories and to adapt the “Preliminary draft reg- page. We are inviting comments and suggestions, which
ulations on current good manufacturing practices for should be sent to [email protected].
PET drugs” of the U.S. Food and Drug Administration Gerrit Westera

Annex I tentially hazardous. The level of risk depends in particu-

lar upon the types of radiation emitted and the half-lives
Draft Guidelines on Good Radiopharmacy of the radioactive isotopes. Particular attention must be
Practices for Radiopharmaceuticals (GRPhP) paid to the prevention of cross-contamination, to the re-
in Nuclear Medicine tention of radionuclide contaminants, and to waste dis-
posal. Continuous assessment of the effectiveness of the
Chapter 1. Quality assurance Quality Assurance system is essential in order to prove
that the procedures applied in the Radiopharmacy De-
General partment lead to the expected results.

Preparation of radiopharmaceuticals involves the regula-

tions on radiation protection as well as the rules of work- Quality control
ing under special aseptic conditions, which are covered
by these guidelines on Good Radiopharmacy Practice The preparation of kit-based radiopharmaceuticals from
(GRPhP). The handling of radiopharmaceuticals is po- licensed materials (kits) and generators should follow the

Eur J Nucl Med Mol Imag (2003) 30:BP63–BP72

Vol. 30, No. 8, August 2003 – © EANM 2003
BP 64

manufacturer’s instructions as described in the respective Radiation protection

Summary of Product Characteristics. This is generally
accepted as the premise by which responsibility for the Control of radiation exposure of personnel is performed
product, should it not perform as expected, is retained by with approved personnel dose-meters, which are regu-
the manufacturer of the individual components. Howev- larly checked and their readings recorded. This control
er, it is recommended that a prospective program of ra- may be supplemented with electronic dose-meters, fin-
diochemical testing on products should be undertaken as ger dose-meters etc. After work, both personnel and
part of planned regular activity of quality assurance. It work places must be checked for radioactive contamina-
must be remembered that every time a kit is reconstitut- tion with suitable monitors. Any contamination must be
ed with eluate from a technetium-99m generator, a new removed immediately or must be contained, and access
chemical entity is being formed. to the contaminated area must be denied until the radio-
Clinical trials with new radiopharmaceuticals should active radiation has decayed to an appropriate dose lev-
follow these regulations on GRPhP as well as the Guide- el.
line on Good Clinical Practice.

Chapter 3. Premises and equipment

Chapter 2. Personnel
General
General
Radioactive products should be stored, processed, pack-
Even if the number of staff involved in the preparation of aged and controlled in dedicated and self-contained fa-
radiopharmaceuticals in the hospital will be small, there cilities. The equipment used should be reserved exclu-
should be separate people responsible for preparation sively for radiopharmaceuticals. The laboratory has to be
and for quality control. All operations should be carried organised in such a way as to minimise the risk of cross-
out under the control of a clearly identified responsible contamination and mix-up. Only the necessary equip-
person. Personnel involved in release of the prepared ra- ment should be located there.
diopharmaceuticals should be appropriately trained in The Tc-99m generator and the working area for the
quality systems, GRPhP and regulatory requirements preparation of Tc-99m labelled radiopharmaceuticals
specific to this type of product. The EANM syllabus on should be located in the department’s isotope laboratory.
radiopharmacy, covering all these aspects, is recom- The room must be approved for work with open radioac-
mended for the responsible person. tive sources. The solutions of Tc-99m eluate and the
All personnel (including those concerned with clean- ready preparations have to be stored in the shielding
ing and maintenance) employed in areas where radioac- compartment.
tive products are handled should receive additional train- In order to contain the radioactive particles, it may be
ing specific to this class of product. In particular, they necessary for the air pressure to be lower where products
should be given detailed information and appropriate are exposed than in surrounding areas. However, it is
training on radiation protection. still necessary to protect the product from environmental
Training should be provided for all staff working in the contamination.
radiopharmacy departments in the aspects of Quality As- The storage and handling of any kind of biological
surance with which they are involved. This includes: prep- material should be avoided in the same place. An excep-
aration, release, quality control and analytical techniques, tion can be made for the preparation of radiopharmaceu-
cleaning, transport, calibration of both equipment and ra- ticals from a patient origin, e.g. the preparation of la-
diopharmaceuticals, working practices in the radiopharma- belled blood components. However, where available, a
cy, preparation of the individual doses, and documentation. separate room or workbench should be used for labelling
The training should be appropriate to the tasks per- of patients’ autologous cells.
formed. A description of the training and records of
completion should be maintained.
Technetium-99m generator location

Personal hygiene In order to minimise the radiation risk to personnel, the

generator must be heavily shielded. The shielding must
Personnel should correctly apply special aseptic tech- not disturb the elution of a generator and must reduce the
nique throughout the preparation of eluate and the radio- risk of radiation from spills or loss of the eluate. The
labelling of kits. This implies a high standard of personal lead surfaces must be painted. The shielding and the ta-
hygiene combined with the use of sterile gloves, sterile ble on which it is located must be easily cleanable. The
vials, syringes, needles and diluents, and entails a well- needle of the generator can be covered between elutions
planned and expedient way of working. using vials or caps with a bacteriostatic agent delivered

European Journal of Nuclear Medicine and Molecular Imaging Vol. 30, No. 1, January 2003
 BP 65

with the generator when applied according to the suppli- Other equipment used for preparation of radiophar-
er’s instructions. maceuticals (water bath, thermometers, heating plates
Access to the Tc-99m generator should be easy, al- etc.) must be checked for correctness of the settings.
lowing its proper handling. A system of planned preventive maintenance should
The dose calibrator(s) should be properly shielded be operated to ensure that all facilities and equipment
from the influence of background activity. used in the preparation of radiopharmaceuticals are regu-
larly maintained and calibrated where appropriate. Re-
cords and logs should be kept for all equipment irrespec-
Production area tive of whether maintenance and calibration are per-
formed in house or by external contractors.
For sterile products, the working zone where products or
containers may be exposed should comply with appro-
priate environmental requirements. This may be Chapter 4. Documentation
achieved by the provision of a workstation with a lami-
nar flow of HEPA-filtered air or a total containment A system of documentation must be in operation at the
workstation. They should be in an environment conform- Department to ensure traceability of each preparation,
ing to at least grade D. This can also be ascertained by starting from the prescription to the administration of the
surrounding the laminar flow workstation by a curtain of individual patient doses.
filtered grade B air. The instructions and Standard Operating Procedures
(SOPs) should be written and independently approved
for each procedure or activity associated with the opera-
Maintenance and cleaning tions of the department.
A specification should be available for each material
All surfaces (walls, floor, tables and furniture) must be used as well as for the finished radiopharmaceutical.
made out of materials that are easy to clean and disinfect A record should be kept of the following:
and to decontaminate in the event of a radioactive spill.
Sinks used should be outside the production area. – Purchase of all ingredients and expedients
– Purchase of radioactive products
– Generator elution, yield, Mo-99 breakthrough and,
Facilities and equipment when appropriate, aluminium ion breakthrough
– Product preparation, quality control and release
Dose calibrators – Laboratory cleaning and maintenance
– Equipment calibration and maintenance
Daily checks must be performed on radionuclide calibra- – Staff training
tors. – Transport of radioactive materials
Background should be checked every time the dose – Radioactive contamination monitoring and radioac-
calibrator is used. Any increase in the background read- tive waste disposal
ings should be investigated. – Product defects and events of non-conformity to
A check of constancy using a long-lived radioactive SOPs
source with a current calibration certificate should be
performed before use for each setting on any day. Detailed distribution records should be maintained and
Regular calibration of radionuclides, in the appropri- there should be procedures describing the measures to be
ate containers (vial, syringe), with the sample volumes taken to prevent the use of defective radiopharmaceuti-
and position in the calibrator used, should be undertaken cals.
with radionuclides traceable to national or international Written procedures have to be prepared in which the
standards. information from the manufacturer on the products is
A linearity check of the dose calibrator-response over considered. Departments’ own instructions for the prepa-
the complete range of activities measured should be un- ration of radiopharmaceuticals should be kept.
dertaken at least annually.
Devices used for radiochemical purity determination
such as a dose calibrator, gamma counter, gamma cam- Chapter 5. Preparation of radiopharmaceuticals
era, TLC scanner and autoradiography apparatus require
determination of background each time they are used for All goods received should be checked against the order
measurements, and verification of detection linearity and for correctness of delivery. Records of batch numbers
accuracy of measurement at least annually. and quantities received should be kept. In addition a vi-
Quantification of HPLC is usually performed using sual inspection should be carried out prior to acceptance.
on-line radioactivity detection. Products or kits with Marketing Authorisation should be

European Journal of Nuclear Medicine and Molecular Imaging Vol. 30, No. 1, January 2003
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used wherever possible. Materials should only be used and the degree of confidence that the person responsible
within the declared shelf life. for product release for use in patients has in the quality
The preparation of radiopharmaceuticals should be of that particular product.
organised in a way that prevents cross-contamination of There should be a written procedure detailing all pro-
the product. Process validation, in process controls and duction and quality control data that should be considered
monitoring of process parameters and environment as- before the batch is dispatched. A procedure should also de-
sume particular importance in cases where it is necessary scribe the measures to be taken by the responsible person if
to take the decision to release or reject a batch or a prod- unsatisfactory test results are obtained after dispatch.
uct before all tests are completed.
Specific information about the handling of the Tc- Parameters to be assessed in every product prior
99m generator, including instructions for generator elu- to release
tion, checking of the elution yield and other tests of gen- – Total radioactivity or radioactive concentration. Since
erator quality, is given in the package insert supplied the radioactivity content determines the radiation dose
with the generator. Similarly, the package insert of the to the patient, each patient dose should have an inde-
kits gives detailed information about the procedure of kit pendent check of its total radioactivity prior to admin-
labelling. Manufacturer’s instructions are based on the istration. The activity of each patient dose must be
experience with and recommendations concerning the carefully dispensed, measured and documented.
particular generator or kit. The package insert is ap- – Appearance and freedom from gross particulate con-
proved by national authorities. It is a prerequisite for tamination.
correct handling of a Tc-99m generator and the labelling
of kits that the package insert be carefully read and fol- Quality control parameters of the Tc-99m generators
lowed. Any diversions from the procedures in the pack-
age insert have to be validated. – Molybdenum-99 breakthrough on the first eluate from
All rubber stoppers, including those on the eluate vi- each Tc-99m generator.
als, must be wiped immediately before each puncture, – Elution yield, calculated according to the information
with a disinfecting agent. The wipe agent should be al- given in the instructions for use of the generator. The
lowed to evaporate completely before puncture, as the yield of generator elution should be no more than
introduction of this agent may influence kit performance. 110% and no less than 90% of the nominal generator
The elution shield and the shields for vials and syringes yield.
must be checked for contamination and cleaned inside – Aluminium ion breakthrough should be checked on
and outside before use, preferably with 70% ethanol. any eluate used to prepare products that are adversely
Transport of eluates and preparations inside the de- affected by the presence of aluminium.
partment must take place within shields, e.g. the elution
shield, the syringe shield. The kits are prepared at the manufacturer’s laboratory
In order to minimise the exposure of personnel to radia- and released for sales after all prescribed quality control
tion, proper shielding is needed as well as proper planning tests have been completed. Therefore, the composition,
of the handling of the radioactive products. The elution chemical purity, apyrogenicity, sterility and particle size
shield delivered with a Tc-99m generator should always be (where applicable) are guaranteed by the producer. The
used and Tc-99m solutions should be stored in suitable instructions for use attached to the kit should be strictly
shielding. Tongs or tweezers should always be used when followed when the labelling procedure is performed.
the Tc-99m solutions are handled outside the lead shield- Any deviation from these instructions has to be validat-
ing, e.g. when measuring activity in the dose calibrator. It ed. Verification of the effectiveness of the applied label-
is recommended not to touch directly any vials containing ling procedure is done by checking the final activity (at a
Tc-99m eluates or radiolabelled preparations. stated time), the labelling yield and/or the radiochemical
purity of the preparation, and particulate contamination.
If possible, parameters such as particle size (if applica-
Chapter 6. Quality control ble), sterility, pH and isotonicity should also be con-
trolled.
The specifications and quality control testing for most of
the currently used radiopharmaceuticals are given in the Quality control parameters for Tc-99m labelling kits
European Pharmacopoeia or other suitable Pharmaco- – Integrity upon receipt
poeia (BP, USP etc.). It is accepted that full testing of – Radiochemical purity (RCP) testing of products pre-
products to Pharmacopoeia standards in the Radiophar- pared from licensed labelling kits should preferably
macy Department is impossible. The minimum level of be undertaken on every new batch. When a new kit is
testing for Tc-99m generators and radiolabelled kits is prepared or a kit has once failed to pass the RCP test,
given below. The frequency of testing will depend upon subsequent preparations should be tested for RCP pri-
such factors as the source and stability of the material or to patient application.

European Journal of Nuclear Medicine and Molecular Imaging Vol. 30, No. 1, January 2003
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– Unlicensed radiopharmaceuticals, whether purchased ceuticals have to be followed when preparing the radio-
as finished products, prepared from unlicensed kits or pharmaceutical in house. Every starting material should
prepared to in-house formulae, should be tested on be checked for identity and purity. The quality control
each occasion. certificates supplied by the manufacturer of the starting
– Sterility should be controlled randomly. material should be verified for compliance with the ma-
– Measurement of the particle size of particulate radio- terials specification. A written procedure describing the
pharmaceuticals used for lung perfusion imaging or of preparation of the radiopharmaceutical should be avail-
colloidal radiopharmaceuticals may be valuable in en- able. The quality control of the in-house preparation in-
suring consistent pharmacokinetics of the product. cludes:
This involves light microscopic methods or mem- – Control of all quality control parameters in test runs.
brane filtration. – Control of all quality control parameters of every
preparation, if possible, completed before administra-
Measurements of pH using narrow range pH paper may tion to the patient.
be undertaken on Tc-99m generator eluates and products
known to have a significantly different pH, e.g. succimer
or exametazime. Chapter 7. Release/failure of products
Sterility and bacterial endotoxin testing An authorised person should take a formal, recorded de-
The purpose of sterility testing is to ensure that the pro- cision of approval before a product is released.
cedures used in the radiopharmacy result in sterile prod- The authorised person should not normally be the
ucts. The frequency of testing depends on the experience person who prepared the product, although there may
of the department. The special aseptic preparation and be no alternative. The authorised person should be suit-
dispensing should be regularly controlled, especially if ably trained and have documented evidence of compe-
new personnel are involved. Usually the samples for ste- tence.
rility testing are stored for radioactivity decay and then There should be a written procedure for dealing with
sent for external sterility testing. Internal sterility testing products failing to meet the required standard. Such
is only recommended if, in accordance with the Europe- events should be documented and investigated.
an Pharmacopoeia, dedicated rooms and equipment are There should be a written release procedure.
available.
Pyrogen testing of radiopharmaceuticals is not rou- Release can only be effected if:
tinely carried out because of the small volumes of solu- – The product complies with the specifications.
tion administered. The limulus amoebocyte lysate (LAL) – The product has been prepared according to Good Ra-
test may be usefully employed as part of the verification diopharmacy Practice.
of new systems or changes in working practice.
There should be a written procedure for the recall of de-
Preparations from autologous patient material fective products and a log of errors/near misses should
Strict requirements on special aseptic handling of patient be maintained.
autologous material have to be followed. All starting ma-
terials should be identified. In the case of any reagent,
material or solution specifically intended for human use, Chapter 8. Self-inspection
it must be tested and documented that its specifications
meet the required standards. Use of materials and re- The Quality Assurance System established at the Radio-
agents certified for human use is recommended. pharmacy Department should be verified by internal in-
spection.
The following checks should be performed:
– Calculation of the labelling yield of every preparation
– Control of RCP (as far as possible) on every prepara-
tion before administration
– Control of patient identity prior to administration
– Control of cell viability on the first five preparations,
then randomly

In-house preparations:
Good Manufacturing Practice requirements similar to the
GMP for Positron Emission Tomography Radiopharma-

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Annex II whether errors have occurred. If errors have occurred,

or a production batch or its components fail to meet
Draft Guidelines on Good Manufacturing any of its specifications, the quality assurance unit
Practices for Positron Emission Tomography should ensure that the errors or failures have been ful-
(PET) Radiopharmaceuticals ly investigated and corrective action taken.
e) To ensure that the responsibilities of the quality assur-
A Summary ance unit are known to all involved in PET radiophar-
maceutical production, the responsibilities of the unit
a) Good manufacturing practices for PET radiopharma- and the procedures they will follow should be put in
ceuticals are the minimum requirements for the meth- writing.
ods, facilities and controls for the production, quality
control and distribution of an effective PET radio-
pharmaceutical for human use. 3. Equipment and facilities
b) Good manufacturing practices for PET radiopharma-
ceuticals should cover the factors which ensure that a) Facilities should be adequate to ensure the orderly
each PET radiopharmaceutical is safe, has the required handling of materials and equipment, the prevention
identity and meets its quality and purity specifications. of mix-ups and the prevention of contamination of
These are: (1) personnel and resources, (2) quality as- equipment or products by substances, personnel or
surance systems, (3) equipment and facilities, (4) con- environmental conditions that could reasonably be ex-
trol of components, in-process materials and finished pected to have an adverse effect on product quality. In
product, (5) production and process controls, (6) labo- small PET centres, the same area or room can be used
ratory controls, (7) acceptance criteria, (8) labelling for multiple purposes. For example, the production
and packaging controls, (9) distribution controls, (10) (e.g. radiochemical synthesis), laboratory operation
complaint handling and (11) record keeping. (e.g. release testing) and storage of approved compo-
nents, including containers and closures, can be locat-
ed in the same room.
B Necessary Factors b) The aseptic work area should be suitable for the prep-
aration of a sterile PET radiopharmaceutical. Air
1. Personnel and resources quality in the aseptic processing area should be ade-
quately controlled to limit the presence of microor-
Sufficient personnel with the necessary education, back- ganisms and particulate matter. Critical activities in
ground, training, and experience must be in place, and the production and testing of a PET radiopharmaceu-
they must have the resources, including equipment and tical that expose the PET radiopharmaceutical or the
facilities, to enable them to perform their functions. sterile surface of the container/closure system to the
environment should be conducted within an aseptic
workstation with a rating of class A (e.g. a LAFW or
2. Quality assurance isolator). The Class 100 rated workstation may be
placed in a class C environment, which may be in a
a) There has to be a quality assurance unit that can over- class D environment without further locks and chang-
see production operations to ensure that a quality PET es of clothing, provided a strict working regime is
radiopharmaceutical is produced. maintained. Examples of such activities include (1)
b) The quality assurance unit should have the authority the aseptic assembly of sterile components (syringe,
to examine and approve or reject components, con- needle, filter and vial) for sterile filtration of the PET
tainers, closures, in-process materials, packaging ma- radiopharmaceutical, (2) sampling of the sterility
terials, labelling and finished product to ensure com- samples and (3) sterility testing of the finished PET
pliance with procedures and specifications affecting radiopharmaceutical.
the identity, concentration, quality and purity of a Working regime:
PET radiopharmaceutical. – The aseptic workstation should be sanitised at least
c) The quality assurance unit should also be able to ap- once per day.
prove or reject procedures or specifications and any – Timing of sterile component assemblies should be
changes to a specification, method, process or proce- organised in such a way that during that time no
dure that affect the identity, concentration, quality or additional personnel enter the room.
purity of a PET radiopharmaceutical before they are – Items within a laminar airflow aseptic workstation
implemented. It should also assess the need for revali- should be kept to a minimum and should not inter-
dation after a change has been made. rupt the airflow to a major extent.
d) The quality assurance unit should also have the au- – Operators should wear designated lab coats and
thority to review production records to determine sterile arm protection and sterile gloves when con-

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ducting an aseptic manipulation within the aseptic nation, mix-ups or deterioration and ensures that they
workstation. are suitable for their intended use.
– The surface of non-sterile items (e.g. test tube rack, e) A record should be kept for each shipment of each lot
the over-wrap for sterile syringes and filters) of components, containers, and closures that includes
should be sanitised immediately before being the identity and quantity of each shipment, the suppli-
placed in the aseptic workstation. er’s name and lot number, the date of receipt, the re-
c) All equipment that influences the quality and purity sults of any testing performed, the disposal of rejected
of a PET radiopharmaceutical, or gives erroneous or material and the expiry date.
invalid test results when improperly used or main-
tained, should be clean, suitable for its intended pur-
poses, properly installed, properly maintained and ca- 5. Production and Process Controls
pable of repeatedly producing valid results. These ac-
tivities should be documented. a) Production and process controls should ensure the
d) Equipment should be constructed so that surfaces consistent production of a PET radiopharmaceutical
which come into contact with components, in-process that meets the quality standards.
materials or radiopharmaceuticals are not reactive, b) Production and process controls should include writ-
additive or absorptive (as this could alter the quality ten production and process control procedures, master
of the radiopharmaceutical). and batch production and control records, and valida-
e) New equipment should be qualified. tion of the production process and controls.
f) Procedures for cleaning and calibration of production c) Written production and process control procedures
equipment have to be validated. should include a master production and control record
g) Cleaning, calibration and maintenance should be per- that documents all steps in the production process.
formed at adequate intervals and be properly docu- The procedures should also ensure and document that
mented. key process parameters are controlled; deviations
from the procedures should be documented and justi-
fied. Master production and control records should in-
4. Control of Critical Materials clude:
1. The name and concentration of the PET radiophar-
a) Written procedures should be established, maintained maceutical.
and followed describing the receipt, storage in quar- 2. The name and weight or measure of each active in-
antine, log-in, identification, storage, handling and gredient and a statement of the total weight or mea-
testing of a representative sample, approval and rejec- sure of any dosage unit.
tion of components and radiopharmaceutical contain- 3. A complete list of components designated by suffi-
ers and closures. ciently specific names or codes.
b) Appropriate written specifications should be estab- 4. A statement of the weight or measure of each com-
lished for the identity, concentration, quality and puri- ponent, using the same weight system for each
ty of components and radiopharmaceutical containers component. Reasonable variations may be permit-
and closures. ted in the amount of component necessary if they
c) Upon receipt, each lot of components, containers and are justified in the master production and control
closures should be identified and examined to deter- record.
mine whether it complies with specifications. Any lot 5. A statement of practical yield, including the maxi-
that does not meet its specifications, including any mum and minimum percentages of practical yield
expiry date if applicable, or that has not yet been re- beyond which investigation is required.
leased should not be used in PET radiopharmaceutical 6. Complete manufacturing and control instructions,
production. sampling and testing procedures, specifications,
Representative samples of components, containers special notations, and precautions to be followed.
and closures from each lot should be tested for con- 7. A description of the radiopharmaceutical contain-
formity to written specifications. Instead of such test- ers, closures and packaging materials, including a
ing, a certificate of analysis may be accepted from the specimen or copy of each label.
supplier provided the reliability of the supplier’s test d) Each time a batch of a PET radiopharmaceutical is
results is established. produced, a unique batch production and control
The PET centre should perform an identity test on record should be prepared. The batch production
each lot of the active components, and should conduct record should identify by number or other unique
at least visual identification of each lot of containers identifier the specific batch that was produced, and
and closures. include the equipment used, each production step (ob-
d) Components and containers and closures should be tained from the approved appropriate master produc-
handled and stored in a manner that prevents contami- tion or control record), the actual amounts of compo-

European Journal of Nuclear Medicine and Molecular Imaging Vol. 30, No. 1, January 2003
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nents used, dates, testing results, labelling, and the performed according to specifications. This can be ac-
names (initials or signatures) of persons performing complished by performing a pressure-retaining test or
or checking each significant step in the operation and the bubble-point test to show that the integrity of the
any investigations conducted. filter was not compromised during or before use.
e) The production and dispensing area and all equipment Environmental monitoring is crucial to maintain-
should be inspected to ensure cleanliness and suitabil- ing aseptic conditions. Microbiological testing of the
ity immediately before use. Activities should be docu- aseptic workstation should be performed periodically.
mented. Methods can include using swabs or contact plates for
f) Process controls should include control of in-process surfaces, and settling plates or dynamic air samplers
materials to ensure that the materials are controlled for air quality.
until required tests or other verification activities have h) The process for producing each PET radiopharmaceu-
been completed, or necessary approvals are received tical should be validated according to established pro-
and documented. cedures, and the quality assurance unit should ap-
g) Microbiological Control on Aseptic Processing and prove both the validation process and the results of
Sterilising Filtration each validation activity. Validation activities and re-
Most PET radiopharmaceuticals are designed for par- sults should be documented. Documentation should
enteral administration and are produced by aseptic include the date and signature of the individual(s) ap-
processing. The goal of aseptic processing is to make a proving the validation, the monitoring and control
product that is free of microorganisms and toxic mi- methods and data, and the major equipment validated.
crobial by-products, most notably bacterial endotox- i) For thirty (?) days after the date on which a batch of a
ins. The use of aseptic technique and control of micro- PET radiopharmaceutical has been produced, a re-
biological impurities in components can eliminate mi- serve sample from the batch should be retained, to
crobial and endotoxin contamination from PET drugs. permit a repeat quality control.
Aseptic processing of PET drugs should involve mi-
crobiological control over relevant components.
The selection of a reliable vendor and of high- 6. Laboratory Controls
quality materials is an effective way to limit the risk
of microbiological contamination. Components that A. Laboratory requirements
support microbial growth during storage should be
kept under controlled conditions and periodically as- a) Each laboratory used to conduct testing of compo-
sessed for microbial growth/contamination. nents, in-process materials and finished PET radio-
Only personnel trained in aseptic techniques pharmaceuticals should have and follow written pro-
should conduct aseptic processing. Personnel per- cedures for the conduct of each test and for the docu-
forming aseptic processing should be qualified by mentation of the results.
media fill, which is a simulation of the production b) Each laboratory should have scientifically sound sam-
process. pling and testing procedures designed to ensure that
Aseptic processing in PET radiopharmaceutical components, radiopharmaceutical containers and clo-
production normally consists of, but is not limited to: sures, in-process materials and PET radiopharmaceu-
(1) the aseptic assembly of the container/closure ticals conform to appropriate standards, including
system (syringe, needle, filter and vial) and (2) sterile standards of identity, concentration, quality and puri-
filtration of the PET radiopharmaceutical. Prospective ty, when such standards exist.
operators can qualify for aseptic processing by per- c) Laboratory analytical methods should be suitable for
forming media fill runs using bacterial growth media their intended use and should be sufficiently sensi-
instead of the actual radiopharmaceutical. An opera- tive, specific, accurate and reproducible. Alternate
tor should complete three successful media fills to testing methods can be used, provided the PET cen-
qualify as a new operator. Each operator should be re- tre has demonstrated at least equivalence to the reg-
qualified periodically. ulatory method. Analytical test methods should be
Even if care is taken to minimise microbiological validated, if they are different from Pharmacopoeia
contamination during synthesis, a drug is considered methods.
to be non-sterile until it is passed through a sterilising d) The identity, purity and quality of reagents, solutions
grade filter. Generally, PET centres can use commer- and supplies used in testing procedures should be ade-
cially available, pre-sterilised filters to sterilise these quately controlled. All prepared solutions should be
solutions, provided that the vendor has been shown to properly labelled to show their identity and composi-
be reliable and that the filter is certified as compatible tion.
for the product and meets acceptable specifications. e) All equipment used to perform the testing should be
Integrity testing of the membrane filter should be suitable for its intended purposes and capable of pro-
performed post filtration to ensure that the filter has ducing valid results.

European Journal of Nuclear Medicine and Molecular Imaging Vol. 30, No. 1, January 2003
 BP 71

f) Each laboratory should have and follow written pro- its established acceptance criteria, except for sterility,
cedures to ensure that equipment is routinely calibrat- before it is released.
ed, inspected, checked and maintained, and that these b) Sterility testing need not be completed before release
activities are documented. but should be started as soon as possible after produc-
g) Each laboratory performing tests related to the pro- tion. If the product fails the sterility test, the results
duction of a PET radiopharmaceutical should keep should be immediately communicated to all receiving
complete records of all tests necessary to ensure com- facilities, with appropriate recommendations and fol-
pliance with established specifications and standards, low-ups. In addition, the doctor who wrote the pre-
including examinations and assays, as follows: scription for the PET radiopharmaceutical should be
1. A description of the sample received for testing, notified. Such notifications should be documented.
including its source, batch or lot number, date and c) Prior to release, each PET radiopharmaceutical should
time the sample was taken, date and time the sam- be tested to show that it meets the acceptance criteria.
ple was received for testing, and its quantity. The accuracy, sensitivity, specificity and reproducibil-
2. A description of each method used in the testing of ity of the test methods should be documented.
the sample, a record of all calculations performed d) The PET radiopharmaceutical may not be released un-
in connection with each test and a statement of the til:
weight or measure of the sample used for each test. 1. Appropriate laboratory testing has been completed.
3. A record of relevant data obtained in the course of 2. Associated laboratory data and documentation
each test, including graphs, charts and spectra have been reviewed.
from laboratory instrumentation, properly identi- 3. Release has been authorised by the dated signature
fied to show the specific component, in-process of a designated, qualified individual.
material or radiopharmaceutical for each lot tested. In many cases, modifications to this standard proce-
4. A statement of the results of tests and how the re- dure for product release may be appropriate. For ex-
sults compare with established acceptance criteria. ample, transportation deadlines may justify a pre-re-
5. Deviation from written procedures should be docu- lease for distribution before all elements of testing
mented and justified. Any out-of-specification re- and review have been finalised. Other than sterility
sults obtained should be investigated and docu- and apyrogenicity testing, all end-product tests should
mented. be completed or in progress at the time of shipment or
6. The initials or signature of the person performing distribution. These tests should be completed prior to
the test and the date the test was performed. final release for human administration. When it is de-
termined that all acceptance criteria have been met,
the PET centre should then provide a notice of final
B. PET radiopharmaceutical stability release to the receiving facility so that the dose can be
given to the patient. There should be effective proce-
a) The stability characteristics of PET radiopharmaceuti- dures for immediate notification of the receiving fa-
cals should be assessed according to a written testing cility if there is evidence of an out-of-specification re-
program. This stability program should include suit- sult and for documenting the fate of such a radiophar-
able storage conditions as well as the use of reliable, maceutical.
meaningful and specific test methods. e) Products that fail to meet acceptance criteria should
b) The results of such stability testing should be docu- be rejected. Appropriate reprocessing may be per-
mented and used in determining appropriate storage formed. If the material is reprocessed, pre-established
conditions as well as expiry dates and times. At least procedures should be followed (see Production and
three production runs of the final product should be Process Controls) and the finished product should
studied for a time period equal to the labelled shelf meet acceptance criteria before release.
life of the PET radiopharmaceutical.

B. Actions if a batch of PET radiopharmaceutical does

7. Controls and Acceptance Criteria for Finished PET not meet the acceptance criteria
Radiopharmaceuticals, and Actions in the Event
of Non-compliance a) If a batch of PET radiopharmaceutical does not meet
the acceptance criteria, the product should be clearly
A. Controls and acceptance criteria labelled and segregated to avoid mix-ups and the
quality assurance unit notified. Procedures to investi-
a) Acceptance criteria should be established for the ra- gate the cause(s) of the non-conformity should be in
diopharmaceutical, including criteria for identity, con- place and followed. Such an investigation should in-
centration, quality, purity and, if appropriate, sterility. clude, but is not limited to, examination of processes,
Each batch of a PET radiopharmaceutical should meet operations, records, complaints and any other relevant

European Journal of Nuclear Medicine and Molecular Imaging Vol. 30, No. 1, January 2003
BP 72

sources of information concerning the non-conform- 2. The name and quantity of the PET radiopharma-
ing product. ceutical shipped
b) Whenever a PET radiopharmaceutical does not meet 3. The patient’s prescription, if applicable, or any
acceptance criteria, this should be documented, and control number(s) used
the fate of the rejected PET radiopharmaceutical re- 4. The date and time the product was shipped.
corded.
c) Action should be taken to correct any identified prob-
lems so as to prevent recurrence of failure of the 10. Handling of Complaints
product to comply with the criteria or any other quali-
ty problem. a) Written procedures should be followed for the receipt
and handling of all complaints regarding a PET radio-
pharmaceutical.
8. Labelling and Packaging b) Such procedures should include provisions for review
by the quality assurance unit of any complaint involv-
a) Packaging and shipping containers are designed and ing the possible failure of a radiopharmaceutical to
constructed to protect against alteration or damage meet any of its specifications and any investigation
during the established conditions of storage, handling, conducted to determine the cause of the failure.
distribution and use. c) A written record of each complaint should be main-
b) Each PET radiopharmaceutical should be labelled tained in a file designated for radiopharmaceutical
with the name of the product, its concentration, the complaints. The record should include the name and
batch number or other unique batch identifier, the concentration of the radiopharmaceutical, its batch
date and time it was prepared, and an expiry date and number, the name of the complainant, the date the
time determined by appropriate stability testing. complaint was received, the nature of the complaint
c) Labels should be legible and applied so as to remain and the response to the complaint. It should also in-
legible and affixed during the established conditions clude the findings of any investigation and follow-up,
of processing, storage, handling, distribution and use. or a reason why no investigation was conducted and
d) Labelling and packaging operations should be con- the name of the person who determined this.
trolled to prevent labelling and product mix-ups. d) A PET radiopharmaceutical that is returned because
e) Relevant information from each label should be con- of a complaint may not be reprocessed and should be
tained in each batch production record. destroyed.

9. Distribution 11. Records

a) Procedures should be followed for the distribution of a) All records should be maintained at the PET centre or
PET radiopharmaceuticals to ensure that only those at another location accessible to responsible officials
products approved for release are used, that prescrip- of the PET centre and to government employees des-
tions (if applicable) are reviewed to ensure that they ignated to perform inspections (inspectors). Such re-
have been properly filled, and that the process of cords, including those not stored at the inspected es-
shipping will not adversely affect the quality, purity tablishment, should be legible, stored to prevent dete-
and identity of the PET radiopharmaceutical. rioration or loss, and readily available for review and
b) Distribution records for PET radiopharmaceuticals copying by inspectors.
should be maintained that include or refer to the fol- b) All records and documentation referred to in these
lowing: guidelines should be kept for a period of no less than
1. The name and address of the receiving facility that 10 years from the date of release of a PET radiophar-
received a batch of a PET radiopharmaceutical maceutical

European Journal of Nuclear Medicine and Molecular Imaging Vol. 30, No. 1, January 2003
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