Production

Report
Radiopharmaceutical Production
Production Environment USA
STOP
Basic principles
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
• Any facility used for FDG production
should follow regulations, standards and
guidelines ensuring the protection and
safety of the staff, patients , and the
environment as well as to provide
products meeting the specifications.
• In the US model, production of
radiopharmaceuticals for distribution or
sale must follow the regulations contained
in 21 CFR 212. If radiopharmaceuticals
are only being produced for clinical
research and not diagnosis, the facility
may choose to comply with the
regulations contained in USP chapter 823
and USP chapter 797 instead of 21 CFR
212.
• Most of the GMP requirements are the
same as the WHO and EU guidelines, but
there are some subtle differences
contained in the following pages.
Content
US FDA Philosophy
Radiation protection and facility
design
GMP and facility design
Cleanrooms and facility design
Ergonomics and facility design
Areas within the FDG
production facility
US FDA Philosophy
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
• Here is a drawing for a
typical US facility. The
uncontrolled area is shown in
white. There are two
controlled areas. The
production area (yellow),
contains the cyclotron room,
mini-cells (which contain the
chemistry modules), QC area
and the laminar flow room
(which contains the laminar
flow hood for preparing vials).
• The second is the
pharmacy area (green),
which contains the hot cells
used to dispense unit doses
from multi-dose vials.
1.1. Radiation protection
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
The facility should be designed
and used in such a way that the
• release of radioactive effluents
into the environment is within the
permitted limits;
• radiation dose received by the
common public via internal and
external radiation is within the
permitted limits; and
• radiation dose received by the
staff via internal and external
radiation is within the permitted
limits.
This can be achieved by
following the related national
regulations and standards,
certain design principles, and
work procedures (standard
operating procedures – SOP’s).
International guidelines for
radiation protection
• International Basic Safety
Standards for Protection against
Ionizing Radiations and for the
Safety of Radiation Sources,
Safety Series No. 115, IAEA,
Vienna, 2003.
• Radiological Safety Aspects of
the Operation of Proton
Accelerators, Technical Report
Series No. 283, IAEA, Vienna,
1988.
• Cyclotron Produced Isotopes:
Guidelines for Facility
Development, Technical Report
Series No. 471, IAEA, Vienna,
2009.
• Recommendations of the
International Commission on
Radiological Protection, ICRP
Publication 103, Annals of the
ICRP Volume 37/2-4 (2007).
1.2. GMP and facility design
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
Examples of GMP and cGMP
Good Manufacturing Practices (GMP) guidelines
or in certain countries current Good
• WHO: Quality assurance of
Manufacturing Practices (cGMP)
pharmaceutical products.
represent a set of guidelines to be
• US: Current good
followed in order to ensure that the
manufacturing practice in
products produced meet specific
manufacturing, processing,
requirements for identity, strength,
packing, or holding of drugs,
quality, and purity. These national
US FDA, 21 CFR Part 210.
and international guidelines are
related to the design of premises,
• EU: Good Manufacturing
their organization, operation and
Practice guidelines for
quality management.
medicinal products for human
Concerning the premises used for
and veterinary use, Eudralex,
production of pharmaceutical
on-line edition.
products (which includes
radiopharmaceuticals), the key-word
in each guideline is “fit for purpose”.
1.3. Cleanrooms
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
A cleanroom is a controlled environment
where contamination sensitive products,
e.g. pharmaceuticals are dispensed. It
is an enclosure in which the
concentration of airborne particles of
certain size and origin is maintained
within specified limits. Eliminating submicron airborne contamination
generated by personnel, process,
facilities and equipment is achievable
only by careful design and construction
of cleanrooms and by applying strict
rules and procedures for production and
maintenance.
Additional information related to cleanroom design
• WHITE, W. (Editor): Clean Room Design, 2nd edition,
John Wiley & Sons, Chichester (2000).
• International standard ISO 14644-1:1999,
Cleanrooms and associated controlled environments
- Part 1: Classification of air cleanliness.
• International standard ISO 14644-2:2000,
Cleanrooms and associated controlled environments
- Part 2: Specifications for testing and monitoring to
prove continued compliance with ISO 14644-1.
• International standard ISO 14644-3:2005,
Cleanrooms and associated controlled environments
- Part 3: Test methods.
• International standard ISO 14644-4:2001,
Cleanrooms and associated controlled environments
- Part 4: Design, construction and start-up.
• International standard ISO 14644-5:2004,
Cleanrooms and associated controlled environments
- Part 5: Operations.
• International standard ISO 14644-6:2007,
Cleanrooms and associated controlled environments
- Part 6: Vocabulary.
• International standard ISO 14644-7:2004,
Cleanrooms and associated controlled environments
- Part 7: Separative devices (clean air hoods,
gloveboxes, isolators and mini-environments).
• International standard ISO 14644-8:2006,
Cleanrooms and associated controlled environments
- Part 8: Classification of airborne molecular
contamination.
1.4. Ergonomics
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
Ergonomics is indirectly related to the
safety of operation and quality of
products: if the operators are working in
a hostile environment, in dim light, if the
air is too dry, cold, humid or warm, if
they have to run around chaotically due
to misplaced equipment, etc., these
factors can lead to a loss of
concentration and they will become
prone to mistakes and error.
Work under excessive stress ultimately
leads to personal injuries and/or
defective products. In worst case,
defective products might even reach the
patients.
In addition to careful optimization of flow
of material and personnel, one should
follow the local architectural standards
and guidelines related to ergonomics
and general working conditions.
Common ergonomic issues:
• ensure that there is daylight in offices;
• include a sufficient number of offices for
the number of people on the staff;
• provide space for short breaks and rest;
• provide sufficient number of toilettes;
• provide large enough changing rooms
(if needed separate male and female);
• provide workbenchs of different height s
according to the personnel;
• provide a large computer monitors and
ergonomic keyboards;
• provide adequate seats even in
cleanrooms;
• provide adequate lightning;
• provide air conditioning in the whole
facility;
• separate the personnel and material
flow throughout the facility;
• distribute the equipment in a logical
order
• etc.
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
1.5. Areas within the production
facility
A facility that is suitable for FDG
production can be divided into two
areas: the first is a general purpose
area with offices, storage rooms, restrooms, technical room for the heating,
ventilation and air-conditioning (HVAC),
etc. (non-controlled area), while the
second is a radiological controlled area
built according to the radiation
protection regulations allowing work
with open radioactive sources.
The controlled area provides space for
housing the cyclotron and its
infrastructure with hot cells for
production, a room for dispensing of
the radiopharmaceutical, appropriate
space for packaging and quality control
of the product and temporary storage
space for batch samples, recalled
products and radioactive waste.
These areas differ in many
aspects. The most prone
differences are:
• air pressure;
• air cleanliness;
• floor, wall and ceiling covering;
• access restriction;
• gowning, etc.
The passage of personnel and
materials between different areas
should be made through
appropriate personal and material
airlocks, which should be
separated from each other.
The flow of raw materials should
be clearly separated from the flow
of products within each area.
2. Non-controlled area
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
The non-controlled, general purpose
area houses the offices, storage rooms,
rest-rooms, technical room for the
heating, ventilation and air-conditioning
(HVAC), etc.
The offices should be designed
according to the number of people on
the staff and local national standards.
Sufficient space should be provided for
the storage of documentation related to
this technology (manuals, standard
operating procedures, installation,
operation and performance qualification
records, purchasing orders, training
records, batch production records, etc.).
The technical room for the HVAC is
often placed on the roof of the facility
since it is easy to optimize the
placement of ventilation ducts. The
whole ventilation system must be leak
free in order to avoid any release of
radioactive gases and this is made
easier if the ducts are as short as
possible.
Rooms and utilities in the noncontrolled area:
• Entrance for personnel
• Offices
• Entrance for raw materials
• Storage for non-released raw
materials (quarantine)
• Storage for released raw
materials
• Storage for transport containers
• Storage for compressed gases
• Toilettes
• Data center
• Break room
• Janitorial
• HVAC
3. Controlled area
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
The controlled area as a whole
should be built following the radiation
protection and pharmaceuticals
manufacturing regulations and a set
of commonly accepted design
principles.
Each room should be classified (and
built appropriately) for handling a well
defined amount and type of
radioactive material in certain form
(open or closed sources, gases,
liquids, solids, powders, etc.).
The hotcells for FDG production and
dispensing are typically categorized
as class “C”, the FDG production
laboratory and the cyclotron vault are
typically class “B”, while the rest of
the rooms within the controlled area
are usually classified as class “A”
areas according to the radiation
protection classification.
Specific issues related to
design of controlled areas
3.1. Floors
3.2. Walls and ceilings
3.3. Doors and windows
3.4. Benches
3.5. Waste disposal sinks and
drainage pipes
3.6. Radioactive storage
facilities
3.7. Ventilation and
containment
3.8. Other facilities
3.1. Floors
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
The floor of the controlled area
should be covered with an easily
cleanable surface such as a
continuous sheet of PVC or
linoleum at least 2.5 mm thick.
The covering should be coved
(extending up the wall) to a
height of about 15 cm contiguous
with the floor surface.
All edges at the walls and
between sheets should be sealed
or welded to prevent seepage of
spilled materials. As an
alternative, an epoxy resin
coating may provide an
acceptable finish on smooth
concrete, particularly in the
cyclotron vault, due to its high
radiation stability.
Typical floor in a controlled
area, showing the cowed
corner.
3.2. Walls and ceilings
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
The walls and ceilings should
generally be smooth and painted
with a hard gloss or high quality
waterproof vinyl emulsion to
facilitate cleaning. The use of
stippled surfaces or a paint finish
applied to un-plastered concrete
blocks is unacceptable.
Paint-coated aluminium based
sandwich-type plates used to
build cleanrooms are ideal for
building controlled areas as well.
Joints between plates should be
sealed with silicone type
materials to facilitate cleaning.
Service penetrations in walls and
ceilings should be sealed and
coved.
Typical joint of two walls and
the ceiling. All elements are
sandwitch-type aluminum
plates. A lightning fixture on the
ceiling is also visible.
3.3. Doors and windows
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
Wooden surfaces should be covered
with plastic laminate material or
painted with a good quality
polyurethane gloss paint or varnish.
Doors should be lockable to ensure
safe keeping or to restrict access. A
high level of security for a building
and/or an entire site is preferable to
securing an individual laboratory
within a building.
Windows that can be opened to the
outside are not permitted in
controlled areas. Windows which do
not open are acceptable, but should
generally be avoided on the external
walls of controlled areas.
Typical door for controlled
areas – acceptable for
cleanrooms as well.
3.4. Benches
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
Working surfaces should be smooth, hard
and non-absorbent and have necessary
heat and chemical resistant properties. All
gaps and joints should be sealed with a
silicone type material. The bench-tops
should be coved (upstanding) at the rear
against walls. A raised front lip on the
bench can help prevent a spillage running
off the bench onto the floor. Exposed
wood, including under-benches and
under-bench cupboards, should be
painted with a good quality hard gloss
paint or polyurethane varnish or
laminated. The use of wood surfaces
should be avoided in laboratories.
Dedicated areas of bench should be set
aside for radioactive work and be clearly
marked. It is good working practice to
work in plastic or metal trays on bench
tops to minimize spills and spread of
contamination.
Typical workbench in a
controlled area. Note the
coved edges preventing
spillage running off the
bench.
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
3.5. Waste disposal sinks and
drainage pipes
Sinks for the disposal of radioactively
contaminated aqueous liquid waste
should be constructed of suitable
material: for most applications, stainless Typical sink suitable for installation
in a controlled area.
steel is preferred. Where possible,
combined sinks and draining boards
should be used, with rounded front
edges and coved (upstanding) at the
rear against walls. A rear splash plate
should extend a reasonable distance up
the wall behind the sink.
Small diameter U-shaped or bottle traps
should be used, instead of large traps
or catch pots, so as to avoid
accumulations of radioactive sediments.
Holding tanks may be required for
confirming compliance with discharge
consent conditions. Drainage pipes for
radioactive effluents should be labelled
with the ionizing radiation symbol.
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
3.6. Radioactive storage
facilities
Waste disposal bins in the laboratory (used
for storing solid waste awaiting disposal)
should be constructed of a material which is
robust, and preferably should be foot
operated. The lid should be closed when
not in use and the contents in the bag
sealed or secured before removing them
from the bin.
All sharps, bottles, tubes, etc should be
placed in special containers to ensure safe
handling of the materials.
Adequate storage space should be
available for temporary storage of
radioactive waste within the controlled area.
The storage space must be kept locked and
may need to be under surveillance.
Radioactive waste
disposal bin
3.7. Ventilation and containment
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
Dispensing or preparation of radioactive
materials which may cause airborne
contamination should be carried out under
conditions to prevent dispersal of the
substances. In particular, volatile radioactive
materials should never be used in the open
laboratory; only in appropriate containment
such as a fume cupboard.
Re-circulating ventilation systems are
inappropriate for controlled areas where
open radioactive sources are handled. A
guiding principle for effective control of
contamination is that air movement should
be maintained from less-contaminated
areas to more-contaminated areas by
means of pressure difference in the rooms.
Ideal pressure gradient in a
facility with radiation
protection controlled area.
Non-controlled area:
atmospheric
Preparation areas:
slightly bellow atmospheric
Hot laboratories:
bellow atmospheric
Cyclotron vault:
well bellow atmospheric
Hotcell’s containment:
lowest pressure
3.8. Other facilities
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
Adequate decontamination facilities,
including decontamination solutions,
should be available. A designated hand
wash basin and a shower cabin for
decontamination should be provided: it
must never be used for the disposal of
radioactive substances (other than traces
from the decontamination of personnel).
Warning signs, clearly and legibly marked
with the word "Radioactive", with the
ionizing radiation symbol, and any other
information necessary (contact person,
telephone number, etc.), should be placed
on doors, cupboards, equipment,
refrigerators, working areas, drainage
pipes, sinks, storage facilities, sewers,
exhausts, etc., as appropriate.
Emergency shower for
decontamination with
integrated eye-wash basin
4 Cleanrooms
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
A clean room or clean area is a
controlled environment where
contamination sensitive products,
e.g. pharmaceuticals are
manufactured or dispensed. It is
an enclosure in which the
concentration of airborne
particles of certain size and origin
is maintained within specified
limits. Eliminating sub-micron
airborne contamination
generated by personnel, process,
facilities and equipment is
achievable only by careful design
and construction of cleanrooms
and by applying strict rules and
procedures for production and
maintenance.
Cleanroom design issues
• Particle contamination limits
• Microbial contamination limits
• HVAC systems for cleanrooms
• Cleanroom design guidelines
• Validation of cleanrooms
Cleanrooms are classified
according to the number of
particles per unit volume
and air flow pattern. The
next two slides provide
requirements for the four
cleanroom air classes
according to cGMP which
can be found in Guidelines
for Aseptic Processing
4 Cleanrooms
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
In the US model, the regulations specify that separate or defined
areas of operation in an aseptic processing facility should be
appropriately controlled to attain different degrees of air quality
depending on the nature of the operation. Design of a given area
involves satisfying microbiological and particle criteria as defined
by the equipment, components, and products exposed, as well as
the operational activities conducted in the area. Clean area control
parameters should be supported by microbiological and particle
data obtained during qualification studies. Initial cleanroom
qualification includes, in part, an assessment of air quality under
as-built, static conditions. It is important for area qualification and
classification to place most emphasis on data generated under
dynamic conditions (i.e., with personnel present, equipment in
place, and operations ongoing). An adequate aseptic processing
facility monitoring program also will assess conformance with
specified clean area classifications under dynamic conditions on a
routine basis.
4.1. Particle contamination limits
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
•
Maximum number of airborne particles in 1 m3 air in the
cleanroom of designated class. Cleanrooms of class A shall
provide a unidirectional laminar air flow within the containment
with a homogeneous air speed in a range of 0.36 – 0.54 m/s.
These conditions should be maintained for the most critical
operations, e.g. aseptic filling of vials, or sterility testing of
products. The air flow pattern in cleanrooms of class B, C and D
can be turbulent or mixed.
Clean Area
Classification
A
B
C
D
GMP Classifications
At rest
In operation
0.5 μm
5 μm
0.5 μm
5 μm
3,500
1
3,500
1
3,500
1
350,000
2,000
350,000
2,000
3,500,000
20,000
3,500,000
20,000
n.d.
n.d.
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
4.2. Microbial contamination
limits
•
Recommended limits for microbiological monitoring of clean
areas during operation. Class “A” condition should be
maintained for the most critical operations, e.g. aseptic filling of
vials, or sterility testing of products.
Limits for microbial contamination
GMP
Class
A
B
C
D
Air
sample,
cfu/m3
<1
10
100
200
Settle plates
(diam. 90 mm),
cfu/4 hours
<1
5
50
100
Contact plates
(diam. 55 mm),
cfu/plate
<1
5
25
50
Glove print 5
fingers,
cfu/glove
<1
5
n.d.
n.d.
4.2. ISO Microbial
contamination limits
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
Class
maximum particles/ft³
≥0.1
µm
≥0.2
µm
≥0.3
µm
≥0.5
µm
≥5
µm
ISO
equivalent
1
35
7
3
1
ISO 3
10
350
75
30
10
ISO 4
750
300
100
ISO 5
100
1,000
1,000
7
ISO 6
10,000
10,000
70
ISO 7
100,000
100,000
700
ISO 8
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
4.3. HVAC systems for
cleanrooms
The basic elements of an air
supply system maintaining the
required air quality in cleanrooms
are presented on the next slide.
Cleanrooms used for the
production of
radiopharmaceuticals must be
supplied by 100% fresh air in
order to comply with radiation
protection regulations (no
recirculation of air is permitted in
radiation protection controlled
areas).
The air quality of the cleanrooms
(temperature, humidity,
differential pressure between
rooms, differential pressure
before and after the filters, etc.)
should be monitored and
recorded.
Typical air handling unit (AHU)
supplying clean air to
cleanrooms.
Typical clean air supply system
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
1-air inlet grill; 2-silencer; 3motorized damper; 4-panel filter
type G4; 5-bag filter type F8; 6air heating unit; 7-air cooling unit;
8-drain; 9-variable speed fan
section; 10-steam humidifier; 11filter type H10; 12-motorised fire
damper; 13-air outlet grill; 14heat pump with heat exchangers;
15-constant air flow regulator;
16-electric heater; 17-sound
absorber; 18-terminal absolute
filter type U15; 19-variable air
flow regulator; T-temperature
sensor; P-pressure sensor.
Filters are classified according to
standard EN 779.
1
2
3 4
5
6
7
+
-
8
9
10 8 11
2
14
13
2
9
8
12
2
12
Additional clenrooms
15
19
16
17
17
15
19
16
17
17
18
P
T
Cleanroom 2
18
P
T
Cleanroom 1
4.4. Cleanroom design guidelines
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
Although the air quality in a cleanroom is essential, this is not the only
element that makes the cleanroom “clean”. Its design, construction,
maintenance and particularly the operations performed within the
cleanroom are also very important. Some common engineering guidelines
that can help in designing cleanrooms are summarized in this table.
EU GMP Class
Area per occupant, m2
Room overpressure, Pa
Air changes per hour
Clean air inlet as % of ceiling
(wall) area
Clean air inlet locations
Return air location
A, B
30
15
500
C
10
10-15
20-40
D
5
5-10
10-20
90
10-20
5-10
Ceiling (wall)
Ceiling
Ceiling or high
sidewall
Low level or floor
(opposite wall)
Low sidewall
Sidewall
Terminal velocity at clean air
inlet, m/s
Airlock entrance needed
Occupants properly attired
0.36-0.54
0.15-0.45
0.15-0.45
Yes
Full gowns
No
Smocks
Occupant activity
Minimum
Traffic in/out per hour
Equipment in room
Housekeeping
Routine particle count interval
Minimum
Minimum
Meticulous
Weekly
Yes
Coverall
Occasional
movement
2-6
≤ 30% floor
Good
Monthly
Constant activity
>6
≤ 50% floor
Mediocre
Quarterly
4.5. Validation of cleanrooms
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
Validation is defined as the
establishing of documented evidence
which provides a high degree of
assurance that a planned process will
consistently perform according to the
intended specified outcomes. Once
the system or process has been
validated, it is expected that it
remains under control, provided no
changes are made. In the event that
modifications are made, or problems
occur, or equipment is replaced or
relocated, revalidation is required.
One very helpful practice is to make
up a validation master plan. This
document will guide the validation of
all the equipment and spaces.
Validation of cleanrooms should be
performed according to the validation
master plan.
Validation of cleanrooms is
performed in three phases:
• installation qualification (IQ),
• operational qualification (OQ)
and
• performance qualification (PQ).
These qualification procedures are
closely linked to the design of the
cleanrooms and their aim is to show
that the cleanroom has been built
according to the design
requirements and that it provides
the required environment for the
safe production of pharmaceuticals.
5. Example of facility layout
Radiopharmaceutical
Production
Description of the
facility
5.1. Rooms in the noncontrolled area
5.2. Rooms in the
controlled area
5.3. Cleanrooms and
isolators
5.4. Pressure gradient in
the facility
5.5. Material flow
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
Non-controlled area
Controlled area
Cleanrooms in the controlled area
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
5.1. Rooms in the noncontrolled area (1/3)
5
•
4
3
2
1
The offices, janitorial, rest-rooms and
material storage areas and the access
restricted entrance into the facility will
be in a non-controlled area. The main
entrance for personnel (1) leads to the
main corridor (2). From this corridor one
can access three offices: the office of
the technical secretary and the office
for the physicist operating the cyclotron
(typically the same person is the
radiation protection officer – RPO),
radiopharmacist responsible for quality
assurance and release of products and
radiochemists responsible for the
production and quality control of
radiopharmaceuticals (3) , the office of
the head of the facility (4), and the
break room which is also a meeting
room, (5).
Radiopharmaceutical
Production
5.1. Rooms in the noncontrolled area (2/3)
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
7
10
9
11
8
STOP
6
(6) is the access controlled entrance
for goods. Next to it is the temporary
storage (quarantine), (7), where all
received materials are temporarily
stored until they are released for
usage. Returned reusable transport
containers are further stored in the
storage room (8) where they are
inspected and cleaned prior to
transfer into the controlled area (9).
Released raw materials are stored in
the storage room (10), which should
be equipped with closets, ventilated
safety storage cabinets for acids,
bases and flammable chemicals and
refrigerators whose inside
temperature is constantly monitored
and recorded for storing temperature
sensitive precursors. These raw
materials and chemicals are
transferred into the controlled area
through the door (11).
5.1. Rooms in the noncontrolled area (3/3)
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
13
14
16
12 15
The janitorial room (12) is used for storage
of housekeeping and cleaning utensils, the
kitchen (13) is a place foreseen for short
breaks, while (14) is the toilette. There is a
data centre, (15), housing the network
printers, scanner, telefax, photocopier and
cabinets for storing the batch records and
other GMP and QA related documents. In
most countries the safety regulations
require that cylinders with compressed
gases are stored in rooms with natural
ventilation. For easy replacement of empty
cylinders it is useful to foresee a cylinder
storage room that is directly accessible by
a transport vehicle (16).
Typically, FDG production facilities require
several compressed gases for cyclotron
and laboratory operations. These
cylinders should be connected to a fixed
network of tubing delivering the gases to
the equipment requiring them.
Radiopharmaceutical
Production
5.2. Rooms in the controlled
area (1/8)
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
17
18
The radiation protection controlled area
can be accessed through the personnel
frisking area (17). This room should be
equipped with lockers for labcoats and
other Personal Protective Equipment
(PPE), Ideally it should have a step-over
bench separating the clean area from the
potentially contaminated area. The
entrance should be equipped with a
hand-foot contamination monitor and it
should have at least one hand basin and
one shower for decontamination
purposes. Due to the small number of
operators working in the controlled area
of an FDG production facility, in most
cases one entrance for entering the
controlled area is sufficient. However, in
certain countries it is obligatory to have
separate male and female entrances.
Through the entrance one enters the
workspace (18) within the controlled
area.
Radiopharmaceutical
Production
5.2. Rooms in the controlled
area (2/8)
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
20
22
21
23
19
STOP
(19) is a material airlock used for taking
out the transport containers with the
product from the controlled area to the
transport vehicle. This route serves
also as an emergency exit from the
controlled area for the personnel.
The cyclotron block should have
typically four rooms: the shielding vault
housing the cyclotron (20), the service
area (21), the control room (22) and
the power supply room (23).
Radiopharmaceutical
Production
5.2. Rooms in the controlled
area (3/8)
.
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
20
The cyclotron vault (20) should provide
the protection from ionizing radiation
created by the operation of the cyclotron
and irradiation of the targets typically
installed directly on the cyclotron. The
vault is usually made of ordinary steel
reinforced concrete (having a density of
2350 kg/m3) and depending on the
performance of the cyclotron (proton
beam energy and maximum current on
target or targets if run in dual beam
mode) it has 1.5-2.2 m thick walls.
In case the facility uses a self shielded
cyclotron, the vault will have significantly
thinner walls (around 50 cm), however
the footprint of the vault will be practically
the same as in case of unshielded
cyclotrons, since quite large space must
be left available within the vault for
service
Radiopharmaceutical
Production
5.2. Rooms in the controlled
area (4/8)
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
21
23
The service area (21) should have
space for a workbench and several
cabinets. The workbench should be
equipped with a lead window working
station for servicing activated parts of the
cyclotron, particularly for targets that
require regular cleaning and
maintenance. At this place most of the
critical parts of the cyclotron can be
repaired or serviced. A set of common
tools (wrenches, screwdrivers, tweezers,
pliers, soldering stick, etc.). A selection of
spare parts (window foils, stripping foils,
o-rings, cathodes for the ion source,
different fittings and tubing, etc.) should
be stored in the closets located in the
power supply room (23). There should be
a control panel for operating the
shielding door if the cyclotron is not selfshielded.
Radiopharmaceutical
Production
5.2. Rooms in the controlled
area (5/8)
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
22
The cyclotron control area (22) should
have an appropriate workbench and
several cabinets. The control room
houses typically three computer working
stations: one for controlling the cyclotron
and the targets, one for controlling the
radiation protection monitoring and
safety system and one for controlling the
HVAC system of the facility. The cabinets
can be conveniently used for the storage
of operating manuals and other technical
documentation. If the facility is equipped
with a video surveillance system, this is
the right place to install the
corresponding monitors and video
recording facility.
Radiopharmaceutical
Production
5.2. Rooms in the controlled
area (6/8)
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
23
The power supply room (23) is used for
the installation of the power supplies for
the cyclotron: for the magnetic coils,
radiofrequency system (RF), safety and
control system, etc. It should be located
close to the cyclotron and the distance is
very often limited by the maximum
permitted length of the RF cables. Due to
the fact that the penetrations through the
cyclotron vault’s walls are usually located
below the ground level, it is common to
have a false floor in the power supply
room for easy installation of large
number of cables.
In case a cyclotron with self shielding is
to be installed, the power supplies may
be installed in the same room with the
cyclotron.
Radiopharmaceutical
Production
5.2. Rooms in the controlled
area (7/8)
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
24
25
26
27
STOP
In the US model, the vial for use in the
FDG synthesizers must be prepared in
a ISO Class 5 area (Class 100) . This
preparatory room (24) should be
equipped with cabinets for supplies and
a laminar flow hood. This area should be
locked to access during the preparation
of the vial. Once the vial is prepared, it
can be transferred into the production
area, and placed in the FDG synthesis
unit contained in a hot cell (25).
Once the synthesis is completed, the vila
can be tranferred into the dispensing
room (26) where the unit doses are
dispensed into single use vial or
syringes. The packaging area (27) is
used for labeling the shielding
containers, inserting them into the
adequately labeled transport packages,
securing the packages, checking the
transport documents against the content
of the packages and dispatching the
products.
Radiopharmaceutical
Production
5.2. Rooms in the controlled
area (8/8)
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
28
29
The quality control area (28) should be
large enough to install the necessary
general purpose QC equipment and a
shielded laboratory hood. For a typical
FDG production facility, a room
containing about 10-12 m of workbench
space in total should be sufficient. The
laboratory hood (29) should be
integrated into the ventilation system of
the facility. It is necessary to install
additional flexible ventilation tubes for
local suction, which can be positioned
above the equipment such as the
detectors of gas chromatographs, that
releases potentially contaminated gases
or aerosols.
It is common to subcontract a specialized
laboratory for sterility testing of the final
product. In case this is not possible, a
dedicated room should be allocated for
this purpose.
Radiopharmaceutical
Production
5.3. Cleanrooms and isolators in
the controlled area (1/3)
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
24
The area for FDG vial preparation,
(24), should be an aseptic work area
suitable for the assembly of the aseptic
components required for the
preparation of a sterile PET drug.
Although no specifications are required
in Part 212, we recommend that air
quality in the aseptic processing area
be controlled to limit the presence of
microorganisms and particulate matter
so that the area of vial preparation is
ISO class 5 (Class 100) and the room
is ISO class 8 (Class 10000). Critical
that expose the PET drug or the sterile
surface of the container/closure system
to the environment should be
conducted within an aseptic
workstation (e.g., a LAFW or barrier
isolator).
Radiopharmaceutical
Production
5.3. Cleanrooms and isolators in
the controlled area (2/3)
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
25
30
The room for production of FDG should
house the hot cells for the synthesis
modules, (25), (typically two modules are
used for redundancy in separate hot
cells). In the US model, the hot cell for
the dispenser (30) is in a separate room
and is controlled under the practice of
pharmacy. This room may also contain a
workbench for printing labels and
performing DOT radiation rate checks
before shipping.
The FDG production area should be
located as close as possible to the
cyclotron The hot cells should be located
in the area so that the doors can be fully
opened in order to access the modules
for preparation or service. The inner
containment enclosure and the air quality
inside the hot cells housing the
production modules should be GMP
class C.
Radiopharmaceutical
Production
5.3. Cleanrooms and isolators in
the controlled area (3/3)
The hot cell housing the dispenser (30)
should have a material airlock for
inserting the sterile vials and the sterile
dispensing kit into the containment,
which should be class B. The class B
environment serves as the background
for the class A environment which is
created locally at the place the vials are
filled.
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
30
Radiopharmaceutical
Production
5.4. Pressure gradient in the
facility
+20 Pa
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
+5 Pa
0 Pa
-10 Pa
-200 Pa
The areas where there is a
chance of radioactive
contamination should be
kept at below atmospheric
whereas the areas for sterile
preparation should be kept
above atmospheric .
5.5. Material flow
Radiopharmaceutical
Production
Content
US FDA Philosophy
Radiation protection and
facility design
GMP and facility design
Cleanrooms and facility
design
Ergonomics and facility
design
Areas within the FDG
production facility
Non-controlled area
Controlled area
Cleanrooms
Example of facility layout
Rooms in the noncontrolled area
Rooms in the controlled
area
Cleanrooms and isolators
Pressure gradient in the
facility
Material flow
STOP
Personnel
Material
Product
gas
cylinder
delivery
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