Radiopharmaceutical Production

1. Radiopharmaceutical Production Production Environment STOP

2. Introduction This module provides basic information on FDG production facilities. After reviewing this module one should be able to: • draft a facility layout; • organize the material flow, production and quality control following the GMP guidelines; • comply with radiation protection principles. Content • Basic principles • Non-controlled area • Controlled area • Cleanrooms • Example of facility layout STOP

3. Basic principles Any facility used for FDG production should follow a number of regulations, standards and guidelines (national and international), ensuring the protection and safety of the staff, patients , and the environment as well as to provide products meeting the specifications. Facilities should typically be divided into two areas: • non-controlled area housing the offices, storage rooms, rest-rooms, technical room for the heating, ventilation and air-conditioning (HVAC), etc., and • controlled area housing the cyclotron and its infrastructure, the cleanroom (or cleanrooms) with hot cells for production and 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. Content Radiation protection and facility design GMP and facility design Cleanrooms and facility design Ergonomics and facility design Areas within the FDG production facility

4. 1.1. Radiation protection 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; • 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 and international guidelines, 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. 4XX, IAEA, Vienna, 200X. • Recommendations of the International Commission on Radiological Protection, ICRP Publication 103, Annals of the ICRP Volume 37/2-4 (2007).

5. 1.2. GMP and facility design Good Manufacturing Practices (GMP) or in certain countries current Good Manufacturing Practices (cGMP) represent a set of guidelines to be followed in order to ensure that the products produced meet specific requirements for identity, strength, quality, and purity. These national and international guidelines are related to the design of premises, their organization, operation and quality management. Concerning the premises used for production of pharmaceutical products (which includes radiopharmaceuticals), the key-word in each guideline is “fit for purpose”. Examples of GMP and cGMP guidelines • WHO:Quality assurance of pharmaceutical products. • US: Current good manufacturing practice in manufacturing, processing, packing, or holding of drugs, US FDA, 21 CFR Part 210. • EU: Good Manufacturing Practice guidelines for medicinal products for human and veterinary use, Eudralex, on-line edition. • CA: Good manufacturing practices guidelines, 2002 edition, Ver. 2. • AU: Australian code of good manufacturing practice for medicinal products, 2002 edition.

6. 1.3. Cleanrooms A cleanroom is a controlled environment where contamination sensitive products, e.g. pharmaceuticals are manufactured. 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. FDG production can be classified as aseptic manufacture with final sterilizing filtration. This is dealt with in GMP guidelines under aseptic processing, which requires production in a class C isolator contained in a minimum class D cleanroom. The classification of cleanrooms is further detailed in Section 5. 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.

7. 1.4. Ergonomics 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., they will get bored, tired and hectic, which will ultimately lead to 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; • design sufficient number of offices according to the number of staff; • provide space for short breaks and rest; • provide sufficient number of toilettes; • provide large enough changing rooms (if needed separate male and female); • adjust the workbench height according to the average height of personnel; • provide 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.

8. 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, rest-rooms, 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, the cleanroom (or cleanrooms) with hot cells for production and 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.

9. 2. Non-controlled area 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 non-controlled 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 • Canteen • Janitorial • HVAC

10. 3. Controlled area 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

11. 3.1. Floors 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.

12. 3.2. Walls and ceilings 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.

13. 3.3. Doors and windows 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.

14. 3.4. Benches 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. Gaps should be sealed with a silicone type material. 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.

15. 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 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. Typical sink suitable for installation in a controlled area.

16. 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

17. 3.7. Ventilation and containment 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

18. 3.8. Other facilities 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

19. Cleanrooms A cleanroom is a controlled environment where contamination sensitive products, e.g. pharmaceuticals are manufactured. 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 the EU GMP.

20. 4.1. Particle contamination limits 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.

21. 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.

22. 4.2. ISO Microbial contamination limits

23. 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.

24. Typical clean air supply system 1-air inlet grill; 2-silencer; 3-motorized damper; 4-panel filter type G4; 5-bag filter type F8; 6-air heating unit; 7-air cooling unit; 8-drain; 9-variable speed fan section; 10-steam humidifier; 11-filter type H10; 12-motorised fire damper; 13-air outlet grill; 14-heat 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.

25. 4.4. Cleanroom design guidelines 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.

26. 4.5. Validation of cleanrooms 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.

27. 5. Example of facility layout Description of the facility 5.1. Rooms in the non-controlled area 5.2. Rooms in the controlled area 5.3. Cleanrooms and isolators 5.4. Pressure gradient in the facility 5.5. Material flow Non-controlled area Controlled area Cleanrooms in the controlled area

28. 5.1. Rooms in the non-controlled area (1/3) • 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 building entrance for personnel should preferably be separated from the entrance for supplies to avoid congestion and for personnel safety. 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 (3), the office of the head of the facility (4), which is also a meeting room, 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 (5). 5 1 3 4 2

29. 5.1. Rooms in the non-controlled area (2/3) (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 through the airlock (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 material transfer airlock (MAL), (11). 9 8 10 7 11 6

30. 5.1. Rooms in the non-controlled area (3/3) 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). 12 13 15 14 Typically, FDG production facilities require compressed helium (for cooling of the target windows and transfer of enriched water), hydrogen (for the ion source of the cyclotron and for the operation of the FID of gas chromatographs), argon/methane mixture (for the operation of certain types of radiation detectors), etc. These cylinders should be connected to a fixed network of tubing delivering the gases to the equipment requiring them. 16

31. 5.2. Rooms in the controlled area (1/9) The radiation protection controlled area can be accessed only through the personnel airlock (PAL) (17). This room should be equipped with lockers for street garments, smocks, boots and overshoes. It should have a step-over bench separating the clean area from the potentially contaminated area. The personnel airlock 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 personnel airlock for entering the controlled area is sufficient. However, in certain countries it is obligatory to have separate male and female personnel airlocks. Through the personnel airlock one enters the corridor (18) within the controlled area. 17 18

32. 5.2. Rooms in the controlled area (2/9) (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; however it should be never used for entering the controlled area. The doors of these airlocks (17 and 19) should be interlocked and equipped with audio or visual alarms warning the personnel in case both of the doors of the airlock are open or if any of the doors is open for a long period of time. The cyclotron block should have typically four rooms: the shielding vault housing the cyclotron (20), the service room (21), the control room (22) and the power supply room (23). 21 20 23 22 17 19

33. 5.2. Rooms in the controlled area (3/9) 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 . 20

34. 5.2. Rooms in the controlled area (4/9) The service room (21) is used for the installation of the cooling system of the cyclotron and it provides space for the concrete plug while it is moved on rails out of the vault’s door, 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. For this end a set of common tools (wrenches, screwdrivers, tweezers, pliers, soldering stick, etc.) and 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 this room. There should be a control panel for operating the shielding door. 21

35. 5.2. Rooms in the controlled area (5/9) The control room (22) should have an appropriate workbench and several cabinets. It is handsome if the control room is located next to the power supply room, since the cyclotron operator can visually control the power supplies through a conveniently placed window. 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. 22

36. 5.2. Rooms in the controlled area (6/9) 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. 23

37. 5.2. Rooms in the controlled area (7/9) The preparatory room (24) should be equipped with cabinets and a workbench. It is used for unpacking the kits and other consumables from the bulk packing boxes prior to taking them into the production room via the material airlock (MAL), (25), in order to prevent the contamination of the cleanroom. This is the place for final inspection of all raw materials prior to their application. The packing room (26) is used for labelling the shielding containers, inserting them into the adequately labelled transport packages, securing the packages, checking the transport documents against the content of the packages and dispatching the products. The containers are taken out from the production room through the material airlock (27). 24 26 25 27

38. 5.2. Rooms in the controlled area (8/9) The quality control laboratory (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. 28 29

39. 5.2. Rooms in the controlled area (9/9) It is very useful to have a service corridor behind the hot cells (30). Having the rear access to the hot cells allows for servicing of the ventilation system of the hot cells and for replacing the charcoal and HEPA filters outside of the cleanroom. Moreover, the target transfer line and the corresponding valves can be easily accessed for service and maintenance without compromising the atmosphere of the cleanroom. There should be a room for temporary storage of radioactive waste and activated parts of the cyclotron, as well as for the storage of recalled products (31). Finally, there should be a janitorial room (32), used for storage of dedicated cleaning utensils needed for cleaning the rooms in the controlled area, including the cleanrooms. 32 30 31

40. 5.3. Cleanrooms and isolators in the controlled area (1/3) The room for FDG production, (33), (radiopharmaceutical production laboratory) should be classified minimum as class “D” cleanroom. It can be only entered through the personnel airlock (34), which should be equipped for common gowning for entering cleanrooms. It should have cabinets for storing cleanroom garment, a waste bin, hand basin, mirror and a step-over bench. The doors of the airlock should be interlocked and equipped with audio or visual alarms warning the personnel in case both of the doors of the airlock are open or if any of the doors is open for a long period of time. The clean side of the airlock should be designed to be of the same class as the production laboratory. 33 34

41. 5.3. Cleanrooms and isolators in the controlled area (2/3) The cleanroom for production of FDG (33) should house the hot cells for the synthesis modules, (35), (typically two modules are used for redundancy in separate hot cells), the hot cell for the dispenser (36), a laminar flow hood, (37), and a workbench. The FDG production cleanroom should be located as close as possible to the cyclotron and the hot cells should be installed along the wall that is closest to the cyclotron in order to reduce the losses of 18F in the capillary used for the transfer of irradiated enriched water. The hot cells should be located in the cleanroom 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. 37 35 36 33

42. 5.3. Cleanrooms and isolators in the controlled area (3/3) The hot cell housing the dispenser (36) 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. If more than one product is to be produced in the facility, more cleanrooms should be built; however the personnel airlock can be common for entering all cleanrooms. In case of maintenance or service the air quality of the cleanroom degrades due to mechanical operations that excessively generate particles, which prevents the normal production schedule with the other modules. If they are installed in separate rooms, service of one does not influence the operation of the others. 36

43. 5.4. Pressure gradient in the facility +20 Pa +5 Pa 0 Pa -5 Pa -10 Pa -25 Pa -60 Pa -200 Pa

44. 5.5. Material flow Raw materials Empty containers Semi-final products Final product

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