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Radiopharmaceutical Production

Facility Equipment

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Laboratory Equipment• Radiopharmaceutical production

laboratories must be equipped with a range of production and analytical instrumentation.

• The major equipment will be the cyclotron, the hot cells and all the analytical equipment needed to comply with GMP.

• In all cases equipment should be chosen to be able to meet GMP requirements, but it is not necessary to purchase more expensive equipment which goes far beyond these requirements.

• Some critical pieces of equipment may need back-ups in case of equipment failure.

• The cyclotron and targets are covered in another section and will not be covered here.

Contents• Production Equipment• QC Analytical Equipment• General Laboratory Equipment

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Equipment

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Production Equipment Hot cells Laminar flow hoods Dispensing Equipment Material Airlocks

QC Analytical Equipment Overview: QC of [18F]FDG HPLC Radio-TLC GC pH Osmolality Gamma Spectrometer Dose Calibrator Membrane Filter Testing Endotoxin testing

General Laboratory Equi

pment Fume Hoods Balances Refrigerators and Freezers Ovens and Incubators Melting Point Apparatus

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Production Equipment

• The FDG production equipment includes the hot cells in which the synthesis and dispensing modules will be placed, the automated FDG synthesis module, and the laminar flow hoods where the sterile preparations are done.

• The synthesis modules are covered in another section.

Contents• Hot cells• Laminar flow hoods• Dispensing Equipment• Material Airlocks

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http://www.iaea.org/index.html


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Hot Cells• The hot cell provides a shielded enclosure for handling highly

radioactive materials and can serve as an isolator providing clean environment for the preparation of radiopharmaceuticals.

• The number of hot cells and their size is determined by the production capacity of the facility and the particular synthesizer being used. The thickness of lead shielding is determined by the quantity of FDG being processed; 75 mm of lead or equivalent is typical, but the Radiation Safety Officer should be consulted for an final determination..

• For radiation safety reasons, the air pressure inside the hot cells should be maintained well below the pressure of the room where the hot cell is situated. Furthermore, the hot cells should be equipped with an appropriate air handling system and monitor (inlet and outlet air filters as a minimum).

• Lead glass windows or TV monitors should be provided with the hot cells. Production hot cells will generally not need manipulators. Dispensing hot cells may need tongs or manipulators depending upon the dispenser used.



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Large Production Hot Cells

• The hot cell provides space and handling facilities for operations on highly radioactive materials. These can include the synthesis of radiotracers, processing of irradiated targets, radwaste processing and storage and other operations which involve high levels of radioactivity.



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Large Production Hot Cells

• Manipulators can be used for manual synthesis when an automated synthesis unit is not available.



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Smaller Hot Cells (Minicells)

• It is common to have two smaller hot cells in the FDG production facility for housing the synthesis modules (two FDG synthesis modules are recommended for redundancy) and one additional dedicated hot cell for dispensing of the product.

• Hot cells for the synthesis modules should provide class C environment.

• A typical hot cell for housing two synthesis units is shown on the right.



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Synthesis Unit in the Hot Cell

• FDG Synthesizer installed in a small hot cell.



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FDG Synthesis Unit in a Minicell

• Minicell next to laminar flow hood for QC testing• Room is GMP compliant• Sep-pak is shielded behind additional leaded glass window to

reduce radiation exposure during cleaning



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Dual Mini-cells

• Here are mini-cells with a shielded laminar flow ot cell next to it to handle the quality control testing.

• There is a ionization chamber in the floor of the laminar flow hood to enable dose measurement

• Only applicable in the US



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Laminar Flow Hoods• In addition to chemical fume hoods, there need to be separate

laminar flow hoods where the preparation of sterile materials, testing of the product for pyrogens and dispensing of doses may take place.

• The most important part of a laminar flow hood is a high efficiency bacteria-retentive filter. Room air is taken into the unit and passed through a pre-filter to remove gross contaminants (lint, dust etc). The air is then compressed and channeled up behind and through the HEPA filter (High Efficiency Particulate Air filter) in a laminar flow fashion--that is the purified air flows out over the entire work surface in parallel lines at a uniform velocity. The HEPA filter removes nearly all of the bacteria from the air.

• With poor technique it is easy to overcome the established airflow velocity and introduce reverse currents that can re-introduce contaminants into the work area. Any equipment in the laminar flow hood can also potentially disturb the laminar flow.



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Laminar Flow Hoods

• Provide clean air to the working area.

• Provide a constant flow of air out of the work area to prevent room air from entering.

• The air flowing out from the hood suspends and removes contaminants introduced into the work area by personnel.

• The environmental control of air is of concern because room air may be highly contaminated. Example: Sneezing produces 100,000 - 200,000 aerosol droplets which can then attach to dust particles. These contaminated particles may be present in the air for weeks. (Have you ever viewed the air around you when you open the curtains on a sunny day?)...

• Laminar hoods should remain on 24 hours a day. If turned off for any reason, it should be on for at least 30 minutes and thoroughly cleaned before reusing.



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Laminar Flow Hoods

Laminar flow hood ready for first cleaning

• Number one rule: always think of the patient.

• A well thought out training program for aseptic technique should focus on safety and accuracy. Periodic retraining is advisable.

Array of syringes, needles and filters ready for assembly in the hood.



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Aseptic FDG production

W.F.I.

STERILE

EtOH

STERILE

0.3 M NaOH

STERILE

10 % NaCl

STERILE

Syringes, filters, needles, vials, etc…



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Dispensing Units• Once the

radiopharmaceutical is prepared, it must be dispensed.

• The dose may be prepared as a multi-injection vial which allows several doses to be drawn from a single container, or it may be dispensed into syringes to be used as a single unit dose

• Commercial dispensers are available for both these operations

• The type of enclosure for these operations is a matter for local regulations

• A simple hand dispenser is shown at right

Jong O Park et al ARI 2005



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Dispensing Units• At right is a commercial

dispensing unit which will prepare unit doses of FDG or any other radiopharmaceutical

• The unit is contained in a hot cell and is controlled by a PC on the outside of the hot cell

• Below: Dispenser for vials



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Dispensing Units

Below is the interior of the dispensing unit shown in the last slide.

Syringes being filled through sterilizing filter

Syringe in holder ready for packaging and shipping



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Material Airlocks• Integral to the working of a

cleanroom is the passage of material in and out of the clean environment. A pass-through must provide a tight seal between clean and non-clean areas and allow enough space for the passage of materials.

• Pass-throughs can be made in various sizes and fit in modular walls, drywall, block or other partitions. Options include shelves, stainless steel construction, mechanical or electrical interlocks, full vision doors or solid doors with windows. The can also be customized to include gas purge systems, water tanks, and other specialty requirements.



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QC Analytical Equipment• The Quality Control laboratory

will have two primary functions: to qualify the FDG bulk radiopharmaceutical; and to qualify raw materials and supplies used in production of FDG.

• The QC lab should be equipped with the typical analytical instrumentation, plus some specific equipment allowing performance of these tests

• The tests which are required to release a radiopharmaceutical such as FDG are outlined in the QC section and the instruments needed to carry out these test are listed at right

• The correlation diagram between the required test and the instrument are diagramed in the following slide.

Contents• Overview: QC of [18F]FDG• High Pressure Liquid Chro

matography• Radio-Thin Layer

Chomatography• Gas Chromatograph• pH Measurement• Osmolality• Gamma Spectrometer• Dose Calibrator• Membrane Filter Testing• Endotoxin testing



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QC of [18F]FDG

Identity

radionuclide

Chemical (molecule)

Purity

Radionuclidic

Chemical

Radiochemical

InjectabilitypH

Osmolality (isotonic?)

Biological Purity

EndotoxinSterility

Dose Calibrator

Radio-TLC

TLC

Radio-TLC

GC

Dose calibratorg-spectrometer

HPLC-UV

HPLC-g

pH-paper

Osmometer

LAL-test



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HPLCpH

TLC

Printer

QC laboratory for FDG

GC

It is possible to measure 15 QC parameters with 5 QC instruments in 30 min



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High Pressure Liquid Chromatograph

• The HPLC can be used both to separate the final product from the starting material and to measure radiochemical purity in quality control testing.

• It may also be used to test the radiochemical purity although here validation studies are required to ensure that there is quantitative recovery of the sample.

• Regardless of the use, both semi-preparative and analytical columns may be used in daily operations. The semi-prep columns can be used to purify product or starting material while the analytical columns will be used for QC.



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Thin Layer Radiochromatograph• Thin layer chromatography (TLC) is

used for both, determining the radiochemical identity and radiochemical purity of the final FDG product. A radioactivity scanner is required for quantitative measurement of the radioactivity distribution corresponding to the individual spots on TLC. The TLC plate can be either plastic or glass and is developed in the usual process in a developing tank.

• The TLC scanner can be either a gas proportional counter, phosphor or scintillation counter mounted so that the entire plate is scanned.

• It can also be used for doing routine separations for development of new radiotracers or improvements in synthetic procedures.



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Gas Chromatograph

• Identification and quantitation of the residual solvents (acetonitrile, and perhaps ethanol and ether) in the final product may need to be performed prior to release of the FDG.

• The test is performed with a gas chromatograph equipped with a flame ionization detector (FID) and an appropriate column (packed column or capillary column).

• An integrator with software to identify and quantitate the residual solvents is a useful feature and is generally supplied with the equipment.



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GC and TLC

• Placement of GC and TLC in typical Quality Control Laboratory

• Solvent analysis and radiochemcial purity

TLC scan results for FDG



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pH Measurement

• The measurement of pH is one on the requirements for release of the final product. The pH may be measured either with a pH meter or with pH paper.

• The latter method is preferred due to need for a smaller test sample. It is, however, necessary that the pH paper is validated for its suitability.

• A pH meter may also be required for other purposes in the lab.


http://upload.wikimedia.org/wikipedia/commons/0/0f/PH_Meter.jpg


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Osmolality

• A radiopharmaceutical preparation should ideally be isotonic (250-350 mOsm/kg is considered isotonic). In most cases, the product may be released without performing this test.

• An Osmometer is used for measurement of osmolality of the radiopharmaceutical solution. The equipment is calibrated with known standard prior to use.



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Gamma Spectrometer• To determine radionuclidic purity, a

gamma spectrometer is required. This will allow the determination of small amounts of a radionuclidic impurity in the final product.

• This can be carried out either before the release of the product, or as is more often the case with shorter lived radionuclides, this test is carried out at validation and if changes are made to the cyclotron target.

• A very simple gamma spectrometer is shown on the right

High purity germanium detector (HPGE)



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Dose Calibrator

• A dose calibrator is required for measurement of the radioactivity (radioassay) in the product vials to be dispatched to PET facilities.

• Dose calibrators are available from several commercial companies



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Membrane Filter Testing

• At majority of facilities, FDG is not sterilized with steam, but rather manufactured in aseptic conditions with final product being filtered through a membrane filter.

• Assessment of the membrane filter integrity is the indirect measure of sterility, which can be assessed through a relatively simple test measuring the point at which the filter allows nitrogen gas to pass through.

• There are automated systems as well as manual systems available for carrying out this test.



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Endotoxin Testing• The bacterial endotoxin test

(BET) is based on the formation of a gel clot by LAL reagent in the presence of endotoxins. The formation of the gel may be inspected manually or with use of a device known as endotoxin test reader.

• The test with endotoxin test reader is simpler and saves great deal of time, which is an important factor for quick release of the FDG radiopharmaceutical post production. The device is based upon turbidity or kinetic measurement. The test requires about 20 minutes and gives a more easily readable test result and assessment of the endotoxin level.

Typical endotoxin test reader is kit based



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General Laboratory Equipment

• General laboratory equipment may be required for a fully functional manufacturing facility. Not all equipment is listed here, and the planners need to envisage additional requirements.

• This equipment is identical to that used in any normal chemistry laboratory and needs the same care in selection and maintenance.

Contents• Fume Hoods• Balances• Refrigerators and Freeze

rs• Ovens and Incubators• Melting Point Apparatus



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Fume Hoods

• For environmental and personal protection from chemicals and volatile solvents, at least one fume hood should be available in the lab.

• Fume hoods should have no air recirculation and should be located as to minimize cross-drafts and turbulence. A face velocity of 0.5 - 0.6 m/sec (100-125 linear feet per minute) of air is typically required, and should be continuously monitored.

• Typical safety measures, including fire safety and prevention of small pieces from being sucked up the exhaust, etc. should be specified during selection of the equipment.

• The development of new synthetic procedures can also be carried out in these hoods as long as the amount of radioactivity is kept low and there is not a serious hazard of airborne radioactivity.



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Fume Hoods

Equipment type Consideration

Fume hood Use the bypass style. Don’t use auxiliary air hoods.

Located to minimize cross-drafts and turbulence.

Face velocity of 0.5 - 0.6 m/sec.

Needs a continuous face velocity monitoring device.

No fire dampers should be placed in the exhaust ducts.

Debris screen to prevent small pieces from being sucked up by the exhaust.

Single vertical sash.

Hood fire suppression system.

Visual or audible local alarm if regular alarm system cannot be heard inside the room.

Base should be strong enough to hold any shielding. Purchase of a shielded fume hood is an alternative.

Here are some general considerations for the choice of fume hoods



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Balances

• Balances are used to weigh out precursors, to make calibration standards and many other tasks in the laboratory

• Balances are preferably in a separate room from production (in the preparation room)

• Separate balances for production and QC are required by GMP guidelines.



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Refrigerators and Freezers

• Many of the reagents used in chemical synthesis are temperature sensitive and therefore must be kept refrigerated.

• Other supplies such as the pyrogen test kits are also temperature sensitive. Refrigerators should be specified for the required temperature range, and also sufficiently large to accommodate supplies necessary for the required lead time for procurements.

• Some supplies for synthesis (for example mannose triflate) may require storage at -20 ºC and if so a freezer will be necessary.

• A 24 hour continuous recording of the temperature (with an alarm) will ensure that the malfunction is detected quickly and does not detrimentally affect the stored material.



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Ovens and Incubators

• Ovens, incubators and sterilizers are required only if the facility plans to prepare sterile and pyrogen free product components (vials, stoppers, glassware), and also plans to perform sterility testing. Samples for testing sterility are kept in an incubator at 37°C prior to test for the presence of bacteria in the product.



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Melting Point Apparatus• Assessment of the melting point could be used as an

identification test for reagents used in FDG manufacturing. A melting point apparatus may be required for qualification of these materials.

• It is necessary that the equipment is calibrated with primary standards with known melting points.


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Documents

production hot cells

number of hot cells

air pressure

minute of air

air recirculation

required lead time

freezers ovens

production capacity