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The preparation and quality control of diagnostic radiopharmaceuticals labeled with the very short-lived positron-emitting nuclides (e.g.,15O, 13N, 11C and 18F having half-lives of 2, 10, 20, and 110 minutes, respectively), are subject to constraints different from those applicable to therapeutic drugs: (1) Synthesis must be rapid, yet must be arranged to protect the chemist or pharmacist from excessive radiation exposure. (2) Except to a limited extent for 18F, synthesis must occur at the time of use. (3) With the exception of 18F, each batch of radiopharmaceutical generally leads to only a single administration.
These factors raise the importance of quality control of the final drug product relative to validation of the synthesis process. Since with few exceptions every dose is individually manufactured, ideally every dose should be subjected to quality control tests for radiochemical purity and other key aspects of quality before administration. Because quality testing of every batch is not possible, batches are selected at regular intervals for examination to establish and completely characterize their radiopharmaceutical purity. This routine and thorough quality testing of selected batches forms the basis of process validation, which is absolutely essential for prospective assessment of batch quality and purity when dealing with such extremely short-lived radiopharmaceuticals. Since radiopharmaceuticals used in positron emission tomography (PET) are administered intravenously or (for radioactive gases) by inhalation, batch-to-batch variability in bioavailability is not an issue. Furthermore, the very small scale of radiopharmaceutical syntheses (almost always less than 1 milligram and often in the microgram range) and the fact that patients generally receive only a single dose of radioactive drug minimize the likelihood of administering harmful amounts of chemical impurities. These statements are not intended to contest the need for quality control in the operation of automated synthesis equipment, but to place the manufacture of positron-emitting radiopharmaceuticals in an appropriate perspective and to reemphasize the overwhelming importance of prospective process validation and finished product quality control.
The routine synthesis of radiopharmaceuticals can result in unnecessarily high radiation doses to personnel. Automated radiochemical synthesis devices have been developed, partly to comply with the concept of reducing personnel radiation exposures to “as low as reasonably achievable” (ALARA). These automated synthesis devices can be more efficient and precise than existing manual methods. Such automated methods are especially useful where a radiochemical synthesis requires repetitive, uniform manipulations on a daily basis.
The products from these automated radiosynthesis devices must meet the same quality assurance criteria as the products obtained by conventional manual syntheses. In the case of positron-emitting radiopharmaceuticals, these criteria will include many of the same determinations used for conventional nuclear medicine radiopharmaceuticals, for example, tests for sterility and bacterial endotoxins. Many of the same limitations apply. Typical analytical procedures such as spectroscopy are not generally applicable because the small amount of product is below the minimum detection level of the method. In all cases, the applicable Pharmacopeial method is the conclusive arbiter (see Procedures under Tests and Assays in the General Notices).
Preparation of Fludeoxyglucose F 18 Injection and other positron-emitting radiopharmaceuticals can be adapted readily to automated synthesis. In general, the equipment required for the manual methods is simpler and less expensive than that used in automated methods but is more labor-intensive. Of special concern are the methods involved in validating the correct performance of an automated apparatus. For a manual procedure, human intervention and correction by inspection can nullify many procedural errors. In an automated system, effective feedback also can begin during the synthesis. For example, radiation detectors can monitor activity at various stages of radiosynthesis. Failure to obtain the appropriate activity could activate an alarm system that would lead to human intervention.

Radiochemicals versus Radiopharmaceuticals—
It is appropriate to draw a distinction between a radiochemical and a corresponding radiopharmaceutical. In research PET centers, automated equipment is used to prepare labeled compounds for animal experiments. These radiochemicals are not regarded as radiopharmaceuticals if (1) they are not prepared according to a validated process that provides a high degree of assurance that the preparation meets all established requirements for quality and purity; and (2) have not been certified by qualified personnel (licensed pharmacists and approved physicians) in accordance with published Pharmacopeial methods for individual radiopharmaceuticals.

Automated Equipment—
The considerations in this chapter apply to synthesis conducted by general purpose robots and by special purpose apparatus. Both are automated devices used in the synthesis of radiochemicals. The exact method of synthesis device control is variable. Both hard-wired and software-controlled synthesis devices fall under the general designation, and there is a spectrum ranging from traditional manual equipment through semi-automated devices to completely automatic devices.
Common Elements of Automated Synthesis Equipment— To manipulate a chemical apparatus to effect the synthesis of a radiochemical, control of parameters such as time, temperature, pressure, volume, and sequencing are needed. These parameters can be monitored and constrained to fall within certain bounds.

Equipment Quality Assurance—
The goal of quality assurance is to help ensure that the subsequent radiopharmaceutical meets Pharmacopeial standards. Although the medical device good manufacturing practice regulations (21 CFR 820) are not applicable, they may be helpful in developing a quality assurance program. As a practical matter this involves documented measurement and control of all relevant physical parameters controlled by the synthesis apparatus.

Routine Quality Control Testing—
Routine quality control testing of automated equipment implies periodic testing of all parameters initially certified during the quality assurance qualification. Depending on the criticality and the stability of the parameter setting, testing may be as often as daily. This process performance assessment must be augmented by regular end product testing. For example, variations in the temperature of an oil bath may be acceptable if the radiochemical (end product) can be shown to meet all relevant testing criteria.

Reagent Audit Trail—
Materials and reagents used for the synthesis of radiopharmaceuticals should conform to established quality control specifications and tests. Procedures for the testing, storage, and use of these materials should be established. In this context, a reagent is defined as any chemical used in the procedure leading to the final radiochemical product, whereas materials are defined as ancillary supplies (tubing, glassware, vials, etc.). For example, in some processes compressed nitrogen is used to move liquid reagents. In this case, both the nitrogen and the tubing should meet established specifications.

Documentation of Apparatus Parameters—
Key synthesis variables should be identified, monitored, and documented. These characteristics include meaningful physical, chemical, electrical, and performance attributes. A method for specifying, testing, and documenting computer software and hardware is especially important for microprocessor- and computer-controlled devices. This program should include periodic generalized testing of the computer hardware. In addition, the software program code should be periodically examined to determine that it has not been modified and that it continues to result in the final product's meeting all specifications. In-process feedback is one means of confirming that the synthesis is under control. Changes to the software code should involve a formal authorization procedure, and changes should be documented.
Each type of radiochemical synthesis device requires a set of specific procedures for testing and monitoring the reliability and reproducibility of the various subsystems that make up the total synthesis system.
It is essential that calibration of each of the components be confirmed according to an established maintenance timetable and that measurements or monitoring be made under actual synthesis conditions.
Delivery times, reagent volumes, temperatures, gas pressures, and rates of flow need to be measured and shown to be stable and reproducible within established limits. Delivery of the reagents and solvents needs to be calibrated periodically. Other components to be routinely calibrated include the radiation detection system and process monitoring sensors and system.
For illustration, elements of system validation of several representative components of an automatic synthetic device are as follows:
Reaction vessels may be cleaned and inspected by an established documented method. The vessels themselves may be numbered and their performance tracked.
Heating and cooling systems (such as oil baths) may be monitored by thermometers or thermocouples. The temperatures may be recorded in a batch sheet, or they may be automatically printed out as part of a computerized log. Maintenance involves periodic calibration.
Gases and gas delivery system performance may be tracked by pressure gauges and flowmeters. Gas purity may be established via supplier certificates of analysis or may be verified by independent testing. Maintenance of gauges and flowmeters involves periodic calibration with standards.
Position-dependent motor performance may be verified by limit switches. Maintenance could involve actual measurement of distance traversed and elapsed time.
Solenoid valves may be checked electrically, by flow and pressure tests.
Heater output is evidenced by proper thermocouple readings. Additional tests could involve resistance measurements.
Reagents may be accepted on the basis of suppliers' certificates of analysis. Alternatively, the chemical could be tested in-house or sent to an independent testing laboratory. Periodic retesting may be necessary depending on stability.
Computer programs may be tested by documenting elapsed time of synthesis, with printouts verifying that all appropriate manipulations occurred, including printing of relevant parameters such as times, temperature, pressures, and activities.
Patterns of activity distribution such as absolute amount of product, percentage yield, and individual impurity activity levels afford the experienced user an opportunity to discern systems failures.

Changes in the Synthesis Method—
Some changes in the synthesis apparatus can be considered to be trivial. This category would often include changes not affecting any of the monitored parameters. However, it is important that care be taken to ensure that seemingly innocuous changes do not have an unexpected impact. For example, changes in a comment line of a computer program may result in inadvertently changing or deleting a vital instruction. Any changes in monitored parameters have the potential for changing the process output. If the resultant radiochemical does not meet specifications or if the subsequent radiopharmaceutical does not meet Pharmacopeial criteria, the process change is unacceptable; the fault must be corrected and the process revalidated.

Auxiliary Information—
Staff Liaison : Andrzej Wilk, Ph.D., Senior Scientific Associate
Expert Committee : (RMI05) Radiopharmaceuticals and Medical Imaging Agents 05
USP29–NF24 Page 2801
Phone Number : 1-301-816-8305