The preparation and quality control of diagnostic radiopharmaceuticals labeled with the very short-lived positron-emitting nuclides (e.g.,15O,13N,11Cand 18Fhaving half-lives of 2,10,20,and 110minutes,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 1milligram 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 Proceduresunder Tests and Assaysin the General Notices).

Preparation of Fludeoxyglucose F18Injection 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.

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.