PET standardization and site qualification, Revised

March 18, 2017

PET standardization and site qualification

The Japanese Society of Nuclear Medicine (JSNM) established the Molecular Imaging Strategic Committee (MISC) in February 2010 to raise the quality of PET research in Japan and, thereby, to facilitate regulatory approval of PET drugs and their synthesizing devices. MISC has issued guidelines and standards on PET drugs and their in-house production as well as on the PET scanning protocols. MISC has also launched two site qualification programs: “PET drug manufacturing site qualification” and “PET imaging site qualification”. These programs now managed by the JSNM PET Committee, which is also in charge of education, training and qualification of individuals on PET.

JSNM standards and qualification on in-house PET drugs:

Japan has two special rules of PET drug regulation. First, in-house PET drug, which is the PET drug produced and used within a hospital/clinic, is out of the regulation by Pharmaceutical Affairs Law as a drug. No regulatory approval is required as a drug. No GMP is applied, nor JP (Japanese Pharmacopeia). On the other hand, commercially delivered PET drug should be regulatory approved as a drug. Second, radiosynthesizer (also called radiosynthesizing device or box) used for in-house production of PET drugs is subject to regulatory approval as a medical device. For a synthesizer to be approved, not only the PET drug that comes out of the device should have appropriate quality but also the PET drug itself should have sufficient safety and efficacy to be used in clinical practice. Therefore, it is virtually equivalent to approval of the PET drug itself. It is noted that unapproved synthesizers can be used for clinical research and clinical trials.

Because of these regulations, the hospital/clinic is totally responsible for the in-house PET drug, and the process of in-house production is not under direct control of the regulatory authorities nor supervised by the vendor of the synthesizer. Therefore academic society has issued guidelines on the in-house produced PET drugs. It was 1981 that the initial guideline on the in-house PET drug were issued by a committee in JRIA (Japan Radioisotope Association), which was subsequently revised several times to include a total of 15 PET drug monographs. However, as a matter of course, the JRIA committee’s guideline was not based on GMP. In view of the global trend toward GMP, JSNM talked with the regulatory authorities and decided to take over the JRIA committee’s role in this field. As a result, JSNM published its own quality assurance standard on in-house PET drug production (JSNM’s GMP) in 2011 and in-house PET drug standards (JSNM’s PET drug standards) in 2012. They have gone through revisions, and the current versions are posted on the JSNM web site in Japanese.

JSNM’s GMP is similar to cGMP by FDA in principle and is applicable to clinical research requiring high quality assurance. JSNM’s GMP is also applicable to clinical practice using a designated PET drug produced with a designated regulatory-approved synthesizer, for which 18F-florbetapir, 18F-flutemetamol and 18F-florbetaben are designated together with their respective approved synthesizers now. The JSNM’s PET drug standards consist of general chapters on the QC tests of PET drugs and monographs for a number of PET drugs. The current version contains monographs for 11C-methionine and 18F-NaF in addition to the above three amyloid PET drugs.

JSNM has launched a PET drug manufacturing site qualification program, in which the site is audited by the designated auditing organization for being compliant with JSNM’s GMP as well as for the process validation data of the in-house production of a specific PET drug. Based on the audit, the site is qualified for JSNM’s GMP-based in-house production of the PET drug.
JSNM standards and qualification on PET scanning:

Image quality and quantitative capability of PET data depends on the PET camera model and the details of PET scanning methods including subject preparation, injection activity, accumulation time, scan time, and reconstruction parameters. Therefore, standardization of the PET imaging protocol is essential for making PET a universal tool of patient diagnosis and management as well as evaluation of pathophysiology and treatment response. The camera and scanning parameter should also be qualified by phantom tests based on the physical image performance.

JSNM has issued the standard PET imaging protocols for a number of PET scans including 11C-methionine PET for brain tumor, brain PET with FDG and amyloid agents, and whole-body FDG scan. JSNM has also determined the phantom test procedures and criteria for standardization between different cameras. JSNM has further launched a site qualification program that qualifies PET imaging sites and their cameras for their capability of standardized PET imaging of high quality. A site is qualified based on an audit by the designated auditing organization, which examines the organizational structure, maintenance and calibration of devices, and the phantom data for specific PET scans on specific PET cameras. The following link describes an executive summary of the standard PET imaging protocols as well as phantom test procedures and criteria.