New quality assurance standards for the production and compounding of Positron Emission Tomography (PET) drugs are being proposed by the US Pharmacopeial Convention (USP)-the scientific, non-profit organization responsible for establishing quality standards for pharmaceutical products marketed in the United States. USP is seeking public comment on revisions to General Chapter <823>, Radiopharmaceuticals for Positron Emission Tomography-compounding, until March 31, 2011.
Used to aid in diagnosing disease and assessing specific health concerns, PET drugs are radioactive drugs administered to patients so that a specialized scanner can take images of internal organs and tissues. Unlike X-ray or MRI images, which show only body structure, PET images show the chemical functioning of organs or tissues. PET drugs contain a small amount of radioactive material and must be administered to patients within a few hours of being produced, making it necessary for drug production to occur as needed in a manner that ensures their identity, strength, quality and purity.
Most individual PET drug monographs and chapters in USP-NF were published in the 1990s. Although PET drugs primarily were developed as research and investigative tools, the environment in which they have been produced and used over the last decade has changed significantly. This includes: expanded use and supply of PET drugs in routine diagnostic imaging; the potential use of PET imaging agents as tools to accelerate and reduce the cost of traditional drug discovery efforts; and the development of new routine diagnostic imaging agents for use in cardiology, oncology and neurology. Diversification of PET production and use prompted USP to review trends and changes in this area, which led to the conclusion that the current version of Chapter <823> does not fully meet the needs of today's PET drug environment.
Among the areas addressed by the proposed revisions to General Chapter <823> are: differences between the organization of <823> and the provisions of the Food and Drug Administration (FDA) Final Rule and Guidance issued for PET drugs in 2009 Defined frequency for certain quality control tests, timing of completion of certain QC tests relative to product release, given the short time frame in which a PET drug must be administered after its production Inclusion of requirements for out-of-specification (OOS) investigations for QC tests.
Whatever version of <823> is current is always applicable, with compendial requirements enforceable by FDA under the adulteration provisions of the Federal Food, Drug, and Cosmetic Act (FDCA 501(b)). However, USP's PET standards also have a special role under FDA's Current Good Manufacturing (CGMP) requirements. When the FDA Modernization Act became law in 1997, it required that PET drugs be compounded according to USP monographs and general chapters until FDA established CGMP regulations for PET.
In 2005, FDA issued a proposed rule for PET CGMP and indicated that different CGMP requirements should be applied to investigational and research PET drugs to allow more flexibility during the development of these drugs. FDA determined that <823> would be adequate to ensure that investigational and research PET drugs are produced safely. In 2009, FDA issued final regulations and an accompanying guidance document for PET CGMP. The new CGMP requirements are codified in the Code of Federal Regulations Title 21 Part 212 (Part 212) and are aimed at PET drugs with marketing-approval status or potential (as opposed to those for investigational or research use).
When Part 212 becomes effective on December 12, 2011, the CGMP requirements for investigational and research PET drugs may be met by complying with either Part 212 or USP's General Chapter <823> (1998 version). All other PET drugs (not for investigational or research uses) are expected to meet CGMP stipulations of Part 212. Based on the feedback received during the public comment period, USP will determine whether additional review of the <823> revisions will be necessary or if the chapter is then suitable for publication. Once the revised <823> is published, USP will petition FDA to update its reference to cite the newly revised version in its regulation. Until that is accomplished, investigational and research PET drug manufacturers will have to comply with the 1998 version of <823> or the Code of Federal Regulations Title 21 Part 212 to meet CGMP requirements.
The United States Pharmacopeial Convention (USP) is a scientific, non-profit, standards-setting organization that advances public health through public standards and related programs that help ensure the quality, safety, and benefit of medicines and foods. USP's standards are relied upon and used worldwide.
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