General Chapter <823>
Posting Date: 26–Jan–2011
What is General Chapter <823> ?
General Chapter <823>, Radiopharmaceuticals for Positron Emission Tomography (PET)—Compounding, provides quality assurance standards for compounding of PET drugs in the United States. General Chapter <823> was originally published in 1998 in the U.S. Pharmacopeia 23 —National Formulary 18 (USP 23–NF 18), 8th Supplement. Monographs for individual drugs and dosage forms as well as general chapter guidelines are published in USP–NF, the print and online compendium of official quality standards for drugs in the United States.
How are the provisions of General Chapter <823> enforced?
The 1997 Food and Drug Administration Modernization Act (FDAMA) added a provision to the Federal Food, Drug, and Cosmetic Act (FDCA) stipulating that a compounded PET drug is adulterated unless the methods used in, or the facilities and controls used for its production are in conformity with USP compounding standards (including <823>) and official monographs for PET drugs. (This is described in FDCA 501(a)(2)(C).) In addition, under a separate longstanding provision of the FDCA, to avoid being deemed adulterated drugs recognized in USP–NF must also comply with compendial identity standards, as well as compendial standards for strength, quality, and purity, as set forth in applicable USP monographs and General Chapters. (This is described in FDCA 501(b).) USP has no role in enforcement, which is the responsibility of FDA and other government authorities.
Why is General Chapter <823> being revised?
At the time that monographs and chapters for PET drugs were published by USP in the 1990s, most PET drugs were produced and used within research or medical institutions. Since that time, the environment in which PET drugs are produced and used has changed significantly. This has included the 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. This diversification prompted USP to review trends and changes in the PET environment, which led to the conclusion that the current version of General Chapter <823> does not meet the needs of today's PET drug environment.
What are some of the areas addressed by the revisions to Chapter <823>?
- Differences between the organization of <823> and the provisions of the FDA Final Rule and Guidance issued for PET drugs in 2009
- Defined frequency for certain quality control (QC) 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.
To better understand the changing landscape of the PET environment, USP jointly sponsored two symposia with the Society of Nuclear Medicine in 2008 and 2009. Members of the USP Radiopharmaceutical and Medical Imaging Agents Expert Committee (RMI EC) and USP staff presented talks and led discussions on the topic in order to gather feedback from the PET community about USP general chapters on PET drugs. The RMI EC concluded that these chapters needed to be revised, identifying specific areas for updating in the current version of <823>. To ensure updates were thorough and accurate, the RMI EC proposed the establishment of an Ad Hoc Advisory Panel composed of academic and industrial members of the PET community. The Panel was given the charge of advising RMI EC on suitable revisions to <823> in accordance with USP's mission, and the outcome of this effort is the Proposed Revision to USP General Chapter <823>
How can I be involved in the General Chapter <823> revision process?
USP invites and encourages practitioners involved in PET production and compounding in the fields of nuclear medicine, radiology, diagnostic imaging and related fields to review the proposed revisions to General Chapter <823> and provide comments to USP823@usp.org by March 31, 2011.
In 2009, FDA issued final regulations and an accompanying guidance document to establish specifically tailored current good manufacturing practice (CGMP) requirements for PET drugs to accommodate the unique nature of these drugs and their production process. 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. 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 General Chapter <823> as published in USP 32–NF 27. All other PET drugs (not investigational or research uses) are expected to meet CGMP stipulations of Part 212.
The open period for public comment to the proposed revisions to General Chapter <823> will end on March 31, 2011. Based on the feedback received, USP will determine whether additional review will be necessary or if the chapter is then suitable for publication. Upon completion of the review process, the revised General Chapter <823> will be published. As of the official date specified for the updated <823>, all of the new standards will be considered applicable by USP. In terms of legal recognition, with regard to the CGMP implications, upon publication USP intends to petition FDA to update the reference in its regulation. Until that is accomplished, investigational and research PET drug manufacturers will have to comply with the Chapter <823> as published in USP 32–NF 27 or the Code of Federal Regulations Title 21 Part 212 to meet CGMP requirements. All other PET drugs (not for investigational or research uses) are expected to meet CGMP stipulations of Part 212.
The stopper must be removed by contacting only sterile surfaces, e.g., sterile forceps. If stopper and content removal occur within an ISO Class 5 environment, and if the vial is one of three or fewer sterile ingredients, then this qualifies as either a Low-risk Level CSP or a Low-Risk Level CSPs with 12-Hour or Less BUD, depending on whether or not the primary engineering control, PEC or ISO Class 5 source is located in an ISO Class 7 buffer area. If the vial is one of more than three sterile ingredients, then this requires compliance with Medium-Risk Level CSPs standards. If the stopper is removed by contacting only sterile surfaces in worse (dirtier) than an ISO Class 5 environment, then this qualifies as an Immediate-Use CSP.
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