1. Overview of FDA's Regulatory Framework for PET Drugs
Ravindra K. Kasliwal, Ph.D.
Office of New Drug Quality Assessment
Center for Drug Evaluation and Research
U. S. Food and Drug Administration
SNM June 2009

2. Background
As mandated by Section 121(c)(1)(A) of FDAMA (1997), FDA has been developing CGMP regulations for PET drugs under 21 CFR 212
Concurrently, a guidance is being developed to help PET drug producers better understand FDA’s thinking regarding compliance with the new PET CGMP requirements
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3. Current Status Proposed CGMP regulations for PET drugs
Federal Register: September 20, 2005 (Volume 70, Number 181), 55038
Draft Guidance on CGMP for PET drugs
Notice of availability - Federal Register: September 20, 2005 (Volume 70, Number 181), 55145
Draft guidance available at
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4. Current Status – Rule and Guidance
The rule and guidance are not yet finalized and published by FDA
FDA intends to finalize and publish the rule and guidance
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5. Current Status of PET Drugs
Section 501(a)(2)(C) of the Federal Food, Drug, and Cosmetic Act (the Act):
A compounded PET drug is adulterated unless it is produced in compliance with USP compounding standards (i.e., Chapter <823>) and the official monograph for the PET drug (i.e., USP monograph)
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6. Status of PET Drugs
Section 501(a)(2)(C) will expire 2 years after the date on which FDA establishes approval procedures and CGMP requirements for PET drugs
After which compliance with the PET CGMP regulations will be required
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7. Applicability of PET CGMP Regulations 21 CFR 212 -Current Thinking-
Part 212 will apply to the production, quality control, holding and distribution of PET drugs
Producers of investigational PET drugs and research PET drugs (for human administration)
Option to follow the requirements in part 212 or to produce PET drugs in accordance with USP Chapter <823>
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8. Applicability of PET CGMP Regulations -Current Thinking-
PET drugs, other than investigational and research PET drugs, must meet the regulatory requirements set forth in finalized 21 CFR 212
PET drugs marketed under an approved new drug application (NDA) or an approved abbreviated new drug application (ANDA) must be produced in accordance with the requirements in finalized 21 CFR 212
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9. Proposed 21 CFR 212 Subpart A - General Provisions
Subpart B - Personnel and Resources
Subpart C - Quality Assurance
Subpart D - Facilities and Equipment
Subpart E - Control of Components, Containers, and Closures
Subpart F - Production and Process Controls
Subpart G - Laboratory Controls
Subpart I - Packaging and Labeling
Subpart J - Distribution
Subpart K - Complaint Handling
Subpart L - Records
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10. Laboratory Controls - Current Thinking
Establish specifications for each PET drug product
Critical quality attributes (CQA) that are indicative of product’s safety and effectiveness
Before final release, conduct an appropriate laboratory determination to ensure that each batch of a PET drug product conforms to specifications, except for sterility
Sterility is assured by process monitoring and controls, and confirmed by end product testing (sterility test should be started within 30 hours of end of production).
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11. Laboratory Controls - Current Thinking
Appropriate laboratory determination could involve
Finished product testing of each batch
In-process testing of an attribute that is equivalent to the finished-product testing of that attribute
Continuous process monitoring of one or more attributes with statistical process controls
QbD, PAT
Some combination of the above approaches
Approach should be set forth in the product’s marketing application
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12. Non-Critical Quality Attributes
Some product attributes may not be critical to the safety or efficacy of the product, but nevertheless are important in assessing the ongoing quality of the product and to assure that the manufacturing process is in control
Radionuclidic purity (sometimes)
Certain non-toxic solvents (Class 3 residual solvents)
When justified, these could be tested as periodic quality indicator tests (PQIT)
Performed at predetermined intervals rather than on a batch-to-batch basis
Included in product's marketing application - listed separately from the specification
Established and refined under firm's internal quality system
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13. Final Release - Current Thinking
Final release can only occur after the completion of laboratory determination to ensure conformance to specifications (except for sterility)
A product can be shipped under manufacturer’s control while certain tests are undergoing
Results must be available and meet the acceptance criteria before final release is granted and the product is administered to a human subject
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14. Multicenter Clinical Trials of PET Radiopharmaceuticals -CMC Information / Data-
File site-specific CMC information and data in the IND submitted by the sponsor
PET drug producer provides complete information / data to the IND sponsor, who then submits this to the IND.
File CMC information and data in DMF with FDA
PET drug producer submits a DMF to the FDA
Letter of Authorization (LOA) – DMF holder submits a copy with the DMF, sponsor files LOA with IND
DMF must be filed with FDA before it is referenced in an application
IND sponsor’s responsibility
Must determine that products from different sites are equivalent
Has overall responsibility for the conduct of research
Must be in control of conduct of IND research at different sites
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15. IND Resources Regulations: 21 CFR 312 Guidance:
Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs
INDs for Phase 2 and Phase 3 Studies Chemistry, Manufacturing, and Controls Information
IND Meetings for Human Drugs and Biologics Chemistry, Manufacturing and controls Information
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16. Drug Master Files (DMF) Resources
Guidance:
Guideline for Drug Master Files
Send all comments or questions regarding DMFs to
All inquiries MUST have an entry in the "Subject" field of the .
Current DMF submission address:
Food and Drug Administration Center for Drug Evaluation and Research Central Document Room B Ammendale Road Beltsville MD
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17. New Drug CMC Questions? newdrugcmc@fda.hhs.gov
Inquiries should have an entry in the "Subject" field of the indicating the subject of the question.
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