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
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2. PET Drug Regulatory Framework
PET Drug Current Good Manufacturing Practice (CGMP) Regulations
New Drug Application (NDA)
Abbreviated New Drug Application (ANDA)
Investigational / Research Studies with PET Drugs
Drug Master Files (DMF)
Other PET Drug Information Resources
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3. PET CGMP Regulations
FDA issued final rule for CGMP for PET drugs (21 CFR part 212) in the Federal Register of December 10, 2009 (74 FR 65409).
FDA also announced the availability of a guidance entitled ‘‘PET Drugs—Current Good Manufacturing Practice (CGMP)”.
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4. CGMP Rule and Guidance Availability
PET CGMP Rule and Guidance are available at
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5. PET Drugs Regulatory Framework
The 21 CFR part 212 regulation is effective December 12, 2011.
The regulation will become mandatory for PET drug production on this day.
Starting on this date, FDA will require the submission of a new drug application (NDA) or abbreviated new drug application (ANDA) for any PET drug product marketed for clinical use in the United States.
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6. Applicability of PET CGMP Regulations 21 CFR 212
Current good manufacturing practices for PET drug products are the minimum requirements for the methods to be used in, and the facilities and controls used for, the production, quality control, holding, or distribution of a safe and effective PET drug product intended for human use.
After Dec 12, 2011, 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 21 CFR 212.
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7. PET Drugs-IND and RDRC
Producers of investigational PET drugs (IND) and research PET drugs (RDRC):
Option to follow the requirements in part 212 or to produce PET drugs in accordance with USP Chapter <823> ‘‘Radiopharmaceuticals for Positron Emission Tomography— Compounding,’’ (USP 32/NF 27) (2009).
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8. Current Regulation for PET Drug Production
Under section 501(a)(2)(C) of the Act, a compounded PET drug is adulterated unless it is produced in compliance with the USP’s PET drug compounding standards and the official monograph for the particular PET drug.
As per the Modernization Act (section 121(b)), section 501(a)(2)(C) of the Act will expire after Dec 11, 2011.
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9. Investigational Studies
All human investigational / research studies must be performed:
Under an IND (21 CFR 312)
As RDRC approved study (21 CFR 361)
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10. 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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11. Laboratory Controls 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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12. Laboratory Controls 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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13. 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 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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14. Final Release
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
The manufacturer must have a mechanism to recall (prevent administration to a human subject) the lot that fails testing
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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15. Drug Registration and Listing of PET Drug Producers
All PET drug producers are required to register before December 12, 2011
Submit drug establishment and drug listing information through electronic submissions
Website for information
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16. NDAs and ANDAs
FDA intends to soon finalize the guidance, “PET drug Applications – Content and Format for NDAs and ANDAs”.
Draft guidance website:
Provides information to assist in preparing NDAs and ANDAs for certain PET drugs (Fludeoxyglucose F 18 injection, Sodium fluoride F 18 injection and Ammonia N 13 injection).
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17. Types of NDAs
505(b)(1) – studies submitted for seeking approval are performed by the applicant.
505(b)(2) - rely for approval on references to studies conducted by others and/or on published literature.
Applicants submitting 505(b)(2) NDAs for PET drugs can rely on the FDA's review of the literature as described in the PET Safety and Effectiveness Notice (65 FR, 12999) and/or on previous approvals of PET drugs for certain indications.
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18. Content and Format of NDAs
Current preferred format for submitting an application is the Common Technical Document (CTD)
Paper CTD or
electronic CTD (E-CTD) format
The items cited in the PET NDA / ANDA guidance should be organized in a manner which corresponds to the modules of the CTD as indicated on the Checklist
Guidance:
Submitting Marketing Applications According to the ICH-CTD Format —General Considerations
M4Q: The CTD — Quality; M4: The CTD — Quality Questions and Answers/ Location Issues
website:
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19. ANDAs ANDA is submitted for a drug that is same as RLD
Approved NDAs (RLDs) exist for:
Fludeoxyglucose F 18 injection
Sodium fluoride F 18 injection
Ammonia N 13 injection
Same means that the proposed drug has identical
Active ingredient(s),
Dosage form,
Strength,
Route of administration,
Conditions of use as its RLD (with certain exceptions)
Is bioequivalent to that RLD
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20. ANDA RESOURCES Office of Generic Drugs (OGD) webpage:
Current preferred format for submitting an application to the OGD is the Common Technical Document (CTD)
Paper CTD or
electronic CTD (E-CTD) format
The twelve items cited in the PET NDA /ANDA guidance should be organized in a manner which corresponds to the modules of the CTD as indicated on the Checklist
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21. ANDA Questions? Contact the Office of Generic Drugs:
Martin H. Shimer
Branch Chief, Regulatory Support Branch
FDA, Office of Generic Drugs
240 ( )
Submit completed application to:
Director, Office of Generic Drugs
Center for Drug Evaluation and Research
Food and Drug Administration
Metro Park North II, Rm. 150
7500 Standish Place
Rockville, MD
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22. 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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23. NDA and IND Questions?
Kyong "Kaye" Kang, Pharm. D. Chief, Project Management Staff Division of Medical Imaging and Hematology Products Office of Oncology Drug Products (301) (office) (301) (fax)
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24. Drug Master File (DMF)
A DMF contains information about a drug substance, a component, or a container/closure system that is proprietary (i.e., belongs to someone else)
Type II - Drug substance, drug substance intermediate, and materials used in their preparation, or drug product
Type III - Packaging materials
Type IV - Excipient, colorant, flavor, essence, or materials used in their preparation
Type V - FDA accepted reference information
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25. Drug Master File (DMF)
The information may not be available to you, but you may need it as part of your NDA, ANDA.
The chemistry section of Form FDA 356h may ask you to provide this information.
This information is usually available from the supplier or manufacturer of the subject of the DMF.
Rather than providing the information directly to you, the manufacturer may choose to hold a DMF. The DMF holder provides the information directly to the FDA (submits DMF to FDA).
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26. DMF Reference
If a manufacturer holds a DMF that you would like to reference, you should ask them to provide you with a letter of authorization (LOA), which you must include with (and reference in) your application and list on your Form 356h.
LOA from the DMF holder grants the FDA authorization to refer to information in their DMF during the review of your NDA, ANDA or IND.
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27. Drug Master Files (DMF) Resources
The regulatory requirements for a DMF-21 CFR
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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28. Web Resources for You
NDA
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29. Web Resources for You ANDA
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30. Web Resources for You IND
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31. User Fees Waiver, Reduction, Refund or Questions
Michael Jones Food and Drug Administration New Hampshire Ave, Building 51, Room 6216 Silver Spring, MD Phone: Fax:
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32. Conclusion PET Drug Regulatory Framework CGMP NDA ANDA IND and RDRC
DMF
Resources for Submitting and application to CDER / FDA
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33. 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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