Transcript Slide 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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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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Current Status
• Proposed CGMP regulations for PET drugs
– Federal Register: September 20, 2005 (Volume 70,
Number 181), 55038
– http://www.fda.gov/OHRMS/DOCKETS/98fr/0518509.pdf
• Draft Guidance on CGMP for PET drugs
– Notice of availability - Federal Register: September
20, 2005 (Volume 70, Number 181), 55145
– Draft guidance available at
http://www.fda.gov/OHRMS/DOCKETS/98fr/98d0266-gdl0002.pdf
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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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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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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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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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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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Proposed 21 CFR 212
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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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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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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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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-tobatch 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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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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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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IND Resources
• Regulations: 21 CFR 312
• Guidance:
– Content and Format of Investigational New Drug
Applications (INDs) for Phase 1 Studies of Drugs
• http://www.fda.gov/cder/guidance/phase1.pdf
– INDs for Phase 2 and Phase 3 Studies Chemistry,
Manufacturing, and Controls Information
• http://www.fda.gov/cder/guidance/3619fnl.pdf
– IND Meetings for Human Drugs and Biologics
Chemistry, Manufacturing and controls Information
• http://www.fda.gov/cder/guidance/3683fnl.pdf
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Drug Master Files (DMF) Resources
• Guidance:
– Guideline for Drug Master Files
• http://www.fda.gov/cder/guidance/dmf.htm
• Send all comments or questions regarding DMFs to
– [email protected].
– All inquiries MUST have an entry in the "Subject" field of the email.
• Current DMF submission address:
Food and Drug Administration
Center for Drug Evaluation and Research
Central Document Room
5901-B Ammendale Road
Beltsville MD 20705-1266
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New Drug CMC Questions?
[email protected]
• Inquiries should have an entry in the "Subject"
field of the e-mail indicating the subject of the
question.
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