Overview of FDA's Regulatory Framework for PET Drugs

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

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 FDAs
  thinking regarding compliance with the new PET
  CGMP requirements

3
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/05-18509.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• Draft Guidance on CGMP for PET drugs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• Draft guidance available at http//www.fda.gov/OHR
  MS/DOCKETS/98fr/98d-0266-gdl0002.pdf

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

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 lt823gt) and the official
  monograph for the PET drug (i.e., USP monograph)

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

7
Applicability of PET CGMP Regulations21 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 lt823gt

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

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

10
Laboratory Controls - Current Thinking

• Establish specifications for each PET drug
  product
• Critical quality attributes (CQA) that are
  indicative of products 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 products
  marketing application

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

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 manufacturers
  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

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 sponsors 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
• dmfquestion_at_cder.fda.gov.
• All inquiries MUST have an entry in the "Subject"
  field of the e-mail.
• 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?

• newdrugcmc_at_fda.hhs.gov
• Inquiries should have an entry in the "Subject"
  field of the e-mail indicating the subject of the
  question.