SNM June 2009 1

Overview of FDA's Regulatory Framework for PET Drugs

Ravindra K. Kasliwal, Ph.D.

Office of New Drug Quality AssessmentCenter 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/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• Draft Guidance on CGMP for PET drugs– Notice of availability - Federal Register: September

20, 2005 (Volume 70, Number 181), 55145– Draft guidance available at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/OHRMS/DOCKETS/98fr/98d-0266-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 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 <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

• 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-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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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– dmfquestion@cder.fda.gov. – All inquiries MUST have an entry in the "Subject" field of the e-

mail. • Current DMF submission address:

Food and Drug AdministrationCenter for Drug Evaluation and ResearchCentral Document Room5901-B Ammendale Road Beltsville MD 20705-1266

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New Drug CMC Questions?

newdrugcmc@fda.hhs.gov

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