snm midwinter 20101 overview of fda's regulatory framework for pet drugs ravindra k. kasliwal,...

SNM MIDWINTER 2010 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


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


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)”.


CGMP Rule and Guidance Availability

• PET CGMP Rule and Guidance are available at– http://www.fda.gov/Drugs/DevelopmentApprov

alProcess/Manufacturing/ucm085783.htm

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm085783.htm

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm085783.htm


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.


Applicability of PET CGMP Regulations21 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.


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).


• 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.

Current Regulation for PET Drug Production


Investigational Studies

• All human investigational / research studies must be performed:– Under an IND (21 CFR 312)– As RDRC approved study (21 CFR 361)


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


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)


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


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


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


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– http://www.fda.gov/Drugs/GuidanceComplianc

eRegulatoryInformation/DrugRegistrationandListing/default.htm

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/DrugRegistrationandListing/default.htm




NDAs and ANDAs

• FDA intends to soon finalize the guidance, “PET drug Applications – Content and Format for NDAs and ANDAs”.

• Draft guidance website: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM078738.pdf

• 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).


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.


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:

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065006.htm




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


ANDA RESOURCES• Office of Generic Drugs (OGD) webpage:

http://www.fda.gov/Drugs/GuidanceComplinceRegulatoryInformation/Guidances/ucm064995.htm)

• 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

http://www.fda.gov/Drugs/GuidanceComplinceRegulatoryInformation/Guidances/ucm064995.htm

http://www.fda.gov/Drugs/GuidanceComplinceRegulatoryInformation/Guidances/ucm064995.htm


ANDA Questions?• Contact the Office of Generic Drugs:

Martin H. ShimerBranch Chief, Regulatory Support BranchFDA, Office of Generic Drugs240 (276-8419) [email protected]

• Submit completed application to:Director, Office of Generic DrugsCenter for Drug Evaluation and ResearchFood and Drug AdministrationMetro Park North II, Rm. 1507500 Standish PlaceRockville, MD 20855


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

http://www.fda.gov/cder/guidance/phase1.pdf

http://www.fda.gov/cder/guidance/3619fnl.pdf

http://www.fda.gov/cder/guidance/3683fnl.pdf


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) 796-2050 (office) (301) 796-9849 (fax) [email protected]


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


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).


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.


Drug Master Files (DMF) Resources• The regulatory requirements for a DMF-21 CFR 314.420• 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 e-

mail

• Current DMF submission address:Food and Drug AdministrationCenter for Drug Evaluation and ResearchCentral Document Room5901-B Ammendale Road Beltsville MD 20705-1266

http://www.fda.gov/cder/guidance/dmf.htm

mailto:[email protected]


Web Resources for You

• NDA http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/NewDrugApplicationNDA/default.htm



• ANDA

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/default.htm



• IND

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/default.htm


User FeesWaiver, Reduction, Refund or Questions

Michael JonesFood and Drug Administration10903 New Hampshire Ave, Building 51, Room 6216Silver Spring, MD 20993-0002Phone: 301-796-3602Email: [email protected] Fax: 301-847-8711


Conclusion

• PET Drug Regulatory Framework– CGMP– NDA– ANDA– IND and RDRC– DMF– Resources for Submitting and

application to CDER / FDA


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

mailto:[email protected]

snm midwinter 20101 overview of fda's regulatory framework for pet drugs ravindra k. kasliwal,...

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