Fdg and its intended regulation by fda in the usa points to ponder
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FDG and its intended regulation by FDA in the USA: Points to Ponder. Pradeep K. Garg, Ph.D. Director, PET Center Wake Forest University Health Sciences Winston Salem, NC; USA. STOP. PET Center. Three major domains: Radiopharmaceutical area: Chemist

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FDG and its intended regulation by FDA in the USA: Points to Ponder

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Fdg and its intended regulation by fda in the usa points to ponder

FDG and its intended regulation by FDA in the USA: Points to Ponder

Pradeep K. Garg, Ph.D.

Director, PET Center

Wake Forest University Health Sciences

Winston Salem, NC; USA

STOP


Pet center

PET Center

Three major domains:

  • Radiopharmaceutical area: Chemist

  • Imaging and data acquisition: Technologist

  • Reading scans and reporting: Physician

STOP


Radiopharmaceuticals

Radiopharmaceuticals

Among several choices:

FDG is widely accepted and dominates the market share

STOP


Fdg regulations

FDG regulations

In US:

  • Expectation is to be compliant with cGMP

  • FDA requiring CMC

  • FDA differentiates between small and large manufacturers

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Fdg and its intended regulation by fda in the usa points to ponder

cGMP

current Good Manufacturing Practices

Broad coverage, covers four major areas

  • Safety

  • Purity

  • Strength

  • Quality

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Cmc the full form

CMC: The full form

Chemistry, Manufacturing, and Controls Section

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Fdg and its intended regulation by fda in the usa points to ponder

CMC

CMC covers following points:

  • Drug product component and quantitative composition

  • Controls for components/raw materials

  • Reference standards

  • Manufacturing and testing facilities

  • Manufacture of drug substance

  • Manufacture of drug product

STOP


Cmc contn

CMC (contn..)

  • Containers/closures

  • Controls for the finished dosage form

  • Analytical test procedures

  • Microbial Validation

  • Stability and Batch Records

  • Vials and outer packaging labels

STOP


A drug product component and quantitative composition

A. Drug product component and quantitative composition

  • Drug substance:

    • Name/description: 2-Deoxy-2[18F]fluoro D-glucose, FDG.

    • Composition/mL: 10-20mCi at 9:30AM (EOS)

    • Composition/batch: 100-250mCi at 9:30AM (ESO)

  • Other ingredients:

    • Name/description: Sodium chloride injection, USP

    • Composition/mL: 1 mL

    • Composition/batch: 10-12 mL

STOP


B controls for components raw materials

B.Controls for components / raw materials

  • Organic substrates:

  • Target material (radioactive fluoride)

  • Other ingredients

  • Reagent

STOP


B controls for components and raw materials contn

B.Controls for components and raw materials (contn)

  • Organic substrates:

    • Component name: 1,3,4,6-Tetrafluoro methanesulfonyl-D-mannopyranose (triflate)

    • Supplier: Name and address

    • Is this further purified: yes/no, if yes, how?

    • Acceptance specs: Tests and criteria

      • Appearance, Identity (nmr, ir), Purity (mp hplc).

    • COA

    • Identity test: test procedure and criteria in SOP

    • Storage condition: refrigerator, room temp, dry glove box,..

STOP


B controls for components and raw materials contn1

B.Controls for components and raw materials (contn)

  • Target Material (O-18 water):

    • Name of Material

    • Manufacturer/supplier

    • Specifications

    • Identity test to release lot: as attachment

    • COA

    • Recycled: yes/no, if yes:

      • Procedure as attachment

      • Acceptance specs

    • *If F-18 purchased: supply all this info on it

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B controls for components and raw materials contn2

B. Controls for components and raw materials (contn)

  • Reagent, solvents, gases, columns, and other auxiliary

    • Name

    • Supplier

    • Grade, quality, COA, and acceptance criteria

      The above info is needed for all materials used in the manufacturing

STOP


B controls for components and raw materials contn3

B. Controls for components and raw materials (contn)

  • Other ingredients (may not apply)

    • Name

    • Purpose

    • Manufacturer

    • Specifications

STOP


C reference standards

C. Reference standards

Items:

  • 2-Fluoro-2deoxy-D-glucose

  • 2-Chloro-2deoxy-D-glucose

  • Kryptofix 222

    On each of these items, supply:

    • Name of these standards

    • Suppliers info

    • Specifications, COA, acceptance criteria

STOP


D manufacturing and testing facilities

D.Manufacturing and testing facilities

  • Name of PET facility and address

  • Contact person name

  • Contact person phone number

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E manufacture of drug substance

E. Manufacture of drug substance

  • Batch formula: Name, function, and quantities of each component

    • Triflate; used as a precursor, 10 mg

    • F-18 fluoride, radioisotope, 100-2000mCi

  • Radionuclide production

    • F-18 produced at site? Yes/no ; if yes:

      • Cyclotron

        • make and model, operating parameters, specifications on target body (volume, material, windows info, acceptance criteria on windows and body…)

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E manufacture of drug substance contn

E. Manufacture of drug substance (contn)

  • Synthesis and purification of drug

    • Synthesis and purification equipment

      • Description of equipment, its components, acceptance criteria, flow diagram: an attachment

        • Synth and purifi. Unit: make and model

    • Synthesis and purification operation

      Step wise description, amount of reagents, solvents, acceptable yields: an attachment

    • In process control

      Number of azeotropic evaps, temp for heating precursor, delivery rates, pressure for air and gases, hydrolysis temp, time for each steps, etc: a master production and control record section

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E manufacture of drug substance contn1

E. Manufacture of drug substance (contn)

  • Post synthesis procedures:

    • Set up of synthesis units, cartridges

    • Cleaning and purging procedures

    • Provided as an attachment

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F manufacture of drug products

F. Manufacture of drug products

  • Production operation

    General procedures provided as an attachment

    Master production and traceable control records provided as an attachment

  • Reprocessing of drug product

    • Yes/no, if yes, circumstances (Attachment)

  • Packaging and labeling

    • Detail descriptions as an attachment

STOP


G containers and closures

G. Containers and closures

  • Using USP Type 1 glass, grey butyl stopper, and aluminum crimp seal

    • Manufacturer name and address

    • Catalog number and description

    • DMF # (attachment #)

STOP


H controls for finished dosage

H. Controls for finished dosage

  • Sampling procedure

    • Produced as multidose or aliquot in multiple vials

      • If multi-vials, sampling procedure to assure unbiased representation

STOP


H controls for finished dosage contn

H. Controls for finished dosage (contn)

  • Regulatory specs, procedures and testing schedules

    • Provide:

      • Test, acceptance criteria, procedure, and test schedule

        Each batch should meet these criteria during entire shelf life

STOP


H controls for finished dosage contn1

H. Controls for finished dosage (contn)

Regulatory specs (itemized)

  • Appearance

  • Radionuclide identity

  • Radiochemical identity

  • Radionuclide purity

  • Radiochemical purity

  • Radiochemical impurities

  • Assay (concentration)

  • Specific activity

STOP


H controls for finished dosage contn2

H. Controls for finished dosage (contn)

  • pH

  • K222 concentration

  • Residue solvents

  • Chloro-deoxy glucose

  • Membrane filter integrity

  • Bacterial endotoxins

  • Sterility

STOP


I description of analytical test procedures

I. Description of Analytical test procedures

  • For each (major) tests described, provide:

    • Test, STP #, Attachment #, Page number

STOP


J microbial validation

J. Microbial validation

  • Includes procedures that ensure sterility

    • In manufacturing facility

    • Synthesis box and its components

    • Facility environmental controls

    • Clean room

    • Aseptic techniques

    • Final filtration

    • Finished product microbial testing

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K stability and batch data

K. Stability and batch data

  • Expiration dating period

  • Stability data (a curve)

  • Post approval commitment

    • Annually, minimally one batch tested for the following tests

      • List these tests

STOP


L vials and outer label

L. Vials and outer label

  • Copies of proposed vial description and outer packaging and label

    • As an attachment

STOP


Pet center1

PET Center

  • Scanner

  • Cyclotron

  • Chemistry Laboratories

  • Radiopharmacy

  • Offices

  • Personnel

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Scanner

Scanner

Several options, but does not necessarily affects our task at hand:

  • CTI-Siemens HR+

  • GE Advance

  • CTI CT/PET

  • GE CT/PET

  • Philips PET and CT/PET

STOP


Cyclotron

Cyclotron

Is an important factor in preparing this document

Several to choose from:

  • CTI RDS 111; 11 MeV

  • GE 10MeV or 18.5 MeV

  • IBA (various)

  • Others…

STOP


Medical cyclotron

Medical Cyclotron

Are deutrons as common and important?

  • Acceleration Capability

    • Particle

      • + v/s –ve ions

      • Single particle (Protons) v/s dual particles (proton & deuteron)

      • Energy

    • Nuclear Reaction

    • Target Material and Design

STOP


Isotope production

Isotope Production

Issues may not be pertinent to FDG book, but would impact on what document we prepare

  • Small Medical Cyclotron (<15 MeV)

    • C-11

    • N-13

    • O-15

    • F-18

  • Large Cyclotron (>15 MeV)

    • Br-75, Br-76

    • Ga-68

    • I-122

  • STOP


    Cyclotron target yields

    Cyclotron Target Yields

    These factors would influence the details for the document

    • Dependent on:

      1. Nuclear Reaction

      2. Target Design

      Physical (silver, tantalum, HP, LP, HV)

    STOP


    Radiochemistry laboratories

    Radiochemistry Laboratories

    • Hot Cells

    • Fume Hoods

    • Laminar flow Hood

    • HPLC

    • GC

    • Synthesis Modules

    • Dose drawing station

    STOP


    Other issues

    Other Issues

    We may want to emphasize on radiation safety factor as guidance (FDA does not cover it)

    • Radiation Exposure from 1 mCi unshielded

      • General Nuclear Medicine clinic

        • 0.02 – 0.22 mR/h at 1 meter

      • PET clinic

        • 0.58 mR/h at 1 meter (5.8 R/h at 1 cm)

  • Patient handling

  • STOP


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