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

Ponder

Pradeep K. Garg, Ph.D.Pradeep K. Garg, Ph.D.Director, PET CenterDirector, PET Center

Wake Forest University Health SciencesWake Forest University Health SciencesWinston Salem, NC; USAWinston Salem, NC; USA

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PET Center

Three major domains:Three major domains: Radiopharmaceutical area: ChemistRadiopharmaceutical area: Chemist Imaging and data acquisition: Imaging and data acquisition:

TechnologistTechnologist Reading scans and reporting: PhysicianReading scans and reporting: Physician

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Radiopharmaceuticals

Among several choices:Among several choices:

FDG is widely accepted and dominates the FDG is widely accepted and dominates the market sharemarket share

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FDG regulations

In US: In US: Expectation is to be compliant with Expectation is to be compliant with

cGMPcGMP FDA requiring CMCFDA requiring CMC FDA differentiates between small and FDA differentiates between small and

large manufacturerslarge manufacturers

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cGMP

current Good Manufacturing Practicescurrent Good Manufacturing Practices

Broad coverage, covers four major areasBroad coverage, covers four major areas

SafetySafety PurityPurity StrengthStrength QualityQuality

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CMC: The full form

Chemistry, Manufacturing, and Controls Chemistry, Manufacturing, and Controls

SectionSection

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CMC

CMC covers following points:CMC covers following points:A.A. Drug product component and quantitative Drug product component and quantitative

compositioncompositionB.B. Controls for components/raw materialsControls for components/raw materialsC.C. Reference standardsReference standardsD.D. Manufacturing and testing facilitiesManufacturing and testing facilitiesE.E. Manufacture of drug substanceManufacture of drug substanceF.F. Manufacture of drug productManufacture of drug product

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CMC (contn..)

G.G. Containers/closuresContainers/closuresH.H. Controls for the finished dosage formControls for the finished dosage formI.I. Analytical test proceduresAnalytical test proceduresJ.J. Microbial ValidationMicrobial ValidationK.K. Stability and Batch RecordsStability and Batch RecordsL.L. Vials and outer packaging labelsVials and outer packaging labels

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A. Drug product component and quantitative composition

1.1. Drug substance:Drug substance:i.i. Name/description: 2-Deoxy-2[Name/description: 2-Deoxy-2[1818F]fluoro D-F]fluoro D-

glucose, FDG.glucose, FDG.ii.ii. Composition/mL: 10-20mCi at 9:30AM (EOS)Composition/mL: 10-20mCi at 9:30AM (EOS)iii.iii. Composition/batch: 100-250mCi at 9:30AM (ESO)Composition/batch: 100-250mCi at 9:30AM (ESO)

2.2. Other ingredients:Other ingredients:i.i. Name/description: Sodium chloride injection, Name/description: Sodium chloride injection,

USPUSPii.ii. Composition/mL: 1 mLComposition/mL: 1 mLiii.iii. Composition/batch: 10-12 mLComposition/batch: 10-12 mL

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B. Controls for components / raw materials

1.1. Organic substrates:Organic substrates:2.2. Target material (radioactive fluoride)Target material (radioactive fluoride)3.3. Other ingredientsOther ingredients4.4. ReagentReagent

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B.Controls for components and raw materials (contn)

1.1. Organic substrates:Organic substrates:i.i. Component name: 1,3,4,6-Tetrafluoro Component name: 1,3,4,6-Tetrafluoro

methanesulfonyl-D-mannopyranose (triflate)methanesulfonyl-D-mannopyranose (triflate)ii.ii. Supplier: Name and addressSupplier: Name and addressiii.iii. Is this further purified: yes/no, if yes, how?Is this further purified: yes/no, if yes, how?iv.iv. Acceptance specs: Tests and criteriaAcceptance specs: Tests and criteria

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

v. COAvi. Identity test: test procedure and criteria in SOPvii. Storage condition: refrigerator, room temp, dry glove

box,..

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B.Controls for components and raw materials (contn)2.2. Target Material (O-18 water):Target Material (O-18 water):

i.i. Name of MaterialName of Materialii.ii. Manufacturer/supplierManufacturer/supplieriii.iii. SpecificationsSpecificationsiv.iv. Identity test to release lot: as attachmentIdentity test to release lot: as attachmentv.v. COACOAvi.vi. Recycled: yes/no, if yes:Recycled: yes/no, if yes:

i.i. Procedure as attachmentProcedure as attachmentii.ii. Acceptance specsAcceptance specs

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

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B. Controls for components and raw materials (contn)3.3. Reagent, solvents, gases, columns, and Reagent, solvents, gases, columns, and

other auxiliaryother auxiliaryi.i. NameNameii.ii. SupplierSupplieriii.iii. Grade, quality, COA, and acceptance Grade, quality, COA, and acceptance

criteriacriteriaThe above info is needed for all materials used The above info is needed for all materials used

in the manufacturingin the manufacturing

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B. Controls for components and raw materials (contn)4.4. Other ingredients (may not apply)Other ingredients (may not apply)

i.i. NameNameii.ii. PurposePurposeiii.iii. ManufacturerManufactureriv.iv. SpecificationsSpecifications

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C. Reference standards

Items:Items: 2-Fluoro-2deoxy-D-glucose2-Fluoro-2deoxy-D-glucose 2-Chloro-2deoxy-D-glucose2-Chloro-2deoxy-D-glucose Kryptofix 222Kryptofix 222On each of these items, supply:On each of these items, supply:

i.i. Name of these standardsName of these standardsii.ii. Suppliers infoSuppliers infoiii.iii. Specifications, COA, acceptance criteriaSpecifications, COA, acceptance criteria

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D. Manufacturing and testing facilities

1.1. Name of PET facility and addressName of PET facility and address2.2. Contact person nameContact person name3.3. Contact person phone numberContact person phone number

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E. Manufacture of drug substance

1.1. Batch formula: Name, function, and Batch formula: Name, function, and quantities of each componentquantities of each component

i.i. Triflate; used as a precursor, 10 mgTriflate; used as a precursor, 10 mgii.ii. F-18 fluoride, radioisotope, 100-2000mCiF-18 fluoride, radioisotope, 100-2000mCi

2.2. Radionuclide productionRadionuclide production F-18 produced at site? Yes/no ; if yes:F-18 produced at site? Yes/no ; if yes:

CyclotronCyclotron make and model, operating parameters, specifications on make and model, operating parameters, specifications on

target body (volume, material, windows info, acceptance target body (volume, material, windows info, acceptance criteria on windows and body…)criteria on windows and body…)

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E. Manufacture of drug substance (contn)3.3. Synthesis and purification of drugSynthesis and purification of drug

i.i. Synthesis and purification equipmentSynthesis and purification equipment Description of equipment, its components, acceptance Description of equipment, its components, acceptance

criteria, flow diagram: criteria, flow diagram: an attachmentan attachment Synth and purifi. Unit: make and modelSynth and purifi. Unit: make and model

ii.ii. Synthesis and purification operationSynthesis and purification operationStep wise description, amount of reagents, solvents, Step wise description, amount of reagents, solvents, acceptable yields: acceptable yields: an attachmentan attachment

iii.iii. In process controlIn process controlNumber of azeotropic evaps, temp for heating precursor, Number of azeotropic evaps, temp for heating precursor, delivery rates, pressure for air and gases, hydrolysis delivery rates, pressure for air and gases, hydrolysis temp, time for each steps, etc: temp, time for each steps, etc: a master production and a master production and control record sectioncontrol record section

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E. Manufacture of drug substance (contn)4.4. Post synthesis procedures:Post synthesis procedures:

i.i. Set up of synthesis units, cartridgesSet up of synthesis units, cartridgesii.ii. Cleaning and purging proceduresCleaning and purging procedures

iii.iii. Provided as an attachmentProvided as an attachment

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F. Manufacture of drug products1.1. Production operationProduction operation

General procedures provided as an attachmentGeneral procedures provided as an attachmentMaster production and traceable control records Master production and traceable control records provided as an attachmentprovided as an attachment

2.2. Reprocessing of drug productReprocessing of drug product Yes/no, if yes, circumstances (Attachment)Yes/no, if yes, circumstances (Attachment)

3.3. Packaging and labelingPackaging and labeling Detail descriptions as an attachmentDetail descriptions as an attachment

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G. Containers and closures

1.1. Using USP Type 1 glass, grey butyl Using USP Type 1 glass, grey butyl stopper, and aluminum crimp sealstopper, and aluminum crimp seal

i.i. Manufacturer name and addressManufacturer name and addressii.ii. Catalog number and descriptionCatalog number and descriptioniii.iii. DMF # (attachment #) DMF # (attachment #)

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H. Controls for finished dosage

1.1. Sampling procedureSampling procedure Produced as multidose or aliquot in Produced as multidose or aliquot in

multiple vialsmultiple vials If multi-vials, sampling procedure to assure If multi-vials, sampling procedure to assure

unbiased representationunbiased representation

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H. Controls for finished dosage (contn)2.2. Regulatory specs, procedures and Regulatory specs, procedures and

testing schedulestesting schedules Provide:Provide:

Test, acceptance criteria, procedure, and test Test, acceptance criteria, procedure, and test scheduleschedule

Each batch should meet these criteria during Each batch should meet these criteria during entire shelf lifeentire shelf life

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H. Controls for finished dosage (contn)Regulatory specs (itemized)Regulatory specs (itemized)1.1. AppearanceAppearance2.2. Radionuclide identityRadionuclide identity3.3. Radiochemical identityRadiochemical identity4.4. Radionuclide purityRadionuclide purity5.5. Radiochemical purityRadiochemical purity6.6. Radiochemical impuritiesRadiochemical impurities7.7. Assay (concentration)Assay (concentration)8.8. Specific activitySpecific activity

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H. Controls for finished dosage (contn)

9.9. pHpH10.10. K222 concentrationK222 concentration11.11. Residue solventsResidue solvents12.12. Chloro-deoxy glucoseChloro-deoxy glucose13.13. Membrane filter integrityMembrane filter integrity14.14. Bacterial endotoxinsBacterial endotoxins15.15. SterilitySterility

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I. Description of Analytical test procedures1.1. For each (major) tests described, For each (major) tests described,

provide:provide:

Test, STP #, Attachment #, Page numberTest, STP #, Attachment #, Page number

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J. Microbial validation

1.1. Includes procedures that ensure sterilityIncludes procedures that ensure sterilityi.i. In manufacturing facilityIn manufacturing facilityii.ii. Synthesis box and its componentsSynthesis box and its componentsiii.iii. Facility environmental controlsFacility environmental controlsiv.iv. Clean roomClean roomv.v. Aseptic techniquesAseptic techniquesvi.vi. Final filtrationFinal filtrationvii.vii. Finished product microbial testingFinished product microbial testing

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K. Stability and batch data

1.1. Expiration dating periodExpiration dating period2.2. Stability data (a curve)Stability data (a curve)3.3. Post approval commitmentPost approval commitment

Annually, minimally one batch tested for Annually, minimally one batch tested for the following teststhe following tests

List these testsList these tests

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L. Vials and outer label

Copies of proposed vial description and Copies of proposed vial description and outer packaging and label outer packaging and label

As an attachmentAs an attachment

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PET Center

ScannerScanner CyclotronCyclotron Chemistry LaboratoriesChemistry Laboratories RadiopharmacyRadiopharmacy OfficesOffices PersonnelPersonnel

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Scanner

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

CTI-Siemens HR+CTI-Siemens HR+ GE AdvanceGE Advance CTI CT/PETCTI CT/PET GE CT/PETGE CT/PET Philips PET and CT/PETPhilips PET and CT/PET

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Cyclotron

Is an important factor in preparing Is an important factor in preparing this documentthis document

Several to choose from:Several to choose from: CTI RDS 111; 11 MeVCTI RDS 111; 11 MeV GE 10MeV or 18.5 MeVGE 10MeV or 18.5 MeV IBA (various)IBA (various) Others…Others…

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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

Medical Cyclotron

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Isotope Production

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

Small Medical Cyclotron (<15 MeV) Small Medical Cyclotron (<15 MeV) C-11C-11 N-13N-13 O-15O-15 F-18F-18

Large Cyclotron (>15 MeV)Large Cyclotron (>15 MeV) Br-75, Br-76Br-75, Br-76 Ga-68Ga-68 I-122I-122

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Cyclotron Target Yields

These factors would influence the details These factors would influence the details for the documentfor the document

Dependent on:Dependent on:1. Nuclear Reaction1. Nuclear Reaction2. Target Design2. Target Design

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

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Radiochemistry Laboratories

Hot CellsHot Cells Fume HoodsFume Hoods Laminar flow HoodLaminar flow Hood HPLCHPLC GCGC Synthesis ModulesSynthesis Modules Dose drawing stationDose drawing station

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Other Issues

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

Radiation Exposure from 1 mCi unshieldedRadiation Exposure from 1 mCi unshielded General Nuclear Medicine clinicGeneral Nuclear Medicine clinic

0.02 – 0.22 mR/h at 1 meter0.02 – 0.22 mR/h at 1 meter PET clinicPET clinic

0.58 mR/h at 1 meter (5.8 R/h at 1 cm)0.58 mR/h at 1 meter (5.8 R/h at 1 cm) Patient handlingPatient handling

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