[ 18 F]FBR FOR INJECTION: CHEMISTRY, MANUFACTURING AND CONTROLS

Transcription

1 Table of Contents 1. DRUG PRODUCT COMPONENTS & QUANTITATIVE COMPOSITION FOR COMPONENTS & RAW MATERIALS Organic Substrate (Key Intermediate) Target (Starting Material) Purification (Columns, Gases, Solvents, Reagents, etc ) REFERENCE STANDARDS MANUFACTURING AND TESTING FACILITIES MANUFACTURE OF DRUG SUBSTANCE Batch Formula Production of Radionuclide Cyclotrons Used Synthesis and Purification of the Drug Substance Description of Radiosynthesis Equipment and Its Operation: Radiosynthetic Production Unit: In-Process Controls: Post-Synthesis Procedures: MANUFACTURE OF DRUG PRODUCT Production Operation Reprocessing of Drug Product CONTAINER/CLOSURE FOR THE FINISHED DOSAGE FORM Sampling Procedures Regulatory Specifications, Procedures, and Testing Schedules MICROBIOLOGICAL VALIDATION STABILITY AND BATCH DATA Expiry Dating Period Stability Data/Batch Data VIAL AND OUTER PACKAGING LABELS ENVIRONMENTAL ASSESSMENT LIST OF DOCUMENTS...12 DOCUMENT 1: [ 18 F]FBR for Injection: Chemistry, Manufacturing and Controls Page 1 of 12

2 1. DRUG PRODUCT COMPONENTS AND QUANTITATIVE COMPOSITION Component Composition/batch Drug substance 1 [ 18 F]FBR 5 to 150 mci at EOS 2 Other ingredient(s) 9.5 ml 0.9% Sodium Chloride Injection, USP Dehydrated Ethanol, USP 1 ml 1 Throughout this application [ 18 F]FBR refers to the drug substance and [ 18 F]FBR for Injection to the final product. 2 EOS = End of synthesis calibration time. 2. FOR COMPONENTS & RAW MATERIALS 2.1. Organic Substrate (Key Intermediate) Name of component Name and address of supplier Qualification/ Certificate of Analysis Storage conditions N-(2,5-dimethoxybenzyl)-2-bromo-N-(2- phenoxyphenyl)acetamide Synthesized at PET Radiophamaceutical Sciences, Molecular Imaging Branch, National Institutes of Health, Bethesda, Maryland See DOCUMENT 7, Precursor and Reference Standard Qualification 1. Container/closure screw cap glass vial stored at room temperature. 2. The material is stable for at least 1 year, when stored in above container/closure under described storage conditions. DOCUMENT 1: [ 18 F]FBR for Injection: Chemistry, Manufacturing and Controls Page 2 of 12

3 2.2. Target (Starting Material) All [ 18 F]fluoride required for the production of [ 18 F]FBR for Injection is produced at the NIH Cyclotron Facility. The following target material will be used for the production of [ 18 F]fluoride ion: Target material Manufacturer Release Criteria COA Target material recycling criteria 18 O-Enriched water (> 95% atom percent) Isonics Corporation 6851 Oak Hall Lane, Suite 119 Columbia, MD COA meets manufacturer s specifications A representative copy of supplier s COA is provided in COA Attachment Section N/A 2.3. Purification (Columns, Gases, Solvents, Reagents, etc ) Name Specification Supplier Absolute ethanol 200 proof Acetonitrile Acetonitrile USP anhydrous HPLC Grade Ammonium Formate % C 18 Phenomenex Luna 3 µm (10 x 250 mm) HPLC column C 18 Phenomenex Luna Hexyl-Phenyl 5 µm (4.6 x 150 mm) HPLC Column Dehydrated alcohol NA NA Injection, USP Warner-Graham Co. P.O. Box 249, 160 Church Lane Cockeysville, MD Rael de Haën (a Division of Honeywell) Seelze GmbH Wunstorfer Straße 40 D Seelze Germany Burdick & Jackson 1953 South Harvey Street Muskegon, MI Sigma-Aldrich PO Box St. Louis, MO Phenomenex 411 Madrid Avenue Torrance, CA Phenomenex 411 Madrid Avenue Torrance, CA American Regent, Inc. One Luitpold Drive Shirley NY Document 8 Page # DOCUMENT 1: [ 18 F]FBR for Injection: Chemistry, Manufacturing and Controls Page 3 of 12

4 Nitrogen gas Sterile filter (GV; 4 mm; 0.22 µm vent type; Millex) Sterile filter (MP; 25 mm; 0.22 µm; Millex Sterile Saline Sterile vial, 10 ml Water N-(2,5-dimethoxybenzyl)- 2-bromo-N-(2- phenoxyphenyl)acetamide N-(2,5-dimethoxybenzyl)- 2-fluoro-N-(2- phenoxyphenyl)acetamide Ultra pure carrier Sterile Sterile Injection, USP Sterile HPLC Grade Refer to SOP QA 305 Refer to SOP QA 305 Roberts Oxygen Company, Inc Redland Road Rockville, MD Millipore 80 Ashby Road Bedford MA Millipore 80 Ashby Road Bedford MA Abrexis BioScience (formerly American Pharmaceutical Partners) 1501 East Woodfield Road, Suite 300 East Schaumburg, IL Hospira 275 North Field Drive, Lake Forest, Illinois EMD Chemicals Inc. 480 S. Democrat Rd. Gibbstown, NJ PRSS, National Institutes of Health PRSS, National Institutes of Health REFERENCE STANDARDS The following reference standard is used in the quality control methods of [ 18 F]FBR for Injection: Name of reference standard N-(2,5-dimethoxybenzyl)-2- bromo-n-(2- phenoxyphenyl)acetamide N-(2,5-dimethoxybenzyl)-2- fluoro-n-(2- phenoxyphenyl)acetamide Name and address of the supplier Synthesized at PRSS, Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health Synthesized at PRSS, Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health COA and acceptance criteria Refer to QA# 305, FBR Precursor and Standard Acceptance Criteria Refer to QA# 305, FBR Precursor and Standard Acceptance Criteria DOCUMENT 1: [ 18 F]FBR for Injection: Chemistry, Manufacturing and Controls Page 4 of 12

5 4. MANUFACTURING AND TESTING FACILITIES Facility address PET Radiopharmaceutical Sciences Section (PRSS), Molecular Imaging Branch (MIB), National Institute of Mental Health (NIMH), National Institutes of Health (NIH), 10 Center Drive, MSC 1003 Building 10, Room B3C338, Contact persons Victor W. Pike, Ph.D., Chief (PRSS) Phone: (301) Fabrice Simeon, Ph.D., Scientist (PRSS) Kelly Sprague, M.S., Radiochemist (PRSS) 5. MANUFACTURE OF DRUG SUBSTANCE 5.1. Batch Formula The following components and their quantities are used in the production of each batch of [ 18 F]FBR for Injection: Name of component Component s function Amount [ 18 F]fluoride ion Radiolabeling agent mci Absolute Ethanol Cleaning solvent ml Acetonitrile, anhydrous Reaction solvent 400 µl Acetonitrile, HPLC grade HPLC solvent 50 ml Dehydrated Ethanol, USP Formulation component 0.9 ml Filter (GV; 0.22 µm; 4 mm; Millex) Sterile vent filter 1 Filter (MP; 0.22 µm; 25 mm; Millex) Sterile filtration of product 1 HPLC column Separation of product 1 K2.2.2 solution Fixative for fluoride ion 100 μl N-(2,5-dimethoxybenzyl)-2-bromo-N-(2- phenoxyphenyl)acetamide Radiopharmaceutical precursor Sodium Chloride for Injection (USP; 10 ml vial) Formulation component Sterile 20 and 22G needles Product transfer and vent 1,2 Sterile vial, 10 ml Product container 1 used 0.85 ± 0.1 mg 10 ml NOTE: Upon scale-up or down, only the amount of radioactive [ 18 F]fluoride ion reagent is changed. All other components and their amounts remain as stated in the batch formula. DOCUMENT 1: [ 18 F]FBR for Injection: Chemistry, Manufacturing and Controls Page 5 of 12

6 5.2. Production of Radionuclide All [ 18 F]fluoride is prepared at the NIH Cyclotron Facility. No other source of [ 18 F]fluoride ion is used for the production of [ 18 F]FBR for Injection Cyclotrons Used The following cyclotrons are used for the production of [ 18 F]fluoride ion: Manufacturer General Electric Cyclotron Corporation Japan Steel Works Model PETtrace CS-30 JSW-1710 Specifications for Target Body Target Data JSW-1710 CS-30 General Electric Target Volume 1.8 ml 3.0 ml 1.8 ml Target Body Titanium Titanium Titanium Target Foils Titanium Titanium Titanium Acceptance Criteria Vacuum (10 8 std-cc/s) Vacuum (10 8 std-cc/s) Vacuum (10 8 std-cc/s) 5.4. Synthesis and Purification of the Drug Substance Description of Radiosynthesis Equipment and Its Operation: The descriptions of the radiosynthetic equipment, its cleaning and operation are described in DOCUMENT 2, SOP # MP201 and SOP # MP Radiosynthetic Production Unit: Manufacturer: General Electric Healthcare (formerly, Synthia Lab Systems Sweden AB) Model: Synthia MK II Beatrice Serial Number: 002 DOCUMENT 1: [ 18 F]FBR for Injection: Chemistry, Manufacturing and Controls Page 6 of 12

7 In-Process Controls: The process is monitored visually by the operator to ensure that all transfer steps proceed according to the recipe. The Synthia transducer displays are also monitored by the operator during the process Post-Synthesis Procedures: Descriptions of procedures used to prepare the production equipment, including any cleaning and purging procedures for a subsequent batch are provided in DOCUMENT 2, SOP # MP201 and SOP # MP MANUFACTURE OF DRUG PRODUCT 6.1. Production Operation [ 18 F]FBR is prepared via an automated x, y, z robotic radiochemistry module (General Electric Healthcare (formerly, Synthia Lab System Sweden AB)). The synthesis and purification of the drug substance involves the following steps: Drying of the 18 O target water containing [ 18 F]fluoride ion, potassium carbonate, and Kryptofix via repeated addition-evaporation cycles of acetonitrile; first thermally and then by microwave. Specifically, a 5 ml conical vial containing the [ 18 O]water and [ 18 F]fluoride ion is heated (110 C) and a nitrogen stream (200 ml/min) is blown through the vented vial. Several portions of anhydrous acetonitrile are added for azeotropic removal of the [ 18 O]water, which is not recovered. The residue is then reconstituted in anhydrous acetonitrile and transferred to a 2 ml conical reaction vial and dried again by microwave (90W, 130 C, 2 x 150s) Addition of the N-(2,5-dimethoxybenzyl)-2-bromo-N-(2-phenoxyphenyl)acetamide (750 μg in acetonitrile) to the dried [ 18 F]fluoride ion/ potassium carbonate-kryptofix complex. The microwave reaction is carried out for a total of 120 seconds split into two (or more) series such that the temperature does not exceed 70 C Purification and isolation of the resulting [ 18 F]N-(2,5-dimethoxybenzyl)-2-fluoro-N-(2- phenoxyphenyl)acetamide via reverse phase HPLC. Specifically, the crude reaction mixture is diluted with HPLC grade water and injected onto a Phenomenex Luna C x 10 mm, 3 μm, HPLC column using an acetonitrile-water gradient mobile phase. The DOCUMENT 1: [ 18 F]FBR for Injection: Chemistry, Manufacturing and Controls Page 7 of 12

8 [ 18 F]N-(2,5-dimethoxybenzyl)-2-fluoro-N-(2-phenoxyphenyl)acetamide is collected from the column (t R 80 min) and isolated in 1 ml of dehydrated ethanol, USP via solid phase extraction Formulation and sterile filtration of the final radiopharmaceutical dose. The ethanol containing the [ 18 F]N-(2,5-dimethoxybenzyl)-2-fluoro-N-(2-phenoxyphenyl)acetamide is passed through a sterile, pyrogen-free sterile filter to a 10 ml sterile dose vial containing 9.5 ml sterile saline. The production and quality control procedures that provide the exact procedures used in the controlled production of [ 18 F]FBR for Injection are provided in DOCUMENT 2. Attached to each batch of [ 18 F]FBR for Injection are: Master Batch Record (Document 3) - Preparative HPLC data attached Quality Control Record: (Document 4) - Form contains summary of the pre-release quality control results - Analytical HPLC Report attached - GC report Post Release Test Record: Endotoxin and Sterility: (Document 5) - Form contains summary of post-release quality control results (label, pyrogen testing, sterility testing, volatile organics testing) - GC Report attached Calculations Worksheet Any other ancillary data generated or collected that pertaining to the specific batch of [ 18 F]FBR for Injection Reprocessing of Drug Product The PRSS does not reprocess [ 18 F]FBR for Injection. DOCUMENT 1: [ 18 F]FBR for Injection: Chemistry, Manufacturing and Controls Page 8 of 12

9 7. CONTAINER/CLOSURE The pre-sterilized, pre-sealed, pyrogen-free container/closure is obtained from Hospira, Inc.. Full information on the container/closure along with its contents, sterilization procedures, and sterility assurance are provided in the attached COA (DOCUMENT 8 ). Hospira, Inc. Name and address of supplier 275 North Field Drive, Lake Forest, Illinois NDC/List number Container Flip-top Vial - Glass (LF) Representative COA Document 8, Page FOR THE FINISHED DOSAGE FORM 8.1. Sampling Procedures Each batch of [ 18 F]FBR for Injection will be produced in one vial. A description of the volume amount that is withdrawn from the finished drug product container and how it is distributed among individual tests is provided in DOCUMENT 2, SOP # QA302: Sampling and Quality Control Procedures for [ 18 F]FBR for Injection Regulatory Specifications, Procedures, and Testing Schedules Each batch of [ 18 F]FBR for Injection will meet the following specifications during its entire shelf life (see below). We assure that any batch that fails to meet the acceptance criteria for release will not be released. We also assure that FDA will be notified of any changes to the approved application. DOCUMENT 1: [ 18 F]FBR for Injection: Chemistry, Manufacturing and Controls Page 9 of 12

10 Note: The following tests are related to the production method proposed in this IND submission. In the event that the production method does not use a component listed, uses an alternative production method, or produces additional impurities not seen previously, a set of appropriate tests, acceptance criteria, procedures, and a testing schedule that is more appropriate for such production will be proposed. Test Acceptance criteria Procedures Testing schedule Measurement in an Assay 0.5 mci /ml at EOS (radioconcentration) 1 ionization chamber (dose calibrator). Bacterial endotoxins (LAL) Chemical purity Membrane filter integrity Less than 2.5 EU/mL For the injection NMT μg of FBR impurity equivalent 3 Sterile 0.22 µm filters are used once. Each membrane tested by bubble point test. ph ph paper. Radiochemical identity Retention time within ± 0.5 min of a standard injection of FBR LAL test kit procedure, HPLC QC Procedure. Pressure gauge transducer. No bubbles at 45 p.s.i. HPLC QC Procedure Radiochemical purity NLT 3 95 %[ 18 F]FBR HPLC QC Procedure. Radionuclidic identity Residual solvents Specific radioactivity Sterility testing The measured half-life is between 100 and 120 minutes Acetonitrile: NMT 0.04% (w/v). Ethanol: NMT 10% (w/v) NLT 500 mci/μmol at EOS No aerobic or anaerobic growth observed Calculated half life from two measurements at least 5 minutes apart. Gas chromatography with flame ionization detection. HPLC QC Procedure NIH Clinical Center Microbiology Lab Test completed postrelease Test completed postrelease 1 End Of Synthesis 2 Not More Than 3 Not Less Than DOCUMENT 1: [ 18 F]FBR for Injection: Chemistry, Manufacturing and Controls Page 10 of 12

11 9. MICROBIOLOGICAL VALIDATION Data provided in DOCUMENT 9, Validation Record, show that [ 18 F]FBR for Injection is obtained in a sterile and pyrogen-free form, when prepared according to this application and the submitted batch production record. 10. STABILITY AND BATCH DATA Expiry Dating Period Data provided in DOCUMENT 9, Validation Record, show that [ 18 F]FBR for Injection is stable for 4 h from EOS for [ 18 F]FBR for Injection when stored at controlled room temperature (note: refer to USP for controlled room temperature definition) Stability Data/Batch Data Complete release and stability data were obtained for three batches of [ 18 F]FBR for Injection, prepared and stored at controlled room temperature. See DOCUMENT 9: Validation Record. For each stability batch: The batch is stored in the same container/closure as it was produced. All tests indicated in the specification section were performed at release. The appearance and radiochemical purity were also evaluated at the end of the proposed expiry period. 11. VIAL AND OUTER PACKAGING LABELS Proposed vial and outer packaging labels are shown in DOCUMENT 2. Each batch will be labeled with a lot number, compound name, volume and quantitative assay and will contain the statement: "Caution: New Drug Limited by Federal Law to Investigational Use". DOCUMENT 1: [ 18 F]FBR for Injection: Chemistry, Manufacturing and Controls Page 11 of 12

12 12. ENVIRONMENTAL ASSESSMENT In accordance with 21 CFR 25.31(b), the PRSS claims a categorical exclusion from the environmental assessment requirements of 21 CFR for approval of [ 18 F]FBR for Injection on the basis that the estimated concentration of [ 18 F]FBR at the point of entry into the aquatic environment will be below 1 part per billion. Additionally, no extraordinary circumstances exist. 13. LIST OF DOCUMENTS DOCUMENT 1. DOCUMENT 2. DOCUMENT 3. DOCUMENT 4 DOCUMENT 5. DOCUMENT 6. DOCUMENT 7. DOCUMENT 8. DOCUMENT 9. Chemistry, Manufacturing and Controls. Standard Operating Procedures. Master Batch Record. Quality Control Record. Post Release Test Record: Endotoxin and Sterility. Data Form for the Preparation of Standard FBR Solution and HPLC Calibration Curve. Precursor and Reference Standard Acceptance Form. Certificates of Analyses. Validation Record. DOCUMENT 1: [ 18 F]FBR for Injection: Chemistry, Manufacturing and Controls Page 12 of 12