[ 11 C]Mes-IMPY FOR INJECTION: CHEMISTRY, MANUFACTURING AND CONTROLS

Transcription

1 Table of Contents 1. DRUG PRODUCT COMPONENTS AND QUANTITATIVE COMPOSITION CONTROLS FOR COMPONENTS & RAW MATERIALS... 2 A. Organic Substrate (Key Intermediate)... 2 B. Target Starting Material... 3 C. Purification Columns, Gases, Solvents, Reagents, etc REFERENCE STANDARDS MANUFACTURING AND TESTING FACILITIES MANUFACTURE OF DRUG SUBSTANCE... 6 A. Batch Formula... 6 B. Production of Radionuclide... 7 C. Cyclotrons Used... 7 D. Synthesis and Purification of the Drug Substance... 8 Description of Radiosynthesis Equipment and Its Operation... 8 Radiosynthetic Production Unit:... 8 In-Process Controls... 9 Post-Synthesis Procedures MANUFACTURE OF DRUG PRODUCT... 9 A. Production Operation... 9 B. Reprocessing of Drug Product CONTAINER/CLOSURE CONTROLS FOR THE FINISHED DOSAGE FORM A. Sampling Procedures B. Regulatory Specifications, Procedures, and Testing Schedules MICROBIOLOGICAL VALIDATION STABILITY AND BATCH DATA A. Expiry Dating Period B. Stability Data/Batch Data VIAL AND OUTER PACKAGING LABELS ENVIRONMENTAL ASSESSMENT LIST OF DOCUMENTS Document 1: [ 11 C]Mes-IMPY for Injection: Chemistry, Manufacturing and Controls Page 1 of 14

2 1. DRUG PRODUCT COMPONENTS AND QUANTITATIVE COMPOSITION Component Composition/batch Drug substance 1 [ 11 C]Mes-IMPY 20 to 250 mci at EOS 2 Other ingredient(s) 0.9% Sodium Chloride Injection, USP 10 ml Mes-IMPY Polysorbate 80, N. F. 20 mg Ethanol, USP 0.9 ml 1 Throughout this application [ 11 C]Mes-IMPY refers to the drug substance and [ 11 C]Mes-IMPY for Injection to the final product. 2 EOS = End of synthesis calibration time. 2. CONTROLS FOR COMPONENTS & RAW MATERIALS A. Organic Substrate (Key Intermediate) 1. Name of component methyl 3-(2-(4-(dimethylamino)phenyl)imidazo[1,2- a]pyridin-6-ylthio)propanoate 2. Name and address of supplier Synthesized at PRSS, National Institutes of Health 3. Certificate of analysis (COA) See COA Document 7_19 4. Storage conditions 1. Container/closure screw cap glass vial housed in a plastic canister. 2. Stored at room temperature 3. The material is stable for at least 2 years, when stored in above container/closure under described storage conditions. Document 1: [ 11 C]Mes-IMPY for Injection: Chemistry, Manufacturing and Controls Page 2 of 14

3 B. Target Starting Material All the required carbon-11 is produced as [ 11 C]carbon dioxide at the NIH Cyclotron Facility. The following target material will be used for the production of [ 11 C]carbon dioxide: 1 Name of the target material Nitrogen gas with about 1% oxygen. COA Document 7_8 2 Name and address of the target material manufacturer Matheson Gas 932 Paterson Plank Road East Rutherford, NJ Identity test performed to release each COA lot for production use 4 COA A representative copy of supplier s COA is provided in COA Attachment Section 5 Target material recycling criteria N/A C. Purification Columns, Gases, Solvents, Reagents, etc Name C-18 Phenomenex Luna 10 1 µm (4.6 x 250 mm) C-18 Phenomenex Luna 10 2 µm (10 x 250 mm) 3 Hydrogen gas Name and address of the supplier Phenomenex 411 Madrid Avenue Torrance, CA Phenomenex 411 Madrid Avenue Torrance, CA Matheson Gas 932 Paterson Plank Road East Rutherford, NJ Quality grade (e.g., ACS, USP, etc.), representative COA and acceptance criteria COA Document 7_1 COA Document 7_2 COA Document 7_6 Document 1: [ 11 C]Mes-IMPY for Injection: Chemistry, Manufacturing and Controls Page 3 of 14

4 4 Helium gas 5 Nitrogen gas Absolute ethanol (200 proof; 6 USP) Matheson Gas 932 Paterson Plank Road East Rutherford, NJ Matheson Gas 932 Paterson Plank Road East Rutherford, NJ Warner-Graham Co. P.O. Box 249, 160 Church Lane Cockeysville, MD COA Document 7_7 COA Document 7_9 USP, COA Document 7_10 7 Acetonitrile, HPLC Grade Burdick & Jackson 1953 South Harvey Street Muskegon, MI Burdick & Jackson 8 Methanol, HPLC Grade 1953 South Harvey Street Muskegon, MI Water, HPLC Grade EMD Chemicals Inc. 480 S. Democrat Rd. Gibbstown, NJ EMD Chemicals Inc. 10 Phosphoric acid, 85% 480 S. Democrat Rd. Gibbstown, NJ Mallinckrodt Laboratory Chemicals 11 Iodine, sublimed 222 Red School Lane Phillipsburg, NJ Aldrich Chemical Company 12 Acetonitrile, anhydrous 1001 West St. Paul Ave, Milwaukee, WI tert-butyliminotris(dimethylamino) Fluka Chemical Company West St. Paul Ave, phosphorane Milwaukee, WI COA Document 7_11 COA Document 7_12 COA Document 7_13 COA Document 7_22 COA Document 7_15 COA Document 7_16 COA Document 7_17 Document 1: [ 11 C]Mes-IMPY for Injection: Chemistry, Manufacturing and Controls Page 4 of 14

5 Abbott Laboratories Inc. Dehydrated alcohol, Injection, 200 Abbott Park Rd. USP Abbott, IL Abbott Laboratories Inc. 14 Sodium bicarbonate, 8.4% 200 Abbott Park Rd. Abbott, IL Sterile filter (MP; 25 mm; 0.22 Millipore 15 µm; Millex) 80 Ashby Road Bedford MA Sterile filter (GV; 4 mm; 0.22 Millipore µm vent type; Millex) 80 Ashby Road Bedford MA Sterile vial, 10 ml Abbott Laboratories Inc. 200 Abbott Park Rd. Abbott, IL American Pharmaceutical 18 Saline Partners, Inc Staley Road Grand Island, NY Mallinckrodt Baker, Inc. 19 Polysorbate 80, N. F. 222 Red School Lane Phillipsburg NJ Aldrich Chemical Company 20 Dimethyl sulfoxide, DMSO 1001 West St. Paul Ave, Milwaukee, WI COA Document 7_24 COA Document 7_20 COA Document 7_4 COA Document 7_3 COA Document 7_5 COA Document 7_21 COA Document 7_23 COA Document 7_14 3. REFERENCE STANDARDS The following reference standard is used in the quality control methods of [ 11 C]Mes-IMPY for Injection: Document 1: [ 11 C]Mes-IMPY for Injection: Chemistry, Manufacturing and Controls Page 5 of 14

6 Name of reference standard 1 N,N-Dimethyl-4-(6- (methylthio)h-imidazo[1,2- a]pyridin-2-yl)benzenamine Name and address of the supplier Synthesized at PRSS, Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health Representative COA and acceptance criteria COA Document 7_18 2 Methyl 3-(2-(4- (dimethylamino)phenyl)imida zo[1,2-a]pyridin-6- ylthio)propanoate Synthesized at PRSS, Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health COA Document 7_19 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), Building 10, Room B3C338, 10 Center Drive, MSC 1003 Contact persons Victor W. Pike, Ph.D., Chief, PET Radiopharmaceutical Sciences Section (PRSS) Phone: (301) Lisheng Cai, Ph.D., Radiochemist (PRSS) Jinsoo Hong, Radiochemist (PRSS) Cheryl Morse, Radiochemist(PRSS) Kelly Sprague, Radiochemist(PRSS) 5. MANUFACTURE OF DRUG SUBSTANCE A. Batch Formula The following components and their quantities are used in the production of each batch of [ 11 C]Mes-IMPY for Injection: Document 1: [ 11 C]Mes-IMPY for Injection: Chemistry, Manufacturing and Controls Page 6 of 14

7 Name of component Component s function Amount used Methyl 3-(2-(4- Substrate/starting material/ 0.5 ± 0.1 (dimethylamino)phenyl)imidazo[1,2-a]pyridin-6- radiopharmaceutical precursor mg ylthio)propanoate [ 11 C]Iodomethane Radiolabeling agent Ci Acetonitrile, anhydrous Reaction solvent 400 µl tert-butylimino-tris(dimethylamino) phosphorane (BTP) in acetonitrile, 0.5 M Reaction base 7 µl HPLC column Separation of product 1 Sodium bicarbonate, 8.4% Neutralize acid in the HPLC eluate 200 µl Sodium Chloride for Injection (USP; 10 ml vial) Formulation 10 ml Sterile vial, 10 ml Product container 1 Filter (MP; 0.22 µm; 25 mm; Millex) Sterilization 1 Filter (GV; 0.22 µm; 4 mm; Millex) Sterile vent filter 1 Polysorbate 80, N. F., in 0.9% saline (2 mg per ml) Surfactant 20 ± 5 mg Ethanol Formulation 0.9 ml NOTE: Upon scale-up, only the mci amount of radioactive [ 11 C]carbon dioxide reagent is changed. The other components and their amounts remain as stated in the batch formula. B. Production of Radionuclide All [ 11 C]carbon dioxide is prepared at the NIH Cyclotron Facility. No other source of carbon-11 is used for the production of [ 11 C]Mes-IMPY for Injection. C. Cyclotrons Used The following cyclotrons are used for the production of [ 11 C]carbon dioxide radionuclide: Document 1: [ 11 C]Mes-IMPY for Injection: Chemistry, Manufacturing and Controls Page 7 of 14

8 Manufacturer General Electric Cyclotron Corporation Japan Steel Works Model PETtrace CS-30 JSW-1710 Specifications for Target Body Target Data JSW CS-30 GE PETtrace # 1 GE PETtrace # 2 Target body material Aluminum Aluminum Aluminum Aluminum Entrance target foil material Aluminum Aluminum Havar Havar Target length (cm) Target volume (ml) Gas pressure (atm) Maximum proton energy (MeV) Maximum beam current (µa) D. Synthesis and Purification of the Drug Substance Description of Radiosynthesis Equipment and Its Operation: The descriptions of the radiosynthetic equipment and its cleaning and operation are provided in a copy of the SOP for the unit. See Document 5, SOP # MP201 and SOP # MP202. Radiosynthetic Production Unit: Manufacturer: General Electric MS PET Systems AB Model: GE PETtrace Methyl Iodide Micro Lab Serial Number: Manufacturer: General Electric Healthcare ( formerly, Uppsala University PET center) Model: Synthia Serial Number: Cecillia Document 1: [ 11 C]Mes-IMPY for Injection: Chemistry, Manufacturing and Controls Page 8 of 14

9 In-Process Controls: The radiosynthesis production unit continuously records data from its many transducers as part of each batch record attachment. The batch record provides all pertinent information for the control of the radiosynthesis. 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 5, SOP # MP 201 and # MP MANUFACTURE OF DRUG PRODUCT A. Production Operation The production operation is initiated by manually loading the methyl 3-(2-(4- (dimethylamino)phenyl)imidazo[1,2-a]pyridin-6-ylthio)propanoate dissolved in 0.40 ml of acetonitrile and 7 μl of tert-butylimino-tris(dimethylamino)phosphorane in acetonitrile (0.5 M) into the Synthia Apparatus. [ 11 C]Carbon dioxide, produced from the cyclotron, is then converted into [ 11 C]iodomethane via the GE Micro-lab module. The [ 11 C]iodomethane is then swept into the Synthia Apparatus and reacted with methyl 3-(2-(4-(dimethylamino)phenyl)imidazo[1,2-a]pyridin-6- ylthio)propanoate to produce [ 11 C]Mes-IMPY. The radiolabeled drug substance is purified with HPLC and the HPLC eluate is neutralized and removed by rotary evaporation. The purified [ 11 C]Mes-IMPY is formulated in 10 ml of Sterile Saline for Injection (USP, 0.9% w/v) containing 20 mg Polysorbate 80 and 0.9 ml USP ethanol, and is then sterile-filtered into a sterile and pyrogenfree dose vial. The final sterile vial, vent needle, product needle, and two sterile 0.22 µm filters are assembled in a sterile cabinet (certified laminar flow sterile cabinet in Rm B3C-313) before attachment to the radiosynthesis unit. The master production and control records that provide the exact procedures used in the controlled production of [ 11 C]Mes-IMPY for Injection are provided in Document 2. Attached to each batch of [ 11 C]Mes-IMPY for Injection are (in this order): 1 Production Batch Record 2 Quality Control Form: Document 1: [ 11 C]Mes-IMPY for Injection: Chemistry, Manufacturing and Controls Page 9 of 14

10 - form contains summary of the quality control results - actual HPLC data 3 Radiopharmacy Form: - form contains summary of results (label, pyrogen testing, sterility testing) B. Reprocessing of Drug Product The PRSS does not reprocess [ 11 C]Mes-IMPY for Injection. 7. CONTAINER/CLOSURE The pre-sterilized, pre-sealed, pyrogen-free container/closure is obtained from Abbott Laboratories. Full information on the container/closure along with its contents sterilization procedures and sterility assurance are provided in the attached COA (Document 7_5). Name and address of supplier Abbott Laboratories Inc., 200 Abbott Park Rd., Abbott, IL NDC/List number Container Flip-top Vial - Glass (LF) Representative COA and acceptance criteria COA ( Document 7_5) 8. CONTROLS FOR THE FINISHED DOSAGE FORM A. Sampling Procedures Each batch of [ 11 C]Mes-IMPY 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 5, SOP # QA301: Post-filtration sampling for QC. Document 1: [ 11 C]Mes-IMPY for Injection: Chemistry, Manufacturing and Controls Page 10 of 14

11 B. Regulatory Specifications, Procedures, and Testing Schedules Each batch of [ 11 C]Mes-IMPY 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 will not be released. We also assure that FDA will be notified of any changes to the approved application. Note: The following tests are related to a commonly used production method. In the event that the production method does not use a component listed below or uses an alternative method of production or produces additional impurities, appropriate tests, acceptance criteria, procedures, and a testing schedule that is more appropriate for such production will be proposed. Test Acceptance Procedures Testing criteria schedule Radionuclidic identity The measured half-life is Measurement of a between 18 and 22 min sample in a dose annually or before calibrator over 20 min use of new target period. See Document design 6, and Document 5, SOP # QA 306. Radiochemical Retention time within ± HPLC QC Procedure identity 0.5 min of a standard injection of Mes-IMPY See Document 3, Document 8, and before release of drug product Document 5, SOP # QA 303. Radiochemical purity NLT 1 95 % [ 11 C]Mes-IMPY Chemical purity For the injection NMT μg of Mes-IMPY impurity equivalent 3 HPLC QC Procedure. See Document 3. HPLC QC Procedure. See Document 3. before release of drug product before release of drug product Document 1: [ 11 C]Mes-IMPY for Injection: Chemistry, Manufacturing and Controls Page 11 of 14

12 Assay 2.0 to 25 mci /ml Ionization chamber (radioconcentration) at EOS 4 (dose calibrator). before release of See Document 3. drug product Residual solvents Acetonitrile: NMT 0.04% (w/v). Ethanol: NMT 10% (w/v) Gas chromatography with flame ionization detection. See Document 5, SOP # QA 302. ph ph paper. See Document 3 Test performed on three qualifying runs. before release of drug product Specific radioactivity NLT 500 Ci/mmol at HPLC QC Procedure EOS See Document 3, Document 8, Document before release of drug product 5, SOP # QA 307, and SOP # QA 303. Sterility testing Sterile NIH Microbiology Building 10 Clinical Center, Document 4. Bactec Test initiated as soon as feasible. Typically, less than 24 h after release of drug product Membrane filter Sterile 0.22 µm filters are Pressure gauge integrity used once. Each transducer. No bubbles before release of membrane tested by at 45 p.s.i. See drug product bubble point test. Document 5, SOP # GP 102. Document 1: [ 11 C]Mes-IMPY for Injection: Chemistry, Manufacturing and Controls Page 12 of 14

13 Bacterial endotoxins Less than 2.5 EU/mL LAL test kit procedure, Test performed on (LAL) See Document 4 and each batch. Drug Document 5, SOP # QA product may be 305. released before test completion. 1. NLT = No less than 2. NMT = No more than 3. i.e. < 10% impurity of maximum allowed dose of 10.0 μg 4. EOS = End of synthesis 9. MICROBIOLOGICAL VALIDATION Data provided in Document 9 (Validation Runs) show that [ 11 C]Mes-IMPY 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 A. Expiry Dating Period Expiry-dating period is 1 h from EOS for [ 11 C]Mes-IMPY for Injection stored at controlled room temperature (note: refer to USP for controlled room temperature definition). B. Stability Data/Batch Data Complete release and stability data were obtained on three batches of [ 11 C]Mes-IMPY for Injection, prepared at the upper range of the proposed radio-concentration and stored at controlled room temperature. See Document 9: Validation Runs. Also for each stability batch: The batch was stored in the same container/closure as it was produced. Document 1: [ 11 C]Mes-IMPY for Injection: Chemistry, Manufacturing and Controls Page 13 of 14

14 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 5, SOP # QA 304. Each batch will be labeled with a lot number, compound name, volume and assay and will contain the statement: "Caution: New Drug Limited by Federal Law to Investigational Use". 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 [ 11 C]Mes-IMPY for Injection on the basis that the estimated concentration of [ 11 C]Mes-IMPY 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. Chemistry, Manufacturing and Controls. Document 2. Master Batch Record. Document 3. Quality Control Record. Document 4. Radiopharmacy Test Results. Document 5. Standard Operating Procedures. Document 6. Standard Operating Procedures and Form of Annual Radionuclide Identity Test. Document 7. Certificate of Analysis. Document 8. Data Form for Preparation of Standard Solution. Document 9. Precursor and Reference Compound- Acceptance Testing and Forms. Document 10. Validation Runs. Document 1: [ 11 C]Mes-IMPY for Injection: Chemistry, Manufacturing and Controls Page 14 of 14