[118CF](-)-RNNC112WAYFALLYPRIDE FOR INJECTION: CHEMISTRY, MANUFACTURING AND CONTROLS
PET Radiopharmaceutical Sciences Section, Date of review: 085/0617/054
Molecular Imaging Branch,
National Institute of Mental Health,
National Institutes of Health,
Bldg. 10, Rm. B3 C338,
Bethesda, MD 20892
13
CHEMISTRY, MANUFACTURING AND CONTROLS: [18F]FALLYPRIDE FOR INJECTION
Table of Contents
1. DRUG PRODUCT COMPONENTS AND QUANTITATIVE COMPOSITION
2. CONTROLS FOR COMPONENTS / RAW MATERIALS
A.Organic substrate (Key Intermediate)
B.Target Starting Material
C.Reagents, Solvents, Gases, Purification Columns, etc
3. REFERENCE STANDARDS
4. MANUFACTURING AND TESTING FACILITIES
5. MANUFACTURE OF DRUG SUBSTANCE
A.Batch Formula
B.Production of Radionulide
C.Cyclotrons Used
D.Synthesis and Purification of the Drug Substance
Description of Radiosynthetic Production Equipment and Its Operation.
Radiosynthetic Production Unit
In-Process Controls
Post-Synthesis Procedures
6. MANUFACTURE OF DRUG PRODUCT
A.Production Operation
B.Reprocessing of PET Drug Product
7. CONTAINER/CLOSURE
8. CONTROLS FOR THE FINISHED DOSAGE FORM
A.Sampling Procedures
B.Regulatory Specifications, Procedures, and Testing Schedules
9. MICROBIOLOGICAL VALIDATION
10. STABILITY AND BATCH DATA
A.Expiration Dating Period
B.Stability Data/Batch Data
11. VIAL AND OUTER PACKAGING LABELS
12. ENVIRONMENTAL ASSESSMENT
1. DRUG PRODUCT COMPONENTS AND QUANTITATIVE COMPOSITION
Component / Composition/batchDrug Substance
[11C](-)-NNC 112RWAY / 20 to 225000 mCi at EOS1
Other ingredient(s)
0.9% Sodium Chloride Injection, USP / 10 mL
- EOS = End of synthesis calibration time.
2. CONTROLS FOR COMPONENTS / RAW MATERIALS
A.Organic substrate (low case) (Key Intermediate)
1. / Name of component / Desmethyl-(S)-NNC 112 RWAY (2,3,4,5,6,7-Hexahydro-1{4-[1[4-(2-Hydroxyphenyl)-piperazinyl]]-2-phenylbutyryl}-1H-azepine (RWAY) ((+)-5-benzofuran-4-yl-8-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol )2. / Name and address of supplier / Axon Biochemicals BV, Biotech Center, UMCG Bldg 53, Postbus 770, 9700 AT Groningen, The NetherlandsKarolinska Institute. Dept. of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, Stockholm, Sweden.
3. / Certificate of analysis / HPLC chromatogram, NMR, and LC-MS chromatogram are provided. See Document 910.
4. / Storage conditions / 1. Container / Closure 4 mL screw cap vial housed in a plastic canister
2. Stored at 4oC
3. The material is stable for 2 years, when stored in above container/closure under described storage conditions.
B.Target Starting Material
All radioactive[11C] carbon dioxide is produced at the NIH Cyclotron Facility.
The following target material will be used for the production of short-lived radioactive [11C]carbon dioxide
1. / Name of the target material / Nitrogen Gas with about ca. 1% oxygen2. / Name and address of the target material manufacturer / Matheson Gas
932 Paterson Plank Road
East Rutherford, NJ 07073
3. / Identity test performed to release each lot for production use / COA
4. / Certificate of analysis, COA / A representative copy of supplier’s certificate of analysis is provided in COA Attachment Section
5. / Target material recycling criteria. / N/A
C.Reagents, Solvents, Gases, Purification Columns, etc
Name / Name and address of the supplier / Quality grade (e.g., ACS, USP, etc.), representative COA and acceptance criteria1 / Acetonitrile, HPLC Grade / Burdick & Jackson
1953 South Harvey Street
Muskegon, MI 49442 / COA Document 87.
2 / Water, HPLC Grade / EMD Chemicals Inc.
480 S. Democrat Rd.
Gibbstown, NJ 00827 / COA Document 87.
3 / N,N-Dimethylformamide / Aldrich Chemical Company
1001 West St. Paul Ave,
Milwaukee, WI 53233 / COA Document 87.
4 / PBeckman C-18 Ultrasphere 5 henomenex Luna 10µm (10 x 250mm) / PBeckmanhenomenex
411 Madrid Ave. Torrance4300 N. Harbor Blvd.
Fullerton, CA 90501-14302834 / COA Document 87.
5 / Absolute ethanol (200 proof ; USP) / Warner-Graham Co.
P.O. Box 249, 160 Church Lane
Cockeysville, MD 21030 / USP
6 / Sterile filter (MP; 25mm; 0.22 µm; Millex) / Millipore
80 Ashby Road
Bedford MA 01730 / COA Document 87.
7 / Sterile filter (GV; 4 mm; 0.22 µm vent type; Millex) / Millipore
80 Ashby Road
Bedford MA 01730 / COA Document 87.
8 / Sterile vial, 10 mL / Abbott Laboratories Inc.
200 Abbott Park Rd.
Abbott, IL 60064 / COA Document 87.
9 / Tetrabutylammomium hydroxide (1M in methanol) / Aldrich Chemical Company
1001 West St. Paul Ave,
Milwaukee, WI 53233 / COA Document 7
3. REFERENCE STANDARDS
The following reference standards are used in the quality control methods of [11C]NNC 112 RWAY for injection:
Name of reference standard / Name and address of the supplier / Representative COA and acceptance criteria1 / (-)-RNNC 112WAY / Karolinska Institute, Dept. of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, Stockholm, Sweden.Axon Biochemicals BV, Biotech Center, UMCG Bldg 53, Postbus 770, 9700 AT Groningen, The Netherlands / 1H-NMR spectrum, LC/MS, HPLC chromatogram. See
Document 9: Acceptance Testing and Forms
2 / Desmethyl -(-)-NNC 112 RWAY / Axon Biochemicals BV, Biotech Center, UMCG Bldg 53, Postbus 770, 9700 AT Groningen, The Netherlands Karolinska Institutet, Dept. of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, Stockholm, Sweden. / 1H-NMR spectrum, LC/MS, HPLC chromatogram. See Document 9: Acceptance Testing and Forms.
4. MANUFACTURING AND TESTING FACILITIES
Facility Address / Contact PersonsPET Radiopharmaceutical Sciences Section (PRSS), Molecular Imaging Branch (MIB)
National Institute of Mental Health
National Institutes of Health (NIH)
Building 10, Room B3C338
10 Center Drive, MSC 1003
Bethesda, MD 20892 / Victor W. Pike, Ph.D., Chief, PET Radiopharmaceutical Sciences Section (PRSS)
Phone: (301)- 435-7847
John L. Musachio, Ph.D., Radiochemist (PRSS)
Jinsoo Hong, Radiochemist (PRSS)
5. MANUFACTURE OF DRUG SUBSTANCE
A.Batch Formula(lower case)
The following components and their quantities are used in the production of each batch of [11C](-)-RNNCWAY 112 for injection: (not the same form , say as in 3)
Name of component / Component’s function / Amount usedDesmethyl-(-)-RNNC 112WAY / Substrate starting material – radiopharmaceutical precursor / 1.00.3 + 0.1 mg
[11 C]iodomethanemethyl iodide / Radiolabeling agent / 100 to 1000 mCi
N,N-Dimethylformamide / Reaction solvent / 80 µL
Tetrabutylammonium hydroxide 0.17 M / Reaction base / 4.5 µL
HPLC column / Separate product / 1
Sodium Chloride for Injection, (USP; 10 mL vial) / Formulation / 1
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
NOTE: Upon scale-up, only the mCi amount of radioactive [11C]carbon dioxide reagent is changed. The other components and their amounts remain as stated in the batch formula.
B.Production of Radionulide (lower case)
All radioactive [11C]carbon dioxide is prepared at the NIH Cyclotron Facility. No other source of material is used for the production of [11C](-)-RNNC 112WAY for injection.
C.Cyclotrons Used
The following cyclotrons are used for the production of [11C]carbon dioxide radionuclide:( delete radionuclide?)
Manufacturer / ModelGeneral Electric / PETtrace
Cyclotron Corporation / CS-30
Japan Steel Works / JSW-1710 (did you use this?)
Specifications for Target Body
Target Data / JSW - 1710 / CS-30 / GE PETtrace #1 / GE PETtrace #2Target body material / Aluminum / Aluminum / Aluminum / Aluminum
Entrance target foil material / Aluminum / Aluminum / Havar / Havar
Target length, cm / 30 / 25.4 / 25 / 10
Target volume, mL / 212 / 129 / 75 / 11
Gas pressure, atm / 5 / 17 / 10 / 25
Maximum proton energy, MeV / 9 / 20 / 16.5 / 16.2
Maximum beam current, µA / 30 / 25 / 50 / 30
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 MP202.
Radiosynthetic Production Unit (also include the Bioscan loop?)
Manufacturer:General Electric MS PET Systems AB
Model:GE PETtrace Methyl Iodide Micro Lab
Serial Number:27740
In-Process Controls:
The radiosynthetichesis 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 radiosynthesistic 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 5, SOP # MP 201 and MP 202.
6. MANUFACTURE OF DRUG PRODUCT
A.Production Operation
The production operation is initiated by manually loading the desmethyl-NNC 112 RWAY dissolved in 0.08 mL of DMF and 4.5 μL of methanolic 0.17M tetrabutyl ammonium hydroxide into the Bioscan Autoloop module. [11C]Ccarbon dioxide, produced from the cyclotron, is then converted into [11C]iodomethane via the GE methyl iodide Micro-lab module. The [11C]iodomethane is then swept into the Autoloop module and the radiolabeling reagent is reacted with desmethyl-NNC 112 RWAY to produce [11C](S)-RNNC 112WAY. The radiolabeled drug substance is purified by HPLC and the HPLC eluent removed by rotary evaporation. The purified [11C](-)-RWAYNNC 112 is formulated in Sterile Saline for Injection (USP, 0.9% w/v; 10 mL) and sterile-filtered into a sterile, pyrogen-free 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 [11C](-)-RWAYNNC 112 are provided in document 2.
Attached to each [11C](-)-RWAY NNC 112 batch (in this order):
1 / Production Batch Record2 / Quality Control Form:
- 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 PET Drug Product
The PET Radiopharmaceutical Sciences Section of the Molecular Imaging Branch of NIMH does not reprocess [11C](-)-RNNC 112WAY.
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 is provided in the attached certificate of analysis (COA).
Name and Address of Supplier / Abbott Laboratories Inc.200 Abbott Park Rd. Abbott, ILNDC/List number / 5816-11
Container / Flip-top - Vial- Glass (LF)
Representative COA and acceptance criteria / COA ( Document 78)
8. CONTROLS FOR THE FINISHED DOSAGE FORM
A.Sampling Procedures
Each batch of [11C](-)-RWAYNNC 112 for injection will be produced in one vial, a description of the amount of volume that is withdrawn from the finished drug product container and how it is distributed among individual tests is provided in the standard operating procedure entitled, “SOP # QA301: Post-filtration sampling for QC.”
B.Regulatory Specifications, Procedures, and Testing Schedules
Each batch of [11C](-)-RWAYNNC 112 for injection will meet the following specifications during its entire shelf life (see below). We assurecommit that any batch that fails to meet the acceptance criteria will not be released. We also assurecommit 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 alternate method of production or produces additional impurities, appropriate tests, acceptance criteria, procedures, and a testing schedule that is more appropriate for such production should be proposed.
TEST / ACCEPTANCECRITERIA / PROCEDURES / TESTING
SCHEDULE
Radionuclidic identity / The measured half-life is between 18–22 min / Measurement of a sample in a dose calibrator over 20 min period. / Test completed annually or before use of new target design
Radiochemical identity / Retention time ± 0.51.0 min in comparison to standard injection of RWAYNNC 112 / HPLC QC Procedure
See Document 3. / Test completed before release of drug product
Radiochemical purity / NLT1 95 %
[11C](-)-RWAYNNC 112 / HPLC QC Procedure
See Document 3. / Test completed before release of drug product
Chemical Purity / For the injection NMT2 0.1654 g of impurity (RNNC 112 WAY equivalent)3 / HPLC QC Procedure
See Document 3. / Test completed before release of drug product
Assay
(radioconcentration) / 2.0 mCi to 2250 mCi /mL
at EOS4 / Ionization chamber (dose calibrator)
See Document 3. / Test completed before release of drug product
Residual solvents: / Acetonitrile: NMT 0.04% (w/v).
Ethanol: NMT 10% (w/v) / Gas chromatography with flame ionization detection
See Document 3 and Document 5 SOP #QA 302. / Test performed on 3 vaildating runs each batch. Test completed before release of drug product.
pH / 4.5−7.5 / pH paper
See Document 3 / Test completed before release of drug product
Specific radioactivity / No carrier added
[11C]NNC 112
NLT 500 Ci/mmol at EOS / HPLC QC Procedure
See Document 3. / Test completed before release of drug product
Sterility testing / Sterile / NIH Microbiology
Bldg 10
Clinical Center / Bactec Test initiated as soon as feasible. Typically, less than 24 hours after release of drug productTest initiated within 192 hours of preparation
Membrane filter integrity / Sterile 0.22 µm filters are used once. Each membrane tested by bubble point test. / Pressure gauge transducer. No bubbles at 45 p.s.i
See Document 5: SOP # GP102. / Test completed prior to release of drug product
Bacterial endotoxins
(LAL) / Less than 1.252.5 EU/mL / LAL test kit procedure (see Document 4: Radiopharmacy Form) / Test performed on each batch. Drug product may be released before teat completion completion of test.
Optical purity / > 90% / HPLC procedure
See document 3 / Test performed on 1 validating run (see document 10) and once after receiving a new batch of precursor.
- NLT = No less than
- NMT = No more than
- i.e. < 10% impurity of maximum allowed dose of 6.5410 g
- EOS = End of synthesis
- Chiralpak AD, 4.6 mm x 250 mm, 95:5:0.1 hexane;2-propanol; triethylamine, 254 nm, 2.0 mL/min. tR [11C](-)-RWAY 9.2 min tR [11C](+)-RWAY 6.1 min
9. MICROBIOLOGICAL VALIDATION
Data provided in Document 10 (Validation Runs) show that [11C](-)-RWAY for injection is obtained in a sterile and pyrogen-free form, when prepared according to this application and the submitted batch production record
Data validating that the [11C]NNC 112 injection can be produced in a sterile and pyrogen-free form, when prepared as described in this application and in the submitted batch production record are provided in Document 9: Validation Runs.
10. STABILITY AND BATCH DATA
A. Expiratioyn Dating Period
Expiratioyn-dating period is 1 h from the EOS calibration time for [11C](-)-NNC 112 RWAY for injection when stored at controlled room temperature (note: Refer to USP for controlled room temperature definition).
B. Stability Data/Batch Data
Complete release and stability data on three batches of [11C](-)-NNC 112 RWAY for injection were prepared at the upper range of the proposed radioconcentration and stored at controlled room temperature. See document 910: Validation Runs.
AAdditionallylso for each stability batch:
- The batch was 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 proposed expiration dating period.
11. VIAL AND OUTER PACKAGING LABELS
Draft copies of proposed vial and outer packaging labels are provided in Document 5: SOP # 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." A copy of the printed representative label is found in the standard operating procedure entitled “SOP # QA 304: Release of [C-11](-)-R]NNC112WAY NIMH ppProduction and quality control laboratories.”
12. ENVIRONMENTAL ASSESSMENT
In accordance with 21 CFR 25.31(b), the National Institute of Mental Health PET Radiopharmaceutical Sciences Section claims a categorical exclusion from the environmental assessment requirements of 21 CFR 25.20 for approval of [11C](-)-NNC 112 RWAY for injection on the basis that the estimated concentration of [11C](-)-NNC 112 RWAY at the point of entry into the aquatic environment will be below 1 part per billion. Additionally, no extraordinary circumstances exist.
Table of Contents
1. DRUG PRODUCT COMPONENTS AND QUANTITATIVE COMPOSITION...... 2
2. CONTROLS FOR COMPONENTS &AND RAW MATERIALS...... 2
A...... Organic Substrate (Key Intermediate) 2
B...... Radionuclide 3
C...... Other Ingredients 3
D...... Reagents, Solvents, Gasses, Purification Columns, and Other Auxiliary Materials 4
3. REFERENCE STANDARDS...... 5
4. MANUFACTURING AND TESTING FACILITIES...... 5
5. MANUFACTURE OF DRUG SUBSTANCE...... 6
A...... Batch Formula: 6
B...... Production Oof Radionuclide 7
C...... Synthesis Aand Purification Oof Tthe Drug Substance 8
6. MANUFACTURE OF DRUG PRODUCT...... 9
A...... Production Operation 9
B...... Reprocessing Oof PET Drug Product 9
C...... Packaging Aand Labeling 9
7. CONTAINER &AND CLOSURE...... 10
8. CONTROLS FOR THE FINISHED DOSAGE FORM...... 10
A...... Sampling Procedures 10
B...... Regulatiory Specifications, Procedures Aand Tests 10
9. MICROBIOLOGICAL VALIDATION...... 12
10. STABILITY AND BATCH DATA...... 12
A...... Expiration Dating Period 12
B...... Stability Data/Batch Data 12
C...... Post-Approval Commitments 13
11. VIAL AND OUTER PACKAING LABELS...... 1313
Chemical and Manufacturing Control Document
...... Page
Introduction………………………………………………………………………..
1. Drag Drug Product Components and Quantitative Composition…………………
2. Controls for Components / Raw Materials…………………………………
Organic substrate.
Target Starting Material.
Other Ingredients
Reagents, Solvents, Gases, Purification Columns, and Other Auxiliary Materials.
3. Reference Standards.
4. Manufacturing and Testing Facilities.
5. Manufacture of Drug Substance
Batch Formula.
Production of Radionuclide.
Synthesis and Purification of the Drug Substance.
6. Manufacture of Drug Product
Production Operation.
Processing of PET Drug Product.
7. Container/ Closure.
8. Controls for the Finished Dosage Form.
Sampling Procedures.
Regulatory Specifications, Procedures and Testing Schedules.
9. Microbiological Validation.
10. Stability and Batch Data.
Expiration Dating Period.
Stability Data / Batch Data.
Postapproval Commitments.
11. Vial and Outer Packing Labels.
12. Environmental Assessment.
13. Preclinical Investigations.
14. Clinical Investigations.
15. Investigator’s experience.
16. Pharmacology and Toxicology
17. Additional Information.
CHEMICAL AND MANUFACTURING CONTROL DOCUMENT
INTRODUCTION
The Fallypride
FALLYPRIDE 18F INJECTION
Chemistry, Manufacturing, and Controls Section
1. DRUG PRODUCT COMPONENTS AND QUANTITATIVE COMPOSITION
Component / Composition/BatchDrug Substance
[18F]Fallypride* / 2010−-2060 mCi @at EOS†
< 2 µg per injection
Other Ingredient(s)
1. Ethyl Alcoholanol for Injection (USP) / 1−-1.5 ml mL (≤ 10%)
2. NaCl Sodium Chloride for Injection (0.9 % w/v; USP) / 9−-13.5 ml mL (≤ 90%)
...... *Throughout this application [18F]fallypride denotes the drug substance and [18F]Fallypride for Injection denotes the finished drug product.
† EOS = End of sSynthesis and cCalibration tTime.
2. CONTROLS FOR COMPONENTS AND/ RAW MATERIALS
Organic Substrate (Key Intermediate)
1. / Name of component / Tosyl-_fFallypride,{(S)-2,3-dimethoxy-5-[3-[[(4-methylphenyl)sulfonyl]oxy]propyl]-N-[[1-(2-propenyl)-2-pyrrolidinyl]methyl]- benzamide }.
2. / Name and address of supplier / ABX Advanced Biochemical Compounds, Wilhelm-RöoÖnsch Str. 9, D-01454 Radeberg, Germany.
3. / Representative certificate of analysis (COA) from supplier / Copy of a representative certificate of analysisCOA is provided in AttachmentDocument 8, page 3.
4. / Storage conditions / 1. Container / Closure; 2 mg in dark glass vial packed under argon atmosphere, sealed with Teflon-faced rubber stoppers and tear-off crimp caps . (ABX Advanced Biochemical Compounds)
2. Store at − -20 o± 5 oC.
Radionuclide