US Regulatory Requirements: Clinical & Clinical Research Production, SPECT & PET Radiopharmaceuticals (RPs) 20 th International Symposium Radiopharmaceutical Sciences Jeju, Korea Pre-Symposium Workshop May 12, 2013 Sally W. Schwarz, M.S., B.C.N.P. Director Clinical PET Radiopharmaceutical Production Washington University St. Louis Department of Radiology
US FDA Regulations: SPECT & PET RP Clinical Production (CGMP) Regulations: 1) 21 CFR Part 211 SPECT: The regulation contains the minimum Current Good Manufacturing Practice (CGMP) for preparation of drug products (excluding PET) for administration to humans 2) 21 CFR Part 212 PET as of June 2012
Clinical Production (CGMP) 21 CFR Part 211 SPECT: The regulation contains the minimum Current Good Manufacturing Practice (CGMP) for preparation of drug products (excluding PET) for administration to humans Must file New Drug Application (NDA) or Abbreviated Drug Application (ANDA) with FDA Air Quality is defined for production areas e.g. ISO Class 7, buffer area (clean room), airlock, ante room Testing requirements different than Part 212 Examples: Production of all Tc-99m sterile kits used for compounding Ga-67 Citrate Injection Tl-201 Chloride Injection Mo-99/Tc-99m generators Clinical Practice Using SPECT RP: follow USP Chapter <797>
Clinical Production (CGMP) Regulations: 2) 21 CFR Part 212 PET as of June 2012 The regulation contains the minimum Current Good Manufacturing Practice (CGMP) for preparation of PET drugs for administration to humans Air Quality only defined for Laminar Flow Hood (ISO Class 5) Testing requirements different than Part 211 unique quality of PET drugs Must file New Drug Application (NDA) or Abbreviated Drug Application (ANDA) with FDA Examples : F-18 FDG Injection F-18 Fluoride Injection N-13 Ammonia Injection C-11 Choline Dispensing PET drugs: follow USP Chapter <797>
Good Manufacturing Practice (CGMP) Regulations 21 CFR Part 2ll CGMP for Finished Pharmaceuticals Subpart A--General Provisions Subpart B--Organization and Personnel Subpart C--Buildings and Facilities Subpart D--Equipment Subpart E--Control of Components and Drug Product Containers and Closures Subpart F--Production and Process Controls Subpart G--Packaging and Labeling Control Subpart H--Holding and Distribution Subpart I--Laboratory Controls Subpart J--Records and Reports Subpart K--Returned and Salvaged Drug Products 21 CFR Part 212 CGMP For Positron Emission Tomography Drugs Subpart A: General Provisions Subpart B: Personnel and Resources Subpart C: Quality Assurance Subpart D: Facilities & Equipment Subpart E: Control of Components, Containers, & Closures Subpart F: Production & Process Controls Subpart G: Laboratory Controls Subpart H: Finished Drug Product Controls & Acceptance Subpart I: Packaging and Labeling Subpart J: Distribution Subpart K: Complaint Handling Subpart L: Records
Clinical Research Production 1) New Drugs First in Man: require Investigational New Drug Application (IND) (Rule: FDA 21 CFR Part 312) Phase 0: Proof of concept Phase 1: Tolerability studies metabolism and pharmacologic action, side effects, SAR, explore biological phenomena or disease process Phase 2: Evaluate effectiveness Phase 3: Effectiveness and safety--commercialization 2) Exploratory IND (EIND or eind) 2004 Phase 0 3) SPECT RP: Phase1 IND In vivo diagnostics are exempt from 21 CFR Part 211 requirements Production of Phase 1 SPECT drugs: FDA Guidance for Industry: CGMP for Phase 1 Investigational Drugs, July 2008; http://www.fda/gov/cder/guidance/index.htm Phase 2-3: must follow Part 211 (Information at http://www.fda.gov/dcer/gmp/21stcenturysummary.htm 4) PET RP: PET and SPECT Clinical Research Phase 0, 1 and 2: allows production of Investigational PET drugs according to either USP <823> or Part 212 Phase 3: must follow Part 212 FDA Guidance: IND Applications for PET Drugs, February 2012 http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm291573.pdf 5) Drugs with known human pharmacology may be produced under Radioactive Drug Research Committee (RDRC) (21 CFR Part 362)
USA Regulatory Pathway for Radiopharmaceuticals Radiotracers subject to same process as development of new therapeutic pharmaceutical: PET/SPECT Radiotracer First in humans? Yes No EIND Phase 0 *Radioactive Drug Research Committee (RDRC) * FDA oversight IND Clinical Phase 0-1, 2, & 3 Approval
What are the components of a US Investigational New Drug (IND) Application? 21 CFR Part 312 General investigational plan Investigator s brochure, if required Protocol(s) Chemistry Manufacturing & Controls (CMC) Production Process Quality Control Process Pharmacology and Toxicology--2 species Previous human experience Dosimetry Estimates (not specified section)
Exploratory IND Guidance 2006 Microdose: 1/100 th of the dose calculated to yield a pharmacologic effect Introduced in European Union, 2004 Mass dose 100 µg (protein products 30 nmoles) Reduced pharmacology, toxicology requirements One mammalian species (both sexes) 100 times human dose Study period 14 days Phase 0 studies Subject enrollment: number not stated in the guidance Transition to Phase 1 IND
Exploratory IND Facilitates first-in-human imaging studies Biologics Drugs Bridges preclinical --- Phase 0 to Phase 1 Ideal for proof-of-mechanism studies (POM)
Radioactive Drug Research Committee (RDRC) 21 CFR Part 361 Purpose: to study basic research No clinical decisions allowed Pharmacology must be known in humans Drug generally recognized as safe and effective (GRASE) No observed pharmacological effect can be noted from mass dose administered (NOEL) No First in Human Studies Radiation Dose Limits: adults and children (10% of adult radiation dose is maximum, often not adequate) Regulatory revisions needed in pediatric dose limits Federal funding requires children be included in studies
SPECT Clinical Research 1) SPECT RP: Phase1 IND in vivo diagnostics are exempt from 21 CFR Part 211 requirements Production of Phase 1 SPECT drugs: FDA Guidance for Industry: CGMP for Phase 1 Investigational Drugs, July 2008 2) GCMP during Phase 1 Well-defined, written procedures Adequately controlled equipment and manufacturing environment Accurately & consistently recorded data from manufacturing and testing 3) Available technologies & resources Use of Disposable equipment & processes Prepackaged Materials (e.g. Water for Injection, pre-sterilized containers & closures) Use closed process equipment alleviate need for stricter room classification for air quality 4) FDA Guidance: CGMP for Phase 1 Investigational Drugs http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070273.pdf Sterile Drug Products Produced by Aseptic Processing--CGMP http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070342.pdf
What is the United States Pharmacopeia? United States Pharmacopeia (USP): Sets legal, enforceable standards for drugs (including radiopharmceuticals) in the United States General Chapters under 1000 are enforceable General Chapters over 1000 are for information Chapter <797> and <Chapter <823>
United States Pharmacopeia (USP) Chapter <797>: Pharmaceutical Compounding Sterile Preparations (CSPs) (official June 2008) Risk Levels: assigned according to potential for microbial contamination during compounding Low Medium High: Non-sterile components Immediate-use Chapter <823>: Radiopharmaceuticals for Positron Emission Tomography (PET) Compounding (32 nd edition, official 1998)
USP Chapter 797 Pharmaceutical Compounding Sterile Preparations Compounded Sterile Preparation = CSP CSPs include any of the following: compounded biologics, diagnostics, drugs, nutrients, and radiopharmaceuticals Compounding, for purposes of this chapter, includes preparation of manufactured sterile products, whether or not according to package insert instructions includes transfer of sterile products from one container to another (e.g., transfer of sterile liquid from a vial into a sterile syringe) BUD = beyond use date
USP Chapter 797 Pharmaceutical Compounding Sterile Preparations Low Risk: BUD Time 12 h Compounded from sterile components in ISO Class 5 Mixing 3 sterile products & 2 entries into sterile vial Located in ISO Class 8 or segregated compounding area (Most traditional Tc-99m RPh are included) Medium Risk: White Blood Cells High Risk: Non-sterile components used in the production ( 123 I-MIBG) Immediate-use: prepare and dispense within 1 h ( 99m Tc-MAA)
International Organization of Standardization of Particulate Matter in Room Air Class Name Particle Count* Grade ISO Class U.S. FD 209E ISO 14644-1 3 Class 1 35.2 4 Class 10 352 A and B 5 Class 100 3520 6 Class 1000 35,200 C 7 Class 10,000 352,000 D 8 Class 100,000 3,520,000 * particles 0.5 µm and larger per cubic meter ISO Class 5 (Grade A) Laminar Flow Enclosure
Low-Risk Level CSP with 12 Hr BUD If the ISO Class 5 primary engineering control (e.g., laminar flow hood) NOT located in an ISO Class 7 buffer area (clean room), then the maximum BUD for low-risk level CPS is 12 hours
Facility Design Low-Risk Level CSP with 12-hour BUD ISO Class 5 device Segregated Compounding Area Critical Site Low-Risk Level CSP with 12-Hour BUD
USP Chapter <797> Low-Risk RP as CSPs ISO Class 5 Primary Engineering Control (PEC) Designated Space Demarcated area or Separate room Evaluate for ISO Class 8 conformity Restricted to prep CSPs with 12 h Beyond Use Dating (BUD) No unsealed windows No connection to outdoors or high traffic flow No sinks next to ISO Class 5 PEC Personnel Garbing
SPECT RP Dose Drawing Area Laminar Flow Hood: ISO Class 5 Syringe and Vial Shield L-Shield
Chapter <797> Low-Risk RP as CSPs Generator storage in demarcated area Generator may be eluted in ISO Class 8 environment
Chapter <797> High-Risk RP Compounding High Risk Conditions: Facility Design Example: Dissolving non-sterile components to make solutions that will be terminally sterilized MIBG sterile powder Radiochemical grade I-123 ISO Class 7 buffer area (cleanroom) ISO Class 8 ante area Critical area ISO Class 5 device
Terminal Filtration in ISO Class 5 Terminal Sterilization performed Move reaction to ISO Class 5 environment Using 0.22 m sterile filters Bubble Test sterile filter post preparation
Why is PET Unique? Short half-life, usually minutes to hours High energy radionuclides (5ll kev) Batch produced provides a limited supply usually hours and can be produced for a single dose Mass contained in the final product is usually nanogram-microgram Quality control issues due to short half-life Complete quality control testing performed for every batch, all but sterility testing is pre-release
FDA Published Final Rule 21 CFR Part 212; Current Good Manufacturing (CGMP) for Positron Emission Tomography (PET) Drugs December 10, 2009 Regulation became effective June 12, 2012 Regulation applies solely to PET drugs for routine clinical use Submission of an New Drug Application (NDA) or an Abbreviated New Drug Application (ANDA) required for all FDA PET drugs no later than 2 years from the date of publication of the Final Rule. (Extended to 6/12/12) F-18 FDG, F-18 Fluoride, N-13 Ammonia considered safe & effective for certain uses when produced under conditions specified in approved applications
21 CFR Part 212; Final Rule CGMP for PET Drugs December 10, 2009 The rule 212.5(b) provides that investigational and research PET drugs, CGMP may be met by producing PET drugs in accordance with Part 212, or in accordance with USP General Chapter <823> Radiopharmaceuticals for Positron Emission Tomography Compounding, May 1, 2009, 32 nd Edition, and USP Monographs if available 1. PET Drugs produced under Investigational New Drug (IND) Application in accordance with Part 312 of this chapter or 2. PET Drugs approved through a Radioactive Drug Research Committee (RDRC) in accordance with Part 361 of this chapter FDA has indicated that IND Phase 0, 1 and 2 are research. Phase 3 usually indicates moving to commercialization & must follow Part 212.
FDA Guidance What is an FDA Guidance? Guidance describes FDA s current thinking on individual issues addressed by the CGMP rule that is not binding on FDA or the public. Guidance documents recommend approaches to complying with statutory requirements or regulations. Not binding requirements Guidance are suggestions how to comply with the broad requirement Part 212 Part 212 is broad requirement Guidance: PET Drugs-Current Good Manufacturing Practices 2012 http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm266640.pdf Chapter <823> USP <823> contains many essential elements of CGMP The organization of USP <823> is not as vague as Part 212, it provides more specifics
USP <823> Part 212 PET CGMPs Investigational PET radiotracers IND = Clinical Trial/Research RDRC Basic science only Not for diagnosis or therapy Not for safety or efficacy Pharmacology must be known in humans Mass dose no pharmacological effect Radioactive dose limit Clinical PET radiopharmaceuticals Drugs administered as part of clinical care Information used to guide patient care decisions Approved under NDA/ANDA Legally marketed For sale Interstate distribution
USP <823> Specifies Procedures/Processes: Components, Materials and Supplies Compounding Procedure Verification Acceptance Criteria Compounding Procedures Computers & Automated Equipment Controls Verification studies (3 consecutive runs) Stability Testing & Expiration Dating PET RP Compounding for Human Use Quality Control Sterilization & Sterility Assurance Part 212 PET CGMPs Describes Accountabilities/Assurances of Quality Systems: Subpart A: General Provisions Subpart B: Personnel and Resources Subpart C: Quality Assurance Subpart D: Facilities & Equipment Subpart E: Control of Components, Containers, & Closures Subpart F: Production & Process Controls Subpart G: Laboratory Controls Subpart H: Finished Drug Product Controls & Acceptance Subpart I: Packaging and Labeling Subpart J: Distribution Subpart K: Complaint Handling Subpart L: Records
Thank-you!