Distributed Manufacturing via the SNM Multicenter FLT IND

Distributed Manufacturing via the SNM Multicenter FLT IND Part I SNM Midwinter Clinical Trials Network Albuquerque, New Mexico February 1, 2010 Sally W. Schwarz, MS, BCNP Director Clinical PET Radiopharmaceutical Production Washington University St. Louis Department of Radiology

US Food & Drug Administration Modernization Act (FDAMA) 1997 § 1997: US Food & Drug Modernization Act (FDAMA) required revisions to Current Good Manufacturing Practice (c. GMP) for PET Radiopharmaceutical (RP) production § FDAMA required a new approval path and separate Current Good Manufacturing Practices (c. GMPs) for PET from c. GMPs for drugs § Prior to adoption of final PET c. GMP rule, FDAMA requires PET Radiopharmaceutical (RP) production to follow: ü United States Pharmacopeia (USP) PET RP monographs, if available ü USP General Chapter <823> for Production of PET RPs USP subcommittee is in process of reviewing/revising

21 CFR Part 212; Final Rule CGMP for PET December 10, 2009 § Regulation is effective December 12, 2011 § Submission of an NDA or an ANDA required for all FDA approved PET drugs no later than 2 years after the enactment date of the Final Rule – F-18 FDG, F-18 Fluoride, N-13 Ammonia

21 CFR Part 212; Final Rule CGMP for PET December 10, 2009 The rule § 212. 5(b) provides that for investigational and research PET drugs, CGMP would be met by producing PET drugs Ø in accordance with Part 212, or Øin accordance with USP General Chapter <823> “Radiopharmaceuticals for Positron Emission Tomography – Compounding, ” May 1, 2009, 32 nd Edition. 1. PET Drugs produced under Investigational New Drug Application (IND) 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

Overview USP Chapter <823> (32 nd Edition) § Procedures/Process (<823> revision is planned) – Components, Materials and Supplies – Compounding Procedure Verification ü Acceptance Criteria üCompounding Procedures üComputers & Automated Equipment Controls üVerification studies (3 consecutive runs) § § Stability Testing & Expiration Dating PET Ra. Ph Compounding for Human Use Quality Control Sterilization & Sterility Assurance

Overview USP Chapter <823> (Revision? ) A. Personnel Qualifications 1. 2. Responsible Person Aseptic Training (current) B. Control of Facilities & Equipment 1. 2. 3. 4. C. D. E. F. G. H. I. Facilities (current) Environmental Controls Aseptic Hood Compounding & QC Equipment Control of Components, Materials and Supplies Compounding Procedure Verification Stability Testing and Expiration Dating PET RPh Compounding for Human Use Quality Control Sterilization & Sterility Assurance Reprocessing

FDA Audit Inspectional Observations (FDA-483) ØInadequate training of personnel § Failure to train personnel to perform assigned tasks ØNo media fill testing performed

A. Personnel Qualifications (add) 1. Responsible person: designated, qualified & trained person shall be responsible for ensuring that compounding activities are carried out & properly completed by qualified & trained personnel 2. Aseptic Training (current) ü ü Didactic training: pass written exam Training in proper garbing & gloving Documented visual observation audits of garbing Media-Fill Test Procedures – New preparer: Pass 3 separate Media-Fill Procedures Annually for personnel who currently prepare (compound) PET RPh Any time procedures are changed

Cleansing & Garbing 1. 2. 3. 4. 5. Dedicated shoes or shoe covers Head covers Face masks & eye protection Hand cleansing procedure Gowns with fitted sleeves (sleeve covers) 6. Sterile gloves (disinfect before entering, then periodically with sterile 70% IPA ) 7. Garb exposed in patient car e area can’t cross line of demarcation into compounding

Overview USP Chapter <823> (Revision? ) A. Personnel Qualifications 1. 2. Responsible Person Aseptic Training (current) B. Control of Facilities & Equipment 1. 2. 3. 4. C. D. E. F. G. H. I. Facilities (current) Environmental Controls Aseptic Hood Compounding & QC Equipment Control of Components, Materials and Supplies Compounding Procedure Verification Stability Testing and Expiration Dating PET RPh Compounding for Human Use Quality Control Sterilization & Sterility Assurance Reprocessing

FDA Audit Inspectional Observations (FDA-483) Ø Aseptic workstation is not suitable for aseptic operations § Use of non-sterile disinfectant to sanitize LAF Ø Frequency of environmental monitoring—does not reflect the volume of manufacturing operations § Weekly is not acceptable § Should “monitor” environment for each set-up of final product vial § Can assemble all final product vials for the day, and keep them in LAF

B. Control of Facilities and Equipment (current) 1. Facilities 2. Environmental Controls a) b) c) d) e) Work area is clean Aseptic hood located in low traffic area Clean laboratory clothing worn Aseptic techniques used Disinfect final product septum with sterile 70% alcohol

B. Control of Facilities and Equipment 3. Aseptic Hood (LAF or Isolator) a) PET RPh final product containers must be assembled in Class 100 environment (LFH or Isolator) b) LFH internal surface is cleaned and disinfected with sterile disinfectant daily before and after use a) Gloved hands are disinfected before entering hood

PET Ra. Ph Final Product Vial Assembly Performed In Aseptic Hood §PET Ra. Ph final product containers must be assembled in Class 100 environment (LFH or Isolator) §Gloved hands are disinfected before entering hood §Daily disinfection of surfaces before use §Microbiological Testing periodically e. g. weekly (per FDA, NOT monitoring) üContact plate-surfaces üSettle plate/dynamic air sampler üAirborne, nonviable particle count less often

FDA Audit Inspectional Observations (FDA-483) Ø Frequency of environmental monitoring— contact plates, touch plates § Weekly is not acceptable § Should “monitor” environment for each set-up of final product vial § Can assemble all final product vials for the day, and keep them in LAF Ø Use of non-sterile disinfectant to sanitize LAF Ø No media fill testing performed

B. Control of Facilities and Equipment (add) 3. Aseptic Hood (cont’d) d) Microbiological monitoring performed periodically ü ü e) Contact plate-surfaces Settle plate/dynamic air sampler Airborne, nonviable particle count less frequently Frequency of monitoring may be reduced once routine sterility of drug product is established Frequency: microbiological testing of the aseptic hood should be performed after each critical aseptic manipulation such as set-up of final product vial and after sterility inoculations

B. Control of Facilities and Equipment (add) 4. Compounding Equipment (current) a) Equipment used to prepare PET drugs üProperly cleaned üMay be processed to remove endotoxin üMay be sterilized v. Verification of sterilizer performance repeated periodically

C. Control of Components, Materials and Supplies § Establish written specifications üIdentity, purity & quality of components üAppropriate storage § Log-in each lot of shipments of components; If no expiration date, must assign one. § Determine each batch of components in compliance with written specifications (procedures, tests, and/or certificates of analysis) § Store components in controlled access area according to established conditions.

D. Compounding Procedure Verification 1. Written acceptance criteria for identity, purity & quality of each PET drug (If USP monograph exists = minimum acceptance criteria) 2. Written procedures for compounding ü ü ü Master file of Written compounding procedures (Outdated copies retained) Incorporate 0. 22 um for parenteral administration; 0. 45 um for inhalation Routinely updated at least annually 3. Verification Studies ü ü Three consecutive runs are required initially & for any change having potential to alter identity quality or purity Stability testing and expiration dating—meet acceptance criteria at expiry

E. Stability Testing & Expiration Dating

F. PET Radiopharamceutical (RPh) Compounding for Human Use § Inspect compounding area and equipment before use for cleanliness § Label final PET Ra. Ph container prior to starting ü PET drug name and lot number § Compound PET Ra. Ph according to written, verified procedure with appropriate written batch record ü Use appropriate components ü Responsible individual initials—including each critical step ü Raw analytical data ü Signature & date of individual assuming overall responsibility

G. Quality Control § Written QC procedures § Verification of QC equipment and procedures used ü System suitability testing (Chromatography <621>) must be confirmed on installation of QC equipment and after repair (HPLC, GC, analytic instruments) ü Check correct operation on scheduled basis (system suitability) ü Maintenance performed—written scheduled basis ü Dose Calibrators: Perform applicable tests • Used to assay bulk radioactivity and dispensed dosages § Accept or reject PET drug § Investigate unacceptable QC tests results ü Document outcome

Quality Control Requirements Pre-Release: § PET Ra. Ph T 1/2 ≥ 20 minutes (on Batch); T 1/2 ≤ 20 minutes ( on QC Sub Batch) – Post-filtration integrity test of 0. 22 m sterile filter (e. g. Bubble Test) – p. H – Visual inspection – Radiochemical purity /identity *** – Radionuclidic identity – Specific activity – Residual solvent analysis, and other toxic chemicals – BET (20 min gel clot, or other recognized procedure) Post-Release: § Sterility ü may inoculate test, within 24 h following preparation

Endosafe PTS® System § PTS® is a software-driven spectrophotometer for measuring and documenting endotoxin. § Unique cartridge containing dry, precalibrated reagents. § Each cartridge contains duplicate channels for analysis of sample and positive control. § PTS® is particularly suited for PET Ra. Ph because test requires ü ~17 -20 minutes ü Requires < 0. 1 m. L of diluted product ü NO preparation of endotoxin standards.

FDA Audit Inspectional Observations (FDA-483) Ø Failure to audit procedures (SOPs) on regular basis & update SOPs Ø Found production equipment: § Not qualified § Not calibrated § Not properly maintained Ø Failure to investigate failed batch & deviations (should be in writing)

FDA Audit Inspectional Observations (FDA-483) Ø Lack of assurance that QC test results are reliable & accurate § QC equipment; – Not qualified – Not calibrated – Not maintained § No equipment suitability performed (USP Chapter <621>) § Inadequate reference standards used Ø Inadequate QA/QC oversight

H. Sterilization and Sterility Assurance • Compounding Equipment & Components – Equipment may be processed to remove endotoxin – May be sterilized ürequires verification of sterilizer • • • § § Environmental Controls Aseptic Hood Aseptic Technique Qualification of the Filtration Process Microbiological Testing of Finished Products

Qualification of Filtration Process § Sterile Filters: § COC examined and maintained for each lot of filters § COA obtained from the company listing microbial retention challenge § Each lot of filters must be tested for integrity : Acceptance Criteria § After PET drug production, filter tested for integrity prerelease e. g. Bubble Point Test § The bubble point pressure is the pressure at which bubbles first appear from a submerged inlet tube in the receiving vessel. § Nitrogen gas flow increased until the bubbles appear (e. g. most filters must reach > 50 psi. * Nitrogen Gas * Pressure depends on the filter used

Microbiological Testing of Finished Product § Innoculated no later than 24 (30) hours after compounding § If sterility test fails, an investigation must be initiated to identify the cause

FDA Audit Inspectional Observations (FDA-483) Ø Lack of assurance that PET drug is sterile § No growth promotion testing of media performed § Must have validation data for hold time (eg. 24 hours); assure still have viable product § Inadequate incubation temperature control § Automatic sterility re-test without investigation

Class 100 (ISO Class 5) PET Dose Drawing Station § Chapter <823> supersedes Chapter <797> for PET RP compounding, but upon release of PET RP as finished drug product, further manipulation such as dispensing, contents of Chapter <797> apply. PET Dose Drawing Device In Class 100 Environment Shielded Dose Calibrator

Thank-you! schwarzs@wustl. edu