United States GMP PET & SPECT Drug Production International Atomic Energy Agency International Conference on Integrated Medical Imaging in Cardiovascular Disease (IMIC) Vienna, Austria October 13, 2016 Sally W. Schwarz, RPh, MS, BCNP President SNMMI Professor of Radiology Co-Director Cyclotron Facility Director Clinical PET Radiopharmaceutical Production Washington University School of Medicine in St. Louis
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United States GMP PET & SPECT Drug Production
International Atomic Energy AgencyInternational Conference on Integrated Medical
Imaging in Cardiovascular Disease (IMIC)Vienna, AustriaOctober 13, 2016
Sally W. Schwarz, RPh, MS, BCNPPresident SNMMI
Professor of RadiologyCo-Director Cyclotron Facility
Director Clinical PET Radiopharmaceutical ProductionWashington University School of Medicine in St. Louis
Overview
1. What is GMP?2. US Code of Federal Regulation Part 211 & Part 212:
Current Good Manufacturing Practice (cGMP) for SPECT & PET Drug Production
3. Why is PET unique?4. Production of clinical research PET & SPECT
radiophareamceuticals CGMP
What is Current Good Manufacturing Practice (cGMP) ?
A rule (or regulation) that contains binding requirements that manufacturers must follow, and is enforceable in the courts.
CGMP is the minimum standard that each manufacturer must follow to produce the drug to help ensure a drug remains safe and effective over its labeled shelf-life.Broad requirements-what you must do, How to do, the details of compliance, is detailed in manufacturer’s
SOPs
The quality of a product cannot be established by end product testing alone. Quality must be built into the product
21 CFR Part 211 Clinical Manufacturing Current Good Manufacturing Practice (CGMP)
• The regulation contains the minimum CGMP for preparation of drug products (excluding PET) for administration to humans• For new drugs: must file a New Drug Application (NDA) or
Abbreviated New Drug Application (ANDA) with FDA• For manufacturers: air quality is defined for production areas -
i.e. ISO Class 6, airlocks• Testing requirements significantly increased over PET drug
production (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 CT and MR contrast agents
SPECT Clinical Research
SPECT Radiopharmaceuticals (& all therapeutic drugs)
• Phase 1 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/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070273.pdf• Phase 2-3: must follow Part 211
• 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• Required facilities to register as FDA Drug Manufacturers• 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 approved PET drugs no later than 2 years from the date of publication of the Final Rule (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
Investigational and Research PET Production
• The rule §212.5(b) investigational and research PET drugs for human use produced under an
1. Investigational New Drug (IND) Application in accordance with Part 312 of this chapter or
2. With the approval of a Radioactive Drug Research Committee (RDRC) in accordance with Part 361 of this chapter
• …the requirement under the act to follow cGMP is met by complying with1. Part 212 or2. in accordance with USP General Chapter <823>
“Radiopharmaceuticals for Positron Emission Tomography –Compounding”
FDA has indicated that IND Phase 0, 1 and 2 are research. Phase 3 usually indicates moving to commercialization & must follow Part 212.
Overview 21 CFR Part 212
Subpart A: General ProvisionsSubpart B: Personnel and ResourcesSubpart C: Quality AssuranceSubpart D: Facilities & EquipmentSubpart E: Control of Components, Containers, & ClosuresSubpart F: Production & Process ControlsSubpart G: Laboratory ControlsSubpart H: Finished Drug Product Controls & AcceptanceSubpart I: Packaging and LabelingSubpart J: DistributionSubpart K: Complaint HandlingSubpart L: Records
Comparison: Personnel & Resources
§ 212.10 What personnel & resources must I have?Sufficient personnel with necessary education, background, training & experience to perform their assigned functions…with adequate resources to enable personnel to perform functions
Part 212
Personnel and Resources
§ 212.10 *Guidance: PET Drugs - cGMP December 2009* B. Organization & StaffingResponsibilities & assigned duties clearly identified in
written policiesSmall PET drug production - producing 1-2 batches of a
PET drug daily or weekly - may employ 2 people for production and quality assurance (QA)
One individual can be designated to perform production and QA (highly qualified person)
Conventional drugs (Part 211) normally require second-person checks at various stages - for small PET drug operation, can perform documented self-checks
Personnel and Resources
§ 212.10 Guidance: PET Drugs -cGMP December 2009
*C. Personnel QualificationsAppropriate education, training & experienceTrained in GMPOngoing training for new proceduresFile for each employee
(CV, degree certificates, certificates of training)
Personnel-Gowning & Garbing• Training in Aseptic TechniqueTraining in proper garbing, hand washing and glovingTraining in techniques & equipment used to achieve ISO
Class 5 environment
Include all manipulations required for aseptic assembly of final product vial
Represent worse-case scenario for operations
Performed in triplicate for new operators
Afterward, perform annuallyPerform any time procedures
are significantly changed
Personnel—Media Fill Testing
Media Fill Test Procedure: PET Manufacturing
In LFH add media into a FPV through sterilizing filter
In the Hot cell’s delivery chamber, add media through the sterilizing filter
Transfer FPVs into LFH w/manipulator arms, add media through the sterilizing filter
Withdraw QC samples
Perform contact plate testing Incubate
them for 2 weeks
Quality Assurance
§ 212.20 What activities must I perform to ensure drug quality?
a) Production operations: Ensure that each PET drug meets the requirements of the act (safety,
identity & purity) PET drug meets required quality & purity
b) Materials: Examine & approve or reject components…in-process materials…finished dosage forms to ensure compliance with procedures specifications
c) Specifications & processes: Approve or reject before implementation..specifications, methods, procedures
d) Production records: Review production recordsto determine whether errors have occurred, investigate and take action
e) Quality assurance: Establish & follow written QA procedures
Starting materials
Traceability
Records (SOP, MBR, QC Release Specifications)
Written procedures
Appropriate Equipment
Personnelqualification
Quality Assurance (QA)
AppropriateFacilities
Process design
Testing and samplingTesting and samplingQA
Validationand re-validation
Audit
In-process controls
QA
Quality Assurance (QA)
• Quality assurance aims to assure that quality work and qualitydeliverables will be built in before work is done covers all matters that individually or collectively influence the
quality of a product is the sum total of the organized efforts to ensure that products posses
the quality required for their intended use
• Quality control aims to determine that quality work and qualitydeliverables did occur after work was done
• Quality control is conducted by inspection and testingOf materials, workmanship and product Testing and sampling according to written SOP and established
specifications
QC
Facilities & Equipment
§ 212.30 What requirements must my facilities & equipment meet?
(a) Facilities: adequate to ensure orderly handling, prevention of mix-ups & prevention of contamination
Washington University Cyclotron Facility (WUCF)Controlled PET Manufacturing Facility
ISO Class 5Laminar Air Flow HoodHotcell & ante-chamber
Quality Control Area
Ante Room ISO 7 Facility
ISO Class 7 Facility
Biosafety Cabinets ISO 5 Dispensing Hotcell
Pass through to QC LaboratoryShipping AreaGE FX Pro F-18 Synthesis module
ISO Class 5 (Class 100)Laminar Air Flow Hood (LAFH)
Diagram
International Organization of Standardization (ISO)of Particulate Matter in Room Air
Class Name Particle Count*
Grade ISO ClassU.S. FD
209EISO 14644-1
3 Class 1 35.24 Class 10 352
A and B 5 Class 100 35206 Class 1000 35,200
C 7 Class 10,000 352,000D 8 Class 100,000 3,520,000
*≥ particles 0.5 µm per cubic meter
LAFH Certification required annually for USP Chapter <823> and every 6 months for FDA Part 212
Laminar Air Flow (LAF) Hood Preparation
• Disinfect LAF at beginning of each shift• Routinely disinfect gloves with sterile
70% isopropyl alcohol prior to working in LAF hood
• Clean LAF with appropriate disinfectant prior to working in LAF, for example Sterile Isopropyl Alcohol 70% (IPA) Bleach 100-5000 ppm or Spor-klenz®
(Need to cover the spectrum of bacteria spore forming not killedby IPA)
Facilities and Equipment
ISO Class 5 Aseptic Workstation a) Aseptic operations performed in
Class 100 Laminar Flow Hood or isolator
b) Located in low traffic areac) Clean laboratory clothing wornd) Aseptic techniques usede) Gloved hands disinfected before
entering aseptic hoodf) Disinfect final product septum
with sterile 70% alcoholg) Certify at inception & every 6
months
ISO Class 5 Laminar Flow HoodEnvironmental & Personnel Monitoring
Microbiological Testing Requirements: During Final Product Set-Up and Sterility Testing
Finger Touch Plate Air Sampling PlateContact Plate
Final Product Vial Set-up
*Guidance: PET Drugs - CGMP December 2009
Sterility Test Inoculation
Recommended Action Levels for Microbial Contamination*
Classification Fingertip SampleSurface sample(Contact Plate)(cfu per plate)
ISO Class 5 > 3 > 3
ISO Class 7 N/A > 5
ISO Class 8 N/A > 100
*USP Chapter 797
Facilities and Equipment
Production Equipment (including QC equipment)• Newly installed equipment
Calibration of Equipment• Calibration performed before use• Recalibrate on a schedule
Preventive Maintenance• Develop maintenance schedule• All qualifications, calibrations & maintenance must be
documented, including date and who performed them
System Suitability for QC Equipment
• Checked prior to each day of use, according to established written procedures
• Used to verify the peak resolution & reproducibility of chromatographic system
• Gas chromatograph (GC) or High performance liquid chromatography (HPLC)
Inject at least one injection of the standard preparation(If you have a standard curve.)
e.g. Tailing factor, T : measure of peak symmetry– is1.0 for perfectly symmetrical peaks, and the valueincreases as tailing becomes more pronounced.
Control of Components, Container & Closures
§ 212.40 How must I control components used for PET drug & containers, closures I package them in?
(a) Written procedures(b) Written specifications(c) Examination & testing
Establish minimum standards for controlling components containers & closures.
If you conduct finished-product testing which ensures correct components have been used, may rely on COA from suppliers. Need justification why identity testing is not required.
(d) Components be handled and stored to prevent contamination, mix-ups & deterioration
(e) Keep a record of each shipment of components
Control of Components…
Raw Materials Specifications: Receipt & Release (green sticker)
ProductionControlled Storage
Lab Supplies
Quarantine
Raw Materials (RM) Storage
• Materials Management Process • Logged in at receipt• Quarantined on arrival• Received for usage according to RM
specifications • Released for use by Pharmacist• RM entered into PETra - material
management database • Defined storage areas (Quarantined, Released, Rejected, Controlled)• Environmental monitoring
performed
Controlled Storage
Process Controls
§ 212.50 What production & process controls must I have?
a) Written control procedures: document all key process parameters are controlled & deviations are justified
a) Master production & control records Name and strength of PET drug Name & amount of rective pharmaceutical ingredient (API) Components Identification of all major pieces of equipment used Statement on minimum percentage yield allowed
b) Batch production & control record created for each new batchc) Area & Equipments checkse) In-process materials controls
Finished Drug Product Controls and Acceptance
§ 212.70 What controls and acceptance criteria must I have for my finished PET drug products?
a) Establish specifications for each PET drugb) Test Procedures
Establish & document accuracy sensitivity & reproducibility of the procedure; if compendial—demonstrate test works under conditions of use
c) Before release assure each batch or sub-batch conforms to specifications (except sterility)
Laboratory Controls
• PET drugs QC Pre-Release Specifications Post-filtration integrity test of 0.22 m sterile filter (e.g. Bubble Test) pH Visual inspection: clear and colorless Radiochemical purity /identity Radionuclidic identity Specific activity Residual solvent analysis, and other toxic chemicals BET
• Post-Release Specifications Sterility Testing
Inoculate within 30 hours after completion of production
Bubble Test: Post Synthesis
Product Filter
Bubble Test Vial Bubbles Observed
Pressure at 60 psi
Stability Testing
§ 212.61 Guidance: PET Drugs—cGMP • PET drug are expected to remain stable during storage.• Perform stability testing at highest radioactive
concentration•Withdraw sample from the intended final
container/closure• Parameters to evaluate:
Radiochemical identity & purity (including levels of radiochemical impurities)