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

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?cfrpart=211

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• 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

Installation qualification (IQ) Operational qualification (OQ) Performance qualification (PQ)

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)

Appearance pH Stabilizer effectivenessChemical purity

Conclusion

1. What is GMP?2. Unique features of PET drugs3. US Code of Federal Regulation Part 211 for SPECT &

Part 212 for PET GMP Production 4. Production of clinical research PET & SPECT

radiophareamceuticals CGMP

Thank you!

schwarzs@wustl.edu