The ABCs and Challenges of GMP The American Experience

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1 The ABCs and Challenges of GMP The American Experience The Canadian Association of Nuclear Medicine Toronto, Ontario April 22, 2017 Reiko Oyama, R.Ph., B.C.N.P. Washington University School of Medicine Department of Radiology

2 CANM CANM ANNUAL SCIENTIFIC MEETING APRIL 20-23, 2017 TORONTO, ONTARIO I do not have a financial interest, arrangement or affiliation including receipt of honoraria or expenses with a commercial organization that may have a direct interest in the subject matter of my presentation.

3 What is cgmp or GMP? C = Current GMP = Good Manufacturing Practice 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 Manufacturing Standards (for quality production of drug)

4 Ten commandments of any cgmp 1. You shall write good procedures 2. You shall follow your procedures 3. You shall document your work 4. You shall validate your processes 5. You shall design and build proper facilities and equipment 6. You shall maintain your facilities and equipment 7. You shall be competent 8. You shall make cleanliness a daily habit 9. You shall build quality into your products 10. You shall audit for compliance

5 To be GMP Compliant Bottom line We need to have written procedures follow written procedures document what you have done

6 Regulations Approved Clinical Drug Regulatory Oversight A. 21 CFR Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals (since 1975) SPECT radiopharmaceuticals & all therapeutic drugs B. 21 CFR Part 212 Current Good Manufacturing Practice for Positron emission Tomography Drugs (since 2012) PET drugs

7 Regulations for PET and SPECT Clinical Research 1) 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; mation/guidances/ucm pdf Phase 2-3: must follow Part art=211 2) PET Radiopharmaceuticals (RPs): Phase 0, 1 and 2: allows production of Investigational PET drugs according to either USP Chapter <823> or Part 212 Phase 3: must follow Part 212 FDA Guidance: IND Applications for PET Drugs, December mation/guidances/ucm pdf

8 SPECT, Therapeutic, and Generator-Produced Radiopharmaceuticals Facility needs to be registered as manufacturer by the FDA Manufacturing: 21 CFR Part 211 Current Good Manufacturing Practice (cgmp) for Finished Pharmaceuticals FDA regulation (since 1975) Contains the minimum current Good Manufacturing Practice (cgmp) requirements for preparation of all drug products (excluding PET) for administration to humans Product Examples: 1. All Tc-99m cold kits used for compounding 2. Tl-201 Chloride Injection 3. Mo-99/Tc-99m generators 4. Sr-82/Rb-82 generators CardioGen-82 and Ruby Fill 5. Lutathera Testing requirements significantly increased over Part 212 (PET drugs) Clinical Practice, Compounding of SPECT kits and Dispensing USP Chapter <797> Pharmaceutical Compounding--Sterile Preparations (since 2004)

9 What is the United States Pharmacopeia? United States Pharmacopeia (USP): Sets legal, enforceable standards for drugs (including radiopharmaceuticals) in the United States o General Chapters under 1000 are enforceable Enforcement of USP standards is FDA and other government authorities o General Chapters over 1000 are for information Chapter <797> Pharmaceutical Compounding Sterile Preparations (2004) Chapter <823> Radiopharmaceuticals for Positron Emission Tomography Compounding (1998)

10 Example SPECT, Therapeutic, and Generator- Produced Radiopharmaceuticals Generator 21 CFR Part 211 Cold Kits 21 CFR Part 211 Compounding and dispensing USP Chapter <797> Laminar Flow Hood: ISO Class 5

11 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

12 21 CFR Part 212 cgmp for PET drugs Regulation became effective June 12, 2012 Requires facilities to register as FDA Drug manufacturer Must file New Drug Application (NDA) or Abbreviated New Drug Application (ANDA) with FDA The regulation contains the minimum Current Good Manufacturing Practice (cgmp) for preparation of PET drugs for administration to humans Testing requirements different than Part unique quality of PET drugs

13 PET Radiopharmaceuticals Manufacturing: 21 CFR Part 212 Current Good Manufacturing (cgmp) for Positron Emission Tomography (PET) Drugs FDA regulation (since 2012) The regulation contains the minimum Current Good Manufacturing Practice (CGMP) for preparation of PET drugs for administration to humans Examples: 1. F-18 FDG Injection 2. F-18 Sodium Fluoride Injection 3. N-13 Ammonia Injection 4. C-11 Choline Compounding Research PET Radiopharmaceuticals USP Chapter <823> Radiopharmaceuticals for Positron Emission Tomography (PET) Compounding Approved PET drugs Dispensing PET drugs USP Chapter <797> Pharmaceutical Compounding--Sterile Preparations (CSPs) o Provides minimum practice and quality standards for CSPs Maintain or achieve sterility of CSPs in ISO Class 5

14 PET Radiopharmaceuticals Manufacturing 21 CFR Part 212 PET Drug Compounding USP Chapter <823> Dispensing USP Chapter <797>

15 PET Dispensing Classification Particle Count* ISO Class U.S. FD 209E ISO, m 3 3 Class Class Class Class ,200 7 Class 10, ,000 8 Class 100,000 3,520,000 * particles 0.5 µm per cubic meter Wash U example USP Chapter <797> Dispensing requires use of laminar airflow hotcells Use Manipulator arms due to exposure rates

16 Overview 21 CFR Part 211 vs CFR Part 211 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 Control 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 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

17 21 CFR part CFR Part 212 vs Part 211 Multiple operations in the same area is allowed as long as the area is well organized and other adequate controls are in place to prevent any mix-up Self-check, same person oversight of production/qa Defined Quality Assurance function Oversee production operation Examine, approve or reject materials, labels, etc. Approve or reject specifications, methods, processes, procedures and changes Review production record Streamlined aseptic processing requirements Streamlined QC requirements for components Conditional Final Release is allowed

18 21 CFR 212 details ---Personnel and Resources Personnel Qualifications Appropriate education, training, and experience Trained for the assigned job duties Example GMP training Aseptic Training Production training for the particular process Ongoing training for new procedures Retraining Maintain documents for each employee CV, license, certificates of training The same person who oversees the production can review the batch record and release the product

19 Personnel Media Fill Testing 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 annually Perform any time procedures are significantly changed Wash U examples

20 PET Manufacturing Facility Multiple operations in the same area is allowed as long as the area is well organized and other adequate controls are in place to prevent any mix-up Hotcell & ante-chamber (in ISO Class 8 room) Wash U examples Laminar Air Flow Hood ISO Class 5

21 ISO Class 7 Facility Wash U examples Biosafety Cabinets Bio Safety Cabinet (ISO Class 5) Laminar Airflow Hotcell (ISO Class 5) Pass through Pass through- QC Laboratory Shipping Area ISO 7 appropriate coverall

22 ISO Class 5 Laminar Flow Hood Environmental & Personnel Monitoring Microbiological Testing Requirements: During Final Product Set-Up and Sterility Testing Wash U examples Final Product Vial Set-up Contact Plate Finger Touch Plate *Guidance: PET Drugs - CGMP December 2009 Air Sampling Plate

23 Recommended Action Levels for Microbial Contamination* Classification Fingertip Sample Surface 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

24 Environmental Monitoring with APs and CPs What is going to happen if the numbers of colony exceed the action level? For example, if a sterility inoculator had 3 colonies on CP for his/her gloved fingers o o o Remove personnel from inoculation duty Provide re-training (observation, discussion, 3 media fill tests) Return personnel to inoculation duty after successful 3 media fill test Alert/Action Levels for each plate at WUSM Cyclotron Facility and Nuclear Pharmacy

25 21 CFR 212 details ---Control of Components, Containers, & Closures Raw Materials How must I control components used for PET drug & containers, closures I package them in? (a) (b) (c) (d) (e) Written procedures Written specifications 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. Components be handled and stored to prevent contamination, mix-ups & deterioration Keep a record of each shipment of components

26 21 CFR 212 details ---Control of Components, Containers, & Closures Raw Materials Raw Materials Specifications: Receipt & Release (green sticker) Wash U examples Quarantine Controlled Storage Production

27 Inspections Purpose: To ensure compliance with cgmp, focus on activities up to point of final release of a PET drug product. Routine Surveillance 212 GMP Inspection Pre-Approval Inspection (PAI) Compliance Inspection Evaluate or verify corrective actions after a regulatory action has been taken For cause inspection---investigate a specific problem (Field Alert reports, industry complaints, recalls, etc.)

28 Full Inspection Option Inspection Approaches Inspection of at least four of the systems, one of which must be the Quality System and include coverage of the aseptic processing controls Abbreviated Inspection Option Generally done when a firm has a record of satisfactory 212 cgmp compliance Inspection of the Quality System and aseptic sterility control and one additional system

29 Inspection Coverage PAI more focused on Environmental monitoring Sterility assurance Personnel training Process verification Deviation and OOS Investigations Corrective and Preventive Actions (CAPA)

30 Challenges Infrastructure---difficult to modify/update the existing facility Great paperwork and administrative burden---capa and other reports, keep SOPs up-to-date, routine training, change request, and audit More testing required More training required Need more personnel Cost---facility, maintenance, garbing, training, more personnel, more testing Inconsistent Inspection for 212 Clearly defined GMP and Not-so-clearly defined GMP Cleary defined GMP: Clear objectives - easy to identify and anticipate Not-so-clearly defined GMP : Interpretive, subjective - hard to identify and anticipate Comments regarding not-so-clearly defined GMP are more frequent, leading a risk of setting regulation by inspection

31 Acknowledgements Sally W. Schwarz, MS, BCNP Washington University School of Medicine St. Louis, MO

32 Thank you! Contact information: