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  • “… havet pharmaceutical quality…” I believe that you meant “.. have…” without “t”
  • Thermal sterilization is possible with 18FDG…I agree it’s not possible with other RPs
  • You will see I made some spelling correction in blue
  • Be careful with the spelling of OFFICINAL and MAGISTRAL!
  • Be careful with the spelling of OFFICINAL and MAGISTRAL! … these spanish rules are the same in Italy The difference between officinal and magistral is: Officinals are medicines which originally were prepared and kept in stock by the pharmacists. The opposite of officinal is magistral, a medicine prepared for the occasion according to a physician's prescription. Is the same in USA?

Transcript

  • 1. Comparison of National PET Radiopharmaceutical Regulations Carmen S. Dence, Pharm D., M.S. Hoapital Pharmacy 5 th . Congress Bogota, Colombia 2008
  • 2. Unique Features of PET RPs
    • Cyclotron produced radionuclides
    • Starting materials and radionuclides may not have pharmaceutical quality used for PET RPs
    • Significant radioprotection measures required
    • Short shelf-life, and thus limited time for quality controls (QC), and which ones?
  • 3. Unique Features of PET RPs
    • Few existing monographs for PET RPs
    • Most are injectable RPs; thermal sterilization mostly not possible, therefore aseptic procedures needed
    • Small mass amounts of tracer (micrograms) injected
  • 4. What Issues Need to be Addressed For PET RPs Use?
    • What are the facility requirements?
    • Who can prepare PET RPs?
    • Who should be the “responsible person”?
    • How will new PET RPs be developed as PET gains importance for use in clinical diagnosis, for preclinical evaluations of pharmaceutical therapies, and as a tool in drug development?
    • How do various countries address these issues?
  • 5. National PET Regulation Comparisons
    • European Union (EU)
      • UK
      • Spain
    • Japan
    • USA
  • 6. EU Glossary
    • European Regulations are mandatory in all countries being directly applied without translation into the national legislation, and they are mandatory .
    • Directives: are rules addressed to the Member States to be translated into the respective national legislation and effectively implemented. Directives are mandatory .
    • Guidelines are recommendations for the effective implementation of Directives by the Member States. Guidelines are not mandatory .
  • 7. EU Directive 2003/94/EC 8 October 2003
    • Guidelines for good manufacturing practice ( GMP, directive 91/356/EEC ) for medicinal products for human use should also be applied to investigational medicinal products ( IMPs) for human use
    • IMPs: substance being tested or used as a reference in a clinical trial, including products with a marketing authorization, used for an unauthorized indication
    • Guidelines given for GMP for
        • Personnel
        • Premises and equipment
        • Documentation, Production, Labeling , Quality Control
  • 8. EUDRALEX Rules Governing Medicinal Products in EU
    • Volume 4 :
      • Medicinal Products for Human Use
      • IMPs (Investigational Medicinal Products)
    • Manufacture :
      • RPs undertaken in accordance with the basic principles of GMP (Part I and II)
  • 9. EUDRALEX Annex 3 Manufacture of Radiopharmaceuticals EU Directive 2004/27/EC 31 March 2004
    • Addresses some practices specific for RPs that differ from basic principles
    • Applicable to RPs used in clinical trials
    • Acceptable methods other than those described which are capable of achieving the principles of quality assurance (QA)
      • Proposed exclusion of cyclotron from the GMP process requirement
  • 10. EUDRALEX Annex 3 Manufacture of RPs
      • For sterile product work station of a laminar flow of HEPA-filtered air with fitting air-locks to entry ports.
      • Should be in an environment at least Grade D (Class 100,000)
      • Production of different RPs in same work stations and at the same time should be avoided
      • Reference samples of every batch should be retained
  • 11. European Association of Nuclear Medicine ( EANM ) Guidelines on Current Good Radiopharmaceutical Practice ( cGRPP ) for Preparation of RPs
      • Part A- kit-based RPs
      • Part B - cGRPP for PET
      • Equipment and facilities: same room used for multiple purposes
      • Environment: production in Grade A located in Grade C, no further locks to Grade D
      • Post Filtration filter testing: single use filters
      • Test of starting material: Certificate of analysis (COA) sufficient without full vendor qualification
  • 12. EANM Initiative “Responsible Person for Preparation of RPs http://www.eanm.org/
    • Need for specific training & knowledge
      • qualified for the preparation of RPs
    • Different from Conventional RPs
    • EANM Radiopharmacy & RPs Chemistry Certificate: 1. Didactic and Practical Experience postgraduate coursework, pass an exam given by Board
        • 2. Two-year practical training
  • 13. Background in Europe
    • Regulations for the extemporaneous preparation of RPs vary
      • From: Full GMP compliance (England)
      • To: No enforcement of pharmaceutical regulations
  • 14. International Organization of Standardization of Particulate Matter in Room Air * particles 0.5 µm and larger per cubic meter 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
  • 15. United Kingdom Radiopharmacy Regulation
    • GMP began to be introduced in late 1970’s
    • Initially some relaxation for radiopharmacy
    • Now, no distinction
    • Full GMP is required:
      • Isolator-based (Class A) units located in Class D
      • Conventional clean rooms: Class A
      • workstations in Class B rooms
      • Changing rooms, controlled access, clean-room clothing
  • 16. UK Regulation of Radiopharmacy
    • Provided by Medicines and Healthcare Products Regulatory Agency (MHRA)
      • License products
      • (through normal EU system)
      • License facilities
      • through system of manufacturing licenses
  • 17. UK Regulation of Radiopharmacy
    • All RPs must be prepared either:
      • In a licensed facility (“Specials Manufacturing license”)
      • By a pharmacist (“Registered Pharmacy”)
    • Facilities and procedures must be the same in both
  • 18. UK Personnel
    • “ Specials Manufacturing” facility:
    • Individuals responsible for Production and QC must be named
    • Normally at least one would be a pharmacist
    • No specific qualification in radiopharmacy required, but both must show “suitable experience and training”
    • No “Qualified Person” required
  • 19. UK Clinical Trials
    • Most experimental clinical studies controlled by European Clinical Trial Directive (2004) and resulting UK regulations
    • There is a separate system for licensing units able to manufacture IMPs
    • Standards similar to those for non-IMPs
    • Requires release by “Qualified Person”
  • 20.
    • Radiopharmacy is highly regulated in the UK
    • Inappropriate balance between “risk” and regulation
    • “ Special” license system works well:
    • Regulates people and premises, not products
    • Shortage of experienced staff
    • The United Kingdom Radiopharmacy Group (UKRG): Very valuable organization for radiopharmacists
    • Provides support, advice, shares the work
    UK Summary
  • 21. Spanish National Legislation
    • Specific Characteristic
        • V ery ambiguous
        • Out-dated (1993)
        • No clear inspection requirements
    • Radiopharmacists trying to obtain clear regulations for:
        • Radiopharmacy units; premises, equipment, personnel
        • RPs compounding and extemporaneous preparation
        • Clinical trials with non-commercially available RPs (mainly PET)
    • Pharmacopoeia has Guidelines on RPs Procedures
        • Recommendations; NOT legally binding
    Radiopharmacy Practice in Spain
  • 22. Spanish Personnel: Qualified Person
    • Radiopharmacy as a Specialty
      • Officially recognized 3-yr Residency
      • Access after passing a national exam for Pharmacists and Chemists
      • In-hospital education & training
    • Around 100 Specialists in Radiopharmacy
      • Pharmacists comprise 65%
    • Not Nuclear Medicine Physicians
      • involved in RPs preparation till early 90’s
  • 23. Spanish Radiopharmacy Models
    • Two models coexist:
    • Commercial Centralized Radiopharmacies
      • Provide unit dose RPs to nearby hospitals and nuclear medicine centers
    • 2. Hospital Radiopharmacies
      • Extemporaneous preparation of kit-based RPs
      • Blood-cell labeling
      • Compounding of PET RPs exclusively for in-house use
  • 24. Spanish Commercial Centralized Radiopharmacies
    • Authorized either as:
      • Radiopharmaceutical Laboratory
    • Radiopharmacy Unit
    • Prepare unit-dose RPs from multi-dose vials
    • Convenient for small hospitals and stand-alone nuclear medicine centers
    • Only commercial interest: no Research and Development
  • 25. Spanish Hospital Radiopharmacies
    • Premises & equipment: many differences among sites
    • Personnel: Specialist in Radiopharmacy is Head of the Unit
    • Hierarchal dependence:
        • Nuclear Medicine (most )
        • Hospital Pharmacy
        • Independent (few)
  • 26. Preparation of PET RPs
    • Industrial manufacturing under MA
      • Only one PET RPs: 18 FDG
      • Directive 2001/83 EC applies
      • GMP compliance
    • In-hospital compounding
      • Compounded as “officinal preparations”
      • Directive 2001/83 EC does not apply
    • (exemption of art 3)
      • Wide variety of PET RPs
      • National Regulation applies
      • [Good Pharmacy Practice (GPP)]
  • 27. Magistral and Officinal Compounding
    • Officinal formula must be…
      • Described in the National Formulary
      • Follow the rules of the Royal Spanish Pharmacopoeia
      • Compounded in Pharmacies or Hospital Pharmacies
      • Compounded and guaranteed by a Pharmacist
    • Magistral formula must be…
      • Prepared from substances with actions and indications legally recognized in Spain
      • Prepared following “Good Pharmacy Practices for Compounding (GPP) and QC of Magistral and Officinal Medicinal Products”
      • Compounded by a Pharmacist
  • 28. Problems for PET RPs Compounding
    • Pharmaceutical companies-little interest in PET RPs
      • They cannot be sold due to extremely short half-life
      • Extremely reduced market
      • There is a real need for PET RPs use
      • Diagnosis of specific pathologies
    • Daily clinical use of unlicensed PET RPs
      • None are described in National Formulary
      • NO officinal formula?
      • No official indications for any PET RPs
      • NO magistral formula?
    • * 18 FDG, the only PET RPs with MA
  • 29. Clinical Trials with Unlicensed RPs
    • If designation of IMP for RPs is necessary
      • Authorization as Pharmaceutical Laboratory is required
      • Hospital Radiopharmacy is NOT a Pharmaceutical Laboratory
    • Possibility of using non investigational medical product (NIMP*) PET RPs
      • Medicinal Product (MP) used to assess end-points in clinical trials are NIMPs
      • * Guidance on IMPs and MPs used in clinical trials; Eudralex Vol 10
  • 30. Main Problems in Spain
    • Ambiguous and out-dated legislation
      • Unclear requirements for personnel, premises, equipment, documentation
      • Differing interpretations in different territories
      • No inspection requirements established
      • National Formulary from 2005 needs updating
    • Limited knowledge of authorities about radiopharmacy
    • Use of unlicensed PET RPs
    • Clinical trials with unlicensed PET RPs
  • 31. Proposed Solutions
    • Establish SPECIFIC legislation for RPs
      • Requirements for facilities
      • Preparation procedures
      • Inspection
    • Regulate PET RPs compounding
    • Consider unique characteristics of RPs in general legislation of medicinal products
      • Study possibility of exceptions
      • Adapt legislation on clinical trials to unlicensed RPs
    Implement EANM cGRPP guidelines in national legislation
  • 32. Japanese National Regulations
      • Medical Science and Pharmaceutical Committee
        • Subcommittee on Medical Application of Cyclotron-Produced Radionuclides
          • Prepare Standards For Compounds Labeled with Positron Nuclides Approved as Established Techniques for Medical Use (1999, revised 2001)
  • 33. Japanese Standards for PET RPs For Medical Use
    • Minimum Requirements for PET RPs in a Medical Institute
    • Standards for specific PET RPs
      • F-18 FDG
      • O-15 oxygen gas
      • O-15 carbon monoxide gas
      • O-15 carbon dioxide gas
    • Guidelines for manufacturing environment and process at manufacturing facilities for PET RPs
    • ````
  • 34. Japanese Guidelines for Manufacturing
    • Environment:
      • Aseptic manipulations > Class 100 (Class A/B)
      • Hot cell ≥ Class 10,000 (Class C)
      • Working area (hot lab, dispensary, QC room)
      • > Class 100,000 (Class D)
    • Monitoring: monitoring air particles and environmental microorganisms
    • FDG modules must be approved by Pharmaceutical Law
    Production Facility :
  • 35. Japanese Guideline for Manufacturing
    • Pharmacist is the responsible individual
    • Pharmacist or other trained individual can prepare FDG or other PET RPs—not specifically defined
    Personnel:
  • 36. Food & Drug Administration Modernization Act (FDAMA) 1997
    • FDA required to set new approval path and separate PET CGMPs from CGMPs
    • Prior to adoption of final PET GMPs, FDAMA requires preparation and controls conforming to USP monographs and Chapter 823
    • Requires filing of New Drug Application (NDA) or Abbreviated NDA (ANDA) for clinical use of PET drugs within 2 years after publication of final PET GMP regulations
  • 37. Proposed Good Manufacturing Practice for PET (GMP for PET)
    • Fundamentals of GMP are essentially the same for conventional Drug GMP (US Code of Federal Regulations Part 210/211) and Proposed PET GMP (Part 212)
    • Part 212 removes those specific requirements in 211 that are not appropriate to PET, and adds elements specific for PET
  • 38. 21 Code of Federal Regulation (CFR) Part 212 US Current Good Manufacturing Practice for PET Drugs Proposed Rule , September 20, 2005
    • Minimum requirements for PET drug production
    • Covers all types of PET production facilities but differs
      • Not-for-profit academically oriented facilities vs.
      • Commercial producers
    • Provisions of USP Chapter 823 are CGMP requirements for:
      • PET drugs produced under Investigational New Drug Application (IND)
      • Radioactive Drug Research Committee (RDRC)-approved drugs
  • 39. US Proposed CGMP for PET-1
    • Fewer personnel is consistent with scope of operation
    • Allowance for multiple operations in same area—with controls
    • Streamlined requirements for aseptic processing
    • Streamlined QC requirements for components
  • 40. US Proposed CGMP for PET-2
    • Self-verification of significant steps in PET drug production
    • Same-person oversight of production, review, and release consistent with complexity of operation
    • Specialized QC requirements for PET drug produced in multiple sub-batches
    • Simplified labeling
  • 41. US Proposed CGMP Guidance Include
    • Facilities:
      • Restricted access to work areas
      • Environmental conditions minimize possibility of microbiological contamination
      • As complexity increases, separate areas needed
      • Aseptic Processing Area
        • Critical activities in production and testing:
          • Laminar Air Flow Workbench (LAFW), or barrier isolator; air class suitable for operation
          • Low traffic area
          • Assembly of final product vial
          • Sterility Testing
  • 42. Authorized PET Personnel
    • Nuclear Regulatory Commission (NRC) will regulate cyclotron produced radioactive materials (2008)
    • Facilities will be licensed by NRC
      • Commercial PET Radiopharmacy
      • Academic PET Cyclotron Facility
    • NRC requires an authorized individual at each PET facility to be responsible for production of PET
      • Authorized Nuclear Pharmacist (ANP)
      • Authorized Nuclear Medicine physician (AU)
  • 43. Authorized Nuclear Pharmacist (ANP)
    • NRC Routes to ANP
    • 1. Board Certification in Nuclear Pharmacy (BCNP) by the American Pharmacists Association (APhA) Board of Pharmaceutical Specialties
        • a. Pharmacy License
        • b. Requires 4000 hours of training/experience
        • in nuclear pharmacy post graduation
        • c. Pass an exam given by Board
          • 2. Alternate pathway training
          • a . 200 hours didactic training--specified courses
          • 3. Preceptor statement for either route
  • 44. New Radiopharmaceuticals First-in-Man Applications
    • Biomarker identification and imaging play an important role in pharmaceutical development pathway
    • Imaging biomarkers are used to assess therapies
    • Development of new diagnostic RPs
  • 45. Regulatory Pathway RDRC study North America and Europe North America Phase 0 Microdose Exp IND Clinical Development Phase 1 Phase 2 Phase 3 Phase 0 Microdose Exp IND
  • 46. Regulatory Pathway Radiotracers for clinical use are subject to the same process for the development of a new pharmaceutical For human studies the following provide the path forward: IND Exploratory IND / Microdosing (Phase 0) RDRC (Radioactive Drug Research Committee)
  • 47. EU Clinical Trials Directive 2001/20/EC
      • EU Directive states that GMP must be applied to the preparation of Investigational Medical Products (IMPs) in clinical trials involving medicinal products for human use
      • Guideline on Chemical & Pharmaceutical Quality was developed by European Medical Association, Committee for Human Use Medicinal Products (CHMP) Quality Working Party (QWP) inspectors to facilitate implementation of 20001/20/EC
    • Guideline attempts to harmonize requirements throughout the EU for chemical & pharmaceutical quality documentation for IMPs
    • Compliance: October 2006
  • 48. Guidance for European Microdosing Committee for Medicinal Products for Human Use (CHME)
    • Microdose ( CPMP/SWP/2599/02/Rev1) defined as less than 1/100 th of the dose calculated to yield a pharmacological effect of the test substance… and at a “maximum dose of ≤ 100 microgram”
    • CHMP adopted a position on non-clinical safety studies supporting clinical trials with single microdose
  • 49. US Exploratory IND (E-IND)
    • Microdose: 1/100 th of the dose calculated to yield a pharmacologic effect
    • Mass dose ≤ 100 µg
    • Reduced Pharmacology, toxicology requirements
      • One mammalian species (both sexes)
      • 100 times dose
    • Diagnostic dose only
    • Limited subject enrollment: 5 to 30
    • Transition to Phase 1 IND or RDRC
  • 50. Exploratory IND
    • Facilitates “first-in-human” imaging studies
      • Biologics
      • Drugs
    • Bridges preclinical --- Phase I
    • Ideal for “proof-of-concept” studies
  • 51. Regulatory Pathway RDRC study North America Phase 0 Microdose Exp IND
  • 52. Radioactive Drug Research Committee (RDRC)
    • Regulation - 21 CFR 361.1
    • Established by the FDA in 1975
    Center for Drug Evaluation & Research
  • 53. Radioactive Drug Research Committee (RDRC)
    • Purpose: to study basic research
    • No clinical decisions
    • Pharmacology must be known in humans
    • No pharmacological response can be noted from mass dose administered (NOEL)
    • Radiation Dose Limits
    • No ‘First in Human’ Studies
  • 54. Conclusions
    • PET RPs applications are continuing to expand
    • National PET regulations should provide the minimum standards for quality production of PET drugs for all types of PET production facilities
  • 55. Conclusions
    • Regulations should not be over restrictive—this will impact development of a newly emerging science
    • Micro dose approach can allow first-in-man studies to expand development of new RPs more rapidly
  • 56. PET Regulations Work In progress!!
  • 57. Acknowledgements
    • Sally Schwarz, MS Washington University St Louis, MO USA
    • Stephen J. Mather, Ph.D.; St Bartholomew’s
    • Hospital, London, England
    • Ivan Penuelas, Ph.D.; Department of Nuclear Medicine, Clinica University, Pamplona, Spain
    • Henry F. Van Brocklin, Ph.D.; Department of Radiology, University of California, San Francisco, CA, USA
    • Alphons Verbruggen, Ph.D., Katholieke University Lueven, Belgium