PET Regulations


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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?
  • PET Regulations

    1. 1. Comparison of National PET Radiopharmaceutical Regulations Carmen S. Dence, Pharm D., M.S. Hoapital Pharmacy 5th . Congress Bogota, Colombia 2008
    2. 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. 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. 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. 5. National PET Regulation Comparisons • European Union (EU) UK Spain • Japan • USA
    6. 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. 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. 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. 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. 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. 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. 12. EANM Initiative “Responsible Person for Preparation of RPs • 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. 13. Background in Europe • Regulations for the extemporaneous preparation of RPs vary – From: Full GMP compliance (England) – To: No enforcement of pharmaceutical regulations
    14. 14. International Organization of Standardization of Particulate Matter in Room Air 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 *particles 0.5 µm and larger per cubic meter
    15. 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. 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. 17. UK Regulation of Radiopharmacy • All RPs must be prepared either: 1. In a licensed facility (“Specials Manufacturing license”) 2. By a pharmacist (“Registered Pharmacy”) • Facilities and procedures must be the same in both
    18. 18. UK Personnel “Specials Manufacturing” facility: 1.Individuals responsible for Production and QC must be named 2.Normally at least one would be a pharmacist 3.No specific qualification in radiopharmacy required, but both must show “suitable experience and training” 4.No “Qualified Person” required
    19. 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. 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. 21. Spanish National Legislation • Specific Characteristic Very 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. 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. 23. Spanish Radiopharmacy Models Two models coexist: 1.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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 45. Regulatory Pathway RDRC study Phase 0 Microdose Exp IND Clinical Development Phase 1 Phase 2 Phase 3 Phase 0 Microdose Exp IND North America and Europe North America
    46. 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. 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. 48. Guidance for European Microdosing Committee for Medicinal Products for Human Use (CHME) • Microdose (CPMP/SWP/2599/02/Rev1) defined as less than 1/100th 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. 49. US Exploratory IND (E-IND)  Microdose: 1/100th 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. 50. Exploratory IND  Facilitates “first-in-human” imaging studies – Biologics – Drugs  Bridges preclinical --- Phase I  Ideal for “proof-of-concept” studies
    51. 51. Regulatory Pathway RDRC study Phase 0 Microdose Exp IND North America
    52. 52. Radioactive Drug Research Committee (RDRC)  Regulation - 21 CFR 361.1  Established by the FDA in 1975 Center for Drug Evaluation & Research
    53. 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. 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. 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. 56. PET Regulations Work In progress!!
    57. 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