PET Regulations

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<ul><li>1.Comparison of National PET Radiopharmaceutical Regulations Carmen S. Dence, Pharm D., M.S. Hoapital Pharmacy 5th . Congress Bogota, Colombia 2008 </li></ul><p>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 &amp; knowledge qualified for the preparation of RPs Different from Conventional RPs EANM Radiopharmacy &amp; 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 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 m and larger per cubic meter 15. United Kingdom Radiopharmacy Regulation GMP began to be introduced in late 1970s 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: 1. In a licensed facility (Specials Manufacturing license) 2. By a pharmacist (Registered Pharmacy) Facilities and procedures must be the same in both 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. 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 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. 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 &amp; training Around 100 Specialists in Radiopharmacy Pharmacists comprise 65% Not Nuclear Medicine Physicians involved in RPs preparation till early 90s 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. 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 &amp; 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 &gt; Class 100 (Class A/B) Hot cell Class 10,000 (Class C) Working area (hot lab, dispensary, QC room) &gt; 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 RPsnot specifically defined Personnel: 36. Food &amp; 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 areawith 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 Phase 0 Microdose Exp IND Clinical Development Phase 1 Phase 2 Phase 3 Phase 0 Microdose Exp IND North America and Europe North Ameri...</p>

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