Download - PET Regulations
Comparison of National PETRadiopharmaceutical Regulations
Carmen S. Dence, Pharm D., M.S.
Hoapital Pharmacy 5th. Congress
Bogota, Colombia 2008
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?
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
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?
National PET Regulation Comparisons
• European Union (EU)
UK
Spain
• Japan
• USA
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.
EU Directive 2003/94/EC8 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
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)
EUDRALEX Annex 3Manufacture of Radiopharmaceuticals
EU Directive 2004/27/EC31 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
EUDRALEX Annex 3Manufacture 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
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
EANM Initiative“Responsible Person for Preparation of RPs
http://www.eanm.org/
• Need for specific training & knowledgequalified 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
Background in Europe
• Regulations for the extemporaneous preparation of RPs vary
– From: Full GMP compliance (England)
– To: No enforcement of pharmaceutical regulations
International Organization of Standardization of Particulate Matter in Room Air
Class Name Particle Count*
Grade ISO Class U.S. FD 209E ISO 14644-13 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 and larger per cubic meter
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
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
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
UK Personnel
“Specials Manufacturing” facility:
1.Individuals responsible for Production and QC must be named
2.Normally at least one would be a pharmacist3.No specific qualification in radiopharmacy
required, but both must show “suitable experience and training”
4.No “Qualified Person” required
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”
• 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
Spanish National Legislation
• Specific CharacteristicVery ambiguousOut-dated (1993)No clear inspection requirements
• Radiopharmacists trying to obtain clear regulations for:
Radiopharmacy units; premises, equipment, personnelRPs compounding and extemporaneous preparationClinical trials with non-commercially available RPs
(mainly PET)• Pharmacopoeia has Guidelines on RPs Procedures
Recommendations; NOT legally binding
Radiopharmacy Practice in Spain
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
Spanish Radiopharmacy Models
Two models coexist:
1.Commercial Centralized RadiopharmaciesProvide 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
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
Spanish Hospital Radiopharmacies
• Premises & equipment: many differences among sites
• Personnel: Specialist in Radiopharmacy is Head of the Unit
• Hierarchal dependence:Nuclear Medicine (most )Hospital PharmacyIndependent (few)
Preparation of PET RPs
• Industrial manufacturing under MA– Only one PET RPs: 18FDG– 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)]
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
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?
*18FDG, the only PET RPs with MA
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
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
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
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)
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
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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 :
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:
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
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
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
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
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
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
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)
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
New RadiopharmaceuticalsFirst-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
Regulatory Pathway
RDRCstudy
Phase 0 MicrodoseExp IND
Clinical Development
Phase 1 Phase 2 Phase 3
Phase 0 MicrodoseExp IND
North America and Europe
North America
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)
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
Guidance for European MicrodosingCommittee 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
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
Exploratory IND
Facilitates “first-in-human” imaging studies– Biologics– Drugs
Bridges preclinical --- Phase I
Ideal for “proof-of-concept” studies
Regulatory Pathway
RDRCstudy
Phase 0 MicrodoseExp IND
North America
Radioactive Drug Research Committee (RDRC)
Regulation - 21 CFR 361.1
Established by the FDA in 1975
Center for Drug Evaluation & Research
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
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
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
PET RegulationsWork In progress!!
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