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Comparison of National PET
Radiopharmaceutical Regulations
Carmen S. Dence, Pharm D., M.S.Hoapital Pharmacy 5th. Congress
Bogota, Colombia 2008
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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?
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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
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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?
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National PET Regulation Comparisons
European Union (EU)
UK
Spain
Japan
USA
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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 tobe translated into the respective national legislation and
effectively implemented. Directives are mandatory.
Guidelinesare recommendations for the effectiveimplementation of Directives by the Member States.
Guidelines are not mandatory.
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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
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EUDRALEXRules Governing Medicinal Products in EU
Volume 4:
Medicinal Products for Human Use
IMPs (Investigational Medicinal Products)
Manufacture :
RPs undertaken in accordance with the basicprinciples of GMP (Part I and II)
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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
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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 (Class100,000)
Production of different RPs in same work stations
and at the same time should be avoided
Reference samples of every batch should be retained
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European Association of Nuclear Medicine (EANM)Guidelines on Current Good Radiopharmaceutical Practice
(cGRPP) for Preparation of RPs
Part A- kit-based RPs
Part B-cGRPPfor PET
Equipment and facilities: same room used formultiple 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
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EANMInitiative
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
http://www.eanm.org/http://www.eanm.org/8/3/2019 PET_Regulations C. Dence
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Background in Europe
Regulations for the extemporaneous
preparation of RPs vary
From: Full GMP compliance (England)
To: No enforcement of pharmaceuticalregulations
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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 35.24 Class 10 352
A and B 5 Class 100 3520
6 Class 1000 35,200
C 7 Class 10,000 352,000D 8 Class 100,000 3,520,000
*particles 0.5 m and larger per cubic meter
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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
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UK Regulation of Radiopharmacy
Provided by Medicines and Healthcare Products
Regulatory Agency (MHRA)
License products
(through normal EU system)
License facilitiesthrough system of manufacturing licenses
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UKRegulation of Radiopharmacy All RPs must be prepared either:
1. In a licensed facility (Specials Manufacturinglicense)
2. By a pharmacist (Registered Pharmacy)
Facilities and procedures must be the same in both
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UKPersonnel
Specials Manufacturing facility:
1.Individuals responsible forProduction and QC
must be named
2.Normally at least onewould be a pharmacist
3.No specific qualification in radiopharmacy
required, but both must show suitable
experience and training4.No Qualified Person required
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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
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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
UKSummary
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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
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Spanish Personnel: Qualified Person
Radiopharmacy as a SpecialtyOfficially 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 90s
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SpanishRadiopharmacy Models
Two models coexist:
1.Commercial Centralized Radiopharmacies
Provide unit dose RPs to nearby hospitals and nuclearmedicine centers
2. Hospital Radiopharmacies
Extemporaneous preparation of kit-based RPs Blood-cell labeling Compounding of PET RPs exclusively for in-house use
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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 andDevelopment
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SpanishHospital Radiopharmacies
Premises & equipment: many differences among
sites
Personnel: Specialist in Radiopharmacy is Head of
the Unit
Hierarchal dependence:
Nuclear Medicine (most )Hospital PharmacyIndependent (few)
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Preparation of PET RPs
Industrial manufacturing under MAOnly one PET RPs: 18FDGDirective 2001/83 EC appliesGMP compliance
In-hospital compoundingCompounded as officinal preparationsDirective 2001/83 EC does not apply
(exemption of art 3)Wide variety of PET RPsNational Regulation applies
[Good Pharmacy Practice (GPP)]
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Magistral and Officinal Compounding
Officinal formula must be
Described in the National FormularyFollow the rules of the Royal Spanish PharmacopoeiaCompounded in Pharmacies or Hospital PharmaciesCompounded 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 ProductsCompounded by a Pharmacist
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Problems for PET RPs Compounding
Pharmaceutical companies-little interest in PET RPsThey cannot be sold due to extremely short half-lifeExtremely reduced marketThere is a real need for PET RPs use
Diagnosis of specific pathologies
Daily clinical use of unlicensed PET RPsNone 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
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Clinical Trials with Unlicensed RPs
If designation of IMP for RPs is necessaryAuthorization as Pharmaceutical Laboratory is
required
Hospital Radiopharmacy is NOT a PharmaceuticalLaboratory
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
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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
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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
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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)
http://www.jrias.or.jp/index.cfm/11,html8/3/2019 PET_Regulations C. Dence
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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 :
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Japanese Guideline for
Manufacturing
Pharmacist is the responsible individual
Pharmacist or other trained individual can prepare
FDG or other PET RPsnot specifically defined
Personnel:
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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 controlsconforming to USP monographs and Chapter
823
Requires filing of New Drug Application
(NDA) or Abbreviated NDA (ANDA) forclinical use of PET drugs within 2 years after
publication of final PET GMP regulations
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ProposedGood 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 211that are not appropriate to PET, and adds elements
specific for PET
21 C d f F d l R l ti (CFR) P t 212
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21 Code of Federal Regulation (CFR) Part 212USCurrent 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
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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
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US Proposed CGMP for PET-2
Self-verification of significant steps in PET drugproduction
Same-person oversight of production, review, andrelease consistent with complexity of operation
Specialized QC requirements for PET drug produced
in multiple sub-batches
Simplified labeling
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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 operationLow traffic area
Assembly of final product vial
Sterility Testing
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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 PETAuthorized Nuclear Pharmacist (ANP)
Authorized Nuclear Medicine physician (AU)
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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 Licenseb. Requires 4000 hours of
training/experience
in nuclear pharmacy post graduationc. Pass an exam given by Board
2. Alternate pathway training
a. 200 hours didactic training--specified courses
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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
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Regulatory Pathway
RDRC
study
Phase 0
Microdose
Exp IND
Clinical Development
Phase 1 Phase 2 Phase 3
Phase 0Microdose
Exp IND
North America and Europe
North America
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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 ResearchCommittee)
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EU Clinical Trials Directive 2001/20/EC
EU Directive states that GMP must be applied to thepreparation 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 forHuman Use Medicinal Products (CHMP) Quality Working
Party (QWP) inspectors to facilitate implementation of
20001/20/EC
Guideline attempts to harmonize requirements throughout theEU for chemical & pharmaceutical quality documentation for
IMPs
Compliance: October 2006
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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 testsubstance and at a maximum dose of 100
microgram
CHMPadopted a position on non-clinicalsafety studies supporting clinical trials with
single microdose
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USExploratory IND (E-IND)
Microdose: 1/100th of the dose calculated toyield a pharmacologic effect
Mass dose 100 g
Reduced Pharmacology, toxicology requirementsOne mammalian species (both sexes)
100 times dose
Diagnostic dose only
Limited subject enrollment: 5 to 30
Transition to Phase 1 IND or RDRC
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Exploratory IND
Facilitates first-in-human imaging studies
Biologics
Drugs
Bridges preclinical --- Phase I
Ideal for proof-of-concept studies
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Regulatory Pathway
RDRC
study
Phase 0Microdose
Exp IND
North America
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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
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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
C i
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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 ofPET production facilities
C l i
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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
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PET Regulations
Work In progress!!
Acknowledgements
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Acknowledgements
Sally Schwarz, MS Washington University St Louis,
MO USAStephen J. Mather, Ph.D.; St Bartholomews
Hospital, London, England
Ivan Penuelas, Ph.D.; Department of NuclearMedicine, 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