Professional Documents
Culture Documents
Carmen S. Dence, Pharm D., M.S. Hoapital Pharmacy 5th. Congress Bogota, Colombia 2008
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?
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/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
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)
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 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
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 & 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
Background in Europe
Regulations for the extemporaneous preparation of RPs vary From: Full GMP compliance (England) To: No enforcement of pharmaceutical regulations
Class Name
Grade ISO Class 3 4 5 6 7 8 U.S. FD 209E Class 1 Class 10 Class 100 Class 1000 Class 10,000 Class 100,000
Particle Count*
ISO 14644-1 35.2 352 3520 35,200 352,000 3,520,000
A and B C D
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 pharmacist 3.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
UK Summary
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
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
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)]
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
Limited knowledge of authorities about radiopharmacy Use of unlicensed PET RPs Clinical trials with unlicensed PET RPs
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
Guidelines for manufacturing environment and process at manufacturing facilities for PET RPs
Monitoring: monitoring air particles and environmental microorganisms FDG modules must be approved by Pharmaceutical Law
Minimum requirements for PET drug production Covers all types of PET production facilities but differs
Not-for-profit academically oriented facilities vs. Commercial producers
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)
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
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
Regulatory Pathway
North America and Europe
Phase 0 Microdose Exp IND Clinical Development Phase 1 Phase 2 Phase 3
North America
Phase 0 Microdose Exp IND RDRC study
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:
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
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
North America
Phase 0 Microdose Exp IND RDRC study
Radioactive Drug Research Committee (RDRC) Regulation - 21 CFR 361.1 Established by the FDA in 1975
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-inman studies to expand development of new RPs more rapidly
Acknowledgements
Sally Schwarz, MS Washington University St Louis, MO USA Stephen J. Mather, Ph.D.; St Bartholomews 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