PET_Regulations C. Dence

8/3/2019 PET_Regulations C. Dence

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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/


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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,html


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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
http://www.pharmacist.com/


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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

Documents

PET_Regulations C. Dence