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

````

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