Regulatory Compliance, Quality Control and

the Manufacture of Radiolabelled

Compounds

Anthony T. Rees

Quality Control Lead, Chemistry Manufacturing

Quotient Bioresearch

Bioanalytical Sciences

Chemistry &

Metabolism

Clinical

Services

Quotient Bioresearch

The Facility

Preferred Site

• Trident Park, Ocean Way, Cardiff

• Assessment against criteria:

�Existing 80 metre stack

�Limited proximity to residential property and

farmland to limit local dose (Industrial area

acknowledged by planners to meet criteria)

�Proximity to existing Amersham site to maintain

key skills/employees - Five miles from existing

facility

Trident Park was the environmentally preferred site of

all those studied by Quotient

Building Transformation

August 2009

June 2010

June 2010

Business Regulation

Health and Safety, Radioactivity and Waste

Key License Approvals Required

• Euratom Treaty Article 37 Approval from EU (impact of waste disposal on other member states)

• Guidance from Nuclear Installations Inspectorate on Nuclear Site License requirement

• Environmental Permitting Regulations 2010, Environment Agency (EA)

• Radiation (Emergency Preparedness and Public Information) Regulations, REPPIR Assessment, HSE

• Planning approvals

• Welsh Water trade effluent agreement

• Environmental Permitting Regulations 2010, Environment Agency (EA)

– Key authority in terms of holdings and disposals

– Waste strategy critical

• REPPIR Assessment, Health & Safety Executive (HSE)

– HSE insisted that total building loss due to fire must be modeled in assessing off-site emergency risk

– Most significant impact on design

• Planning approvals

– limited due to site and existing building

– Dialogue with local stakeholders important

• Trade effluent agreement – Welsh Water

– Innovative water treatment important

Key License Approvals Required

Key Design Criteria

• REPPIR

– Limit inventory of material in main building

– Develop storage solution with minimal risk of fire

(ignition and control)

– Look at non-Fire risks – Flood and Vehicle impact

(also Article 37 questions)

– Current design has an off-site dose of 3 mSv in case of

total building loss against 5 mSv limit threshold for an

off-site emergency plan

License Holdings

• Carbon-14 24 TBq (648 Ci)

• Tritium 160 TBq (4324 Ci)

of which10 TBq of carbon-14 and 133 TBq of tritium are

allowed in the main building at any one time.

The Facility

Men and Machines

� What?

- Synthesis of a product with a

radioactive isotope in a single

stable position

- Isotopes typically used 14C or 3H

� Why?

- Radiochemical acts as a tracer

- Tracers behave the same as the

non labelled product, can follow

where things go and what they

become.

- Key to registration of new drugs,

agrochemicals and large scale

industrial chemicals

Radiochemistry – What & Why?

Inside The Old Glassworks

• 7 Chemistry laboratories

– Wide range of organic chemistry equipment

– Preparative and analytical HPLC systems

– GC systems

Large 14C Lab

Laboratories

Inside The Old Glassworks – Quality Control

3 Analytical laboratories

– 8 analytical HPLC Systems

– 2 GC systems

– 1 NMR System

– 3 Mass Spectrometers

– 1 Differential Scanning Calorimeter

– 1 Thermogravimetric analyser

Science Based Workforce

• 98 People work on The Old Glassworks site

• 82 have a Science background

• 77 of these have a Chemistry background

• 57 work in the laboratories on a daily basis

– 16 have technical qualification below first degree

– 41 have first degrees

– Of that 41, 15 have a PhD

Legislation of Manufacture

GMP, GLP and ISO9002

Legislation of Manufacture

Regulations born out disasters:

• 1902 : Diptheria vaccine – 130 child deaths

• 1906 : US Pure Food and Drug Act (FDA)

• 1937 : Sulphanilimide Elixir – 100 deaths from renal

failure

• 1941 : Sulfathiazole tablets – 300 deaths

• 1945 : Premature detonation of bombs in factories

• 1960 : Thalidomide – 12 000 cases of physical

abnormality world wide

• 1996 : Haiti – contaminated paediatric paracetamol

syrup – 87 child deaths

Legislation of Manufacture

From these disasters the Good Practices emerged

• Good Laboratory Practice

– Official in the US in 1979

– Adopted in ROW inc. UK in 1981 under OECD Guidelines

• Good Manufacturing Practice

– Official in the US in 1978

– Adopted in UK with publication of the first Orange Guide in 1971

• Good Clinical Practice

– ICH E6 1996 adopted worldwide

– EU Directive 2005/28 EC in 2005

• ISO9000

– 1920’s Bell telephone company

– Post 1945 Military standards Mil-Q-9858a, Def. Stan. 05-21, AQAP-1.

– 1979 BS5750

– 1987 ISO9000 was born out of BS5750

• The objective of GMP is to ensure that products are consistently

produced to particular quality standards to their intended use and

as required by the marketing authorisation or product

specification.

• Good Laboratory Practice (GLP) embodies a set of principles that

provides a framework within which studies are planned,

performed, monitored, recorded, reported and archived. These

studies are undertaken to generate data by which the hazards and

risks to users, consumers and third parties, including the

environment, can be assessed for pharmaceuticals,

agrochemicals, veterinary medicines, industrial chemicals,

cosmetics, food and feed additives and biocides.

• ISO 9001 is a set of internationally agreed standards that provide

guidelines for a Quality Management System.

GMP, GLP and ISO9001:2008

Regulatory Documentation

Documentation Hierarchy

Quality Management Systems

Quality Control Regulated

StandardQuality Assurance

Quality Management Systems

QUALITY CONTROL

Equipment

Facilities

Utilities

Test Methods

Specifications (in

process and finished

product)

Process Control

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Quality Control

Then of course there is the analysis!

High Performance Liquid Chromatography of

[3H]Compound 1

Proton NMR Spectrum of Compound 1 Reference

Material

T-NMR Spectrum of [3H]Compound

1

Size and design of the building determined by original concrete building shell

Main Building

Comparison of the Proton and Triton NMR Spectrum

for Compound 1

Triton

Proton

Electrospray Ionisation of Compound 1 Reference

Material

Electrospray Ionisation of [3H]Compound 1

Concluding Remarks

• Operating and complying to GMP, GLP and ISO9000 are

the visible tip of regulatory compliance.

• Regulation and law are a moving feast – auditing and

continual improvement are the only way to ensure

regulated, compliant best practice.

• Can only be achieved by people who have committed

themselves to years of study and practise as professional

chemists.

• 20% of the slides in this presentation are of practical

work!

• Thank you for listening and your time .

Acknowledgements

Dr Grant Johnston – Director of Chemistry, QBR

Dr Mark A. Waring – Site Director, The Old Glassworks

Alun Griffiths – EHS Director, The Old Glassworks

Marilyn Emery QP, of Marilyn Emery Consulting

Rhodri Llewellyn, Photographer and chemist

Any Questions?