Radiopharmaceutical Production

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Radiopharmaceutical Production

• Cyclotron Facilities and FDG Radiopharmaceutical
  Production

Click here to proceed to the Introduction
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Forward

• The application of radionuclides in medicine has
  undergone significant growth in the last decade
  and one of the major factors contributing to this
  increased growth is the availability of a large
  number of cyclotrons exclusively dedicated to
  this purpose. Many of these cyclotrons are
  dedicated to the production of PET isotopes and
  more specifically, fluorine-18 for the production
  of 18F-FDG (fluorodeoxyglucose).
• Grateful acknowledgement is given to the
  Brookhaven National Laboratory for supporting the
  electronic distribution of this material and to
  David Schlyer for final editing.
• The contact points for this material are
• David Schlyer (schlyer_at_bnl.gov)
• and
• Mohammad Haji-Saeid (M.Haji-Saeid_at_iaea.org)

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• Web Information Presentation

This series of presentations is intended to be a
readily accessible platform with background
material and practical information on operating a
radiopharmaceutical production facility with an
emphasis on the production of FDG. The material
was assembled by a group of people who are
involved in PET radiopharmaceutical production.
This tutorial describes processes and procedures
that may be used in the preparation of PET
radiopharmaceuticals. Other processes and
procedures that are not described in this
tutorial may also be acceptable
Click here or on the forward arrow to proceed
with the
Explanation and Navigation
Click here to proceed directly to the Overview
(not recommended for first time visitors)
Overview
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Philosophical Organizational Structure
This series of presentations is intended to be a
readily accessible platform with background
material and practical information on operating
an FDG production facility,
As an example the operation of the cyclotron at
different levels
Few Details Level 2 What are the major
components of the cyclotron?
More Details Level 3 How do the components work
together and what is the basic theory?
Complete (Not in these presentations) Level
4 What is the theory and all the parameters
behind the operation of each component?
Basics Level 1 What is a cyclotron?
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Introduction

• This informational module is designed to give
  you an introduction to the production of
  radiopharmaceuticals. It is a self guided tour
  and you can learn about any specific topic by
  clicking on the pictures in the overview or by
  navigating to a specific presentation.

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Radiopharmaceutical Production
Quality Control Product Release Dispensing -
shipping
Cyclotron Operations Cyclotron Targetry
Radionuclide Transfer
FDG Production
GMP
Quality Assurance
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Production Environment Equipment
Requirements Radiation Protection Validation
Personnel
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Good Manufacturing Navigation Tree
US FDA Regulations
Good Manufacturing Practices
GMP Regulations
EU Regulations
WHO Quality Guidance
WHO GMP Powerpoint
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about Good Manufacturing Practices or jump
directly to a presentation by clicking on the
name.
Intro to GMP Pradeep Garg
Intro to GMP Nicholas Buhay
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Good Manufacturing Practices

• The purpose Of GMP is to assure the identity,
  strength, quality, and purity of drug products.
  This is accomplished by requiring that
  manufacturers of pharmaceuticals adequately
  control manufacturing operations.  This includes
  establishing strong quality management systems,
  obtaining appropriate quality raw materials,
  establishing robust operating procedures,
  detecting and investigating product quality
  deviations, and maintaining reliable testing
  laboratories.  This formal system of controls at
  a radiopharmaceutical production facility, if
  adequately put into practice, helps to prevent
  instances of contamination, mix-ups, deviations,
  failures, and errors.  This assures that drug
  products meet their quality standards.

GMP can be summarized as the necessary level of
control over the operation and administration of
facilities, methods and processes which will lead
to the manufacture of radiopharmaceutical
products of consistently high quality (to assure
that the products meet the requirements as to
safety and effectiveness which the product
purports). More about GMP can be found here.
More
GMP Regulations
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Quality Assurance Navigation Tree
Site Master File
Quality Assurance
Quality Management
Quality Manual
Job Responsibility
Operating Instructions
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about Good Manufacturing Practices or jump
directly to a presentation by clicking on the
name.
SOPs
Documentation
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Quality Assurance

• Quality Assurance is a systematic process focused
  on providing confidence that quality requirements
  will be fulfilled.
• Quality Assurance (QA) encompasses all aspects of
  radiopharmaceutical production.
• The development of a good quality assurance
  program requires a series of documents which can
  be confusing to the newcomer

To learn more about the development of a
Quality Assurance program, follow the arrow
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Quality Management
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Personnel Navigation Tree
Personnel and Quality Assurance
Personnel
Job Responsibilities
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about Personnel and Quality Assurance or jump
directly to a presentation by clicking on the
name.
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Personnel

• The facility for production of PET radioisotopes
  and radiopharmaceuticals/radiotracers will
  require a staff representing a wide range of job
  titles and training requirements. The staff
  should have the formal education, training and
  experience necessary to carry out the assigned
  tasks. The job functions include both production
  personnel and quality control personnel as well
  as some support functions
• Quality Assurance is a way of thinking to ensure
  that the product being produced is effective and
  safe for human use. Quality Assurance includes
  the validation of equipment, the validation of
  the process, and the documentation.

Personnel
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Job Responsibilities
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Production Environment Navigation Tree
Production Environment EU
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about Facilities and Equipment or jump directly
to a presentation by clicking on the name.
Production Environment USA
Radiation Protection
Production Environment
Validation Master Plan
Equipment Requirements
Equipment Validation
Validation
Quality Management
Process Validation
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Production Environment

• A radiopharmaceutical production facility
  includes several types of areas and the equipment
  that resides in those areas. There are
• Open or Uncontrolled areas These are the normal
  laboratory and controlled areas that are used to
  manufacture the radiopharmaceutical and must
  comply with GMP regulations
• Radiation Protection Radiation protection is a
  concern in a production facility. There are
  regulations concerning the handling of radiation
  and instruments are required to measure the
  levels of radioactivity in a laboratory to ensure
  it is always contained
• Production Equipment and Instruments These
  include all the equipment to produce the
  radiopharmaceutical and the instruments used to
  analyze the final product. A List of Required
  Equipment can be found here.

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Production Environment EU
More
Production Environment USA
Radiation Protection
More
Equipment Requirements
More
The equipment and process must be validated as
described here
Validation
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Validation

• The first step in validation is to create a
  validation master plan (VMP). The VMP documents
  the way the facility will operate, who has
  control over the various aspects of the
  validation activities, and how production,
  quality control, and personnel management will be
  directed. To learn more about the VMP, follow the
  arrow.
• All the equipment used in the manufacture of any
  radiopharmaceutical must be validated to be sure
  that it will give accurate and meaningful results
  for all the tests required before the product is
  released for human use. This includes being sure
  that the equipment is designed to perform the
  tests, that it is installed properly, that it is
  operating properly and that it is performing
  properly. This is part of the QA function. To
  learn more about Equipment Validation Specifics,
  follow the arrow
• To learn about Quality Assurance and Quality
  Management, see
• Some tests such as the sterility test cannot be
  completed before the product is delivered.
  Because of this, it is very important that the
  whole process be validated. Read more about
  process validation.

Validation Master Plan
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Equipment Validation
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Quality Management
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Process Validation
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Cyclotron and Targetry Navigation Tree
Cyclotron History
Cyclotron Operations
Cyclotron Basics
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about Cyclotrons and Targetry or jump directly to
a presentation by clicking on the name.
Commercial Cyclotrons
Cyclotron and Targetry
Nuclear Reactions Target Physics
Beam Heating Density Reduction
Cyclotron Targetry
Target Foils
Radionuclide Transfer
Practical Target Design
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Cyclotron and Targetry

• The cyclotron is a particle accelerator which is
  used to produce the radionuclides. It accelerates
  a charged particle to very high energies. In most
  cases considered here, this charged particle will
  be a negatively charged hydrogen ion. Learn about
  cyclotrons here.
• Once the charged particle reaches high enough
  energies, it is directed out of the cyclotron and
  hits a target material and makes the
  radionuclide. An example of this process is the
  reaction of oxygen-18 enriched water with protons
  to make fluorine-18. Learn more about cyclotron
  targetry.
• Once the radionuclide is made, it may be
  extracted from the target material used in the
  irradiation. In the case of FDG, the F-18 can be
  extracted from the O-18 water using a resin
  column. It must then be transferred out of the
  cyclotron vault and into the chemistry
  laboratory. This may be a short distance through
  a wall or a rather long distance depending on the
  placement of the cyclotron in the facility. Learn
  more about radionuclide transfer.

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Cyclotron Operations
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Cyclotron Targetry
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Radionuclide Transfer
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FDG Production Navigation Plan
You may continue to the next slide to learn more
about FDG production or jump directly to a
presentation by clicking on the name.
FDG Synthesis Chemistry
FDG Production
How FDG Synthesizers Work
FDG Synthesizers
Troubleshooting Guide
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FDG Production

• In order to produce a radiopharmaceutical, it
  necessary to set up a laboratory to accommodate
  all the equipment and personnel, and to carry out
  production in a safe and clean environment. The
  laboratory usually will usually contain
• General laboratory equipment for usual chemical
  operations as described in the Facility and
  Equipment section
• Analytical equipment to analyze the final product
  to ensure it is safe and meets all standards of
  purity and identity as described in the Facility
  and Equipment section
• Production equipment to produce the
  radiopharmaceutical. This is usually a synthesis
  module and there are several for FDG by various
  manufacturers. More information about the
  synthesis of FDG, the operation of the
  synthesizers and the synthesizers available can
  be found by following the arrow

FDG Synthesizers
More
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Quality Control TestingProduct Release
Navigation Tree
You may continue to the next slide to learn more
about Quality Control Testing and Product Release
or jump directly to a presentation by clicking on
the name.
This tutorial describes processes and procedures
that may be used in the preparation of PET
radiopharmaceuticals. Other processes and
procedures that are not described in this
tutorial may also be acceptable
GMP Regulations
Quality Control Testing Product Release
Quality Control
Product Release
Shipping
IAEA Pub 1225
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Quality Control TestingProduct Release

• Quality Control of the final product is one of
  the most critical steps in the production of the
  radiopharmaceutical. It is where the final
  determination is made as to whether or not the
  radiopharmaceutical can be used in a patient.
  There are extensive regulations from different
  governing bodies which govern these tests and
  regulate production. The regulations can be found
  here.
• The testing that is done for PET
  radiopharmaceuticals has to be done quickly since
  the half-life of the radiopharmaceutical is so
  short. There are a series of very specific tests
  which must be carried out. These include tests
  of both chemical and radiochemcial purity,
  conformation of radiochemical identity, pH,
  sterility and to ensure the dose does not contain
  dangerous levels of pryogens. More information
  about these tests and a discussion of the methods
  can be found by following the arrow.
• Before a product can be released for clinical
  use, it must approved. This can only be done by
  an authorized person (qualified person). To
  learn more about the qualifications necessary and
  the formal documents that are used to document
  the release, follow the arrow.

GMP Regulations
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Quality Control
Product Release
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