1. Radiopharmaceutical Production
Cyclotron Facilities and FDG Radiopharmaceutical Production
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2. Introduction
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3. 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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4. Radiopharmaceutical Production
GMP Regulations
Quality Control
Product Release
Dispensing - shipping
Cyclotron Operations
Cyclotron Targetry
Radionuclide Transfer
FDG Production
Quality Assurance
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Production Environment
Equipment Requirements
Radiation Protection
Validation
Personnel

5. Quality Assurance Navigation Tree
US FDA
Regulations
Part
Good Manufacturing
Practices
GMP
Regulations EU
Regulations
Part 212
WHO Quality
Guidance TRS 908
WHO
GMP Powerpoint
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Intro to GMP
Pradeep Garg
Intro to GMP
Nicholas Buhay

6. Good Manufacturing Practices
Good Manufacturing practices (GMP) encompasses all aspect of radiopharmaceutical production
Organization
and Personnel
Storage and
Distribution
Buildings
and Facilities
Records
and Reports
Good
Manufacturing
Practices
Equipment
Laboratory
Controls
Packaging and
Labeling Control
Control of
Components
Production and
Process Controls

7. 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.
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8. Personnel and Quality Assurance Navigation Plan
Job Responsibilities
Personnel and
Quality Assurance
Quality Assurance
Quality Manual
Job Responsibility
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Operating Instructions
SOPs
Documentation

9. Personnel and Quality Assurance
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.
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10. Production Environment Navigation Plan
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Production
Environment
Radiation
Protection
Production
Environment
Validation
Master Plan
Equipment
Requirements
Equipment
Validation
Validation
Quality
Management
Process
Validation

11. 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 areas.
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
Radiation
Protection
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Equipment
Requirements
The equipment and process must be validated as described on the next page
Validation

12. 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.
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13. Cyclotron and Targetry Navigation Plan
History
Cyclotron
Operations
Cyclotron
Basics
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Commercial
Cyclotrons
Cyclotron and
Targetry
Nuclear Reactions
Target Physics
Beam Heating
Density Reduction
Cyclotron
Targetry
Target
Foils
Radionuclide
Transfer
Practical
Target Design

14. 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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15. FDG Production Navigation Plan
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FDG Synthesis
Chemistry
FDG Production
FDG Synthesizers
How FDG
Synthesizers Work
Troubleshooting
Guide

16. 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
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17. Quality Control Testing Product Release Navigation Plan
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GMP
Regulations
FDG Quality
Control - Hung
Quality Control Testing
Product Release
Quality
Control
FDG Quality
Control - Yu
Product
Release
Shipping
IAEA Pub 1225

18. Quality Control Testing Product 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.
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