Features of radiopharmaceuticals production

by Mariam Ramazanova, Quality and validation Consultant @PQE Group

Radiopharmaceuticals, which are medicinal products containing radioactive isotopes, have become essential tools in both diagnostic imaging and therapeutic treatments. The manufacturing of radiopharmaceuticals involves a series of intricate processes, including production, quality control, release, and delivery. To ensure that all manufactured radiopharmaceuticals are of the highest quality, it is crucial to adhere to Good Manufacturing Practices (GMP) throughout the entire process until the delivery stage. In addition to GMP compliance, the manufacturing and production of radiopharmaceuticals, whether in-house or on a large commercial scale, should also comply with guidelines set by the World Health Organization (WHO), European GMP rules, FDA regulations, and Eurasian Economic Union GMP rules. These guidelines are in place to ensure the safe production and release of radiopharmaceuticals. Radiopharmaceuticals can take various forms, with the majority being administered intravenously in the form of solutions. This article will delve deep into the manufacturing practices of radiopharmaceuticals, shedding light on the bright prospects of theranostic radiopharmaceuticals, a pioneering approach that integrates therapeutic and diagnostic techniques. It will also highlight the significance of complete adherence to Good Manufacturing Practices (GMP) to ensure the production of safe and top-notch radiopharmaceutical products that benefit patients. 

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Radiopharmaceuticals is the term for a medicinal products that is ready for use and contains one or more radionuclides (radioactive isotopes).   

The manufacturing of radiopharmaceutical products includes production, quality control, release, and delivery of radiopharmaceuticals from the active substance and starting materials. It can be the manufacturing site, which resides on its own and sells radiopharmaceuticals to hospitals.  

Radiopharmaceuticals should be prepared according to GMP rules; all processes must be validated and prepared according to a validated process that provides a high degree of assurance that the preparation meets all established requirements for quality and purity.  

Radiopharmaceuticals used for molecular imaging (diagnosis) require a single-photon emission computed tomography radionuclide diagnostic imaging or a positron emission tomography. In addition, there is another type of radiopharmaceutical - radiopharmaceuticals for therapy.  We believe that the future of radiopharmaceuticals is Theranostic. Theranostic Radiopharmaceuticals (Radiotheranostics) is a term in the medical field to define the combination of therapeutic and diagnostic techniques developed by a suitable radiopharmaceutical agent.  Radionuclides are isotopes that emit radiation or have excess nuclear energy, making them chemically unstable, with the tendency to change into another atom. Various types of radiation can be emitted by radionuclides, e.g., alpha particles, beta particles and gamma energy. In radiotheranostics, a pharmaceutical agent (drug) is needed to be a carrier molecule that introduces the radionuclide to its target. Radionuclides are then used as a source of radiation in radiotheranostics that are responsible for diagnosing or treating various diseases. 

Radiopharmaceuticals can be produced in different forms.  More than 80% of them are solutions for intravenous administration. Then there are solutions for internal use or capsules (an example of capsules includes Sodium Iodide I-131,131I NaI therapeutic capsules prepared in a centralized radiopharmacy and can quantify the amount of volatile 131I released from a dispensing vial containing a compounded 131I-NaI therapy capsule).  

Radiopharmaceutical manufacturing can be done as a large-scale industrial manufacturing (commercial) manufacture as well as in a small-scale “in-house” hospital radiopharmacy unit. “In-house” hospital radiopharmacy units can be three non-commercial sites, such as   hospital radiopharmacies,   nuclear medicine departments, research PET centers and in general, any healthcare establishment. In Site I, general issues which apply to all types of radiopharmaceutical preparations for diagnostic and therapeutic use are addressed. Site II covers small-scale radiopharmaceutical preparations (SSRP) from licensed generators or radionuclide precursors and kit preparations. Site III addresses the preparation of SSRP from non-licensed starting materials. This part is described in a Guideline on current good radiopharmacy practice (cGRPP) for small-scale preparation of radiopharmaceuticals, written by experts from the European Association of Nuclear Medicine.  

Radiopharmaceutical production is structured according to requirements regulated according to the requirements of GMP: 

  • WHO (World Health Organization), Annex 3, Guidelines on Good Manufacturing Practices for radiopharmaceutical products, Section 6. 2003  
  • European GMP Rules. EU Legislation: EudraLex 4.0  
  • FDA Current Good Manufacturing Practice (cGMP) Regulations Code of Federal Regulations (CFR). CFR is in Title 21.  
  • Eurasian Economic Union GMP Rules  Decision No. 77 of the Council of the Eurasian Economic Commission of 3 November 2016 RULES of Good Manufacturing Practice of the Eurasian Economic Union 

With respect to features of radiopharmaceutical production, pharmaceuticals with small-scale preparation are considered first.  Radiopharmaceuticals have a short shelf life and are generally administered via intravenous route. With cGMP rules, some radiopharmaceuticals may have to be distributed and used on the basis of an assessment of batch documentation and before all chemical and microbiology tests have been completed. Radiopharmaceutical product release may be carried out in two or more stages, before and after full analytical testing, and requires:  a) Assessment by a designated person of batch processing records, which should cover production conditions and analytical testing, performed thus far, before allowing transportation of the radiopharmaceutical under quarantine status to the clinical department; and b) Assessment of the final analytical data, ensuring all deviations from normal procedures are documented, justified and appropriately released prior to documented certification by the Qualified Person. Where certain test results are not available before use of the product, the Qualified Person should conditionally certify the product before it is used and should finally certify the product after all the test results are obtained.   

Special and specific equipment is used for radiopharmaceutical production.  

One such piece of equipment is hot–cells, which are shielded workstations for the manufacture and handling of radioactive materials. Hot-cells can be designed as an isolator.  Closed or contained equipment should be used whenever appropriate. Where open equipment is used or equipment is opened, precautions should be taken to minimize the risk of contamination. The risk assessment should demonstrate that the environmental cleanliness level proposed is suitable for the type of product being manufactured. Hot-cells are used in the production of radiopharmaceuticals according to GMP guidelines. Radiochemistry systems are the unique integrated cassette-based design systems with GMP quality components (e.g., vials) which enable and ease the regulatory reliability and compliance in tracer production. Pre-measured quantities of every chemical and component needed for the synthesis of a radiopharmaceutical are contained in a single cassette. That means it only takes two simple steps to start producing virtually any clinical tracer needed. This unique, cassette-based system not only simplifies this step of tracer production, it also makes it more reliable and secure compared to other methods. Cassettes are manufactured in a controlled environment, pre-loaded with reagents produced under cGMP standards, barcoded for automatic identification and sealed shut. They are also disposable, so when a run is complete, each component that comes into contact with the chemical is replaced to ensure clean operation. Radiochemistry systems stationed inside the hot-cells can be one system, one box, or can compare a few multiply radiochemistry system in one box. However, production of different radioactive products in the same working area (i.e., hot-cell, LAF unit) at the same time should be avoided in order to minimize the risk of radioactive cross-contamination or mix-up.  The hot-cell for dispensing systems consists of a Class B pre-chamber for the introduction of the materials, while the dispensed vials are extracted by means of an automatic and ventilated transfer system from the dispensing chamber (Class A) to the shielded container placed in the drawing system (Class B).  This hot-cell supports aseptic dispensing and can support dispensing with final sterilization in an autoclave: the autoclave can be requested as an accessory at the moment of system configuration.  The dispenser receives the radiopharmaceutical in a bulk vial and it can calculate its concentration, thanks to the integrated calibrator and the scale. The dispensing of the final vial is based on the measurement of the weight/volume with the verification of the activity dispensed in a second dose calibrator.   

The critical parameters should normally be identified before or during validation and the ranges necessary for the reproducible operation should be defined.  Examples of critical process parameters (CPP) include synthesis processes – temperature, activity, volume, pressure inside the hot-cells,   LAF speed, etc. 

Radiopharmaceutical preparations must comply with labelling requirements set by GMP guidelines.  Due to radiation exposure, it is accepted that most of the labelling of the direct container is done prior to manufacturing. Sterile empty closed vials may be labelled with partial information prior to filling, provided that this procedure does not compromise sterility or prevent visual control of the filled vial. A statement that the product is radioactive is required OR the filled vial should have the international symbol for radioactivity.  

A radiopharmaceutical is not only a radioactive chemical substance, but first of all, it is a pharmaceutical drug and the organization of the entire production must be subject to GMP rules, including the use of qualified equipment and personnel, the premises and utilities validated processes, and computerized systems. All these components can help us to organize the best production centers with the highest quality of radiopharmaceuticals for patients; products that meet compliance with high quality standards.  This is to ensure patient safety and the health of patients using quality therapy developed using the most stringent industry standards.  

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