RADIOPHARMACY MANUFACTURING, STORAGE AND QC LINE ACCORDING TO CPOB 2012 PRODUCTION Radioactive facility procedures (hot lab) All radiopharmaceuticals should be handled in fume hoods, glove boxes or hot cells, biohazard safety cabinets. Glove boxesshould be equipped with adequate shielding and remote handling facilities. Loading materials into glove boxes or hot cells and removing the product should be carried out without the spread of radioactivity. The transfer, storage and handling of radioactive substances outside glove boxes or hot cells should be carried out with adequate shielding and remote handling equipment to minimize radiation exposure to personnel. All operational activities should be carefully designed and standardized to minimize the spread of radioactivity. GlovesBoxes or hot cells should be equipped with appropriate ventilation for handling radioactive substances. The air quality in the equipment should meet the CPOB requirements for injection preparations and other preparations. The facilities below must meet the requirements: hot cells,It should be kept clean according to the type of product being processed. Use Class A equipment for sterile products. Use class C equipment for nonsterile products. Radioactive laboratories, preparation rooms and quality control rooms should meet class D requirements to avoid contamination by microorganisms and dust. If the hot cell is not completely airtight, the surrounding environment should meet class C requirements. Glove box/hot-cells for handling radioactive substances should be properly standardized, however, the combination of radiation protection requirements and clean room requirements is still not fully standardized. For this purpose, a biohazard safety cabinet with some modifications can be used. All other equipment should be selected to maintain air quality during operation. Other facilities required in a radioactive laboratory: Shielded facilities are required to store radioactive samples; Collection of radioactive waste should be separated from non-radioactive waste and provided with a lead shield; Personnel monitoring Radiation personnel who handle radioactive materials in the form of powder or gas are likely to be exposed to radioactivity in the body through inhalation and the mouth. Exposure to radiation due to radionuclides stored in the personnel's body should be determined periodically by means of a whole body count (whole body counting) or monitoring of excreta such as urine (by determining biological levels -bioassay-) or by scanning special organs; If an accident occurs that results in extensive contamination of the laboratory environment, urine samples should be taken from the personnel for immediate analysis. In addition, all personnel who handle radioactive materials in powder or gas form should be asked to undergo a whole body count for gamma rays and actinides in the lungs at least once a year or if necessary from a safety perspective; Radiation monitoring should be carried out during processing; And In the event of contamination, measures as outlined in the radiation protection procedures must be implemented. See Radiation Protection and Safety paragraph, Item 148. Production of different radioactive products in the same room and at the same time should be avoided to minimize the risk of cross-contamination or mix-up. Process validation, in-process monitoring and monitoring of process and environmental parameters become especially important in cases that require making a decision to approve or reject a batch of product before all quality testing has been completed. Fixed procedures (Protap) must be available for all activities. Procedures for manufacturing products should be reviewed periodically and made up to date. All critical stage data entered by an operator in the batch record should be checked separately by another operator or supervisor. Starting material specifications should include detailed information about the supplier, the original of the material and, if applicable, the manufacturing and quality control methods used to ensure the correct use of the material. Finished products are approved only if the initial material test results meet the requirements. Various types of equipment are used to manufacture radiopharmaceuticals. In general, chromatographic equipment should be used specifically for the preparation and purification of one or more products bearing the same radionuclide signature so that radioactive crosscontamination can be avoided. The lifetime (life span) of the column should be determined. Great attention needs to be paid to the cleaning, sterilization and operation of the freezedrying equipment used to prepare the kit. A list of critical equipment should be prepared, such as scales, depyrogenation ovens, dose calibrators, sterilization filters, etc., where errors in reading or function in the equipment could harm patients receiving the finished radiopharmaceutical product. The equipment should be calibrated and tested at regular intervals and its condition should be checked every day or before the production process begins. The results of the inspection are recorded in the log book. Special equipment for measuring radioactive materials is required, as are radioactive comparison standards. Instruments for measuring radioactivity should be calibrated by institutions that have been accredited by the Government. Radiopharmaceutical Processing Activity steps during the radiopharmaceutical processing process should be as minimal as possible. Reagents that may be used are only reagents that have been previously tested and certified and, if necessary, new preparations. The use of a closed system process can reduce contamination and allows the application of "single step formulation". Fume hoods and workplaces with clean, laminar flow air that are well maintained should be used. Turning on UV lamps in the workplace before use can reduce the number of microbes. Both areas should be disinfected with 70% ethanol or surface disinfectant before work begins. Sterile gloves should be used during the process. The waste produced should be moved, stored separately and disposed of according to applicable procedures. All equipment and surrounding work areas must be cleaned thoroughly every day after work. Ceilings, walls and other structural surfaces should be cleaned regularly. Room fumigation must be done every month. Disposable sterile filter sets should be used for aseptic filtration processes. This filter should be tested for its integrity with a bubble test or its ability to filter cultures of the microorganism Serratia marcescens. Reception and Quarantine On arrival of materials and before acceptance, each container or group of containers of materials should be visually inspected for correct labeling (including correlation between name used by supplier and in-house name, if this is different), damage to containers, broken seals and evidence of damage or contamination. Materials should be quarantined until they have been sampled, tested in an appropriate manner and cleared for use. Before incoming materials are mixed with existing stocks (e.g. solvents or stock in silos), they should be properly identified, tested if necessary and released. Procedures should be in place to prevent the wrong entry of incoming materials into existing stocks. If bulk product shipments are made using tankers that are not dedicated to one product, there must be a guarantee that there will be no cross-contamination originating from the tanker. Ways to provide this guarantee may include one or more of the following: cleaning certificate; testing for sespore impurities; And audit of suppliers. Large storage containers and accompanying manifolds and their filling and discharging lanes should be properly identified. Each container or group of containers (batches) of materials should be marked and identified with a distinct code number, batch number or receipt number. This number should be used to record the disposition of each batch. There should be a system for identifying the status of each batch. Sampling and Testing of Incoming Production Materials At least one test should be carried out to verify the identity of each batch of materials, except for the materials described in Item 7.13. A supplier's Certificate of Analysis may be used in lieu of performing other tests, provided that the manufacturer has a system for evaluating suppliers. Supplier approval should include an evaluation that provides sufficient evidence (e.g., quality history) that the manufacturer can consistently provide materials that meet specifications. Complete analysis should be performed on a minimum of three batches before reducing inhouse testing. However, as a minimum, a complete analysis should be carried out at appropriate intervals and compared with the certificate of analysis. The reliability of the certificate of analysis should be checked at regular intervals. Process aids, hazardous or highly toxic raw materials, other special materials or materials transferred to other units under the control of the company do not need to be tested if a Certificate of Analysis is obtained from the manufacturer, which shows that the raw materials meet the specified specifications. Visual inspection of the container, label and batch number record should facilitate identification of the material. Waiver of on-site testing of such materials should be justified and documented. Samples should be representative of the batch of material from which they were taken. The sampling method should specify the number of containers and which part of the container is taken for the sample, as well as the amount of material taken for the sample from each container. The number of containers for samples and sample size should be based on sampling patterns taking into account material criticality, material variability, supplier quality history and quantities required for analysis. Sampling should be carried out at designated locations and according to procedures designed to prevent contamination from the material taken for sampling and contamination from other materials. The container from which the sample was taken should be opened carefully and immediately closed again. The container should be marked to indicate that the sample has been taken. Storage Materials should be handled and stored in such a way as to prevent degradation, contamination and cross-contamination. Materials stored in fiber drums, bags or boxes should not be placed directly on the floor and, where appropriate, provided with space to facilitate cleaning and inspection. Materials should be stored in conditions and times that do not have a negative impact on quality, and controlled so that the oldest stock is used first. Certain materials in appropriate containers may be stored outside the building, provided the identification label remains legible and the container is properly cleaned before opening and use. Rejected materials should be identified and controlled by a quarantine system designed to prevent unauthorized use in manufacturing. Reevaluation Materials should be reevaluated as appropriate to determine suitability for use (e.g. after prolonged storage or exposure to heat or moisture). Quality Control Gamma ray spectrometers are used to monitor the quality of radionuclide purity of radiopharmaceuticals. In order to use a high performance gamma ray spectrometer, the entire system needs to be precisely tuned and maintained. The pulse shape and amplifier gain should be adjusted periodically. Energy calibration, Full Width at Half Maximum (FWHM) and peak counting efficiency and peak area checks, radioactivity testing, accuracy and precision should be carried out periodically. For radiopharmaceuticals characterized by radionuclides whose half-life is more than 20 minutes, it is recommended that each product batch be tested for pH, description, radiochemical purity, specific activity (if there is a risk of toxicity or if the localization depends on tissue mass (mass-dependent)). Sterility, pyrogenicity, chemical purity, radionuclide purity, and radiochemical purity should be established as part of final quality control tests during preparation process validation and for initial production batches. Each cause of failure to meet specifications should be explained. Investigations should be carried out into critical failure events such as for sterility or radiochemical purity. If the investigation requires procedural changes, then revalidation should be considered. Radiation stability for all components exposed to high levels of radiation should be established, as should maintenance and replacement schedules. Particular attention should be paid to the irradiation conditions to determine the impact of changes to each parameter of radionuclide purity, radiochemistry or chemistry of the final product. Critical parameters include beam current, threshold energy, particle energy, isotopic composition of the target material, target placement, irradiation time, composition of the support material and chemical purity of the target. For radiopharmaceutical kits, the effect of product age on product stability after reconstitution should be demonstrated. Reconstitution should be carried out under extreme reconstitution conditions and measurements should be carried out at the time of reconstitution and on or after the reconstituted product has expired. Additional stability data should be available, including the stated shelf life of the inactive product when reconstituted with the highest and lowest 99mTc activity for use in 99mTclabeled radiopharmaceutical preparations using maximum and minimum reconstitution volumes. Data should be available for the highest radioactive concentration that will be used for reconstitution. If the final shape of the package is changed, the stability data should be updated. RADIOPHARMACY PRODUCTION, STORAGE LINES AND QC ACCORDING TO cGRPP QUALITY CONTROL Specifications and quality control testing procedures for radiopharmaceuticals currently still use the European Pharmacopoeia. This states that full testing of the product by the methods in the pharmacopoeia of the Radiopharmaceutical Department before release is often not possible. There must be a written procedure detailing all Preparation and Quality Control data that must be considered before the preparation is shipped. A procedure should also describe the steps the responsible person will take if the test results obtained are unsatisfactory. Parameters to be assessed on each product before release Labels should be checked for correctness and completeness Total radioactivity. Because the level of radioactivity determines the radiation dose to the patient, each patient's dose should have an independent assessment of his or her total radioactivity prior to administration. The activity of each patient dose must be carefully measured and documented. Appearance and freedom from dirty particle contamination Quality control parameters of technetium-99m generator eluate Molybdenum - 99 breakthrough in the first eluate from each technetium-99m generator Elution activity must be measured on each eluate. Aluminum breakthrough ions should be checked for any eluates used to prepare products that are affected by the presence of aluminum ions. Labeling kits are prepared at the factory and released for sale after all prescribed and quality control tests are completed. Therefore, the composition, chemical purity, apyrogenicity, sterility and particle size (if any) are guaranteed by the producer. Instructions for using the kit should be included in the labeling. Any deviation from these instructions must be validated. Verification of the effectiveness of the applied labeling is carried out by checking the final activity (at another time), labeling results and/or radiochemical purity of the preparation as well as particle contamination. Parameters such as particle size (if applicable), sterility, pH, and isotonicity should be controlled at regular time intervals as well. Quality control parameters of the kit for labeling with technetium-99m and producing radiolabelled preparations Integrity after receiving Radiochemical purity (RCP) testing of products prepared from licensed labeling kits must be performed on each preparation. Unlicensed radiopharmaceuticals, whether purchased as a finished product, prepared in a licensed kit or prepared according to an in-house formula, must be fully tested on every occasion. Sterility must be controlled in random sampling of decay following radioactivity. The particle size of radiopharmaceutical particles used for imaging lung perfusion or the particle size of radiopharmaceutical colloids may be valuable in ensuring consistent pharmacokinetics of the product. This involves light microscopic methods or membrane filtration. Preparation of radiopharmaceuticals and their quality control should, if possible, be carried out in separate rooms. pH measurements using narrow range pH paper can be carried out on the TechnetiumEluate 99m Generator and on products known to have a non-physiological pH or products for which the pH must be adjusted during the labeling procedure. Sterilization and bacterial endotoxin testing The purpose of sterility testing is to ensure that the procedures used in radiopharmaceuticals produce sterile products. The frequency of testing depends on the Department's experience. Aseptic preparation and dispensing procedures should be regularly checked, especially if new personnel are involved. Typically, samples for sterility testing are stored for sufficient radioactivity decay and then sent for sterility testing by an external, validated laboratory. According to the European Pharmacopoeia, internal sterility testing is only recommended if dedicated rooms and equipment are available. Pyrogen or bacterial endotoxin testing for radiopharmaceuticals is not routinely performed. The Limulus amoebocyte lysate (LAL) test can be usefully used as part of the validation of a new system or change in work practice. When one or more purification columns are involved in the preparation of a radiopharmaceutical, a bacterial endotoxin test must be performed on the final preparation. The procedure must be validated before the introduction is used routinely and the preparation can be released for use before completion Bacterial endotoxin assay. Environmental monitoring is essential to maintain aseptic conditions. Microbiological testing of aseptic workstations should be carried out periodically. Methods may include using swabs or contact plates for surfaces, and settling plates or dynamic air samplers for air quality. Preparation of patients' autologous material Strict requirements regarding aseptic handling of the patient's autologous material must be followed. All starting materials must be identified. For each reagent, substance or solution specifically intended for human use it must be tested and documented that its specifications meet the required standards. Only materials and reagents certified for human use should be used. Preparation of labeled cells must be done one by one or with different people in different locations. The following checks must be carried out: Calculation of labeling results for each preparation Radiochemical purity control (as far as possible) on each preparation prior to administration Control of patient identity before administration Control cell viability, morphology or function, depending on cell type, in three preparations (same reagents and personnel).