Pharmaceutical quality assurance system
To consistently and reliably prepare medicinal products of high quality, there should be a comprehensively designed and correctly implemented pharmaceutical quality assurance (QA) system. The quality assurance system must include a systematic process for risk management (ICH Guideline Q9 on quality risk management, 2014). QA represents the sum of all organised arrangements made with the objective of ensuring that medicinal products are of the quality required for their intended purpose. More details can be found in (PIC/S Guide to good practices for the preparation of medicinal products in healthcare establishments, 2014; EU GMP, n.d.).
The extent of the QA system will depend on the scale and complexity of the operations carried out, and will thus differ between Part II and III. However, each system must address at an appropriate level all the topics below. A small scale radiopharmacy must have a responsible person for radiopharmaceuticals (RPR) with the following responsibilities:
To establish procedures for the examination and evaluation of incoming materials and ensure that each lot of incoming material is examined and evaluated against specifications before use.
To review the preparation batch records and laboratory control records for accuracy, completeness, and conformance to established specifications before authorizing the final release or rejection of a batch or lot of SSRP.
To approve procedures, specifications, processes, and methods including related standard operating procedures (SOPs).
To ensure that all personnel are appropriately trained and qualified.
To investigate errors and ensure that appropriate corrective actions are taken to prevent their reoccurrence.
To ensure that SSRPs have adequately defined identity, strength, quality and purity.
Additionally, the person responsible for the QA system at the radiopharmacy should have the following responsibilities:
To manage the general QA system.
To verify that the documentation is correctly written and administered
To conduct periodic audits to monitor compliance with established procedures and practices.
To monitor, in cooperation with the other staff members, the general management of the activities performed in the small-scale radiopharmacy (e.g. personnel training, radioactive waste management, etc.)
The RPR will most often also be responsible for the QA system. For more efficient management, some QA tasks may be delegated to other staff members or outsourced to help the RPR to oversee and implement the areas mentioned above.
Deviations, changes, OOS and CAPA
Written procedures for dealing with deviations should be in place. Deviations from the production protocols should be documented both to identify trends and to guarantee that corrective and/or preventative actions will take place. A change management system should be in place to deal with all changes that may affect the quality of the SSRP. This includes changes in preparation methods as well as in QC, equipment, software, manufacturing and suppliers. Systems for handling OOS (out of specification) results and corrective and preventative actions (CAPA) should be in place.
There must be a sufficient number of personnel with the necessary education and appropriate training and experience. The roles in the organization must be described, for example by creating an organizational chart.
Small-scale radiopharmacies must maintain an up-to-date file including curriculum vitae (CV), job description and relevant certificates (training, education, authorizations etc.), for each staff member.
Staffing levels should be appropriate for the activities of the radiopharmacy and there should ideally be a minimum of two, one of whom is the RPR with appropriate credentials. The second person must be well trained in cGRPP procedures. Where only one person is directly involved in preparation of SSRPs, all procedures including preparation, quality control (QC) and release of the product may have to be done by this person (the RPR). In this case rigorous SOPs must be in place and should be strictly adhered to. A second suitably qualified and trained person should review all results to confirm their compliance. This individual could be anyone trained to review appropriate results, understand their meaning and confirm their correctness.
All personnel (including those concerned with cleaning and maintenance) employed in areas where radioactive products are handled (exposed workers) must categorised according to article 40 and monitored according to article 41 of the European Council Basic Safety and Standards Directive (as implemented in national law) (European Council Basic Safety and Standards Directive, 2013) and should receive additional training specific to this class of products. In particular, detailed information and appropriate training on radiation legislation, protection, decontamination, handling and storage of radioactive materials should be given.
Training must be provided for all staff working in a radiopharmacy. This includes:
Working practices in the radiopharmacy including aseptic techniques and radiation protection
Radiopharmaceutical preparation and preparation of individual doses
Quality control and analytical techniques
Hygiene, pharmaceutical microbiology and microbiological monitoring
Calibration and qualification of equipment
Transport of radioactive material (IAEA Safety Standards, 2018)
The level of training required will depend on the intended task(s). A description of the training and records of completion and requalification must be kept. The responsibilities should be outlined in job descriptions and/or authorizations, considering clear distinctions between research activities and preparations for clinical use.
A detailed discussion on the requirements for a Medical Physics Expert (MPE) and/or Radiation Protection Expert (RPE) is covered by national and European regulations and is beyond the scope of this guideline.
Premises and equipment
Facilities should be adequate to assure the orderly handling of materials and equipment, the prevention of mix-ups and the prevention of contamination of equipment or product by substances, personnel or environmental conditions that may have an adverse effect on product quality.
Radioactive products must be stored, processed, packaged and controlled in dedicated facilities. Only the necessary equipment should be located there. Access to controlled areas should be via a gowning area and should be restricted to authorised personnel. Visitors, cleaning staff and technical staff should follow appropriate rules for access, which should be described in written instructions. After maintenance and repairs, premises must be cleaned and decontaminated appropriately.
Appropriate measures should be taken to avoid the spread of radioactivity from controlled areas and to protect them from particulate and microbial contamination. Measures to monitor key environmental parameters (e.g. temperature, humidity, particle levels) should be applied and the frequency of measurement/assessment should be defined. Appropriate equipment should be in place for the detection and monitoring of personnel for radiation exposure.
Workplaces, as appropriate, must be classified into controlled or supervised areas; signs indicating the type of area, the nature of the sources and their inherent risks shall be displayed (article 36–38 of the European Council Basic Safety and Standards Directive (European Council Basic Safety and Standards Directive, 2013)).
The use of the same area for multiple purposes at the same time should be avoided and there should be physical segregation of operations wherever possible. Different operational areas should be clearly defined and separated, especially regarding the unidirectional flow of starting materials, intermediates and finished products to avoid mix-up and unintended use. For example, preparation (e.g. radiochemical synthesis), QC and laboratory operations (e.g. release testing), and storage of approved components (including containers and closures) should be performed in segregated areas wherever possible or otherwise physically separated.
For labelling of blood cells, a dedicated laminar air flow bench should be used, and preferably a dedicated clean room.
Where both research and clinical preparation activities are carried out at the same location, these should be physically or organisationally separated from each other to avoid research activities impacting on the quality of products for clinical use.
Materials should be clearly identified as “In quarantine”, “Approved” or “Rejected” and kept physically separated where possible.
Aseptic manipulations must take place in a grade A environment. The grade of the surrounding area will depend on the containment system used, the method of preparation, the risk of contamination for the preparation, the shelf-life of the preparation and the number of units prepared during a preparation run. Following a risk assessment, a grade C surrounding area for laminar air flow workbenches (LAFW), or a grade D surrounding area for isolators is generally considered suitable (PIC/S Guide to good practices for the preparation of medicinal products in healthcare establishments, 2014). Examples of aseptic manipulations include assembly of sterile components (syringe, needle, filter and vial) for sterile filtration and containment of the SSRP, elution of a technetium-99 m generator, reconstitution or dilution of a kit, removal of QC test samples, and sterility testing of the finished SSRP.
All surfaces including walls, floors, ceilings, tables and furniture in the radiopharmaceutical preparation and quality control areas must consist of materials easy to clean, disinfect and decontaminate in case of a radioactive spill. Cleaning and sanitising must be performed regularly according to approved procedures, and documented to ensure consistent control of environmental quality. Sinks should be outside the preparation area. Secondary packing, such as cartons and boxes, should not be taken into the preparation area, to minimize ingress of dust and other particulate matter. A technical area for maintenance (technical corridor) could be constructed such that hot cells are approached from a room other than the cleanroom.
Operators should wear designated cleanroom clothing appropriate to the grade of cleanroom and sterile or sanitised gloves when conducting aseptic manipulations. Recommendations for appropriate clothing can be found in Annex 1 of the PIC/S guide (PIC/S Guide to good practices for the preparation of medicinal products in healthcare establishments, 2014). Additional protective garments (e.g. safety glasses, visors and arm coverings) should be worn when necessary and in line with radiation protection requirements. Only people directly involved should be present during the preparation of a SSRP.
Areas and equipment for aseptic manipulation should be regularly monitored with respect to microbiological quality and airborne particles (PIC/S Guide to good practices for the preparation of medicinal products in healthcare establishments, 2014).
There must be appropriate procedures for the sanitisation of materials and equipment being transferred into the aseptic work area. An isolator should have a material air lock with interlocking doors for transfer of material.
Items within a laminar air flow aseptic workstation should be kept to a minimum and should not interrupt the airflow delivered to the critical grade A area.
Equipment must be qualified before initial use (Todde et al., 2017) and undergo regular and recorded preventative maintenance and recalibration. The need for recalibration and requalification should be based on risk assessment (EANM Guideline on “Quality Risk Management guidelines applied to radiopharmaceuticals”, 2021). Details on equipment used for measurement of radioactivity as well as automated synthesis and dispensing modules can be found elsewhere (European Pharmacopoeia, 2016; Aerts et al., 2014).
Other equipment used for preparation of radiopharmaceuticals such as water baths, thermometers, heating plates, etc., must be checked for accuracy and records of these should be kept. Equipment used for verification of critical parameters (e.g. thermometers, flowmeters, particle counters, etc.) related to production and QC instrumentation should be regularly calibrated, based on risk analysis, using suitable traceable calibration standards.
A system of planned preventive maintenance and calibration should be operated to ensure that all facilities and equipment used in the preparation and quality control of radiopharmaceuticals are regularly maintained and calibrated where appropriate. Records and logs should be kept for all equipment irrespective of whether maintenance and calibration are performed in-house or by external contractors.
Good documentation practice is critical to provide written proof that activities have occurred. It applies to everyone who documents activities related to cGRPP. A document management system must be in place to ensure traceability of all procedures. Documentation may be paper-based, electronic, or a combination of the two.
Instructions and Standard Operating Procedures (SOPs) should be written and independently approved for each procedure or operation within the small-scale radiopharmacy. These operations include production, quality assurance and management aspects. SOPs should be reviewed at least every 2–3 years unless they require immediate revisions. There must be version control such that only the currently approved version is accessible.
A specification should be available for each starting material/radiolabelling kit used as well as for radiopharmaceutical products.
Among records to be kept are:
Purchase and control on arrival of all starting materials, excipients and radionuclides/radionuclide generators.
Product preparation: batch records, results of quality control tests and release decisions
Laboratory cleaning and maintenance
Equipment maintenance, calibration, cleaning, qualification and use
Training of personnel
Transport of radioactive materials
Radioactive contamination monitoring and radioactive waste disposal
Microbiological and particulate monitoring
Temperature monitoring, particularly refrigerators and freezers
Product defects and events of non-conformity to SOPs (deviations)
Qualification/validation protocols and reports (facilities, equipment, processes and analytical methods)
Corrections to paper entries should be dated and signed or initialled, leaving the original entry still legible. Records should be retained for a sufficient period to satisfy national legislative requirements. More information on documentation can be found in the PIC/S guide for healthcare establishments (PIC/S Guide to good practices for the preparation of medicinal products in healthcare establishments, 2014).
All goods received should be checked against the order for correctness of delivery. In addition, a visual inspection should be carried out prior to acceptance. Records should be kept for materials used for preparation. Products or kits with a marketing authorisation should be used whenever possible.
Production of SSRPs should be organized in such a manner as to prevent cross-contamination of the product. Process validation, in-process controls and monitoring of process parameters and environment are particularly important in cases where it is necessary to take the decision to release or reject a batch or a product before all tests are completed, which is often applicable to SSRPs.
All containers for SSRP preparations (including syringes and shields) must be labelled. Labels should be legible and applied to remain legible and affixed during the established conditions of processing, storage, handling, distribution and use (World Health Organization, 2003).
Due to risk of radiation exposure, it is a common practice to prepare much of the labelling in advance.
Dispensing of patient doses should be individual, and all syringes must be identified by product name and amount of radioactivity at a defined time.
Packaging and shipping containers designed and constructed to protect personnel from radiation and the product during storage, distribution and handling should be used.
Any deviation from approved procedures should be avoided. In the event of deviations, these must be documented and approved in writing by a responsible person. Deviations should be investigated where deemed appropriate.
Radiolabelling of blood cells
When preparations from patient material (blood cells or platelets) are performed, strict requirements regarding aseptic handling must be followed. All starting materials should be identified. For any reagent, material or solution specifically intended for human use, it must be documented that its specifications meet the required standards. Materials and reagents certified for human use should be used. More details can be found in the respective guidelines (Roca et al., 2010; de Vries et al., 2010), and local legislation must be considered.
Preparation of labelled cells must be performed separately to prevent cross contamination. Samples from different patients must always be handled separately; two preparations must never occur at the same time. Strict procedures must be in place to prevent mix-ups.
Each laboratory performing quality control testing related to the preparation of SSRPs should have and follow written procedures for the conduct of each test and for the documentation of the results. Complete records of all tests necessary to ensure compliance with established specifications and standards, including examinations and assays should be kept.
Each laboratory should have scientifically sound sampling and testing procedures designed to assure that SSRPs conform to specifications.
Laboratory analytical methods should be suitable for their intended use and should be sufficiently sensitive, specific, accurate and reproducible.
All prepared solutions should be properly labelled to show their identity and composition.
All equipment used to perform the testing should be suitable for its intended purpose and capable of producing valid results. Each laboratory should have and follow written procedures to ensure that equipment is routinely maintained, calibrated and qualified, and that these activities are documented.
Specifications and quality control testing procedures for many of the currently used SSRPs are given in specific monographs in the European Pharmacopoeia (Ph. Eur.) and/or the Summary of Product Characteristics (SmPC) distributed with each licensed product. Analytical methods, specifications and acceptance criteria might also be defined internally, provided that they are scientifically sound, validated, and of a comparable level with those described in Ph. Eur. (Guide for the elaboration of monographs on radiopharmaceutical preparations, 2018).
There should be written procedures detailing all preparation and quality control data that should be considered before the preparation is released for human use (release specifications). A procedure should also describe the actions to be taken by the RPR if OOS results are obtained.
Sterility and bacterial endotoxin testing
The purpose of sterility testing is to ensure that the procedures used in the radiopharmacy result in sterile products. For most radiopharmaceuticals, it is not possible to obtain results of certain tests, e.g. sterility test, before the product is released. However, these tests should be performed to monitor the preparation process. Usually samples for sterility testing are stored for sufficient radioactivity decay, and then sent for sterility testing to an external laboratory. Internal sterility testing is only recommended for products with half-lives > 7 h, when the external testing laboratory has no radiation license and if it is performed according to the European Pharmacopoeia.
Bacterial endotoxin testing (BET) is specified separately in Section 2.6 and Section 3.6.
Finished radiopharmaceutical controls and acceptance criteria
These processes are specified separately in Section 2.6 and Section 3.6.
Any activity that is outsourced should be appropriately defined, agreed and controlled to avoid misunderstandings which could result in a product or operation of unsatisfactory quality. There must be a written contract between the radiopharmacy and the contractor which clearly establishes the duties and responsibilities of each party.
Examples for which a contract could be required are:
Microbiological and environmental monitoring, sterility testing
Air handling plant monitoring and preventative maintenance
Chemical testing, e.g. mass spectrometry, solvent analysis
Periodic verification of calibrated reference instrumentation (e.g. thermometers, flowmeters, etc.)
Qualification of instruments and/or ancillary equipment such as HVAC
Sterilization of starting materials/equipment
Cleaning of the facility
A system for evaluation and approval of services providers (contractors) should be in place. Auditing prior to approval may be appropriate.
Complaints and recalls
Written procedures should be followed for the receipt and handling of complaints regarding SSRPs, including collection of information, root cause analysis and corrective and preventative actions. A documented recall procedure should be in place.
The QA unit (e.g. the RPR at small facilities) should monitor compliance with the QA system periodically by performing an internal inspection (self-inspection). Self-inspections should be performed in the form of an audit, for which specific topics may be selected (e.g. personnel, equipment, batch records) allowing recognition of shortcomings. Any failures in the QA system must be documented including appropriate measures to overcome them, and any corrective or preventative measures must be reviewed during the next self-inspection. Self-inspections may also be outsourced to a quality department within the hospital, or to an external consultant. Records of self-inspections must be kept.