Preamble
Background
Risk assessment in the preparation of radiopharmaceuticals
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Radiopharmaceuticals are generally used within a few hours of their preparation (microbiological growth in case of contamination is negligible).
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Very small quantities of starting materials are normally used (e.g. in the mg scale). Masses associated with radiopharmaceuticals are often very low (micro-dosing concept), and thus toxicity concerns are often minimal.
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Toxicity is further reduced by the small number of times (often one time only) a radiopharmaceutical is typically administered during the whole life of a patient.
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Shelf lives of radiopharmaceuticals are often short or very short (from less than 1 h up to a few days), and risks related to long-term storage are negligible.
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Finally, “in-house” prepared radiopharmaceuticals are typically used internally, and there are no risks associated with a complex distribution chain.
Quality risk management
1) Initiation of a risk assessment
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Clearly define the aim.
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Select people with a thorough knowledge of the topic to be involved in the assessment process. It is useful to identify a leader.
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Define timelines, if applicable.
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Define the risk criteria and the acceptance levels (quantitative, qualitative, ranks of severity), which are needed for subsequent risk evaluation.
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A deviation (either planned or unplanned) from an established procedure
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An out of specification (OOS) result
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An adverse trend
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An unusual event or abnormal result, which does not necessarily represent a deviation but needs to be assessed and investigated.Changes:
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Substantial changes related to a process, product, method, equipment or material
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Introduction of a new radiopharmaceutical product, method, equipment and material
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Commissioning of a new radiopharmaceutical preparation laboratory
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Development of a new environmental monitoring programStandard processes:
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Requirements for storage of retention samples
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Vial labelling prior to radiopharmaceutical preparation
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Batch release before completion of quality control testing
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Approval of suppliers
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Requirements for chemical precursors for small-scale radiopharmaceutical preparation
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(Re)validation of facilities, equipment and processes
2) Risk assessment
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What might go wrong (identification of hazards)?
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What will happen, if it really goes wrong (impact on product quality, patient safety and efficacy)?
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How serious are the consequences (severity)?
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What is the probability of it going wrong (occurrence)?
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How easy is it to detect (detectability)?
Risk identification
Risk analysis
Risk evaluation
Risk assessment tools
Qualitative risk assessment
Risk ranking
Severity (S) | Description | |
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Low | 1 | Expected to have little negative impact |
Medium | 2 | Expected to have a medium negative impact |
High | 3 | Expected to have a high negative impact |
Occurrence (O) | Description | |
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Low | 1 | Failure expected to happen less than once per year |
Medium | 2 | Failure expected to happen once per year |
High | 3 | Failure expected to happen more than once per year |
Detectability (D) | Description | |
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High | 1 | All failures are expected to be detected early enough |
Medium | 2 | Some, but not all failures are expected to be detected early enough |
Low | 3 | None of the failures are expected to be detected or are expected to be detected too late |
FMEA
3) Risk control
4) Risk communication
5) Risk review
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Regularly to consider new knowledge and experience
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After changes to assess their impact
Practical examples
Risk assessment required for a standard process
Introduction |
Annex 3 “Manufacture of Radiopharmaceuticals” outlines the requirements for manufacture of radiopharmaceuticals. Adherence to this annex is associated with the following premise (as stated in the annex): Due to short shelf-life of their radionuclides, some radiopharmaceuticals may be released before completion of all quality control tests. In this case, the exact and detailed description of the whole release procedure including the responsibilities of the involved personnel and the continuous assessment of the effectiveness of the quality assurance system is essential |
Aim |
The aim is to decide if and under which conditions it can be accepted to release the product before completion of all QC tests (here: test for sterility and radionuclidic purity) |
Risk identification |
The following hazards can occur, when the product is released before completion of the test for sterility and radionuclidic purity test: • Sepsis in the case of microbial contamination • Extra radiation dose due to radionuclidic impurities |
Risk analysis |
The risk of releasing radiopharmaceuticals before completion of all quality control tests is high as this could lead to a negative impact on the patient. This risk is mitigated by the fact that only small amounts of the product are administered to patients, all processes are validated, an adequate quality management system is in place and personnel involved in production, quality control and release of radiopharmaceuticals are appropriately trained in specific radiopharmaceutical aspects of the quality management system. All manufacturing steps take place in self-contained facilities dedicated to radiopharmaceuticals, accessible only by authorised personnel. Measures are established and implemented to prevent cross-contamination. Preventative maintenance, calibration and qualification programmes ensure that all facilities and equipment used in the manufacture of radiopharmaceutical are suitable and qualified. The facilities are routinely monitored so that the appropriate level of environmental cleanliness is maintained. The starting materials, packaging materials and critical process aids are purchased from approved suppliers. All documents related to the manufacture of radiopharmaceuticals are prepared, reviewed, approved and distributed according to written procedures. A written procedure detailing the assessment of production and analytical data is followed before the batch is released |
Risk evaluation and control |
With the adopted risk reducing activities, the risks are considered to be tolerable. All risks are accepted, on the condition that the described risk reducing activities are conducted |
Introduction: |
The precursor used for the preparation of PET radiopharmaceutical XXX is fully compliant with Ph. Eur. monograph 2902 except for the requirements for microbial contamination and bacterial endotoxins |
Aim |
The aim is to decide if and under which conditions the chemical precursor for a radiopharmaceutical preparation can be used, although there is no data on microbiological and endotoxin contamination |
Risk identification: |
The product may not be sterile and contain excessive levels of bacterial endotoxins |
Risk analysis: |
Severity: (3) |
The risk of using a product that does not meet the sterility and endotoxin requirements is high as this could be detrimental to the patients health |
Detectability: (1) |
Controls and procedures are in place which will detect any microbial or endotoxin contamination of the precursor. A bioburden test of the radiopharmaceutical product (without terminal sterile filtration) is performed for every new batch of precursor as part of the incoming goods approval process. Endotoxin testing is performed on the radiopharmaceutical product before release |
Occurrence: (1) |
This failure is expected to happen less than once a year. The precursor is provided with a certificate of analysis which certifies the chemical purity which is specified at > 97%. YYY is a well trusted supplier and has been audited regularly and found to have a well-established quality management system. Each batch of product is sterile filtered, and each filter is tested for integrity after use. Each batch of product is tested for endotoxins prior to release |
RPN = 3 × 1x1 = 3 Low, acceptable |
Risk evaluation and control |
The risk is considered acceptable with the installed reducing activities including at least a bioburden test of the product with every new batch of precursor and an endotoxin test of the radiopharmaceutical product before release |
Risk assessment triggered by deviations
Risk assessment triggered by changes
Process | Potential failure mode | Potential failure effects | Severity | Current controls | Occurrence | Detectability | RPN | Actions for the proposed plan, which complete the current controls |
Label production | Labels contain incorrect information | Product incorrectly labelled | Medium (2) | Current label process to be used. The labels are double checked before approval for use and before use | Very low (1) | High (1) | 2 | New labels needed |
Manufacturing | Production fails | Radiopharmaceutical batch is not ready for the patients | High (3) | Current validation policy will ensure that processes are validated | Very low (1) | High (1) | 3 | Validation of the new manufacturing process |
QC | QC fails | Radiopharmaceutical batch may not be released | High (3) | Current validation policy will ensure reliability of the process. The analytical method will be validated. The equipment is already validated | Very low (1) | High (1) | 3 | Validation of new analytical methods |
Release | Product is not released | Radiopharmaceutical is not available for the patients | High (3) | The process will be performed according to approved procedures, by trained operators | Very low (1) | High (1) | 3 | New procedures needed. Training to be performed |