Quality risk management
Risk is the combination of the probability of occurrence of harm and the severity of that harm (5, 6). The value of risk assessment models is the formalized evaluation criteria that comes from agreed-upon ranking tables. Even though some may argue that the assessment is not quantitative, the benefit derived from framing the evaluation to an agreed upon risk criteria dramatically improves the ability to objectively evaluate the process risk profile. Per ICH Q9, there are two primary principles of quality risk management (3):
• The evaluation of risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient
• The level of effort, formality, and documentation of the quality risk management should be commensurate with the level of the risk.
Formal risk management tools such as failure mode effects analysis (FMEA) or failure mode effects and criticality analysis (FMECA) (7) can be used to provide a structured semi-quantitative summary of risk. For Stage 1, however, often a qualitative risk assessment evaluating low, medium, and high risk is sufficient to distinguish relative differences in risk.
Continuum of CQAs
Prior to the development of a new drug, companies frequently decide and document a therapeutic need in the marketplace for a new pharmaceutical. It is through this effort that the quality and regulatory aspects of the new drug are defined such as the type of dosage form, the target dose, the in-vivo drug availability, and limit of impurities. Current guidance identifies this documentation as the quality target product profile (QTPP). The QTPP provides the basis of the desired quality characteristics of the drug product, taking into account safety and efficacy (i.e., purity, identity, strength, and quality). The QTPP should not be confused with the drug product specification, which created later, is generally a list of specific test methods to perform and their acceptance criteria designed to ensure drug efficacy and safety. The QTPP is an input to these activities whereas the quality attributes and specifications are outputs.
The initial list of quality attributes from the QTPP should be created as early as possible in the development process so that data can be collected from experimental runs. To assign the continuum of criticality to that initial list of quality attributes, knowledge of the severity of the risk of harm to the patient is paramount. This comes from prior knowledge such as early safety trials and scientific principles.
Quality attributes are rated as the highest criticality level because they have a high severity of risk of harm. Severity is the primary criteria for assessing quality attribute criticality because it is unlikely to change as understanding increases over the life-cycle. For example, an impurity may be determined to severely harm the patient (high severity score) if beyond its limit. If its level does not increase in the process or on stability testing, the occurrence score is low and its overall risk to the patient may be low. However, it is still rated as high risk due to its high severity. That severity will not change and as a high-risk CQA, it has to be tested and monitored.
Examples of risk levels for CQAs:
• High: assay, immunoreactivity, sterility, impurities, closure integrity
• Medium: appearance, friability, particulates
• Low: container scratches, non-functional visual defects.
For a quality attribute to be designated as “not critical,” it has to have no risk to the patient (e.g., yield, process duration). Attributes that are not critical to quality are sometimes named process performance attributes to distinguish from quality attributes.
Not all CQAs are tested as part of finished-product testing. Some are tested in-process to define limits such as pH and conductivity. Although frequently designated as “in-process controls,” they are still quality attributes that should be assessed for their criticality. Consideration should be given to the relationship between in-process controls and finished-product CQAs when making this decision. While this is one example of how to assign a continuum of criticality to quality attributes, other examples are also available (8-10).