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Moving from a Reactive to a Systemic Approach to Manage Risk
Risk assessment is not a new concept to the pharmaceutical industry, but lately the phrase has become a mantra. FDA’s recent guidance on process validation relies heavily on the concept, which regulators partly view as a way to make process changes possible. The industry has performed risk assessment in manufacturing and validation to reduce disruptions and ensure patients’ safety. But ICH Q9 has prompted regulators to ask for more formal documentation of the assessments than before. A systemic, science-based way to manage risk is becoming essential to meeting the spirit and letter of FDA requirements.
In addition to quantitative process data, it’s crucial for the technical risk profile to include scientists’ and engineers’ assessments about what the main sources of variability in the manufacturing process are, says Cini. The experts’ knowledge lends weight to certain process data over others, which makes it easier to understand correlations between the input (i.e., raw-material properties and process conditions) and the output (i.e., finished-product properties). After experts identify areas of risk, the company designs experiments to confirm them before developing means to control them.
To determine the probability of various failures, personnel may calculate process capability as one of several strategies. This effort requires a significant amount of data—as much as 100 or 200 lots’ worth. To come up with an estimate before these data are collected, companies “can look to similar processes for evidence of process capability and probability of defects,” says Jason Orloff, engineering statistician at PharmStat. Companies that run many processes with long histories can take this approach, but startup companies will need to rely more heavily on subject-matter experts, advanced statistical techniques, and the design of experiments.
Regulators expect firms to use a formal process to determine what risk is excessive, what risk needs to be reduced, and what can be accepted, says Mike Long, director of consulting services at Concordia ValSource. The failures that have the most severe effects on patients or processes, have relatively high occurrence rates, and are poorly controlled should be addressed first. When companies identify a way to modify the process to reduce a given risk, they must follow the change-control procedure, which includes documenting that process change and checking its effectiveness.
Review of risk assessment
Any time a deviation happens or a process is changed, personnel should update the risk assessments to include the new information. “The risk assessments are living documents. They’re not just there to sit on the shelf,” says Long.
In next few years, the pharmaceutical industry is likely to become more data-driven, and to embrace and exploit quality by design to a greater extent. These changes will enhance product and process knowledge, thus improving companies’ ability to design robust processes and mitigate risk effectively. As a result, firms will enjoy fewer disruptions, and patients will benefit from medicines with high and reliable quality.