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Supporting particle investigations with risk-based decision-making

9 January 2022
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BioPhorum

BioPhorum’s Visual Inspection workstream has invested considerable time and effort to add clarity to the uncertainty around how to assess the risk of atypical particles during investigations. The team’s Standardized methodology to support particle investigations and classification in biopharmaceutical parenteral products was recently published by BioPhorum and provides practical, risk-based guidance to support the decision-making process.

What’s the problem?

The presence of visible particles is a perennial issue for the industry. With the broad expectation from regulatory authorities that particles be kept to a bare minimum, the reality is that particles are a rare, but ever-present reality of making biopharmaceuticals.  While particle reduction programs are ongoing across the industry, how do companies manage particles when they are found, and how can a particle impact the future of a batch of a biopharmaceutical product?

The particles that are most commonly found both during inspection and from market feedback are often termed ‘typical’ particles. Typical particles are those one might potentially expect to find in a process, arising from materials used throughout the process, or from incoming materials, such as rubber from stoppers or fibers from wipes. Rarely, though, atypical particles might be found in a product. An atypical particle event might be the result of an unusually high number of a typical particle, or a particle from an unexpected or unknown source. Atypical particles potentially impact patient safety, product integrity, and company reputation, so when found, atypical particle events require investigation. Companies have a responsibility to identify the particle, to understand the downstream implications of that particle, the reason it has been found in the product, and to prevent a recurrence.

Adding clarity through assessing risk

There is no clear or consistent guidance on how companies should approach investigations, and as a result, practices vary across the industry. However, there is a growing expectation, not limited to particles, that risk-based approaches be taken to address potential issues.

The team published a proof-of-concept paper An industry-wide standardized methodology and risk classification tool for particle classification in biopharmaceutical parenteral products in 2019, which was developed to support companies existing approaches to classifying particles. The value in adapting the approach to assisting in particulate investigations was immediately obvious. The team has reviewed various company approaches to particle investigations and leveraged the principles in their original publication to develop an aligned approach to introducing a risk-based classification system to investigating particles.

Through evaluation of the severity of a particle, its rate of occurrence, and probability of detection, it is possible to establish the relative risk of a visible particle to the disposition of a given batch and provides a framework through which the tool can be used to demonstrate the impact of risk mitigation.

A Standardized methodology to support particle investigations and classification in biopharmaceutical parenteral products is not intended to replace established investigations procedures but instead is a valuable add-on tool to generate a risk-based output for the classification of visible particles to support decision-making during particle investigations. The criteria built into the approach allows multi-disciplinary investigation teams to examine risk through a series of logical steps, removing some of the uncertainty inherent in decision making about the disposition of a batch.

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