By Scott Ewan, BioPhorum Operations Group
The presence of visible particles in parenteral biopharmaceuticals remains a hot topic in the industry. Despite regulatory bodies targeting a goal of no visible particles, and despite industry’s focus on further improving the efficacy of inspection processes, particles will continue to be found during production and in the marketplace.
The risks to patients of visible particles in parenteral biopharmaceuticals, though, may be overstated and are at best poorly understood. Bukofzer et al summarize the current understanding of the risks of visible particles to patients and conclude that the associated risks are low.1 In addition to Bukofzer et al’s summary, there are other works indicating that a hierarchy of risks from visible particulates may exist, with a number of factors requiring consideration before the true risk can be approximated.2
Industry Practices Vary Widely
Industry practice as it pertains to classifying the risk of visible particles owes less to direct rational assessment than it does to the conservative nature of the industry. BioPhorum conducted a cross-industry survey through its Particulate Control workstream, seeking detail on how industry classifies visible particles and how these impact acceptable quality limits (AQLs) and release criteria. Because there is no clear guidance for industry on how to apply criticality to visible particles, it was not surprising to find that practices vary widely across the industry. One aspect of the survey’s results that is surprising, however, is that few, if any, companies had a scientific or logical rationale for why they classified particles the way they did. Citing justifications such as “historical reasons” or the influence of one specific department, industry has no common or rational approach to classifying visible particles. There have been calls for a risk-based, consensus approach in recent literature,3 a need that BioPhorum is working toward meeting.
With the aim of providing clarity to classifying visible particles, BioPhorum’s Particulate Control team has developed “an industry-wide standardized methodology and risk classification tool for particle classification in biopharmaceutical parenteral products.” This proof-of-concept methodology, together with an associated risk classification tool, provides a means through which biopharmaceutical companies can underpin their current particle classification practices with a rational, risk-based approach.
A Standardized Methodology
The standardized methodology draws upon current industry practice and builds in factors taken from recent guidance and papers on the topic. We surveyed the team’s membership to understand how approaches to particle classification and AQLs varied across the industry. We compared this data with other industry surveys, guidance, and pharmacopoeial requirements on visible particles to identify common practices, key differences, and opportunities to add clarity. The team also identified a range of prerequisites - expectations that must be in place before considering applying the method or tool. Prerequisites include the expectation that a validated 100 percent visual inspection process is in place, together with an AQL procedure and process or control limits for particulate defects. Further expectations, such as detailed product and process knowledge and identification of potential particle sources and written investigation procedures are outlined in the standardized methodology.
The methodology assesses a range of patient risk factors and applies a simple scoring system to allow industry users to calculate an overall risk score for a visible particle in any given product or presentation. The method considers such risk factors as route of administration, patient exposure, particle source, and others — developing an overall picture of patient risk. These factors are among those regularly highlighted in literature as most relevant to patient risk.4 The relative risk of the various factors is derived from current literature, with additional medical input from industry medical and safety specialists. For example, the team has assessed subcutaneous routes of administration as representing a lower risk than intravenous injections.
The proof-of-concept version of the standardized methodology is intended for use across the biopharmaceutical industry and for application with parenteral products. The primary purpose of the proof-of-concept version is to provide data to underpin current industry practices — not to change how companies classify visible particles, but to provide data that supports the current classifications.
Any given particle that is found during any part of the inspection process might be applied to the tool, regardless of its current classification. As an illustration, let’s consider a particle is identified in a vial of a vaccine. As it is low dose, given just once to a recipient, exposure would be scored as a low risk. Continuing the example, if the dose is given to a healthy person subcutaneously, the patient factor and route of administration would also be scored as low risks. Combining these low risks with an intrinsic particle in this hypothetical illustration would result in an overall low risk for that particle for that product. Higher-risk patient populations, routes of administration, and frequent, high-volume doses would all result in higher risk profiles.
Some of the companies involved in developing the proof-of-concept standard methodology have also used the approach to support discussions arising from investigations. By leveraging risk scores from the risk classification tool, the data can facilitate decision making by key stakeholders.
Work has already begun on a second, updated version of the methodology and tool. Version 2 will focus on applying the tool in investigations, facilitating internal discussions on how to classify visible particles and expanding the cross-industry approach presented in the proof-of-concept version - providing documented, rational data to support discussions with third parties. Version 2 will also reassess some of the areas that were redacted from the proof-of-concept version to make version 2 more comprehensive and global in its scope.
The proof of concept standardized methodology and risk classification tool have been published to a dedicated section on BioPhorum’s website at https://www.biophorum.com/category/resources/particulate-control/particulate-control-about/. Both the methodology and tool are free to download and use. Your feedback is welcomed.
About The Author:
Scott Ewan is a facilitator with the BioPhorum Operations Group. In over 25 years in the pharmaceutical industry, he's been involved in roles from drug discovery through manufacturing and into the commercial side. The majority of his pharmaceutical experience, though, has been in creating and managing process improvement activities in manufacturing operations for small molecule and solid dosage forms. Laterally, he moved into activities dealing with transfer of new products from development sites into commercial facilities, and in technology development and transfer. Ewan now facilitates the Visual Inspection/Particulate Control workstream for BioPhorum, helping visual inspection global leaders to implement positive change across the industry.