John Shabushnig, PhD, of Pfizer Global Quality Operations, began his talk at AAPS 2010 in New Orleans—“Regulatory and Compendial Considerations for Particles in Parenterals”—with a short list of what he titled “Ancient Chinese Curses”:

•    May you live in interesting times.
•    May you come to the attention of those in authority.
•    May you find what you are looking for.

Whether or not these maxims are actually “ancient” and “Chinese” is debatable, Shabushnig said, but the important point is that they all apply to the issue of particles in parenteral drugs. These are interesting times, and the “authorities” (FDA, et al) have indeed been very interested of late.

“The marriage between the regulatory/compendial side, evolving technologies, and changes in formulations are bringing these topics to a head at this time.” The issue of parenteral particulates—how to define them, identify them, and minimize them—is a critical one, he noted.

USP (and EP) Considerations

USP, Shabushnig noted, requires that parenterals are “essentially free” of visible particulates, while the EP prefers the term “practically free”. In general, he said, these terms mean the absence of visible particulates.

“But inspection isn’t just a sorting process—it gives us good information that we can use to improve our processes.” The compendial goal is the production of parenterals free of visible particulates, which can only be approached through 100% inspection. “But we also know that 100% inspection (man or machine) is not 100% effective,” he said. “As a result, we know that ‘zero’ is not a practical, meaningful limit. And that’s why we have the term ‘essentially free’—it recognizes the limitations of the inspection process.”

Stimuli

Shabushnig was one of a group of authors who, in the fall of 2009, wrote a Stimuli article to encourage the revision of current USP standards—see “Visible Particulates in Injections—A History and Proposal to Revise USP <1> Injections,” available here.)

Among other things, the article proposes harmonizing USP standards with the EP, to establish greater global consistency. It also proposes a definition of a visible particulate based upon:
•    Illumination (including intensity)
•    Background (contrast)
•    Duration (inspection time, rate or pace)
•    Agitation (particle movement)

Duration is an area of increasing interest, Shabushnig said. “There have been interesting studies in the psycholgy labs of Harvard that if you inspect something too long, the mind gets bored . . . So it also has to do with how we’re wired as human beings. Whatever definition is developed must also consider other factors which can affect how visible a particulate is,” such as the use of large containers or syringes, and whether a product is cloudy or viscous.

Shabushnig then discussed the Stimuli’s Proposed Acceptance Criteria, for batch release and product with the customer. Both depend on ANSI/ASQ and ISO standards, and consider not just acceptable quality levels (AQLs), but also unacceptable quality levels (UQLs). While the manufacturer may be primarily concerned with AQLs, “the patient concern is with the UQL,” he said.

In May 2010, Shabushnig and his coauthors held discussions at USP offices and received feedback from various stakeholders. One key revision that came from those sessions is that proteins and biologicals would be exempt, needing to be addressed in individual monographs rather than in a blanket requirement. 

Beyond these revisions, the response to the Stimuli proposal has been mostly positive, he stated. For one, it has encouraged further momentum regarding the issue of lowering the detection limits in USP <788>. “We hope that this Stimuli article will help generate discussion about the need and usefulness of tighter limits based on recent data,” he said. In addition, of particular interest is the recent issue of whether or not subvisible particles in therapeutic proteins may cause immunogenic response . . . “we need to set some meaningful limits, and thus we need good measurements, so this is an area where we’re going to see a lot of work, and discussion as to whether we should set limits such as through USP.”

FDA Not on Board

What does FDA think of the Stimuli proposal? At this point in time, they’re not in support, Shabushnig admitted. “They’re concerned about setting any kind of limits, and want firms to establish their own limits on a case-by-case basis . . . If they set the bar, there will not be a continuous effort to reduce the amount of particulates in products.” He added, “We need to work with USP to further engage FDA on this topic.”

Later, Shabushnig emphasized that FDA is nonetheless keenly aware of the parenteral particulate issue. “Every year the FDA finds something they don’t like about somebody’s inspection process—so it’s not at top of the list but it’s an area of continuing concern within the Agency.” There may not have been an increase in 483s of late, he said, but “it just means we’re going more quickly to warning letters . . . there have also been more recalls, especially for glass and metal particles; and finally we’ve seen Consent Decrees in this area.”