In April 2012, industry experts discussed the issue of atypical visible particles in pharmaceutical raw materials, including
excipients, at the joint International Pharmaceutical Excipient Council's (IPEC) Regulatory Conference and ExcipientFest-Americas
Conference in San Juan, Puerto Rico. On the panel were Dr. Lucinda Buhse, director of the Division of Pharmaceutical Analysis
in FDA's Office of Pharmaceutical Science at CDER; Ann Van Meter, chair of the IPEC GMP Committee and of the IPEC Atypical
Visible Particles Working Group; Dave Schoneker, director of Global Regulatory Affairs at Colorcon and past IPEC–Americas
Chairman; and Dale Carter, current chair of IPEC–Americas. The following pages include an edited excerpt of the transcribed
roundtable, which was moderated by Pharmaceutical Technology Editorial Director Angie Drakulich. To listen to the complete and unedited discussion,
click here.
Background
(EXCIPIENTFEST AMERICAS)
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A primary cause of drug recalls during the past year has been the presence of visible particles, that is off-colored particles
or black or tan specs, in pharmaceutical products. The presence of visible particles affects both excipients manufacturers
and users with regard to standard expectations for mitigating the atypical visible particles and with regard to decision-making
about raw material acceptance criteria. The International Pharmaceutical Excipients Council (IPEC) is working to develop and
fast-track a guideline on how to measure and properly assess the significance of these visible particles, particularly within
white polymer powders. The guideline is meant to dispel any confusion around the presence of particles in excipients and to
provide information for excipients users and makers on how to proceed when making decisions about these particles. The following
is an edited transcript of a roundtable discussion that took place in April 2012 at the IPEC/ExcipientFest Americas conference
in San Juan, Puerto Rico. Featured panelists are listed at left.
Q&A with panelists
The Speakers Roundtable session on atypical visible particles at IPEC/ExcipientFest Americas 2012 in San Juan.
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PharmTech: When elevated temperatures are used with organic substances for drying or solvent removal, these temperatures, even though
they're beneficial for solvent removal and reduction of bioburden, can actually char the white powder materials and leave
the so-called black specs. Could you comment on this and what other manufacturing or processing techniques may cause these
visible particles?
Schoneker (Colorcon): Probably the most common cause of the particles that everybody sees is charring. There are various points in the process
where it's going to get charred and turn a little bit brown or black, and there are various points where there's motion, or
compression, that over time will form such particles. It's important to understand that these particles are inherent to the
excipient manufacturing process and always will be. There are also errant particles, particles that you don't typically see
that show up and probably need a different level of assessment.
What IPEC really wants to talk about with the industry is zero tolerance (that is, absolutely no visible particles in the
excipient material). Zero tolerance should not be the goal because it's unrealistic. What we're trying to do (with the IPEC
guideline) is to figure out how to look at the particles that are inherent versus the particles that are not inherent, and
how one can come up with procedures and controls to deal with each type. Right now, there is no regulatory guidance on this
subject, and everybody is assuming that every particle is atypical—or not inherent—when in fact, they are. This is creating
a lot of controversy throughout the industry.
Carter (IPEC): To add to that, if you have an abrasive product going through stainless-steel pipes and other things, you're going to scour
that product. When you have big crystallizers and large dryers, there is buildup. Even in crystallizations, the color can
be just how the crystal formed. It may appear slightly different in color than the next particle. Trying to remove these aesthetically
unpleasing specks should not be the industry's main interest. What should be focused on is identifying the reasonable state
of art for individual products, following GMP, and separating those occasional off-colored materials from real contamination.
