PharmTech: Because there are no existing guidelines about how to handle these visible particles, the user's discovery of black specks
in raw materials can in many cases lead to an entire batch of material being rejected. Currently, how does one distinguish
between the normal specks that may be formed during the manufacturing process and potentially harmful foreign contaminants?
Van Meter (IPEC): From an excipient manufacturer point of view, we work very closely with customers to analyze the particles. About 80 to 90%
of any particles that I have analyzed that are returned from a customer are off-colored polymer. Unfortunately, when you're
dealing with pure white powders, it is common to have these very, very small dark particles, and even though they're very
small in number, they do stand out. I understand that they cause alarm; but again, 90% of them are purely the listed polymer.
Schoneker (Colorcon): From an excipient user perspective, we've learned that most companies don't talk to their suppliers about these particles.
Instead, all kinds of analyses are done to prove that a charred particle is something it's not. Users then have tons of data
and still don't know what to do about the particles and they end up rejecting the batch.
The supplier, however, could probably explain why the particles are there, what they are, and how they control them. For example,
a supplier might say, 'If the particles are brown, that's normal and you probably don't have to do a whole lot of analyses
unless you have some reason to think it's something else. If the specks are purple, however, you need to go to the next step
in analysis.' The missing link here is communication.
PharmTech: When such a batch rejection occurs based on atypical visible particles, that decision affects not only cost but also the
supply chain, and potentially can lead to a drug shortage. What are your thoughts on this?
Van Meter (IPEC): Yes, very few particles can cause the rejection of an entire batch of materials. But I'd like to clarify that when we're
talking about these particles, we're not talking about something that is pervasive or gross, we're talking about just a very,
very few micron-size particles in an entire batch of material. At a customer location, if those are seen at receipt, then
the entire batch could be quarantined and shipped back. As an excipient manufacturer, that rejection incurs tremendous cost
because the material has already been manufactured and shipped. Then you have to bring the material back and perform an appropriate
disposition; there's often no rational thought as to why the material was rejected. Sometimes, the recipient decision is just
visual— 'I see black specks; I can't accept this lot.' The alternative is for the user to take a controlled approach to call
the material manufacturer, do the appropriate investigation, and release the material.
PharmTech: FDA does not have an official position on this subject yet, but are there any visible particles that are considered acceptable
in raw materials today or should everything be ruled out?
Buhse (FDA): As an agency, we want to know that you understand what product you're making, so that you know what is or isn't acceptable....
There are risk-based, science-based decisions that you need to make as the manufacturer of the final drug about what you can
tolerate in your incoming raw materials, including the excipients. So if you have particles, we would look to see that you
understand what they are. Perhaps it's as simple as having a discussion with your supplier and being able to explain to the
agency what the particles are and why they are not a risk to public safety or patient safety, which is our prime concern.
Risk management, good science, and always keeping the safety of the patient in mind is what we're looking for.