PharmTech: From FDA's perspective, what is your take on the IPEC approach discussed so far?
Buhse (FDA): This is a conversation that's going back and forth between manufacturers of excipients and the users of the excipients because
perhaps the communication has not been there between those two groups, and I think this guideline will really help move that
communication forward so people understand the excipients that they're using and then can use the good science they need to
decide what to do moving forward.
And then they can have a better understanding of what 'out of normal' is because, obviously, if an excipient does come in
and you are used to 2 particles in 200,000 kilos and one day it comes in as 10 particles out of 200,000 kilos, that raises
a red flag. You need to have the ability to call your supplier and talk about it. And maybe they already know that the particles
are there, or maybe it's something completely different, and you both need to go back and do a complete CAPA and take a look
at perhaps that pipe that needs to be replaced because it's 25 years old, and so forth. And if you aren't communicating, then
perhaps some material could get into the market that maybe should have been stopped had there been better communication.
Overall, it's a good place for both the suppliers and the users to start talking and figuring out what they want to put in
this guideline. As an agency, we're happy to take a look at the guideline when a good draft exists and see what we think.
PharmTech: There is clearly frustration on both sides, user and maker, with this issue. What types of dialogue do you think need to happen
beyond what's already taking place?
Carter (IPEC): There's got to be an understanding of how products are made, their capabilities, and how they are used. The makers of excipients
have concerns over their own intellectual property. In making excipients, you don't typically, for equipment or certain processes,
patent them. This confidentiality is what gives a certain company an ability to make a certain product of a certain quality.
But companies have to get beyond this frame of mind in order to talk about sources. They have to build a quality partnership.
This dialogue, however, needs to start in the development process when companies are choosing excipients. Early conversations
Van Meter (IPEC): Having this guidance in place will provide the safe environment that not only says it's okay for these particles to exist,
but that also encourages makers and users to talk about this issue because, as we have has alluded to, it's been there all
along. When you have these discussions, not only do you build a much higher degree of trust, supplier to maker, but you also
Buhse (FDA): [These ideas about dialogue] support a lot of the initiatives that the agency has been pushing, such as quality by design
and understanding better how raw materials affect the final product. So it can only help to be having that communication between
manufacturers and users and being able to understand the variability in your raw material and how then you can make sure that
that variability in your raw material can be taken care of in your own manufacturing process so that the end product is potentially
less variable or at least will no longer have a high probability of being rejected down the road.
"Your write up on the visible particles conference was very useful, particularly hearing FDA's perspective. I also liked
D. Schoneker's comment on FDA's acceptable level of particles (and filth) in food. It's extremely helpful that FDA says unequivocally
that these particles don't present a health risk. Similarly, most particulates in drugs, particularly oral ones, don't present
a health risk, they present a quality issue. From my experience, atypical matter from supplier excipients is less common than
atypical matter that occurs during manufacturing. The latter are usually associated with manufacturing equipment or items,
e.g., a piece of teflon or other polymer, particle of stainless steel, etc. The materials are usually present an extremely
low hazard and don't present a risk to patients (I'm a toxicologist by training). However, we still must do toxicology assessments
of each. The issue with the JNJ plant in Fort Washington also included this kind of particulate matter. Hence, it's a general
challenge within industry." --Dave, Large Pharma Company, US