In classical fermentation, history would be, the fermentation operation itself is obviously in a closed vessel and the environment around that vessel is non-controlled, quite frankly. I hear you saying, in the biotech area, or the cell culture area, that you’re suggesting or saying that you need at least a 100,000 classification. Can you explain to the people here as to why, number one, that has evolved, and two, are you suggesting that you need that kind of environment than classical fermentation too?

I think it’s easier to address the second question first. No, we’re not implying that that’s something
that would have to be in place for classical fermentation. My presentation showed that a relatively
high percentage of non-host organisms could be in the fermenter and yet ultimately not affect the
product quality. So it’s not necessarily the same level of control that you’d expect to see in a
classical fermentation area. Typically a biotech fermentation area is going to look somewhat like a
clean room, albeit, you’re going to have associated piping, etc., so it’s not intended to be a sterile
area. By and large, they are relatively clean. Part of the problem you run into, especially with the
mammalian cultures, is that they are sensitive to contamination, and so from an economic
standpoint, you need to protect them as well as you can. Whether you need to go to the extra
level of control and raising the air classification, it’s going to depend, again, on the types of
manipulations. Arguably, you know, if you had a E. coli fermenter that’s running for 20 hours, you
might consider a less rigorous set of controls than you would for a mammalian culture that’s going
to be running over six months.
My recollection is that the Class 100,000 notion for contained or enclosed fermentation areas was
never a written requirement, but rather may have arisen over time as a compromise position
acceptable all parties. It is sort of arbitrary. But one also has to remember that it’s hard to really
define what a closed system is. There are a lot of avenues for things to enter, even into a
fermenter, you’re drawing samples off, you’re doing a lot of manipulations, and so I think the
thought was to keep the environment as controlled as possible without being too onerous. Most
manufacturers, at one point, were putting fermenters into Class 100,000 areas. Some still are.
Some are choosing to say it is controlled but not classified. I am also aware of some fermenters,
especially the larger ones, where it’s impossible, you’ve got a two-story fermenter, you’re not
going to have the thing in a controlled environment. So basically what you have is all the controls
and all the interferences in a controlled environment, and the rest of the fermenter is essentially in
an unclassified gray space, which is probably more similar to what you’d see for the classical
fermentation.
The thing that’s really important is to have good controls wherever you have open operations, and
where you’ve got closed or contained operations; it’s far less important what those controls might
be.