Monday, January 6, 2014

Contamination Time Window Redux

There's a little LinkedIn brouhaha going on regarding the calculation of contamination time windows.

In the perfect world, there are no bioreactor or fermentor contaminations.

But if you were to have contaminations, the next best thing would to omnisciently know exactly what the true root cause is.

Since omniscience is not an option here, the next best thing is to narrow down the list of sterile-envelope manipulating actions on the contaminated bioreactor and perform root cause analysis to come up with MPC (most probable cause).

crime scene There are a lot of parallels between a crime scene investigation and bioreactor decontamination response. Just as crime-scene investigators attempt to determine the time of death to rule out potential causes outside the time frame, it is a good idea to compute a contamination time-window to rule in/out potential causes.

There are several assumptions in the contamination time-window calculation and which assumptions you use depends on your organization's risk profile. As in, which is worse?
  • Coming up with too narrow a time window and risk eliminating the true root cause
  • Coming up with too wide a time window and having too many potential causes to investigate?
To summarize, you run the exponential growth equation twice: the first use is to try to figure out the growth rate of the organism.

Step 1: Collect sterility samples and send samples to QC Micro.

Step 2: Get 2 pieces of information from QC Micro:
  1. Concentration of contaminants in last sample (X)
  2. Timestamp of last clean sample. (t0)
Note, you already know the timestamp of the last sample (t).

Step 3: Pick an X0 and try to compute μ.
X = X0 eμ(t - t0)
bold is known.
blue is estimated.
red is what you're trying to determine.

The rational number to input here is the limit of detection of your sampling method.   If you're going for a narrower window, pick a higher number.

Now you have an estimated growth rate (μ) of the contaminant.

Step 4: Now try to determine the earliest insult (t0)
X = X0 eμ(t - t0)
Again, bold is known; blue is estimated; and red is what you're trying to determine.  Here, the key is to guess the concentration of the initial insult.  If you're afraid of ruling out the true root cause, pick 1 CFU.  If you're going after a realistic time frame to reduce scope, pick what you think a small bolus of contaminants would contain.

When you've solved for t0, the second time, you now have computed the earliest time of contamination.

As you can see from this process, there are some serious assumptions.  But if applied correctly, you have a scientific and defensible basis for narrowing down potential bioreactor contamination causes and focusing your limited resources on rooting out the most probable cause.

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4 comments:

Sergey Klykov said...

Sergey Klykov Hi,Oliver! Do you have a pilot application example?
2 days ago

Anonymous said...

What about the time taken for spore to germination....
This approach doesn't work as there are too many assumptions, variables and exeptions

Oliver Yu said...

You could argue that this doesn't work for spores. But you could also argue that the initial insult isn't 1 CFU, which is what's being used here to accommodate spores.

Sergey Klykov said...

Hi Oliver!

I sent you a few emails but I have not received a response from you so far.
Could you tell about the reason?

https://www.linkedin.com/groups?mostRecent=&gid=4410338&trk=my_groups-tile-flipgrp

Sincerely,

Sergey Klykov

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