Modification #1: effect of a filter flush step
Most leachables generated from a filter occur during the first few liters. By incorporating a 5-L flush step, the contribution
of TOC from the filter would be reduced from 31.2 mg carbon (C)/filter to 2.9 mg C/filter, resulting in a reduction in the
final concentration of the unknown leachable from 7.175 mg/L to 5.408 mg/L. The revised patient exposure to the leachable
for the four drugs would then be: Drug A at 1.55 µg/person/day; Drug B at 1.74 µg/person/day; Drug C at 0.001 µg/person/day;
and Drug D at 0.007 µg/person/day.
Once again, Drugs C and D have a total daily intake of the leachable that does not pose a risk to the patient. However, it
is uncertain if the total daily intake of the leachable for drug A and drug B poses a risk to the patient. Based on the TTC
limits in Table I, the total daily intake would fall just above the allowable limit for a genotoxic compound (i.e., 1.5 µg/person/day).
Modification #2: effect of residence time
In the initial conditions, it was stated that the assemblies were being used to deliver buffer solutions. As such, it is unlikely
that the solutions would be stored for 30 days prior to use. If a one-day residence time is used, the contribution of TOC
from the 500-L bag would go from 80.7 mg C/bag down to 35.3 mg C/bag. This reduction in residence time results in the final
concentration of the unknown leachable going from 7.175 mg/L down to 4.340 mg/L. The revised patient exposure to the leachable
for the four drugs would then be: Drug A at 1.24 µg/person/day; Drug B at 1.40 µg/person/day; Drug C at 0.001 µg/person/day;
and Drug D at 0.006 µg/person/day.
Once again, Drugs C and D have a total daily intake that does not pose a risk to the patient. However, it is uncertain if
the total daily intake for Drug A and Drug B pose a risk to the patient. Based on the TTC limits in Table I, the total daily
intake concentrations are below the allowable limit for a genotoxic compound (i.e., 1.5 µg/person/day).
Modification #3: effect of UF/DF step
Figure 3: Concentration of leachable compounds decreases with each diafiltration volume processed.
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As leachable compounds tend to be small molecules, they will not be retained by the UF/DF membrane. As shown in Figure 3,
the concentration of the leachable compounds decreases with every diafiltration volume processed.
Table IV: Patient exposure to leachables from five assemblies following diafiltration.
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Assuming a conservative estimate of compound retention of 20%, the patient exposure will be reduced based on the number diafiltration
volumes processed. If two diafiltration volumes are processed, the concentration of the unknown leachable is reduced by 80%,
from 7.175 mg/L to 1.435 mg/L. If four diafiltration volumes are processed, the concentration is reduced by 96% to 0.287 mg/L.
If six diafiltration volumes are processed, the concentration is reduced by 99% to 0.072 mg/L. Table IV summarizes the patient
exposure to the leachable for the four drugs based on various diafiltration volumes processed. By using four diafiltration
volumes, patients are no longer exposed to risk from the leachable.
The risk of leachables can also be assessed in downstream processes. In this case study, the total leachables from a fill–finish
assembly were assessed. The drug is stored in a 100-L mix bag, which contributes 34.9 mg carbon as leachable. The assembly
also has a 2-L bag to control steady state flow, which contributes 2.4 mg carbon as a leachable, a Lynx S2S connector contributing
0.03 mg carbon, intermediate tubing adding 6.7 mg carbon, tubing in the manifold adding 47.1 mg carbon, and an Opticap 4"
Durapore filter adding 12.5 mg carbon. The total amount of leachable carbon is 103.6 mg or 1.04 mg C/L of drug product.
Using the assumption that the leachable is 40% carbon, we have a leachable concentration of 2.59 mg/L in the drug product.
Table V: Patient exposure to leachables from final-fill assembly.
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Table V shows the calculation of patient exposure to leachables for two drugs—one administered subcutaneously and another
by IV infusion. The total quantity of extracted compounds is 0.740 µg/person/day for the drug delivered subcutaneously and
0.833 µg/person/day for the IV infusion. Both values are well below the 1.5 µg/person/day limit for a genotoxic compound.
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