Assessing the Risk of Leachables from Single-Use Systems - This article is the second in a two-part series on extractables and leachables. - BioPharm International

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Assessing the Risk of Leachables from Single-Use Systems
This article is the second in a two-part series on extractables and leachables.


BioPharm International
Volume 25, Issue 2, pp. 32-40

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 g/person/day; Drug B at 1.74 g/person/day; Drug C at 0.001 g/person/day; and Drug D at 0.007 g/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 g/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 g/person/day; Drug B at 1.40 g/person/day; Drug C at 0.001 g/person/day; and Drug D at 0.006 g/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 g/person/day).

Modification #3: effect of UF/DF step


Figure 3: Concentration of leachable compounds decreases with each diafiltration volume processed.
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.
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.
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 g/person/day for the drug delivered subcutaneously and 0.833 g/person/day for the IV infusion. Both values are well below the 1.5 g/person/day limit for a genotoxic compound.


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