ASSESSING THE RISK
The following case studies demonstrate the use of TTC to assess the risk associated with leachables from both upstream and
downstream single-use assemblies.
Five assemblies, each containing a 500-L PureFlex bag, an Opticap sterile high-retention filter, and silicone tubing were
evaluated. Each assembly was used at different stages of the process and may have included buffer solutions for the bioreactor,
elutent solutions for the chromatography step, or exchange buffer for the ultrafiltration/diafiltration (UF/DF) step. The
final drug product and all leachables were collected in a 200-L tank. No leachables from the tank were included in this case
study.
Table II: Leachables generated from five assemblies.
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Based on the total organic carbon (TOC) data from several internal studies, the five assemblies would generate the leachables
shown in Table II.
Assuming all the TOC is coming from one, unknown compound and that the compound is 40% carbon by weight, the concentration
of this compound in the final container would be 7.175 mg/L (9).
Table III: Patient exposure to leachables from five assemblies.
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The risk of leachables to a patient will depend on how the drug is administered, the dosage, and frequency of dosing. Drug
A may be administered subcutaneously once a week at a dose of 2 mL. Drug B may be administered by intravenous infusion once
every 18 weeks at a dose of 18 mL. Drug C may be a vaccine administered annually at a dose of 0.1 mL. Drug D may be a vaccine
administered annually at a dose of 0.5 mL. The effect on the patient is determined by multiplying the concentration by the
dose and dividing by the frequency.
For example, drug A from Table III is delivered at at a volume of 2 mL per dose and a frequency of once per week. The exposure
of the leachable to the patient can be calculated as follows:
As seen in Table III, the two vaccine drugs (C and D) have a total daily intake of the leachable that does not pose a risk
to the patient (< 0.15 µg/person/day). 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 shown in Table I, the total daily intake of the leachable would
fall between the allowable limit for a genotoxic compound (1.5 µg/person/day) and that of a neurotoxic organophosphate compound
(18.0 µg/person/day).
If the potential exposure concentration is unacceptable, one might consider modifying the original assumptions to be more
representative of the actual operating conditions. These modifications may include a filter flush step, a shorter residence
time in the mixing bag, or accounting for some removal of the leachable during the UF/DF step.
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