CASE STUDY 2: EXTRACTABLES AND LEACHABLES STUDY DESIGN FOR DISPOSABLE TUBING
Like disposable bags, the tubing used in the bioprocess also requires qualification for extractables and leachables. However,
because the tubing has a short contact time with the drug product formulation during the manufacturing process, leachables
can be evaluated in parallel with a controlled extraction study, as a short-term compatibility study with drug formulation.
An E/L study design is presented here.
Step 1: Information Gathering. Information regarding the tubing should be collected in the same manner as for the bag in case study 1. In the present case
study, the drug placebo is an aqueous solution, the batch size is 10 liters, and the dosage for the final drug product is
a one-milliliter dose at three doses per day.
Step 2: Calculation of Analytical Evaluation Threshold. Based on information collected in Step 1, the AET can be calculated for each extractable per tubing (the SCT of 0.15 µg/day
is used here per PQRI recommendation for OINDP; however, the value could differ for other dosage forms.):
Extractables above the AET should be evaluated, but extractables below the AET are of no significant safety or toxicity concern.
Step 3: Design Combined Extractables and Leachables Study. For extraction solvents, because the tubing has a relatively short contact time with the drug solution, only a placebo buffer
and the product formulation are needed, plus an organic solvent, such as 20% ethanol, to cover a worst-case scenario. For
analysis of metals, a dilute acidic solution is used.
The extraction temperature is 50 °C for the placebo buffer and the 20% ethanol; the extraction time for both is 24 hours.
Ambient conditions for the drug product formulation are for 1, 4, 8, and 24 hours (to obtain short-term compatibility and
The remaining procedures for Step 3 are the same as those listed in case study 1.
Step 4: Extractables Evaluation. The analytical evaluation should include extractables and short-term leachables identity, amount, and potential TDI, as well
as a toxicological evaluation. These evaluations can qualify or disqualify the tubing, based on extractables or leachables,
from its intended use as bioprocess disposable tubing.
Step 5: Leachables Method Development and Validation. Leachables method development and validation may not be necessary because the tubing has a short contact time with the drug
product formulation during the manufacturing process.
Step 6: Leachables Analysis of Stability Samples. Leachables analysis of long-term stability samples for tubing is not necessary. On the other hand, short-term tubing leachables
information should be acquired and evaluated in parallel with extractables as described in Step 3.
Step 7: Leachables Trending, and Extractables and Leachables Correlation Analysis. Data acquired from Step 3 can be used for a leachables trending analysis and for the correlation of extractables and leachables.
The remaining steps (8 and 9) are the same as described in case study 1.
SUMMARY OF CASE STUDIES
E/L studies should be designed to achieve their intended purposes as demonstrated in case studies 1 and 2 for bags and tubing
used in a disposable bioprocess. The data obtained through E/L studies designed for different materials and manufacturing
processes can be compiled into a well-organized system, such as a library system, to increase scientific understanding and
the knowledge base for future use.