Tolerance interval approach for the determination of overfill of liquid parenteral drug products

Abstract

Liquid parenteral products contain an overfill to ensure withdrawal of the declared volume. The overfill must be sufficiently high to compensate for the expected loss during product preparation and administration, but it should also be minimized to prevent accidental over-dosing and not foreseen dose splitting of single dose products. Finding the right balance between too much and too little overfill with an acceptable risk of product failure is challenging and requires consideration of the relevant sources of variability of the extractable volume. This paper provides a novel approach for the calculation of the required overfill based on tolerance interval methodology. In a first step, a tolerance interval multiplier from literature is proposed, and a simulation study is conducted to assess the appropriateness of its use for overfill determination. In a second step, this multiplier is adapted to cover operator-to-operator variability in the loss data and compared to other multipliers via a second simulation study. Using a tolerance interval multiplier enables adapting the overfill such that the risk of not reaching the minimum extractable volume fulfills pre-defined acceptance criteria. By this, the scientific justification of the selected overfill is strengthened and control over a critical quality attribute is improved.