Determining the capability of a drug product to be terminally sterilized: a case study involving a heat-sensitive, oxygen-sensitive drug product.

A decision scheme for determining the capability of a finished product dosage form to be terminally sterilized was presented and followed for a heat-sensitive, oxygen-sensitive drug product (DP). Studies were conducted first in a laboratory steam sterilizer and then in a production unit. When a nonheat-sensitive steam sterilization cycle produced unfavorable loss of potency and increases in the amount of impurities, a new heat-sensitive steam sterilization cycle was investigated. An acceptable product was produced by reducing the headspace oxygen level and reducing the heat delivered to the product during terminal sterilization. The amount of sterilizing steam heat delivered to the product was reduced by reducing the allowable temperature range from set-point of the terminal steam sterilizer, and by developing a new heat-sensitive cycle. The heat-sensitive cycle, with a model based upon a known relationship of the biological indicator, product D value, and the environmental bioburden, can achieve a 10(-6) sterility assurance level when it delivers an F0 > or = 4 min. When the standard terminal sterilization model and cycle produced unacceptable levels of degradation, formulation/production changes, and terminal sterilization model and cycle modifications were explored, before the DP was directed to aseptic filling. Acceptable moist heat terminal sterilization the DP was then achieved.