DETERMINING ACCEPTABLE LEVELS OF LEACHABLES INTO PHARMACEUTICAL PRODUCTS-A TOXICOLOGICAL PERSPECTIVE

摘要

The biopharmaceuticai industry is under increased scrutiny to make their products "safe" by meeting stringent quality assurance standards. Potential leachables in very small quantities may get into the product during manufacturing. This might occur from product packaging or closure systems, from disposables that may come into contact with the drug product during manufacture, or from devices used to administer the drug product. Moreover, the leachables might not have been identified while investigating for the presence of extractable substances. The European Medicines Agency, US Food and Drug Administration, and other regulatory bodies, along with the drug, device, or product manufacturers, want to ensure that identified materials do not change the quality of the product, or cause potential toxicity to an exposed patient. A toxicological risk assessment of the leachable is needed in order to provide scientific support to the safety of the product. This assessment is performed to ensure that levels of known leachable(s) in drug products are below acceptable limits. Alternative approaches, such as Threshold for Toxicological Concern, are available, especially for compounds with little or no data. However, if sufficient data are available, the use of health-based risk assessment approaches is recommended. Such assessments are performed by applying safety and uncertainty factors from a No-Observed-Adverse-Effect-Level, or by utilizing benchmark dose modeling. In either approach, an Acceptable Daily Exposure for patient safety protection may be calculated for the leachable. This paper will describe how to conduct an appropriate and scientifically-defensible toxicological risk assessment for materials that may get into drug products including how to determine an Acceptable Daily Exposure.