Assessing safety of extractables from materials and leachables in pharmaceuticals and biologics - Current challenges and approaches.

Leachables from pharmaceutical container closure systems can present potential safety risks to patients. Extractables studies may be performed as a risk mitigation activity to identify potential leachables for dosage forms with a high degree of concern associated with the route of administration. To address safety concerns, approaches to toxicological safety evaluation of extractables and leachables have been developed and applied by pharmaceutical and biologics manufacturers. Details of these approaches may differ depending on the nature of the final drug product. These may include application, the formulation, route of administration and length of use. Current regulatory guidelines and industry standards provide general guidance on compound specific safety assessments but do not provide a comprehensive approach to safety evaluations of leachables and/or extractables. This paper provides a perspective on approaches to safety evaluations by reviewing and applying general concepts and integrating key steps in the toxicological evaluation of individual extractables or leachables. These include application of structure activity relationship studies, development of permitted daily exposure (PDE) values, and use of safety threshold concepts. Case studies are provided. The concepts presented seek to encourage discussion in the scientific community, and are not intended to represent a final opinion or "guidelines."

Challenges of general safety evaluations of biologics compared to small molecule pharmaceuticals in animal models.

IMPORTANCE OF THE FIELD: The prediction of human toxicity by employing animal models for nonclinical safety evaluation of pharmaceuticals poses numerous challenges. Each type, biologics, vaccines and small molecules, has unique features, which may impact the ability to effectively assess safety. AREAS COVERED IN THIS REVIEW: The importance of taking a case-by-case approach is highlighted in this review of the challenges encountered in general safety evaluations for biologics and vaccines compared to small molecules. WHAT THE READER WILL GAIN: The reader will gain insights in specific issues related to building a successful predictive nonclinical safety program for biologics. TAKE HOME MESSAGE: While there is fair concordance for small molecules, animal models used for the safety evaluation of biologics may have limitations with regard to human relevance. For small molecules, this is commonly because of differences in metabolism profiles or off-target effects. For biologics, which are highly targeted molecules, it may be because of differences in physiological processes or biologic pathways that limit pharmacologic relevance. For vaccines or immunomodulatory biologics, it may be related to the complexities of modeling the human immune system in a nonhuman species. While international guidances are available to govern the nonclinical safety assessment process for human pharmaceuticals (such as ICH M3), in many instances a case-by-case approach is employed for novel agents.