ToxSci Advance Access published online on March 16, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm058
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Development of Safety Qualification Thresholds and Their Use in Orally Inhaled and Nasal Drug Product Evaluation
Aradigm Corp., 3929 Pt. Eden Way, Hayward, CA 94545; blanchardj{at}aradigm.com
Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993; timothy.mcgovern{at}fda.hhs.gov; david.jacobsonkram{at}fda.hhs.gov
University of New Mexico Health Sciences Center and Toxicology and Risk Analysis, 13701 Quaking Aspen Place NE, Albuquerque, NM 87111; roger.o.mcclellan{at}att.net
¶ Boehringer Ingelheim Pharmaceuticals, Inc; dnorwood{at}rdg.boehringer-ingelheim.com
# Safety Sciences, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105; w.mark.vogel{at}pfizer.com
** Nektar Therapeutics; rwolff{at}ca.nektar.com
tt Drinker Biddle and Reath, LLP, 1301 K Street, NW, Suite 900, East Tower; Washington, DC, 20005; Phone: 202-230-5165. FAX: 202-230-5365; lee.nagao{at}dbr.com
* To whom correspondence should be addressed. Safety Sciences, Groton Laboratories, Pfizer Global Research and Development, Eastern Point Road MS 8274-1215; Groton, CT 06340; douglas.j.ball{at}pfizer.com
Received December 5, 2006; revision received February 23, 2007; accepted March 3, 2007
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Abstract |
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Safety thresholds for chemical impurities and leachables in consumer products such as foods and drugs have helped to ensure public health while establishing scientifically sound limits for identification and risk assessment of these compounds. The Product Quality Research Institute (PQRI) Leachables and Extractables Working Group, a collaboration of chemists and toxicologists from FDA, industry, and academia, has developed safety thresholds for leachables and extractables in orally inhaled and nasal drug products (OINDP), for application in United States pharmaceutical submissions. The PQRI safety concern threshold (SCT) is 0.15 µg/day, and the qualification threshold (QT), 5 µg/day. OINDP are important in the treatment of lung diseases such as asthma and chronic bronchitis, as well as systemic diseases such as diabetes. Analysis of extractables and minimization of leachables in OINDP are vital to ensuring the quality and safety of the final product. It is expected that the thresholds developed by the PQRI Leachables and Extractables Working Group will be used by both industry and regulators to ensure and assess such quality and safety in OINDP applications. In this paper, we describe the importance of the PQRI safety thresholds in the OINDP pharmaceutical development process; the background and context of safety thresholds for consumer products; how these safety thresholds were developed using well-established, robust databases and quantitative risk assessment approaches; and how these thresholds can be applied in a pharmaceutical safety qualification process, including FDA regulatory perspectives on the use of safety thresholds for OINDP.
Key Words: qualification threshold; safety concern threshold; leachables; extractables; inhalation; nasal; PQRI.
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