As scientific progress continues to be made, methodologies are advanced, sources are better controlled, materials improve,
and processes are upgraded and better measured and controlled, the best practice to assess the risk of leachables will further
evolve. Science and understanding are not static. However, the fundamental understanding of all the technical issues regarding
leachables and toxicological safety will continue to be applied to achieve a knowledge-based risk assessment.
Thomas E. Stone, PhD, is a principal scientist in the analytical technologies group at EMD Millipore, email@example.com
1. R. Kroes, J. Kleiner, and A. Renwick, Toxicol. Sci.
86 (2), 226–230 (2005).
2. Nordic Council of Ministers, Threshold of Toxicological Concern (TTC): Literature Review and Applicability, TemaNord 559:2005 (Nordic Council of Ministers, 2005).
3. S. Barlow, Threshold of Toxicological Concern (TTC) – A Tool for Assessing Substances of Unknown Toxicity Present at Low Levels in the
Diet. (ILSI Europe Concise Monograph Series, Brussels, 2005), pp. 1–32.
4. G.M. Cramer et al., Food Cosmet. Tox. 16 (3), 255–276 (1976).
5. EMA, Guidelines on the Limits of Genotoxic Impurities (London, 2006).
6. L. Müller et al, Regul. Toxicol. Pharmacol.
44 (3) 198–211 (2006).
7. Product Quality Research Institute, Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products (Arlington, VA, 2006).
8. A.M. Rulis, "De Minimis and the Threshold of Regulation," in Food Protection Technology, C.W. Felix, Ed. (Lewis Publishers, Chelsea, MI, 1st ed., 1986), pp. 29–37.
9. A.P. Shanklin and S. Cahill, Food Safety Magazine,
14, 12 (2008).
10. W.M.S. Russell and R.L. Burch, The Principles of Humane Experimental Technique (Methuen & Co., London, 1959).
11. K. Van der Jagt et al, "Alternative Approaches Can Reduce the Use of Test Animals under REACH." Addendum to Report EUR
21405. (European Commission, Joint Research Centre Ispra, Italy) 2004.
12. G. Schaafsma et al, Regul. Toxicol. Pharmacol.
53 (1), 70–80 (2009).
13. ICH, Q3A(R2), Impurities in New Drug Substances, Current Step 4 version 25 (2006).
14. ICH, Q3B(R2), Impurities in New Drug Products, Step 4 version 2 (2006).
15. ICH, Q3C(R5), Impurities: Guideline for Residual Solvents, Step 4 version (2003).
16. Code of Federal Regulations, Title 21 Food and Drugs (Government Printing Office, Washington DC) Part 221.65.
17. FDA, Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics (Rockville, MD, May 1999).
18. J. Bennan et al., BioPharm. Int.
15, 23–24 (2002).
19. Extractables and Leachables Information Exchange. http://www.elsiedata.org/
20. D. Jenke and S. Swanson, PDA
J. Pharm. Sci. Technol.
59 (6), 360–380 (2005).
21. C. Stults, et al., (IPAC-RS OINDP Materials Working Group), poster presentation, IPAC-RS Conference (North Bethesda, MD,
22. D. Jenke, J. Pharm. Sci.
22 (10), 2566–2581 (2007).
23. D.L. Norwood, Am. Pharm. Rev.
23, 32–39 (2007).
24. J.P. Frawley, Food Cosmet. Toxicol.
5 (3), 293–308 (1967).
25. A.M. Rulis, presentation at International Life Sciences Institute Annual Meeting, (San Juan, PR 2006).
26. A.C. Schroeder, presentation at Pharmaceutical Quality Research Institue L/E Workshop, (Bethesda, MD, 2005).
27. FDA Workshop on Plasticizers: Scientific Issues in Blood Collection, Storage and Transfusion (Plasticizers in Blood Bags).
(Bethesda, MD, 1999).
28. S.O. Akapo and C.M. McCrea, J. Pharm. Biomed. Anal. 47 (3), 526–534 (2008).
29. I. Markovic, Am. Pharm. Rev. 9, 20–27 (2006).
30. K. Boven, et al., Neph.
20 (suppl. 3), iii33–40 (2005).
31. P. Kushwaha and A.K. Madan, Pharm. Technol. 31 (2008).