It’s been four years since the International Conference on Harmonization adopted ICH Q3B(R2), which harmonizes the content and qualification of impurities in drug substances, including extractables and leachables (E&L) produced by the interaction of a drug substance and its container-closure system. And yet, there still seem to be a huge amount of questions surrounding these degradation byproducts, stability testing, thresholds, and reporting requirements.
Before ICH Q3B, there was ICH Q6A, harmonized in 1999, which addresses testing container-closure systems for extractables (mainly in parenteral products) and when tests can be eliminated based on developmental and stability data.
In early 2002, the Product Quality Research Institute (PQRI) E&L working group, representing industry, academia, and FDA, introduced a threshold concept to qualify E&L in nasal and inhalation products based on total daily intake rather than the percentage of API. FDA used the paper to shape its own guidance on the subject in July 2002. The European Medicine Agency’s Committee for Medicinal Products for Human Use followed suit in 2005. PQRI issued additional proposed safety thresholds and best practices for qualification of E&L in nasal and inhaled products in September 2006, and since then, many in industry have questioned whether the PQRI approach can be applied to other dosage forms.
Finally, if one turns to the pharmacopeia, USP offers chapter <87> on biological reactivity, <661> on containers-plastics, and <1031> on biocompatibility of materials, while Ph.Eur. 3.1 and 3.2 guidance documents focus on raw material extractions and finished containers. There are also guidance and standards documents from FDA, ISO, and other regulatory bodies on this topic. Currently EU and US leachable levels are slightly different with the EU approach similar to ICH Q6A and the FDA approach a bit more stringent.
With so many disparate standards for qualifying and testing for E&L, it’s no wonder that industry may be slightly confused. For those interested in learning more about current regulatory expectations, Pharmaceutical Technology is hosting a free webinar on the subject on June 22, 2010 and June 24, 2010. Be sure to listen in.
-J. Fleitman, Allergan, “Extractable/Leachable Testing and Regulatory Requirements for Opthalmic Dosage Forms,” presentation to AOAC-SCS/WCDG,Nov. 5, 2009.
-D.J. Ball, “Derivation and Justification of Safety Thresholds,” presentation to PQRI L&E Workshop, 2006.
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