Regulatory Guidance

There is a substantial amount of regulation and guidance for extractables and leachables testing, and much of it was published or made into law within the last few years. Understanding what applies to your pharmaceutical or contact material can be daunting. The following is a brief overview of the landscape for regulations in the U.S. and Europe, and the general guidances for E&L that have been provided by various organizations.

U.S. Regulations

In the U.S. the requirement for E&L testing was established by the Food and Drug Administration (FDA) in CFR 211.65, which requires that materials used to manufacture and package pharmaceuticals “…not be reactive, additive or absorptive so as to alter the safety, identity, strength or purity of the drug product.”

FDA provided further definition of the requirements for E&L testing for final container/closures, with an emphasis on the data required for an NDA or BLA submission, with the Guidance for Industry: Container Closure Systems for Packing Human Drugs and Biologics (1999).

U.S. Pharmacopeial Convention (USP) provides more detailed guidelines for E&L testing of pharmaceutical manufacturing and packaging materials in general chapter <661>, its sub-chapters (<661.1>, <661.2>, <665>). These chapters include specific test methods and specifications that should be used for qualifying pharmaceutical contact materials. Note USP <665> is only included in the Pharmacopeial Forum currently.

USP has also published limits for elemental impurities in general chapter <232>, and as of January, 2018, all drug manufacturers must provide data showing that each of their drug products do not exceed these limits. USP general chapter <233> describes analytical methods for evaluating levels of elemental impurities, and criteria for acceptable alternative methods.

European Regulations

The requirement for extractables and leachables testing in the European Union was established in EudraLex Volume 4, Chapter 3, which states that pharmaceuticals must be manufactured in a way that “presents minimal risk of causing contamination of materials or products,” and that “…equipment should be constructed so that surfaces […] do not alter the quality of the intermediates and APIs beyond the official or other established specifications.”

The European Medicines Agency (EMEA) provided a more specific guidance document for submitting extractables & leachables data for final container & closure systems called the Guideline on Plastic Immediate Packaging Materials, which was last updated in 2005, and which is similar to the previously-mentioned FDA guidance document.

International Regulations

The International Conference on Harmonisation (ICH) drafted guidelines for elemental impurities, which were adopted as law by the FDA and EMEA (along with Switzerland, Japan, and Canada) for all pharmaceuticals in 2017. ICH Q3D established a risk assessment framework for elemental impurities, and includes Permitted Daily Exposure (PDE) levels for each element. ICH Q3D includes only a paragraph about analytical methods.

Guidance Documents

USP informational chapters <1663> and <1664> provide additional support for E&L testing practices, with a scientific framework for designing and supporting the extraction process, and guidelines for the evaluation of potential impacts from leachable compounds.

The USP informational chapters <1663> and <1664> are based on work performed by the Product Quality Research Institute (PQRI). The PQRI established scientific best practices regarding extractable/leachable assessments. As part of their work they established the concept of a Safety Concern Thresholds (SCT). SCTs are used to guide the establishment of an Analytical Evaluation Threshold, which the PQRI defines as “the threshold at or above which a chemist should begin to identify a particular leachable and/or extractable and report it for potential toxicological assessment.” AETs are relative values that are assigned based on the SCT and the dosage.

ICH has also drafted multiple guidelines covering impurities in drug products, providing guidance on topics including the generation of impurities in the synthesis of small molecules, validation of analytical procedures, degradation products from drug substances, excipients, and container closure systems, and residual solvents in drug products. 

The BioPhorum Operating Group (BPOG) is an organization which represents end users (drug developers), and that provided a protocol for conducting extractables studies in 2014. The BPOG recommendations include additional solvents and time points compared to the USP guidelines. These differences have resulted in much debate on the subject. (NB: VR Analytical has conducted significant research on this subject – contact us for a presentation).

For an educational presentation of the regulatory landscape and key considerations for end users or suppliers, please contact us today.