Understanding and Implementing the New ICH/USP Elemental Impurity Guidelines

Topic Background:

Mandatory ICH Q3D/USP testing for elemental impurities (EI) in current, finished drug products becomes law on January 1, 2018. In both Europe and the US, the EQDM/EMA and FDA deadlines for compliance of new marketing authorization and new drug applications, respectively, with ICH Q3D became effective June 2016. Implementation requires extensive prior work. The new EI limits require more sophisticated analytical technology, such as ICP-MS, not routinely used in QC labs. The ultra-sensitive analytical method must be validated specifically for all of your different dosage forms. Additionally, a risk managed approach is required to understand the contributions from your entire manufacturing process to 27 different designated trace elements of concern. Each EI has different limits, which vary depending upon the dosing volume of each different dosage form. Implementation requires considerable additional resources including capital expenditure for instrumentation in each plant and back-up with highly trained analysts (and back-up).

Practical implementation of ICH Q3D establishes a risk based approach. The fundamental challenge, however, is to find a means to categorize risk. This means an exhaustive assessment of all the components of manufacturing including API, excipients, water, manufacturing equipment, processing aids, and container closure system to determine their contributions to all 27 EI. Alternatively, it is possible to simply do final product testing on finished dosage forms. This carries the risk, however, that failure here involves discarding the batch.

Regulatory dossiers for all products must be updated to include: an updated drug product specification table (test, method(s), limits); non-compendial test method(s), relevant reference standards used, and validation package; summary of identified EI and observed or projected levels; data from representative commercial batches (component or drug product dependent upon the approach taken); summary of product risk assessment (discussing risks and controls); conclusion of the product assessment, demonstrating compliance with established Permissible Daily Exposures (PDE) of identified EI; post-approval stability protocols if updated for EI testing.

Implementation imposes considerable new requirements upon the company pharmaceutical quality system. These include: drug product specification table (test, method(s), limits); non-compendial test method(s), relevant reference standards used, and validation package; GMP related processes to limit the inclusion of EI, change management processes (triggers for updates); periodic review; original data used in the product assessments, quality agreements, supplier qualification, etc.