Elemental Impurities per ICH Q3D, USP <232> and USP<233>

Implementation of ICH Q3D (see ICH Quality Guidelines) and USP <232>/USP <233> Elemental Impurity guidelines are now complete.  Avista Pharma staff members have extensive knowledge and experience providing consultation and analytical support to navigate and achieve compliance with the elemental impurity guidances.  We can assist in developing a risk assessment strategy regarding elemental impurities via documentation, analytical screening and method development/validation to achieve compliance.  Analytical testing for elemental impurities is performed using redundant Inductively Coupled Plasma – Mass Spectrometer (ICP-MS) instruments with microwave digestion available.


Key FDA and EMA Timelines

New Product submissions should follow the recommendations of ICH Q3D and USP <232>/USP <233>, which include executing a formal elemental impurity risk assessment.


Existing Drug Products should perform elemental impurity risk assessments to ensure compliance with ICH Q3D and USP <232>/USP <233>; by January 2018. The risk assessment document and additional necessary controls will be included the appropriate regulatory documents.


Common Risk Assessment Tenets and Considerations:

Excipients – Source of Materials: Location, Mined, Naturally Derived, Synthetic

Drug Substance – Intentionally Added Catalysts: Removal, Potential Carryover

Utilities – Water: Potential Elemental Impurity Source

Manufacturing Equipment – Materials of Construction: Stainless-steel, Hastelloy

Manufacturing Reaction – Extreme Conditions: High/Low pH, High Temperature

Drug Product – High Energy Processing: High Shear Granulation, Particle Size Reduction

Container Closure Systems –Extractable/Leachable Studies and Literature Review

Change Control Management – Document Strategies for Triggers, Assessment, and Resolution

Supply Chain Management – Risk Assessments Often will be Specific to a Vendor, or Location


Approaches to generating elemental impurity data to generate or support risk assessment activities:


Elemental Impurity Risk Assessment Method

Avista Pharma Services has developed a method to analyze for all listed ICH Q3D elements utilizing the parenteral limits (ICH Q3D, Table A.2.2). This quantitative evaluation includes validation activities at the level of 30% of the parenteral limits, including precision and accuracy by recovery. The executed validation studies provide information on the reliability of the provided data at the ICH Q3D-defined control threshold of 30% (ICH Q3D, Page 8). The validation activities would be performed on each novel material per submitted samples for analysis. This method is intended to support the elemental impurity risk assessment as part of the filing.


Development and Validation of a Material-Specific Method

When requested based on the elemental impurity risk assessment results or due to client policy, a method may be developed utilizing specific elements and limits.


Two methodology options are available:


1) Quantitative Method

2) Limits Method


As part of method development, validation studies will be evaluated per USP <233>.