Key FDA and EMA Guidelines
Recent guidance from the FDA details the requirement for analytical methods utilized to generate elemental impurity data in support of a risk assessment, or as part of routine testing; must be shown to achieve suitable validation criteria.
New Product submissions should follow the recommendations of ICH Q3D and USP <232>/USP <233>, which include executing a formal elemental impurity risk assessment as part of submission packages.
Existing Drug Products need to have elemental impurity risk assessments executed to ensure compliance with ICH Q3D and USP <232>/USP <233>.At Cambrex, 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.
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
Cambrex 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>.
Find out more
To learn more about our Elemental Impurities services, get in touch with us at Cambrex.