Nowadays, elemental impurities is a major concern for pharmaceutical products. The global regulatory authorities are actively focused on this issue to control the elemental impurities limit in drug product. Because these impurities do not provide any therapeutic benefit to the patient and increase the health risk.


As per ICH guideline,

Elemental impurities in drug products may arise from several sources; they may be residual catalysts that were added intentionally in synthesis or may be present as impurities.


ICH Q3D advocates a 3 step process:

Identify

Review API, excipient and drug product manufacturing process to identify known and potential sources of Elemental Impurities.


Evaluate

Collect predicted and/or observed levels of elemental impurities and compare data with the established Permitted Daily Exposure (PDE).


Summarize Control

Summarize and document the risk assessment and Identify additional control requirements, if required, to ensure PDE is met.


Classification of Elements

Class 1: The elements, As, Cd, Hg, and Pb, are human toxicants that have limited or no use in the manufacture of pharmaceuticals.

Class 2: Elements in this class are generally considered as route-dependent human toxicants. Class 2 elements are further divided in sub-classes 2A and 2B based on their relative likelihood of occurrence in the drug product. The class 2A elements are: Co, Ni and V and the elemental impurities in class 2B include: Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se and TI.

Class 3: The elements in this class have relatively low toxicities by the oral route of administration (high PDEs, generally > 500 µg/day) but may require consideration in the risk assessment for inhalation and parenteral routes. The elements in this class include: Ba, Cr, Cu, Li, Mo, Sb, and Sn.

Other elements: Some elemental impurities for which PDEs have not been established due to their low inherent toxicity and/or differences in regional regulations are not addressed in this guideline. Some of the elements considered include: Al, B, Ca, Fe, K, Mg, Mn, Na, W and Zn.


Risk Assessment and Control

The risk assessment should be based on scientific knowledge and principles. In developing controls for elemental impurities in drug products, the principles of quality risk management, described in ICH Q9, should be considered. It should link to safety considerations for patients with an understanding of the product and its manufacturing process (ICH Q8 and Q11).


Elements to be Considered in the Risk Assessment


Evaluation

The elemental impurity identification process is concluded, there are two possible outcomes:

1) The risk assessment process does not identify any potential elemental impurities. The conclusion of the risk assessment and supporting information and data should be documented.

2) The risk assessment process identifies one or more potential elemental impurities. For any elemental impurities identified in the process, the risk assessment should consider if there are multiple sources of the identified elemental impurity or impurities and document the conclusion of the assessment and supporting information.


Permitted Daily Exposures (PDE) for Elemental Impurities


  • PDEs reported in this table (µg/day) have been established on the basis of safety data described in the monographs.
  • Classification as defined earlier.
  • Note: Permitted Daily Exposure (PDE) is the maximum acceptable intake of elemental impurity in pharmaceutical products per day.


Elemental Impurities Assessment Process 

1. Review the components of drug product for any elements intentionally added in the production (the primary source is the drug substance). For those used, record the elements for further consideration in the assessment.

2. Identify any potential elements or impurities that are associated with excipients used in the preparation of the drug product. Record the source(s) for further consideration in the assessment.

3. Identify any elemental impurities known or expected to be leached from the manufacturing equipment. Record the specific elemental impurities for further consideration in the assessment.

4. Identify any elemental impurities known or expected to be leached from the container closure system. Record the specific elemental impurities for further consideration in the assessment.

5. Calculate the total contribution of the potential elemental impurity by summing the contributions across the components of the drug product.

6. Assess the variability of the elemental impurity level(s) in the components.

7. Enter the control threshold of each potential elemental impurity identified. If the variability is known and it is within acceptable limits, the control threshold (30% of the PDE) for each elemental impurity can be applied.

8. Describe action taken – none if the value of total elemental impurity contribution is less than or equal to the control threshold (30% of the PDE). Define control element if material variability is high or control threshold is exceeded.