Elemental Impurities: Risk Assessment and Significances

The ICH Q3D Guideline for Elemental Impurities came into effect in January 2018 for all products for human use. It is supplementary safety-based guidance for toxic impurities that added the existing ICH Q3C and ICH M7 as well as the existing guidelines for non-toxic impurities ICH Q3A and non-toxic degradants ICH Q3B.

However, it does not specify limits for the major components of drug products. This brings excipients in particular under examination, being they, unlike APIs, lack established daily doses. 

Due to the low limits of elemental impurities, there is a requirement for most advanced instruments ICP-MS.  The new guidance address not only the most toxic metals but also the number of elements introduced intentionally, fetching the total number of elements that are 24.  The requirements are shown below in Table.

Permitted daily exposure (PDE) limits in μg/day.

• Limits in the drug material analyzed must be corrected for daily dosage and route of administration.
• Drugs intended for inhalational or parenteral (injectable/intravenous) administration have much lower limits than drugs taken orally.
• Class 1: known human toxicants with limited or no use in pharmaceutical manufacture; It assumes daily intake of the drug product is 10 g or less.
• Class 2A: route-dependent human toxicants with a relatively high probability of occurrence in the drug product; it uses an actual maximum daily intake (versus assuming 10 g)
• Class 2B: route-dependent human toxicants with a reduced probability of occurrence that are only of concern if deliberately added, i.e. catalysts and; sums of known component impurity levels
• Class 3: elements with relatively low toxicities by the oral route of administration, PDEs >500μg/day, but which may require consideration for inhalation and parenteral routes. It measures the concentration of elements in the final drug product

Risk Assessments:

Risk assessments should consider all potential sources of elemental impurities, including water, starting materials, manufacturing equipment, process materials, and packaging materials (Figure 1).

Figure 1. Drug manufacturer’s perspective of possible sources of elemental impurities

The risk in turn can then be expressed using four approaches;

1. Elemental impurity levels that could exceed the PDE in the drug product,
2. Elemental impurities that could exceed the control threshold (30% of PDE) but not the PDE
3. Elemental impurities that could be present < control thresholds.
4. Elemental impurities excluded from risk assessment (ICH Q3D)

Elemental impurity requirements are subject to regulatory assessment, including examinations. As a result, when testing is conducted, it will require more expensive testing procedures. The component assessment approach allows drug product manufacturers to assess elemental impurity risk in compliance with ICH Q3D.

Implementing a risk assessment technique to assess the impact and development of a science-based strategy for control of elemental impurities has the potential to significantly reduce the amount of testing that must be performed regularly, subsequently savings in testing, time, and costs.

References:

1. USP <232> Elemental Impurities – Limits
2. ICH Q3D. Guideline for Elemental Impurities.
3. ICH Q3C(R7). Impurities: Guideline for residual solvents.
4. ICH M7(R1). Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk.
5. ICH Q3A(R2). Impurities in new drug substances.
6. ICH Q3B(R2). Impurities in new drug products.
7. Teasdale A, Chery C, Cook G, Glennon J, Lee C, et al. 2015. Implementation of ICH Q3D Elemental Impurities Guideline: Challenges and Opportunities. Pharm. Tech.
8. Reichert U. Elemental Impurities: Implications for Manufacturers of Drug Products, APIs, and Excipients. Amer. Pharm.
9. Elder D, Teasdale A. 2013. ICH Q3D: Metal Impurities: A Critical Evaluation. Eur. Pharm. Rev., https://www.europeanpharmaceuticalreview.com/article/22277/ich-q3d-metal-impurities-critical-evaluation/. Accessed on 07 December 2018.
10. Eur., 2015. Policy on Element impurities.
11. FDA, 2018. Elemental Impurities in Drug Products. Guidance for Industry. August 2018.

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