Residual Solvents and Elemental Impurities: Classification & Exposure Limits as per ICH Q3C AND Q3D

✅ICH Q3C is a guideline established by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). It specifically addresses the control and limitation of residual solvents in pharmaceuticals. Residual solvents are organic volatile chemicals used or produced in the manufacture of drug substances, excipients, or in the preparation of drug products, and they can be present in the final product.

✅ICH Q3D is another crucial guideline by the ICH, focusing on the control of elemental impurities in pharmaceutical products. Elemental impurities are potentially harmful elements that may be present in drug products and can arise from various sources such as raw materials, catalysts, and equipment.

💥A. Classifications of Residual Solvents and Elemental Impurities:

Both residual solvents and elemental impurities share similarities, but also have distinct classifications and limits. Let's break these down for better understanding:

Class 1: The High-Risk Category

a. Residual Solvents: Solvents in this class are avoided due to severe toxicity or harmful environmental impact. Key examples include benzene and carbon tetrachloride, among five total in this class.

b. Elemental Impurities: Class 1 elements are toxic to humans, with arsenic, cadmium, mercury, and lead being prime examples.

Class 2: Moderately Hazardous

a. Residual Solvents: These solvents are limited owing to their inherent toxicity. Examples include acetonitrile, chlorobenzene, and methanol, with a total of 31 solvents in this category.

b. Elemental Impurities: Divided into Classes 2A and 2B based on the probability of occurrence and route-dependent toxicity:

i. Class 2A: Elements like cobalt, nickel, and vanadium, known for their higher probability of occurrence.

ii. Class 2B: Elements with a reduced occurrence in nature, encompassing ten elements like silver, gold, and platinum.

Class 3: Lower Risk

a. Residual Solvents: These are solvents with low toxic potential, including acetic acid, ethanol, and 27 others.

b. Elemental Impurities: Elements in Class 3 are less toxic orally, with higher permissible daily exposure. Examples include barium, chromium, and copper. The exposure limits vary based on the administration route (oral, inhalation, or parenteral), with oral typically allowing higher limits.

💥B. Exposure Limits of Residual Solvents & Elemental Impurities:

Key Differences in Exposure Limits:

Residual solvents typically have common limits for oral, inhalational, and parenteral routes. In contrast, elemental impurities have varying permissible exposures based on the administration method, with oral usually having higher limits. This differentiation is crucial for accurate risk assessment in pharmaceuticals.

Option 1: The applicant may select any of these options as long as the resulting permitted concentrations assure that the drug product does not exceed the PDEs.

Example:

Residual Solvent: Methanol (PDE= 30mg/day): 1000 x 30/10 = 3000ppm

Elements: Ni (Oral PDE= 200μg/day): 200/10 = 20ppm

Option 2:

Example:

Actual product mass: 20g/day

Residual Solvent: Methanol (PDE= 30mg/day): 1000 x 30/20 = 1500ppm

Elements: Ni (Oral PDE= 200μg/day): 200/20 = 10ppm

Option 2b:

Example: Ni (Oral PDE = 200 μg/day)

Option 3:

Conclusion: Understanding the classifications and exposure limits of both residual solvents and elemental impurities is vital in pharmaceutical manufacturing. The ICH guidelines Q3C and Q3D provide a framework for ensuring product safety and efficacy. As we navigate these guidelines, it's essential to remember their distinct approaches to classifying and limiting various solvents and elements, reflecting their individual toxicological profiles.