Toxicological Risk Assessment of Impurities: Scientific and Regulatory Approach

Impurities are an inherent part of the manufacture of pharmaceuticals, cosmetics, medical devices, and industrial chemicals. They may arise from raw materials, synthesis processes, degradation, or storage conditions. Although often present at trace levels, their toxicological significance cannot be underestimated.

Regulatory authorities such as the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), the U.S. Food and Drug Administration (USFDA), the European Medicines Agency (EMA), and the European Chemical Agency (ECHA) emphasize a science-based toxicological risk assessment of impurities to ensure they remain within toxicologically acceptable limits. The core principle is simple yet critical: the safety of a product depends not only on what is intentionally added, but also on what is unintentionally present. 

Types and Source of Impurities

Impurities are broadly classified based on their origin and chemical nature.

Organic Impurities

Arise from synthesis, formulation, or degradation.

Examples: starting material residues, intermediates, by-products, degradation products.

Inorganic Impurities

Derived from reagents, catalysts, or manufacturing processes or equipment.

Examples: heavy metals, residual catalysts, inorganic salts, processing aids.

Residual Solvents

Inorganic or organic chemicals are used during the synthesis, purification, or formulation of a drug substance. Their presence must be controlled based on toxicity classification, as outlined in ICH Q3C.

Degradation Products

Formed during product shelf life, environmental factors such as heat, light, moisture, oxidation, or pH changes.

Extractables and Leachables

Packaging materials, container closure systems, and processing equipment may introduce unintended substances into the product. These extractables and leachables must be assessed, particularly for products with prolonged contact or chronic exposure scenarios.

Scientific Framework for Toxicological Risk Assessment

A structured toxicological risk assessment of impurities follows internationally accepted scientific principles. The objective is to determine whether an impurity poses a health risk at its anticipated exposure level.

The assessment is based on four core steps:

• Hazard Identification

• Dose–Response Assessment

• Exposure Assessment

•  Risk Characterization

This risk-based framework ensures impurity limits are scientifically justified, toxicologically acceptable, and aligned with global regulatory expectations.

Regulatory Guidelines and Control of High-Risk Impurities

Regulatory authorities globally require a science-based, risk-driven approach for impurity evaluation and control. Key frameworks include:

• ICH Q3A & Q3B and USP <466> - Organic Impurities

• ICH Q3C and USP <467> - Residual solvents

• ICH Q3D and USP <232>/<233> - Elemental impurities

• ICH M7 - Assessment and control of mutagenic (genotoxic) impurities

In addition, authorities expect documented scientific justification for impurity limits across sectors. A regulatory-aligned impurity strategy is therefore essential to ensure compliance, inspection readiness, and product safety.

Establishing Acceptable Limits

Determining acceptable limits for impurities is a critical part of toxicological risk assessment. It ensures that any impurity present does not pose a health risk under intended use.

A risk-based evaluation typically includes:

• Hazard Identification & Derivation of Point of Departure (POD): For impurities lacking experimental data, apply predictive tools such as (Q)SAR modeling or read-across.

• Apply Uncertainty Factors (when needed): Account for interspecies differences, human variability, and data gaps.

• Calculate or use Health-Based Guidance Values:

  • Permitted Daily Exposure (PDE)

  • Acceptable Daily Intake (ADI)

  • Threshold of Toxicological Concern (TTC) - useful for low-level or data-poor impurities

• Exposure Comparison: Ensure estimated product use does not exceed the calculated safe limit.

This risk-based approach allows for scientifically justified specifications, supports regulatory compliance, and ensures consumer or patient safety.

Risk-Based Control Strategy

A risk-based control strategy ensures impurities remain within safe levels throughout the product lifecycle. Key elements include:

• Process Controls: Optimize synthesis, purification, and handling to minimize impurity formation.

• Analytical Monitoring: Use validated methods to detect, quantify, and track impurities regularly.

• Specification Setting: Define clear impurity limits in raw materials, intermediates, and final products.

• Documentation and Justification: Maintain a complete record of risk assessment, control measures, and scientific rationale.

• Lifecycle Management: Continuously review impurity profiles with changes in raw materials, suppliers, or manufacturing processes.

A proactive, risk-based strategy not only ensures regulatory compliance but also strengthens product safety, quality assurance, and inspection readiness across pharmaceuticals, cosmetics, medical devices, and chemicals.

Conclusion 

Toxicological risk assessment of impurities is a critical component of product safety and regulatory compliance across pharmaceuticals, cosmetics, medical devices, and chemicals. By understanding impurity types, applying a structured scientific framework, and aligning with global guidelines such as ICH, USP, and Ph. Eur., companies can establish defensible limits and demonstrate product safety.

A proactive, documented, and risk-based approach not only ensures compliance but also strengthens confidence in product quality and protects end-users. SciQra supports organizations with structured impurity risk assessment, raw material qualification, and toxicological evaluation, enabling brands to achieve product safety and compliance while maintaining formulation flexibility and innovation.

FAQs — Toxicological Risk Assessment of Impurities

Why is impurity risk assessment critical for product safety?
Even trace-level impurities can be hazardous if they are genotoxic, carcinogenic, or accumulate over time. A structured risk assessment ensures product safety and regulatory compliance.

Does every product require a risk assessment for impurities?
Yes. Across pharmaceuticals, cosmetics, medical devices, and chemicals, risk-based evaluation of impurities is essential to demonstrate safety and regulatory compliance.

What impurities are most concerning in cosmetics?
Heavy metals, residual solvents, PAHs, pesticides, degradation products, and packaging leachables are most commonly evaluated.

What is the approach for genotoxic impurities without experimental data?
Predictive tools like (Q)SAR, read-across, and TTC thresholds are used to estimate potential risk and justify limits scientifically.

What documentation is sufficient to demonstrate regulatory compliance?
Comprehensive records should include: toxicological rationale, exposure calculations, impurity specifications, and justification for limits with references to guidelines.