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Every medicinal dose contains, in addition to the active pharmaceutical ingredient, a complex matrix of intentional excipients and unintentional impurities. Some of these impurities are routine; others are introduced by the synthetic route, the container-closure system, or the supply chain. Determining which impurities are acceptable—and at what level—is the work of toxicological risk assessment.
Few areas of Regulatory science demand as much interdisciplinary judgment as impurity and extractables/leachables (E&L) assessment. The science draws on toxicology, analytical chemistry, materials science, and process knowledge—and the consequences of getting it wrong include refused submissions, label restrictions, or recall.
What Is Toxicological Risk Assessment?
A toxicological risk assessment evaluates whether a chemical entity present in a drug product—whether an organic impurity, residual solvent, elemental impurity, mutagenic impurity, leachable from primary packaging, or extractable from device or process components—poses a meaningful risk to patient health at the proposed dose, route, frequency, and duration of exposure.
The output is typically a Permitted Daily Exposure (PDE), an Acceptable Intake (AI), or a Threshold of Toxicological Concern (TTC) value, with documented scientific justification and references.
Regulatory Frameworks
The relevant guidance landscape includes ICH Q3A (impurities in new drug substances), ICH Q3B (impurities in new drug products), ICH Q3C (residual solvents), ICH Q3D (elemental impurities), ICH M7(R2) (assessment and control of mutagenic impurities), and the developing ICH Q3E for E&L. United States Pharmacopeia chapters <232>, <233>, <1663>, and <1664>, along with PQRI recommendations on E&L for Orally Inhaled and Nasal Drug Products (OINDP) and Parenteral and Ophthalmic Drug Products (PODP), supplement the ICH framework.
Impurities Under ICH Q3A and Q3B
For organic impurities in new drug substances and drug products, ICH defines reporting, identification, and qualification thresholds based on daily dose. Above the qualification threshold, an impurity must be qualified—either through dedicated nonclinical studies, exposure during clinical trials, or a robust scientific rationale based on structural class, metabolism, and toxicology data. Sponsors who attempt to qualify impurities solely through assertion, without supporting data, often face deficiency questions.
Mutagenic Impurities and the TTC
ICH M7 establishes a tiered classification system for actual and potential mutagenic impurities, ranging from Class 1 (known mutagenic carcinogens) through Class 5 (no alerts, treated as ordinary impurities). Class 1 and Class 2 impurities are typically controlled to a Threshold of Toxicological Concern of 1.5 µg/day, with adjustments under the Less-Than-Lifetime (LTL) framework for shorter exposures. In silico (Q)SAR assessments using two (2) complementary methodologies are increasingly the starting point for identifying potential mutagenic impurities at the design stage.
Extractables and Leachables
E&L assessment evaluates compounds that may migrate from container closure systems, device components, single-use bioprocessing materials, or administration sets into the drug product or, ultimately, the patient. Risk is greatest for parenteral, ophthalmic, and inhalation products, but no dosage form is fully exempt from at least a screening assessment.
A typical workflow includes an extractables study under exaggerated solvent and temperature conditions, identification and quantitation of detected compounds, a leachables study under actual storage and use conditions, toxicological evaluation against established thresholds (e.g., the Safety Concern Threshold of 0.15 µg/day for OINDP), and inclusion of the assessment in Module 3 of the registration dossier.
Special Considerations for Biologics and Advanced Therapies
Biologics, cell and gene therapies, and biosimilars introduce additional E&L considerations. Single-use systems used throughout upstream and downstream processing can contribute leachables that interact with sensitive proteins, potentially affecting potency, aggregation, or immunogenicity. Risk assessment must therefore consider not only patient toxicity but also the impact on product quality—a dual-lens evaluation that requires close coordination among toxicology, analytical development, and process science teams.
Lifecycle Considerations
Toxicological risk assessment is not a one-time submission activity. Process changes, new starting material sources, alternative packaging suppliers, or new indications (especially pediatric extensions) can each trigger reassessment. Sponsors who maintain a living impurity and E&L knowledge base—linked to change-control workflows—respond to Regulatory questions far faster and avoid duplicating earlier evaluations.
Common Pitfalls
Recurring problems include applying the TTC to non-mutagenic impurities (where Q3A/Q3B thresholds apply instead), failing to adjust thresholds for pediatric populations or chronic dosing, inadequate characterization of starting materials and reagents, overlooking E&L in single-use bioprocess components, and inconsistent assessment approaches across submission regions. Another common issue is justifying levels solely based on precedent or product comparisons, without underlying toxicological data—an approach that frequently fails on review. Each of these pitfalls is avoidable with a structured, science-led approach.
How Freyr Can Help
Freyr's toxicology experts deliver toxicological risk assessments for organic impurities, residual solvents, elemental impurities, mutagenic impurities under ICH M7, and extractables and leachables. We prepare ICH Q3 and M7 expert reports, review and report E&L studies, calculate PDEs for shared facilities (cleaning validation), and integrate findings into Module 2.3 Quality Overall Summary and Module 3 narratives. Contact us to know more.
