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How We Built a Defensible NDSRI Risk Assessment Workflow for Pharma

Nitrosamine drug substance-related impurities (NDSRIs) create significant challenges for pharmaceutical companies. However, many struggle to determine which impurities require assessment.

Across global client projects, chemistry, quality, and regulatory teams applied different assessment criteria. Consequently, companies faced inconsistent expert evaluations, conflicting submissions, and regulatory scrutiny.

Our team at Zamann Pharma Support developed a structured NDSRI risk assessment workflow to standardize decisions and strengthen scientific justification across products and sites.

Challenges Faced

A detailed GAP analysis in Quality Management Systems is essential for identifying process deficiencies effectively.

  • Inconsistent NDSRI Assessments: Teams used different criteria, resulting in conflicting assessments.

  • Unclear Structural Classification: Teams disagreed on amine and vulnerable structure definitions.

  • Uncertain Impurity Scope: Teams disagreed on which impurities to assess.

  • Undefined CPCA Requirements: Companies excluded Categories 2–5 without justification.

  • Inconsistent Data Sources: Teams relied on different API and impurity data.

  • Missing Decision Criteria: Unclear thresholds led to conflicting API assessments.

  • Regulatory Findings and CAPAs: Inconsistent assessments triggered regulatory scrutiny and lengthy CAPAs.

  • Limited Workflow Self-Assessment: Companies lacked consistent checks for key NDSRI decisions.

Zamann Pharma Support’s Approach

  • Define Structural Classification Rules: We set clear rules for amines and vulnerable structures, supported by examples and decision trees.
  • Standardize Impurity Scope: We define which impurities to assess, including specified, unspecified, and API-related impurities.
  • Establish CPCA Category Requirements: We clarify which CPCA categories need assessment, further review, or justified exclusion.
  • Define Authoritative Data Sources: We standardize the use of API specifications, laboratory data, development records, and supplier information.
  • Document Inclusion and Exclusion Decisions: We set clear thresholds and require scientific justification for including or excluding NDSRIs.
  • Train and Harmonize Across Sites: We align teams through training and testing to ensure consistent assessments across sites.

Results Achieved

  • EMA Required Additional Structural Assessment: EMA challenged a low-risk amine classification and required a full evaluation.
  • Three Agencies Challenged Inconsistent Submissions: Three regulatory agencies challenged conflicting impurity assessment approaches.
  • A 120-Product Portfolio Required Reassessment: FDA questioned unjustified CPCA exclusions, triggering a review of 120 products.
  • A Structured Remediation Framework Was Defined: A six-step framework established consistent assessments and documented decisions. Post-implementation results were not reported.
Laboratory
Pharmaceutical quality team reviewing nitrosamines risk assessment documentation aligned with ICH M7 and current regulatory compliance requirements
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FAQ

1. Should unspecified API impurities and degradants be included in an NDSRI risk assessment?

An NDSRI risk assessment workflow must define how specified impurities, unspecified impurities, secondary amines, and API degradants are evaluated.

The inclusion criteria should address impurity concentration thresholds, structural plausibility, and potential nitrosation conditions.

The source does not prescribe one universal threshold. Instead, it emphasizes consistent, scientifically justified decisions and documented inclusion or exclusion criteria.

 

2. How should CPCA Categories 2–5 be addressed in an NDSRI risk assessment?

A documented CPCA strategy should define which categories require assessment, which require additional toxicology review, and when Categories 4–5 may be excluded.

The source describes a company that assessed only Category 1 NDSRIs without documenting its rationale for excluding Categories 2–5.

FDA questioned the exclusion, leading to reassessment of a 120-product portfolio. Therefore, category decisions need clear scientific justification.

3. Which API and impurity data sources should support an inspection-ready NDSRI assessment?

An NDSRI assessment workflow should define the authoritative data sources used to support impurity decisions.

Depending on the documented policy, these may include API specifications, raw LC/MS data, chromatograms, forced degradation studies, historical development reports, and supplier qualification records.

Furthermore, inclusion and exclusion decisions should be traceable to the selected evidence, structural considerations, and defined assessment criteria.