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How a Pharma Company Updated Its Drug Product Risk Assessment After Manufacturing Changes

Manufacturing changes can quickly make a drug product risk assessment (DPRA) outdated. New equipment, process changes, supplier changes, or formulation updates may affect the risk of nitrosamines, NDSRIs, or mutagenic impurities.

Therefore, pharma companies must connect every relevant manufacturing change to the latest DPRA. Manufacturing, QA, RA, analytical laboratories, project management, and the MAH holder all need consistent risk information.

In one client case, a site changed a rubber stopper used for a vial closure. Because the change was not reflected in the DPRA, it created a new NDSRI pathway. Routine testing identified the risk only after multiple batches had already been released.

This case shows why a DPRA must remain a living, traceable document.

Our team supported the case by linking manufacturing changes, DPRA updates, expert assessments, analytical testing, and regulatory decisions through a structured process.

Challenges Faced

A detailed GAP analysis in Quality Management Systems is essential for identifying process deficiencies effectively.
  • Manufacturing Changes Could Alter the DPRA: Minor changes may introduce new nitrosamine pathways, amines, NDSRIs, or analytical gaps.
  • DPRA Versions Could Become Outdated: Without centralized control, teams may rely on outdated versions for risk and regulatory decisions.
  • Changes Needed to Trigger Risk Review: Relevant changes should prompt risk triage for nitrosamines, NDSRIs, and mutagenic impurities.
  • Analytical Testing Required Coordination: Analytical laboratories needed timely access to updated risk information and clear testing requirements.
  • Batch Testing Needed Consistency: The defined approach included two previous batches and one new batch when testing was required.
  • RA Needed Timely Updates: Regulatory affairs depended on current DPRA and analytical results for regulatory reporting.
  • End-to-End Traceability Was Essential: The process needed a clear link: Manufacturing change triggers DPRA review, expert assessment, testing, and RA decision.

Zamann Pharma Support’s Approach

  • Centralized DPRA Control: We stored DPRAs in a controlled repository with versioning, change logs, approvals, and clear superseded versions.
  • Linked Changes to Review: Relevant manufacturing changes notified the DPRA owner and triggered risk triage for nitrosamines, NDSRIs, and mutagenic impurities.
  • Updated Risk Assessments: When needed, reviews covered CPCA category, acceptable intake, and analytical testing requirements.
  • Linked DPRA to Testing: Testing plans were tied to DPRA updates and included two historical batches and one new batch when required.
  • Confirmed Risk by Testing: In one case, a new solvent raised a dimetrosamine risk, so two historical batches and one fresh batch were tested.
  • Created a Central Dashboard: The dashboard tracked manufacturing changes, expert assessments, and analytical test status.
  • Used Alerts and Deadlines: QA, RA, and analytical teams received update notifications, assigned actions, and deadlines.
  • Integrated the Workflow: The process connected manufacturing, DPRA review, expert assessment, testing, RA, and health-authority activities.
  • Maintained Audit Trails: Records captured approvals for risk assessments, analytical results, and final decisions.
  • Closed Changes Properly: In a granulation case, the team reassessed risk, tested two old and one new batch, reviewed results, and RA updated EMA/FDA.
  • Applied a Self-Diagnostic: Seven criteria assessed DPRA control and visibility. Scores were 0–2 good, 3–5 needs improvement, and 6–7 high risk.
  • Maintained Regulatory Traceability: The review used EMA Q&A Nitrosamines, FDA Nitrosamine Guidance, and ICH M7 Q&A as key references.
  • Defined Clear Actions: The final process focused on controlled documentation, timely reviews, testing, consolidated results, regulatory updates, and dashboard monitoring.

Results Achieved

  • No Regulatory Action: The granulation-process example resulted in no regulatory action.
  • Faster Decision-Making: The connected workflow enabled quicker review of manufacturing, testing, QA, and RA information.
  • Inspection-Ready Documentation: The change was closed with a complete audit trail and traceable documentation.
  • Product Risk Was Confirmed Through Testing: When testing confirmed no new risk, the product could be de-risked and RA could update health authorities.
  • Better Cross-Functional Visibility: Manufacturing, QA, RA, analytical, PM, and DPRA activities were linked through one structured process.
  • Stronger Risk Management: The approach supported more proactive management of nitrosamine and NDSRI risks rather than fragmented responses.
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Pharmaceutical quality team reviewing nitrosamines risk assessment documentation aligned with ICH M7 and current regulatory compliance requirements
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Nitrosamines Regulatory Compliance

We assist pharmaceutical teams in assessing and managing nitrosamines risks by aligning processes with ICH M7 requirements and current regulatory expectations.

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FAQ

1. Which manufacturing changes should trigger a drug product risk assessment update?

Changes should trigger DPRA review when they may affect nitrosamine formation, NDSRIs, or mutagenic impurities. Examples in the source include equipment, process, supplier, formulation, closure, and solvent changes.

2. How should analytical testing support a DPRA update?

Analytical testing should directly verify the risk identified in the updated DPRA. When required, the plan should include two historical batches and one post-change batch, with results documented against the identified nitrosamine or NDSRI risk. QA, RA, and PM should review the data together, and the final conclusion should remain traceable to the revised DPRA.

3. What traceability is needed between manufacturing change control and a DPRA?

Traceability should show a complete, auditable link from the approved manufacturing change to the affected DPRA, updated expert assessment, analytical testing, and final RA decision. Each step should retain version history, approvals, test results, and audit records so reviewers can reconstruct why the risk conclusion changed and how the change was ultimately closed.