Securing the Supply Chain: Managing Raw Material Risks in API Manufacturing

This informal CPD article ‘Securing the Supply Chain: Managing Raw Material Risks in API Manufacturing’, was provided by Pharmalliance Consulting, who offer specialist support to pharmaceutical companies to maintain and increase quality compliance levels.

In active pharmaceutical ingredient (API) manufacturing, quality begins well before production starts. The safety and efficacy of a medicine depend directly on the quality of the raw materials used in its manufacture, and regulators increasingly identify supply chain weaknesses as a critical risk to product integrity (4,5).

Recent industry events, including nitrosamine contamination incidents and cases of falsified supplier data, have reinforced a clear message: inadequate control of raw materials can directly compromise patient safety (1,6).

Nitrosamines: A Turning Point

The global recalls of sartans such as valsartan, losartan, and irbesartan beginning in 2018 marked a significant shift in regulatory expectations. Nitrosamine impurities, classified as probable human carcinogens, were identified in products due to both process-related formation and contaminated raw materials such as solvents and reagents (1,6).

In response, regulators now require manufacturers to perform comprehensive risk assessments across their entire product portfolio, evaluating synthetic routes, raw material sources, and process conditions for nitrosamine formation potential (1,2).

Reliance on supplier certificates of analysis (CoAs) alone is no longer acceptable. Manufacturers are expected to implement confirmatory testing, validated analytical methods, and, where necessary, process redesign to mitigate risks (1).

These developments have reinforced that supplier oversight is a core element of GMP compliance, not a peripheral activity.

Supplier Qualification: No Longer a Paper Exercise

Despite increased regulatory focus, warning letters and inspection findings continue to highlight deficiencies in supplier qualification. Acceptance of raw materials based solely on supplier documentation remains a recurring issue (4,5).

Regulators expect a comprehensive and risk-based approach, including:

• Supplier audits. On-site or remote assessments to verify GMP compliance (4).
• Ongoing qualification. Continuous monitoring of supplier performance, not one- time approval (3).
• Independent verification. Testing of high-risk materials, including solvents, catalysts, and intermediates, prior to release (4,7).
• Risk-based oversight. Application of Quality Risk Management principles to align control measures with material criticality (3).

Without these controls, manufacturers risk introducing substandard or adulterated materials into their processes, issues that cannot be corrected later in production.

Weak Incoming Testing: A Persistent Red Flag

Inadequate incoming material testing remains a frequent regulatory observation. In some cases, identity testing is incomplete; in others, materials are used without sufficient verification (4,5).

This is particularly concerning for high-risk substances. Glycerin, sorbitol, and ethanol have been associated with fatal poisoning incidents when contaminated with diethylene glycol (DEG), ethylene glycol (EG), or methanol (7). Regulators therefore require testing of each lot using validated, specific analytical methods.

Similarly, solvents and reagents must be assessed for potential impurities, including nitrosamines and heavy metals, where risk has been identified (1,6). Incoming controls are expected to reflect the potential patient impact of contamination, not simply rely on supplier assurances.

Physical Handling and Segregation Risks

Raw material risks are not limited to chemical composition. Poor physical handling and storage practices can also introduce contamination.

Inspection findings have identified issues such as:

• Damaged or leaking containers left unaddressed.
• Storage of materials under uncontrolled environmental conditions.

Such deficiencies represent failures in contamination control and GMP compliance, as improper storage and handling can compromise material integrity before manufacturing even begins (4,5).

Building a Resilient Raw Material Strategy

To effectively manage supply chain risks, API manufacturers must implement a structured and proactive approach to raw material control. Key elements include:

• Comprehensive risk assessments. Evaluation of synthetic routes and raw material inputs to identify potential impurity risks, including nitrosamines (1,3.
• Robust supplier qualification. Integration of audits, quality agreements, and ongoing performance monitoring (4).
• Targeted incoming testing. Verification of high-risk materials using validated analytical methods (7).
• Segregation and storage controls. Ensuring materials are stored and handled in conditions that preserve their integrity (5).
• Quality-driven procurement. Aligning purchasing decisions with quality and compliance requirements, not solely cost considerations.

The Regulatory View

Regulators consistently emphasise that manufacturers retain full responsibility for their supply chains. The use of external suppliers does not transfer accountability (4,5).

Manufacturers must be able to demonstrate that all raw materials are suitable for their intended use, supported by data, risk assessments, and ongoing monitoring. As regulatory focus on contamination risks intensifies, firms are expected to justify and document every decision related to material selection and control (1,6).

Conclusion

The quality of an API is fundamentally dependent on the materials used in its manufacture. Weaknesses in supplier qualification, insufficient testing, or poor material handling cannot be corrected later in the process; they compromise the entire manufacturing lifecycle. The nitrosamine crisis demonstrated that supply chain risks are real, global, and capable of impacting entire product classes.

For API manufacturers, the path forward is clear: establish resilient supply chains, treat supplier qualification as an ongoing process, and ensure all incoming materials are thoroughly tested and controlled. These measures are not only regulatory expectations, they are essential to protecting patients and maintaining trust in pharmaceutical products. 

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References

(1)    U.S. Food and Drug Administration, 2024. Control of Nitrosamine Impurities in Human Drugs (Guidance for Industry; September 2024), Silver Spring, MD, United States of America.
(2)    U.S. Food and Drug Administration, 2023. Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) (Guidance for Industry; August 2023), Silver Spring, MD, United States of America.
(3)    International Council for Harmonisation, 2023. ICH Q9(R1) – Quality Risk Management, Geneva, Switzerland.
(4)    International Council for Harmonisation, 2000. ICH Q7 – Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, Geneva, Switzerland.
(5)    U.S. Government Publishing Office, n.d. 21 CFR Part 211 – Current Good Manufacturing Practice for Finished Pharmaceuticals, United States of America.
(6)    European Medicines Agency, 2020. Questions and Answers for Marketing Authorisation Holders/Applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 Referral on Nitrosamine Impurities in Human Medicinal Products, Amsterdam, Netherlands.