Jun 10, 2025
As scientific understanding of nitrosamine impurities deepens, regulatory agencies are preparing to significantly raise the bar on acceptable risk levels — and the pharmaceutical industry must be ready to respond.
On May 11, 2025, the International Council for Harmonisation (ICH) released a Final Concept Paper outlining its intent to revise the ICH M7(R2) guideline. The revision, led by the ICH M7 Nitrosamine Subgroup, focuses on risk assessment and control of mutagenic nitrosamines in drug substances and drug products. With regulatory adoption expected across the U.S., EU, and other key regions, this development signals a new chapter in impurity control.
What Are Nitrosamines, and Why the Heightened Concern?
Nitrosamines are a class of chemical compounds that can form during drug manufacturing or storage — often through interactions between amines, nitrites, solvents, or packaging materials. While some nitrosamines are considered relatively harmless, others such as NDMA, NDEA, and related analogs are recognized as probable human carcinogens.
Since their unexpected detection in widely used drugs like sartans, ranitidine, and metformin, nitrosamines have triggered product recalls, regulatory warnings, and deeper investigations into how they form and how they can be controlled. Their ability to appear unpredictably and at trace levels — yet still pose serious long-term health risks — has made them a top priority for regulators worldwide.
What’s Changing with the New Guidance?
The forthcoming ICH M7(R3) revision will introduce more precise and proactive strategies for nitrosamine detection and control, including:
Stricter acceptable intake (AI) thresholds, with many nitrosamines expected to fall below 18 ng/day
Adoption of structure–activity relationship (SAR)-based screening approaches to proactively identify mutagenic potential
Enhanced emphasis on risk-based assessments that account for total daily intake across combination products
Expanded scope of control, including raw materials, excipients, reagents, and manufacturing equipment
Greater focus on root cause investigation, supplier qualification, and preventive controls, especially for contract development and manufacturing organizations (CDMOs)
These updates reflect a shift toward lifecycle-based impurity management, requiring sponsors to address nitrosamine risk early and systematically across the entire development process.
Why Early Planning Is Critical for Biotech Developers
For emerging biopharma companies and lean development teams, these evolving guidelines represent more than a regulatory hurdle — they are a potential roadblock to approvals if not addressed early and thoroughly.
Failure to meet nitrosamine expectations could lead to:
IND or BLA rejections
Clinical trial delays or holds
Additional stability or reformulation studies
Market withdrawals, recalls, or reputational damage
What’s often overlooked — and now essential — is the quality and control of raw materials, intermediates, and final drug substances. Nitrosamine formation can originate upstream from reagents, solvents, or contaminated excipients and go undetected until late-stage testing or post-market review. That’s why supplier qualification, traceability, and comprehensive impurity testing across the entire supply chain must be embedded early in development.
With the FDA and ICH aligning to raise the bar, companies must now integrate nitrosamine control into their core CMC strategy — not as a late-stage fix, but as a proactive, cross-functional safeguard for regulatory success and patient safety.
How Pharmefex Helps Clients Navigate Compliance, CDMO Selection & Supply Chain Strategy
At Pharmefex, we understand that nitrosamine mitigation is not just a testing challenge — it’s a strategic, regulatory, and operational imperative. Our team offers deep expertise across regulatory CMC, quality assurance, and CDMO sourcing and oversight, helping clients embed impurity risk control into every phase of development.
We support clients by:
Identifying and qualifying CDMOs with advanced nitrosamine detection, validated methods, and compliance readiness
Developing risk-based impurity control strategies aligned with ICH and FDA expectations
Designing raw material and intermediate testing strategies that detect and eliminate root causes early
Assisting with supplier qualification, vendor audits, and supply chain mapping to ensure quality and traceability
Supporting robust documentation and readiness for IND, BLA, and global submissions
Pharmefex’s agile model allows biotech teams to stay ahead of evolving guidelines without increasing internal overhead, enabling scalable compliance, reduced development risk, and greater regulatory confidence.
Final Thoughts
The May 2025 ICH concept paper signals a critical shift: drug developers must treat nitrosamine control as a foundational component of quality and regulatory strategy. As impurity limits tighten and regulatory expectations rise, the companies that prepare now will be best positioned to avoid costly delays — and bring safer therapies to patients faster.
Pharmefex is ready to help you build a future-ready strategy. Reach out today to learn how our regulatory, quality, and CDMO expertise can support your development goals in this evolving landscape.