IPC Launches Seven Nitrosamine Impurities Reference Standards to Detect Carcinogenic Impurities

The Indian Pharmacopoeia Commission (IPC), functioning under the Ministry of Health and Family Welfare (MoHFW), launched seven Indian Pharmacopoeia Nitrosamine Impurities Reference Standards on 25 August 2026 at Kolkata to improve the precise detection and measurement of cancer-causing impurities in medicines. The launch took place during the interactive meeting titled “IP 2026: Perspectives, Suggestions, & Way Forward” held at the Central Drugs Laboratory (CDL) and Central Cosmetics Laboratory (CCL). This is the first time IPC has introduced dedicated reference standards for nitrosamines, a class of impurities classified as highly potent genotoxic and carcinogenic substances.

What Are Nitrosamine Impurities?

Nitrosamines are a class of chemical compounds that contain the N-N=O (N-nitroso) functional group. In simple terms, they are unwanted chemical impurities that can form when secondary or tertiary amines react with a nitrosating agent such as sodium nitrite, usually under acidic conditions. They appear unintentionally during drug manufacturing, storage, packaging, or through contaminated raw materials.

What makes nitrosamines dangerous is their biological effect. They are genotoxic, which means they can directly damage DNA (deoxyribonucleic acid), the genetic material inside cells, and cause mutations. This type of damage is detected through a bacterial reverse mutation assay, commonly known as the Ames test. Many nitrosamines are also carcinogenic, which means they can cause cancer even at very low levels of long-term exposure. The International Agency for Research on Cancer (IARC), an agency of the World Health Organization (WHO), classifies several nitrosamines including N-Nitrosodimethylamine (NDMA) as Group 2A, probably carcinogenic to humans.

Because of this potency, nitrosamines belong to what the ICH M7(R1) guideline calls the “cohort of concern”. ICH stands for International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Its M7 guideline deals with assessment and control of DNA reactive impurities to limit potential cancer risk. For ordinary mutagenic impurities, ICH M7 allows a Threshold of Toxicological Concern (TTC) of 1.5 micrograms per person per day, which corresponds to a theoretical excess cancer risk of less than 1 in 100,000 over a lifetime. For nitrosamines, this TTC cannot be routinely applied. Instead, a compound-specific Acceptable Intake (AI) must be calculated. For example, the AI for NDMA is 96 nanograms per day and for N-Nitrosodiethylamine (NDEA) is 26.5 nanograms per day. These limits are extremely low, which is why highly sensitive analytical methods are needed to detect them.

Nitrosamines are not only a pharmaceutical issue. They are also found in small amounts in processed meat, beer, cosmetics, drinking water, and tobacco smoke. In medicines, they have drawn global attention since July 2018, when NDMA was first detected in valsartan, a medicine belonging to the angiotensin II receptor blocker (ARB) or sartan family used for hypertension. Later, levels of NDMA were found in ranitidine (commonly sold as Zantac), metformin, pioglitazone and other products, leading to recalls, import alerts, and a worldwide regulatory response led by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

How Nitrosamines Form in Medicines

Nitrosamines can form through several routes. One common route is during synthesis of the tetrazole ring in sartan drugs, where the step that quenches remaining azide with nitrous acid can create NDMA or NDEA if amines and nitrites are present together. A second route is degradation of the drug substance itself during storage, as seen with ranitidine where time and higher temperature increase NDMA levels. A third route is cross contamination from recovered solvents, reagents, or equipment that carry traces of amines or nitrites. A fourth route is the reaction of residual amine impurities with nitrosating agents present in excipients or primary packaging materials. Controlling nitrosamines is especially important for drugs taken daily for many years for conditions such as hypertension, gastric disorders, diabetes, and tuberculosis, where cumulative exposure matters most.

The Seven New Nitrosamine Impurities Reference Standards

IPC has introduced seven Indian Pharmacopoeia Nitrosamine Impurities Reference Standards for the first time. These are N-Nitrosodimethylamine (NDMA), N-Nitrosodiethylamine (NDEA), N-Nitrosoethylisopropylamine (NEIPA), N-Nitrosodibutylamine (NDBA), N-Nitrosomethylphenylamine (NMPA), N-Nitrosodiisopropylamine (NDIPA), and N-Nitroso-N-methyl-4-aminobutyric acid (NMBA). According to IPC and the Ministry of Health and Family Welfare, the launch represents a significant step to strengthen India’s capability for accurate detection and measurement of these impurities in drug substances and finished products.

All seven are small-molecule nitrosamines that have been found as contaminants in various medicines globally. NDMA and NDEA are the most frequently cited in regulatory actions, while NMBA, also called N-Nitroso-N-methyl-4-aminobutyric acid, was notably detected in sartan medicines and later became part of extended monitoring lists. NEIPA, NDIPA, NDBA, and NMPA have also been included in global assessments of nitrosamine risk, especially under ICH M7 and EMA and FDA guidance documents.

One important concept to understand is the difference between simple nitrosamines and Nitrosamine Drug Substance-Related Impurities (NDSRIs). NDSRIs are nitrosamines that are structurally related to the specific drug’s active ingredient itself, for example when the drug molecule contains a secondary amine that can be nitrosated. The seven standards launched by IPC are for the simpler, non-drug-specific nitrosamines that serve as well-characterised benchmarks. However, the same reference standards help laboratories develop and validate methods that can also be adapted for NDSRI screening. IPC has indicated that these standards will support work on NDSRIs as well.

The availability of these physical specimens means Indian laboratories no longer need to depend entirely on imported reference materials from the United States Pharmacopeia (USP), European Pharmacopoeia (Ph. Eur) or British Pharmacopoeia (BP) for these specific impurities.

What Is a Reference Standard and Why Does It Matter?

A reference standard is a highly characterised physical sample of a pure substance that laboratories use as a benchmark to identify, compare, and measure the same substance in a drug sample. In this context, what is reference standard in pharma and what is reference standard and working standard are closely linked. The Indian Pharmacopoeia Reference Substances (IPRS) are the official primary standards issued by IPC. They are primary standards, which means their assigned purity or potency is accepted without needing comparison to another substance. They are certified, maintained, and distributed by IPC or laboratories authorised by it, and they are the official standards to be used in cases of dispute or arbitration. Where the letters RS appear after a substance name in a pharmacopoeial test, the relevant IPRS must be used.

Because IPRS are costly and supplied in very small quantities, typically a few milligrams, laboratories prepare a working standard for routine daily testing. A working standard is a secondary standard whose properties are assigned by direct comparison with the primary IPRS. It is prepared in larger amounts, qualified through identification tests such as infrared spectroscopy, and for assay by liquid chromatography, and must remain traceable to the IPRS. It is rechecked periodically and assigned a defined validity period, usually up to 12 months, with the opened vial typically used within one month if it is stable.

Without a reference standard, a laboratory cannot reliably say whether a tiny peak seen on an instrument is NDMA or some other impurity, nor can it accurately calculate how much is present. Regulators worldwide require methods for nitrosamine testing to be validated using authentic reference materials. Common analytical techniques include liquid chromatography coupled with mass spectrometry (LC-MS), including LC-HRMS (high-resolution mass spectrometry), LC-MS/MS, gas chromatography-mass spectrometry (GC-MS) headspace, and Orbitrap platforms. The new IPC standards will allow laboratories to validate such methods against an Indian source, with a Certificate of Analysis (CoA) and storage guidance provided by IPC.

Indian Pharmacopoeia Commission and IP 2026: The Institutional Backbone

Understanding the launch requires knowing what IPC and the Indian Pharmacopoeia (IP) are. The IP is the official book of standards for drugs manufactured and marketed in India. It lays down authoritative procedures for identity, purity, and strength of medicines. Its standards are legally enforceable under the Drugs and Cosmetics Act, 1940 and Rules, 1945. The IP is listed in the Second Schedule of the Act. Any drug that claims to be of IP quality must comply with the monograph in the edition currently in force. If a monograph does not appear in the current edition, the preceding edition continues to apply.

The history of the pharmacopoeia in India goes back to 1833, when a committee of the East India Company’s Dispensary recommended a pharmacopoeia, followed by the Bengal Pharmacopoeia in 1844 and IP 1868 based on the British Pharmacopoeia 1867. After independence, the Indian Pharmacopoeia Committee was constituted in 1948 under MoHFW. The first post-independence edition, IP 1955, was followed by IP 1966, IP 1985, IP 1996, IP 2007, IP 2010, IP 2014, IP 2018, and IP 2022, which is the 9th edition and became effective from 1 December 2022. In 2005, MoHFW established the Indian Pharmacopoeia Commission as an autonomous institution to publish the IP regularly and to develop reference standards. IPC became fully operational on 1 January 2009 and is headquartered at Sector 23, Raj Nagar, Ghaziabad, Uttar Pradesh. It is chaired by the Secretary, Ministry of Health and Family Welfare, with the Chairman of the Scientific Body as co-chair. The Secretary-cum-Scientific Director is the chief scientific and executive officer. The current office holder at the time of the launch was Dr. Rajeev Singh Raghuvanshi.

The meeting in Kolkata was significant for two additional reasons. First, it was the first-ever interactive meeting organised by IPC at the Central Drugs Laboratory and Central Cosmetics Laboratory, Kolkata. CDL Kolkata is a national statutory laboratory for testing drug quality. Second, the meeting’s theme was “IP 2026: Perspectives, Suggestions, & Way Forward”. This signals preparation for the 10th edition of the Indian Pharmacopoeia, IP 2026. Although news summaries referred to IP 2026 in meeting titles, the edition that had most recently been formally released before this event was IP 2022. IP 2026, when published, is expected to contain updated monographs, general chapters, and new impurity controls, building on the work of editorial groups in 2025 and 2026. Early highlights shared in draft overviews indicate 121 new monographs expanding coverage of essential medicines, biotechnology products, and updated chromatographic methods. The new nitrosamine reference standards align with that direction, and will likely feed into future IP general chapters on nitrosamine testing and limit tests.

Why This Launch Matters for Drug Safety and Regulation

The launch directly strengthens pharmaceutical quality control. Accurate detection and measurement of nitrosamines requires comparison against a known pure sample. The seven new IPRS provide that anchor for method validation, routine testing, quality assurance, and regulatory compliance. IPC has stated that the initiative will also support harmonisation with international quality standards and strengthen self-reliance in critical reference materials, reducing dependence on imported standards.

For manufacturers, the standards help in several practical ways. Companies can validate risk assessments required by regulators, confirm the effectiveness of control strategies, and set specification limits expressed in parts per million (ppm) or parts per billion (ppb). The limit for any nitrosamine in a product is calculated by dividing its Acceptable Intake (in nanograms per day) by the maximum daily dose (in milligrams) of the drug. For example, for valsartan with a maximum daily dose of 320 mg, the NDMA limit is 96 ng per day divided by 320 mg, which equals 0.30 ppm. Having domestic reference materials makes it easier for small and medium enterprises and public testing laboratories to perform such calculations reliably.

For the regulator, the standards improve the post-market surveillance ecosystem. India is the world’s largest supplier of generic medicines by volume, and the Central Drugs Standard Control Organisation (CDSCO) depends on a network of testing laboratories. Standardised impurity materials allow more uniform testing across central and state drug testing laboratories and support faster investigations if a contamination episode occurs. This reduces the risk of large-scale recalls and protects patient confidence.

Globally, the move aligns India with practices already adopted by the European Directorate for the Quality of Medicines and Healthcare (EDQM), USP, and regulators in the United States, European Union, and Health Canada, which publish their own nitrosamine guidance. ICH is also developing an Addendum to ICH M7 focused specifically on nitrosamines, expected to be published as ICH M7(R3), to provide harmonised principles for setting acceptable intakes and to introduce the Carcinogenic Potency Categorisation Approach (CPCA) that assigns nitrosamines to five potency categories with corresponding limits ranging from 18 ng per day to 1500 ng per day.

How This Differs From Earlier Impurity Controls

Earlier Indian Pharmacopoeia general chapters and impurity controls focused on related substances, residual solvents, and elemental impurities, with broad limits such as those in ICH Q3A and Q3B. Nitrosamines require a different approach because they are effective at nanogram levels. The General Chapter 5.20 on elemental impurities or the Heavy Metals test (Chapter 2.3.13), which IP 2026 has removed from individual active ingredient monographs except for herbal and veterinary products, operates at microgram or ppm levels. Nitrosamine control operates at ppb levels, often measured with mass spectrometry rather than ordinary ultraviolet detection. The new reference standards therefore fill a gap that older impurity tests could not address.

The Way Forward

The Kolkata meeting served as a platform for regulators, laboratory scientists, and pharmacopoeial experts to exchange views on the future of IP 2026. Contributions from participants including V. Kalaiselvan, Secretary-cum-Scientific Director of IPC, Professor Suparna Chatterjee, Head of Pharmacology at IPGMER Kolkata, and Rakesh Kumar Rishi, Director of CDL Kolkata, underlined the need for collaboration between pharmacopoeial and testing institutions to ensure medicine quality.

Looking ahead, three developments are likely. First, monographs for commonly used drugs that are known to be at risk for nitrosamine formation may be updated in IP 2026 to include specific limit tests and reference to the new impurity standards. Second, a dedicated general chapter on nitrosamine impurities, risk assessment, and control strategy may be introduced, similar to USP Chapter 1469 on nitrosamine impurities. Third, IPC is expected to expand its catalogue of impurity standards and IPRS to cover more NDSRIs, as global databases continue to grow and Indian manufacturers seek specific standards for their products.

For laboratories and companies, the immediate step is procurement and qualification. IPC has listed the new standards on its website for purchase by stakeholders. Laboratories will need to establish working standards traceable to the IPRS, train analysts on sensitive LC-MS methods, and participate in collaborative studies to verify method performance. For patients, the benefit is indirect but vital. More precise testing means a lower chance that a tablet containing a carcinogenic impurity above the acceptable level reaches the market.

Key Takeaways

• The Indian Pharmacopoeia Commission (IPC) launched seven Nitrosamine Impurities Reference Standards on 25 August 2026 at the Central Drugs Laboratory, Kolkata, during the meeting “IP 2026: Perspectives, Suggestions, & Way Forward”.
• The seven standards are NDMA, NDEA, NEIPA, NDBA, NMPA, NDIPA, and NMBA, introduced for the first time by IPC to enable precise detection of carcinogenic impurities.
• Nitrosamines contain the N-N=O group and are classified as highly potent genotoxic and carcinogenic impurities that can damage DNA and cause cancer.
• IPC, an autonomous body under the Ministry of Health and Family Welfare, is headquartered in Ghaziabad, Uttar Pradesh, became fully operational on 1 January 2009, and publishes the Indian Pharmacopoeia (IP), the official book of drug standards under the Drugs and Cosmetics Act, 1940.
• NDMA was first detected in valsartan in July 2018, later in ranitidine and metformin, triggering global recalls and guidance from FDA and EMA and controls under ICH M7(R1).
• The Acceptable Intake for NDMA is 96 nanograms per day and for NDEA is 26.5 nanograms per day, and these low limits require sensitive LC-MS and GC-MS methods validated against authentic IPRS.