Safeguarding Modern Medicine
In the intricate world of drug development, even the smallest unwanted molecule can have a profound impact on your health.
When you take a pill or a syrup, you trust that it contains only the ingredients meant to heal you. Yet, every medicinal product contains a hidden world of minor components—unwanted chemical substances known as impurities. Though often present in tiny amounts, their impact on drug safety, efficacy, and stability can be significant. The rigorous science of controlling these impurities is a silent guardian of public health, ensuring that the medicines we rely on are both safe and effective.
In the precise language of pharmacy, an impurity is formally defined as "any component of the drug product that is not the chemical entity defined as the drug substance or an excipient" 3 . In simpler terms, it's any unwanted chemical that tags along with the active drug (the API) or the inactive ingredients (excipients) in a pill, capsule, or syrup.
These are the most common type and are closely related to the drug itself. They can arise during the complex multi-step synthesis of the active ingredient, appearing as unreacted starting materials, intermediates, or by-products. They can also form later, as the drug degrades over time due to factors like exposure to light, heat, or humidity 3 5 .
These typically come from the manufacturing process rather than the drug molecule itself. Examples include reagents, ligands, catalysts, heavy metals, and inorganic salts 5 . Heavy metals, for instance, might leach from manufacturing equipment or come from the water used in processes 3 .
These are volatile organic chemicals used during the manufacturing process that may remain in the final product. The International Council for Harmonisation (ICH) classifies them based on toxicity 5 :
| Impurity Type | Description | Common Sources |
|---|---|---|
| Organic Impurities | Unwanted organic chemicals related to the drug substance | Starting materials, synthesis by-products, degradation products from hydrolysis, oxidation, or light exposure |
| Inorganic Impurities | Unwanted inorganic chemicals | Reagents, catalysts, heavy metals, salts, filter aids from the manufacturing process |
| Residual Solvents | Volatile organic chemicals leftover from production | Solvents used in the synthesis or purification of the drug substance or excipients |
Table 1: Classification and Sources of Pharmaceutical Impurities
A fundamental concept in toxicology is that the dose makes the poison. Even substances generally considered safe can be harmful in large quantities, and conversely, potentially toxic substances might be harmless at very low levels. This is why a Threshold of Toxicological Concern (TTC) concept is used, generally setting an acceptable intake of 1.5 micrograms per day for many unstudied impurities to pose a negligible risk .
Some impurities are so potent that they are dangerous even at trace levels.
Since 2018, numerous medications, including those for heartburn and blood pressure, have been recalled due to contamination with nitrosamine drug substance-related impurities (NDSRIs). These impurities, some of which are classified as probable human carcinogens, can form during manufacturing or storage from the interaction of specific chemical building blocks (amines and nitrosating agents) 4 7 .
In a tragic series of events, over 1,300 deaths, predominantly among children, have been linked to contaminated liquid medicines over the past 90 years. A 2025 WHO/UNODC report highlighted incidents where diethylene glycol (DEG) and ethylene glycol (EG)—toxic industrial solvents and antifreeze agents—were illegally substituted for safe pharmaceutical-grade ingredients like glycerin in cough and paracetamol syrups 9 .
Impurities can cause adverse effects or toxicity
Impurities may reduce drug potency
Impurities can accelerate drug degradation
Impurities affect overall product quality
The global effort to detect nitrosamines exemplifies the cutting-edge science of impurity control. Let's walk through a typical experiment a quality control lab would run to screen a drug product for these hazardous impurities.
The first challenge is extracting the trace-level nitrosamines from the complex matrix of the drug product. Scientists use advanced techniques like Solid-Phase Extraction (SPE) or Liquid-Liquid Extraction (LLE) to isolate the impurities and reduce matrix interference 4 .
The instrument compares the signal of the nitrosamines in the sample to a calibration curve created using certified reference standards. These standards, often with ISO 17034 certification, have a known concentration and are traceable to international standards 1 .
A successful experiment will detect and quantify any nitrosamines present at levels far below the established Acceptable Intake (AI) limits. For example, the AI for N-Nitrosodimethylamine (NDMA) is in the nanogram-per-day range. The analytical method must be validated to have detection limits typically at 30% of the AI or lower to ensure a sufficient safety margin 4 .
| Drug Product Sample | Nitrosamine Detected | Concentration Found (ppb) | Acceptable Intake (AI) Limit (ppb) | Compliance Status |
|---|---|---|---|---|
| Sample A: Blood Pressure Tablet | NDMA | 5.2 | 96 | Compliant |
| Sample A: Blood Pressure Tablet | NDEA | Not Detected | 26.5 | Compliant |
| Sample B: Heartburn Tablet | N-nitroso-Example | 15.0 | 10.0 | Not Compliant |
Table 2: Hypothetical Results from a Nitrosamine Screening Test
If an impurity like the one in "Sample B" is detected above the threshold, the manufacturer must conduct a root cause analysis to identify how it formed—whether from raw materials, specific processing conditions, or even the packaging—and implement targeted mitigation strategies 4 .
The fight against impurities relies on a sophisticated arsenal of chemical and technological tools. The table below lists some of the most critical items in an impurity control scientist's toolkit.
High-purity chemical references with a Certificate of Analysis (COA); used to identify and quantify unknown impurities in a drug sample. Often ISO 17034 certified 1 .
Internal standards where atoms are replaced with heavier isotopes (e.g., Carbon-13, Nitrogen-15); crucial for achieving high accuracy in LC-MS quantification by correcting for matrix effects 1 .
A core instrument for impurity profiling. It separates complex mixtures (LC) and provides detailed structural information on molecules (MS/MS), enabling identification of unknown impurities 3 .
Used to determine the exact mass of a molecule and its fragments with exceptional precision. This is vital for confirming the elemental composition of newly discovered impurities 7 .
Certified mixtures used to calibrate instruments like Gas Chromatography-Mass Spectrometry (GC-MS) for detecting and measuring leftover Class 1, 2, and 3 solvents 5 .
Advanced software for data analysis, method development, and regulatory compliance documentation, ensuring accurate interpretation of complex analytical results.
| Tool / Reagent | Function and Importance |
|---|---|
| Certified Impurity Standards | High-purity chemical references with a Certificate of Analysis (COA); used to identify and quantify unknown impurities in a drug sample. Often ISO 17034 certified 1 . |
| Stable Isotope-Labeled Standards | Internal standards where atoms are replaced with heavier isotopes (e.g., Carbon-13, Nitrogen-15); crucial for achieving high accuracy in LC-MS quantification by correcting for matrix effects 1 . |
| LC-MS/MS (Liquid Chromatography-Tandem Mass Spectrometry) | A core instrument for impurity profiling. It separates complex mixtures (LC) and provides detailed structural information on molecules (MS/MS), enabling identification of unknown impurities 3 . |
| High-Resolution Mass Spectrometry (HRMS) | Used to determine the exact mass of a molecule and its fragments with exceptional precision. This is vital for confirming the elemental composition of newly discovered impurities 7 . |
| Residual Solvent Standards | Certified mixtures used to calibrate instruments like Gas Chromatography-Mass Spectrometry (GC-MS) for detecting and measuring leftover Class 1, 2, and 3 solvents 5 . |
Table 3: Essential Toolkit for Pharmaceutical Impurity Analysis
The control of impurities is not left to the discretion of individual companies. It is a globally harmonized effort governed by strict guidelines from bodies like the International Council for Harmonisation (ICH), the FDA, and the European Medicines Agency (EMA) 1 5 . These regulations, such as ICH Q3A-Q3C, provide a comprehensive framework for the identification, qualification, quantification, and control of all classes of impurities 5 .
Pharmacopeias worldwide—including the United States Pharmacopeia (USP), European Pharmacopoeia (EP), and others—are continuously incorporating stricter limits on allowable impurity levels, making these standards legally binding 3 6 .
The field is continuously evolving. Looking ahead, several trends are shaping the future of impurity control.
The industry is moving from reactive testing to continuous monitoring and building nitrosamine risk mitigation directly into the design of new products 4 .
Tragic contamination incidents have highlighted the need for stronger collaboration between regulatory authorities, law enforcement, and customs agencies 9 .
The unseen world of pharmaceutical impurities is a domain where meticulous science saves lives. From the chemist synthesizing a certified standard to the regulator updating a guidance document, thousands of professionals work tirelessly to ensure that the invisible components in your medicine pose no threat, allowing the healing ingredients to do their job safely.