Even trace amounts of impurities in medication can spell trouble. Yet, recent research shows that nearly one-third of FDA-approved drugs have faced safety concerns after hitting the market. The consequences are far-reaching, affecting not just patient safety but also the reputation and finances of pharmaceutical companies.

What Are Impurities and Why Do They Matter?

Impurities in pharmaceuticals refer to any unwanted chemicals that remain in the drug after manufacturing. They can come from various sources, including raw materials, solvents, or by-products of the synthesis process. Impurities can also form due to degradation over time, environmental exposure, or interactions with packaging materials.

These contaminants may be present in minuscule amounts, but their impact can be significant. Some impurities are inert, having little or no effect on the drug or the patient. Others, however, can be toxic, mutagenic, or carcinogenic, posing serious health risks. The presence of such impurities can reduce the effectiveness of a drug or even cause adverse reactions.

Regulatory agencies around the world have developed comprehensive guidelines to control and limit the presence of impurities in pharmaceuticals. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) has established guidelines like ICH Q3A, Q3B, and Q3C, which provide a framework for impurity testing and control in drug substances and products.

These guidelines define acceptable limits for different types of impurities and outline the necessary steps for testing and qualification. For instance, any impurity present at a level above 0.1% must be identified and justified, while higher thresholds might necessitate additional safety studies. The goal is to ensure that any potential risks associated with impurities are thoroughly evaluated and mitigated before a drug reaches the market.

Drug Recalls

Between 2001 and 2010, 71 out of 222 novel therapeutics approved by the FDA were flagged for safety concerns. These issues led to three drugs being withdrawn, 61 receiving boxed warnings—the FDA’s most serious type of warning—and 59 safety communications to alert the public.

A striking example occurred in 2018 when various angiotensin receptor blockers (ARBs) were found to contain N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA), both of which are probable human carcinogens.

The presence of these impurities in drugs meant to treat hypertension, heart failure, and kidney disease sparked alarm. Subsequent recalls affected multiple batches of ARBs, including valsartan, losartan, and irbesartan. The concern spread to other medications, with the FDA calling for the withdrawal of all ranitidine products in 2020 and voluntary recalls of the diabetes medication metformin continuing today.

A Global Problem with Deep Roots

The issue of pharmaceutical impurities isn’t isolated. It’s a systemic problem, exacerbated by global supply chains and manufacturing practices. Generic drugs, which make up 90% of prescriptions in the U.S., are especially vulnerable. The manufacturing landscape is international—only 28% of active pharmaceutical ingredient (API) facilities for U.S.-sold drugs were in the U.S. in 2019. India and China, the world’s largest suppliers of pharma products, face less rigorous FDA inspections and impurity standards than in past years, raising concerns about oversight.

Impurities can arise at any stage of drug production. Environmental factors, such as temperature and humidity, and contamination from equipment or degradation over time are all contributing factors.

Different types of impurities have different sources. Organic impurities may come from incomplete reactions, degradation of the active ingredient, or contamination during manufacturing. Inorganic impurities can result from catalysts or heavy metals used in the production process. Each type requires specific techniques for detection and control, often involving high-performance liquid chromatography (HPLC) to ensure purity.

The Path Forward: Rigorous Testing and Quality Control

As pharmaceutical companies navigate this complex landscape, rigorous quality assurance (QA) processes become their best defense. Regular testing of multiple product batches against reference standards—highly characterized materials used to verify a substance’s identity, strength, and purity—is essential.

Preventing impurities in pharmaceuticals requires a multi-faceted approach, combining good manufacturing practices (GMP) with advanced analytical techniques. High-performance liquid chromatography (HPLC), gas chromatography (GC), and mass spectrometry (MS) are commonly used to detect and quantify impurities. These techniques allow for precise identification of contaminants at extremely low levels, ensuring that any potential risks are addressed early in the development process.

Additionally, the industry is increasingly adopting advanced technologies such as artificial intelligence and machine learning to predict and monitor impurity formation. By analyzing vast amounts of data from different stages of drug development and manufacturing, these technologies can help identify patterns and predict potential contamination risks.

If we want progress, we’ll need collaboration between regulatory bodies and manufacturers to ensure consistent and thorough inspections, both domestically and internationally. As the global pharmaceutical market continues to expand, safeguarding consumer health demands more vigilant monitoring and stricter controls.