Dextromethorphan is a common cough suppressant used throughout the world. But, in September 2013, 11 children in Paraguay were admitted to the hospital shortly after receiving cough syrup for their cold symptoms. These children experienced severe breathing problems, hallucinations and seizures — and over the following weeks, dozens of other Paraguayan children were hospitalized with the same alarming drug reactions.

As it transpired, the culprit was not dextromethorphan, but contamination by the drug’s mirror version. Levomethorphan has the same size, weight and chemical makeup as dextromethorphan, but with a reversed structure. This subtle change has major ramifications, as the compound is an opioid five times stronger than morphine. Paraguayan authorities and the World Health Organization (WHO) subsequently traced the defective drug back to a factory in India, which had previously shipped a similarly contaminated batch of cough syrup to Pakistan. "It was ultimately implicated in the deaths of more than 50 people in Pakistan," says Leonel Santos, director of chemical medicines at USP, also known as the United States Pharmacopeia.

Fortunately, close vigilance by manufacturers and regulators mitigates and intercepts most drug impurities before they can harm people. “Issues related to impurities represent a significant factor in drug recalls throughout the world,” says Jaap Venema, USP’s chief science officer.

USP plays a central role in medicine safety. “We design tests and quality standards that help detect and control for impurities at various stages of production, not only in the end-product, but during manufacturing,” Venema says.

However, staying on top of this ever-changing industry is a daunting task, with a steady influx of increasingly sophisticated medicines being developed, manufactured and distributed through a complex web of facilities around the world.

Controlling and detecting impurities

Impurities can creep into drugs at many stages of the manufacturing process. According to Venema, they fit into three major categories. The first are process-related, arising from chemicals or materials used to synthesize pharmaceuticals. The second are product-related, which includes chemical intermediates or unwanted derivatives of a drug, such as the levomethorphan in the contaminated cough syrup, as well as drug degradation byproducts. The third are impurities that are introduced through factors such as poor oversight or quality control.

Virtually every medicine is a combination of an active pharmaceutical ingredient with a host of other compounds, called excipients, which affect how a drug tastes, looks, or is absorbed in the body. Although ‘inactive ingredients’, these excipients must also be carefully policed. “Most medicines taste awful, and saccharin is commonly used to make them palatable,” Venema says. “Saccharin may contain about ten known impurities from some manufacturing processes, and although very few of them are harmful, it’s very important to control for that.”

Pharmaceutical manufacturers are accountable for detecting and preventing impurities. “They are expected to understand the product along its entire manufacturing cycle and life cycle,” Venema says. A key part of USP’s job is to develop monographs based on data that the pharmaceutical industry provides to regulators regarding possible impurities and their toxicities, and produce standards on how manufacturers should test their products to achieve consistent quality. “By the time we get that information, regulators have already invested significant work in safety evaluations and other determinations about what is acceptable in terms of impurities,” he explains.

Quality standards can evolve in response to a crisis, as in the aftermath of the 2013 cough syrup contamination incident. “We revised the monograph so that there was a better tool specified to detect levomethorphan at concentrations as low as 0.1%,” Santos says. “We also developed a reference standard — a substance by which to measure against — to confirm the presence of levomethorphan in a drug.”

Biological byproducts

Biologic medicines, or biologics, also create challenges with respect to impurities. These therapies are produced by living organisms and are based on proteins, nucleic acids, or cells. Therapeutic proteins such as insulin and antibody drugs for cancer and autoimmune diseases fall into this category, which, in 2016, represented 25% of the pharmaceutical market.

Most biologics are produced in large bioreactor cultures of cells, and without adequate purification, host cell proteins (HCPs) naturally produced by the manufacturing cell line can creep into the drug preparation. These HCPs can be toxic or provoke a strong immune response, and USP is developing standards and assays to rapidly detect known high-risk contaminants. “We’ve identified a set of five to 10 HCPs that we will target for reference standard development,” explains Fouad Atouf, head of biologics at USP.

However, the hunt for HCPs is clouded by the fact that not all drugs are produced in the same cells. Contamination is typically detected with panels of antibodies that recognize HCPs from commonly-used cell lines, but these may falter with extracts prepared from alternative cell lines. Even genetically ‘identical’ cells can behave differently depending on culture conditions. “If something changes in the components that you use in the culture system, you may see differences in the kinds of impurities that you generate,” Atouf says.

Cultured cells can also become infected and sick, and manufacturers must be vigilant for viruses, bacteria and other ‘adventitious agents’ that might infiltrate a drug preparation. In 2009, for example, a biologics manufacturer suspended production of a pair of therapeutic proteins at one of its facilities after determining that their producer cells had become infected with vesivirus — a virus that doesn’t infect humans, but can sabotage safe drug manufacturing.

USP and its network of independent volunteer experts work with both regulators and industry to identify impurities and develop quality standards. Credit: USP

A moving target

Quality standards cannot be set in stone, with new classes of medicines continuously emerging and new risks arising from established drugs. For example, although US consumers have been taking acetaminophen since the 1950s, it wasn’t until the early 2000s that regulators discovered the harmful effects of a degradation byproduct known as 4-aminophenol. “It’s a toxin in your kidneys,” explains Venema. “And if you leave acetaminophen in your cupboard for a half a year or longer, there will be higher levels of 4-aminophenol due to degradation, just not to levels that would be considered unsafe.” To address this degradation, USP issued new testing recommendations, and manufacturers set a lower maximum dose to reduce risk to patients.

As technology advances, it may be tempting for a company to explore faster or more efficient manufacturing processes for an approved drug. However, this can also introduce new risks of impurities, which may create the need for new quality standards or testing procedures.  

"There’s a balance to strike when designating testing methods that are sensitive and powerful, but also verified and accessible," explains Clydewyn Anthony, scientific liaison at USP. “We need that balance between what is the state-of-the-art instrumentation, and what is mostly used in the pharmaceutical industry,” says Anthony.

USP is committed to continually advancing quality for public health. As a trusted partner for both regulators and industry, and working with a network of independent volunteer experts, the organization brings together information and data essential for informed decision-making.  “USP is really in a unique spot,” Atouf says. “To identify impurities and develop quality standards, it’s truly about what you can learn through collaboration and data-sharing.”

To learn more about the need for quality standards in medicines, visit The Science of Quality.