Impurity standards for antibiotics relaxed…confusing product recalls

Impurities in clarithromycin and roxithromycin classified as "non-mutagenic"

Several products that were announced for voluntary recalls have since been canceled announcement

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The pharmaceutical industry's concerns have eased as nitrosamine impurities detected in macrolide antibiotic active pharmaceutical ingredients have been classified as "non-mutagenic." However, because health authorities finalized their safety reviews after the testing data submission deadlines, pharmaceutical companies have repeatedly faced administrative confusion, voluntarily recalling products only to reverse the decisions, prompting calls to strengthen the regulatory framework.

The current domestic and international impurity management system underwent a major shift after the 2018 incidents involving the hypertension drug 'valsartan' and the 2019 gastrointestinal drug 'ranitidine,' in which nitrosamine impurities, including the probable human carcinogen NDMA (N-nitrosodimethylamine), were detected.

Moving away from universal regulations and total sales bans, an ongoing management system in which pharmaceutical manufacturers independently evaluate and test risks and voluntarily decide whether to initiate recalls when limits are exceeded has become the global standard.

Under this self-regulatory system, the Ministry of Food and Drug Safety (MFDS) recently classified 'N-nitroso-N-desmethyl roxithromycin,' an impurity in roxithromycin, as non-mutagenic, easing concerns for pharmaceutical companies marketing this active ingredient. This follows the July recognition that clarithromycin's impurity, 'N-nitroso-N-desmethyl clarithromycin,' is non-mutagenic.

"Non-Mutagenic" with no genetic alteration risk... Relaxed to the level of general organic impurities

"Non-mutagenic" means that the impurity poses no risk of damaging human cellular genetic material (DNA) or inducing mutations.

Under current global standards, for 'mutagenic (genotoxic)' impurities carrying carcinogenic risks, pharmaceutical companies must preemptively execute voluntary recalls even if traces exceed a threshold of merely tens of nanograms (ng) per day. Conversely, if additional mutagenicity testing proves an impurity carries no genetic risk and confirms it as "non-mutagenic," it falls under the general organic impurity management standards of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH Q3A/B). As acceptable limits are relaxed by hundreds of times or more, products are effectively freed from quality non-compliance or recall risks.

Safety cases continue across macrolide antibiotics as a whole. Previously, 'N-nitroso-N-desmethyl-azithromycin' and 'N-nitroso-azaerythromycin' in azithromycin were recognized as non-mutagenic, and genotoxicity concerns have now been cleared sequentially for impurities in clarithromycin and roxithromycin as well.

The problem arises within a framework where pharmaceutical manufacturers must independently judge whether to conduct recalls based on their own testing results. Yet, the regulatory authorities' final review schedules for non-mutagenicity exceed data submission deadlines. Pharmaceutical companies that preemptively decided on voluntary recalls under strict, existing interim limits repeatedly cancel recalls once the non-mutagenicity of the impurities is belatedly confirmed.

In fact, JW Shinyak's clarithromycin product, "Lithromycin Dry Syrup 125mg/5mL," initially reported a voluntary recall for exceeding the existing limits, but canceled the recall and resumed normal distribution immediately after the non-mutagenicity determination.

Roxithromycin formulations are following the same footsteps. SamaPharm recently announced a voluntary recall for certain lot numbers of 'Roxithromycin Tab. Sama' currently in distribution; however, after confirming the impurity as non-mutagenic, the company is reportedly actively considering retracting the recall, similar to JW Shinyak.

"Reflecting the purpose of the self-regulatory system"... Administrative flexibility and policy improvements needed

Industry voices together that policy flexibility is required during the review process to preserve the system's core purpose of voluntary quality control and preemptive action by pharmaceutical companies. If premature voluntary recalls take place while impurity safety reviews are still underway, public announcements alone undermine product credibility, creating substantial societal costs from returns and restocking across clinics, hospitals, pharmacies, and wholesale distributors.

An official from the pharmaceutical industry stated, "While an advanced system where pharmaceutical companies manage risks on their own has been established since the valsartan crisis, currently, verifying the mutagenicity of an impurity takes considerable time," adding, "For substances currently undergoing safety reviews, urgent administrative policy improvements are needed, such as deferring data submission or voluntary action deadlines until the final results are released."