Many blood pressure tablets containing a possible carcinogen have been recalled worldwide during the last three years. While pharmaceutical firms tried to find a solution, they found an altogether new issue: another potentially hazardous chemical is being detected in the same medicines. Here listed are some major callbacks. 

What is the toxic contaminant?

The contaminants were discovered in blood pressure medications that were recalled earlier this year in Canada and Europe. US authorities aided in 2018 recalls of similar medicines contaminated with the potential carcinogen N-Nitrosodimethylamine, or NDMA, but they have not yet recalled any for having azido impurities. We already described the medicines containing NDMA in the article- 4 commonly-prescribed medications found to contain carcinogenic poison

Connection with India 

Meanwhile, according to papers seen by Bloomberg, a US Food and Drug Administration investigator discovered that at least one major producer in India had a faulty method for managing contaminants. According to the papers, the lab also failed to properly verify that a residue of contaminants does not accumulate on manufacturing equipment, which may cross-contaminate future batches.

The FDA inspector spent ten days in August at the lab's manufacturing facility in south-central India. The facility produces the active component for valsartan, a blood pressure medication, which it sells to other pharmaceutical firms for further processing into a completed tablet. The manufacture of valsartan may result in the formation of azido impurities. Requests for comment were not responded to by the business.

Medications on radar

The regulatory body for pharmaceuticals, Health Canada in May, recalled valsartan, a medication classified as an angiotensin II receptor blocker, or ARB, due to high levels of azido contaminants.

Other medicines in the same family, losartan and irbesartan, were recalled in the following months due to the presence of the same contaminants.

1. ARBs were recalled in the United Kingdom in June and August, respectively, according to the country's Medicines and Healthcare products Regulatory Agency. According to emailed responses to a list of queries from Bloomberg, the MHRA is aware of three possible azido contaminants in cardiac medicines. Other European nations, including France, Switzerland, and Ireland, have also recalled ARBs containing azido impurities.
2. Some irbesartan-containing products were withdrawn in Canada in June due to high levels of azido impurities but continued to sell some of the same products in the United States. The drug manufacturer which made the recall is nearing the completion of testing for all batches of irbesartan-containing medication manufactured between 2018 and 2020.

Most have not exceeded the permissible amount of azido contaminants. According to the spokesman, the firm intends to work with health authorities in mid-October to recommend recalls of any non-conforming batches. According to the spokesperson, the impurities are a by-product of a prior manufacturing method, and irbesartan has not included unacceptable amounts of azido impurities since January.

1. Another manufacturer recalled 40 batches of ARBs in May and has now expanded the recall to 49 batches of specific losartan tablets. According to an emailed statement from a representative for the parent firm, the medicines' active component was manufactured by another business, but the company was not identified.
2. Both pharmaceuticals were also engaged in another significant recall in 2019 involving NDMA-tainted medicines, which resulted in the withdrawal of the heartburn treatment Zantac and its generics from the market.
3. Valisure, a New Haven, Connecticut-based independent testing facility, identified NDMA in the medicine and alerted authorities. Ranitidine, the active component in Zantac, was discovered to convert to NDMA over time or when kept at elevated temperatures. Zantac was not the first recall involving NDMA or similar compounds, which are classified as nitrosamines. Metformin, a commonly used diabetic medication, was recalled last year due to NDMA contamination, while all lots of Chantix, a smoking cessation medication was withdrawn last month due to the presence of a nitrosamine.

The lab in question provided the active component to many businesses who were forced to recall their products due to the presence of NDMA and other related compounds. While the recalls began that year, authorities and industries discovered further contamination in the blood pressure medications valsartan, losartan, and irbesartan, resulting in recalls that lasted almost two years as contaminated medicines were found. The NDMA was most likely generated during the process of producing the active components, but drugmakers and regulators were unaware of the issue for many years.

The FDA refused to comment on whether it has discovered medicines containing azido impurities or on whether it expects any recalls in the United States.

The lab's manufacturing facility in the Sangareddy region is one of ten sites in India registered with the FDA to assist in the manufacture of medicines marketed in the United States. It was last inspected in 2018 and earned the agency's lowest rating, which indicates the business is likely to have difficulty obtaining FDA permission to manufacture new medicines there unless it resolves its problems.

However, the FDA usually permits firms with a lengthy list of infractions resulting from inspections to continue manufacturing medicines at inadequate facilities while they try to resolve their issues.

Additionally, the papers indicate that a substance employed early in the medication manufacturing process contributes to the formation of azido contaminants. While the lab's manufacturing standards require that material be kept to a specific level to prevent creating unacceptable impurity levels, the FDA papers indicate that the company's research used to establish that safe level is flawed.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author is a practising super specialist from New Delhi.