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By Sophie Bullimore January 30, 2019
regulation
The US agency said a manufacturing problem was the likely source of contaminants
The recall of hundreds of contaminated lots of blood pressure medications last summer has been the subject of an ongoing FDA investigation. Although the agency's investigation is still ongoing and has not identified the exact cause, it has determined that impurities can be generated when specific chemicals and reaction conditions are present in the manufacturing process. the active pharmaceutical ingredient (API) of the drug. Contamination can also result from the reuse of materials, such as solvents.
Global reminder
In the summer of 2018, the FDA was informed of the possible presence of nitrosamine impurities in the angiotensin II receptor antagonist drug (ARA). The impurities of nitrosamine are probably carcinogenic to humans. The findings have highlighted global recalls of valsartan, irbesartan and losartan, commonly used medications for lowering blood pressure.
The original API impurity reported to the FDA was manufactured by Zhejiang Huahai Pharmaceutical (ZHP) in China. The company was then reprimanded for changing the production process without thinking enough about how it would affect the end product. At the time of discovery, the impurity would have been present in the US market for approximately four years.
Findings of the investigation
Although ZHP manufactured the finished drug, it also produced the API for use in other ARA drugs. As a result, many product lines from other companies have been affected.
The companies involved have long been working with the FDA to recall all products posing a risk to humans. These reminders have been ongoing since last week.
There was a voluntary recall of one lot of irbesartan and seven batches of combined irbesartan and hydrochlorothiazide tablets distributed by Solco Healthcare LLC. The API for these recalled drugs came from ZHP.
Manufacturing issues
The investigation has hitherto allowed to infer that an undeclared change in the manufacturing process of the IPA had probably led to this production of contaminants. A recent statement from the FDA said: "Our ongoing efforts have shown that impurities can be generated when specific chemicals and reaction conditions are present in the drug's IPA manufacturing process and may also result from the reuse of materials, such as solvents. . "
The agency has expressed concern that it is unlikely that this type of impurities will be detected during a routine inspection of cGMP. Although the inspections revealed systemic supervisory issues at ZHP, they could have created conditions conducive to the emergence of quality problems.
As part of this investigation, the FDA conducted an badysis and identified specific factors in manufacturing processes that may contribute to the formation of nitrosamine impurities. Prior to the badysis, no one fully understood how these contaminants could form during this manufacturing process.
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Preventive steps
The FDA has announced that it is taking steps to prevent such a situation from recurring. Actions to detect and prevent contaminants.
When detecting a type of nitrosamine impurity, NDMA, the substance has properties that make it difficult to detect in standard laboratory tests, such as surveillance inspections. The agency's scientists have developed and perfected three new test methods specifically designed to detect and quantify NDMA and the other problematic type of nitrosamine, NDEA, in all ARA drugs.
To prevent this type of contamination from recurring, the organic chemists employed by the FDA have been busy identifying the circumstances of the manufacturing process or the modifications made, likely to create this type of impurities.
Incidents similar to these will be addressed as the FDA plans to work with international regulators to create standards to mitigate the risk of this type of chemical impurity, known as "genotoxic" impurity. In March 2018, the FDA issued a guideline for manufacturers offering risk badessments that they can use to badess the presence of genotoxic impurities. It is an internationally harmonized directive in which the agency reviews information on the testing of impurities in product applications during the inspection of facilities. This includes the directive that manufacturers must test known impurities during their manufacturing processes.
The lasting impact
The agency said: "Overall, the risk for each patient remains very minimal, although this does not diminish the importance of this episode nor our concerns. FDA scientists estimate that if 8,000 people took the highest daily dose of valsartan (320 mg) containing NDMA for four years, there could be one additional case of cancer beyond the average cancer rate among these 8,000 Americans.
As a result of the recalls, the drug is starting to see drug shortages on the market. As part of the investigation and next steps, the FDA has badessed the risk of taking the recalled drug for a short time compared to not having access to it at all. Despite the low risk, the agency advised patients to continue taking their recalled medications until their pharmacist offers them a replacement or their doctor offers them another treatment option.
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