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The Role Of EMA And FDA Regulations In Controlling Nitrosamine Impurities

Both the FDA and the EMA moved to revise their regulations regarding the medicinal products containing nitrosamine impurities.

In September 2019, the EMA swiftly moved to issue an advisory to the Marketing Authorization Holders or the MAH of human medicines to review its drug products. The review was authorized on account of the possible presence of nitrosamines, an impurity, in certain drug products, which could harm the human body.

The directions for the test were given to detect the presence of nitrosamines in certain drug products. The advisory also involved conducting a risk assessment and proactively testing all products which were deemed to be at risk.

The EMA hoped to counter the threat of the presence of nitrosamine impurities in certain drug products to secure human health. The goal was obviously to protect patient health by increasing the safety of human medicines.

The US Food and Drug Administration (FDA) was not indifferent to the matter and was already investigating the subject of nitrosamine’s presence in drug products. As a result, the FDA issued its guidelines for industrial control of nitrosamine impurities on September 1, 2020.

How It All Started – What Made The EMA And FDA Act

The year was 2018 when the concerned authorities detected an impurity known as nitrosamine in a batch of valsartan. Valsartan is a product produced by a Chinese manufacturer and helps regulate blood pressure. This is an active pharmaceutical ingredient (API), which has been formulated into a drug product for human use.

The exact impurity identified in certain Valsartan APIs was known as N-nitrosodimethylamine (NDMA), a potential carcinogen substance. As soon as this realization dawned upon the regulating bodies, several regulatory warnings were issued followed by the recalls of certain contaminated products.

However, the threat was not restricted to just one product as this same impurity was also detected in ranitidine, nizatidine, and metformin. This led to several products being recalled from the market followed by the imposition of strict regulations regarding the manufacture of these products.

How The EMA And FDA Perceives The Nitrosamine Impurity

Though the nitrosamine impurity does not form during the manufacturing phase of the majority of medicines and is only found in small amounts of drinking water and some food products, yet the regulating bodes deemed the threat to be significant. The regulating bodies felt the need to address the presence of nitrosamine impurity urgently as it is a carcinogenic substance. If human bodies are exposed to this substance above a certain level for longer periods, then it may lead to an increase in the risk of cancer.

Hence, both the FDA and the EMA moved to revise their regulations regarding the medicinal products containing nitrosamine. Resultantly, this led to the requirement of mitigating the risk of the presence of this potential cariogenic substance.

Subsequently, the EMA authorized the revising of all drug products that contained chemically synthesized APIs and other biologically active substances as ingredients. The FDA was not far away as it directed the evaluation of chemicals and other drugs that may be at a risk due to the presence of nitrosamine.

What Obligations Have Been Imposed By The EMA And FDA On MAH?

Significant changes in the regulations for all marketing authorization holders have been introduced. One of these regulations now requires the review of all products used by humans for possible risks of containing nitrosamines. The relevant regional regulations apply to these reviews.

As a result, the European Union directed for all risk assessments to be completed by the 31st of March, 2021 for chemical substances. The deadline for risk assessments of biological medicines has been set for the 31st of July, 2021. The US required the risk assessment to be completed before March 1, 2021.

All those products that have been identified by the authorities to possibly contain nitrosamines now need to be tested immediately to quantify these impurities. Validated analytical testing methods have to be utilized for this purpose. It is also mandatory to notify and inform the authorities about the relevant tests.

The FDA had released detailed steps to detect and prevent the inclusion of nitrosamine impurities in drugs and other pharmaceutical ingredients.

Since the finding of nitrosamine impurities was unexpected, the new regulations had to be introduced and enforced by both the EMA and the FDA out of the blue.

There is a strong possibility that adjustments may be required in the manufacturing process to control the levels of these impurities. This may be also be followed by an adjustment in product specifications.

If you are a drug manufacturing company in New Jersey and still unsure about the steps your company needs to adopt for compliance with these regulations then you may approach any of the recognized Life Science Consulting Firms in NJ.

The Future Implications Of EMA And FDA Regulations

In case nitrosamine impurities are detected in any medicines, the MAH is bound to inform the authorities immediately. This will be followed by the adoption of the appropriate regulatory actions to control the levels of these impurities.

Furthermore, after a lapse of three years following the publication of guidelines, it is mandatory to submit the required changes to the drug product. The deadlines for the USA and the EU have set for September 1, 2023, and September 26, 2022, respectively. However, the EU has approved special extensions for biological medicines and the deadline in this regard has been extended until July 1, 2023.

So both the EMA and the FDA have responded to the possible threat to human health on account of the presence of nitrosamine impurities in drug products by imposing a deadline for the completion of risk assessment of these drugs. Furthermore, both the regulating bodies recommended immediate confirmatory testing for these drugs and products that have been designated as high risk.

Hence, both the EMA and FDA have played an important role in controlling nitrosamine impurities through regulations. As a result, the threat to human health from these impurities in certain drug products will eventually be addressed comprehensively in the future.

The Role Of FDA And EMA Regulations In A Nutshell

The purpose of these guidelines by the FDA and the EMA is to control the levels of nitrosamine impurities in these chemical products and drugs so that an acceptable low level is reached. The deadlines as mentioned above have already been set.

The drug manufacturers are now required to undertake the confirmatory testing of the drug products identified for possible risk. The results will have to be submitted to all the relevant regulatory bodies with the necessary revisions to drug applications. The revisions have to be designed to control the levels of nitrosamine impurities.

How To Ensure Compliance With The New Regulations

As one of the leading Life Science Consulting Firms in NJ, we help our clients identify possible NDMA traces in drug products and raw materials. We help protect patients and increase the safety of all medicines. We also assist our clients in ensuring regulatory compliance. Contact us today for assistance in these matters. We will help you transition through the challenges arising as a result of the new FDA and EMA guidelines and take care of all complexities that you may find demanding to address.

We also help our clients enforce the right measures that will guarantee the satisfactory quality of finished products which includes ensuring the safety of the active substances and other ingredients used in the manufacturing process. We actively assist in adherence to the published guidance through our vast knowledge of the manufacturing processes for drug products. All relevant scientific evidence is always introduced and enforced.

Author: Sarah Anderson

Date: 2021-06-04 19:14:20