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FDA Guidelines to Manufacturers for Nitrosamine Impurity Risk Mitigation Plan

Ever since the discovery of impurities known as nitrosamine was made in some types of drugs in 2018, the U.S. Food and Drug Administration (FDA) initiated numerous steps including to tackle this threat. It has also launched a thorough investigation to protect patients using these drugs.

Life Science and Technology Consulting Firms in NJ believe that, though nitrosamines are commonly found in water and food, yet if humans are exposed to nitrosamine levels above the acceptable levels for long periods, then the risk of contracting cancer increases. This is the reason why the FDA took this threat seriously and in collaboration with different regulatory bodies has published its guidance to control the nitrosamine impurities in drugs used by humans.

The purpose of implementing these guidelines is to ensure the drugs manufactured are safe and effective for the patients. 

The Guidelines

The FDA has issued a list of guidelines and this checklist will take you through the main points since it is not all-inclusive. These steps outlined below are sufficient enough to provide all manufacturers a base from which to start the nitrosamine impurity risk mitigation plan.

The Starting Point

First of all, starting with each drug substance, an appropriate risk assessment needs to be conducted by utilizing quality risk management tools. All the related risk factors need to be considered during this process.

The Supplier Qualification Program

As far as the supplier qualification program is concerned, manufacturers need to ensure that all the vendors supplying the raw products and other items are made aware of the fact that impurities may be added to the products during the phases of transportation and production.

All the vendors have to be monitored vigorously for any possible raw materials that are deemed to be at risk. This also applies to the starting materials and intermediates. All the documented records of the raw materials need to be obtained from the concerned manufacturers and the suppliers.

In case other manufactures of these materials and supply chain entities were involved in the process, then the relevant documents of those operations must also be requested. This case applies when there were manufacturers and other supply chain entities involved in handling the materials before the API manufacturer.

Another task that needs to be completed is verification of the recovery of the purchased materials after they went through the processes. In case there are at-risk materials, then it is your responsibility to determine if additional controls need to be implemented or if the specifications need to be revised.

Evaluating Incoming Materials

All incoming materials need to be evaluated. This includes all starting materials which tend to contain sodium nitrate and raw materials that may have possibly been contaminated. All other materials ranging from fresh solvents to recovered solvents and potable water need to be evaluated too.

To ensure that a thorough evaluation of the incoming materials is undertaken, the appropriate procedural controls need to be utilized. This will pave the way for materials that contain nitrosamine impurities to be rejected.

Dealing With Lack of Process Optimization And Control

The lack of process optimization and control needs to be identified by focusing on reaction conditions which include the temperature and pH. It also involves identifying the sequence of adding the related reagents and intermediates. You also need to pay attention to the relevant solvents involved in the process.

Evaluating Facilities and Equipment

All the facilities and equipment need to be evaluated to ensure adequate cleaning of equipment through all phases. This includes the phase between the different customers and also between different materials. All processes must be evaluated to ensure impurities are removed.

If you are still uncertain about this step, then it would be better to approach any Life Science and Technology Consulting Firms in NJ to avoid any legal issue.

Analytical Testing Methods Should Be Reviewed

The review needs to be undertaken to ensure the testing of several factors. First and foremost, the established methods must be adopted to keep both the limits of quantitation and limit of detection as low as possible for all those products that require the patients to take a maximum daily dosage.

The validated analytical methods for limits of quantitation (LOQs) must be at the same level as 0.03 ppm or below this quantity.

Furthermore, if there is any risk for the possible presence of nitrosamine impurities then confirmatory testing along with suitable analytical methods must be employed.

Laboratory Controls and Testing

The laboratory controls and testing needs to be evaluated to ensure that whenever a nitrosamine impurity is detected in the confirmatory testing, then a thorough investigation is launched to identify its root cause. Also, all the intermediates need to undergo upstream testing.

Analyzing Nitrite and Nitrosamine Levels In Water

This analysis needs to be carried out to ensure that the water being used is purified and does not contain unacceptable impurities.

Review of Stability Testing Data

This step is necessary to determine the possibility of the nitrosamine impurities level increasing with time and eventually exceeding the acceptable levels.

Developing an Appropriate Control Strategy

This step includes applying specification limits in case you detect a nitrosamine impurity exceeding the LOQ.

Reviewing the Manufacturing Process

The entire manufacturing process needs to be reviewed to determine if the process in any way is susceptible to the formation of nitrosamine impurities. To ensure a thorough review the route of synthesis of all the key starting materials needs to be carried out.

A review of the nitrites in the presence of amines needs to be undertaken while the amines added as reagents and catalysts also need to be reviewed. All those reagents that contain amine functional groups also need to be reviewed.

Bottom Line

Life Science Consulting Firms are dedicatedly helping their clients detect and measure nitrosamine impurities with the physical reference standards. This helps customers or manufacturers compare their test results with the regulations and also comply with the legal standards. In short, consulting firms through their experts help and support manufacturers in adopting proactive measures to protect patients’ health by preventing exposure to unacceptable levels of nitrosamine impurities.

Author: Sarah Anderson

Date: 2021-06-10 14:32:42