PowerPoint Presentation

Hi everyone regulatory team is back with regulatory Flash.

Today we are going to learn the new topic, Nitrosamine Impurities.

today we are covering the point as per the nitrosamine structure.

Global Concern & Potential Risk N-nitrosamines in drug products is global concern. Excipients are considered as a potential risk factor during the drug product risk assessment. The most substantial risk for the presence or formation of N-nitrosamines in medicinal products comes from the confluence of three factors: a nitrosating agent, a secondary or tertiary amine, and appropriate conditions (eg. elevated temperatures, acidic conditions).

What is N-nitrosamine Impurities ? N-nitrosamines (nitrosamine) are a class of organic compounds that are associated with mutagenic carcinogens. Nitrosamine are formed by the reaction of secondary amines, amides, carbamates, derivatives of urea with nitrite or nitrosating agent.

We'll be looking at the General root causes of Nitrosamine impurities.

First Formation of Nitrosamine in Drug product Formation of nitrosamine is possible in the presence of secondary, tertiary, or quaternary amines and nitrite salts under acidic reaction conditions. Now lets see the Representative reaction to form Nitrosamine. Let us understand the stepwise formation in detail

[Audio] Nitrates can be reduced enzymatically to nitrites. In mildly acidic conditions, the nitrite can form reactive species nitrous anhydride, or N2O3. Nitrites and nitrates present in excipients can act as nitrosating agents, which can then be transformed into N2O3 in certain environments, such as high temperatures or acidic media..

Second point Sources of Amines Amines may be present in manufacturing process for various reasons & may also be added intentionally as reagents or catalysts. All of these types of amines can react with nitrous acid or other nitrosating agents to form Nitrosamine. Let see the Formation of NDMA from N,N-Dimethylformamide

Third point Contamination in Sourced Raw Materials Nitrosamine impurities can be present when sourced materials, including starting materials and raw materials, are contaminated. Below are few potential root cause. 1. Contamination can occur in water used during manufacturing. 2. Nitrate/Nitrite containing raw materials, such as Azo dyes may lead to nitrosamine impurities.

Fourth point Lack of Process Optimization and Control Another potential source of formation of nitrosamine impurities is lack of optimization of the manufacturing process for APIs when reaction conditions such as temperature, pH, or the sequence of adding reagents, intermediates, or solvents are inappropriate or poorly controlled. * Deviation/Error in process optimization & Control can lead to the formation of nitrosamines, due to present of nitrite. FDA has observed instances of Deviations/Errors in which reaction conditions varied widely between batches and even between different processing equipment in the same facility for the same API.

Lets check the Acceptable limits of Nitrosamine Impurities

[Audio] The United States Food and Drug Administration (FDA) has released the recommended acceptable intake limits for six nitrosamine impurities, NDMA, NDEA, NMBA, NMPA, NIPEA, and NDIPA, in nanograms per day. A table of these limits is available..

Now lets see what our ACG Capsules speak on Nitrosamine impurities. Capsule manufacturing is a physical pin moulding process which does not involve any chemical reaction. Capsules are made up from Gelatin & HPMC. Gelatin which contains various amino acids & HPMC which is synthetic polymer. There are no acidic conditions, solvents or nitrosating agents used during manufacturing of capsules which may rule out formation of Nitrosamine impurities. * * Capsules containing Azo dye colorant when comes in contact with Nitrate/Nitrite containing API can lead to formation of Nitrosamine.

The ingredients used in the manufacturing of our product “Hard Gelatin Capsule Shells & Cellulose Capsule Shells” does not contain the Nitrosamine impurities. Therefore, there is no risk of presence of Nitrosamine impurities in our “Hard Gelatin Capsule Shells & Cellulose Capsule Shells”.

Based on the information, we have prepared a questionnaire based on IPEC guidelines on Nitrosamines for our Hard Capsule Shells. This will enable us to perform a comprehensive evaluation of the potential risks and take the necessary steps to ensure the safety and quality of our products.

The Regulatory Affairs department is available to answer any questions regarding N-nitrosamines. You can reach us at regulatory.acpl@acg-world.com. We appreciate your attention.