I need your knowledge ragarding potential risks of nitrosamine formation during manufacture and storage depending on the dosage form. Assuming we have nearly the same bill of materials, one formulation is an oral powder manufactured involving a wet granualtion step and acids, and one formualtion is a soft gelatine capsule, manufactured in solution and temperatures above 40°C without acids. What do you think: in which dosage form would you expect more nitrosamines? Many thanks for your feedback!
Ultimately it comes down to a few things including:
presence of nitrites
pH
temperature
presence of water
Predicting which formulation is “most likely” to form nitrosamines is likely to catch you out at some point, potentially even with the knowledge above.
In your case, without knowing the exact formulations involved then it is very difficult to make a prediction. Materials used in powder formulation can have higher nitrite levels than those potentially used in a soft gel. The wet granulation is possibly aqueous, and potentially involves heat in the drying process. Your soft gel may be a bigger dose format and so have higher levels of excipients in the formulation to provide nitrites.
In reality, at this moment in time, I don’t feel that anyone can adequately and accurately predict whether or not there will definitely be nitrosamines present in most solid/semisolid dose formats.
If you have identified a risk for both formulations then I would test both, and I would also recommend keeping an open mind to any differences in levels you may see between the different formats, and look for reasons why.
This situation is similar to what we experienced with Metformin IR versus ER. If the formulation and the final product differ, then a separate risk assessment must be conducted. I agree that there will be considerable overlap, but one cannot substitute one assessment for the other.
Vielen Dank für Ihre Antworten. Mir ging es tatsächlich nur um den Herstellprozess und ob Sie ein höheres Risiko bei der Nassgranulierung sehen (Wasser, Temperaturen ca. 60°C) oder wenn die APIs mit den Nitriten aus den Hilfsstoffen in Lösung sind und auch bleiben (Prozesstemperaturen ca. 50°C). Natürlich kommt es auch noch auf weitere Bedingungen an. Bei der Naßgranulierung sind auch Säuren vorhanden, bei der Weichkapselherstellung nicht.
I agree with everyone that the truth is we won’t know without actually measuring, but reading the paper by Moser et al. may help in understanding which factors influence nitrosamine formation.
N-Nitrosamine Formation in Pharmaceutical Solid Drug Products: Experimental Observations
Based on circumstances you have mentioned; Solid dosage form with lower pH, high temp. processing condition, high processing time, (considering Powder must involves milling). All the factors indicates there is much more possibility of formation of nitrosamine even if having similar bill of material because the factors affecting Rate of nitrosation is high in oral solid dosage form than soft gelatin capsule. It might possible that value of nitrosamine observed at 1 month CRT in solid dosage form will be apparently appears after 3-4 month or later time point in soft gelatin capsules. At relase stage if confirmatory testing performed then difficult to conclude.
100% could not agree more. Without getting further into the details than I should, I was bit on this. I presumed that since the only high temperature step was in an extremely non-polar solvent, this was the only step with notable nitrite levels, and that the hold time was short, little to no formation would occur. Boy was I wrong.
My two takeaways are: (1) The big issue is nitrite movement. Always consider the microenvironment surrounding the API. How far does the nitrite need to travel to contact the API & how much available water is there to transport that water? (2) Different APIs react with a different activation energy or temp. This product is rock solid at room temperature, but even after processing, if you raise it to 50C, all of the nitrite will react with the API within 48 hours. For other products, this process took weeks.
Again, without knowing the structure of the API, it is tough to predict. If this is a secondary amine, the oral powder may be highly risky. Remember, that the surface area being more in the finished dosage form, it would also react with the oxides of nitrogen in the atmosphere. Gelatin capsules on the other hand carry a risk of having nitrites. But even as a dosage form, a capsule is more marketable than oral powder. So, go for the capsule. Add a scavenger if needed.
regarding the difference in the nitrosation reaction, in one of our products the rate of conversion reaction is continuing and after 18 months almost stable, while in the majority of other cases, a plateau is being reached between 6-12 months.