5 lessons learned from the nitrosamine crisis about impurity detection – watch on demand

Any company creating products that impact human health can learn from the recent nitrosamine contamination of heart drugs and look at their own quality processes for anything that could result in a similar contamination issue. Analytical data should have been able to support confidence in the quality of manufacturing and did in fact first identify the presence of nitrosamines, but not before the contamination had spread.

In this important on-demand webinar, Heather Longden, Waters Corporation, discusses key analytical tests, how to improve methods and gain more information about your samples, and how Waters’ analytical expertise can help your scientists and chemists support the quality of your products, be they food, cosmetics, or drugs.

Read on for highlights from the Q&A discussion at the end of the live webinar or register to watch the full webinar on demand >>

Q: What is a USP method for nitrosamine testing?

HL: Yes, most people expect there to be a method for doing every kind of testing and the USP really has methods for products or for excipients or for things that are meant to be in the product. So, the nitrosamine testing is an interesting one, and we have been talking closely with the USP and they are putting together a chapter specifically to call out what needs to be done for nitrosamines, how to approach that, because, really, we don't expect those nitrosamines to be in there. There have been some methods that have been put together by various vendors, experts, and some of the regulators as well, but as far as I know, the USP hasn't decided what they think is the best method for this. So, it's up to people to look at the instruments they have, look at what level they need to get to, and come up with an appropriate method for that. So, I'm afraid there really isn't any USP method yet, but watch out, there will be something soon, I'm sure.

Q: What would be the right technology to quantify nitrosamine impurities? Do labs need high-resolution MS, LC, or GC?

HL: Generally, whenever you want to do an analysis of a very targeted, known compound, then you are going to use an LC or GC with a triple quad mass spectrometer. That's usually the technique of choice to go to for low-level quantitation of known compounds.

It's what's used for any kind of screening test generally, or any quantitation of known pesticides will be done with that technique, and so that's going to give you the lowest levels of analysis that you can reach to. However, depending on where you are in the process, you may not need to get to that level. Obviously, if you are testing final drug products, you might need to be at the very, most sensitive levels. If you are testing, the further that you go towards the beginning of the manufacturing process, the higher the levels that you need to look at. So, for instance, testing solvents for NDMA would probably be done pretty simply with a GC or UV kind of method.

One other caveat in there is that the proposed source of the NDMA in the Renacidin products is actually a breakdown. It's not proven, but that's the proposed source of it and when you put those kinds of compounds, Renacidin, through a GC, it's quite like you are going to be actually creating NDMA during the analysis. So, GC would not be the technique of choice for looking at Renacidin. So, it does depend what compound you are looking at, where in the process you are, and what levels of sensitivity you need to get to.

Q: If the FDA or another regulatory body put out a method, do I still need to validate it? Can I use my method if it's better?

HL: I would look at what I need to do, and if I have a method that is much better suited to the task at hand or has the analytical QBD process as the analytical target profile, I would be using the best method for the job. Even a USP method needs to be verified on your equipment in your lab. So, if there was a USP method, you would still do some level of validation on that method. The methods that you can find by searching the different regulator websites are very useful. They have given you all of the conditions they have used for testing those methods, but just because you see a method on there and just because that lab has validated, you probably do need to validate in your lab on your equipment.

Quite a lot of the methods we have seen on the regulator websites don't even use internal standards and for an MS method, or in particular an MS-MS method, an internal standard is normally the most common thing that you would always do to ensure reproducibility. So, I wouldn't take those methods and just run them without trying to improve them in my own lab, and then validating them. Because you need to do the validation anyway.

Q: How could I know whether to trust a certificate of analysis from a supplier of my raw material?

HL: You need to have very good confidence in the work that either that supplier is doing or whoever or wherever that supplier has outsourced that testing to. They may be outsourcing that testing to a different lab. It'll just create the certificates of analysis and there have just been so many horror stories around this recently.

In one case, I seem to remember a case where they said that the salespeople were writing up the certificate of analysis in the car before they came in to sell you the product. We had a big case just in the U.S. a few weeks ago where there was a lab that was manufacturing dietary supplements and they had outsourced the testing to a lab, and the lab said, “We are not qualified to do GMP kind of testing.” Yet those products were being put out, and certificates of analysis were being done from that lab, even though they didn’t have any awareness of regulatory requirements. So, you really need to do a proper supplier assessment. You know, I have talked about sending auditors to that company, to ask about their data integrity, about their methods and how they validate them, and about the qualification and the training of the people in the lab — everything about how I can trust that data that's coming to me. And if that's the only supplier and you're really not happy with that quality and oversight, you want to get all the data they create, but you're probably going to end up doing your own testing as well.

Q: How can I find out more about the analytical method life cycle approach?

HL: We’re hoping that the ICH guidance comes out soon. There are lots of people who, in the industry, are very involved. We're finally getting into the last mile of a very long race on this. It started around 2004. So, the process of that guidance is evolving, and what that is going to mean when it all gets released and then gets adopted by the regulations, we're waiting in anticipation.

Waters, as I mentioned, we have a website methods.waters.com and if you go there, our pharmaceutical experts are keeping track of new and updated information. We have a lot of interviews and podcasts as well by some of these experts, who are talking about how we think this would change the landscape of the laboratories, and allow people to be able to move on and improve methods and not have to live with really bad methods, where analysts are spending so much time trying to estimate the origin, the chromatographic peaks. Whichever technique it is, we want to be able to improve methods so that we can get more accurate and trustworthy and robust results being associated with the quality of our product.

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