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Polpharma API & Waters partnership overview

As the largest Polish manufacturer of APIs, we constantly work to stay ahead of ever-evolving regulatory guidelines on contaminants, most recently detecting nitrosamines in pharmaceutical products. We partnered with Waters, a leading provider of lab equipment, to address this issue. We met the stringent regulatory standards by upgrading our laboratories with liquid chromatography and mass spectrometry (LC-MS) equipment.

The challenge of N-nitrosamines control in API

Like all pharmaceutical companies worldwide, we were impacted by the regulatory guidance that followed the discovery of nitrosamines in pharmaceutical products, which potentially pose a significant health risk to patients. Nitrosamines are potentially carcinogenic / mutagenic impurities found in groundwater, treated water, foods, beverages, and consumer products. As concerns grew about nitrosamine impurities in pharmaceutical products, regulatory agencies have imposed stringent limits on their presence in medications.

Dr. Pawel Olszowy, Head of Analytical Development Section at Polpharma API, explains:
“Adapting to evolving regulatory requirements is an intrinsic part of our journey. With a rich history of engagement in nearly every corner of the globe, we have amassed invaluable expertise in API development and testing, successfully navigating shifting regulatory landscapes. A decade ago, our focus was on genotoxic impurity testing, whereas today, we must diligently monitor a spectrum of contaminants, including nitrosamines. Change is the constant in our domain, and we remain steadfast in our commitment to addressing emerging challenges as they arise.”

Dr Pawel Olszowy, Head of Analytical Development Section at Polpharma API

LC-MS/MS for identification and quantification of nitrosamines

One of the preferred analytical techniques for quantifying nitrosamines is LC-MS/MS because the technique allows for the separation of complex mixtures of impurities from the API itself, excipients, and other matrix components present in the drug formulation, followed by the sensitive detection and robust quantification of trace impurities to beyond regulatory required levels.

To manage the control of nitrosamines impurities in both API and final drug product, regulatory bodies assign a range of Acceptable Intake (AI) limits for N-nitrosamine impurities in the final drug product, which can be challenging. In most cases, limits required a level of sensitivity that only a triple quadrupole instrument could deliver. Procuring such advanced instrumentation and acquiring the necessary expertise to operate them can be challenging for most companies. However, at Polpharma, investing in more sensitive and robust instrumentation to meet these limits and support their supply chain was an easy decision to make.

Mr. Mariusz Kurowski, Analytical Expert at Polpharma API, describes the impact:
“As an API producer, we must always prove that our products are free of contaminants – not only nitrosamines, but all kinds of genotoxins, carcinogens, and other impurities. About 10 years ago, we were focused on testing for genotoxic impurities, which could be done on a single quadrupole mass spectrometer. Nitrosamines require more sensitivity, so when we brought our analysis in-house, we moved to triple quads and MS/MS techniques. These MS systems have become more robust and more precise in terms of the sample integration, injection, and other factors, which offers the capabilities we need for these types of analyses.”

Mr Mariusz Kurowski, Analytical Expert at Polpharma API

With that, we invested in two Waters XevoTM TQ-S micro Mass Spectrometers, which added the ability to deliver consistently low levels of quantitation with a wide dynamic range to other Waters instrumentation. We also use MassLynxTM Security to provide the tools for maintaining 21CFR11 compliance, safeguarding data, and documenting audit trails from acquisition through archiving.

AQbD – future of impurities control in API

With the API development and testing field always in flux, the Polpharma team continues to position itself for what’s coming.

Recent developments from regulators have reframed the initial AI limits for some nitrosamines, known as NDSRIs, increasing the range of limits from ppb up to ppm levels in some cases. This change is supported by instrumentation that offers versatility of detection sensitivity or scope for QDa or other single quadrupole MS where detection limits are higher. However, for Polpharma API, the role of UPLCs with tandem mass spectrometry systems remains clear in method development and identification of impurities and other trace-level applications.

Another significant change Mr. Kurowski sees for Polpharma API future is the increasing focus on Analytical Quality by Design (AQbD), a systematic approach favored by regulatory agencies that can be used in analytical method development to ensure that the quality of analytical results is consistently achieved and maintained throughout the life cycle of the method.

Our team is already working on the tools we need for AQbD, particularly regarding software. The goal is to make the development of an AQbD method as automated as possible.

Of course, our recent investments in the Waters analytical instrumentation will also play a role. The capabilities of the Waters Xevo TQ-S micro mass spectrometers will likely help our team navigate the constant changes in API development and testing.

Waters analytical instrumentation

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