The Impact of Complex Global Supply on the Nitrosamine Crisis

When a crisis occurs, hindsight is a great teacher. Any company developing or manufacturing products that impact human health can learn from the recent nitrosamine impurity contamination of angiotensin II receptor blockers (ARBs) by reviewing their own quality processes for risks that could result in a similar contamination issue.

Analytical data should assure confidence in the quality of manufacturing and trigger quality investigations when that data indicates something is not correct.  In fact, analytical testing did eventually identify the presence of nitrosamines in ARBs, but not before the contamination spread to other families of pharmaceutical products. Was this a result of a complex global supply chain relying on a few critical manufacturers?

Today, in light of COVID-19, there are many questions being asked about the current pharmaceutical supply chain and specifically, concerns about business continuity. In the automotive industry, although there is a strong belief in the “just-in-time” supply paradigm, it is now becoming common to develop and qualify local supply chain options, in order to enable business continuity when global supply chains prove unreliable. In the pharmaceutical industry, the drive for lowering cost can introduce risks into the supply chain stemming from a reliance on a limited number of global manufacturers; risks such as disruptions to export and transport systems, as well as compliance and quality issues. Now, most pharmaceutical companies are putting in place new measures to ensure local supply chain options, by reorganizing their corporations or their partnerships just like the auto industry did earlier.

In the case of the nitrosamine impurity crisis, the risks of a complex supply chain resulted in a key product, valsartan API, and a key raw material, recycled solvents, being contaminated with unexpected cancer-causing substances. When the world’s drug manufacturers rely on a small number of raw material providers, scientific assessments of critical product or process changes are essential to assure patient safety because of the amplifying global impact possible from quality issues in one company.

When manufacturing outsourcing occurs, how do leading pharmaceutical suppliers rely on process validation performed by suppliers far from them in a complex global supply chain? Do niche manufacturers, particularly of low value raw materials, have the expertise and equipment to ensure that CMC (Chemistry, Manufacturing, and Controls) changes do not have a detrimental impact on their own product and any other product relying on this material? How many layers of suppliers, each with their own quality system, can a pharmaceutical company effectively oversee to ensure quality in the final marketed product?

The presence of nitrosamine impurities in API was only detected through analytical testing, many years after the initial CMC changes that allowed the formation of nitrosamines, and long after the impurity had contaminated unrelated raw materials and pharmaceutical products. It was eventually discovered when one manufacturer’s analytical assessment of incoming raw material used a more sensitive analytical method than may have been used in the API’s QC release tests, demonstrating the importance of testing raw materials when the supply chain is complex.

Recent FDA inspection reports clearly demonstrate that the agency has concerns about monitoring and controlling the quality of raw materials in complex supply chains. Numerous 483 citations, specifically for over the counter (OTC) manufacturers, call out limited or missing analytical testing of raw materials and an over reliance on certificates of analysis (CoA’s). These certificates are not substitutes for analytical testing unless they are accompanied by good quality assessment and oversight of the raw material suppliers. Specifically, when the raw material or its impurities could be hazardous, like the genotoxic nitrosamines, or di-ethylene glycol contamination of glycerin, it is critical that manufacturers assess such risks and execute appropriate analytical tests.

This nitrosamine example of a complex supply chain, along with other impurity challenges around analytical methods used in Process Development and Quality Control departments, are outlined in a recent on-demand webinar to better understand:

• How regulatory ‘registration’ processes can stifle innovation and improvement of analytical methods,
• How method constraints might hinder the ability to observe potential quality issues, especially when those issues are ‘unexpected’
• How practices labelled as ‘data integrity’ concerns may have a root cause in the same analytical constraints that failed to identify the contamination of ARB medications with nitrosamines.
• How Waters’ analytical expertise can help your scientists and chemists support the quality of your products, be they food, cosmetics, or drugs.

Further learning:

• Webinar: How to avoid the next nitrosamine crisis: 5 lessons to learn about impurity detection
• Webinar: How to develop analytical methods for impurity detection in pharma with a quality by design approach
• Website: Method Lifecycle Management
• Article: Sanofi to spin-out and launch European API manufacturer