Is ‘lack of control’ in supply chains the root cause of API impurities?
In recent years, recalls of ‘sartan’ drugs have been on the rise. Treatments like valsartan and losartan, among others, have been both voluntarily and otherwise recalled after trace amounts of the possible carcinogens, N-Nitrosodimethylamine (NDMA), N-Nitrosodiethylamine (NDEA) and N-Nitroso N-Methyl 4-amino butyric acid (NMBA), were found.
These recalls have led industry members to examine both the possible causes of the presence of these impurities and the ways in which they can be mitigated.
In-PharmaTechnologist spoke with Andrew Anderson, VP of business development at ACD Labs, which manages companies with software applications for analytical experiments used to measure attributes of chemical materials.
Anderson explained ways in which processes, as well as regulatory changes, can result or prevent future impurities.
He told us, “When you see things like recalls there are a couple of approximate factors. One is certainly a lack of control over a process, but I think there’s an industry trend that we’re observing where you’re potentially increasing the risk of quality failures and that’s increasing fracturing of supply chains.”
Looking back 20 years, Anderson said drug products were all made "under a sponsor’s company’s umbrella – devoted manufacturing supply.”
“As you look to be more global and more efficient with supply, you will outsource some of your manufacturing work and with that potential lack of control over quality processes, you’re relying a lot on testing in every step in a manufacturing process, especially a fractured one,” he added.
Quality by design is key
While, according to Anderson, processing is a major factor in the creation of impurities, the quality of design measures can mitigate the risk of developing impurities.
The first step in designing a manufacturing process should be quality by design, establishing a risk profile that can then build controls for processing This is important because there is a common trend in pharmaceutical manufacturing to use additives in processes that need to be purged and there need to be standards for purification measures for quality assurance.
“What people should strive to do is either change the process to mitigate the presence [of additives]. Or, if they can’t do that, they have to have a sufficient control measure, in this case, test methods, that detect the impurity and quantifies the amount, such that when you release a batch that may have an impurity you can unequivocally say it’s below a quality threshold,” said Anderson.
Beyond quality by design methods, Anderson told us that root cause analyses are necessary for processing to mitigate impurity risks. As he explained, active pharmaceutical ingredients (APIs) undergo multiple process steps before entering the market, though manufacturers should be able to state wherein an impurity potentially came from if detected – in order to do so, root cause analysis is key, Anderson said.
Additionally, this type of analysis can be a safeguard as regulations continue to change. “Regulatory rules on toxicity and toxic impurities – that’s a changing world,” he explained. “Over time, you may detect classes of molecules that are problematic and then the impurities that exhibit that classification you want to develop control methods for.”
‘Burdensome’ regulations
Anderson compared pharmaceutical impurities to pesticides and related regulations. Just like pesticides, there are a lot of assays that go into the detection and quantification of problematic impurities.
However, this list changes rapidly and regulatory exposure limits are updated at the same speed. Said Anderson, “I’ve seen this happen in food and beverage where a new pesticide was deemed unsafe for humans and the food and beverage companies had to go back to their supply chain and determine where it exists.”
In pharma though, companies need to be able to rapidly assess the entire supply chain to prevent exposing its customers to a toxicology risk if there is not a root cause analysis established.
Regulatory affairs for impurities exist far beyond the possibility of a new compound being deemed toxic. Anderson explained that the exchange of information between regulatory agencies and pharmaceutical companies can be “burdensome and costly.”
The information exchange requires data to be abstracted and summarized. Currently, there is no software or interface that is standardized to do so, he said.
Anderson stated that one thing the pharmaceutical industry has been advocating for in regard to this exchange is a mechanism that can be used to reduce the amount of human interactions with the information.
“By changing the way we interact through data exchange, and implementing quality by design, I think we’re going to have a much better overall efficient process and a higher quality process, and that’s really all you can ask for when it comes to innovation,” said Anderson.
He added, “If we can innovate along those two places I think that’s a really big win.”
