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Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.
Confidence in the quality systems and scientific competence of the API manufacturing team is essential.
The presence of the probable carcinogens N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) found in APIs used for the production of a number of generic versions of angiotensin II receptor blocker (ARB) medicines has raised concerns about how manufacturers and regulatory bodies address the potential for production of undesirable impurities (1). The products in question complied with regulations yet contained genotoxic compounds. FDA has taken several steps to address this particular issue (2,3). Drug makers also clearly need to consider what approaches they should be taking to ensure their API suppliers are supplying high-quality material that is safe for use in final drug formulations.
“Despite the fact that manufacturers have the process knowledge and experience that regulatory bodies do not have, we are still dealing with massive recalls of very important medications, the scope of which just keeps increasing,” observes Macniell Esua, chief compliance officer at CordenPharma International.
In this particular case, Esua points out that it appears that a trace impurity in a solvent reacted with a process reagent used, resulting in a genotoxic impurity. “Surprising levels of the impurity are being found in the drug that exceed the levels one might have predicted and that are allowed. One guess is that recycled solvents may be a contributing factor,” he notes. Esua adds that it is critical that the full investigation findings be shared with the industry in an open fashion, so everyone can learn from this potentially tragic situation.
Looking specifically at the issues concerning valsartan, it is also important to note that after the initial recall of drug product containing an API manufactured by Zhejiang Huahai China, additional API manufacturers in China and India had their approvals recalled for the same reason. “The presence of nitrosamines is not only a ‘variation’ problem but has also been shown to be a GMP cross-contamination problem at some of the manufacturing sites involved,” says Rolf Arndt, senior quality assurance and regulatory affairs specialist with Cambrex.
He adds that the fact that different nitrosamines were identified for both APIs and drug products makes the problem more challenging, because the required maximum specification limits of nitrosamines are substantially lower than for normal impurities.
“The issue is not a simple question of ‘approval systems,’ but more a combination of better evaluation of the risks of formation of nitrosamines as well as better analytical techniques; but most importantly, that API manufacturers have sufficient controls within their GMP procedures to avoid cross contamination,” Rolf asserts. “Furthermore,” he states, “Because this field is so fast moving, it is not enough to merely comply with the regulations; it is important to be ahead of them.”
During a process validation exercise related to an investigational new drug, a full fate and purge study should normally be conducted, according to Esua. In the current situation with valsartan and related products, Esua suggests a fate and purge study would have correctly identified NDMA as a potential impurity in the process. “As a result, work would have been conducted to identify the potential risk of introduction of NDMA in the final product and to develop mitigation strategies. Through the change control process, full consideration should have been given to the change in solvent, the potential impurities that the change was introducing, and the downstream implications,” he says. He also points out that this issue is again related to the scientific competence aspect-and whether the study was conducted with sufficient rigor or paid “mere lip-service.”
Any process change must involve a risk assessment that includes a judgement of whether the proposed changes have the potential to result in the production of new or additional impurities, according to Arndt. The assessment should also identify whether there is a risk of formation of impurities that may fall under International Council for Harmonisation M7 guidelines.
“If there is a risk of formation of so-called ‘M7 impurities,’ further investigation must be performed, and the basis to exclude any process change must rest fully on supportive analytical data,” Arndt states. “These types of impurities cannot normally be detected by simple chromatographic methods that are used for ‘related substances’-substances similar to the API, so more advanced techniques must be used, for example, [tandem mass spectrometry] MS/MS,” he adds.
When considering drug process changes, the burden resides rightfully with the manufacturer, according to Esua. It is also the manufacturers’ responsibility to complete a comprehensive scientific review of the proposed changes, with thorough consideration of all possible implications, and a detailed impact assessment as part of the change control process.
“In the case of the NDMA contamination of valsartan, is it known that dimethylamine could be an impurity in the solvent [drug master file] DMF? Yes. Is it known that dimethylamine would react under the reaction conditions to give NDMA? Yes. Where, then, did the manufacturer go wrong? Were dimethylamine levels higher than anticipated in the DMF (since it’s not a typical impurity that would be screened during a DMF solvent release), or was the combination of these two factors (the presence of dimethyl amine and reactivity in the reaction) simply not considered?” Esua asks.
What is important to remember, according to Esua, is that although a regulatory inspection is a tool to measure compliance against current manufacturing regulations, it does not, nor can it, dictate a certain level of scientific competence on the part of the manufacturers, or unfortunately, the regulatory agencies themselves.
So how can drug makers be sure they are selecting API suppliers with the appropriate level of scientific competency? “It is imperative that pharma/biotech companies understand the partners they choose to do business with,” asserts Stephen Houldsworth, director of global small molecules and antibiotics platforms at CordenPharma International. “They must have confidence in the company’s quality systems and its manufacturing team, as well as the team’s scientific competence and ability to make the correct decisions,” he explains.
Houldsworth points out that there are suppliers in the marketplace today that perhaps make decisions based on incorrect assumptions or poor science, the consequences of which are often not discovered until much later, as in the case of valsartan and similar drugs. “Unfortunately, price drives a lot of purchasing decisions-especially in the generic API business-but this cannot be the only priority. Considerations such as quality controls, process development, project management, and scientific expertise must also be factored into these decisions,” he stresses.
The first and most important step is to evaluate and audit the API manufacturer to ensure that it has a sufficient standard of GMP protocols and procedures in place to minimize the risk for cross contamination, according to Jonathan Knight, director of marketing intelligence for Cambrex. The second step is to ensure further evaluation where necessary, such as for potential toxic elemental impurities originating from the environment, the raw materials used for manufacturing, and/or corrosion of manufacturing equipment. “Confirmation is needed that these types of impurities are not present in the API and thus do not impact the product quality,” Knight observes.
In addition, Cambrex suggests reviewing the company’s regulatory history and its corrective actions around observations and GMP compliance and training. Additionally, Knight notes, it is important to assess the company’s experience in developing new chemical entities, and the proficiency and experience of its chemical-development, analytical-development, and quality-assurance departments. That includes checking the investment history of a manufacturer, especially with respect to the acquisition of the most up-to-date analytical equipment.
“Having a good understanding of what the potential risks are can be determined by the development of good design of experiments. In addition, ensuring openness between parties and clear documentation can avoid problems,” Knight adds.
The success of a company’s outsourcing efforts is driven by the quality of their vendor qualification and management systems, according to Houldsworth. “They need to be robust, structured, and detailed to provide a high level of confidence that the API suppliers in question are reliable and competent,” he concludes.
Esua cautions that regulatory agencies should not respond to the valsartan contamination issue with a simple knee-jerk reaction and demand that all process changes must be approved by regulatory agencies before implementation. “Apart from crippling both the manufacturers (via delays in change approvals) and the regulatory agencies (by drastically increased burden of work), this approach would lead to rising costs in an industry that is already under intense pressure from a costing point of view, without any guarantee that problems will be avoided in the future,” he states.
1. A. Shanley, “After Valsartan Recalls, Regulators Grapple with Nitrosamine Contamination in APIs,” www.PharmTech.com, Sept. 26, 2018.
2. FDA, “Statement from FDA Commissioner Scott Gottlieb, M.D., and Janet Woodcock, M.D., Director of the Center for Drug Evaluation and Research on the FDA’s Ongoing Investigation into Valsartan and ARB Class Impurities and the Agency’s Steps to Address the Root Causes of the Safety Issues,” fda.gov, Jan. 25, 2019.
3. FDA, “Zhejiang Huahai Pharmaceutical 11/29/18,” Warning Letter, Nov. 29, 2018.
Vol. 43, No. 4
When referring to this article, please cite it as C. Challener, “Select Suppliers with Demonstrated Expertise to Avoid Sourcing ‘Bad’ APIs," Pharmaceutical Technology 43 (4) 2019.