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Carcinogenic compounds have been found in a number of top-selling drugs, leading to recalls and bans. Preventing problems requires working closely with contract testing and development partners as well as API and other suppliers.
Nitrosamines are a group of genotoxic compounds that have been studied widely in the food, water treatment, and chemical industries. In fact, the compound N-Nitrosodimethylamine (NDMA, also known as dimethylnitrosoamine) may be one of the most closely studied carcinogens in the world, noted David Light, CEO of Valisure, an independent analytical pharmacy, who spoke on a webcast on nitrosamine contamination on July 14 (1). First identified as toxic in 1956, NMDA was the topic of a US Senate panel investigation in 1977, and a World Health Organization and United Nations Summit in 1978, Light told attendees at the webinar. Analytical methods have been available to detect the compound and other nitrosamines for over 50 years, he noted.
Yet the pharmaceutical industry was blindsided in 2018, when trace levels of NDMA were found in finished blood-pressure and heart medications, the ARBs (angiotensin receptor blockers) valsartan and losartan and a number of their APIs (2). The problem led to a cascade of product recalls around the world and confusion, as healthcare providers and patients sought substitutes.
This particular set of recent contamination events was traced to a number of problems. One API manufacturer had optimized its manufacturing process yet failed to detect potential chemical synthesis problems that could lead to generation of contamination. In other cases, manufacturers had been using recycled solvents and other materials but failed to work through the potential manufacturing risks.
In September 2019, for very different reasons, NDMA was found in ranitidine and the name-brand drug Zantac. As Ramin (Ron) Najafi, CEO of Emery Pharma, noted during the webinar, ranitidine products had been on the market since the 1980s, and in 2017 ranitidine was the 48th most widely prescribed medication in the United States.
In this case, extensive research verified that the NDMA was not a process impurity, but the result of the ranitidine molecule’s inherent instability, so that it formed NDMA when exposed to high temperatures and humidity. Emery and Valisure both filed citizen’s petitions with FDA (3,4), and Emery developed an ultra high-pressure liquid chromatography-mass spectrometry (UHPLC-MS/MS) method to quantify NDMA down to 1 ng/tablet. Eventually the drug was taken off the market. However, in late 2019 and early 2020, NDMA contamination was found in yet another high-volume pharmaceutical, metformin, used to treat diabetes and a number of other illnesses. Valisure filed a citizen’s petition with FDA to draw attention to this problem in March 2020 (5).
As these events suggest, gaps remain in the industry’s knowledge regarding genotoxic compounds and how they may form in pharmaceutical processes, and how to prevent their presence in pharmaceutical products.
An informal poll of the audience at the July webcast, even if statistically irrelevant, sketched the framework for potential problems. When asked whether their companies had formal quality control (QC) testing procedures in place to test for NDMA and nitrosamines, 32 professionals responded, with nearly 41% saying that their companies had no QC procedures in place identify nitrosamines in their products and process streams. Approximately 16% said that they routinely test all products for nitrosamines, 24% that they test for nitrosamines in some products, and 19% that they only test for products that are in developmental, rather than commercial stages.
Although the agency’s scientists continue to study the problem, FDA has not issued any new guidance on nitrosamines since 2017, although FDA supports the use of the International Council for Harmonization’s (ICH’s) M-7 guidance, a key reference for many in the industry (6).
During the July webcast, Ed Gump, vice president for small molecules with the United States Pharmacopeial Convention (USP), emphasized the need for risk-based approaches to preventing genotoxic contamination. As he noted, the ICH M7 guidance requires identification, categorization, qualification and control of DNA reactive mutagenic impurities to limit carcinogenic risk. A risk level of 1 in 100,000 is currently considered negligible, he said, but where a potential risk has been found for an impurity, manufacturers must develop an appropriate control strategy that leverages process understanding. In addition, analytical controls should be developed to ensure that any mutagenic impurities are present at or below the acceptable cancer risk level.
To this end, Gump suggested, manufacturers of all types must prioritize the evaluation and testing of specific drugs, drug classes, and manufacturing materials that are more likely to contain unsafe levels of genotoxic impurities, using predictive and risk-based approaches. In addition, he noted the need to use an analytical method that has been widely demonstrated to be fit for its intended purpose for testing impurities.
Finally, Gump said, there is a need for greater transparency and more sharing of information within the industry. He sees long term opportunities to harmonize global approaches for dealing with this issue.
In July 2020, USP launched a broad-based outreach program to provide more direction to pharma manufacturers on how they might prevent supply chain vulnerabilities relating to nitrosamines. The organization released six new reference standards designed to support manufacturers and regulators in analyzing and monitoring potentially harmful NDMA and other nitrosamine impurities in the supply chain. USP will soon propose for public comment a new United States Pharmacopeia—National Formulary general chapter standard to provide guidance on assessing materials for nitrosamine presence, establishing control strategies for these impurities and ensuring the performance of analytical procedures to monitor nitrosamine levels in drug products.
Specifically, USP is proposing a new informational General Chapter <1469> Nitrosamine Impurities, which is aligned with current scientific and regulatory approaches for controlling nitrosamine impurities. This chapter provides a science-based approach for identifying and assessing the presence of these impurities in drug products in order to eliminate or reduce levels to help ensure quality as it relates to safety. General Chapter <1469> is scheduled for publication in September 2020 in USP’s online Pharmacopeia Forum, with the goal receiving stakeholder comments to proposed standards, says USP spokeswoman Theresa Laranang-Mutlu. The comment period will be open for 90 days, and stakeholders are strongly encouraged to provide input.
The chapter provides an introductory overview of concerns related to nitrosamine presence and identifies possible sources of nitrosamines in drug products along with observed or assessed risks associated with each source. It also includes a list of nitrosamines of recent concern in the pharmaceutical industry compiled from information shared by multiple global health authorities and input from members of USP’s Nitrosamines Joint Subcommittee.
The chapter would provide recommendations on nitrosamine risk assessment and the development of relevant control strategies to ensure that nitrosamine presence is avoided or below acceptable intake levels. A section on test method performance characteristics provides guidance on the verification process, procedures being implemented in the laboratory, and validation of alternative procedures.
The general chapter would also contain analytical procedures that have been validated or verified in USP’s laboratories and includes examples of quantitative analytical procedures. It also provides a compilation of procedures currently referenced on the websites of FDA and the European Directorate for the Quality of Medicines & HealthCare (EDQM), which users can verify as alternative procedures by meeting the requirements recommended in this chapter, says Laranang-Mutlu.
Focused on predictive tools and approaches, USP has gathered a group of volunteer experts to develop the nitrosamines general chapter, the USP Nitrosamines Joint Subcommittee, chaired by Mark Schweitzer, PhD, global head of analytical science and technology at Novartis, as well as representatives from FDA and the EDQM, which is responsible for drug quality standards in the European Pharmacopeia.
In August, USP will also be launching a new training webinar, “The ICH Q3 Impurity and the M7 Mutagenic Impurities Guidelines.” Designated as an ICH officially recognized training program, it will address the application of the ICH guidelines Q3-A, B, C, D and M7 for controlling organic, inorganic and solvent impurities. It will also aid professionals in developing strategies for dealing with actual and potential impurities that are most likely to arise during synthesis, purification, manufacturing, and storage of drug substances and drug products.
In the meantime, there are some basic steps that companies can take every day to help prevent nitrosamine contamination, says Najafi, who has also been called as an expert witness in a number of cases and has seen scenarios of what can go wrong within a typical company when approaching this problem.
Ensuring that the right staff is involved in the problem is crucial, Najafi says. “The first step will be to employ experienced process development professionals and analytical chemists to oversee any outsourced manufacturing processes, specifically if changes or optimizations are being made at the partner site,” he says, “and it is important to evaluate the entire workflow with regard to use of amines, nitrosating agents, and recycled solvents, and to implement modern analytical testing for nitrosamines at strategic intervals.” He also suggests that the quality assurance department work in tandem with process chemistry and play a complementary role in preventing contamination. “This includes establishing Standard Operating Procedures for change control, frequent audits to ensure compliance, and launching investigations (e.g., during Phase I) when out-of-spec observations are made for impurities, and/or if unknown impurities are detected, however insignificant they seem,” he says.
“It is imperative that ‘for-profit’ corporations strive to increase revenue and implement changes to make manufacturing more efficient. However, the sponsor and the contract partner should collaborate on any such optimizations to ensure that efficiency does not come at the cost of patient safety. For example, recycling solvents is good for the environment and great for the company’s bottom line, however, there is a potential for carryover and new impurity introduction to an established manufacturing process from solvent reuse,” he says. Hence, the recycling process should be thoroughly validated, and stakeholders should incorporate extensive analytical tests for detection of unwanted contaminants that may result, he explains.
He notes problems that he has seen in the field. “Launching investigations is critical to ensuring process quality and compliance to regulatory guidance documents. One of most common errors I see is not conducting a thorough Phase I investigation when needed—companies either outright fail to launch one, do not properly document the process, or come to premature or faulty conclusions that are not backed by data or that lack scientific merit. I have seen all of these being committed by a company recently for a single manufacturing process,” he says.
It is also very important that contract manufacturers involved in multiple APIs and processes pay special attention to equipment cleaning to ensure that processes do not cross-contaminate each other. “Cleaning protocols should be validated, and suitable analytical tests performed to ensure that equipment is residue-free. In another recent example, I have seen a company implement an unvalidated cleaning strategy, and then apply an irrelevant analytical workflow to test for residues. Needless to say, that the company was cited by regulatory inspectors,” Najafi notes.
During the webcast, Najafi offered the following advice. First, to process development chemists: “If you intend to change or optimize manufacturing processes, look for potential development of NDMA. “If any of your processes contain an amine or nitrosating agent, be overly cautious and plan on testing for nitrosamines at every step,” he said.
Quality control departments, meanwhile, should be careful not to dismiss unknown peaks as “ghost” or “air” peaks, Najafi said, while quality assurance teams should be sure to conduct headspace gas chromatography and MS (HS-GCMS) on API routinely and identify all peaks. If the process is new, conduct HS-GCMS tests on the drug product as well, Najafi said.
“Aim to identify every unknown compound. Use HS-GCMS or liquid chromatography and mass spec (LCMS) if available and specifically look for NDMA and related nitrosamines,” he said. Attention to fundamentals is key, Najafi noted, cautioning manufacturing departments to remember that 96 ng of NDMA per pill can disqualify a batch “Proper cleaning of the equipment, and use of clean-in-place is important. One should be cognizant of potential cross-contamination problems,” he said.
Although Najafi joked, “It’s not rocket science,” on the webcast, it is clear that careful work and collaboration are key. New guidance and educational programs aim to address this need within the industry.
1. PharmTech, “Preventing Genotoxic Contamination: Lessons from the Nitrosamine Contamination Crisis,” Webcast, July 14, 2020.
2. A. Shanley, PharmTech 42 (10), pp. 60-64.
3. Emery Pharma Citizen’s Petition to FDA, emerypharma.com, January 2, 2020.
4. A. Shanley, “Problems with Ranitidine May Transcend Manufacturing Issues,” pharmtech.com, Oct. 2, 2019.
5. Valisure, Citizen’s Petition to FDA, valisure.com, March 3, 2020.
6. ICH, ICH M7(R1), Assessment and Control of DNA-Reactive Impurities in Pharmaceuticals, www.database.ich.org, March 31, 2017.
Supplement: Outsourcing Resources 2020
When referring to this article, please cite it as A. Shanley, " Collaborating to Prevent Genotoxic Contamination," Outsourcing Resources Supplement (August 2020).