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September 26th, 2022 for chemical medicines
Let Quantum Analytics Group, Inc. support your company by:
- Clarifying the regulatory requirements in relation to nitrosamines
- Qualifying your risk assessment
- Providing the appropriate testing
- Interpreting the information for FDA review
The Formation of Nitrosamine Impurities in API and Finished Dosage Forms
A discussion on potential root causes
Organic impurities, can originate from various sources and from various phases of the manufacture of API and the preparation of pharmaceutical dosage forms. Impurities formed may be the result of the synthesis pathway, overall manufacturing processes or degradation products.
The differentiation between synthesis-related impurities, process-related impurities and/or degradation products is not always possible. There may be several possible synthetic routes for the preparation of the same AP, especially when it comes to generic drugs.
Degradation products may be formed during synthesis and isolation of the end-product API. Degradation products may also form during storage of the API, and especially during formulation and storage of the finished dosage form. Furthermore, impurities not previously identified may subsequently be found as measurement technologies improve, with improvements in analytical sensitivity resulting in the ability to measure at even lower levels.
The discovery of theretofore unknown organic impurities as a result of improvements in analytical sensitivity from synthesis pathway, overall manufacturing process or degradation products is not new. Over the years, a number of API and finished dosage forms have been the subject of the discovery of the presence of unknown organic impurities of potential concern, whose discovery was made possible by improvements in analytical sensitivity. Consequently, the discovery of nitrosamines, and the potential toxicological concerns and impact, in certain API and finished dosage forms at very low levels has been made possible by these improvements.
Since the 1950s, nitrosamines in food has been of interest, particularly due to their potential carcinogenic properties. Nitrosamines and/or their precursors can be found in a diverse range of products such as processed meats, alcoholic beverages, cosmetics, elastomers, cigarette smoke, and more recently in drug products. They can also form in the mouth or stomach if the food contains nitrosamine precursors. Under the acidic pH in the mouth or stomach, nitrite or nitrates added to food or naturally occurring may combine with any amines present to form nitrosamines.
There are a 5 potential root causes
for the formation of nitrosamine impurities in API and finished dosage forms. These include:
- Synthesis pathways
- Raw materials, recycled solvents, reagents and catalysts
- The quenching process
- Process optimization
- Storage conditions of the API and finished dosage form
Nitrosamines formation is possible in the presence of secondary, tertiary, or quaternary amines and nitrite salts under acidic reaction conditions. There is a greater risk of nitrosamine formation if nitrous acid is used to quench residual azide in the presence of precursor amines. Nitrites used as reagents in one step can carry over into subsequent steps and react with amines to generate nitrosamine impurities. When present, Nitrite salts can carry over into subsequent steps and react to generate nitrosamine impurities.
In general, processes that use nitrites in the presence of secondary, tertiary, or quaternary amines are at risk of generating nitrosamine impurities.
Nitrosamine impurities can be introduced from vendor supplied materials, including starting materials and raw materials, which are contaminated. For example, sodium nitrite is a known impurity in some starting materials and when present, can react with amines under acidic conditions to form nitrosamines. Other nitrate-containing raw materials, such as potassium nitrate, may contain nitrite impurities. Fresh solvents, such as toluene, may contain secondary or tertiary amines as impurities.
Nitrosamine impurities can be introduced from vendor supplied materials, including starting materials and raw materials, which are contaminated.
Recycled/recovered solvents, reagents, and catalysts may pose a risk of nitrosamine impurities due to the potential presence of residual amines, such as trimethylamine or diisopropylethylamine. Where the recovery process involves a quenching step, as with nitrous acid used to decompose residual azide, nitrosamines may form during solvent recovery. These nitrosamines may be entrained, thus further increasing the risk of contamination in material recovery.
Recycled Solvents, Reagents and Catalysts
Residual amines, such as trimethylamine or diisopropylethylamine are a cause for concern.
When a quenching step is performed directly in the main reaction mixture, such as when nitrous acid is added to the reaction mixture to decompose residual azide, formation of nitrosamines can occur. This step results in nitrous acid coming into direct contact with residual amines in the raw materials used in the manufacturing process. With the nitrosamine impurities formed being carried to subsequent process steps. If there are not adequate removal or purification operations in place, or the process optimized for removing specific impurities of concern, the entire downstream process can be contaminated with nitrosamines.
Another potential source of formation of nitrosamine impurities involves the control of critical process parameters such as temperature and pH, and the sequence of adding reagents, intermediates, or solvents. When there is a lack of optimization or poor control of the manufacturing process for these parameters, conditions favorable to the formation of nitrosamines can exist. Failure to effectively control these parameters can result in widely varied conditions resulting in different nitrosamines in different amounts across batches from the same process with contamination detected in some batches but not others.
In view of the potential sources of nitrosamine impurities formation, manufacturers should evaluate each part of their manufacturing process for the potential of nitrosamine formation. In support of the risk assessment, testing a representative number of samples of the relevant starting material, intermediate, API or finished product should be conducted.
Manufacturers are challenged to “test every batch” to help rid the supply chain of unwanted methanol.
If you are a manufacturer who regularly uses ethyl alcohol in your production process, you’ve undoubtedly received statements regarding the new testing requirements mandated by the USP.
Methanol has found its way into the ethanol supply chain and the new regulations will change the way your company works. Annual or spot-testing has been replaced with a scenario where testing every batch is the new normal in the face of this new threat.
QUANTUM Analytics Group provides accurate, efficient and consistent testing for a wide variety of manufacturers including cosmetics, flavor & fragrance, OTC pharmaceutical, medical device and private label contractors.
Whether you use a few gallons a week or thousands of gallons a day, QUANTUM can manage your methanol tests and safeguard your production process timelines. Let us know how your processes are affected by the new regulations. Call 866-840-6948 to speak with one of our experts.
INSIDE ADVICE #1
It may seem obvious, but you’d be surprised how many companies miss this simple strategy when faced with the new “test-every-batch” scenario. You might be used to buying alcohol one gallon at a time. But you’ll pay to test each gallon. Consider moving up to a 55-gallon drum and pay once to test the entire drum. Quite simply – with these new regulations…buy in bulk!
Food Contamination Today: Not just heavy metals
A recently released congressional report found heavy metals in some popular brands of baby food. Read the Report
Arsenic, cadmium, lead and mercury have dominated the news for the past few months when elevated levels were found in some batches of baby food. But while the FDA struggles to place new standards and limits in lieu of this seemingly rare occurrence of the big 4, a much broader issue faces food and beverage manufacturers on a daily basis.
60 years ago the industrialization of farming began. Since then, global pesticide use has grown steadily to 4.1 million tons per year in 2017, an increase of nearly 81% from 1990. Countless tests have proven that humans and animals have been exposed to increasing levels of chemical contaminants and although they are beneficial for crop production extensive use of pesticides can possess serious consequences due to their bio-magnification and persistent nature. Today there are nearly 1,000 pesticide ingredients registered in the U.S. and many are produced at increasingly higher toxicity to stay ahead of poison resistant weeds and insects.
Pesticides don’t make headlines every day...
Pesticide contamination is a constant concern for food and beverage manufacturers. Maximum residue levels for a specific pesticide chemical that is permitted in or on a specific human or animal food can change overnight. And the media storm associated with warning letters, fines or a re-call from the EPA for non-compliance is detrimental.
Finding pesticide residue is more difficult – here’s why
Food product contamination (including the big four and some 800 registered pesticides) comes from some combination of 3 main sources; biological, physical or chemical. Currently, many food manufacturers have internal staff with instrumentation that can identify a certain pathogen (biological) or target a defective closure (physical). Detection of chemical contaminants, however, can be much more complex. It takes improved systems and techniques to achieve reliable ppm or ppb detection along with a high level of experience with sample prep and adoption of a rigorous method.
Top categories of pesticides that have affected our food chain for decades
Organochlorine pesticides like DDT, methoxychlor, dieldrin, chlordane, toxaphene, mirex, kepone, lindane, and benzene hexachloride are chlorinated hydrocarbons that were used extensively from the 1940s through the 1960s in agriculture and mosquito control. Most have been taken off market, yet some are still registered for use in the US.
Organophosphorus pesticides include malathion, parathion, diazinon, fenthion, dichlorvos, chlorpyrifos and ethion. These chemicals account for a large share of all insecticides used in the United States. The residues of OPs are found on fruit trees, grains, cotton, sugarcane, lettuce, and cabbage and other vegetable crops.
Herbicides like Glyphosate and Atrazine. The active ingredient in the herbicide Roundup, which was made by Monsanto (now owned by Bayer). It is by far the most widely used pesticide in the world. It can now be found in the majority of rivers, streams, ditches and wastewater treatment plants, as well as in 70 percent of rainfall samples.
Hexachlorobenzene was introduced in 1945 as a fungicide for crop seeds, and is now found in all food types. It was banned for agricultural purposes in the EU as of 1981. Unfortunately it is still used as an industrial chemical and is released to the environment through waste incineration and a host of other high temperature, poor combustion processes. Worse still are highly toxic chlorinated dibenzo-p-dioxins, chlorinated dibenzofurans, and polychlorinated biphenyls with the major route of human exposure through our food supply.
Surprisingly, many pesticides that were outright banned or in the process of phasing out in the EU, China and Brazil are still widely used in the USA, at the level of tens to hundreds of millions of pounds annually.
Most pesticide residue issues are solved with little fanfare
Over 40 years ago, Quantum Analytics Group was hired by a major baby food manufacturer to test apples used in baby food for trace levels of Ethylene Dibromide – used as a pesticide and fumigant for grains and fruit, water-proofing preparations and an ingredient for anti-knock gasoline mixtures.
We tested raw, whole apples as well as finished product (apple sauce) utilizing GC analysis with electron capture/Hall detector and then double-confirmed with GCMS.
Our analysis concluded that the apple skin had EDB residue resulting in a noticeable level of EDB in the finished product – but not at levels that were deemed dangerous by the EPA at the time.
Ultimately, EDB was removed from use as a soil fumigant in the United States in 1983 but still used in other applications.
An increase in recalls
Last year, the USDA found 58 percent of foods sampled had detectable pesticide residue. There were 337 food recalls in 2019… and 363 in 2020.
Growing numbers could suggest that more companies are voluntarily recalling their products as soon as a potential public health threat surfaces, a trend that is likely related to the Food Safety Modernization Act (FSMA), a 2011 law that gave the FDA more powerful enforcement mechanisms.
“Some of the most glaring food safety headlines of the second quarter (of 2020) were fueled by food safety and public health advocates who continue to pressure companies and regulators alike for more safeguards,” the Recall Index reports.
“We’re used to seeing their perspective in the media, but in some cases, they’ve turned it up a notch.”
FDA employs a three-fold strategy to enforce EPA’s tolerances for pesticide chemical residues in human and animal foods. In its regulatory pesticide residue monitoring program, FDA selectively tests a broad range of imported and domestic commodities for approximately 800 pesticide residues.
Read the 2020 Food and Beverage FDA Pesticide Residue Monitoring Program Q&A Report.
Our advice to the food and beverage industry:
With nearly 800 different pesticides being reported, we highly recommend all food and beverage companies set up regular screening programs and a proper risk assessment. Call (866) 840-6948 to discuss recommendations on developing a custom screening program that will keep your specific ingredients and finished products ahead of varying standards and limits.
In addition, your questions about specific contaminant issues like allegations of plastic contamination; chemical migration in packaging; unknown substances found in products; complaints of off-odors or off-flavors and products exposed to environmental contamination…can all be answered.
- Stay ahead of the regulators who are under pressure to perform more routine surveillance checks of products at random food markets.
- Be proactive. Understand where ALL your ingredients come from along with their associated risk.
- Make certain your globally sourced ingredients are monitored for any banned substances.
- Respond to warning letters from regulators who perform routine surveillance samplings with supporting data including corrective action documentation.
Remember, the real cost of a recall…is your reputation.