What Goes Wrong When API Quality is Compromised?

Published on: 
Pharmaceutical Technology, Pharmaceutical Technology, August 2022, Volume 46, Issue 8
Pages: 16-19

The nitrosamines contamination in “sartan” drugs emphasized the importance of risk assessment in the manufacture of active pharmaceutical ingredients.

Effective and safe APIs provide the necessary element of drugs to treat patients with a variety of health conditions. It is, therefore, crucial that the quality of APIs, along with other ingredients that make up a medicine, is of primary importance to drug developers and manufacturers.

“It is the API, that attributes the efficacy of a drug,” says Aloka Srinivasan, principal and managing partner at RAAHA LLC. “In other words, a drug is a drug because of the API, otherwise it is just a placebo. Thus, it is of utmost importance that the pharmaceutical manufacturers assure the safety of the API.”

According to Meera Khullar, senior vice president of Quality and Compliance, Curia Global, API quality is an essential requirement. “Current regulations worldwide provide zero flexibility when it comes to the quality of APIs released from [manufacturing] sites and reaching the market,” Khullar states. “Without global standards of quality, production of much-needed treatments can be derailed just when patients need them the most.”

“The clue is in the name; the API has an ‘active’ impact on the patient. The pharma manufacturer is ultimately responsible for the safety of the drug product and therewith of the API. In the worst case, an unsafe API can do harm to a patient, which can result in recalls, damage to reputation, financial loss, and potentially punitive actions by regulatory agencies,” warns Siegfried Schmitt, vice president, Technical at Parexel.

Best practices for API manufacturing

So how do API manufacturers and sponsor companies ensure the quality of their product? It’s all about assessing risk. Performing robust risk assessments of the manufacturing process is crucial.

“Robust risk assessments help manufacturers understand their processes, including degradation pathways and impurity formation, and optimize them to meet quality targets. In this way, manufacturers can ensure quality by design—developing a process that detects and minimizes impurities and guarantees quality,” says Ankur Deshpande, director, Process Development Quality at BIOVECTRA.

“One of the key considerations for API and resulting [drug product] safety is assessing potential impurities that may be introduced from the interaction of the manufacturing process stream to manufacturing component materials (e.g., filter membranes, polymeric or elastomeric tubing, polymeric storage vessels and closures, etc.),” says Xiaochun Yu, senior principal scientist, PPD. “The approach for evaluating and controlling this risk is well described in United States Pharmacopeia <1665>.”

A quality system that employs good manufacturing practices (GMPs) is also necessary, adds Schmitt, and the personnel involved in the quality system are key. “A system is only as good as the persons who apply it and adhere to it. Thus, having suitably trained and qualified staff and of course, also suitably designed and equipped facilities are a prerequisite. It sounds simple and logical, but it requires a quality mindset to implement and follow.”

Documentation is also key, continues Mike Johnson, senior director, Quality, Cambrex High Point. “A sponsor might develop an API that is a miracle to the patient, but if the quality system has not been properly built or continuously managed, missing parts or inaccuracies within the development package may arise. This can cause delays in approvals and rework, as auditors and regulatory reviewers may question the quality and validity of the API being developed,” he says.

A crucial area in API quality is cleaning with contamination controls, specifies Johnson. He also points to facility design, equipment, and personnel training as part of a robust cleaning program. “When an API is produced in a reactor or isolated for final pack out, we must confirm that only the one API is present and there are no concerns for contamination from other materials,” says Johnson.

Testing effectiveness. Performing testing on APIs, whether produced in house or obtained from a supplier, is essential to establishing the quality of the API used in the finished drug product. High-performance liquid chromatography (HPLC) is a key testing method for ensuring API purity, asserts Johnson, and it is a common and critical testing method. Mass spectrometry (MS) and gas chromatography (GC) are also effective testing methods, but numerous methods should be used to meet regulatory guidelines, stresses Johnson. “A series of different methods and analytical techniques must be used to ensure a full battery of tests is performed to support that the API is effective and safe for patients,” he says.

Other testing methods include charged aerosol detectors and multi-angle light scattering (MALS) detectors, according to Peter Phillips, vice president of Quality at BIOVECTRA. “But the use of these methods depends on the areas of risk identified by the sponsor through their clinical trials. This information drives the manufacturer towards the appropriate technology to detect and eliminate that risk,” he says.

“Continual advances in the sensitivity, specificity, and accuracy of analytical technologies contribute to increasing confidence in the ability of API manufacturers to ensure the quality of final API products,” says James Lawler, general managerat C2 PHARMA. “For small-molecule APIs, common techniques include Raman, ultraviolet, infrared, and UV spectroscopy; HPLC; LC–MS; LC–tandem MS (MS/MS); GC; GC–MS and GC–MS/MS; and particle analysis, among others. These methods are used during product and process development and for final API release. GMP drug substance release testing requirements are extensive and include testing materials against specification for identity, purity, the level of impurities, certain physical properties, among other attributes. The specific requirements depend on the modality.”

Sourcing and the supply chain. Sponsor companies often source APIs from third-party suppliers. Sourcing of these materials often requires a commitment to quality above costs to ensure that the final product is effective and safe.

The selection of low-quality APIs to reduce manufacturing costs can put the whole supply chain at risk, notes Lawler. “The lowest commonly acceptable quality API manufacturer typically put everyone else out of business for that API while also being the one with the highest risk of failure. Once they fail, like a domino effect, they wipe out the whole supply chain leading into shortages which are extremely detrimental to patient health,” says Lawler.

Raw material selection is an important aspect of API quality, especially combined with robust process validation, according to Adriana Malizia, director of Quality, Aceto. “Raw material selection and qualification involve the evaluation of the supplier QMS [quality management system] and lay the foundation for the processing of the material to manufacture the API,” says Malizia. “This is further supported by a thorough validation of the manufacturing process which should identify critical process parameters that will act as the control mechanisms to establishing consistent process and product quality.”


A holistic approach to qualifying suppliers is also key, emphasizes Khullar. This approach should consider the quality aspects of the supplier at the beginning of the relationship and include the supplier’s technical capabilities, equipment, technology, and personnel. “The assessment also should evaluate a supplier’s track record of reliability for producing consistent products in line with emerging requirements, including its history of regulatory compliance. Furthermore, it should address whether the supplier’s ongoing quality performance is in line with the sponsor’s standards across the supply chain. Sponsors should gauge and confirm an environment and culture of continuous improvement. Ultimately, the strongest sponsor and supplier partnerships require alignment between each organization’s quality systems,” says Khullar.

Site audits of API suppliers must be performed as part of a sourcing program, asserts Johnson. “Keep in mind that audits are a snapshot in time, so it’s important to incorporate additional technical and business oversight throughout the relationship. Sponsors can ensure a second confirmation of quality checks at periodic timepoints through a use test in the production environment, followed by quality control testing,” Johnson says.

Suppliers should have a robust quality system to detect and correct problems with their product, confirms Phillips, and API manufacturers should have the technical background and expertise to plan for problems. “It is essential that manufacturers can walk sponsors through the technical process, both from a manufacturing and an analytical perspective,” says Phillips.

An additional consideration for sourcing of APIs is ensuring critical quality attributes (CQAs) of the API. “For example, shipping an ingredient at the wrong temperature can cause issues severely impacting quality. Depending on the particular product and its unique [CQAs], some factors might be more important than others, but it is always case-dependent, and there are always multiple areas that can impact API quality,” says Phillips.

Sponsors should request information from the API supplier related to the drug master file, asserts Srinivasan. “The sponsors should make sure that the API was adequately characterized, the impurities were identified, and their limits justified. The controls for the API should be adequate,” she says. “In addition to impurities, one should make sure that assay, polymorphic forms, particle size, and water content are adequately controlled. The sponsors should also make sure that the analytical methods used by the API manufacturer are suitable for the purpose and robust.”

The nitrosamines problem

An example of what can go wrong with APIs when impurities are present is the nitrosamine contamination in sartan drugs (1). Individuals are exposed to nitrosamines, which are common in water and foods, to some level in their environment. However, these impurities may increase the risk of developing cancer in some people, according to FDA, and in 2020, industry began issuing recalls of drug products contaminated with nitrosamines (2).

“The nitrosamine saga is ongoing, and industry is learning new things every day related to nitrosamines,” says Srinivasan. “Currently, the agencies have moved beyond low molecular weight nitrosamines, which arise from reagents and solvents to larger API like nitrosamines, which FDA has termed as NDSRIs (nitroso drug substance related impurities). These nitrosamines are formed when the API itself is an amine (secondary, tertiary, or quaternary) and is capable of forming a nitrosamine in presence of a nitrosating agent like nitrite, which are ubiquitous. This has made the industry aware that they need to make sure that the water or the reagents they use are nitrite free. It has also made the industry more careful regarding the cleaning of shared equipment to avoid any contamination with a nitrosating agent. Industry is rethinking the route of synthesis for many APIs, including “sartans” to see if nitrosating agents can be avoided. Last but not least, industry has started paying serious attention the quality of recycled solvents, which could be a player in the formation of nitrosamines.”

Root cause: the process. The presence of impurities may not be obvious, according to Duu-Gong Wu, Regulatory Affairs, PPD, especially when an interaction with non-toxic excipients results in impurities in the API. With the nitrosamine contamination in sartan medications, the manufacturing process itself was the culprit and dimethylformamide combined with sodium nitrite in the presence of an acid led to the formation of N-nitrosamines.

According to Lawler, the N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) contamination in these drugs occurred because recycled solvents were used to reduce costs, and formulations of some APIs with specific excipients resulted in nitrosamine formation. “When the problem first arose (due to poorly considered process changes), awareness of the need for better risk analysis of the synthetic routes used to manufacture APIs with respect to the potential for production of both known and unknown impurities and how to prevent/control them increased substantially across the industry. The importance of effective process-change control processes and the need for careful oversight of API suppliers was also highlighted,” Lawler says. “Furthermore, the critical need for scientific competence and the negative impact that continuous cost-cutting measures can have on quality was clearly demonstrated from the nitrosamine crisis.”

The nitrosamine situation stressed the importance of a robust process validation, which can identify by-products and/or impurities created during manufacturing, explains Malizia. “The nitrosamine contamination … has underscored the importance of these initial process analyses and risk assessments which should be supported by analytical testing where doubt exists. It further demonstrated that the collaboration of raw material and excipient suppliers in identifying potential risk factors is necessary for early detection and ultimately patient safety,” says Malizia.

Because contaminates can be introduced early in the manufacturing process, which can then impact the entire process, the need for “strict control” over the pharmaceutical supply chain was also emphasized by the nitrosamine situation, emphasizes Deshpande.

Srinivasan believes the scope of the nitrosamines problem has expanded from small nitrosamines created from reagents and solvents to NDSRIs, and the problem may take years to resolve. “Considering that more than 40% of drugs approved by agencies all over the world are secondary and tertiary amines, there are potentially hundreds or thousands of drugs that need to be evaluated for these larger nitrosamines, which have very little to no data in the public domain. Agencies have recommended limits which in most cases are unachievable based on currently available analytical capabilities,” she says. “The API industry should take a holistic look into the route of synthesis of an API and the reagents, solvents used to make sure that they are not missing anything related to mutagenic impurities. The other aspect, which cannot be stressed enough, is the need to follow appropriate GMP during API manufacturing and avoid contamination.”

The nitrosamines situation has shown that an analytical assessment of the manufacturing process, in addition to a paper assessment, is essential, according to Niamh Lynch, Executive Director, Global Head of Quality, Lonza Small Molecules, Basel. “It also became apparent that if a change is made to a process, whether to solvents, catalysts, or a new supplier of starting materials, it can result in the formation of additional impurities,” Lynch says.

Industry and regulators react. Industry and regulatory bodies jumped quickly to tackle the nitrosamine problem. Regulators across the globe have collaborated to assess the risk and develop recommendations, according to Khullar. “For example, the US guidance [issued by FDA] goes beyond products of known concern and applies to all chemically synthesized APIs and drug products containing chemically synthesized APIs.Recommendations for both API and drug product manufacturers cover approved and marketed drugs as well as those in development. This is an ongoing effort, which underscores the need for continuous improvement and the need to adjust to meet evolving standards,” says Khullar.

Regulators are using tools to track potential contamination trends, asserts Phillips, but manufacturers should remain diligent and use risk assessment tools to anticipate potential issues before their products reach patients. “That being said, we are dealing with complex molecules and products, so it can be very difficult to predict everything that can happen. Therefore, it’s important that CDMOs [contract development and manufacturing organizations] and pharma manufacturers work hard to foster a culture where quality is highly valued,” says Phillips.

“In general, awareness of the nitrosamine contamination issue is high within the pharmaceutical industry across the entire value chain,” says Lawler. “Collaboration between international regulatory agencies and API and drug product manufacturers continues with respect to identifying any additional sources of nitrosamine impurities not yet uncovered. As more information is obtained, greater understanding and tightening regulations will likely lead to a reduction of such occurrences in the future. Unfortunately, the root cause of the nitrosamine crisis, namely poor scientific knowledge at the API manufacturer and continuous cost cutting programs for APIs is not addressed,” confirms Lawler.

Malizia stresses that while the nitrosamine problem may not be fully resolved, better control strategies have been implemented across the world that may help the industry avoid similar situations. “The fact that risk assessments and testing are being adopted by less regulated suppliers (raw material and excipient manufacturers) demonstrates that there is a better understanding of the importance of fully comprehending a product’s impurity profile and that collaboration across the industry is key in avoiding similar recurrences for other potential contaminants,” Malizia says.

“Manufacturers are under pressure to better understand the nitrosamine problem, and regulators require manufacturers to perform specific assessments for nitrosamines under M7 ICH [International Council for Harmonisation],” concurs Phillips. “There is always the potential of a new nitrosamine-type issue arising, but the agencies and the companies themselves are continuing to monitor processes and products to ensure this does not happen again.”


Quality control at each stage of API manufacturing is crucial to ensure the quality, safety, and effectiveness of drug products. “The compliance of all stages of manufacturing to CGMP also plays a critical role in maintaining the quality and safety of API, especially after the regulatory approval,” says Derek Wood, senior principal scientist, PPD.

“The moment an API leaves our site, we must have full confidence that we have ensured the API is the correct quality and has been fully tested to meet current product specifications. Strong quality oversight ensures the patient can confidently use their medicine without hesitation. Low-quality and ineffective APIs simply break the trust of the patient, and more importantly, could cause harm to them,” concludes Johnson.


1. FDA, Information about Nitrosamine Impurities in Medications, FDA.gov, accessed July 19, 2022.

2. F. Mirasol, “Pharma Industry Contends with Contamination-based Recalls,” Pharm. Technol. Solid Dosage Drug Development and Manufacturing Supplement, April 2021.

About the author

Susan Haigney is managing editor of Pharmaceutical Technology.

Article details

Pharmaceutical Technology
Vol. 46, No. 8
August 2022
Pages: 16–19


When referring to this article, please cite it as S. Haigney, “What Goes Wrong When API Quality is Compromised?,” Pharmaceutical Technology 46 (8) 2022.