Mitigating Potential Contamination Through Risk-Based Formulation
Oral solid dosage formulation strategies are being reshaped to align with the evolving regulatory landscape and to enhance patient safety by mitigating potential contamination risks.
In July 2018, regulatory authorities issued mass recalls of several drug products containing valsartan — an orally active, selective angiotensin II receptor blocker (ARB) used in treatments for high blood pressure and heart failure — following the detection of a probable human carcinogen impurity, N-nitrodimethylamine (NDMA) (1). After the detection of NDMA, investigatory work was undertaken by regulators, which led to the identification of another nitrosamine impurity, N-nitrosodiethylamine (NDEA), in valsartan produced by the same manufacturer (2). These discoveries highlighted some important quality issues for industry stakeholders and have resulted in renewed focus from formulators of oral drug products to improve processes.
“The ongoing challenge of nitrosamine impurities has become one of the most urgent formulation issues facing oral dosage developers,” stresses Jason Brown, Director, Analytical Sciences, Adare Pharma Solutions. “With approximately 30% of APIs susceptible to nitrosamine formation, this is reshaping formulation strategy across the industry.”
Tightened Controls for Improved Safety
“The pharmaceutical industry has indeed been facing several significant quality and regulatory challenges in recent years, with one of the most notable being the ongoing concern over nitrosamine impurities,” confirms David Vodak, Ph.D., Chief Scientific Officer, Bend Bioscience. “Nitrosamine contamination, which is linked to certain manufacturing processes and raw materials, has raised serious safety concerns and prompted widespread testing and recalls of various products.”
As a result of the concerns and increased regulatory pressures, formulators have been required “to adopt more rigorous quality control measures and implement changes in their manufacturing processes to mitigate the risk of nitrosamine formation,” Vodak continues. “The need for better risk assessment and quality assurance systems has become paramount, especially as new data and regulatory guidance continue to emerge.”
Contamination issues, such as nitrosamine impurities, mean that formulators must perform more careful assessments of APIs and excipients to mitigate potential risks, specifies Brent Moody, Director, Scientific Advisory Services, Catalent. There may even be a need to reformulate products completely or to tighten control of the raw materials, he adds.
“These pressures are encouraging a more risk-based and science-driven approach to formulation,” Moody continues. “For example, the use of modular and flexible formulation platforms, such as multi-particulate systems in sachets or capsules, can provide better control over individual excipient-exposure profiles and reduce the risk of cross-contamination or impurity formation. These systems also offer advantages in patient-centric design, which is an added benefit.”
Various global regulatory agencies, such as FDA, EMA, and the Therapeutic Goods Administration (TGA), have significantly tightened their controls on nitrosamine contamination over recent years as a result of the serious carcinogenic risks these contaminants pose, points out Rebecca Jansen, Associate Vice President — Manufacturing, Technical Services, and PDS, Bora Pharmaceuticals. “In September 2024, FDA issued revised guidance requiring pharmaceutical manufacturers to detect and control nitrosamine impurities at even more stringent limits, down to parts per billion,” she says. “This evolving regulatory landscape is driving pharmaceutical companies to adopt stricter quality control measures and innovate oral dosage formulation to enhance drug safety and stability.”
Potential nitrosamine formation is a significant risk in formulations containing secondary or dimethyl tertiary amines, which can react with trace nitrite impurities, remarks Brown. “To comply [with regulatory controls], companies must establish a product-specific control strategy providing proactive mitigation through formulation science,” he states. “Because the optimal solution varies by API and formulation, a tailored strategy is essential.”
By way of example, Brown highlights a multi-pronged approach that Adare have adopted to mitigate potential nitrosamine contamination. The approach “includes LC–MS [liquid chromatography–mass spectrometry]-based screening, stress testing, and customized formulation studies to identify effective additives that inhibit NDSRI [nitrosamine drug substance-related impurity] formation without compromising stability or efficacy,” he says.
“This regulatory push is fundamentally changing how oral formulations are developed, with an added focus on designing formulations and processes that inherently prevent NDSRI formation and stand up to regulatory scrutiny while increasing patient safety,” Brown asserts.
Reshaping OSD Formulation
“As a result, the pharmaceutical industry is reshaping the OSD [oral solid dosage] formulation strategies to align with evolving regulatory expectations and enhance patient safety,” Jansen confirms. For example, a key change for formulators would include being selective with ingredient sourcing, “prioritizing low-risk APIs and alternative excipients to enhance product safety,” she says.
Some other considerations for OSD formulators are as follows: scrutinizing amine-containing APIs and potential interactions between APIs and excipients more closely; using a modified or alternative excipient as a result of regulatory updates; revising formulations, such as optimizing pH conditions and incorporating nitrosation inhibitors, to mitigate nitrosamine risks; redesigning manufacturing processes; systematically evaluating potential contamination risks through comprehensive assessments; employing innovative analytical techniques to detect impurities at lower thresholds; and exploring advanced drug delivery systems that can improve drug stability and reduce impurity risks, Jansen explains.
“In addition to nitrosamines, regulatory updates such as potential bans or restrictions on certain ingredients and excipients are also having an impact on the oral dosage formulation landscape,” specifies Vodak. “For example, there are increasing concerns around the safety and environmental impact of certain ingredients, such as plasticizers or solvents, which may result in tighter regulatory scrutiny or the need for substitution with safer alternatives. This is forcing formulators to reassess their ingredient selections and often seek novel, safer excipients that align with evolving regulations without compromising product performance.”
Additionally, good manufacturing practices (GMP) guidance is evolving and becoming stricter, Vodak continues. “These evolving standards, combined with the need for more stringent testing for impurities and contaminants, are pushing formulators to adopt more sophisticated analytical methods and technologies to maintain compliance while ensuring consistent product quality,” he says.
Overall, the challenge for OSD formulators is being able to balance safety, efficacy, and patient experience, Vodak remarks. “Formulators must navigate the complexity of meeting evolving regulations while maintaining or improving the performance of oral dosage forms. This often means adopting more advanced technologies, such as continuous manufacturing, to enhance process control and minimize contamination risks,” he says. “Additionally, the development of innovative dosage forms with improved stability, safety profiles, and patient adherence remains a priority, all while staying ahead of regulatory requirements and ensuring compliance.”
When considering regulatory and quality updates, Vodak points out that oral solid dosage formulation has been significantly influenced with greater innovation being seen in manufacturing processes, raw material selection, and analytical techniques. “These changes are ultimately fostering a more resilient and adaptable industry, one that is better equipped to address emerging challenges and meet the growing expectations of regulators and patients alike,” he adds.
“While regulatory and quality drivers can make our jobs more complex, they may also lead to more robust and science-driven formulations, ultimately benefiting both product quality and patient safety,” concludes Moody.
References
Farrukh, M.J.; Tariq, M.H.; Malik, O.; Khan, T.M. Valsartan Recall: Global Regulatory Overview and Future Challenges. Ther. Adv. Drug Saf. 2019, 10, doi:10.1177/2042098618823458.
EMA. Update on Review of Valsartan Medicines: Risk from NDMA Remains Low, a Related Substance NDEA also Being Investigated. Press Release, Sept. 13, 2018.
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