Susan Haigney

Nitrosamines. Doctor in smock points with his finger to a search box. The term Nitrosamines is in focus. Symbol for illness, health, medicine | Image Credit: © 

Nitrosamines, a class of potentially cancer-causing chemicals, were found in certain pharmaceuticals, such as heart pressure medications, in 2018. Regulatory agencies have been working with pharmaceutical companies since then to mitigate the risk of these impurities in drug products (1). In January 2025, FDA posted “Determining Recommended Acceptable Intake Limits for 

-nitrosamine Impurities in Pharmaceuticals: Development and Application of the Carcinogenic Potency Categorization Approach” in the Spotlight on CDER Science on the 

® spoke with Todd Sprouse, associate director, Analytical Services, and Erik Feldmann, PhD, principal technical advisor, Client Solutions & Proposals, both with Cambrex, to find out more about the challenging situation.

What is the carcinogenic potency categorization approach (CPCA)?

 2025 for the development and application of the carcinogenic potency categorization approach (CPCA) to nitrosamines? What is CPCA and how can it be leveraged?

The CPCA approach is a simplified molecular structural assessment for nitrosamines. Many of these compounds, like novel nitrosamine drug substance-related impurities (NDSRIs), are being discovered and characterized as pharmaceutical development progresses. For these new compounds, carcinogenic potency is estimated using data from structurally similar nitrosamines where more data [are] already available, including from pharmaceutical products already on the market and those soon to be on the market. The industry needed a mechanism to quickly assess the potential safety risk of this class of molecules, particularly when limited information is available. This simplified assessment provides an efficient, interim solution in the absence of more advanced health and safety risk data for each specific nitrosamine compound. It establishes a guide to set the initial assessment for any nitrosamine impurity target that drug developers are looking for in their APIs and drug products. 


Why is determining acceptable intake for nitrosamines challenging?

Thinking about it in terms of from a client's perspective or from the analytical laboratory's perspective, what can you tell us about what makes determining acceptable intake (AI) for nitrosamines so challenging?

With the increase in regulatory scrutiny around nitrosamines, we’re seeing continued publication of more toxicology data across this class of compounds that extends into studies of novel NDSRIs but also studies that include more well-known nitrosamines, like NDMA (

-nitrosodimethylamine). Recently, the EMA [European Medicines Agency] 

 for over a dozen compounds, so developers must react to these changes (3). For example, we’ve had clients request supplemental screening and further modifications to existing analytical methodologies to screen nitrosamines in their materials at sensitivity levels that previously established methods may not be suitable for.

Clients may also need to be prepared to update the specification for their materials depending on any specific impacts to their control strategy or their program. That next assessment is really looking at how to translate the intake (AI) into an appropriate specification on the drug product itself (or the API, excipient raw materials, etc.) So, for example, how many dosage units is the patient going to be taking in a day? Based on this information, we can develop a testing plan like we do for any other drug product impurity, which is often based on the product label claim. Clients may want us to determine a specification limit based on the weight of the dosage unit as an alternative. The specification is typically defined by the data that’s available and the client’s preference.

We’ve also been asked if the route of administration impacts limits. While the specification limit units are indeed likely to change with the dosing formulation (i.e., ng/mL, parts per million [ppm], etc.), the acceptable intake limit for nitrosamine targets, at least for now, is still the same if you're delivering 1 gram of material orally or 1 gram of material topically, or intravenously for that matter. The dosage form doesn't impact the limit at the moment, with a caveat. Because we do see the dosage form matter in other genotoxic impurity analyses, where one needs to evaluate how much the patient is expected to consume over the lifetime usage of the drug rather than just the maximum daily intake in the case of nitrosamine guidance. This is because for the time being, nitrosamines are not regulated by ICH [International Council for Harmonisation] M7 as is the case for most other potentially genotoxic/mutagenic impurities.

How can analytics be used to limit nitrosamine risk?

 What are some analytical approaches manufacturers can take to limit the risk of nitrosamines in drug products?

Manufacturers (and developers) need to have a quantitative analytical approach as part of their risk mitigation strategy as they prepare for commercialization. NDA [new drug application], ANDA [annotated new drug application], and BLA [biologic license application] applications must be supplied with confirmatory testing data as part of their application to support the initial risk assessment for nitrosamine formation in their process filed in the clinical phase of development. It’s important to consider [that] current guidance from FDA and EMA requires that methods used must be demonstrated as quantitative in design as opposed to more simplified ‘limit test’-based approaches, despite acceptance of confirmatory testing results from ‘screening’ data. Therefore, the analytical methodology used to report the data must be proven scientifically sound for this intended use. The challenge manufacturers face is finding an analytical laboratory that has suitable instrumentation even capable of quantitating down to sensitivities at the sub-part per million level (i.e., part per billion [ppb]), but also must have the necessary experience to deliver quality results for the applicable sample. Further complicating this challenge, may be the additional requirement of establishing method suitability in a drug product matrix replete with complex components like high-molecular weight polymers, preservatives, and dyes, all in a CGMP [current good manufacturing practice]-regulated environment that meets FDA standards for commercial readiness.

Indeed, our team has been supporting clients with methods demonstrated scientifically sound and providing them with non-GMP/R&D screening data of their registration batches as part of their nitrosamine risk assessment for submissions to regulatory agencies. From there, the decision is based on the results in that assessment as to how much additional analytical work may need to be performed in terms of requiring validation of the analytical method(s) for downstream CGMP testing of their materials to satisfy requirements from regulatory authorities.

For example, if we're reporting results for these batches that show nitrosamine levels at or below 10% of the anticipated specification limit, then CGMP testing may not be required by the agencies. However, if reportable results are observed above that 10% threshold, then CGMP testing is very likely to be required. Regulatory guidance may determine this can be accomplished by ‘skip-lot’ testing or alternatively, more thorough testing of every lot on stability including at every timepoint. We’ve received client feedback that it's quite helpful for them to understand this part of the guidance, where planning ahead to perform historical lot testing as part of analytical method development phase of the risk assessment, can potentially save them a significant amount of time and headache, but also financially, rather than assume CGMP testing is required for all their products going to market before the risk assessment is completed.

Of course, if any products are known to have reportable nitrosamine content, then we can provide assistance where we trace backwards through the drug product and API chemical processes to identify a root cause: what the specific nitrosamine(s) is, when does it form, and at what stage is it becoming enriched? Sources of residual nitrite, the reactive contaminant and predominant source of secondary amine nitrosylation, can be present anywhere throughout the entire chemical process. We take these factors into consideration, and if necessary, we’ll recommend a nitrite analysis of their formulation excipient raw materials if say for example, the impurity is exclusively found in the drug product.

How is ion chromatography used to quantitate nitrite levels?

What are the limitations of using ion chromatography (IC) to quantitate nitrite levels?

In the case of nitrite analytics, we have a lot of first-hand, direct experience with this analyte, not only by IC but other methods as well.

IC is known to be very sensitive for ions, where selectivity becomes particularly important for developing the analytical method because ions are quite ubiquitous. Often, they’re present in the background at levels too prohibitive for trace level IC quantitation with conductivity detection because that background noise adds up into system interference. Excipient raw materials are frequently high in ionic content and this of course often carries over into the finished drug product formulation. Another significant challenge for an IC-based approach is that many of the most common excipients used in solid oral dosage formulations are either poorly soluble or totally insoluble in water. That's really the biggest hindrance there in our experience since IC methods rely heavily on aqueous diluents.

So, if the goal is getting a suitable method at the levels that are needed, you’re potentially facing insurmountable limitations from a combination insufficient signal of the target analyte due to poorly soluble sample coupled with background noise that is too high that trace level analysis just isn’t practical or may even be impossible to adequately pass method accuracy in a validation. Furthermore, if you need to test for nitrite across multiple sample matrices, whether it’s each individual formulation excipient, the API, or the finished drug product, the method onboarding and testing costs can certainly add up and strain the contracted outsourcing budget.

To mitigate some of the challenges with IC, we adopted a headspace GC-MS [gas chromatography-mass spectrometry] approach that is designed as a platform method that minimizes the amount of sample prep changes required to analyze a wide variety of different sample matrices. With this headspace technique, it eliminates many of the negative impacts we just discussed on formulation excipients. Namely the sample solubility issue but also it reduces interference from the matrix components from the sample injection onto the instrument, a notorious problem for chromatographic analyses of drug product and complex polymers. By reacting nitrite with cyclamate to make cyclohexene in a quick and complete reaction, we avoid the matrix interference present in an IC sample preparation.

Our method uses derivatization, because nitrite isn’t volatile. We derivatize any residual nitrite in the sample into cyclohexene and quantitate nitrite indirectly from the converted product. Since we use MS detection, we can achieve trace level sensitivity with great selectivity from the single ion response of the derivatized analyte and with minimal background interference. Our clients prefer this approach because, as mentioned, it’s a platform approach that can be used across a battery of sample types like common industry excipients used in many drug products, translating into a highly economical and novel solution for this growing market demand. We can perform method evaluations instead of full developments for each sample matrix. This shortens the timeline and lowers the expense of performing nitrite testing to assess vulnerable areas for nitrosamine formation.

The method is already validated and is highly amenable to multiple client programs and different formulations. We’re providing the marketplace a competitive and powerful approach to solve a difficult analytical challenge with minimal method onboarding time to help our clients mitigate risk and achieve their regulatory goals.

FDA. FDA Statement 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. Press Release. Jan. 25, 2019.

FDA. Determining Recommended Acceptable Intake Limits for N-nitrosamine Impurities in Pharmaceuticals: Development and Application of the Carcinogenic Potency Categorization Approach. Spotlight on CDER Science. 

EMA.Nitrosamine Impurities: Guidance for Marketing Authorisation Holders. Appendix 1: Acceptable Intakes Established for N-nitrosamines. Reference Number: EMA/245074/2025 Rev. 10. Last Updated 02Sep2025. 

https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/pharmacovigilance-post-authorisation/referral-procedures-human-medicines/nitrosamine-impurities/nitrosamine-impurities-guidance-marketing-authorisation-holders#related-documents-69

Todd Sprouse is associate director of the Analytical Department for Cambrex at the Durham, North Carolina site. He has a master's degree in organic chemistry and has been supporting analytical development in the pharmaceutical CDMO space for drug substance and drug products for 20-plus years. He has supported developing and validating complete analytical packages for clients now for more than 12 FDA submissions. In recent years, he has been responsible for leading a specialized mass spec team primarily focused on genotoxic impurities, that has included extensive support around control of nitrosamines for Cambrex clients. Cambrex has developed dozens of methods to cover their nitrosamine risk assessments to satisfy FDA (and EMA) responses.

Erik Feldmann is principal technical advisor for Cambrex at its Durham, NC site. He has a PhD in biochemistry and previously served as a lead analytical development scientist at the site before moving over to the commercial side where he supported the proposal management team and the business development team as technical director from 2023-2025. He’s been in CDMO pharma and biotech for 12-plus years and has held senior scientist and management roles at multiple start-up companies in the local NC Research Triangle area.

Articles

Nitrosamines, identified as potential carcinogens in pharmaceuticals, have prompted regulatory bodies to collaborate with the industry to mitigate risks. The FDA's Carcinogenic Potency Categorization Approach (CPCA) offers a simplified assessment for nitrosamines, aiding in safety evaluations. Determining acceptable intake limits is challenging due to evolving toxicology data and regulatory updates. Analytical methods, including ion chromatography and headspace GC-MS, are crucial for nitrosamine risk assessment. These methods must be sensitive, scientifically sound, and adaptable to various sample matrices to meet regulatory requirements and ensure drug safety.

Pharmaceutical Technology® spoke with Todd Sprouse, associate director, Analytical Services, and Erik Feldmann, PhD, principal technical advisor, Client Solutions & Proposals, both with Cambrex, to find out more about the challenging situation.  

The Continuous Challenge of Nitrosamines

Communication between the manufacturing plant and retail stores. | Image Credit: © Cagkan - © Cagkan - stock.adobe.com

Medicines Discovery Catapult (MDC), a national life sciences service dedicated to drug discovery, and Crown Bioscience, a contract research organization, announced on Sept. 11, 2025 that they are working together to create an integrated translational biology platform to be used to develop radiopharmaceuticals. The collaboration will support the advancement of radiopharmaceuticals, including new isotopes and optimizing targeting agents, and will enable testing of how radiopharmaceuticals perform in the body.

How will the collaboration help developers of radiopharmaceuticals?

The expertise and technology platforms of MDC and Crown Bioscience will be leveraged to provide the integrated platform that can be used to evaluate radiopharmaceutical therapies. MDC will provide knowledge in cell biology, high-resolution microscopy, radiochemistry, preclinical imaging, mass spectrometry, and multi-omic tissue analysis. Crown Bioscience provides discovery, preclinical, and translations platforms and services for oncology and immune-oncology products.

A preclinical workflow will provide more efficient studies and generate high-quality translational data to support precision medicine strategies, according to the company, accelerating development and improving patient outcomes.

“MDC operates an advanced preclinical drug discovery facility, including world-class radiochemistry capabilities and a translational suite of imaging technologies, to support the growing demand for novel radiopharmaceuticals,” Francesca Sadler, PhD, chief commercial officer at Medicines Discovery Catapult, said in a press release (1). “Our partnership with Crown Bioscience means MDC can expand its current end-to-end translational biology offering even further. Combining the expertise of our two organizations provides a comprehensive platform for drug innovators developing radiopharmaceuticals, helping to accelerate the progress of these novel medicines that have the potential to transform patient outcomes.”

“Advanced radiopharmaceuticals are poised to redefine how we treat cancer, but their successful development requires translational platforms that are both scientifically rigorous and clinically relevant,” John Gu, chief executive officer at Crown Bioscience, said in the release. “By combining MDC’s radiochemistry and imaging capabilities with Crown Bioscience’s preclinical oncology expertise, we are creating a truly integrated solution for innovators in this field. This collaboration reflects our shared commitment to accelerating the delivery of next generation targeted therapies to patients worldwide.”

What other advancements are happening in the field of radiopharmaceuticals?

In August 2025, FDA published a guidance document created to assist drug sponsors with identifying an optimized dosage for radiopharmaceutical therapies for oncology indications during clinical development (2). The guidance addresses clinical development before submitting a marketing application for a new indication and usage. The new draft guidance provides considerations for dosage optimization. According to the document, if there is adequate rationale that the optimized dose of a radiopharmaceutical therapy (RPT) cannot be identified at lower dosages, administered activities per cycle and/or cumulative RPT-administered activities that result in absorbed dosages exceeding external beam radiation therapy (EBRT) organ tolerances can be studied in clinical trials of radiopharmaceutical therapies.

® spoke with Michael Ritchie from Champions Oncology about the FDA guidance and other advancements in radiopharmaceuticals in two interviews (3,4). “Radio pharmaceuticals have been around for about 100 years, and classical radiopharma relied on something called EBRT, or external beam radiotherapy, and that is essentially delivering a radio beam to the patient from an external source,” 

 (3). “But we're now looking at a new wave of therapies which are injected systemically, and quite frankly, we just don't know enough about them. FDA has released new guidance that has said, hey, we want you to come to the table with a better understanding of pharmacodynamics potential liabilities from a toxicity perspective, therapeutic window. But we also want you to design your clinical trials in such a way that we can get an idea on dosimetry.”

MDC and Crown Bioscience. Medicines Discovery Catapult and Crown Bioscience Form Strategic Global Alliance for Radiopharmaceutical Innovation. Press Release. Sept. 11, 2025. 

https://www.businesswire.com/news/home/20250911458780/en/Medicines-Discovery-Catapult-and-Crown-Bioscience-Form-Strategic-Global-Alliance-for-Radiopharmaceutical-Innovation

Draft Guidance for Industry, Oncology Therapeutic Radiopharmaceuticals: Dosage Optimization During Clinical Development. 

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/oncology-therapeutic-radiopharmaceuticals-dosage-optimization-during-clinical-development

Haigney, S. The Impact of FDA’s Guidance on Clinical Trials for Radiopharmaceuticals. 

https://www.pharmtech.com/view/the-impact-of-fda-s-guidance-on-clinical-trials-for-radiopharmaceuticals

Haigney, S. The Evolving Field of Radiopharmaceuticals. 

https://www.pharmtech.com/view/the-evolving-field-of-radiopharmaceuticals

Medicines Discovery Catapult and Crown Bioscience are collaborating to create an integrated translational biology platform for radiopharmaceutical development. This partnership aims to advance radiopharmaceuticals by optimizing targeting agents and testing their in vivo performance. MDC contributes expertise in cell biology, radiochemistry, and imaging, while Crown Bioscience offers preclinical oncology platforms. The collaboration promises efficient preclinical workflows, generating high-quality translational data to support precision medicine strategies. Additionally, the FDA has issued guidance to optimize radiopharmaceutical dosages, emphasizing the need for better understanding of pharmacodynamics and dosimetry in clinical trials.

The two organizations are collaborating on an integrated translational biology platform for the development of radiopharmaceuticals.

Medicines Discovery Catapult and Crown Bioscience Create Alliance for Radiopharmaceuticals

Titanium dioxide, E171, dangerous additive concept. gum, pills, toothpaste, powder and sign with E171 on yellow background. copy space banner | Image credit: ©

According to the European Commission (EC), titanium dioxide (TiO

) is used in 91,000 human drug products to add whiteness, accentuate color, ensure uniformed color, maintain color during shelf life, and preserve the API. In 2021, the European Food Safety Authority determined TiO

 was not safe to use as an additive in food because genotoxicity could not be ruled out. The EC, therefore, requested the European Medicines Agency (EMA) review the safety of using TiO

in drug products in the European Union (1).

The findings of EMA’s updated analysis were released in April 2024 and concluded that while some alternatives to TiO

 performed well when evaluated under certain key performance indicators (KPIs), all were inferior when assessed against all KPIs (2).

The EC announced its findings on the use of titanium dioxide (TiO

) in medicinal products in August 2025 (1); it was decided that the use of TiO

® spoke with Bram Baert, global head of Regulatory Affairs at Lonza CHI, to get industry’s perspective on the EC’s decision.

 is used in many aspects of drug formulation. How does the EC’s decision to continue to allow it to be used in Europe impact industry? How does it impact patients?

 In its recent staff working document evaluating the possibility of replacing TiO₂ in medicines, the EC identified several important factors shaping its decision. The EC concluded that fully replacing TiO₂ in all pharmaceutical products is currently not technically feasible. Where substitution is possible, the process would be lengthy and complex, mainly due to regulatory requirements for re-approval of any new formulations. Since TiO₂ is still allowed in medicines outside the EU, reformulation efforts would likely be limited to products marketed within Europe, potentially disrupting global supply chains and complicating manufacturing and distribution.

Such changes could create significant financial challenges for pharmaceutical companies and, more importantly, threaten the steady supply of vital medications for patients. Additionally, the need to focus resources on finding replacements for TiO₂ may slow investment in new and innovative treatments, especially for conditions with unmet medical needs.

The EC’s decision offers much-needed clarity and stability for both the pharmaceutical industry and patients, since there is currently no definitive evidence highlighting safety risks from oral exposure to TiO₂ in medicines. Drug manufacturers now have regulatory certainty about the continued use of TiO₂ in approved products, enabling them to shift their efforts toward more impactful activities. Patients can also feel confident that they will continue to receive their medicines with consistent appearance and formulation.

Looking ahead, the EC is encouraging ongoing collaboration between drug manufacturers and excipient suppliers, especially in developing new drug products. This keeps the door open for continued research into alternative excipients and supports further investment in creating TiO₂-free options for the market.

Regulatory bodies continually assess the suitability of ingredients and additives in food and pharmaceutical products. With this in mind, drug manufacturers must stay proactive and focus on developing TiO₂-free alternatives that comply with evolving regulations and align with patient preferences while maintaining the highest ingredient quality.

When exploring alternatives to TiO₂, manufacturers encounter a number of challenges. TiO₂ is a unique ingredient as it is capable of delivering a bright white appearance and high opacity even at low concentrations. Excluding TiO2 from the current list of approved colorants still allows [for the] creat[ion of] a huge variety of color options, but those that can replicate both the whiteness and opacity of TiO₂ remain limited. For applications where whiteness is important, calcium carbonate may serve as a viable option while opacity can be achieved through materials such as iron oxides. These alternatives can meet specific performance needs depending on the expectations. Looking beyond currently approved colorants, there are substances that can provide comparable technical performance. Lonza, for example, developed Lumishield capsules, which contain phosphate salts and provide superior whiteness and opacity without jeopardizing the filling performance of the capsule. However, the adoption of such alternatives may involve regulatory complexities.

While it is clear that alternatives exist for certain applications, achieving a balance between technical performance and regulatory compliance often requires thoughtful compromise. To develop truly equivalent solutions, both from a performance and regulatory standpoint, further collaboration among excipient manufacturers, drug product manufacturers and regulatory authorities is essential. By working together, stakeholders can foster an environment that supports innovation and drives progress toward viable, future-ready alternatives.

Should pharma manufacturers continue to try and develop alternatives?

Today’s pharmaceutical marketplace is shaped by a growing diversity of patient and consumer preferences, including religious dietary requirements [such as] Halal and Kosher, lifestyle choices such as veganism, and a desire for organic, non-genetically modified organism, or gluten-free options. There is also an increasing demand for transparency about product ingredients as well as heightened attention to environmental sustainability and safety.

While these considerations have traditionally mattered more in the food and supplement industries, they are now becoming increasingly important in pharmaceuticals, especially for over-the-counter products. As a result, drug manufacturers must factor in these evolving expectations when designing and formulating their products. These changes affect choices about which polymers, excipients, pigments and dyes to use, as consumers become more attentive to ingredient safety, sourcing, and sustainability.

Meanwhile, regulatory authorities are also re-evaluating the acceptability of certain ingredients and additives in both food and medicines. In this dynamic landscape, drug manufacturers must remain proactive and continue to focus on developing TiO₂ alternatives that meet future regulatory requirements and reflect shifting consumer values, all while maintaining product quality, stability, and efficacy.

A supportive regulatory environment is critical for the industry to succeed in creating innovative excipient solutions. The current lack of well-defined approval pathways for new excipients poses a major challenge to innovation. If regulators create clearer frameworks and pathways for novel ingredients, it would encourage the development and adoption of safer, more sustainable, and consumer-focused alternatives in pharmaceutical products.

EC. Commission Staff Working Document on the Use of Titanium Dioxide in Medicinal Products. 

https://health.ec.europa.eu/document/download/34542b69-8507-4fc2-b106-bd15b481e40d_en?filename=mp_working-doc-titanium-dioxide_en.pdf

EMA. Feedback from European Medicine Agency (EMA) to the EU Commission Request to Evaluate the Feasibility of Alternatives to Replace Titanium Dioxide (TiO

) in Medicinal Products and its Possible Impact on Medicines’ Availability. 

https://www.ema.europa.eu/en/documents/report/feedback-european-medicine-agency-ema-eu-commission-request-evaluate-feasibility-alternatives-replace-titanium-dioxide-tio2-medicinal-products-its-possible-impact-medicines-availability_en.pdf

The European Commission (EC) has decided to continue allowing the use of titanium dioxide (TiO2) in drug products, despite safety concerns raised by the European Food Safety Authority regarding its use in food. The European Medicines Agency's analysis found no viable alternatives that meet all key performance indicators. The decision provides stability for the pharmaceutical industry and patients, ensuring consistent drug supply and appearance. However, the industry is encouraged to explore TiO2-free alternatives, considering evolving consumer preferences and regulatory landscapes, while maintaining product quality and compliance.

Bram Baert, global head of Regulatory Affairs at Lonza CHI, gives his perspective on the impact of the EC’s decision on the use of TiO2 in drug products.

The Impact of Europe’s Decision on the Use of Titanium Dioxide 

PDA Regulatory Conference 2025: Wrap Up

Hot topics discussed at the Parenteral Drug Association's (PDA’s) 2025 Regulatory Conference included quality culture, complete response letters, import alerts, artificial intelligence, and transparency. In the above video interview, Susan J. Schniepp, Distinguished Fellow, Regulatory Compliance Associates, joins PDA CEO Glenn Wright and Melissa Seymour, executive vice president, Global Quality, Eli Lilly and Company, to talk about the regulatory and quality topics discussed at this year’s conference.

“One of the topics that came up [is that] we kicked off, really the whole week by a session on Sunday, on complete response letters,” Wright said about one of the more popular topics discussed at the event. “That came up repetitively in several of the sessions. So, you know, I think complete response letters is a topic that's going to continue to be important for the industry, and we're going to have to work on. I think I was surprised. We set out a session for 90 minutes. We thought, we’ll probably get 60 minutes, and that'd be about it. It ran 100 minutes, and we basically had to say, hey, we're going to have to stop the discussion, because we're out of time, right? And so that was a really interesting session, and that there is still a huge amount of industry interest on that topic of complete response letters, and that percentage and number of letters that are coming out.”

Click the above video to watch the interview.

Check out 

Susan J. Schniepp is Distinguished Fellow, Regulatory Compliance Associates, a Nelson Labs company and Chair of the PDA BoD.

Melissa Seymour is Executive Vice President, Global Quality, Eli Lilly and Company and Chair-elect PDA BoD.

Glenn Wright is President and CEO at PDA.

Videos

Susan J. Schniepp, Distinguished Fellow, Regulatory Compliance Associates, joins PDA CEO Glenn Wright and Melissa Seymour, Executive Vice President, Global Quality, Eli Lilly and Company, to talk about the regulatory and quality topics discussed at the 2025 PDA Regulatory Conference. 

Blockchain for transparent supply chain tracking | Image Credit: ©Andrey -stock.adobe.com

The pharmaceutical supply chain is a complex ecosystem consisting of procurement, ingredients suppliers, contract manufacturers, regional regulations, temperature controls, and track and trace technologies. This ecosystem is highly impacted by facility quality deficiencies, which can delay manufacturing and create drug shortages (1). The threat of anticounterfeit drugs is also a spoke in the wheel, with technologies and regulations working together to safeguard patients (2).

“The pharmaceutical supply chain is like a global relay race involving suppliers, manufacturers, distributors, pharmacies, and regulators,” explains Dr Damodharan Muniyandi, chief quality officer–Global Quality & Regulatory Affairs at Sai Life Sciences. “Complexity tends to arise from sourcing APIs and excipients worldwide, meeting diverse regulatory requirements, managing cold chain logistics for biologics, and tackling counterfeit risks. To navigate this complexity, companies are turning to digital supply chain platforms, predictive analytics, and multi-tier supplier networks for resilience. Quality-by-design and continuous manufacturing help maintain consistency, while cross-border regulatory harmonization builds transparency and agility. It’s about blending smart technology with robust partnerships to keep medicines moving safely and efficiently across the globe.”

Integrated digital systems offer real-time visibility and ensure compliance, according to John DiPalo, chief strategy officer for ACSIS, part of Antares Vision Group. “Technologies like serialization and centralized data platforms help manufacturers track product movement, spot irregularities, and quickly respond to issues, protecting patients and preserving brand reputation,” he says.

“Digital technologies—RFID [radio frequency identification], IoT [Internet of Things], and AI [artificial intelligence]—transform fragmented processes into a transparent, resilient, and responsive network, enabling accurate demand planning, reduced waste, and better service levels,” concurs Grethe Bonde, marketing communications specialist at Murata.

Pharmaceutical companies establish quality control departments to manage supply chain issues, according to Sundar Narsimhan, chief procurement officer, Neuland Laboratories Limited. These departments follow guidelines, such as those established by the International Council for Harmonisation (ICH) and local regulatory agencies.

Differing political and regulatory climates can make managing a drug supply chain even more complex. “In the current context, the volatile geopolitical situation coupled with unprecedented tariff escalations and new drug price prospecting have elevated this to a new level,” says Narsimhan.“We are witnessing a real fragile supply chain situation as we speak.”

Sticking to the basics and a commitment to enduring relationships with supply chain stakeholders is key to navigating this ever-changing situation, according to Narsimhan. “Given the scale of damage that loss of business or customers can cause, keep your calm and a watchful eye on the daily developments, such as tariffs, customer and supplier voices, and demand and inventory data,” he advises. “Take very well-thought-out positions on price, concessions, cost-sharing, and commitments for the short-term, keeping in mind that this situation will not last forever. Finally, be very agile and alert to make changes in response to emerging situations—on shipment routing, inventories, and so on.”

The country-to-country variety in regulations from government and standard-setting organizations adds to the complexity of the supply chain. “Fragmented regulations can lead to unexpected compliance issues, product recalls, or halted shipments,” Sade Mokuolu, PhD, regional business development manager, life sciences, Watson Marlow Fluid Technology Solutions, states.

A common regulatory language and standardized regulations enhance supply chain security, says Bonde. “Global standards, like GS1 for product identification and serialization, reduce errors and fraud. In the EU, the Falsified Medicines Directive (FMD) is a prime example: it mandates unique identifiers, tamper-evident features, and verification through the European Medicines Verification System (EMVS). This harmonized framework prevents counterfeit medicines from entering the legal supply chain, strengthens traceability, and ensures consistent product authenticity and quality across markets,” she says.

“Standardized rules foster clearer communication between manufacturers, suppliers, regulators, and consumers,” Mokuolu agrees. “This transparency strengthens relationships across the supply chain and supports responsible product stewardship.”

“Organizations such as ICH, PIC/S [Pharmaceutical Inspection Co-operation Scheme], and WHO [World Health Organization] are driving this harmonization of GMP [good manufacturing practice] standards, making audits easier and compliance less costly. The result is a supply chain that’s more transparent, more trusted, and far better equipped to keep medicines moving quickly and safely from manufacturer to patient, no matter where they’re made,” agrees Muniyandi.

A shared framework for complying with different global supply chain regulations that includes data exchange, product serialization, and traceability is necessary, according to DiPalo. “This consistency allows smooth interoperability among global partners, simplifying compliance and improving visibility and accountability throughout the supply chain,” he explains.

Regulators have been making headway on securing the drug supply chain in recent years. In August 2025, FDA created a new program to decrease US reliance on foreign manufacturers. The FDA PreCheck Program will have a two-phase approach to the development of new manufacturing facilities in the US, allowing manufacturers to communicate more directly with the agency on things like facility design, construction, and pre-production. It will also streamline the development of the chemistry, manufacturing, and controls section of a drug application through pre-application meetings and feedback (3).

The European Medicines Agency (EMA) is dealing with drug shortages by focusing on specific areas. In July 2025, the agency issued recommendations for securing the supply of anti-D immunoglobulins used to prevent RhD immunization during pregnancy in the European Union (4). And in April 2025, EMA published recommendations to strengthen the supply chain of radiopharmaceuticals (5).

Recent political impacts have also added to the complexity of the drug supply chain. The Trump administration’s changing tariff policies in the US have forced companies to reassess their supply chains and operations (6), and the flow of APIs and raw materials has been disrupted.

Jason Waite, an international trade expert at Alston & Bird, stressed that pharmaceutical companies should build cross-functional trade compliance teams in response to rising global trade tensions—particularly potential Section 232 tariffs. Compliance regarding product origin, classification, and valuation, must occur early in R&D and manufacturing to avoid downstream disruptions, he said in an interview with Pharmaceutical Technology®. He also emphasized proactive communication between R&D, finance, logistics, tax, and trade departments to help successfully navigate trade policy changes (7).

Best practices to secure the supply chain

Performing best practices can help minimize disruptions brought about in the manufacturing process. Strict GMP adherence on the shop floor can ensure quality, says Muniyandi, as can using process analytical technology to perform real-time monitoring, validating equipment, and properly training staff. “Machine learning can spot potential quality issues early, optimize processes, and keep batch cycle times under control. IoT sensors enable predictive maintenance to prevent breakdowns, while IoT-enabled logistics track environmental conditions and location once products leave the plant,” he says. “Together, these measures create a clear chain of custody.”

Strong in-line quality controls are key, says DiPalo, specifically machine vision inspection, leak detection, and material verification. “These systems lay the groundwork for the simultaneous use of unique serial numbers and aggregation management, which enables unit-level tracking with serial numbers and aggregation codes,” he says. “Combining this with data from a reliable serialization platform provides complete traceability from manufacturing to the patient, allowing quick responses to recalls, theft, or diversion. These steps together ensure both quality assurance and complete visibility.”

“In manufacturing, quality is ensured through in-process controls, environmental monitoring, and process validation, while traceability is achieved via unique serialization and aggregation,” Bonde says. “RFID and IoT sensors create digital product passports, tracking each unit’s journey and monitoring critical parameters, such as temperature and humidity, in real time. This enables rapid recalls, minimizes waste, and ensures compliance up to the point of care.”

When it comes to using automated inspection systems in the pharma industry, Eran Sinbar, CEO of Yoran Imaging, stresses that they be performed non-invasively and in a way that links inspection data to unique product identification, “two key reasons that thermal imaging-based inspection is beginning to make inroads.”

Utilizing supplier quality management provides a structured approach for ensuring materials, components, and services received by third-party suppliers meet quality and regulatory standards, says Mokuolu. “For drug products that utilize single-use technologies, establishing a consistent set of compliance information across all single-use suppliers enables drug manufacturers to make more accurate comparisons and ensures confidence in dual sourcing strategies,” she continues. “When compliance criteria are open to interpretation, it becomes difficult to assess supplier equivalency.”

Technologies used in the protection of the small-molecule supply chain include tamper-evident packaging and integrated track-and-trace systems that are connected to such platforms as enterprise resource planning and warehouse management systems, according to Bonde. Additional measures are required for biologics, she stresses, such as IoT-based cold chain monitoring, cloud-connected data loggers and blockchain/distributed ledger technology.

Antares Vision Group Life Science uses serialization, aggregation, and automated machine vision inspection in its operations to ensure a secure supply chain for small molecule drugs. For temperature-sensitive large molecules, the company uses real-time cold chain monitoring and RFID-based tracking for reusable assets.

Regarding packaging technologies, Sinbar is seeing increased interest in thermal imaging-based inspection, which Sinbar says gives verifiable, reportable proof of seal integrity and valuable production performance data.

“For small molecules, supply chain security often relies on scale and future-proofing strategies, such as flow chemistry, enzymatic synthesis, short cycle (including greener) synthesis using breakthrough reactions, and derisking strategies, such as supply base and geographic diversification, along with prioritizing reliable partners over mercurial ones,” says Narsimhan.“For large-scale molecules, backward integration is key: adopting novel synthesis methods alongside traditional synthesis, securing raw material supplies despite the geographic concentration, and—if outsourcing—choosing the right supply partner after due diligence for long-term cooperation, since de-risking is often expensive and switching suppliers carries high costs.”

AI is increasingly being utilized in the pharmaceutical industry for supply chain security including automating quality control processes, tracking changing global regulations, predictive analysis for risk detection, counterfeit identification, optimizing logistics, and anomaly detection. According to Sinbar, Yoran Imaging uses AI for big data analysis, root cause investigation, and predictive maintenance. “AI adoption should continue to expand to improve responsiveness, reduce human error, and support real-time decision making,” Sinbar says.

“However, [AI’s] broader adoption is limited by fragmented datasets, lack of interoperability, and regulatory constraints,” Bonde advises.“When integrated with IoT and RFID, AI can proactively reroute shipments, optimize inventory, and identify threats before they cause disruptions.”

AI offers quicker and more accurate detection of problems within the supply chain ecosystem, according to DiPalo, and can drive predictive analytics for managing found risks. “For example,” offers DiPalo, “Antares Vision Group’s AI-GO platform uses deep learning for precise defect detection and adaptive process control, helping to enhance safety, quality, and efficiency throughout the supply chain.”

“By leveraging supplier management tools, organizations can collect and analyze performance data from each supplier,” says Mokuolu. “Integrating machine learning and artificial intelligence enables deeper insights into supplier reliability and operational trends. These technologies help proactively identify potential risks and disruptions, effectively future proofing the supply chain.”

“Challenges [to AI adoption] include high implementation costs, a shortage of skilled talent, data silos, and regulatory uncertainty,” says Muniyandi. “Even so, AI should play a bigger role. It can dramatically boost resilience, efficiency, and security—critical in a post-COVID world in which supply chains must be faster, smarter, and more adaptable than ever.”

A variety of AI tools have entered the chat. In April 2025, SkyCell partnered with Microsoft to integrate SkyMind, SkyCell’s AI-powered supply chain solution, with Microsoft Teams and Copilot based on Azure OpenAI Service. The collaboration will enable those working in the pharmaceutical supply chain to access real-time shipment data, predictive insights, and automated alerts within a Microsoft system, according to SkyCell (8).

The drug supply chain’s many facets allow for multiple avenues for a negative impact on the patients who need medications to live a quality life. Disruptions in the supply chain can stem from such regional problems as natural disasters, quality problems at manufacturing facilities, and political discourse. These disruptions are often out of a drug company’s control. Drug manufacturers should control what they can to minimize these problems by following GMPs and employing the best tools for ensuring quality.

FDA. Drug Supply Chain Security Act (DSCSA). 

FDA. FDA Announces New FDA PreCheck Program to Boost US Drug Manufacturing. Press Release. Aug. 7, 2025.

EMA. Strengthening Supply Chain of Anti-D Immunoglobulins. Press Release. July 4, 2025.

Barton, C. EMA Is Tackling Vulnerabilities in the Supply Chain of Radiopharmaceuticals. 

Cole, C. Survey: Impacts of Tariffs and Trade Policy on the Bio/Pharmaceutical Industry. 

Cole, C. How Pharma Can Build Resilient Supply Chains Amid Trade and Tariff Shifts. 

SkyCell. SkyCell and Microsoft Announce Collaboration to Bring Copilot into Pharma Supply Chains. Press Release. April 7, 2025.

®
Vol. 49, No. 7
September 2025
Pages: 22–25

When referring to this article, please cite it as Haigney, S. Keys to Navigating the Complex Drug Supply Chain. 

The pharmaceutical supply chain is a multifaceted ecosystem involving procurement, manufacturing, and distribution, heavily influenced by regulatory and geopolitical factors. Quality deficiencies and counterfeit threats pose significant challenges, necessitating robust digital technologies and regulatory harmonization for resilience. Integrated digital systems, AI, and IoT enhance transparency, compliance, and predictive capabilities, while standardized regulations improve security and traceability. Political and regulatory complexities further complicate supply chain management, requiring agile strategies and strong partnerships. Ultimately, ensuring supply chain integrity is crucial for patient safety and maintaining drug availability.

Digital solutions help pharmaceutical manufacturers navigate the complex supply chain.

Keys to Navigating the Complex Drug Supply Chain

Text sign showing Industry News. Business photo text delivering news to the general public or a target public | Image Credit: © Artur - © Artur - stock.adobe.com

The European Medicines Agency (EMA) announced on Sept. 1, 2025 that the agency is celebrating its 10-year collaboration with the World Health Organization (WHO) (1). The two agencies signed a confidentiality arrangement in September 2015 (2) to focus on “scientific evaluation, capacity building, enhancing regulatory efficiency to contribute to public health worldwide.”

One specific initiative the two agencies have collaborated on is the EU Medicines for all (EU-M4all) program. This program enables EMA to support global regulatory capacity to protect and promote public health beyond the European Union. In July 2025, the HIV-1 pre-exposure prophylaxis (PrEP), Yeytuo (lenacapavir),was recommended by EMA’s Committee for Medicinal Products for Human Use (CHMP) for approvalfor adults and adolescents at high risk of becoming infected (3). The drug was not only evaluated by CHMP for use in the EU, but also by WHO, and experts from Uganda, Zambia, Kenya, Nigeria, Zimbabwe, South Africa, Thailand, and Vietnam. “This inclusive approach supports regulatory harmonization and strengthens global capacity to protect public health,” EMA stated in the press release (1).

“HIV-1 infection is of major public health significance. According to the WHO, in 2024 an estimated 1.3 million people became newly infected with HIV globally, including 160,000 new HIV infections in the European region and 650,000 in Africa, the region most affected by HIV,” the agency stated in the release at the time (3). “PrEP is a cornerstone of HIV-control efforts in Europe and worldwide and is very effective at preventing infections if taken as prescribed. However, uptake and adherence are often suboptimal because access to some medicines is limited, and other available medicines require strict daily intake. This means that many people at risk in the EU and globally remain underserved by existing PrEP options, highlighting an urgent need to develop additional PrEP modalities.”

Accelerating access to important medicines has also been done through support of clinical development of vaccines and the OPEN framework, where several regulators evaluate a drug parallel with EMA to share expertise, harmonize regulatory approaches, and increase transparency. The partnership between the two agencies has also addressed emerging public health threats, encouraged good reliance practices, ensured quality and safety of drugs through inspections, established strategic partnerships, and promoted regulatory harmonization.

"Global health relies on trusted partnerships. In a very unpredictable world where public health issues go beyond national borders, these partnerships are more necessary today than ever,” Emer Cooke, EMA’s executive director, stated in a press release (1). “Even though EMA’s mandate focuses on Europe, this partnership with the WHO shows that there is a societal value in sharing information, resources and collaborating, and that this can impact people’s lives. EMA remains committed to supporting global efforts and protecting public health with the WHO in the EU and beyond."

EMA. EMA and WHO Mark Ten Years of Collaboration to Advance Global Access to Medicines. Press Release. Sept. 1, 2025. 

https://www.ema.europa.eu/en/news/ema-who-mark-ten-years-collaboration-advance-global-access-medicines

EMA. Confidentiality Arrangement, World Health Organization (WHO). 

https://www.ema.europa.eu/en/partners-networks/international-activities/multilateral-coalitions-initiatives/world-health-organization-who#confidentiality-arrangement-11285

EMA. New Injection for Easier Prevention of HIV Infection in the EU and Worldwide. Press Release. July 25, 2025. 

https://www.ema.europa.eu/en/news/new-injection-easier-prevention-hiv-infection-eu-worldwide

The European Medicines Agency (EMA) and the World Health Organization (WHO) are celebrating a decade of collaboration aimed at enhancing global public health through regulatory efficiency and capacity building. This partnership has fostered initiatives like the EU Medicines for all (EU-M4all) program, which supports global regulatory capacity. A notable achievement is the recommendation of the HIV-1 PrEP drug, Yeytuo (lenacapavir), for approval, evaluated by multiple international experts. The collaboration also focuses on accelerating access to medicines, addressing public health threats, and promoting regulatory harmonization.

EMA and WHO have collaborated for a decade, with WHO utilizing EMA’s scientific expertise to fulfill its mandate to improve access to safe and effective medicines.