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n-nitrosodimethylamine molecular structure, 3d model molecule, n-nitrosamines, structural chemical formula view from a microscope | Image Credit: © Сергей Шиманович - stock.adobe.com

In January 2025, FDA posted “Determining Recommended Acceptable Intake Limits for N-nitrosamine Impurities in Pharmaceuticals: Development and Application of the Carcinogenic Potency Categorization Approach” in the Spotlight on CDER Science section of the FDA.gov website (1). The presence of nitrosamines, which are cancer causing chemicals, in pharmaceuticals has been an ongoing concern since 2018 (2).

® asked Amit Chivate, senior market manager, Greater Asia and China, Roquette, to give us his perspective on FDA’s recommendations on how manufacturers should approach nitrosamines.

What can you tell us about the recommendations FDA published in January 2025 for the development and application of the Carcinogenic Potency Categorization Approach (CPCA) to nitrosamines?

The CPCA provides a comprehensive framework for assessing the carcinogenic potential of and acceptable intake limits for N-nitrosamine drug substance-related impurities (NDSRIs) (1). The need for such specific advice stems from the fact that, in contrast to simpler, small-molecule nitrosamines, NDSRIs present complex and unique chemical structures, which make the establishment of accurate acceptable limits (AI) particularly challenging. The CPCA proposes a new protocol that predicts the carcinogenic potency of an NDSRI by analyzing its chemical make-up—whether known or merely theoretical. The first step is a review of available science from animal studies and human epidemiological data to determine the relative risk associated with each nitrosamine compound. Next, scores are awarded according to the structure of α-hydrogen atoms, and the presence of activating or deactivating features are combined to assign the NDSRI to a potency category, which then dictates its acceptable daily intake limit. This approach represents a notable breakthrough because it allows for a precise, risk-based assessment—even in the absence of specific long-term carcinogenicity data for a particular NDSRI–—making it an ideal case study for how regulatory updates can simplify the drug development process.

The CPCA also brings a dose of much needed clarity and transparent scientific process to the field of nitrosamine mitigation, making it a win for consistency, quality and— above all—patient safety.

What makes determining acceptable intake so challenging?

Determining an acceptable daily exposure limit for any given drug impurity is an incredibly complex task—especially in the case of NDSRIs, which are usually unique to each individual drug. Extreme specificity, in this instance, means increased uncertainty, as there is unlikely to be enough tailored safety information on each NDSRI for manufacturers to determine safe exposure levels. As a result, formulators often turn to information gathered on structurally similar compounds or apply a conservative default acceptable intake limit, neither of which yield perfectly accurate results and can force drug companies to make unnecessary changes to their production practices to meet disproportionately strict standards.

Inconsistent regulatory guidelines across different countries, limited long-term epidemiological data, and the difficulty of quantifying cumulative risk from multiple sources all add another layer of complexity. FDA, for instance, sets its AI limits based on safety assessments that evaluate the mutagenic and carcinogenic potential of nitrosamines. Here, it uses rodent carcinogenic potency data or structure-activity relationships (SAR) to identify comparable compounds in the absence of robust data. In contrast, the European Medicines Agency (EMA) predicts carcinogenic potency categories and corresponding AI limits based on the presence of activating or deactivating structural features in the molecule, which influence carcinogenic potency. The recently published CPCA was developed to harmonize and simplify these approaches, with the aim of giving drug manufacturers a simpler, faster and more precise strategy for remaining compliant and protecting patients, without always having to resort to the most extreme safety measures.

NDSRIs are a subset of nitrosamine genotoxic impurities with complex chemical structures that typically mirror that of an API. They form when secondary or tertiary amines in the drug substance or formulation interact with nitrosating agents during manufacturing and storage. NDSRIs are particularly concerning because they are probable human carcinogens, as classified by the International Agency for Research on Cancer. In contrast to simpler, small-molecule nitrosamines, which are more general contaminants that can affect any drug formulation, NDSRIs are formed through the nitrosation of the API in response to specific production or storage conditions. In short, NDSRIs are complex, unique, and, therefore, more difficult to manage.

 What can pharma manufacturers do to manage the nitrosamine risk?

At this point, manufacturers are well versed in nitrosamine risk mitigation, but there are some underreported strategies that we think should be brought into the spotlight. First is the benefit of weaving the compliance process throughout the entire production line, start to finish. Though testing to determine whether drugs meet AI limits is typically carried out on finished products, we advise that all raw materials should first be evaluated for their potential to introduce nitrosamine impurities—either during production or on their way to patients’ medicine cabinets. This initial step can help save time and potential expense through the early identification of contaminated raw materials, as well as speed up the verification process of the final product.

Excipients are another essential, yet often overlooked, element to the nitrosamine compliance conversation. Fillers, binders, disintegrants, and diluents make up as much as 90% of a drug’s overall volume, so it stands to reason they receive at least some of the scrutiny when it comes to product safety (3,4).One of the simplest and most effective safeguarding options for pharma producers is to select excipients with a demonstrated low nitrate content. The drawback with this strategy, however, is that since regulators do not yet mandate their assessment for nitrosamine risk, comprehensive or consistent data on the nitrite content of many excipients can be hard to pin down. This is where the support of an experienced formulation partner can be invaluable, not only for providing drug manufacturers with high-quality information and products, but also with tailored advice on how to optimize production conditions, for safety and productivity.

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. 

https://www.fda.gov/drugs/spotlight-cder-science/determining-recommended-acceptable-intake-limits-n-nitrosamine-impurities-pharmaceuticals

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.

Abrantes, C.G.; Duarte, D.; Reis, C.P. An Overview of Pharmaceutical Excipients: Safe or Not Safe. 

. 2016;105:2019–2026. DOI: 10.1016/j.xphs.2016.03.019

Haywood, A.; Glass, B.D. Pharmaceutical Excipients—Where Do We Begin? 

2011;34:112–114. DOI: 10.18773/austprescr.2011.060

Amit Chivate is senior market manager, Greater Asia and China, at Roquette.

Amit holds an MBA and a PhD in pharmaceutical drug delivery, and has more than 20 years of experience working across R&D, strategy, sales, marketing, and product management in both India and the United States. At Roquette, Amit serves as the senior marketing manager for the APAC region, leveraging his technical and business expertise to drive marketing initiatives and strategic growth.

Articles

Amit Chivate, senior market manager, Greater Asia and China, Roquette, provides his perspective on FDA’s recommendations regarding nitrosamines. 

Strategies for Mitigating Nitrosamine Risk

Patrick Lavery is an Editor for the MJH Life Sciences brands 

. Previously at MJH, he filled the same role for 

White House | Image Credit: © Zack Frank - stock.adobe.com

United States President Donald Trump has signed an executive order containing several directives to FDA and the Environmental Protection Agency (EPA), aiming to reduce regulatory barriers and restore a robust domestic manufacturing base for prescription drugs (1).

According to a Fact Sheet issued by the White House on May 5, 2025, the order directs FDA to take several steps to reduce the time needed to approve pharmaceutical manufacturing plants located in the US, including eliminating “duplicative and unnecessary” requirements—although, the fact sheet did not clarify what those requirements are—streamlining the review process, and working with domestic manufacturers to offer early support before a facility comes online (1).

Additionally, FDA is being instructed to increase fees for, and inspections of, foreign manufacturing plants, and to improve enforcement of API source reporting by foreign drug producers (1). The administration suggests displaying a public list of those facilities that do not comply.

FDA on May 6 announced an intention to expand unannounced inspections at foreign manufacturing facilities that produce foods, essential medicines, and certain other products (2).

“For too long, foreign companies have enjoyed a double standard—given advanced notice before facility inspections, while American manufacturers are held to rigorous standards with no such warning. That ends today,” FDA Commissioner Martin A. Makary, MD, said (2). “This is a key step for FDA as part of a broader strategy to get foreign inspections back on track.”

Regarding the EPA, the Trump Administration is calling for the acceleration of construction of facilities designed to manufacture prescription drugs, APIs, and any other raw materials necessary. The White House said critical gaps exist in the creation of an affordable and resilient domestic pharmaceutical supply chain, and that current estimates of five to 10 years for building new manufacturing capacity are “unacceptable” in terms of national security (1).

Bio/pharmaceutical companies either headquartered in the US or with major operations within the country have been weighing the potential impacts of the Trump Administration’s tariff policies since the 47th president re-took office in January 2025, with an expectation that 

 sooner or later, one way or another (3). Many companies and executives are 

Some companies have been proactive. In February 2025, 

 that it would be building four new domestic manufacturing sites in the United States, saying that the Tax Cuts and Jobs Act, passed in 2017 during the prior Trump Administration, was the impetus for the company’s decision to expand nationally (5).

The May 5 executive order, the fact sheet said, builds on actions taken in Trump’s first term to reshore production of essential medicines and reduce American reliance on foreign drug producers (1).

“We don’t want to be buying our pharmaceuticals from other countries because if we’re in a war, we’re in a problem, we want to be able to make our own,” President Trump said, as quoted in the fact sheet. “As we invest in the future, we will permanently bring our medical supply chains back home. We will produce our medical supplies, pharmaceuticals, and treatments right here in the United States.”

The May 6 FDA action aligns with the sentiments of the fact sheet, which said that the executive order is designed to ensure FDA prioritizes American manufacturing facilities over foreign ones (1).

“This change builds upon the agency’s Office of Inspection and Investigations Foreign Unannounced Inspection Pilot program in India and China and aims to ensure that foreign companies will receive the same level of regulatory oversight and scrutiny as domestic companies,” FDA’s press release said (2).

Under terms of the May 5 executive order, federal agencies that issue permits for domestic pharmaceutical manufacturing facilities are being directed to designate a single point-of-contact for permit applications with interagency support from the White House Office of Management and Budget to ensure the most efficient process (1).

1. The White House. Fact Sheet: President Donald J. Trump Announces Actions to Reduce Regulatory Barriers to Domestic Pharmaceutical Manufacturing. 

, May 7, 2025.
2. FDA. FDA Announces Expanded Use of Unannounced Inspections at Foreign Manufacturing Facilities. Press Release. May 6, 2025.
3. Bigica, A. 

Pharmaceutical Tariffs Are Imminent: How Industry is Bracing for Impact.

Tariff Pause Reinforces Uncertainty Among Biopharma Professionals.

, April 10, 2025.
5. Eli Lilly and Company. Lilly Plans to More Than Double US Manufacturing Investment Since 2020 Exceeding $50 Billion. Press Release. Feb. 26, 2025.

The White House is instructing FDA to increase fees for and inspections of foreign drug manufacturing plants and reduce the time required to approve such sites that will be newly constructed in the US.

Trump Directs FDA, EPA to Reduce Regulatory Barriers to Domestic Pharma Manufacturing

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Intertek has announced an expansion of its good manufacturing practice (GMP) pharmaceutical services laboratory in Melbourn, United Kingdom, adding 6000 square feet of purpose-built laboratory and office space to bring the site’s total footprint to 46,000 square feet (1).

In a press release on May 7, 2025, the company said the expansion of the Melbourn facility—which for more than 30 years has specialized in analytical, formulation, and clinical manufacturing services for inhaled and nasal drug products—is a response to the globally rising demand from clients for inhaled biologics (1). Such routes of administration are effective in delivering biologics as well as messenger RNA (mRNA), nucleotide-based therapeutics, and vaccines that treat respiratory diseases.

“This GMP lab expansion significantly enhances Intertek’s testing and analytical capabilities, enabling our clients developing novel inhaled biologics to accelerate their drug development timelines and ensure the highest standards of quality and efficacy in their products,” Ross McCluskey, Intertek executive vice president, EMEA and Government and Trade Services, said in the release (1).

While inhaled or nasal routes allow for targeted delivery to the lungs along with the potential of reducing the amount of active ingredient needed, ensuring product performance and manufacturability, as well as clearing regulatory and commercialization hurdles, have been challenges for developers, according to Intertek (1).

"Our growing facility underscores our dedication to supporting innovation and the continuous development of safe and effective inhaled biologics,” Ashleigh Wake, Intertek pharmaceutical services director for UK and Switzerland, said in the release (1). “In partnership with our clients, we are helping to advance innovations in critical medicines that will reach patients in need worldwide."

Some of the planned features of the expanded Melbourn laboratory are advanced mass spectrometry (MS) instrumentation, including high-resolution MS, and a particle characterization laboratory able to support development of both small- and large-molecule inhaled and nasal drugs (1). Capabilities characteristic of Intertek’s Manchester, UK laboratory, such as cell-based potency assays that call for the handling of hazardous biological materials and viral analytical work, will be reflected in the Melbourn site’s new bioassay and cell culture units.

Prior to announcing this facility expansion, Intertek in December 2024 

 with UK-based CrystecPharma, a crystal and particle engineering company that applies proprietary modified supercritical fluid technologies to improve drug performance, aiming to advance formulation science and accelerate development timelines for inhaled medicines, particularly dry powder inhaler products (2).

Intertek is the host of the inhaled and nasal drug product sector’s first dedicated forum for such types of biologics and will be holding its fourth annual 

, in Cambridge, UK, on Sept. 25–26, 2025 (1,3).

1. Intertek. Intertek Expands Pharmaceutical Services Laboratory to Enhance Capabilities in Inhaled Biologics and Accelerate Drug Development. Press Release. May 7, 2025.
2. Intertek. Intertek Partners with CrystecPharma to Advance Formulation Science and Accelerate Development Timelines for Dry Powder Inhaler Products. Press Release. Dec. 11, 2024.
3. Intertek. Inhaled & Nasal Biologics | DNA Forum 2025. 

The company said the expansion is in response to globally rising demand for inhaled biologics, which offer distinct advantages in route of administration, but can be challenging products for developers.

Intertek to Expand UK GMP Facility with 6000 Square Feet of Lab and Office Space

AAPS National Biotechnology Conference 2025: High-Concentration Biologics

Biologic drugs typically have a higher dosage than small-molecule drugs, according to Lun Xin, associate director at WuXi Biologics, and sometimes patients will need to spend hours at an infusion center to receive these treatments. “That's a growing experience for a lot of people, especially folks that [are] dealing with things like cancer or long-term arthritis disease or something of that nature, which is lot of time … So, there's a good amount of need for a patient to take [the drug] home and then be able to use pre-filled syringes or autoinjector cartridges, where they can deliver the dose by themselves in the comfort of their home,” says Xin. “Now the limitation with that is you can only put in so much drug into the subcutaneous space using a prefilled syringe or auto injector. And a lot of that's believed to be about two milliliters to be a good benchmark. So now that you have the ideas, and you have to deliver several 100 milligrams of those into a two milligram, two milliliters of volume, right? So, there's a need to develop the concentration of the protein therapeutics to several 100 milligram per mL.”

 spoke with Xin about these challenges associated with the formulation of high-concentration biologics ahead of his presentation at the AAPS National Biotechnology Conference, which is being held May 4–7, 2025 in Boston. Xin’s presentation, “Accelerating High Concentration Formulation Development with Big Data-Driven High-Throughput Technologies”, occurred on Tuesday, May 6 .

Click the video above to watch part one of our interview with Lun Xin.

Lun Xin is associate director at Wuxi Biologics.

Videos

BioPharm International® spoke with Lun Xin, associate director at WuXi Biologics, about high-concentration biologics and some of the biggest challenges associated with their formulation.

Felicity Thomas is the former Associate Editorial Director of Pharmaceutical Technology, Pharmaceutical Technology Europe, BioPharm International.

Industry Outlook 2025: The Future of Technology in the Biopharma Industry

Technologies such as artificial intelligence (AI) and machine learning (ML) are advancing quickly in many industries, including the biopharmaceutical industry. One challenge in the implementation of these technologies in biopharma, according to Edwin Stone, CEO of Cellular Origins, is the data sets and the sensitivity surrounding it.

“There's a huge amount of proprietary data,” Stone says. “And so, I think [this is] something actually, as an industry, we're really going to have to think about a lot harder than we had previously. And remembering here, we're in an industry where, by solving these problems, we help make people better. How do we collaborate better? How do we understand and separate out the competitive landscape from our ability to make enormous strides for us? And I think [it] will be a massive shame for the industry if we all operate in our silos and we miss out on the benefit that I think a lot of those data processing technologies could have. I think the other piece, of course, with this is AI and ML are having a huge impact on [drug] discovery, and I think in the world, in the virtual world, in the software world, that's unsurprisingly, where they found their home.”

Click the video above to watch the full interview.

The PharmTech Group interviewed Edwin Stone, CEO of Cellular Origins, about how technological advances will impact the biopharma industry in the future.


AAPS National Biotechnology Conference 2025: AAV Vector Production

Adeno-associated virus (AAV) vectors are commonly used for gene therapies, according to Noah Kopcho, field application scientist at Gyros Protein Technologies. AAV vectors come with challenges in productions, however. “Namely, compared to other vectors, AAV often has lower titers,” says Kopcho. “This can present problems with scalability. During the production and purification workflow, there are several different contaminants that need to be kept in mind, and purity is often essential. And at the at the end of the workflow, you know all of these measurements that need to be made can present several different bottlenecks that that can be very time consuming and can often eat into efficiency.”

 sat down with Kopcho to find out how these challenges can be overcome. Click the video above to watch the interview.

Kopcho’s spoke on this topic at the AAPS National Biotechnology Conference 2025, which is happening May 4–7, 2025 in Boston. His presentation, “

Accelerate Development of AAV-based Gene Therapies with Automated Viral Vector Titer and Impurity Analysis

Noah Kopcho is field application scientist at Gyros Protein Technologies.

BioPharm International® sat down with Noah Kopcho, field application scientist at Gyros Protein Technologies, to talk about the challenges in the production of AAV vectors.

Rishi Pimentel, gChem, talks about the company's rebrand, and how it aligns with green chemistry, innovation, and regulatory excellence

Gaylord Chemical is Now gChem

gChem is positioned as a global leader in pharmaceutical excipients and drug delivery solutions. As a key partner for formulators and manufacturers, gChem is committed to providing sustainable, high-performance excipients that enhance drug solubility, stability, and bioavailability. In this interview, Rishi Pimentel, Global Business Development Director of Life Sciences at gChem, talks about Procipient®, an innovative and powerful solvent designed for drugs with low water solubility in the injectable drug delivery space. He also covers the benefits of gChem being a global company based in the U.S., as it allows the company to work closely with partners and formulators around the world.

How gChem (formerly Gaylord Chemicals) is embracing its rebrand that aligns with green chemistry, innovation, and regulatory excellence

Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Protect environement | Image Credit: ©Y. L. Photographies -stock.adobe.com

Drug developers face increasing pressure to accelerate process development and reduce costs while ensuring safety and efficacy of investigational candidates and marketed products. They must achieve these goals while minimizing the impact that development and manufacturing operations have on the environment. Given shorter development times and the challenges associated with making process changes in later development stages, the best approach for improving sustainability is to incorporate sustainable practices into process designs as early as possible.

Considering sustainability from the outset

Sustainability-by-design in bioprocess development, according to Adam Goldstein, senior director of R&D Collaborations at Thermo Fisher Scientific, involves integrating sustainable practices and principles from the very beginning of the development process, which includes considering environmental impacts, resource efficiency, and waste reduction during the design phase, to create processes that are not only efficient but also lower the environmental footprint.

Because 80% of a drug’s final environmental impact is determined during the early stages of process design (1), Kami Krista, CEO of Elio Technologies, adds that sustainability needs to be part of the decision-making process during the early R&D and chemistry, manufacturing, and controls (CMC) phases—particularly before changes become difficult due to regulatory constraints (e.g., once process inputs are defined in the regulatory dossier).

In addition, because 42–47% of a pharmaceutical company’s emissions profile can be attributed to purchased goods and services (2), Krista emphasizes the importance of considering both process inputs and conditions. That means employing more environmentally friendly chemicals and processes.

Incorporating sustainability-by-design into process development activities is most effectively achieved by integrating sustainable practices throughout design, construction, and operation of biopharmaceutical production sites, according to Jacob Skou, sustainability manager at FUJIFILM Diosynth Biotechnologies. Key elements that are considered include resource and energy efficiency, waste minimization, and use of less hazardous chemicals and processes. “Processes are designed that optimize the use of raw materials, energy, and water, and alternative renewable energy options such as solar and wind are used where possible to increase energy efficiency. Furthermore, strategies are implemented for reducing, reusing, and recycling waste material generated during bioprocessing,” he says.

Krista concludes that “to successfully integrate sustainability, it is essential that every scientist, process engineer, and other relevant stakeholders can easily assess the sustainability implications of their decisions—alongside technical and cost considerations—and weigh the associated trade-offs.”

Environmental, operational, and cost benefits

Adopting a sustainability-by-design approach in biopharmaceutical manufacturing offers a wide range of benefits in addition to reducing the impact of development and manufacturing operations on the environment. Skou highlights cost efficiency, compliance and risk management, innovation, and increased social responsibility as important benefits resulting from the integration of sustainability into bioprocess development activities.

“Reducing resource and energy consumption and minimizing waste reduction benefits the environment and contributes to cost reductions. Furthermore, as environmental standards become more stringent, adopting sustainable practices helps ensure continued compliance and reduces the risk of legal penalties and reputational damage. Taking a sustainability-by-design approach can also drive innovation that results in market-differentiating processes. Finally, sustainable practices emphasize ethical considerations; promote the health, safety, and well-being of employees and communities; and thus align with broader social responsibility goals,” Skou explains.

Goldstein emphasizes the importance of the innovations that result from adopting a sustainability-by-design approach because they can lead to improved product quality and process efficiency.“Driving higher titer in smaller volumes means yielding higher throughput of product in a smaller footprint. The benefits are lower cost of goods in manufacturing while simultaneously delivering the product in a much more sustainable fashion with regards to emissions reductions,” he comments.

Another important benefit of taking a sustainability-by-design approach for Krista is the fact that by integrating sustainability improvements from the outset, it is not only possible to dramatically reduce the impact of biopharmaceutical operations and the overall environmental footprint of the product and company, the high costs and challenges to making sustainability improvements during later stages are avoided.

There are marketing advantages as well. For contract development and manufacturing organizations (CDMOs), Skou believes having an improved sustainability profile is a competitive advantage.

Krista also notes that in Europe, many hospital procurement systems (i.e., England’s National Health Service and the Joint Nordic Procurement system) are including sustainability performance as a decision criterion when selecting drug products. For public companies and early-stage firms seeking specific investors, having a good sustainability rating (often based on product stewardship, sustainable raw material selection, or similar ecodesign criteria) can attract more investors. Sustainability is also increasingly featured as a decision criterion by Big Pharma companies when making merger and acquisition decisions, according to Krista.

All aspects of biopharmaceutical manufacturing should be considered when taking a sustainability-by-design approach to bioprocess development, starting with the choice of cell line through methods for waste processing, according to Goldstein.

“High-titer cell lines are more productive, while chemically defined media reduce contamination risks and allow for sourcing of materials from sustainability-minded suppliers. Using centrifugation rather than depth filtration can reduce waste and processing times while improving yields, and higher-capacity chromatography resins can reduce buffer usage,” explains Goldstein.

Intensified processing both upstream and downstream can, meanwhile, reduce manufacturing footprints and resource consumption while reducing waste generation and improving facility throughput.

Upstream intensification examples highlighted by Goldstein include the use of high-density cell banking to skip long drawn-out seed expansions (reducing the six to eight days of standard good manufacturing practice [GMP] expansion) saving time, money, and resources (plastic, water, and media) by employing the use of single-use bioreactors (SUBs) that have high turndown ratios, which allows seeding at very low operating values and the growth of cells to high densities as the volume is expanded in the same unit operation SUB step. Downstream opportunities include the use of membrane separations.These technologies replace larger chromatography columns that use large volumes of buffers and take entire shifts to run.

Real-time monitoring of processes via inline sampling, often an important component of process intensification and continuous processing, also helps ensure more robust and high-quality processes and products, according to Goldstein. “Additional efficiencies are gained using ballroom designs vs. traditional costly, broken-up manufacturing suites, allowing for greater use and flexibility of manufacturing space, while funneling of waste into circular waste streams via collaborations with waste-stream recyclers add further benefits,” he notes.

The choice of water purity for certain activities can also have a significant sustainability impact. Highly purified water (like water for injection) is extremely costly and resource laden from a carbon footprint perspective, due to the vast number of steps (steam evaporation, filtration, heating, cooling) that are involved in its creation per liter, Goldstein explains. Specifying a lower quality of purified water (like reverse osmosis quality water Type 2 vs. Type 1) can and should be considered in the makeup of media, cleaning of equipment, and the creation of general early-stage purification buffers (until the process is in the final formulation stage). “Careful consideration and selection of the standard of water used for many manufacturing operations can drive large impactful improvements,” he states.

Collaborating across the entire supply chain is, in fact, an essential component of a sustainability-by-design approach to bioprocess development, according to Ann-Cathrine Rosendahl, global sustainability manager with FUJIFILM Diosynth Biotechnologies. “When we talk about sustainability-by-design in bioprocess development, it’s not just about what happens on the factory floor—it’s about embedding sustainability into every step of the journey, from raw materials to the end-of-life of a product, to build a more resilient and responsible supply chain,” she notes.

Given that a significant part of bioprocess emissions comes from upstream activities (92%), engaging suppliers early is essential, Rosendahl says. “The sustainability of suppliers should be evaluated early, and we are working towards ensuring that partners who prioritize environmentally friendly practices—such as responsible sourcing and transport—are prioritized in our selection process,” she states. FUJIFILM Diosynth Biotechnologies is also committed to reducing environmental impact by working closely with suppliers to improve energy efficiency, adopt cleaner technologies, and explore innovative solutions that lower emissions. “By integrating sustainability into our business reviews and setting clear expectations, we are building stronger partnerships focused on continuous improvement,” Rosendahl remarks.

Sustainability aspects for final product management must also be considered. Where possible, packaging and logistics should also be optimized to reduce waste and emissions, according to Rosendahl. Promoting transparency and accountability is equally important to her, which she observes can be achieved by developing metrics for assessing sustainability performance and reporting progress to stakeholders. That, Rosendahl underscores, requires access to accurate data to ensure a clearer understanding of the Scope 3 footprint for biopharmaceutical manufacturers (indirect greenhouse gas emissions generated outside the company across its value chain).

“Having better data helps companies identify where the biggest impacts are and explore opportunities with suppliers to make processes more sustainable over time,” Rosendahl adds. “By addressing these aspects, companies can move toward an approach to sustainability that considers not just the products themselves but also the surrounding processes, infrastructure, and practices, leading to a holistic and effective sustainability strategy,” she concludes.

As an example, Goldstein highlights a program his company has established to connect customers with recyclers that can recycle single-use bioprocess containers (BPCs) after use. “This program helps biopharma manufacturers divert waste from landfills or carbon-intensive incineration, advancing their sustainability goals through a convenient recycling service that turns BPCs into high-quality plastic lumber. Approximately 400,000 pounds of plastic waste has been diverted from landfills or incineration since initiation of the program,” he observes.

Work is now focused, Goldstein says, on identifying recyclers that can accept mixed waste from biomanufacturers and convert those materials to bio-oil, which can then be recycled into new polymers. These new polymers can be used either in the biomanufacturing environment or in entirely separate recycled products, such as faux wood, fillers for roads, etc.

The key to successful pursuit of a sustainability-by-design approach to bioprocess development is effective assessment of the environmental impacts of each unit operation. The first step, emphasizes Krista, is to equip scientists, process engineers, and all others involved in process development with tools that allow them to understand the sustainability impact of the decisions they are making.

Those tools must then be employed to thoroughly assess process development activities and identify opportunities for incorporating more sustainable practices, adds Goldstein.

Growing adoption, but several hurdles to overcome

The adoption of sustainability-by-design is growing, driven by regulatory pressures, consumer demand for greener products, and corporate environmental sustainability goals, according to Goldstein.

As environmental responsibility continues to become a major focus, the bioprocessing industry is transforming its approach to sustainability, with a major driver being requests from customers and investors to deliver on this agenda, evidence that strong sustainability strategy and actions is good business, adds Peter Skals, director of global sustainability for FUJIFILM Diosynth Biotechnologies.

In fact, based on 2024 data, nine of the top 10 pharma companies by revenue have ecodesign targets and activities embedded into their sustainability strategies, Krista observes. “The breadth of these ecodesign targets and activities vary from specific targets like green chemistry to programs that cover the entire value chain. In addition, while Big Pharma companies are leading the charge on ecodesign, due to pressures from customers, investors, and regulators, biopharma service providers, small and emerging biotechs, and suppliers are all stepping up activities focused on improving sustainability,” he comments.

Reaching aggressive sustainability targets requires overcoming some notable challenges, however. For instance, broader application in the bioprocessing sector is inhibited by inherent limitations of the bioprocess itself, which requires a different approach due to quality and safety restrictions, according to Skals. In addition, Goldstein notes that designing in sustainability for process development must begin in the pre-clinical phase, with the capability of selected raw materials demonstrated via qualification early in the development stage.

Sustainability also needs to be integrated into pretty much every design decision, leading to a very high volume of decisions that it must be seamlessly embedded into, Krista says. In addition, he notes there are inherent trade-offs to be made, with each right decision context-dependent, increasing the complexity of the decision-making process because more parameters must be considered.

Other important challenges noted by Krista include the lack of available “clean” data for performing sustainability assessments and the time- and cost-intensive nature of current assessment methods. “A lot of the data that [are] required to assess the sustainability impact of process design and process input selection [do] not exist or [are] hard to get,” he says. Much is based on responses to supplier surveys, which are not in sufficient quantity to support effective decision-making. Traditional lifecycle assessments, meanwhile, require weeks to months to complete, and can cost in the hundreds of millions for typical processes if you include the assessments for each of the different process-design and process-input variations at the relevant decision points (3).

Further increasing the challenge is the fact that most technical staff in bioprocessing plants are not sustainability experts. “Upskilling people in sustainability to the level that would be necessary to complete sustainability assessments is not feasible, which means straightforward guidance is needed,” Krista says.

Finally, Krista emphasizes the importance of not only quantifying and naming the sustainability pressures driving ecodesign today, but assessing those that will be present 10 years from today when investigational candidates eventually reach the market. “The most sophisticated pharma companies in the context of ecodesign are considering this impact lag and extrapolating in order to assess sustainability pressures beyond the response of a particular political party in power today, but where the longer arc of history is bending towards,” he contends.

Despite all these challenges and uncertainties, Skals believes that industry innovations and the inclusion of sustainability practices in the design phase is where the big wins can be achieved. But the incremental improvements of traditional designed bioprocess are important as well, he adds, and reduce waste without compromising product quality, stability, or safety.

Advances in digital technologies are making those assessments easier to perform and providing more valuable insights. Advanced technology facilitates access to reliable process monitoring data, allowing identification and prioritization of potential areas of improvement and implementation of appropriate process adjustments, according to Skals.

Technologies such as automation, real-time monitoring, and advanced analytics help in achieving precision and efficiency, adds Goldstein. He comments that innovations in materials science also contribute to more sustainable bioprocesses.

Machine learning (ML) can help overcome many of the challenges that exist in applying sustainability-by-design today, Krista contends. “At Elio, we believe ML is critical to ensuring sustainability-by-design can be adopted as widely as possible, as early as possible, and thereby have the biggest impact. Specifically, it can help with the challenge of insufficient, high-quality data,” he says.

ML models, Krista explains, in combination with data engineering, can help fill in data gaps with sophisticated estimations using data about the specific product, supplier, and/or specific process aspects from a wide variety of data sources that are available publicly (freely or through a license). “Using this approach can enable bypassing of the data bottleneck coming from relying on supplier surveys,” he adds.

“Pharma companies are already making decisions based on very crude generalizations, such as based on product category (e.g., all alcohols have the same footprint) or other characteristics (e.g., a chemical with a higher molecular complexity has a higher environmental footprint),” Krista observes. “ML models can simply be trained on a much higher dimensionality of data and thus can make higher accuracy predictions,” he contends. Using ML tools thus also addresses the time and cost issues associated with sustainability assessments, as the calculations can be completed much more quickly and at scale.

The biopharmaceutical industry does not typically have a first-mover mentality due to stringent regulatory requirements and the need to ensure patient safety. However, Skals believes there is potential for even more intelligent sustainability solutions in the future, particularly through incorporation of improvements in greenfield designs.

It will be necessary, though, Krista emphasizes, to move away from a desire to wait to get enough of the “best” data, which pharma professionals Elio Technologies has spoken to estimate will not be available for another 5–10 years. “Fortunately, sustainability leaders in pharma companies and even pharma suppliers are recognizing that making decisions based on imperfect data earlier is key,” he comments (4,5).

Most importantly for Goldstein is the fact that sustainability-by-design is not merely a passing trend but a fundamental shift in how bioprocesses are conceptualized, developed, and ultimately transferred to commercial operations. “Goals are defined not just in yield and cost, but also by sustainability in delivering a socially responsible product. Collaborative efforts across the supply chain are underway, with companies across the industry committed to driving continuous improvement in sustainability performance,” he asserts. “Ultimately, driving sustainability into the design of our process development strategies ensures that we continue to innovate in a responsible manner while delivering high quality products for our customers,” Goldstein concludes.

Barle, E.; Melton, T.; Judge, E. Sustainability by Design for Pharmaceutical Products. Pharm. Engin. 2023 March/April.

Elio Technologies. Analysis using data from: My Green Lab, The Carbon Impact of Biotech & Pharma. November 2022.

Elio Technologies. Interviews with pharma companies and internal Elio Technologies research and analysis.

Cytiva. 2024 Global Biopharma Sustainability Review.

D’Souza, N. and Fava, J. Episode 13: Merck’s Jeffrey Whitford on Why Optimisim is Opportuity and How to Use Serendipity to Become Systematic. Five Lifes to Fifty. Podcast. Nov. 21, 2024.

Cynthia A. Challener, PhD, is a contributing editor to 

When referring to this article, please cite it as Challener, C.A. Sustainability by Design in the Context of Bioprocess Development. 

Incorporating sustainable practices into process designs as early as possible ensures optimal performance.

Sustainability by Design in the Context of Bioprocess Development

Feliza Mirasol is the science editor for 

Unidentified microbiologist is place the petri dish and tubes into incubator to incubate the culture of bacteria or fungi growth in appropriate condition, concept of microbial laboratory. | Image Credit: © Sukjai Photo – © Sukjai Photo – Stock.Adobe.com

Maintaining a sterile cleanroom environment and stringent cleanroom protocols in biopharmaceutical manufacturing are critical to ensure optimal product quality and, ultimately, patient safety. With the shift toward personalized medicines, new generation therapies, such as messenger RNA (mRNA), cell and gene therapies (CGTs), antibody-drug conjugates, and modern vaccines, are presenting sterility challenges. Therefore, it is becoming increasingly necessary for analytical technologies to advance and keep pace with the evolving, modern-day therapeutic requirements for sterile environments in cleanrooms.

As therapeutic modalities evolve, so do the challenges and methodologies associated with maintaining and verifying cleanroom sterility. Cleanroom standard operating procedures (SOPs) are the foundation to ensuring controlled, contaminant-free environments. Recent regulatory updates have prompted revisions to these procedures to align with contemporary standards and technological advancements.

For example, the International Organization for Standardization (ISO) updated the ISO 14644 series in 2015 (1), which delineates cleanroom classifications and associated protocols. In the series, ISO 14644-1 focuses on classifying air cleanliness by particle concentration, and ISO 14644-2 enumerates the requirements for testing and monitoring to ensure ongoing compliance with designated cleanliness levels. With these updates, a more rigorous approach to contamination control is emphasized, which necessitates that SOPs incorporate enhanced monitoring and maintenance strategies (1).

FDA, meanwhile, has advocated for integrating rapid and advanced detection methods into sterility testing, with the goal of expediting detection of microbial contaminants and reducing product release times without compromising safety. As a result, SOPs now often include provisions for implementing rapid microbiological methods (RMMs) alongside traditional testing techniques (2).

Sustaining sterility within cleanrooms poses multifaceted challenges, both enduring and emerging. Challenges that continue to persist include:

 Personnel remain the primary source of contamination. This is commonly attributed to inadequate gowning procedures, lapses in protocol adherence, and insufficient training—all of which can introduce particulates and microbes into the cleanroom environment (3).

Continuous surveillance of particulate and microbial levels is crucial; however, traditional monitoring methods may not provide real-time data, which potentially allows contaminants to proliferate before detection (4).

 Suboptimal cleanroom design or maintenance can lead to contamination risks. Improper airflow, inadequate filtration systems, and poorly maintained equipment are factors that can compromise sterility (5).

Meanwhile, emerging challenges posed by new therapeutic modalities, such as CGTs and mRNA-based treatments include:

 These new modalities often involve living cells or delicate nucleic acids, which are highly susceptible to environmental conditions. Therefore, maintaining appropriate temperature, humidity, and aseptic conditions is paramount.

 Production of these modalities typically involves intricate procedures, which increases the potential for contamination at multiple stages of the manufacturing process. Each step necessitates stringent controls to preserve product integrity.

 Many advanced therapies have limited shelf lives, necessitating expedited manufacturing and testing processes. Traditional sterility testing methods, which can take up to 14 days, are impractical for these products, prompting the need for rapid testing alternatives (6).

On the other end of contamination prevention is verification of sterility, which is also a critical step to ensuring a product’s safety and efficacy. Verification requires analytical testing methods, including membrane filtration, direct inoculation, and automated culture systems.

In membrane filtration, product is passed through a filter that captures potential contaminants. The filter is then incubated in growth media to detect microbial presence (7). Direct inoculation is applied to products that cannot undergo filtration. In this method, product is directly inoculated into culture media, incubated, and microbial growth is monitored over a specified period of time (8). Meanwhile, automated culture systems were developed to enhance efficiency and reliability. In these systems, product is continuously monitored for microbial growth. This method offers advantages in sensitivity and reduced hands-on time compared to manual methods (9).

The evolving regulatory requirements over the years as well as the increasing biopharmaceutical complexity and growing demand for aseptic processing have prompted significant advancements in cleanroom technologies and analytical testing methods. These innovations have been driven by the need for faster, more accurate contamination detection, improved environmental monitoring, and greater flexibility in biomanufacturing. Innovations include rapid microbiological methods (RMMs), next-generation sequencing (NGS), real-time environmental monitoring, and the use of digitalization and artificial intelligence (AI) in cleanroom analytics.

The adoption of RMMs has been prompted by the lengthy time it takes for traditional sterility testing methods. For example, membrane filtration and direct inoculation can take up to 14 days to get results. RMMs utilize technologies such as nucleic acid amplification (e.g., polymerase chain reaction-based assays), flow cytometry, and adenosine triphosphate bioluminescence to detect microbial contaminants in real-time or within hours rather than days (4). Advanced therapies such as CGTs and mRNA-based therapeutics require faster contamination detection than traditional methods and have been the real drivers behind accelerating the implementation of RMMs.

NGS, meanwhile, has emerged as an important tool for microbial identification in cleanrooms as it enables the detection and characterization of diverse microbial populations, unlike conventional culture-based methods. NGS also enables the detection of previously unculturable organisms. This technology enhances contamination tracing and root-cause investigations and can lead to more effective contamination control strategies (10).

Real-time environmental monitoring has been enabled with the development of advanced sensors. The ability to monitor particles and microbes in real time is changing the way contamination control is handled in the cleanroom. For example, technologies such as laser-induced fluorescence sensors allow for immediate airborne microbial detection without the need for culture-based methods. Systems such as those are often integrated into continuous environmental monitoring platforms and provide instant alerts to deviations in cleanroom conditions (2).

Finally, AI-driven analytics, combined with machine learning algorithms, are being deployed to analyze environmental monitoring data, detect contamination patterns, and predict contamination risks before they occur. Having this predictive approach enables proactive decision-making and reduces the risk of contamination events, which in turn minimizes production shutdowns (11).

Cleanrooms and Associated Controlled Environments Standards

 (2015).
2. Thermo Fisher Scientific. Rapid Sterility Testing: Overcoming Challenges in Cell Therapy Production. 

Cleanroom Technology: Fundamentals of Design, Testing and Operation

; Wiley, 2010.
4. Agalloco, J.; Akers, J. 

Advanced Aseptic Processing and Biopharmaceutical Manufacturing

Cleanroom Microbiology for the Non-Microbiologist

; CRC Press, 2019.
6. Jallow, J. Rapid Sterility Testing for Cell and Gene Therapy Treatments. 

 (Rockville, Md., 2023).
8. PDA. Sterility Testing of Pharmaceutical Products. 

 (2019).
9. Khuu, H. M; Stock, F.; McGann, M.; et al. Comparison of Automated Culture Systems With a CFR/USP-Compliant Method for Sterility Testing of Cell-Therapy Products. 

 (3), 183–195. DOI: 10.1080/14653240410005997
10. Xiao, Y.; Zhang, L.; Yang, B.; et al. Application of Next Generation Sequencing Technology on Contamination Monitoring in Microbiology Laboratory. 

 (1), 25–31. DOI: 10.1016/j.bsheal.2019.02.003
11. Bradshaw, N. Using AI and Machine Learning in Cleanroom Contamination Control. 

®
Vol. 49, No. 4
May 2025
Pages: 28–29

When referring to this article, please cite it as Mirasol, F. Evolving Cleanroom Procedures and Sterility Challenges. 

The shift toward personalized medicines poses new challenges in cleanroom protocols.

Evolving Cleanroom Procedures and Sterility Challenges

GSK is preparing to present data from its respiratory portfolio in more than 40 abstracts at the 2025 edition of the American Thoracic Society (ATS) International Congress, which will be held in San Francisco from May 16–21 (1).

Among a list of 43 scheduled abstracts, including four late-breaking submissions, GSK in a press release on May 2, 2025 offered details on 26 “key presentations” to be made at the event, five of which will be given orally (1). This group of presentations, GSK said, will largely focus on optimal patient care that facilitates prevention and treatment of diseases such as asthma and chronic obstructive pulmonary disease (COPD).

Two of the treatments that will be receiving plenty of attention in GSK’s presentations are mepolizumab and depemokimab, which are both monoclonal antibodies (mAbs) that target IL-5, a key cytokine or messenger protein in asthma with type 2 inflammation. Phase III trials (MATINEE for mepolizumab and SWIFT-1 and SWIFT-2 for depemokimab) have assessed the efficacy and safety of their respective medications in treating type 2 inflammation and, in mepolizumab’s case, COPD (1).

Mepolizumab is currently approved for use in the United States and Europe across four IL-5 mediated diseases, but not for treatment of COPD. Depemokimab is an investigational product that has not yet been approved for use in any country, according to GSK (1).

Meanwhile, GSK has received approvals for several treatments in other areas so far in 2025.

In April 2025, the United Kingdom’s Medicines and Healthcare products Regulatory Agency 

 (brand name Blenrep), an antibody-drug conjugate that comprises a humanized B cell maturation antigen mAb conjugated to the cytotoxic agent auristatin F via a non-cleavable linker, for treatment of adults with multiple myeloma in either of two combinations: with bortezomib plus dexamethasone for patients who have received at least one prior therapy, and with pomalidomide plus dexamethasone for those who have received a prior therapy including lenalidomide (2). Prior to that, in February, FDA 

 for meningococcal disease groups A, B, C, W, and Y, marketed as Penmenvy, for use in individuals aged 10 through 25 in the US (3).

GSK has also announced numerous partnerships and collaborations since the fourth quarter of 2024: 

 with the University of Cambridge and Cambridge University Hospitals to treat immune-related diseases with existing as well as newly-developed therapies, particularly kidney and respiratory diseases; 

The company is presenting data related to its medications designed to advance the prevention and treatment of asthma and COPD.

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