The API is, one might say, the most important element in a pharmaceutical product. Poor-quality APIs that do not meet potency levels and/or those that harbor impurities can create safety risks for the patient. Drug formulations may be destabilized by poor-quality APIs, which could shorten the drug’s shelf life. Poor-quality APIs may result in regulatory actions or recalls that can create production delays for the manufacturer that can impact the supply chain, therefore, keeping drugs from the patients that need them. Poor API quality may also leave the door open for counterfeit drugs to reach the market.

“From a supply chain perspective, poor-quality APIs increase the likelihood of production interruptions, which disrupt the supply to the market,” says Qixuan Lu, vice-president of Process Chemistry at BioDuro. “Because of the poor-quality API, additional quality control measures become necessary, driving up costs and diminishing profit margins. If such issues arise repeatedly, they can harm a company’s reputation and undermine market confidence in its products. Beyond these commercial setbacks, manufacturers also face considerable legal and regulatory risks if they fail to meet the standards required for pharmaceutical quality and patient safety.”

Impurities may result from a lack of a robust process and inadequate quality control, which often evolves from a lack of understanding of critical quality attributes (CQAs). This can manifest in poorly defined design spaces and analytical methods that fail to detect impurities, according to Dirk-Jan van Zoelen, Drug Substance Business Unit director, Ardena. “Moreover, when new impurities are identified, out-of-specification (OOS) results can lead to production delays, affecting the stability and reliability of the supply chain,” van Zoelen explains.

“Poor quality API presents several risks to the drug product, supply chain, and ultimately patients. These risks range from a lack of efficacy to the possibility of toxicity. Poor efficacy may result from low potency API, whereas toxicity may be related to the presence of uncontrolled impurities,” Richard Castledine, head of Drug Substance Operations at Quotient Sciences, says. “Additionally, simple batch-to-batch variability of quality attributes such as particle size and residual solvent concentration may result in differences in downstream manufacturing processes.”

Having strict quality checks, supplier audits, and strong compliance measures are important to maintain a safe and smoothly run system, according to M. Damodharan, chief quality officer, Sai Life Sciences.

A comprehensive control strategy is key for ensuring API quality, according to van Zoelen. This strategy should address an in-depth understanding of the processes involved (e.g., chemical, physical, and cleaning) with defined critical process parameters (CPPs) and acceptable ranges. These processes should then be validated. The critical material attributes of raw materials and starting chemicals should be evaluated using comprehensive fit-for-use assessments to determine impurity clearance. A rigorous supplier qualification process should be put in place to ensure material quality and regulatory compliance. Analytical methods should be developed and validated in accordance with International Council for Harmonisation (ICH) guidelines, and a quality assurance department should be created that has an established quality management system to monitor regulatory compliance, van Zoelen says.

“A strong quality management system, aligned with good manufacturing practice (GMP) requirements, should define detailed production processes and quality control procedures to ensure that every stage of manufacturing is consistently supervised,” Lu agrees. “By actively monitoring the manufacturing workflow, manufacturers can guarantee that each critical step meets the required specifications and prevents potential quality deviations.”

Once parameters are set, they must be understood within the manufacturing process, says Castledine. “By understanding the edge of failure of any given process checks and controls can be implemented to ensure the process remains within the target ranges to produce high quality drug products,” he says. “Establishing a high-quality supply chain for all materials used in the manufacturing operation reduces the risk of introducing substandard materials to the process. Finally, the manufacturing process should be supported by internal analytical capabilities to assess critical quality attributes.”

“When designing a synthetic route for an API, process route design involves finding and selecting a pathway with favorable characteristics to maintain high quality CGMP [current good manufacturing practice] production when the API is manufactured at larger scale,” Castledine continues. “Modification or redesign of the process is often required to prepare for larger batch sizes and ensure that API can be produced in a compliant, efficient manner. Early on, drug developers should be mindful of identifying and developing control strategies for process and degradation impurities which may otherwise remain in the API. Additionally, avoiding niche or expensive starting materials and reagents for API synthesis is recommended; these can result in supply chain difficulties later and possibly lead to poorer quality substitutions being made.”

Sourcing from GMP-certified suppliers can help ensure API quality, according to Subbareddy Inta, vice-president and head of Quality, Dr. Reddy’s Laboratories North America. “Regular audits and inspections of supplier facilities ensure compliance with safety and quality standards,” Inta says.

“To secure high-quality APIs, manufacturers should implement a rigorous supplier evaluation system that carefully selects qualified raw material providers and conducts periodic audits. Incoming raw materials must undergo thorough inspections to confirm compliance with specified standards,” Lu stresses.

“Suppliers should be seen as an extension of internal manufacturing controls and standards, aligning with the drug manufacturer’s quality and compliance goals/objectives,” Timothy Buckley, vice-president of Global Quality, SK pharmteco, says. “Supplier qualification is critical, not only from a quality perspective, but also to ensure reliable supplies to eliminate potential drug shortages and supply interruptions.”

Materials used that are obtained from a third-party vendor must be rigorously qualified to ensure quality. This can be done through spike/fate and purge studies conducted on multiple lots, according to van Zoelen.

The physical and chemical characteristics of these materials, including crystal form, particle size, solubility, purity, residual solvents, and heavy metals, must be tested for CQAs to determine that they meet requirements. “Moreover, understanding the synthetic route used by the vendor is crucial, since the reagents, reaction conditions, and by-product removal methods should be compatible with the downstream manufacturing process,” Lu states. “This alignment ensures efficient conversion of starting materials or intermediates and minimizes impurities that might otherwise compromise the finished product’s quality.”

Tests performed on third-party-sourced materials, according to Ragavendran Vasudevan, director and head of Operations C2 Pharma India Ltd., include identity testing, purity and impurity profiling, assay testing, physical and chemical characterization, microbial and endotoxin testing, and stability and storage condition studies.

“Identity testing using FTIR [Fourier transform infrared spectroscopy], NMR [nuclear magnetic resonance], HPLC [high-performance liquid chromatography], or GC–MS [gas chromatography–mass spectrometry] confirms chemical structure. Purity and impurity profiling detect unwanted byproducts, while potency is measured through titration, UV-Vis [ultraviolet-visible], or HPLC. Residual solvent analysis via GC-HS [headspace-gas chromatography] ensures no toxic solvents remain,” Damodharan explains. “Water content is checked using Karl Fischer titration, and microbial testing screens for bacteria and endotoxins. Particle size and polymorphism studies assess bioavailability impact. Stability testing evaluates degradation risks, and elemental analysis using ICP-MS [inductively coupled plasma mass spectrometry] checks for toxic metals. These steps ensure the API meets safety and regulatory standards.”

Validation is a crucial step in ensuring the quality of APIs and applies to the regulatory compliance requirements of facilities, equipment, and infrastructure, according to Lu. “Stability testing should also be carried out to track changes in the physical and chemical properties of the API, as well as the formation of any degraded products or impurities over time,” Lu says. “These tests help determine appropriate shelf life and storage conditions, ensuring that the API retains its intended quality and efficacy until it is used.”

Other validation exercises, according to Vasudevan, include supplier qualification, raw material testing, process validation, analytical method validation, and regulatory documentation.

“Validating test methods, such as chromatography and spectrometry, ensures accurate purity and potency analysis,” Inta says. “Conducting stability studies under various storage conditions ensures the API remains stable over time. Ensuring compliance with pharmacopeial standards and regulatory requirements maintains high-quality standards.”

“Confirmation of the manufacturing process used is also essential to ensure that methods used for testing are suitable,” Castledine says. “For example, some manufacturing processes have the potential to generate potentially mutagenic impurities (PMI) which need to be controlled to PPM [parts per million] levels, often requiring the development of specialized HRMS [high-resolution mass spectrometry] methods.”

Quality validation of APIs should be a phase-appropriate approach, according to van Zoelen, with analytical methods getting partial validation in early phase development that focuses on process-related impurities and safety data. “As development progresses to later clinical phases, a more comprehensive validation is required, including full validation of the analytical methods for the API, starting materials, and intermediates,” van Zoelen says. “Impurity profiles are set during early-stage development, with tox-batch validation and process validation as essential milestones. Throughout this process, supplier qualifications should also be conducted to ensure consistency and reliability of materials.”

A transparent supply chain is achieved by good distribution practices, according to Damodharan, and helps prevent counterfeit drugs. “Regulatory compliance is a must, including accurate documentation and real-time monitoring. Staying updated on compliance changes and maintaining data integrity [can] ensure long-term quality,” Damodharan says.

Maintaining accurate CGMP records for APIs is necessary to assure regulators of compliance, traceability, and product quality. However, according to Vasudevan, many companies lack complete and accurate documentation and have poor record keeping practices. They also have data integrity violations and insufficient training on compliance with CGMPs.

Poor documentation, including incomplete records or backdating, violate CGMPs and data integrity requirements. “Illegible batch records, unverified calculations, and outdated SOPs [standard operating procedures] lead to errors,” Damodharan says. “Failing to record deviations, corrective actions, or equipment calibrations weakens oversight. These slip-ups can trigger compliance issues, recalls, or even regulatory shutdowns.”

It is important to avoid gaps in impurity data in CGMP records. A mistake some manufacturers make, according to van Zoelen, is not aligning analytical methods with an API’s impurity profile in clinical phases. “As development progresses, particularly through the clinical phases, new impurities may emerge, such as genotoxic or mutagenic impurities,” van Zoelen says. “Multiple analytical methods may be employed at different stages, and these may change as the development advances. It is critical to ensure continuous alignment of these methods with impurity data to avoid gaps or discrepancies in CGMP records, especially as the product progresses through clinical phases.”

“Failing to capture batch-specific information or variations in production conditions can compromise data integrity,” Inta says. “Inadequate documentation of deviations or corrective actions can leave issues unresolved. Lastly, not adhering to proper data integrity protocols, such as avoiding falsification or improper handling of electronic records, can severely compromise data quality.”

“While GMP expectations such as data integrity, GDP [good documentation practices], and facility/personnel controls are the same for APIs and drug products, a key issue for API manufacturers is ensuring appropriate documentation and evaluation of supplier changes,” Buckley explains. “Changes in the route of synthesis for critical raw materials, such as regulatory starting materials, can lead to a new or altered impurity profile of existing impurities. This may introduce concerns related to nitrosamines, heavy metals, and/or PEG [polyethylene glycol] residues. Therefore, while there are many GMP considerations, change control and supplier qualification are especially critical in API manufacturing.”

Highly potent APIs (HPAPIs) have increased pharmacological activity and safety risks according to Vasudevan. Safe production and handling of HPAPIs can be done by implementing stringent quality measures. These include dedicated production areas or isolators and closed-system processing. Using segregated facilities that have independent heating, ventilation, and air conditioning (HVAC) systems can prevent contamination. Maintaining negative pressure environments may contain potent compounds, and using automated handling systems reduces manual intervention, insists Vasudevan.

“More drugs in development than ever are classed as highly potent,” Helen Baker, director of Formulation Design, Quotient Sciences, explains. “HPAPIs present additional CMC [chemistry, manufacturing, and controls] challenges due to the containment requirements to protect both the operators and manufacturing facilities. The production processes may also require greater precision and control due to the very small quantities of drug present in the final dosage form.”

Preventing cross-contamination in the manufacture of HPAPIs is the main concern with ensuring quality for pharmaceutical products that contain these types of ingredients, especially when manufactured in multipurpose facilities, according to van Zoelen, who stresses that stringent cleaning protocols must be adhered to. “The maximum allowed carryover (MACO) should be defined based on health-based occupational exposure limits (HBOEL) to ensure safe transitions between high-potency and low-potency APIs,” van Zoelen says. “Additionally, a comprehensive cross-contamination strategy is essential, including facility design considerations, dedicated equipment, and validated cleaning procedures to mitigate the risk of HPAPI contamination in subsequent batches.”

“If potent compounds are produced in the same facility as less potent products, dedicated production lines or segregated manufacturing areas are essential to eliminate the risk of contamination and to uphold stringent safety standards,” Lu agrees.

“EH&S [environmental, health, and safety] audits are critical to ensure that HPAPIs continually meet CGMP compliance standards and regulatory requirements,” Baker says. “The HPAPI manufacturer should also have a robust risk management program that includes ongoing environmental health monitoring and surrogate monitoring to ensure consistent control over our processes, facilities, cleaning procedures, and SOPs is also critical to ensure that HPAPIs are being manufactured consistently.”

Drug shortages can impede access to life-saving medications, and quality issues are one reason drug shortages may occur (1). Regulatory agencies have guidelines that should be followed to mitigate the risk of poor-quality ingredients, such as APIs. By following these guidelines, having a robust quality system, and qualifying API suppliers, drug manufacturers can help keep the supply chain healthy.

 March13, 2025 (accessed April 11, 2025). 

https://www.fda.gov/drugs/drug-safety-and-availability/drug-shortages

When referring to this article, please cite it Haigney, S. Poor API Quality Threatens a Healthy Supply. 

Articles

Cover Story

Poor API quality may often lead to delays in production and a shortage of supply.

Poor API Quality Threatens a Healthy Supply

While many parenteral products can be stored and shipped in the liquid state at room temperature, some, including most based on biologic drug substances, must be maintained at low temperatures. When refrigeration is not sufficient, two options remain: keeping the products in a frozen state or freeze-drying (lyophilizing) them into a powdered form. There are advantages and disadvantages to both, with many factors to consider when choosing between the two solutions.

The biggest driver for freezing or freeze-drying parenteral products is instability of the drug substance when in solution. This issue does not often arise for small-molecule APIs, but is common for recombinant proteins and antibody-based molecules. “Developing freeze-dried or frozen parenteral formulations is primarily driven by the inherent instability of biological molecules in solution at or below room temperature, limited shelf life in liquid form, high sensitivity to temperature fluctuations and air-liquid interfaces, and excipient-related limitations,” says Maria Fernanda Zuluaga Estrada, principal scientist and formulation development group leader at Lonza.

Protein molecules, explains Jeremy Guo, senior vice president and head of drug-product development and clinical drug-product manufacturing at WuXi Biologics, are physically and/or chemically unstable during long-term storage, suffering from aggregation and visible particle formation, deamidation, oxidation, and other degradation pathways, even in optimized aqueous formulations after formulation screening.

“Freezing or lyophilizing these formulations is the optimal choice, because physical and/or chemical reactions will be inhibited in the frozen glassy state or freeze-dried state with minimal water content,” Guo says. At Lonza, advanced analytical tools are used for diagnosing vulnerabilities potentially leading to instabilities, including mass spectrometry to detect and foresee post-translational modifications, holistic (i.e., stability-indicating) surfactant analytics, subvisible particle characterization to differentiate potential protein-versus-surfactant instability, in-depth root cause analysis in case of surfactant degradation, in-depth host-cell protein, especially lipase, characterization and quantification, and container-closure integrity testing and qualification.

Beyond instability, time can also be a driver for choosing to freeze or lyophilize a drug candidate. “When the development timeline is very limited for early filing of an investigation new drug (IND) application, the final formulation needs to be locked down without completion of comprehensive formulation screening or generation of sufficient stability data. Freezing or freeze-drying can help ensure long-term stability while still meeting these shorter timelines. Comprehensive screening can then be performed during late-stage development to determine the final, commercial formulation,” Guo observes.

There is one other significant reason for moving forward frozen or freeze-dried formulations during the development of biologics, according to Zuluaga Estrada. Many liquid biologic formulations have limited expected shelf-lives when stored at or below room temperature due to surfactant degradation, which is why Lonza conducts so many surfactant-related analyses. “For cases where extensive lipolytic activity is demonstrated, Lonza’s proprietary lipase assay can support the removal of lipolytic activity during downstream processing,” she notes. The company also has a proprietary approach to lipase inhibition that involves addition of low concentrations of citrate to mitigate surfactant degradation, which can potentially prevent the need for frozen or lyophilized storage, Zuluaga Estrada adds.

Advantages and disadvantages of frozen formulations

The primary advantage of frozen formulations is their ability to preserve unstable formulations due to the immobilization of molecular components, thereby extending the shelf life, observes Zuluaga Estrada. Development of frozen formulations also generally takes less time and is less expensive than the development of lyophilized products, according to Guo. The lack of the need for a reconstitution step, which is required for freeze-dried formulations, is another benefit noted by Guo.

There are several disadvantages to frozen formulations, however. “The complexity of developing frozen formulations is often not considered in full, and the related challenges present a substantial risk in the development of biologics,” Zuluaga Estrada contends. She highlights lack of molecule or excipient stability in certain frozen formulations (e.g., cold denaturation and aggregation of proteins, crystallization of excipients, phase separation) and compromised integrity of the container-closure system at ultralow temperatures as two examples.

Beyond stability issues, the key challenge with frozen products is the need for extensive infrastructure and shipping capabilities to support the cold chain, says Zuluaga Estrada. “Robust freezing parameters, appropriate storage conditions, and adequate supply chain management need to be considered,” she notes.

Temperature excursions during storage and shipment of frozen products, adds Guo, can lead to ice crystal formation, protein denaturation, and a potential decrease in drug efficacy. In addition, the need for temperature control during storage and shipment at manufacturing sites, depots, and clinical centers adds significant cost and inconvenience, he comments.

Other concerns pointed out by Guo include the higher risk of vial breakage and the need for lower filling volumes compared to liquid drug products in the same container to reduce this risk.

To avoid these issues, often redevelopment to a liquid or lyophilized formulation is pursued once a candidate reaches later development stages and looks to be commercialized. However, switching to a liquid or freeze-dried product during late-phase development requires significant additional effort and adds cost and time for programs, according to Zuluaga Estrada.

Lyophilized formulations present opportunities and challenges

Freeze drying also has both positive and negative attributes. In addition to overcoming formulation instability issues, one of the biggest benefits is the ability to store and ship products at refrigerated (2–8 °C) or even room temperatures, Guo says.

Appropriate storage of lyophilized cakes within these temperature conditions (i.e., below their glass-transition temperatures), significantly reduces the logistical and storage constraints compared to frozen products, agrees Zuluaga Estrada. “That translates to greater storage and transport efficiency, particularly for global products and patient-centric delivery,” Guo concludes.

As with frozen formulations, however, it is necessary to use lower filling volumes than those of liquid products in the same container to ensure efficiency of the lyophilization process. In addition, Guo observes that the development of freeze-drying processes requires specialized expertise and capabilities and often adds time. The lyophilization process is also energy-intensive and extends the overall manufacturing time.

The need for reconstitution before administration also poses some concerns. Not only does Guo note the potential risk of product contamination by stopper debris after multiple punctures for reconstitution and sampling, high-concentration formulations can be challenging with respect to the time required and the potential for dosing errors and introduction of contaminants.

Despite the complexity, expense, and extended timelines typically associated with the development of lyophilized products, with the right expertise and robust platform cycles, it is possible to develop freeze-dried formulations in similar timeframes compared to liquid formats, according to Zuluaga Estrada. “We employ specialized characterization techniques including modulated differential scanning calorimetry (mDSC) and freeze-drying microscopy (FDM) to identify key thermal changes and, as required, optimize and develop robust lyophilization cycles in cost-effective timelines and with low material requirements,” she explains.

Given the different advantages and disadvantages of freezing and freeze-drying of parenteral formulations, there are some general factors that often influence the choice of one method over another. First is the ability of the drug substance to withstand the lyophilization process and/or freeze-thaw cycles, according to Zuluaga Estrada. The clinical application and route of administration are also important considerations. For instance, she notes that the acceptance of lyophilized formats is lower for emergency medications that must be administered immediately and medicines given via intravitreal administration. Other aspects that should be taken into account include the development phase, supply chain, timelines, and costs.

In general, says Guo, frozen products are often preferred if the development timeline is severely limited (e.g., six months to IND); the product is unstable and sensitive to the freeze-drying process; and the medicine will only require distribution locally or to clinical centers with sufficient cold-chain infrastructure. In addition, he notes that long-term storage at -20 °C is preferred over storage at ultra-low temperatures due to the greater availability of this capability at clinical centers.

Lyophilization is typically preferred, Guo continues, for unstable products that can withstand the freeze-drying process, there is sufficient time for development of an optimal lyophilization process, a long shelf-life is needed, and/or the product will be distributed to globally, including areas where cold-chain management would pose challenges.

“Overall,” Guo concludes, “when selecting between frozen and freeze-dried formulations, scientific, economic, and practical factors should be considered. Stability of the molecule for long-term storage is the primary concern. Other factors such as timeline, costs, storage availability, and distribution logistics should be evaluated as well.”

The evaluation of lyophilized formats can be a backup option for proteins that are unstable in solution at room temperature or under refrigeration or for cases where considerable surfactant degradation (potentially leading to particle formation) is observed, Zuluaga Estrada says.

When lyophilization does not improve protein stability or a lyophilized format is not suitable, such as when large fill volumes or long reconstitution times are involved, frozen storage of the liquid at sub-zero temperatures should be assessed.

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

When referring to this article, please cite it as Challener, C.A. Parenteral Formulation: Deciding When to Go Frozen or Freeze-Dried.

Development

Scientific, economic, and practical factors should be considered when choosing between the frozen state and lyophilization.

Parenteral Formulation: Deciding When to Go Frozen or Freeze-Dried

Variability in bioburden testing presents a significant challenge in ensuring accurate microbial enumeration during biopharmaceutical manufacturing. This study provides a quantitative framework for understanding and minimizing errors in colony-forming unit (CFU) counts, integrating regulatory guidance with statistical modeling. Through detailed analysis, the author demonstrates how factors such as microbial distribution, dilution steps, and test volume selection contribute to variability, particularly at low CFU levels where Poisson-distributed behavior dominates. Using models grounded in relative error and confidence-based metrics, the author calculates the percentage error associated with replicate counts and test conditions. A root sum of squares approach is further proposed to estimate total combined error from independent sources that include CFU/plate variability, number of replicates, serial dilution, and sample volume. This work offers a statistically rigorous method to enhance microbial detection reliability, thereby supporting consistent quality control and regulatory compliance in biopharmaceutical environments.

Bioburden testing plays a crucial role in ensuring the microbiological quality of biopharmaceutical products by quantifying microbial contamination at various stages of production. Accurate microbial enumeration is essential for compliance with regulatory standards, product safety, and process control. However, numerous factors introduce variability in colony-forming unit (CFU) counts, including microbial distribution, test volume selection, dilution errors, and plating techniques. Understanding the statistical principles that govern these factors is critical to minimizing error and improving the reliability of bioburden testing.

One of the key challenges in microbial enumeration is establishing an acceptable range for CFU counts per plate to ensure accurate results while avoiding errors caused by overcrowding or underrepresentation. Regulatory guidelines such as 

Validation of Microbial Recovery from Pharmaceutical Articles

, and American Society for Testing and Materials (ASTM) standards provide specific CFU ranges to maintain consistency in bioburden assessments. Additionally, sources of variability such as pipetting errors and microbial recovery rates can significantly impact CFU enumeration. Addressing these challenges requires the application of statistical models to quantify errors and establish robust bioburden testing methodologies that enhance data integrity.

1. Breed, R. S.; Dotterrer, W. D. The Number of Colonies Allowable on Satisfactory Agar Plates. 

, 1 (3), 321–331. DOI: 10.1128/jb.1.3.321-331.1916
2. Tomasiewicz, D. M.; Hotchkiss, D. K.; Reinbold, G. W.; Read, R. B., Jr.; Hartman, P. A. The Most Suitable Number of Colonies on Plates for Counting 1. 

, 43 (4), 282–286. DOI: 10.4315/0362-028X-43.4.282
3. USP. General Chapter <1227>. Validation of Microbial Recovery from Pharmaceutical Articles. 

, pg. 3053 (Rockville, Md., 2011).
4. ASTM International. Standard Practice for Determining Microbial Colony Counts from Water Analyzed by Plating Methods. 

 (1998).
5. Maturin, L.: Peeler, J. T. BAM Chapter 3: Aerobic Plate Count. In 

Pharmaceutical Microbiology Manual (ORA.007)

; Revision 2; FDA, 2020.
7. US Forum on Environmental Measurements (FEM) Microbiology Action Team. 

Method Validation of US Environmental Protection Agency Microbiological Methods of Analysis (FEM Document No. 2009-01)

; US Environmental Protection Agency, 2009.
8. Sutton, S. The Environmental Monitoring Program in a GMP Environment. 

, 14 (3), 22–29.
9. Stites, R. Sampling Error and Poisson Processes. 

Naveenganesh Muralidharan, nmural@agcbio.com, is senior manager, Manufacturing Science and Technology (MSAT), at AGC Biologics.

When referring to this article, please cite it as Muralidharan, N. Understanding the Variability in Bioburden Test Results in Biomanufacturing. 

Peer-Review Research

This article explores the impact of test volume, microbial distribution, and dilution errors on bioburden testing variability. It presents statistical approaches to estimate percentage error and discusses strategies to optimize microbial enumeration techniques in biopharmaceutical quality control.

Understanding the Variability in Bioburden Test Results in Biomanufacturing

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.

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

Manufacturing

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

Sustainability by Design in the Context of Bioprocess Development

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. 

Analytics

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

Evolving Cleanroom Procedures and Sterility Challenges

A January 2025 report from Vector, a United Kingdom-based recruitment process outsourcing (RPO) partner for pharmaceutical contract development and manufacturing organizations (CDMOs) and contract research organizations (CROs), defined five main trends to watch for regarding outsourcing within the bio/pharmaceutical industry itself (1). Skill specialization, regulatory complexities, the perpetuance of remote and hybrid work, the meteoric rise of artificial intelligence (AI) technologies, and talent retention were all given their place in the pharma workforce of the future.

At least one of these factors—a continued reduction in in-office work—is a stubbornly lingering aftereffect of the COVID-19 pandemic. Erik Wiklund, CEO of Circio, called it the “COVID bubble,” a “nuclear winter” of sorts for smaller biotech companies that made capital difficult to access and caused massive layoffs in the United States and Europe (2).

However, Wiklund sees the winds of change shifting for Circio, and believes the experiences his company has been through in the past five years mirror those of countless industry peers.

“Many companies launch great ambitions, large valuations,” Wiklund explained (2). “People flow into the industry, and then the breaks set in, but then what happens is that the companies that survive, they then suddenly have access to a broad talent pool, and then the capital comes back.”

Central to that broadening of talent, opined Sheryl Johnson, pharma application development manager at Orbia Fluor & Energy Materials, should be endeavoring to continue the strides the industry has made toward diversity, equity, and inclusion—keeping in mind that the pharmaceutical world encompasses far more than the US, where those buzzwords have come under political scrutiny (3).

Johnson says Orbia is taking a variety of proactive approaches to improve gender-diverse representations within their workforce, but full diversity will take ongoing cooperation throughout the field.

“Women, in particular, can bring unique perspectives, talents, [and] approaches that can drive innovation, particularly in the pharma industry,” Johnson said (3). “Female leaders can often excel in collaborative and inclusive leadership styles, which I feel can help foster creativity and new ideas. I find women are very open to sharing of new ideas and provide supportive attitude to research management and development through considered and empathetic communication.”

As part of its coverage of both the International Day of Women and Girls in Science on February 11 and International Women’s Day on March 8, 

® conducted a series of interviews with leading women in the bio/pharma space, Johnson included, explaining some reasons for a gender gap in science, technology, engineering, and math (STEM) that has skewed the balance of skilled workers heavily to the male side, and offering potential ways the industry can foster and incentivize female involvement (4).

While Sabine Gölden, eLearning & Training Lead at the European consulting firm MAIN5, said educational STEM programs aim to provide equal access to all without being gender-specific, she added that persistent stereotypes of what are traditionally seen as gendered career paths should be understood by females at a young age—especially when programs exist that challenge them to break out of those norms (5).

“Scientific research shows that there are cognitive differences and varying talents between men and women,” Gölden said (5). “As a result, some individuals may naturally have advantages in this or that topic or might suit better in a specific position. These talents follow a Gaussian (‘normal’) distribution, and men are more likely to have cognitive advantages for STEM-related work—but women are still underrepresented in these fields.”

Yet to return to another of the Vector report’s key points, talent retention remains a major hurdle. And it may not always be, as in Wiklund’s “COVID bubble” example, the sole burden of the industry, or any specific company.

Gölden said the “work-motherhood challenge” is still one that women are fighting, even within themselves, across various workforces (5). She calls it a “leaky pipeline,” one that may have an unconventional fix.

“Even today, it’s still uncommon for women to be the primary breadwinners and men to take on the role of caretakers,” she said (5). “From my perspective, this is where the biggest challenge lies. It’s not just about providing opportunities and empowerment for women; it’s about breaking down the barriers for men, who often face potential career and reputation impacts when they take on caretaker roles."

The reputations of human workers of all backgrounds could figure to be at stake in the next several years as AI impacts more corners of the industry. Wiklund is in lockstep with the Vector report in theorizing that AI’s most likely usefulness in the near term will be in the earliest stages of the R&D process, such as drug development (1,2). But as far as human decision-making, Wiklund believes the technology’s intrusion is still a long way off.

“Maybe the area which appears most obvious is in diagnostics and prognostics, where an artificial intelligence can start utilizing information and colliding information in a more systematic way, using radiology and other types of scans to give better and more reliable interpretations,” he said (2). “That probably is where artificial intelligence will make an impact first. But again, the business models are not really established yet. The regulatory frameworks are not there yet. So ... I think it’s going to take longer than 2025 for us to start really seeing [the] big impact of this when it comes to therapeutic development, or the real impact on treatment decisions.”

Doing the best to keep a step ahead of the latest AI innovations can only benefit human professionals, and gender diversity plays a distinct role in that as well. Programs such as Girls Who Code, which helps girls build coding and AI skills, are gateways for women in healthcare industries who now must compete against machine as well as man, according to Jean Redmond, chief operating officer at Biologit (4). But there’s a higher purpose here, too: preparing those women to be the decision-makers that Wiklund said AI is not yet ready to usurp.

“By increasing representation in STEM fields, these initiatives help drive diversity in leadership and innovation in pharma and biotech,” Redmond said (4). “Additionally, mentorship, networking, and industry partnerships further support women in transitioning from education to impactful careers.”

As the US rewrites its tariff policies early in the second Trump Administration, companies in Europe and other parts of the world may look elsewhere for development opportunities, according to Wiklund. So even as access to talent is improving five years post-COVID, where people are looking for new work, and which companies will partner with them, and each other, remain question marks.

“Increasing cost levels in the US in particular, [a] strong dollar, and increasing inflation [have] driven up prices,” Wiklund explained, also adding that “it’s become cheaper by comparison to develop drugs in Europe, Asia, [and] Australia, and I think maybe if that trend continues with a strong US economy and increasing prices, then you may see that that kind of European, eastward-oriented trend continuing” (2).

Will the geopolitical climate, artificial intelligence, gender imbalances, or the flexibility of working environments prove to be headwinds or tailwinds for finding, developing, and retaining talent? Finding a definitive answer that fits any of those factors is neither easy nor certain. Skilled workers are out there to be had, but how bio/pharmaceutical companies treat them and encourage their career growth is a destination to which there are many different paths.

The pandemic made it daunting for companies to retain talent and then find it anew, but just as that cloud is lifting and workforce diversity is being embraced, AI beckons as a new challenge.

Pharmaceutical Technology May 2025

Poor API Quality Threatens a Healthy Supply

Parenteral Formulation: Deciding When to Go Frozen or Freeze-Dried

Understanding the Variability in Bioburden Test Results in Biomanufacturing

Sustainability by Design in the Context of Bioprocess Development

Evolving Cleanroom Procedures and Sterility Challenges

Authentic Intelligence: Finding Diverse Talent in the Age of AI

Complying with European versus US GMPs

Quality, Resilience, and Reinvention in Pharma Manufacturing