Adapting to Molecular Complexity: Modern drug development is shifting toward highly complex small molecules, necessitating advanced purification and containment strategies for targeted patient populations.
Embracing Process Intensification: To boost efficiency, manufacturers are integrating continuous manufacturing, automation, and high-throughput technologies into legacy production lines.
Adopting Biologics Innovations: Originally perfected for biopharma, single-use technologies and modular facility designs are now industry standards for flexible small molecule production.
Enhancing Supply Chain Resilience: Manufacturers are overhauling operations to maintain high-quality output despite increasingly fragile global supply chains.
Future-Proofing Facilities: The transition from traditional methods to automated, modular factories is essential for staying competitive in a rapidly evolving pharmaceutical market.
1 Overview
The synthesis of highly complex small molecule APIs generally requires multistep routes leveraging sophisticated methods, often including a combination of a wide range of organic chemistries, chemocatalysis, and enzymatic catalysis (Table 8). The higher potency of APIs today also creates the need for highly specialized facilities and equipment, run by skilled and highly trained operators. Manufacturers are concurrently pursuing strategies to increase the sustainability of their operations, while also realizing greater levels of efficiency and productivity. Here we summarize some of the top trends in API manufacturing.
New Chemistry Technologies
2 Green Processing
2.1. Recognition of the impacts that climate change will have on the world has driven manufacturing sectors to seek means for reducing emissions and otherwise increasing the sustainability of their operations. The pharmaceutical industry is no exception. Since the IQ Consortium’s Green Chemistry Working Group first met with the FDA in 2012 to identify opportunities for promoting green chemistry,[1] it has taken other steps to guide drug manufacturing, including the adoption of the Green Aspiration Level (GAL), originally developed by Boehringer Ingelheim[2][3] as a standardized green-efficiency goal, and development of the Green Scorecard to show the value-added impact of green chemistry and other steps, which illustrates the value-added impact of green chemistry and other steps to increase sustainability.[4]
2.2. There are many approaches to achieving greener processing solutions. Increasing yields and throughput are two basic goals.74 Greater efficiency translates to reduced energy and raw material consumption, as well as reduced waste and emissions. The most successful API producers incorporate the concepts of green chemistry and sustainability into their day-to-day activities, and not only develop greener processes, but use greener raw materials, and recycle and reuse wastes, particularly solvents.
3 Electrochemistry
3.1. In the search for more sustainable small molecule manufacturing solutions, use of electrochemistry has experienced a resurgence. An added driver for their growing adoption is the potential to access molecular structures not possible using conventional organic chemistry.[5]
3.2. Electrochemistry is widely used in medicinal chemistry for oxidation and reduction reactions because it is typically performed under mild conditions using much less toxic and hazardous oxidizing agents.[5] It also tends to be more economical. Implementation at large scale can be challenging, however, but even so, there are a number of successful processes in adjacent industries, and pharmaceutical companies are actively seeking to expand its application beyond discovery and development into manufacturing.
3.3. One of the key challenges to the expanding use of novel technologies such as electrochemistry is the need for specialized equipment rather than established, multipurpose systems and regulatory uncertainty.[6]
4 Chiral Technologies
4.1. Small molecule drug candidates today often have multiple chiral centers, thus many different isomers, and typically only one isomer has the desired activity, with the others potentially being harmful. Control of chirality during the manufacture of these APIs is therefore essential to ensure high yields and minimal production of unwanted isomeric impurities. Achieving such a high level of selectivity, particularly for molecules with multiple centers of chirality and potential other structural isomeric forms, is extremely challenging.
4.2. Fortunately, advances in catalysis are providing small molecule API manufacturers with an ever- widening range of methods for the selective synthesis of complex molecules (vide infra). In addition, several catalysts in use today are no longer patent-protected. This gives process chemists a greater range of tools to develop more efficient synthetic routes to complex chemical products. Simulated moving bed (SMB) and other chiral separation technologies have also become more cost-efficient, with less expensive and more durable stationary phases. Additionally, improvements in techniques that leverage supercritical fluids have enabled their use in the production of certain critical pharmaceutical intermediates.
5 Advances in Chemocatalytic Solutions
5.1. Catalytic transformations using chemical catalysts continue to evolve. Where process chemists once had to settle for separating racemic mixtures of some chiral compounds, thus limiting the maximum yield to 50%, for many reactions today, it is possible to selectively produce one desired enantiomer. In addition, the first catalysts that enabled such transformations, which often involved rare transition metals, and sometimes toxic or hazardous ligands and reaction conditions, are increasingly being replaced with benign alternatives based on common metals, such as iron.[1]
5.2. One key example is the myriad cross-coupling reactions in use today, which enable the selective coupling of chemically differentiated reagents. These reactions have contributed greatly to the improved efficiency of pharma synthesis and have made it possible to produce previously inaccessible starting materials and intermediates. More recently, significant advances have been made to develop more sustainable alternatives to the initial coupling technologies in order to address concerns about the potential genotoxicity of intermediates, the need for highly functionalized raw materials, and the use of rare metal catalysts.[1]
5.3. To facilitate continuous processing and achieve higher turnovers, companies also employ fixed- bed catalysis. The key is to identify an optimum catalytic solution that is both robust and reliable at commercial scale.[7] Techniques such as HTS, combinatorial ligand discovery, computational modelling, and advanced analytical chemistry are used to gain this information.[8]
6 Advances in Enzymatic Technologies
6.1. There are more chemocatalysts than enzymatic catalysts available for pharmaceutical manufacturing, and in some cases transitional metal or organic chemical catalysts provide better results than — or achieve transformations not possible with — the enzymes that are available. Interest in enzymatic reactions, however, continues to grow because they are often performed in water at room temperature, and do not require the use of hazardous or toxic reagents, or challenging process conditions.
6.2. Advances in molecular biology, metabolic and protein engineering, and bioinformatics — notably, AI and ML algorithms leveraging analytical data that is generated through high- throughput experimentation — combined with increasing capabilities in site-specific mutagenesis and protein crystal structure-based rational design, directed evolution, and computational de novo design, are leading to the development of highly selective biocatalysts that provide complex pharmaceutical intermediates in high yields and purities.70, 77 One of the earliest stumbling blocks in the use of biocatalysis — the lengthy time to design and manufacture enzymes for large-scale production — is no longer an issue in most cases.
7 Advances in Purification Technologies
7.1. The focus on increasing efficiency while minimizing cost and waste has led many companies to look for ways to improve extraction, filtration, crystallization, chromatographic, and other widely used methods for the purification of small molecule APIs. The goal is to minimize solvent use, and decrease process times and waste, while generating higher-purity drug substances. Continuous extraction and crystallization are two approaches to reducing energy consumption and obtaining APIs of more consistent quality in a smaller footprint.
7.2. The role of chromatography can be expected to increase alongside the continued shift to small- volume APIs for targeted drugs and precision medicines. Preparative chromatography has historically played a limited role in small molecule API production, having been used only in the discovery and process development phases, while the longstanding techniques for commercial-sale purification of solid and liquid drug substances have predominantly been crystallization and distillation. For small-volume and highly potent drugs, the observed trend, however, is that developers frequently retain chromatography methods through commercial launch when they are developed early in the drug life cycle.
New Market Trends
8 Growing Need for API Processing
8.1. Many complex APIs under development today suffer from poor solubility under physiological conditions (in gastrointestinal fluids) and are considered Class 2 compounds under the Biopharmaceutical Classification System (BCS). Many larger APIs with high polarity and strong crystal lattices also exhibit poor permeability through the intestinal membrane (BCS Class 4). Consequently, these drugs have posed challenges in terms of bioavailability.
8.2. For solid APIs, manipulating the solid form can have an impact on bioavailability. Traditionally, manufacturers of final dosage forms have been responsible for the downstream processing of APIs. There is a growing expectation, however, that API manufacturers will provide the drug substance in a processed form when appropriate.
8.3. One of the most common approaches to increasing the bioavailability of solid APIs is particle engineering, particularly particle-size reduction. Reducing the sizes of bulk APIs enables generation of drug substances that are optimized for formulation.[9] Therefore, adding milling, micronization, and nanoscale particle generation capabilities to API manufacturing is a top priority for many API producers, and several companies have been founded with the aim to specialize in particle-size reduction. One such company is Nanoform, founded in 2015, which provides nanoforming services to develop nanoparticles for high-potency drugs.
8.4. Another particle engineering technique is spray drying. Traditionally, formulators spray-dry a drug substance mixed with polymeric excipients to generate amorphous solid dispersions, but spray drying is a useful technique for API producers as well, who may spray dry drug substances alone to achieve certain physical attributes, or spray dry a mix of APIs together to achieve a uniformly distributed blend of the different active ingredients. This second application of the technique may be useful to formulators in producing combination drug products.
9 Rising Importance of Small-Volume Manufacturing
9.1. The trend toward targeted drugs and precision medicines that require lower doses and treat smaller patient populations is driving the need for small-volume API manufacturing solutions. These solutions must still be compliant with Good Manufacturing Practice (GMP) requirements, and, while they involve smaller volumes than many older small molecule APIs, there are still scale-up issues to be addressed, often for processes that involve highly specialized equipment and sophisticated technologies, such as cryogenic chemistry, advanced chromatography systems, and specialized isolation techniques, such as tangential flow filtration.80 In fact, in some cases the small batch scale may impact the choice of technologies employed for the production and purification of small-volume, small molecule APIs.
9.2. Use of QbD and design-of-experiment (DoE) approaches beginning at the development stage is a strategy that is increasingly employed to identify relevant process parameters and the design space for a robust process at commercial scale.
10 Increasing Containment Needs
10.1. With the percentage of HPAPI candidates growing rapidly, the issue of containment during API manufacture has come to the forefront. Containment is needed to protect workers and the environment from exposure to highly potent compounds, but also to prevent cross- contamination of HPAPIs.
10.2. The use of personal protective equipment (PPE) during API manufacture should be the last line of defense and should be limited as much as possible, as fully body suits present functional challenges — they are not comfortable, often slow down operators, and hinder their ability to perform some tasks. Consequently, there has been a trend in the production of HPAPIs toward the use of closed containment systems, including current GMP (cGMP) isolators.
10.3. The scope of these isolator systems covers charging, filtration, drying, dispensing, and packaging operations. To facilitate their use and reduce downtime between runs, these isolator systems also have clean-in-place (CIP) capabilities However, they are very expensive and require highly skilled and trained operators.
10.4. To eliminate some of these issues, some companies have adopted disposable isolators, which can be dedicated to a single product, used in both the process development and commercial production phases, and disposed of once work is completed. Disposable isolators are particularly attractive for processes that involve flow/continuous chemistry and thus have a much smaller footprint.
11 Increasing Automation
11.1. Advances in automation and sensing technology and in automation software are enabling the implementation of automation solutions by more small molecule API manufacturers. Automation of production processes provides numerous benefits that range from greater efficiency and productivity to improved quality and safety. These benefits are realized to the greatest extent for API production processes with high operational complexity and risk.[10]
11.2. Automating reactor functions, such as heating, stirring, charging, and discharging, that are done alongside process analytical technologies (PAT) that provide process data in real time, allows for more controlled reactions that result in higher yields of API, as well as batches that are more consistent in quality. Additionally, automation reduces the risk of manual error, which in turn increases process safety and reduces batch failures and the need for rework.
11.3. The digital transformation of the pharmaceutical industry is not limited to R&D. It is also taking place on the manufacturing floor. When combined with digital tools that integrate data generated from multiple automated processes within a multistep synthesis with analysis and enterprise management software, automation of small molecule manufacturing can provide additional benefits across the facility and the organization.[11] For instance, more rapid responses to both excursions and trending are made possible.
11.4. Today, an increasing number of manufacturers are leveraging the integration of new technologies, such as robotics, AI and ML, Big Data and predictive analytics, cybersecurity, cloud computing, radio frequency identification (RFID), and biometrics. To aid them in their efforts, the International Society for Pharmaceutical Engineering (ISPE) created the concept of Pharma 4.0TM. The organization’s objective is to provide practical guidance that will help accelerate Industry 4.0 transformations in alignment with pharmaceutical regulations and best practices by enabling organizations to leverage the full potential of digitalization, and thus provide faster innovations for the benefit of patients.[12] In addition, Pharma 4.0 also aligns with the FDA’s 21st century risk-based approach to manufacturing, which requires that companies develop a deeper understanding of their operations through the generation and analysis of relevant process data.
12 Process Intensification / Continuous Processing
12.1. Process intensification of small molecule manufacturing offers many benefits, including greater productivity, reduced costs, and enhanced sustainability. It generally involves the reduction of equipment size without reducing the quantity of API produced, resulting in both reduced energy and resource consumption, and in less waste production.
12.2. Continuous processing is the ultimate form of process intensification. For chemical API production, it is referred to as flow chemistry. Continuous purification processes, notably extraction, crystallization, and distillation, are also being employed at an increasing rate. Continuous processes, because they operate at a steady state, tend to provide higher yields of products with more consistent quality.[12][13] Reducing the risk of human error through automation is another important benefit.
12.3. In addition, when microreactors are used for flow chemistry processes, it is possible to perform processes that are not safe to run in large stirred- tank reactors, because only very small quantities of reagents are present together at any moment.[13][14] Furthermore, reactions that must be run at very low temperatures in batch mode can be run at or near room temperature in flow mode. As a result, manufacturers can produce — at large scale — chemical intermediates not previously available for pharmaceutical manufacturing.
12.4. Flow chemistry also streamlines scale-up of processes.[13][14] Increasing output only involves running the process for a longer period of time rather than increasing volumes, which typically requires significant additional work to determine optimum process parameters. Multiple microreactors can be run in parallel using the established conditions if larger quantities are required.
12.5. The FDA has been vocal about its support for continuous manufacturing, and flow chemistry in particular, since 2015.[15] In addition, in 2016, the 21st Century Cures Act required the FDA to support the development and implementation of continuous manufacturing for drug production as one means for accelerating drug development and commercialization.[16] Also in 2016, then FDA Deputy Director of the Office of Pharmaceutical Quality in the Center for Drug Evaluation and Research Lawrence Yu highlighted in a blog post the greater reliability, safety, efficiency, and responsiveness/flexibility and the reduced costs provided by continuous manufacturing.87 Flow chemistry and continuous processing also fit with the agency’s QbD initiatives.[17]
12.6. The ideal continuous API production process would have each step in the synthetic route integrated together, so that the initial raw materials are input at one end, and the final purified API is the output at the other end. Such fully integrated continuous processes have yet to be implemented for the commercial production of APIs. Flow chemistry and continuous purification processes have, however, been used for individual steps in the production of APIs.
12.7. Given the growing body of work supporting the benefits of flow chemistry in pharmaceutical manufacturing, it is not surprising that both sponsors and CDMOs are investing in the technology. One recent example is Axplora (previously NovaSep), which commissioned a new cGMP pilot-scale flow-chemistry equipment in 2023).89 Grand View Research estimates that the value of the global flow chemistry market is expanding at a CAGR of 10.2% and will reach $2.9 billion by 2028.[18]
13 Adoption of Single-Use Technologies
13.1. Single-use (disposable) technologies are generally associated with biologics manufacturing. Their adoption for small molecule API production is increasing, however, particularly as the potency of these compounds increases and the volumes required decrease.[19] For these applications, single-use equipment offers the advantage of more flexible infrastructure combined with reduced setup and changeover times, because there is no need for CIP or steam-in-place (SIP) processes. The latter also reduces wastewater generation. Cost savings are often achieved as well.
13.2. The focus for HPAPI production is single-use isolator technology for containment. Their use can reduce both capital and operating expenditures, while reducing the likelihood of cross- contamination and protecting workers and the environment. Flexibility in design can also lead to more ergonomic solutions. In many cases, a single-use isolator will be used for an entire production campaign.
13.3. It is also worth noting that, while single-use systems are often associated with continuous processes, they can also reduce the investment costs for reactors used in small-volume API manufacturing. The higher the potency of a compound, the greater the cleaning requirements. Using disposable equipment can simultaneously reduce the risk of contamination and overall waste concerns due to cleaning.
14 Customization and Personalization
14.1. The pharmaceutical industry is experiencing a transformative shift toward precision medicine, aiming to provide therapies tailored to individual patients' genetic and medical profiles. This paradigm shift necessitates a fundamental change in API manufacturing. Traditional batch production methods are ill-suited for the intricacies of personalized medicine. Instead, there is a growing need for highly adaptable and flexible manufacturing processes. Continuous manufacturing, which allows for real-time adjustments and precise control over drug composition, dosage, and formulation, is becoming increasingly vital. This trend extends to dosage form customization, where 3D-printing technologies are gaining traction, enabling the creation of patient-specific medications. As this trend unfolds, it holds the potential to revolutionize treatment outcomes, optimizing drug efficacy while minimizing adverse effects for individual patients.
15 Modular Manufacturing
15.1. The need for CDMOs to offer both small-volume and large-scale manufacturing capabilities has driven growing interest in modular production solutions — self-contained manufacturing units that can be easily configured and reconfigured to produce different APIs. Not only does the use of such units afford significant flexibility in a singular manufacturing facility and the integration of advanced technologies; it facilitates reproducible production at disparate locations around the world, which is an increasing need as more national governments require at least the final stages of manufacturing for drug products marketed in their countries to take place within their own borders.
16 Supply Chain Resilience
16.1. The COVID-19 pandemic laid bare the vulnerabilities of global supply chains in pharmaceutical manufacturing. To mitigate such risks, pharmaceutical companies are reevaluating their supply chain strategies. Diversification is a key theme, with manufacturers seeking to reduce reliance on single-source suppliers and explore dual-sourcing options for critical raw materials. Furthermore, the concept of nearshoring or onshoring gained momentum, although to date there has been more discussion of onshoring than actions taken. By bringing API production closer to home markets, the industry aims to establish more resilient and agile supply chains. Redundancy is also on the rise, with companies investing in multiple production facilities and building stockpiles of essential raw materials to prevent future disruptions. These strategies collectively aim to ensure a consistent supply of APIs to meet global healthcare needs.
17 FAQ: Small Molecule API & HPAPI Manufacturing
What are the benefits of continuous flow chemistry in API manufacturing?
Continuous flow chemistry streamlines the scale-up process and enhances safety by maintaining low volumes of hazardous reagents at any given time. This method allows for high-energy reactions to occur at room temperature, which typically require cryogenic conditions in batch processing. It is a cornerstone of Green Chemistry due to its reduced footprint and waste.
How does Pharma 4.0 improve small molecule drug substance production?
Pharma 4.0 improves production by integrating Artificial Intelligence (AI), Machine Learning (ML), and Robotics to create a fully automated, data-driven manufacturing floor. This digital transformation reduces manual intervention, minimizes batch failures, and ensures compliance with Quality by Design (QbD) standards. It facilitates real-time monitoring of critical process parameters to ensure consistent API purity.
Why is particle engineering critical for modern Active Pharmaceutical Ingredients?
Particle engineering is critical because an increasing number of new drug candidates are categorized as BCS Class 2 or 4, meaning they have poor solubility or permeability. Techniques like micronization and spray drying modify the physical properties of the API to enhance bioavailability. This ensures the drug can be effectively absorbed by the human body after formulation.
What is the role of biocatalysis in sustainable API synthesis?
Biocatalysis serves as a sustainable alternative to traditional synthesis by using natural enzymes to catalyze chemical reactions under mild, aqueous conditions. This reduces the need for toxic solvents and heavy metal chemocatalysts. Recent advances in protein engineering allow manufacturers to "program" enzymes for high selectivity, significantly reducing byproduct waste and environmental impact.
How do modular manufacturing units address supply chain disruptions?
Modular manufacturing units provide the flexibility to rapidly reconfigure production lines or relocate facilities closer to end markets, a strategy known as onshoring or nearshoring. These self-contained "pods" allow for localized API production, reducing dependence on fragile global logistics. This agility is essential for responding to sudden shifts in patient population needs or pandemic-related shortages.
References:
Entwistle, David and Oscar Alvizo. “The Future of API Synthesis.” The Medicine Maker. 28 Oct. 2019.
Trapl, Josef, Wolfgang Winter, Christian Woelbeling, and Thomas Zimmer, “ISPE Accelerating Digital Transformation with Pharma 4.0 Initiative.” iSpeak Blog. 21 Oct. 2021.
