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

Cynthia A. Challener

Downstream processing operations have a direct impact on biopharma product quality and cost. Therefore, optimization of downstream biologics purification steps is not surprisingly focused on increasing productivity and reducing cost, while maintaining the highest possible quality. Two specific areas receiving attention, according to Martin Vollmer, biopharma program manager in the Lifescience Analysis Group at Agilent Technologies, are continuous manufacturing with automation/integration of associated analytics and the adoption of single-use technologies, including a shift from traditional column chromatography to membrane-based techniques.

Capture chromatography, adds Darren Verlenden, head of bioprocessing, MilliporeSigma, has been an early target for improvement due to the high cost of goods associated with this operation. Adoption of advanced capture methods, such as multi-column capture, has been slower than expected, however, due to complexity and regulatory concerns, he observes. The focus has therefore shifted to flow-through polishing. “Analytics in this space are needed to move from monitoring critical process parameters to monitoring critical quality attributes, with in-line or at-line aggregate analysis seen as an important need,” Verlenden says.

Indeed, the biopharmaceutical industry continues to express interest in technologies that enable process control while improving process development times and quality. There is particular need for advances downstream due to the dramatically higher productivity achieved in upstream manufacturing today, according to Phil Vanek, chief technology officer at Gamma Biosciences.

“Increasing interest in automation and continuous manufacturing and the advent of manufacturing strategies for advanced therapies (e.g., cell and gene) are compelling more chained or continuous manufacturing methods to allow for more walk-away operations,” Vanek continues. “These approaches not only improve cost efficiency, but when properly implemented can improve product quality and reduce risk through closed operations and increased use of automation,” he asserts.

Full integration of analytical technologies helps to provide real-time answers, reduce costs, avoid costly failures, and makes processes much more efficient, notes Vollmer. “Online and inline process analytical technologies will provide continuous insight into the process and into the quality of the drug substance,” he states.

Overall, therefore, the incorporation of rapid, high-throughput analytics enables more informed decision making in process development, resulting in improved processes, Verlenden summarizes. However, for these high-throughput development and analytics to also reduce development timelines, he cautions that novel approaches to data collection and processing are needed to overcome the inefficient, largely manual, paradigm of today.

While advanced control is lagging for a variety of reasons, including the different control architectures within the diversity of equipment being deployed in manufacturing today, Jonathan Hartmann, president and CEO of Nirrin Technologies, believes that with new technologies and the market demand for integrated control in operations, the control aspects (for full automation) will quickly catch up.

In addition, Hartmann observes that for next-generation therapies in particular, process analytics promise to improve not only their therapeutic potential and potency, which is often predicated on the manufacturing process itself, but also the ability to assure their safety through process consistency and control, as well as their cost effectiveness through automation and simplified manufacturing.

With Chinese hamster ovary (CHO) cell productivity routinely exceeding titers of 10 g/L, Vanek notes that many biologics manufacturers are looking to address knock-on effects such as column fouling and protein aggregation. “The ability to continuously monitor downstream unit operations and operate under conditions that avoid product yield losses, especially after affinity and polishing steps when the value of the product is at its highest, are of extreme importance,” he comments.

Particularly for advanced therapies, Vanek says that real-time monitoring and control of critical quality attributes, such as full capsid adeno-associated virus productivity, can have a positive and significant impact on product potency, cost, and safety.

Most analytical technologies employed today, however, are still used in an offline manner, and results are not available in real time, which causes delays. Samples are removed from the stream and submitted for testing with results produced hours or days later.

“With those techniques, immediate reaction on fractionation or in optimizing yield and recovery is not possible; the approach today can be compared to performing a post-mortem analysis,” Vollmer explains. “Such delays preclude decision making to inform the next round of experiments and slows overall development,” adds Verlenden.

Any reduction in this timeline should speed development, according to Verlenden. “As biopharma moves to connected and continuous processing, the ability to monitor critical quality attributes in real (or near-real) time will further enable optimization and streamline key decision points,” he states. Vollmer agrees that the goal must be to get results when there is still time to take action in response. He notes that connecting liquid chromatography (LC) or spectroscopy online or inline will provide this capability.

“Using advanced analytical approaches including machine learning,” adds Vanek, “will deliver data that can identify process pitfalls and opportunities for improvement addressing quality and yield, as well as set the stage for predictive analytics that could allow users to intervene or abort processes that are likely to produce out of specification results.” Additionally, real-time data collection and analysis can be coupled to feedback controllers to enable automation and hands-free process management in the future, contends Vanek.

While there are some inline sensor technologies available on the market today, Vanek laments that they can be costly, slow, and/or complex, and often measure surrogate events in the process that are then indirectly correlated to the desired metric. It is important, stresses Hartmann, to consider the physical time needed to not only capture data, but also analyze and integrate the results of that analysis into a real-time control instruction set, to allow for process automation.

Digital innovation and analytical advances now essential and enabling

The desire for faster and more flexible analytical solutions for downstream processing is driving innovation. New “Industry 4.0” digital capabilities will be essential before fully automated feedback loops can be leveraged, according to Vollmer.

One of the key challenges of existing downstream-processing analytics, Vanek observes, is the need to sample product and analyze the material off-line, as many of the on-line technologies measure only surrogate analytes or cannot process the data in real-time. “As new applications are developed, or existing methodologies are being adapted to on-line measurements, it becomes easier to realize improvements in performance. In doing so, integration of the data into manufacturing execution systems and process chaining for continuous manufacturing, together with increased automation, become enabled,” he explains.

Advances in connected and continuous manufacturing, in particular, are increasing expectations for rapid decision making, agrees Verlenden. “Success in this area cannot be fully realized without an advancement in analytics,” he observes. New robust analytical equipment fully integrated into the process and specifically designed for this purpose helps to facilitate adoption as well, Vollmer agrees.

Regulatory is also a key driver with expanded data package requirements, Verlenden says. Design-of-experiment approaches, for instance, require additional analytical data in downstream-processing applications.

“In essence,” Verlenden states, “improving analytics will allow for shorter development cycles to enable manufacturers to accelerate speed to market and reduce costs, while in the future, these analytics will enable the transition to process control based on critical quality attributes.”

As with the adoption of any new technology, the conservative nature of the biopharmaceutical industry has led to slower-than-desired action with respect to the implementation of more advanced analytics that can facilitate downstream process optimization. “Our industry tends to conservatively adopt new technologies, and this continues to slow down adoption,” says Verlenden.

There are other challenges as well. “Inertia within the industry to switch, primarily caused by regulatory constraints and the high cost of implementation, is a key hurdle,” Vollmer notes. In addition, as analytical technologies move from established off-line methods to at-line or inline methods, there is likely to be a period of decreased efficiency where, for instance, methods are run both off-line and at-line or inline, according to Verlenden.

“While this duplication will be a necessary step to realize the future potential of at-line and inline analytical testing, it will require investment and acceptance of this intermediate inefficiency,” Verlenden comments. Ultimately, however, Vollmer believes that the pay-off will be lower-cost production and better drug quality.

Vanek is clear that implementing new technologies into regulated manufacturing environments can introduce many challenges, from data compatibility across legacy systems to methods re-validation and even respecifying acceptance criteria for a product—all of which can be regulatory headaches or worse. “To make it worth the investment from a cost- and risk-perspective, adopters of new technology have to have confidence that the method will be reproducible, reliable, and scalable, with the added information providing significant advantages over existing methods,” he explains.

Advances, while not numerous, are being introduced and demonstrating their benefits. Some downstream process innovations are being spurred by upstream process improvements in conventional biologics manufacturing, such as productivity increases and continuous manufacturing, according to Vanek. The demand is also increasing, he notes, due to the broader array of biologics being manufactured including plasmids, RNA, and viral vectors; the physical nature of these materials makes purification with conventional downstream methods challenging. 

“This diversity of products is one key element driving innovation. Real-time analysis using rapid methods and their integration into existing workflows is another innovation driver. Analysis that addresses not only product quantity, but simultaneously product quality, can be a real-time and cost-saver in the steps towards releasing a therapeutic product,” Vanek adds.

Vollmer points to online LC, new Raman spectroscopy solutions, and new near-infrared (NIR) instruments and LC/capillary electrophoresis (CE)-based analyzers that target very specific single-attribute applications.

Implementation of Raman spectroscopy for bioreactor feedback control, Verlenden notes, is contributing to increased efficiency, productivity, and quality through inline analysis, chemometric analysis, and feedback control. One specific example is MilliporeSigma’s Procellics Raman Analyzer with Bio4C PAT Raman Software, which currently enables upstream scientists to deliver harvest material with more highly controlled quality attributes that should,in turn, reduce downstream purification challenges.

“Eventually this technology should be useful for streamlining future adoption of Raman and other spectroscopic techniques for monitoring critical quality attributes such as concentration, aggregates, and formulation composition,” Verlenden believes.

Other technologies are under development with the goal of moving analytics from offline to at-line and online and enabling the monitoring of not just critical process parameters but also critical quality attributes.

“Process control based on critical quality attributes will provide additional degrees of freedom that are not possible today,” observes Verlenden. “For example, if aggregate levels could be monitored in real time, an excursion early in the process that today would require rework or a deviation could be corrected downstream within identified parameters to meet process purity goals. This type of approach would represent a fundamental change in how we develop and manufacture biologics,” he adds.

Agilent is focused on the development of online-LC solutions because this technology offers significant versatility, according to Vollmer. “Online LC is a very promising technology since it has the power to analyze multiple process and product-related attributes. With LC, it is possible to measure a multitude of parameters and get high-quality data from the analysis. LC is also a technology widely used and well-known in the pharma industry, and it can be connected to a variety of different detectors that provides different angles of insight,” he explains.

The key to successful online LC, Vollmer stresses, is to develop analytical instrumentation that seamlessly plugs into the overall process software environment.

Nirrin Technologies, meanwhile, utilizes the strengths of NIR, including rapid reliable results with a very high dynamic range, by combining new sensor deployment designs with novel laser technology, contends Hartmann.

While many of these developments are still in the early stages, scientist involved in the development of analytical solutions for downstream processing continue to set their sights well beyond what might be possible in the near term.

For instance, Vollmer would like to see the introduction of online LC-mass spectrometry (MS) technologies for downstream processing applications. “Online LC/MS would provide an additional layer of insight into the process,” he says. First, however, simplification and user friendliness must be improved for MS so that operators working on downstream processing lines who may not be analytical experts can operate these platforms with ease.


Volume 45, Number 12
December 2021
Page: 30–32

When referring to this article, please cite it as C. Challener, “Analytics Advances for Optimizing Downstream Processes,” 

Articles

Simple, inexpensive real-time analytics are urgently needed for high value products.

Analytics Advances for Optimizing Downstream Processes

With the majority of APIs under development considered poorly soluble and/or poorly permeable, formulators have been forced to develop new solutions for overcoming these key issues. Lipid-based drug delivery is one of only a few methods effective for increasing both the solubility and permeability of APIs.

Formulations that are designed to spontaneously emulsify upon contact with aqueous media, including self-emulsifying drug delivery system (SEDDS) and self-microemulsifying drug delivery system (SMEDDS), are often preferred because they are relatively easy to formulate, can potentially decrease first-pass metabolism, minimize food effects (minimize the difference in API absorption in the fed and fasted states), and can protect APIs sensitive to degradation in aqueous environments. In addition, because the API is dissolved in a pre-concentrate and not subject to amorphous-to-crystal transitions, which can occur over time with other technologies, SEDDS formulations are relatively more stable.

The key to successful SEDDS formulation is the choice of the right combination of lipid excipients for the particular API and route of administration.

Lipid-based formulations are generally classified into four categories, according to Philippe Caisse, scientific director pharmaceuticals at Gattefossé. Type I are composed 100% of lipids. Type II are SEDDS without water-soluble components that consist of 40–80% oils and 20–60% surfactants with low hydrophilic-lipophilic balance (HLB) values, have a turbid oil-in-water dispersion aspect, and are easily digested.

Type III lipid formulations are SEDDS/SMEDDS composed of <20–80% oils, 20–50% high-HLB surfactants, and 0–50% hydro cosolvents that have water-soluble components, form clear of bluish dispersions, and are less easily digested. Type IV systems are composed of 0–20% low-HLB surfactants, 30–80% high-HLB surfactants, and 0–50% hydro cosolvents and able to form clear micellar solutions but may not be digested.

Typically, SEDDS are isotropic and kinetically stable (SMEDDS are thermodynamically stable) formulations of functional lipids containing one or APIs for systemic delivery, according to John K. Tillotson, pharmaceutical technical business director (Americas) for ABITEC. SEDDS compositions, adds Nitin Swarnakar, North America Application Laboratory manager within BASF Pharma Solutions, comprise precise combinations of oil, surfactant, and cosurfactants to yield low-viscosity, isotropic mixtures.

The nature and selection of each of these components will, Swarnakar says, significantly affect properties such as droplet size, speed of dispersion, digestibility of the droplets, and API absorption.For example, he notes that a less digestible mixture can be formulated by including a lipid with a long carbon chain or by increasing the concentration of a less digestible surfactant.“Depending on the goals of the formulation, an optimal composition can be targeted,” he states.

As of 2019, there were at least 15 commercially available small-molecule drugs formulated as SEDDS (1,2). The relatively simple need to make a small-molecule API soluble to improve drug delivery—rendering it orally available or capable of getting across the lining of the gut—involves differences in lipid structure, according to Jamie Grabowski, vice president, portfolio and sourcing at Curia (formerly AMRI).

The most common classes of lipids employed are solubilizers, emulsifiers, surfactants, and potentially co-surfactants, Tillotson comments.Medium-chain triglycerides serve as solubilizers; mono- and di-glycerides as solubilizers and emulsifiers; and pegylated esters, polysorbates, and ethoxylated oils as surfactants and co-surfactants.

Surfactants can be water-insoluble (e.g., propylene glycol esters), water-dispersible (e.g., linoleyl polyoxyl-6 glycerides), or water-soluble (e.g., polyoxyl-based esters), according to Caisse. Diethylene glycol monoethyl ether is the most common hydrophilic cosolvent.

“These functional lipids are preferred based on their efficacy with regard to solubilization and emulsification capabilities,” says Tillotson. For example, medium-chain triglycerides have a high solubilizing capacity for lipophilic drugs and are especially easy to emulsify using suitable surfactants, such as castor oil derivatives, according to Swarnakar.

SEDDS formulations start as isotropic mixtures that contain the API(s) dissolved in the functional oil, solubilizer, and surfactants. When the SEDDS formulation enters an aqueous environment, such as the GIT, the SEDDS forms API-containing droplets, with the API(s) contained in the hydrophobic interior and the emulsifiers, surfactants, and co-surfactants stabilizing the discontinuous oil phase inside the continuous aqueous phase.

For example, Tillotson notes that greater amounts of hydrophobic lipids tend to increase API solubility in the system for some APIs; in contrast, greater amounts of less hydrophobic lipids, such as emulsifiers and surfactants, tend to reduce globule size and generate micro-emulsions.“The challenge is determining the optimum concentrations of each functional lipid in the pre-concentrate with regard to maximizing API solubilization and emulsion performance,” he concludes.

Often SEDDS formulations may include three, four, or five excipients along with the API, according to Caisse. Formulating an optimal SEDDS may thus require numerous trials and formulation variations. He also notes that some all-in-one self-emulsifying excipient systems are available that can simplify the preparation of type II and Type III lipid-based formulations.

Multiple factors influence lipid selection

Generally, lipids with chain lengths of C8 to C18 are reported in the literature as being ideal for SEDDS formulations, according to Swarnakar. She adds that specific lipids are chosen based on the melting point and crystal lattice properties of the API in question.

Most poorly water-soluble drugs are lipophilic, and thus the solubility of the API in the lipid components of the system will be the first parameter considered, according to Caisse. For highly lipophilic drugs, oils or mixed mono, di-, and triglycerides are often used. For APIs with medium lipophilicity, low HLB (≤ 9) surfactants are often preferred, he says. For APIs with low hydrophilicity, high HLB (> 10) surfactants and hydrophilic solvents are often required.

Another very important consideration is the desired emulsion performance and characteristics of the SEDDS formulation, says Tillotson. “The ideal SEDDS formulation optimally balances the overall solubility of the API(s) while realizing the desired emulsion characteristics, such as globule size and dispersibility. The goal is to develop a system that provides for maximal API loading, while also generating a rapidly-dispersing micro emulsion,” he explains.

SEDDS formulations should also take into account the type of API being delivered, according to Tillotson. For example, Biopharmaceutics Classification System (BCS) Class II APIs are poorly soluble but readily permeable.Therefore, the focus in a BCS Class II carrying SEDDS is on lipids that provide the greatest solubility/carrier capacity for the API.In contrast, a BCS Class IV API is both poorly soluble and poorly permeable.In this case, the SEDDS needs to not only address API solubility in the functional lipids, but also, if possible, permeability issues.

For this reason, Tillotson says a BCS Class IV API-carrying SEDDS may include lipids that open tight junctions between enterocytes (functional lipids composed of C8 and C10 fatty acids) or lipids that inhibit the activity of P-glycoprotein (PGP) efflux pumps (certain mono- and di-glycerides and certain macrogolglycerides).

In addition to the nature of the API, lipids for SEDDS formulations are also selected depending on the delivery strategy, Swarnakar adds. With respect to the API, “like-dissolves-like” is the rule of thumb for choosing the lipid. “Generally, very hydrophobic drugs (log P > 5) can be solubilized in more lipophilic lipids with longer carbon chains,” he says.

Specifically, longer and fully saturated carbon chains are more stable and less digestible within the gastrointestinal tract (GT). “This less digestible nature can be beneficial to the absorption profile by providing a secondary, lymphatic route of absorption in addition to the standard portal vein absorption. This additional route of absorption can be used to enhance the bioavailability of specific APIs and increase API absorption times,” observes Swarnakar.

Other factors related to the API in addition to low in vivo permeability may also be of importance, observes Caisse, such as heat sensitivity and a high first-pass metabolism. “Hence the design of a self-emulsifying formulation as an efficient delivery system for a given API is also related to the targeted strategy for its bioavailability enhancement or physical limits of its manufacturing process,” he says.

The final dosage form should also be considered. Caisse notes that for soft-gel capsules and liquid- filled hard capsules, liquid/low-viscosity formulations are best, while for solid-filled hard capsules, semi-solid/solid excipients are preferred as the main components, although up to 20% liquid excipient is feasible.

Despite the general understanding of how different lipids impact solubility and permeability, formulators have always struggled to predict the best SEDDS formulation prior to costly in vivo and clinical work, according to Swarnakar. “Various reported in vitro methods, such as [United States Pharmacopeia] USP type 2 dissolutions, provide limited discrimination of SEDDS formulation behavior.The interference of turbidity and biphasic media make conventional in vitro screening methods inaccurate for SEDDS formulations,” he explains.

To address this issue, BASF, in partnership with Professor Anette Müllertz at the University of Copenhagen, has recently established a robust in vitro-in vivo correlation of 10 ready-to-use SEDDS compositions using the MacroFlux device from Pion for determining the absorption potential of formulations and finished drug products in vitro. The ready-to-use compositions are categorized based on their compositional HLB values and performance-indicating target product profile attributes, including microemulsion droplet size and enzymatic digestibility.

“Through careful testing and consideration of the chemistries in these formulations, the formulator is able to pre-screen a range of formulations and select according to their preferred API absorption behavior,” says Lindsay Johnson, global technical marketing manager–Pharma Solutions at BASF.She believes this tool will help formulators avoid costly pre-clinical studies and ensure continuity of product quality and performance during product development. “Overall, these tools will enable formulators to choose the best SEDDS formulation based on the API properties for preclinical and clinical trials and accelerate the product development timeline,” she asserts.

New developments with SEDDS are focused on extending the efficacy of the dosage form beyond simple improvements in solubility. Areas of research, according to Tillotson, include chylomicron signaling for tissue targeting, long-chain lipid inclusion promoting lymphatic transport and reduced first pass metabolism, and employing lipids as a delivery system for more specific targeting such as conjugated antibody targeting with APIs.

Liquid SEDDS formulations for oral administration are generally loaded into liquid-filled soft-gelatin or hard-gelatin capsules. “An ongoing challenge is how to administer SEDDS on higher throughput dosage forms, such as tablets,” says Tillotson.

There are many drivers for the development of solid or semi-solid SEDDs formulations in addition to the ability to easily incorporate them into tablets. They may also offer improved stability and enable sustained-release or abuse-deterrent formulations. Liquid SEDDs, according to Caisse, are susceptible to degradation during long-term storage and suffer from in vivo precipitation issues and handling complexity.

Research is ongoing in this application at multiple institutions.“The primary difficulty is generating tablets at industry tableting speeds with minimum or no sticking to the punches that also release the SEDDS formulation,” he observes. Other solid SEDDS technologies are also being developed such as powder and granular SEDDS.

SEDDS compositions formulated as solids can be achieved, according to Swarnakar, using a variety of methods, including adsorption onto solid carriers, freeze drying, spray drying, and melt granulation. Caisse adds that wet granulation and extrusion/spheronization are other solidification techniques used for converting liquid SEDDS into solid SEDDS.

Of these methods, Johnson notes that adsorption onto an inert solid carrier is most common. In this case, a liquid SEDDS solution is mixed onto various solidifying agents such as mannitol, lactose, or calcium carbonate.

The key to this strategy is to retain the solubilization and dissolution enhancing properties of the SEDDS formulations once they are absorbed on the solid carrier materials, Caisse observes.The resulting powders, he says, can be subsequently filled into capsules or formulated as solid dosage forms such as tablets, granules, or pellets in sachets.

Progress has been dramatic in the past few years particularly with respect to the development of lipids that facilitate the absorption of large molecules—notably biologics, according to Grabowski. “Driving the development of these lipids for SEDDS is the need for drug products with expanded methods of administration, notably oral. This is a big challenge for biopharmaceutical companies that want to offer patients the choice of an oral drug instead of an injectable,” he says.

Specifically, Grabowski notes that developers are moving away from relying on off-the-shelf lipids to get hydrophobic drug substances into solution or improve their stability. Instead, they are turning to complex cationic lipids that are actually helping with the functionality and efficacy of biologics by altering their bioavailability and pharmacokinetics, both in SEDDS and lipid nanoparticles (LNPs) such as those used in the formulation of mRNA vaccines against the SARS-CoV-2 virus, he says.

Cationic lipids improve the solubility, oral absorption, bioavailability, and pharmacokinetics of biologic drug substances, according to Grabowski. In LNPs, which have a much more complex structure than SEDDS, they are used along with cholesterol, a minor lipid, and one other typically proprietary compound.

Lipid nanoparticles such as cubosomes, adds Tillotson, contain both hydrophilic and hydrophobic regions and are readily absorbed by cells through typical lipidomic pathways.“The amphiphilic nature of these lipid carriers allows for the incorporation of proteins, RNA and both hydrophilic and hydrophobic APIs.For this reason, lipid nanoparticles composed of high-purity, functional lipids are ideal carriers for biologics and small-molecule actives,” he contends.

Across all research regarding lipid-based delivery, the main focus is on the purposeful design of lipids with specific structural and physiochemical properties. “Ultimately,” asserts Grabowski, “the industry will stop using off-the-shelf compounds such as cholesterol for LNPs and switch to carefully designed lipids with improved and diverse structures that enable fine tuning of the intended pharmacological impacts.”

For instance, Grabowski notes that assessing the structures of cationic lipids through structure-activity relationships will help improve the pharmacokinetics of drug delivery. “It will become less about simply being able to form micelles and more about making lipids that allow the drug substance to get across the gut lining and improve pharmacokinetics. That’s going to be the big issue,” he asserts.

Similarly, Tillotson sees emerging research on lipid-based drug delivery as being focused on the design and manufacture of high-purity lipids for specific applications, such as incorporation into LNPs for the systemic delivery of biological therapeutics. He also notes that ongoing lipidomics research seeks to identify novel lipids and lipid metabolites that can be potentially employed in biomarker discovery programs for specific disease states.

Greater expectations for GMP lipid manufacture

In many advanced lipid-based formulations, including SEDDS/SMEDDS, the lipids are not inactive ingredients, but functional excipients that impact the efficacy of the drug product. Both drug manufacturers and regulators are responding by treating these types of functional excipients more like APIs, according to Grabowski.

“Increasingly drug manufacturers want lipids used in their drug formulations to be made according to [current good manufacturing practice] CGMP requirements,” Grabowski says. “While lipids may not need to be produced in a CGMP environment for early-phase research, if regulators potentially consider them to be additional ‘APIs’ because they affect the bioavailability of the drug substance or efficacy of the drug product, the lipid supplier will be expected to have the ability to produce GMP lipids.” As an example, Grabowski notes that there is movement toward treating cationic lipids as APIs.

One of the biggest challenges with CGMP manufacturing of lipids, observes Tillotson, is maintaining both quality and consistency. “This goal is achieved by maintaining consistent raw material stocks and tight specifications on manufacturing unit operations,” he says. That is important for SEDDS in particular, adds Johnson, because across one monographed chemistry, different manufacturer materials may ultimately perform differently in a final
formulation. “For this reason, the sensitivity of formulations needs to be considered as the choice of supplier is weighed,” she comments.

Another challenge for lipid manufacturing highlighted by Caisse is the need to find new ways to manufacture lipids with sustainable raw materials and more eco-friendly processes that leverage new classes of catalysts.

Additionally, suppliers who start from certified sustainably sourced base raw materials, like palm kernel oil, coconut oil, corn oil, and others, can bring value and awareness to ethical and sustainable sourcing in the pharmaceutical industry, according to Johnson. For example, she observes that many of BASF’s lipid-based pharmaceutical excipients come with an external certification for being responsibly sourced.

25(2), 2575–2582 (2019).
2. S.P. Kovvasu et al., 


Volume 45, Number 11
November 2021
Page: 20–24

When referring to this article, please cite it as C. Challener, “Lipids for Self-Emulsifying Drug Delivery Systems,” 

SEDDS and SMEDDS improve solubility and permeability while expanding efficacy and applicability.

Lipids for Self-Emulsifying Drug Delivery Systems

In the latest Intergovernmental Panel on Climate Change report issued in August 2021, the organization stressed that while some impacts of climate change cannot be reversed, such as continued sea level rise, “strong and sustained reductions in emissions of carbon dioxide (CO

) and other greenhouse gases (GHGs) would limit climate change” going forward (1).

The pharmaceutical industry, like other manufacturing sectors, contributes to CO

 and GHG emissions and is aware of the need to increase the sustainability of its operations. The IQ Consortium’s Green Chemistry Working Group first met with FDA in 2012 to identify opportunities for promoting green chemistry (2).

The IQ Green Chemistry Working Group also adopted the Green Aspirational Level (GAL)—originally developed by Boerhinger Ingelheim (3,4)—as a standardized green efficiency goal for API manufacturing processes that factors in the complexity of the synthetic route; the consortium also developed a Green Scorecard to show the value-added impact of green chemistry and other improvements, including process simplification (5). Individual manufacturers are tackling the issue in many different ways.

This article was originally published on the 

Small-molecule API manufacturing, according to Scott Martin, general manager of W. R. Grace & Co.’s Fine Chemical Manufacturing Services (FCMS), is driven by continuous improvement. “Most companies have pursued continuous improvement programs for many years, and many like Grace FCMS have embedded sustainability into those programs,” he says. “The expectation of sustainable manufacturing and the sustainable use of resources is top of mind for everyone in the industry,” he adds.

More specifically, Martin notes that both increasing yields and increasing throughput by definition result in a reduced environmental footprint. In addition to these types of efforts, improvements are also being made with respect to sources of energy, with drug manufacturers pushing utilities to produce more renewable energy, he continues. “As we see it, being more sustainable and pursuing continuous improvement are not two separate issues,” he concludes

Many technologies for ensuring cleaner energy consumption, abating emissions, and improving waste management have already been developed and, thus, are easier to implement and have more acceptable payback periods, adds Brian Peutherer, health, safety, and environment director at Sterling Pharma Solutions. “For contract development and manufacturing organizations (CDMOs), these solutions are the easiest way to make a significant impact on the sustainability of products without actually impacting API design,” he notes.

Sterling, for instance, has invested in a bio plant to treat wastewater, an anaerobic digestion plant to generate energy from waste, and a combined heat and power plant that generates approximately 98% of the energy used at its headquarters in Northumberland, United Kingdom.

The concepts of green chemistry and sustainability, according to Jeff Song, vice president of chemical development in the United States for Boehringer Ingelheim (BI) Pharmaceuticals, have been broadly accepted in the pharma industry for the past 15 years. At BI, he says, these concepts are incorporated into daily work, leading to the routine development of greener API processes for all projects through innovative chemical research as well as new technologies.

To achieve true sustainability, though, Song emphasizes that other approaches than green chemistry principles should be considered, such as developing an effective waste management protocol at the end of the process. “Some modifications should be also made to the supply chain by replacing existing methods with greener chemicals and materials and by reducing chemical steps to convert commodity chemicals into value-added building blocks for API synthesis. While efforts have already begun within the industry to track the greenness of chemical processes at building-block suppliers, more work is needed,” he observes.

BI, adds Frederic Buono, the company’s senior associate director of chemical development in the US, looks to design the most direct synthetic approach with the least number of chemical steps using commodity chemicals as early as possible in the API development cycle. The commodity chemicals should have minimal cost, short methods of preparation, and wide availability. There is also a focus on process optimization to reduce waste generation and energy consumption by minimizing reaction concentration and avoiding extreme reactions condition (e.g., cryogenic temperatures).

As a member of the ACS Green Chemistry Institute Pharmaceutical Roundtable, BI researchers have also helped to develop tools to measure process performance with respect to sustainability and greenness, including the innovation Green Aspiration Level (iGAL) (6).

The petrochemical industry is vital to the pharmaceutical industry today as a supplier of key raw materials used for the production of most 

synthetic-chemistry-based pharmaceuticals. It also, however, accounts for a large percentage of the world’s energy consumption. According to 

Jing-Ke Weng, cofounder of Double Rainbow Biosciences, a professor of biology at the Massachusetts Institute of Technology, and a member of the Whitehead Institute

current small-molecule intermediate/API manufacturing almost entirely relies on unsustainable precursors.

“The growing need to quickly move away from fossil fuel amid the threat of climate change creates urgent demand for novel sustainable approaches to replace the current supply chain for small-molecule drug production. Other than sporadic uses of biocatalysts in specific steps of some pharmaceutical syntheses, truly sustainably produced synthetic small-molecule pharmaceuticals are very rare,” Weng asserts.

Synthetic biology that integrates metabolic engineering of various biological hosts (e.g., bacteria, fungi, and plant cells) and enzyme engineering, Weng believes, will be a major solution that will lead to the next green revolution in the way future small-molecule pharmaceuticals will be produced. “Several proof-of-principle studies have shown the feasibility of employing biochemistry instead of synthetic chemistry to produce complex drug-like molecules sustainably; however, we are still far from widely adopting this new approach as a new industry standard,” he comments.

The first step, Weng predicts, will be the gradual replacement of synthetic chemistry production processes for small-molecule intermediates/APIs with enzyme-catalyzed reactions, which he notes are usually efficient, highly selective, and occur under mild conditions.

 and GHG emissions, all drug developers and manufacturers need to seriously consider measures to improve sustainability throughout each phase of their industrial processes, according to Weng. “The pharmaceutical industry is due for a major overhaul in all aspects of its unit operations. Essentially, the pharmaceutical industry should be evaluating sustainable alternatives for all current exercises that rely on fossil fuel inputs,” he sates.

The optimal time to consider sustainability is before the construction of a manufacturing plant, and at the design phase of the synthetic route, as these are the stages at which the most efficient technologies and techniques can be incorporated,” Peuthererasserts. “Considering sustainability from the outset allows the opportunity to integrate sustainability into every stage of a molecule’s lifecycle,” he continues.

Buono agrees that sustainability should be considered throughout the API R&D process starting from medicinal chemistry all the way to commercialization, but with different emphasis for each. “In our opinion, one should strive to implement new synthetic routes (hence those with a much higher level of sustainability) starting with the first clinical batch or shortly thereafter to achieve a balance between the overall speed, sustainability, and attrition rate.”

From the point of view of CDMOs, the greater focus on sustainability in the pharmaceutical industry requires greater collaboration with customers at an earlier stage of project planning and development to incorporate sustainable manufacturing techniques into the API process design, according to Peutherer. “Relationships with supply chains are critical when considering the impact of manufacturing on the environment to ensure expectations are clear, and standards are maintained throughout the supply chain process. This safeguards against companies passing on their environmental burden to others,” he says.

The best time to consider optimal, sustainable production solutions is during the design of the synthetic route to an intermediate/API, notes Martin, because once these processes are validated, it is very challenging to introduce any changes, even if they offer significant improvements in productivity and sustainability.

In addition to identifying transformations that require minimal energy inputs, Martin also remarks that it is beneficial to choose solvents and other reagents that if not consumed in the process can be recycled or at least reused or repurposed in some way.

Companies should become more comfortable with using non-virgin, reclaimed solvents, Peutherer agrees. “Solvents often make up the bulk of materials used in API manufacturing and reducing their use can play a huge part in lowering a process’s costs, carbon footprint, and waste management requirements,” he observes. It is also important to consider other alternative raw materials used in production that have a lower environmental impact.

There are many opportunities to improve operations no matter what type of chemistry or chemical products are involved, according to Martin. He points to crystallization as one area that could use some attention. “Many small-molecule intermediates and APIs are solids and automatically purified via crystallization, which requires the use of solvents and often low temperatures. Under certain circumstances, distillation can be a more effective approach,” he explains.

There are, in fact, many opportunities to increase process greenness and sustainability by intensifying unit operations, Buono observes. For example, solvent volumes can be limited using a continuous extraction process, and aqueous/organic separation during work-up can be maximized using some separative commercial membrane units.

Flow chemistry is one of the technologies being employed to some extent in API manufacturing to increase sustainability, because, according to Song, the principles of green chemistry and green engineering are both leveraged in this manufacturing approach.

The versatility of the batch reactor has, until recently, meant any gains from continuous processing were previously unjustifiable, notes Peutherer. “With improving technology and techniques, however,” he notes, “continuous processing, especially in tandem with process intensification, can majorly impact on the inherent safety of a process and lower utility demands, as well as improving process specificity and reducing waste.”

Continuous flow technology, says Buono, can enhance heat and mass transfer by shortening process times with precise residence time control, which can lead to increased safety and reproducibility and thus afford product quality, all combined with easy scalability. “For these reasons, flow chemistry may offer a more sustainable technology for chemical synthesis compared to traditional batch chemistry,” he says.

In one example, BI developed a convergent, robust, and concise synthetic route which reduced the overall complexity (by eliminating a deprotection step) for an API that leverages a continuous flow-based Curtius rearrangement (the thermal decomposition of an acyl azide to an isocyanate with loss of nitrogen gas) (7). The overall process is 160% greener than the industrial average and 58% more efficient than the original batch process, according to Buono.

It is important to remember, though, notes Martin, that flow chemistry, while useful in some cases, is not applicable to all. Drugs produced in only small volumes, such as orphan cancer drugs, will likely not benefit from a continuous process because only limited quantities are required. In addition to lengthening development timelines for drugs where speed to market is essential, the upfront investment in the design of processes and equipment may not be easily recovered.

Digital technologies will play a crucial role in enabling greater sustainability of small-molecule API development and manufacturing. “We need to embrace digital technology to revolutionize the drug discovery process, and to adopt artificial intelligence and machine learning into our processes,” Song asserts. Doing so, he adds, is in concordance with Chemistry 4.0, which calls for the implementation of more digitalization and lab automation.

“To achieve these goals, collaboration across the industry is crucial,” says Song. “Pulling together expertise and insights from chemists, process engineers, theoretical chemists, IT specialists, and computer scientists will allow us to efficiently develop the digitalization solutions of the future for application to process development,” he concludes.

Ideally improvement of the sustainability of all drug manufacturing processes should be achieved; however, the pharma industry needs to establish a mechanism for addressing the shortcomings of older, existing processes for previously approved drugs.

“Altering existing processes is always challenging, but the urgency of available climate projections suggests the effort will be well worth it in the long run,” asserts Weng. “The near-term investment in sustainable solutions will push the industry towards more efficient API production processes while leaving a greatly reduced carbon footprint,” he adds.

In addition, Weng suggests that given the threat of global climate change, a failure to proactively embrace sustainable solutions may result in environmental regulatory agencies mandating sustainability targets for pharmaceutical manufacturers and other chemical industries.

Currently, it is extremely time-consuming and costly to implement changes due to the complex regulatory process that is involved. One possible solution, notes Martin, is to offer simpler regulatory pathways for certain types of changes related to sustainability improvements that do not affect the intermediate or API itself.

In cases where alterations to processes are a challenge, Peutherer says the best way to achieve a more sustainable outcome is through gains in ancillary aspects: cleaner energy generation, improved waste treatment options, pollution incident prevention, and carbon offsetting. This lowers the overall carbon footprint of the manufacturing.

Weng believes, though, that as sustainable means of small-molecule pharmaceutical development are expanded and tested to validate their performance against conventional synthetic chemistry-based approaches, industry peers and regulatory bodies must work together to embrace these solutions.

All drug manufacturers are faced with these challenges. Contract manufacturers such as Grace FCMS work with customers to push the adoption of more sustainable solutions as part of continuous improvement efforts. “It is a combined effort that includes increasing yields, using more sustainable raw materials, and more environmentally friendly packaging equipment to recycling and reuse of solvents and shipping containers, all with the goal of reducing the environmental footprint of small-molecule intermediate and API manufacturing,” Martin states.

“Sustainability,” Martin continues, “is now at the forefront. Most public companies have sustainability targets and hold regular discussions with suppliers regarding their sustainability expectations. Grace FCMS is therefore continually looking at ways to help customers reach their sustainability goals while ensuring continued supply of high-quality API product on time and in full.”

New changes will continue to be made and observed due to the enhanced awareness and continued innovation, agrees Song. “The power of machine learning and digitalization will quickly bring the most efficient synthetic pathways to chemists, not only for reaction design but also for process optimization,” he notes.

Improvements to be made across the industry can be implemented in two ways, according to Peutherer. “Firstly, gradual improvements in the processes that companies presently undertake or redesigning of operations (e.g., microwave versus traditional oven drying) will have cumulative impacts. Secondly, on a more process-specific level, implementation of environmental operation studies at the concept stage, and waste audits on longer-running processes, can bring tremendous benefits,” he explains.

In the near term, Peutherer expects the greatest gains to be made in areas not directly associated with processes, including utility consumption and waste prevention/treatment. “For example, at Sterling we treat waste on site and are currently building an ‘energy-from-waste’ plant as part of our strategy to reduce the company’s overall carbon footprint,” he comments. Longer term, Peutherer predicts wider application of the green chemistry principles and improvements in API design and manufacturing processes will have a major impact on the industry.

Progress that has been made to date should be recognized too, Song adds. He points to the growing development and adoption of flow chemistry for API synthesis, and recent advances in catalysis, particularly in biocatalysis and non-precious metal catalysis (copper, nickel and iron), that offer an improved ability to build complex molecules with much higher efficiencies but less waste. Interest is also resurging in the photochemistry and electrochemistry due to the inherently green nature of these technologies, especially when coupled with flow technology.

Double Rainbow, according to Weng, employs twounique sustainable technology platforms to produce sustainable therapeutics: rich glycosylation biochemistry in all domains of life to produce glycosylated drug products that harbor unique pharmacological activities but are too difficult to be made using conventional synthetic chemistry methods and bioengineered microbial systems to recreate valuable medicinal natural products that are traditionally sourced from fragile natural ecosystems.

“In the near term, we anticipate moving several of our promising early-stage sustainable therapeutic candidates to clinical trials. Longer-term, we believe our bioengineered therapeutics will emerge as a new class of therapeutic modalities that play important roles in the future of health care while contributing to the sustainability of our planet,” Weng concludes.

1. Intergovernmental Panel on Climate Change, “Climate Change Widespread, Rapid, and Intensifying–IPCC,” Press Release, Aug. 9, 2021.
2. IQ Consortium, “Green Chemistry Working Group,” 

, accessed Aug. 23, 2021.
3. F. Roschangar, et. al., 

, 281–285 (2017)
4. F. Roschangar, R. A. Sheldon, and C. H. Senanayake, 

, 752–768 (2015).
5. IQ Consortium, “Inspiring Sustainable Drug Manufacturing,” 

, accessed Aug. 23, 2021.
6. ACS, iGAL 2.0 Scorecard Calculator, 

accessed Sept. 19, 2021.
7. M. Marsini, F. Buono 

Cynthia A. Challener is a contributing editor to 

Drug makers are going beyond continuous improvement and green chemistry to increase the sustainability of small-molecule manufacturing.

Pharma Sets a Foundation for Greener API Manufacturing

Pharmaceutical glass, above all, should be inert to drug formulations and ensure the safe storage of medicines. While borosilicate Type I glass is the industry standard, shortages of some types of glass vials in recent years have been further exacerbated by the COVID-19 pandemic supply chain disruptions and need for high demand for glass containers for vaccines.

Manufacturers that implemented advanced supply-chain planning for fill/finish materials have weathered these challenging conditions so far, but difficulties are expected to continue for some time. Glass manufacturers are helping customers adjust to the situation with validation of alternative glass container solutions, including ready-to-use (RTU) molded glass products and strengthened aluminosilicate glass. Greater flexibility and collaboration across the supply chain have also surfaced as important factors for managing fill/finish material supply.

Drug products produced in glass vials and pre-filled syringes must be safe for the people who rely on the medicine they contain. That is the number-one priority for Curia (formerly AMRI), according to Jon Leisner, the company’s director of US procurement. “We take our responsibility seriously, to both our clients and the end-user, to provide sterile, quality, and compliant products,” he says.

For that reason, the most critical aspect of the glass used for pharmaceutical primary packaging needs to be as inert as possible so that it does not react with, add to, absorb, or allow external factors to change a drug product’s established safety, identity, strength, quality, or purity characteristics, explains Kevin McLean, quality and technical manager—Americas with SGD Pharma.

As such, notes Woocheol Chae, head of the drug product planning group at Samsung Biologics, the glass material must be chemically stable and not generate extractables or leachables (E&L), delaminate, or undergo other changes upon contact with the drug product. Minimizing E&L concentrations, adds Robert Schaut, scientific director of Corning Pharmaceutical Technologies, promotes the stability and purity of the drug product.

In addition, according to McLean, glass containers must protect their contents from the environment, and in some cases protect people from their contents, for example, from cytotoxic drug products.

In the United States, specific requirements for primary packaging as established by FDA are outlined in 21 Code of Federal Regulations Section 211.94. With respect to glass packaging, the global pharmacopoeias list three types of containers distinguished by their compositions and classified by their hydrolytic resistances—the extent to which 121 °C superheated water extracts alkali from the surface of the glass.

Type I borosilicate glass, for instance, has a long history of application and is the global standard for parenteral drugs due to its high hydrolytic resistance and ability to withstand extreme conditions, according to McLean. Type II and III are both soda-lime-silica glasses, but the former is treated on the inner surface to increase hydrolytic resistance.

Borosilicate glass primarily comprises silica and boric oxide and only contains small quantities of sodium. This composition, says Leisner, makes it resistant to heat and to enzymes. Its chemical inertness also makes it non-reactive with pharmaceutical products and reduces the risk of contamination, API degradation, and pH shifts.

All three types of glass must meet the container and closure system specifications of the United States Pharmacopeia and/or the European Pharmacopoeia, says Chae. The use of a colorant (mostly amber) is possible as a means for protecting the contents from exposure to light, he adds.

The COVID-19 vaccines placed additional performance requirements on the packaging system, according to Schaut. Key examples, he explains, include maintaining container-closure integrity below the elastomer’s transition temperature, maximizing filling-line throughput while minimizing particle contamination, ensuring mechanical robustness during freezing and transportation, delivering cosmetic quality to permit inspection of the contents, and serving as a functional barrier to contamination, gas, and light.

“The introduction of messenger RNA vaccines sets more specific needs beyond conventional glass vials, demanding either increased strength for optimal fill volumes in cold storage or a greater number of conventional glass vials with lower fill volumes,” Schaut continues. “These needs have created new challenges for fill/finish manufacturing and drug delivery that traditional pharmaceutical packaging is not able to address and is pushing the industry to move towards new, more advanced solutions to glass manufacturing,” he asserts.

Filling-line throughput has been particularly important for the COVID-19 vaccine due to the need to fill millions of vials as rapidly as possible. “There are many factors that limit the speed and efficiency of pharmaceutical filling machines, including dimensions and friction of the vial being processed,” notes Schaut.

Traditionally, Schaut observes, filling machines have been deliberately engineered with output constraints due to the physical interactions between the machine and conventional borosilicate glass vials. “Stress and friction generation on turn tables, tracks and trays, and particularly at junctions between intermittent and continuous motion can lead to glass breakage and human line interventions, which risks greater contamination of sterile environments,” he says.

Rapidly filling millions of vials with COVID-19 vaccines requires optimal filling efficiency and quality, which can be achieved in part using vials with a low coefficient-of-friction exterior surface, improved dimensional consistency, and strengthening to resist breakage, concludes Schaut.

The supply-chain for the production of tubular glass pharmaceutical-grade vials has been under stress for several years. Notably, the raw cane used to produce these vials was under strain due to changes in regulatory expectations in Asia, where there was demand movement from so-called low-borosilicate to mid- and high-borosilicate compositions, according to McLean.

The COVID-19 pandemic then placed an enormous global demand on the supply of tubular vials, creating concerns for global drug supply lines. “The supply/demand balance can be challenging to maintain when we are in a steady state, so the addition of a once-in-a-generation public health emergency has certainly put additional pressure on the marketplace,” says Leisner.

“The speed at which companies are required to move in order to address supply shortages is impacting every stage of the supply chain, from manufacturing to business processes to people,” Schaut adds.

Many of the large pharmaceutical companies, notes McLean, took a risk and placed orders for vials to package vaccines that were yet to be approved, locking in supply to meet the demand. “Ultimately, the supply-chain challenges for glass packaging materials observed over the last year are a result of a series of events, with a ripple effect across the industry,” he concludes.

An extended delivery period, which caused supply shortages, posed the biggest challenge over the last year, according to Chae. “Where it used to take 4–6 months to get a fill/finish material supply delivered is now extended to 12–20 months.” In particular, glass vials that are widely used for vaccines, such as 10R vials, were difficult to secure due to immediate increase in demand.

Despite such advanced planning by many, there has—and continues to be—a tremendous amount of pressure on the entire supply chain, according to Leisner. “Quite simply, demand has outstripped supply across the entire spectrum of fill/finish. It is not restricted to glassware. There have also been shortages of things [such as] plugs and stoppers, as well as all the consumables we need throughout the manufacturing process to fill and finish vials and pre-filled syringes, such as filters and filter bags,” he comments.

For companies that typically rely on tubular glass vials to package their therapeutics facing supply shortages, one option was to rapidly qualify other solutions, such as molded glass, as a backup or alternative. Molded glass can have some shortcomings compared to traditional glass, such as higher weight, non-uniform thickness, and reduced cosmetic quality, but does meet good manufacturing practice requirements.

“Forward-looking fill/finish operators continue to shore up their supply base and are thinking ahead. As vaccine administration is allowing the world to resume some degree of normal activity, COVID-19-driven demand remains high, and demand for other therapies that dropped during the pandemic is also rebounding. We are seeing more and more interest in molded glass as an alternative or back-up option to tubular glass given its global availability,” McLean observes.

It is not a simple solution, though. “The difficulty here is that the qualification and validation for alternate packaging can be extremely resource-intensive and can overwhelm smaller pharma companies,” says McLean.

Some have therefore turned to glass suppliers like SGD Pharma for regulatory support and to help with providing stability evidence and other needed data, according to McLean. “Many companies are seeking the expertise of their primary packaging partners to ensure approval and mitigate the risk of validations not being accepted. For instance, SGD Pharma is working with fill/finish organizations to provide support and information to help with the scientific justification of material changes,” he says.

There has also been growing interest in RTU glass vials in several pharmaceutical segments. RTU glass vials can be delivered pre-sterilized in optimized secondary packaging ready for fill and finish, skipping up-front washing and depyrogenation steps in an aseptic environment, allowing biotechs and drug manufacturers to speed up time-to-market, according to McLean.

“RTU technology has been around for a while, but only recently have we seen real interest, particularly in markets that require considerable flexibility in their operations, such as veterinary and biotech,” McLean says. For example, he points to the growing trend of personalized medicine as placing demand on innovative biotech companies for more flexible production capacity that can be supported by novel combinations of primary packaging.

To help meet that demand, SGD Pharma has introduced a number of RTU molded glass range extensions for fill/finish, including 50-mL vials in clear and amber glass in pre-sterilized tray secondary packaging and 20-mL vials in clear and amber glass in a nest-and-tub format.

“These new RTU primary and secondary packaging combinations developed in collaboration with Stevanato Group offer drug producers the flexibility they need to deliver innovative medicines to patients significantly faster because the drug master files (DMFs) are available,” McLean comments. “The nest-and-tub format, for instance, protects vials with no glass-to-glass contact and enables combi-line filling, the ideal option for smaller biotech companies looking for optimal flexibility,” he adds. In addition, biopharma manufacturers now have access to an integrated, flexible multiple filling line solution for different sources of primary packaging.

Catalent has not had any direct experience of significant supply shortages during the pandemic because the company honed in on addressing supply-chain needs, according to Melissa Buchanan, supply-chain director at the company’s Bloomington, Ind., site.

“To ensure minimal disruption, Catalent has tightly monitored its inventories, collaborated with supply-chain partners to protect critical supply needs, and committed additional resources to identify, navigate, and resolve potential supply-chain disruptions. This has included expanding safety stocks and extending the buying horizon to ensure sites have the necessary components to manufacture medicines, vaccines, and therapies for customers,” Buchanan remarks. Additionally, Catalent has developed improved business analytics to identify and track potential supply risks earlier, allowing more time to respond to challenges.

Similarly, Samsung Biologics benefited from resilient and flexible supply-chain-management operations, which ensured a stable supply by anticipating such disruptions and adopting proper contingency plans in advance, according to Chae.

The value of early supply-chain management

Even prior to the pandemic, it was important to have supply-chain strategies and contingency plans in place to support biopharma operations in the long-term and withstand market fluctuations and sudden material supply disruptions, Chae asserts.

With the COVID-19 pandemic, the industry has come to understand even more than ever before the value of early supply-chain management, according to McLean. “It may sound obvious, but successful drug manufacturers are those that manage their packaging supply with a proactive, rather than reactive, approach,” he states. Although there is an element of risk involved, he notes that securing supplies before product approval has huge benefits, particularly in situations such as the COVID-19 pandemic. The importance of having a backup packaging supplier has also been highlighted this year, McLean adds.

As a step to address the concerns over packaging supply uncovered during the pandemic, drug manufacturers are encouraged, says McLean, to start stability testing for alternative packaging materials before they experience shortages to mitigate risk and ensure business continuity in an uncertain climate.

Catalent, like many companies, found during the pandemic that the use of online and virtual tools, including improved data analysis for business-decision making, was vital to success. “These types of tools are helping identify and track potential supply risks earlier, allowing more time and better options to react,” Buchanan remarks.

For Leisner, the pandemic has underscored the need for greater flexibility. “The pandemic has shown that the drug-development and manufacturing industry needs to build more diversity and agility into its processes and place an emphasis on phase-appropriate quality practices,” he asserts. “COVID-19 may not be the last pandemic that we’ll face in our lifetime, so we need to learn from the last 18 months and start making changes now,” he adds.

A specific example of how to increase agility in supply chains, Leisner highlights, would be to qualify multiple options for alternative components in the DMF. “That way we could diversify, if needed, and minimize disruption to manufacturing,” he says.

As a pharmaceutical glass packaging company, SGD Pharma has already learned to leverage flexibility, particularly the flexibility of the molded glass production process and run size, according to McLean. “During production, we form vials directly from the glass furnace, rather than converting from tubular cane that originates from a furnace elsewhere. We can therefore produce hundreds of thousands of containers per day on a single line and, when necessary, stop that line short and move to production of another size or design. In this way we can be flexible in production and add capacity quickly when needed,” he explains.

The pandemic, believes Schaut, has also highlighted the demand for increased efficiency and speed in pharmaceutical packaging and vaccine production. “New glass coating technology and high-speed filling lines can help enable pharmaceutical companies and contract manufacturing organizations (CMOs) to ramp-up capacity and throughput based on demand,” he asserts.

A positive outcome of the COVID-19 pandemic has been increased collaboration across the biopharma supply chain. “The pandemic has required unprecedented cooperation between all partners involved, sharing information; working on various activities in parallel; and focus, dedication, and hard work by all the teams involved,” Buchanan states.

“We learned that collaboration is essential to meet demand and overcoming challenges quickly. Companies up and down the supply chain have been required to collaborate and find new solutions, be it material or technical, in order to meet the current need,” agrees Schaut. “Collaboration throughout the entire supply chain is essential to move quickly to implement solutions. From raw materials to fill/finish operations, companies are working together with an understanding that change is inevitable,” he says.

“Over the course of the last 18 months, Catalent has not only seen an increase in demand, but also an increase in collaboration and transparency across the industry, from innovators and other [contract development and manufacturing organizations] CDMOs, to suppliers and even regulators,” Buchanan continues. As a result of these new levels of collaboration, she notes that partners have been willing to make investments at-risk, allowing Catalent to bring more commercial capacity online, faster.

Along with greater willingness to consider other options, Leisner has observed a declining interest in single-source contracts, which he believes may become a thing of the past. “To get there, we will need to work in partnership across the ecosystem, and we all have a role to play,” he says. Fill/finish experts, for instance, need to help their customers understand the supply-and-demand risks of over-specification in regulatory documentation, while regulatory agencies could make re-opening DMFs easier by streamlining the current Resource- and time-intensive process.

Alternative materials, as well as supply-chain planning, are essential to ensure a reliable supply for parenteral drug packaging.