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

Cynthia A. Challener

The pharmaceutical industry is no stranger to fermentation. Synthetic biology has been used for the production of both biologic and chemical APIs for decades. While it has not been the predominant method in either sector, the greater sustainability and ability to access novel structures provided by fermentation processes are driving greater interest, particularly for small molecules.

Synthetic biology “will propel companies that understand the right strategy for the distinct value propositions it offers at each step in the production life cycle,” said Gihan Hewage, previously a Lux Research analyst, in a press release (1). “Companies with products in the ideation and early development stages will differentiate most from flexible production and the ability to create novel products, whereas products in later stages of development can leverage the environmental and marketing benefits of the technology,” he added.

Cell culture, while often more suited for the production of biologics, such as proteins and monoclonal antibodies, is more expensive and often more complex. Microbial fermentation tends to be, according to Jose Luis Barredo, biotechnology business director with AMRI, more straightforward and scalable. One key reason is that the organisms have faster and more stable growth patterns and lower intrinsic metabolic burden, notes Filippo Giancarlo Martinelli, head of global industrial partnerships development at Abolis.

In addition, fermentation often involves the conversion of cheap and readily available raw materials (sugar or other cheap substrates) into high-value products with high yields/titers, ensuring the commercially viable manufacture of high-quality products, observes Nikolay Krumov, senior project leader, upstream development microbial at Lonza.

Processes typically proceed at room temperature and ambient pressure in water, avoiding the use of harmful or toxic solvents or chemical raw materials and production of dangerous waste, according to Martinelli. Operators benefit from safer work environments, and drug makers avoid issues associated with the use and production of hazardous materials. Fermentation facilities and equipment may also be less costly to build and install.

Synthetic biology can in some cases also provide access to molecules that cannot be produced via traditional synthetic organic chemistry. “While this concept is not novel per se, over the last several decades, the development of improved tools and understanding have also enabled greatly increased yields and decreased development costs and risks,” Martinelli states. He points to steroids, analgesics, opioids, and some anti-cancer drugs. Similarly, he observes that some phytochemicals that cannot be practically extracted from plant sources may also be produced via fermentation.

There are also decades of fundamental research and proven manufacturing success supporting the growing interest and application of synthetic biology and fermentation for chemical API production, Krumov asserts. “The expression systems are well known, studied, and characterized, and the processes are well understood and controllable, facilitated by the development and improvement of precise monitoring tools,” he explains.

The key to realizing all of these benefits, however, Martinelli stresses, is to recognize when synthetic biology provides the optimum solutions—either by providing access to novel structures or higher yields/selectivities—and when organic chemistry is the best approach.

AMRI breaks down microorganisms useful for fermentation into two classes: natural, classic producers and engineered host strains (genetically modified organisms). Classic microorganisms widely used in biotechnology processes include bacteria (

), make up the second group, according to Barredo. “These host strains are selected based on suitability for genetic modifications and utility to efficiently produce APIs and compounds, including many products not practical via fermentation previously,” says Peter C. Michels, head of global fermentation at AMRI.

The majority of developmental and commercial processes in the pharma industry involve 

), Krumov adds. “E. coli is probably the most studied and well-known microorganism, a sort of work horse for the biotechnology industry. It provides simple and fast strain development, short fermentation times, high cell densities, and double-digit titers. 

 achieves ultra-high cell densities grown on simple and cheap carbon sources and also secretes the product into the culture medium, delivering a highly pure product with decreased recovery efforts,” he explains.

New species, Krumov notes, including such requiring biosafety level 2 handling, are constantly evaluated and investigated, and some find commercial realization.

Advances in biologic and analytical technologies

A primary driver of recent interest in fermentation is advances in molecular biology and synthetic biology. “These advances allow producer strains to be engineered with greater understanding and effectiveness, which is therefore enabling the development of new processes,” Michels states. They can also be adapted and improved using established fermentation process knowledge and infrastructure that has been built over decades.

The use of synthetic biology, including directed evolution of biosynthetic pathways, offers new, more specific ways of modifying pharmaceutical production, according to Michels. “These new innovations also allow us to get more out of classical fermentation processes. We’ve seen really dramatic advances in metabolic engineering across a broad spectrum, such as directed evolution, that allow us to simply and systematically evolve the biosynthetic pathways and achieve a myriad of advantages—the overproduction of APIs, reduction of related impurities, shortening the fermentation process and making it more cost effective, producing new compounds, improving process safety, and more,” he comments.

Metabolic engineering, therefore, is playing a much greater role because it can be applied to many different goals for continuously improving practical processes. Martinelli agrees that metabolic engineering and genetic engineering play a key role in the development of novel biosynthesis processes because they are crucial to yield enhancement as well as diversity generation. “By rewiring the microbial network, it is possible to drastically divert the flow of material through the cell metabolism and thus achieve production of the target molecule at the desired scale and cost,” he says.

For Lonza, genetic engineering has been most important in its efforts to develop processes for the production of biotherapeutics. “Technical advances in genome editing, next-generation sequencing, and genomics are increasingly important to support the design of productive and scalable production strains,” asserts Joachim Klein, head of strain development and cell banking for Lonza’s microbial development services.

As well as the development and selection of high-performing, stable, and productive strains, high-quality and high-throughput screening—in combination with the development of effective analytical methods for assessing product quality, such as such as post-translational modifications of candidates generated using candidates identified in the screening process—have also been important contributors to the greater application of fermentation in API manufacturing, according to Klein.

Advances in analytical technology, particularly mass spectrometry, nuclear magnetic resonance (NMR), and other analytical techniques that increasingly help to elucidate, in much greater detail, exactly what is going on inside the organisms, have a significant impact in driving much greater understanding and the more efficient design of practical production processes, Michels agrees.

Advances in biologic and analytical technologies have occurred in parallel with similar advances in informatics and other digital technologies. Dual development has been necessary to efficiently process the large quantities of data produced and ensure data integrity.

“Informatics and digital technologies are valuable in genomics, metabolomics, and transcriptomics analyses. They help us to know ‘

’ the modifications in the genome of the microorganisms necessary for the construction of an improved strain,” Barredo states. Special software, Krumov adds, are applied in the elaboration of process models, statistical analysis and predictions, parameter screening, and process optimization, and to establish more precise and agile process control.

In addition, with the growing complexity of target molecules/metabolites to be produced, it is becoming more difficult to design and implement a full genetic engineering campaign and the corresponding large-scale metabolic network rewiring needed to achieve the target yield, according to Martinelli. “Bioinformatics plays a key role in not only the discovery of the relevant enzymatic and cellular regulatory steps, but also in the design of the cloning tools required to implement such changes and the dosing and fine tuning of the changes needed, taking into account the implications of the different omics disciplines, such as transcriptomics, proteomics, metabolomics, and fluxomics,” he asserts.

“Without digital technologies,” Martinelli continues, “it would not be possible to operate at the current level of complexity at the interface between expert scientists and robots.” In fact, to make retro-biosynthesis more feasible, Abolis has developed a proprietary computer algorithm in which artificial intelligence is applied to bioinformatics for gene and pathway selection and manipulation towards the biosynthesis of target molecules.

Advances in process analytical and control technologies are also enabling improved fermentation processes. For instance, new in-process controls (IPCs) are being developed to control the evolution of raw materials, enzymatic activities, product, etc., according to Barredo.

“In addition to more traditional temperature, pH, dissolved-oxygen, carbon dioxide, and oxygen-demand sensors, biosensors are helping to control the fermentation process, and monitoring systems for submerged fermentations have taken a considerable step forward,” Barredo says. He also stresses that the availability of reliable sensors that are able to provide real-time, non-sampling-based process monitoring of physiologically relevant parameters such as cell mass, substrate, and metabolite concentration allows for automatic control of fermentation processes based on suitable process models and control strategies.

In particular, Michels notes AMRI has found a much broader array of practical approaches using NMR, in particular development insights and quality control, and most notably in combination with the use of in-process controls and mass spectrometry.

While much of the substantial capital investments made in the pharmaceutical industry for classical fermentation can be adapted for new synthetic biology processes, there are some new developments in equipment worth noting. Krumov points to new fermentation system concepts and designs that enable greater automation; intuitive, precise, and advanced parameter programming; and online monitoring of essential quality attributes. “New primary recovery equipment (separators, filters, membranes) also ensures better performance, higher productivity, and greater process robustness, facilitating better purification of the products and higher yields,” he adds.

Mobile applications, according to Michels, allow remote monitoring and control of fermentation parameters even from a smart phone and provide much better information, while parallel fermenter systems provide faster and improved development arrays for modified strains and multiple parameters. He also notes that the wider variety of impellers available today afford improved oxygen availability and mass transfer, particularly for the new engineered host strains.

Going forward, the focus will largely be on downstream processing, which according to Martinelli, represents a challenge when scaling up production of small-molecule intermediates and APIs produced via fermentation.

All of these rapid advances in molecular biology and engineering tools will impact fermentation in the pharmaceutical industry over the next several years. “We anticipate that continued exponential growth in molecular biology techniques—actually editing and designing new producer strains at lower cost and higher volumes—will have a significant impact on the design of new biosynthetic pathways in a synergistic way with chemical synthesis in the years ahead, not only in pharma, but in food, agriculture, enzymes for biocatalysis, and more” Barredo asserts.

“A longer-term vision,” Barredo adds, “might include using new competitive fermentation processes based on the circular economy, where food wastes are used as raw materials to design new, sustainable processes that contribute to the safety and quality of the global environment.”

Modern fermentation process development is, according to Krumov, a long, profound process that leverages the knowledge and experience of generations of bioprocess engineers in combination with current cutting-edge technologies and digital tools, to deliver the safest and most effective next-generation medicines. “The steadily increasing worldwide demand for microbial fermentation production capacities is an indicator of the qualities of this biosynthetic approach and recognition of its potential,” he asserts. Martinelli adds that this technology not only brings innovation to create new entities and new treatments, but to limit the environmental impact of their production.

One way to reduce development timelines, Krumov says, is through intensification. “For instance, intensification of process development will reduce the necessary gene-to-vial time through application of current design-of-experiment approaches, soft sensors, and data-based process modeling,” he says. Ensuring and confirming a product’s quality at the very early project stages will also be important, according to Krumov. Where possible, avoiding the use of complex compounds will further facilitate the development of robust, reproducible, and cost-effective fermentation-based manufacturing solutions.

1. Lux Research, “Lux Research Predicts Synthetic Biology Has High Potential as an Alternative Production Method for Chemicals,” Press Release, April 2, 2020.

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


Vol. 44, No. 11
November 2020
Pages: 24–28

When referring to this article, please cite it as C. Challener, “

Fermentation Finds Fans in Small-Molecule API Synthesis

Articles

Biological and analytical advances enable modern fermentation processes to deliver safe and effective next-generation medicines.

Excipients are widely recognized as vital to the development of effective small-molecule and biologic drugs, with a wide range of approved compounds of varying chemistries providing functionality from taste-masking to stabilization. The latter is also crucial for vaccines and live biotherapeutic products (LBPs), which can suffer degradation during both upstream and downstream processing, fill/finish, packaging, storage, and transport. The properties of different LBPs and vaccines can differ widely, and thus careful selection of the right excipients is essential. Doing so is not easy, however, and requires experience with these challenging products and access to effective screening technologies.

As understanding of the role the human microbiome plays in human health and disease has increased, many academic research groups, startups, and Big Pharma firms have developed microbiome-based diagnostics and therapies, a number of which are advancing through the clinic. In 2018, at least 200 companies were active in the microbiome space, and 2400 clinical trials were underway (1); between January 2016 and July 2019, more than $5.4 billion was invested in partnerships and acquisitions related to LBPs (2).

Stability challenges with LBPs and vaccines

LBPs by definition comprise living organisms that exhibit a desired activity within the human body. They have, in fact, been incorporated into probiotic foods and dietary supplements for many years, but typically, excess colony forming units (CFUs) are used to compensate for any loss of viability upon storage. That approach isn’t possible for pharmaceutical products, so the goal during manufacture is to maximize the number of cells that are viable throughout the entire production process, according to Aaron Cowley, chief science officer with Arranta Bio.

“One of the key attributes associated with LBPs is the ability to keep the cells alive and healthy over a duration of time, thus allowing them to function as they are designed,” says Synlogic Therapeutics Chief Operating Officer, Tony Awad. The sum of the stresses that the organisms experience during upstream, downstream, fill/finish, storage, and rehydration will determine if the organisms will retain viability and activity, he adds. Each of the processing steps, therefore, needs to be optimized, because they can all have an impact on subsequent stability.

Processes also need to be designed for scalability, Cowley adds. “Because most of the organisms that comprise LBPs tend to be unstable, it is essential to minimize process times in order to minimize die off. Effective small-scale processes that take much longer to complete when performed at large scale are, therefore, not practical for commercial LBP manufacturing,” he explains.

Viability, and thus stability, depends on a number of factors, including not only the general fermentation conditions and harvest technique, but also excipient/cryopreservative selection and the lyophilization process, according to Cowley. He also stresses that development of an optimum cell bank is crucial as well. “Optimizing the master cell bank is necessary to ensure that the organism being produced is optimally healthy, exhibits the right performance behaviors, and is generated in the maximum yield,” he observes.

Whether the strains are delivered as a single organism or consortium can also affect the stability of LBPs, as can the type of organism. “For example, spore-formers can have greater stability allowing for storage at room temperature but may come with side effects as these bacteria have the potential to become pathogenic,” Awad observes. Comprehensive characterization of LBP strains is also essential. “Knowledge of critical parameters and acceptable ranges—redox, osmolality, etc.—and how to control them is necessary to achieve and maintain the proper functionality throughout the production process,” Cowley asserts.

Stability issues can also occur at any stage of a vaccine’s development lifecycle, according to Jee Look, senior director of drug product development for Emergent BioSolutions’ contract development and manufacturing organization (CDMO) business. “In some cases, instability that occurs during upstream/downstream processing can be mitigated during final drug product manufacturing, but it is important to identify and understand the mechanisms of instability early in the pre-formulation stage as instability in the final drug product would have the largest impact on patient safety and overall production efficiency and would be more costly to fix,” he says.

The instability characteristics possible with a given vaccine also depend on the vaccine type, whether it is a live virus, inactivated virus, virus-like particle, or some other type of subunit, recombinant, or conjugate vaccine. The use of aluminum adjuvants can also create different challenges with respect to vaccine stability. “It is important to understand the mechanism of action of each type of vaccine in order to design the formulation and deal with the instability issue,” Look concludes.

Role of excipients in LBP and vaccine stabilization

Stabilization of LBPs involves different mechanisms and thus different excipients. For LBPs stored at frozen conditions, cryoprotectants are necessary, while those that undergo lyophilization will require lyoprotectants, according to Awad. For these applications, excipients are added to the cell slurry obtained following harvest to maintain viability through the harsh freezing and drying process, which can be damaging to live microorganisms, according to Cowley.

“Both of these options can lead to better shelf life of the LBP,” Awad observes. Excipients are also used in final LBP formulations to influence cellular size and structure and help stabilize LBPs during cryopreservation and/or to preferentially bind moisture to ensure viability and activity are maintained once the product is packaged, Cowley adds.

Many organisms developed as live therapeutics also tend to combine into long chains. “These aggregates can lead to low CFU results because many tens of cells (or more) are detected as just one colony,” Cowley explains. In this case, use of appropriate media can minimize aggregation. “At Arranta Bio, we have found that certain media formulations in particular prevent aggregation regardless of the type of organism, allowing for the development of optimum processes,” Cowley says.

For vaccines, different types of excipients play important roles during vaccine production, formulation, fill/finish, and storage processes, according to Look. “Selection of excipients can be a complex consideration beyond stability issues and can also depend on the target product profile (TPP), logistics, and business market complexities,” he comments.

For instance, if the TPP requires a long shelf life and/or high temperature storage, the vaccine would need to be converted into solid form. In this situation, Look says sugar excipients such as sucrose could play an important role. For live vaccines, which can be susceptible to manufacturing and storage loss, some type of protein stabilizer such as human serum albumin or gelatin may be required.

Antibiotics are also used to prevent growth of bacteria during production and storage, and stabilizers such as monosodium glutamate (MSG) and 2-phenoxyethanol are used to protect vaccines from heat, light, acidity, or humidity during processing and storage.

Cryoprotectants and lyoprotectants are the most critical excipients for LBP stabilization and function by minimizing cell damage caused by ice crystal formation during freezing, according to Awad. Some cryopreservatives penetrate the cells, but all generally influence viscosity, osmolality, surface tension, and other properties, according to Cowley. “The goal is to choose the right mixture that provides the optimum conditions for each specific organism to survive during cryopreservation,” he says.

This type of protection, according to Awad, is important whether the LBP is stored as a frozen liquid or lyophilized to produce a powder for oral suspension. He also notes that additional excipients may be required if the mechanism of instability is known. “For example, antioxidants may be utilized if the strain is susceptible to oxidation or buffering excipients may be utilized if maintaining pH is important,” he explains.

The types of excipients used to formulate a specific vaccine will depend on the type of degradation mechanism of that vaccine. “Degradation mechanisms include aggregation, precipitation, oxidation, deamidation, shear, freeze/thaw, air-water interface, thermal, etc.,” Look states. For instance, different protein stabilizers will be required depending on the causes of aggregation, while antioxidants are important to prevent oxidation. As one example, Look notes that a surfactant such as polysorbate 80 is typically used to deal with aggregation/precipitation due to interactions that occur at the air-water interface. “In this situation,” he observes, “polysorbate 80 would migrate to the air-water interface and prevent the protein from getting through.”

Understanding the mechanisms of instability to identify excipients that have been demonstrated to overcome these mechanisms is the best approach to selecting optimum stabilizing agents for both LBPs and vaccines. For many of these products, however, the role excipients play is still unknown. “Trial and error, empirical approaches, and historical experience are needed when considering excipient options, especially for new gene-therapy vaccines,” Look comments.

For LBPs, the effectiveness of excipients is evaluated by testing for key quality attributes or release criteria, including cell counts, viability, activity, and shelf life, according to Awad. “Excipient screening through compatibility studies is also often required,” he adds.

One of the main challenges for LBPs is a lack of commercially available excipients and media blends that have been specifically developed for use with these new active ingredients, Cowley notes. Based on its more than 10 years of working with LBPs, Arranta Bio has addressed this issue with the development of a number of proprietary Arranta Media Blends and CryoPreservatives, both based only on plant-derived components, that the company uses to rapidly screen against client microorganisms to identify optimum process conditions.

“We have tested both the media blends and cryopreservatives against commercially available formulations for GMP manufacturing with good results. Our media blends provide higher yields and more stable organisms, with additional indirect benefits downstream, including higher resulting viability and shorter lag phases through freeze drying. Our cryopreservative blends also afford higher viabilities and in general help us consistently achieve our minimum viability target of 40%,” Cowley says.

For vaccines, the selection of optimum excipients requires a “risk and benefit” analysis, according to Look. “A vaccine designed for healthy babies would have different considerations than a vaccine designed for terminally ill cancer patients,” he notes. Most vaccines are injectables and applied to large healthy populations, therefore selection of optimum excipients is more rigorous and depends on several factors, Look adds.

“The initial selection of excipients and concentration usually starts with historical information such as those already used in commercial vaccines. From there, the final selection and optimal concentration is done through pre-formulation and formulation development studies with the specific vaccine,” he explains.

Awad recommends that for any drug formulation, it is generally best to use excipients that have been included in prior approved products rather than novel excipients, because the groundwork has been laid and these excipients are likely to have regulatory agency approval. If a novel excipient is needed, though, additional testing, such as an extended animal study (tox study), may be needed, according to Look.

It is also important, Look reiterates, that excipients are not the only means to resolve vaccine—or drug—instability problems. “A more holistic approach is needed, which includes the consideration of processing conditions and any device used for administration. Some instability issues can be mitigated through process optimization and selection of the appropriate device,” he concludes.

1. C.R. Fernandez, “No Guts, No Glory: How Microbiome Research is Changing Medicine,” 

, Jan. 22, 2019.
2. A. Guillermo, “Why Investors Trust Their Gut About the Human Microbiome,” 

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


Vol. 44, No. 10
October 2020
Pages: 20–23

When referring to this article, please cite it as C. Challener, “Factoring Stability in the Biologic Drug Mix,” 

Excipients must be carefully chosen to ensure optimum protection for vaccines and live biotherapeutic products.

Factoring Stability in the Biologic Drug Mix

Through its Operation Warp Speed program for COVID-19 vaccine manufacturing, the US government is paying manufacturers and contract service providers to scale up the manufacture of specific vaccine candidates. If those specific candidates are not successful in the clinic, those facilities must be able to quickly switch to production of different vaccine candidates that have been approved.

While this approach sounds like a practical approach to accelerating vaccine manufacturing, rapid changeover of biologic production process carries numerous challenges. There are a few different strategies for overcoming these challenges, with key components including facility design, equipment selection, operational considerations, and the use of appropriate plant management systems.

Challenges to rapid changeover come from many sources, including the equipment, room configuration, documentation, people, and environmental monitoring, according to Sebastien Ribault, head of end-to-end solutions at MilliporeSigma.

The traditional method of completely stripping down all equipment and installing dedicated materials and components for each product has proven to be a cumbersome and costly process for multiproduct facilities, adds Piergiuseppe Nestola, senior platform technology consultant at Sartorius. “It is not unusual for changeover to require weeks to complete when traditional methods are followed. With the changing industry tide favoring multiproduct manufacturing facilities, methods to enhance efficiency without sacrificing quality or safety are needed,” he says.

Several activities must be performed in a facility to avoid any risk of cross-contamination between Product A and Product B, in particular via a thorough cleaning-in-place of all equipment surfaces in contact with intermediates and the end product, Thibaud Stoll, global head of commercial biologics operations at Lonza, specifies.

For certain biologics, most notably viral vectors, vaccines based on live viruses, and spore-formers, precautions must be taken to prevent spread through the air and more extensive cleaning protocols are generally required, typically with airborne peroxide methodology, says Katarina Stenklo, enterprise solutions commercial activation leader with Cytiva. Any live biological agents, whether they be the host organisms or adventitious agents, must be effectively removed/inactivated from HVAC, facility, and equipment surfaces (both exterior and product paths) prior to introduction of a subsequent product, adds Syed T. Husain, senior vice president and CDMO business unit head at Emergent BioSolutions.

Stainless-steel equipment specifically presents a common challenge, as it requires cleaning and validation of product contact surfaces before the equipment can be used for a subsequent project, according to Evan Shave, director of biomanufacturing—global network operations for Thermo Fisher Scientific. Cleaning and sterilization of stainless-steel equipment is well understood, but often “overdone” in terms of cleaning and rinse times, mostly due to conservatism or a lack of time to properly optimize the process, adds John Machulski, vice president of engineering for Catalent Biologics.

Changeover of processes performed in a ballroom setting can be even more difficult than for processes run in individual suites due to the added risk of cross-contamination with other processes on top of concerns regarding product carryover, notes Steve Gravallese, enterprise solutions program director at Cytiva.

Stoll adds that some product-dedicated equipment must also be installed, in particular chromatography columns with packed resin for drug substance purification. “All these activities may potentially be quite long and on the critical path if not optimized and sequenced properly, and if the facility layout has not been designed accordingly,” Stoll states.

For drug product manufacturing, it is critical to have a lean process design due to its highly kinetic nature, according to Machulski. “Although barrier isolation technology provides the highest level of aseptic processing, long bio-decontamination cycle times remain one of the biggest challenges for achieving a rapid changeover,” he says. Stoll also notes that given the completely different types of equipment, changeover times are difficult to compare. “A change in vial format may require some significant setup activities for a filling line; the number of such changes can be optimized via the proper yearly planning and sequencing of campaigns,” he observes.

For contract manufacturers in particular, the biggest difficulty is the need for processing equipment flexible enough to accommodate different processes/scales corresponding to molecules from different clients. “This challenge is more likely to apply to drug substance rather than drug product because drug substance processes typically have significantly more variability between different products,” Shave notes.

Strategies for optimization of process changeovers differ because the equipment and room configurations for each process are different, but all are driven by the same constraints and rational, according to Ribault. “A combination of primary (process design), secondary (facility design and operation), and procedural controls and studies should be used,” states Husain.

Stoll identifies three key approaches to optimizing changeover activities: making them as short as possible, performing them during “hidden time” or in parallel, and reducing the number of changeovers by running longer campaigns. “Operational excellence/lean methodologies can be quite powerful for optimizing changeover processes, as can the use of redundant equipment or dedicating packing rooms for chromatography columns. In the latter case, there is additional capital expense, but it is usually a good investment,” he says. Running longer campaigns, though, carries a trade-off with the optimization of product inventory.

The ultimate goal, according to Gravallese, is optimizing the facility around unit operations so they can be segregated where open processing cannot be avoided and staggered changeovers are possible. “It really comes down to identifying the best methodologies and designs to stagger processes in facilities without impacting operations in the balance of the site,” he states.

Properly optimizing cleaning and sterilization cycles where stainless-steel equipment is used, validating procedures, having a well-trained staff, and having a robust yet simplified supply chain are keys to facilitating rapid changeovers, according to Machulski. “Additionally, ready-to-use primary and secondary components can be helpful, along with automation and robotic technology for drug product fill/finish manufacturing,” he says.

Ribault also asserts that it is important to look across the entire value chain and consider how to ensure the interface between process development and manufacturing works well; another consideration is to put together a team that will make the project a success in record time. “You do these things by having templates in place for process development and manufacturing that reduce the transition time. So, while rapid changeover is certainly an integral aspect of operations, it is important to keep in mind that it is one piece within the entire value chain,” he says.

In addition, a quality risk management approach may be applied to assess and continuously improve established changeover processes, according to Nestola. “All processes, including changeovers, can be improved with investment of money and resources, parallel activities, equipment design improvements, and standardization,” he asserts.

Enabling changeovers through facility design

Facility design plays an important role in facilitating rapid changeovers. Inclusion of multiple upstream suites can enable better utilization of downstream operations because upstream processing takes much more time, according to Stenklo.

For a multi-product downstream suite, Shave notes that it can be better to have the plant broken up into two or three segregated smaller rooms versus a single ballroom so changeover can start as soon as the unit operation is finished. “This approach affords the opportunity to increase facility throughput,” he says. A phased approach allows for proper and thorough cleaning as the process completes, agrees Husain. In addition, all surfaces should be smooth to allow for easier yet effective cleaning/disinfection, he notes.

Separate mechanical air handling systems should be used for independent spaces to allow some rooms to be shut down while others continue to operate, adds Gravallese. Door interlocking alarm systems are equally important because they ensure that adjacent process spaces remain separated during changeover/cleaning. The ability to monitor spaces quickly is also essential so they can be released back to operations, he adds. “Environmental monitoring of different rooms is necessary to ensure they stay within qualified requirements (temperature, pressure, humidity, bioburden, etc.). Some sampling is manual, but where possible automation of sampling can help speed up changeovers,” Gravallese says.

Other important facility design aspects for rapid changeover, according to Machulski, include: quality by design, design for manufacturability principles (i.e., lean, single-minute exchange of dies [SMED], etc.), integration of lean operating principles such as 5S for optimal equipment, material and personnel flow in the manufacturing suite, and the establishment of SMED quick changeover principles to ensure efficient reconfigurations of the equipment.

Changeovers can also be facilitated if extra rooms are included in the facility where cleaning-in-place activities on equipment can be performed in parallel, Stoll observes. “It’s not just about one aspect, but all of the aspects, including the size of the corridors, equipment placement in the suites, management of sampling, and environmental monitoring working together,” asserts Ribault.

The so-called “facility of the future,” concludes Nestola, would allow rapid changeovers due to its modular approach and because it is fit by design to accommodate single use and minimize any possible cross-contamination while still allowing detection and prevention of possible deviations.

In general, the equipment developed for the biopharmaceutical industry includes built-in functionality—both hardware and software—to make changeovers easier, according to Stenklo. If the same equipment can be used for multiple different processes to avoid having to schedule time during the changeover to move equipment in and out of storage, then changeovers can be faster, adds Shave.

Closed-system design and operation in and between unit operations also mitigates the potential for cross contamination, states Husain. Closed processing is essential because it provides a better response when using a risk-based approach, adds Nestola.

Single-use equipment is therefore one of the biggest equipment-related solutions for facilitating more rapid changeovers. “Pre-gamma irradiated single-use flow paths for all unit operations, standardized pre-sterilized tubing assemblies to connect unit operations, and aseptic quick connectors (rather than welding or heat sealing) are all designed with features that enable rapid changeover,” Shave observes.

The key advantage of single-use equipment is the elimination of cleaning and cleaning validation steps, which significantly reduces cleaning time, according to Stenklo. “With optimized consumables and consumable assemblies, the equipment can be specifically designed for the process and the facility as well,” she adds.

Single-use equipment allows a changeover in a matter of hours because it involves closed bags, according to Ribault. Both the monitoring and documentation steps are simplified because there is lower risk and the process is less complex with single-use versus stainless steel equipment. “Many people who are trained on single-use equipment find it beneficial due to its simplicity and speed of changeover,” he says. Ribault does add, though, that if a hybrid approach is used, all aspects including equipment and sampling, need to be taken into account to ensure there are no bottlenecks that can slow down the changeover process.

Shave adds that flexible hardware with single-use product-contact flow paths are ideal. For instance, he notes that a tangential-flow filtration skid can be equipped with small and large pumps and the ability to take small and larger single-use tubing sizes to accommodate a wide range of processes.

Emergent’s Baltimore Bayview facility, which is the company’s pandemic response facility designated as a Center for Innovation in Advanced Development and Manufacturing (CIADM) by the US Department of Health and Human Services, uses flexible manufacturing and single-use bioreactors to respond to the COVID-19 pandemic. “Flexible design will help enable us to complete rapid changeover and meet the stringent timelines required for producing COVID-19 candidates,” observes Husain.

Even with conventional stainless-steel equipment, there are steps that can be taken to reduce changeover times. “The ability to isolate the process equipment and transfer piping for clean-in-place (CIP) and steam-in-place (SIP) operations is critical,” asserts Gravallese. “Staggering the CIP/SIP of equipment and transfer lines can also accelerate changeovers by ensuring that the critical equipment can be isolated for priority cleaning to facilitate the start of the next campaign. Once all critical equipment and piping has been released back to operations, all secondary equipment can be cleaned for changeover, without impacting the production schedule,” he notes.

Ready-to-use components used within a filling line also allow for the cleaning step in fill/finish operations to be completely removed, while an automated high-speed filling line provides higher capacities than a traditional filling line. “Both of these design elements theoretically allow for more production runs to occur,” Machulski observes. He adds that high operational availability is achieved by reduced line clearance times and changeover times. For example, by design there are 40% fewer parts to change on an automated high-speed filling line than a traditional vial line, and 20% fewer parts to change than a traditional syringe line. Automated servo motor adjustments and robotic arms are the enablers for this step change and result in a reduction of up to 30 minutes per changeover, according to Machulski.

Implementation of rapid real-time testing for bioburden and endotoxin and total organic carbon can also be an advantageous best practice if equipment cleaning is required during change over, according to Shave.

Don’t forget operational considerations

In addition to facility and equipment design, operational aspects can contribute to more rapid process changeovers. In particular, Stoll points out that automation and digital tools are enabling technologies for streamlining changeovers, such as via optimized scheduling of activities and electronic checks and instructions to minimize the risk of errors. “The right manufacturing execution system (MES) can help your facility of the future be both agile and compliant,” asserts Nestola.

Automation software can provide guidance in ensuring that a single-use flow-path is properly connected, thereby saving time performing manual validation, Shave adds. The software can also generate automated batch records of installation and validation, saving the operator time doing manual paperwork. Augmented reality tools, meanwhile, can speed up the changeover process by walking the operator performing the changeover through the process as it is completed.

When one automation platform is used to integrate various pieces of equipment and provide additional functionalities, the ability to scale the whole system with the technology is facilitated, according to Stenklo. “Release handling is much easier when batch reporting, the data historian, and data analytics are maintained in a central place,” she says. “Process data can be accessed while a process is running without the need to gown up and enter the suite. Similarly, systems have been developed to support more rapid changeover approaches.”

In fact, instead of weeks of review, a facility of the future can achieve real-time release without quarantining the product, notes Nestola. “In addition,” he says, “use of analysis of the data collected by the manufacturing execution system can provide information about trends during different changeovers and their possible impacts on the product, if any.”

It is important, though, notes Husain, that automation be designed to allow for plug-and-play operation. “Generally, islands of automation concepts are used. A flexible data historian design also helps in allowing for equipment flexibility yet proper operational control and data analysis,” he explains.

For final drug product manufacturing, Machulski highlights the short bio-decontamination cycle times achieved through optimized injection of hydrogen peroxide vapor and use of catalytic aeration technology within automated filling lines, which enable filling of thousands of components within minutes to hours depending on the total production run. “This allows for more production runs to happen within a set timeframe. Additionally, these automated lines mitigate the risk of human contact with the product, allowing for less variability in the time taken for a human interaction and hence quicker filling times,” he observes.

Plant management systems bring it all together

It is important to keep in mind, though, that automation and software are just tools, not an objective, per se. “They don’t speed up changeover, but can slow it down. Since a facility is the sum of equipment, automation, and people, etc., it should not be considered separately,” Ribault asserts.

In fact, anticipation, training and processes including the mapping of activities and their management through solid project management procedures can eliminate most of challenges, according to Ribault. Electronic or paper procedures that guide shop floor people through all of the steps are key to ensuring fast and error-free changeovers, particularly when combined with MES, electronic batch record systems, and automation, agrees Stoll.

To facilitate rapid changeovers, an overall plant management system should have an adaptive scheduling system that automatically adjusts in response to changes, Shave adds. Supply chain management to ensure supply of consumables is also important, according to Stenklo.

Specific components of a good plant management system include electronic batch record capability, role-based recipe management that optimizes each stage of a recipe lifecycle, data integrity features to help prevent documentation or human errors, and data analytics to monitor, control, and predict any possible variation in the process, according to Nestola.

Overall, Ribault notes that the most important features in a plant management system are people and expertise. “The expertise to run a plant is not in the systems or equipment, but in the team and its experience, including quality, regulatory, and technical experience,” he asserts.

With COVID-19 and the focus on accelerated development and production of potential vaccines, the industry is entering “brave new territory”, according to Gravallese. “It will be even more critical under these circumstances to rely on past experiences to accelerate the approach,” he says.

Any accelerated strategy that involves pushing the boundaries of the usual regulations should be identified up front and discussed with the regulators as early as possible (e.g., use of stable clone cell bank or transient transfection for good manufacturing practice production), Shave stresses. Vaccine developers also need to ensure flexibility with respect to the expected required manufacturing capacity, according to Stoll. “One approach is to work with contract development and manufacturing organizations (CDMOs) to complement internal capacity,” he observes.

When selecting CDMO partners for accelerated COVID-19 projects, vaccine developers should first conduct a risk analysis to identify their capabilities and any gaps related to the projects, according to Gravallese. “It is rare to find a perfect match, but it is important to find CDMOs with the platforms, technologies, and capacities that require the minimum level of retrofits and downtime and will allow for a reasonable best approach. Where customers lack specific knowledge, CDMOs should be able to make assumptions based on their experience combined with good engineering practice, good quality practice, and the available tools in their toolboxes,” he concludes.

It is also important today for CDMOs to specialize in a couple of vaccine platform technologies, adds Nestola. “Most of the vaccines in development are based on one manufacturing platform and many viral vectors processes are similar to each other. The same goes for the mRNA platform, where processes are similar between different candidates. By using multiple platforms, the risk for failure can be mitigated,” he explains.

In addition, given the current increased lead time of most of the critical consumables, Shave says it is imperative that processes be developed using platform raw materials that can be purchased upfront before the process is finalized. “If a CDMO is involved, there will be a need for the drug developer and the CDMO to partner closely together to balance and adjust processes as needed during these unprecedented times,” he remarks.

CDMOs also need to agree with clients on a rapid approach to document review, according to Shave. As an example, he points to the use of templated documents, which can avoid or significantly minimize the need for client review of every batch record. In addition, quality systems may require some flexibility in the usual practices around document control to account for last-minute changes, Shave adds.

One challenge when entering new territory is the rapid pace at which a larger number of activities are occurring. Standardization can, according to Gravellese, help expedite the process. “While the initial reaction of many people is they don’t have time to fit standardized approaches to their specific processes in such an environment, the truth is that standardization actually provides more flexibility. Even if standardization is only achieved on a microlevel, the focus can then be directed to items that are critical and for which true solutions don’t yet exist,” he explains

To start, facilities with segregated production suites should be selected to enable processes to be up and running quickly, but at some point, optimization should be pursued to increase throughput on the same equipment, according to Stenklo. “Similarly, while standalone equipment might provide the fastest pathway to an engineering run, integration of equipment on a single platform will likely provide more efficiency in the long term,” she elaborates.

The parallel investment in CDMOs and vaccine innovation is unprecedented and critical to being able to rapidly respond to the COVID-19 pandemic, Husain concludes. “The potential success or failure of a vaccine candidate cannot be predicted. It’s important that CDMOs continue to focus on supporting all innovators and have clinical and commercial capabilities to continuously pave the way for innovation and development of life-saving medicines for patients,” he says.

Cynthia A. Challener is a contributing editor to Pharmaceutical Technology

Vol. 44, No. 10
October 2020
Pages: 48–54

When referring to this article, please cite it as C. Challener, “Strategizing for Rapid Changeovers in Biologics Manufacturing,” 

Facility and equipment design are important, but the team and its experience matter most.

Strategizing for Rapid Changeovers in Biologics Manufacturing

Rapid changeover of biologic production processes carries numerous challenges. Challenges to rapid changeover come from many sources, including the equipment, room configuration, documentation, people, and environmental monitoring, according to Sebastien Ribault, head of end-to-end solutions at MilliporeSigma.

Cynthia Challener is a contributing editor to 

Equipment and facility cleaning is crucial, with more extensive protocols needed for some biologics.

Considering Changeovers in Multiproduct Biologics Manufacturing Facilities

With additional safety protocols required in the manufacturing environment, gatherings of large people generally prohibited, and onsite inspections limited due to restricted travel, ensuring quality throughout the supply chain from raw material to API is more challenging. API producers have responded rapidly, implementing safety protocols, leveraging digital tools and technologies for virtual audits and inspections, and generally taking a reasoned, risk-based approach for making use of available resources.

FDA has conducted mission-critical inspections, assessed records remotely using the authority under Section 704(a)(4) of the Food Drug & Cosmetic Act, and has developed a risk assessment system to help the agency use dynamic information to qualitatively assess COVID-19 cases in a local area based on state and national data and make informed risk-based decisions on when and where to resume prioritized domestic surveillance inspections.

Importance of using a risk-based approach

In a time of crisis, risk-based decision making and strong leadership take on new meaning, according to David Waddington, NSF International’s executive director of pharmaceutical services for Europe, Middle East, and Africa. “It’s simply not possible for companies to operate their pharmaceutical quality systems (PQSs) and meet all their commitments with such a drastic reduction in available resources. Forward-thinking organizations have taken a proactive approach to deciding what activities can be stopped or delayed. Stopping an activity may seem to be extreme, but taking this decision proactively, before the quality system slips out of control, is a sensible approach,” he says.

For example, Waddington notes that change controls that have not yet been implemented could be halted without reducing validation effort, regulatory affairs work, quality control (QC) testing, and documentation updates. “Being extremely stringent with limiting change controls can free up [quality assurance] QA and QC resources,” he adds. Similarly, improvement plans such as introducing new systems could be halted, again freeing up resources. While delaying compliance activities feels wrong, Waddington says that in extreme situations it can be done using the quality system.

Activities that should be continued are those linked to batch release and testing. “It is important to ensure that there are sufficient QA/QC staff to support production activity and, if necessary, to reduce planned output. Deviations and out-of-specification/trend activities should also be performed in a timely manner to ensure product flow and also to identify any problems as early as possible,” observes Waddington. If action has been taken to stop some activities at the site and delay others, then, he comments, some staff may be re-deployed to bolster frontline staff.

“Taking a hard look at all activities that consume resources and applying a risk-assessment approach can help to free up some resources to bolster direct product fulfillment activities and thereby keep critical medicinal products flowing to patients,” Waddington concludes.

Because of the nature of pharmaceutical manufacturing and the need to ensure both operator safety and product quality, extensive systems and procedures are already in place at facilities producing pharmaceutical intermediates and APIs, including regular use of personal protective equipment (PPE) and good hygiene practices. Manufacturers, as a result, have been able to adapt quickly to new safety requirements and ensure continued supply of critical medicines according to current good manufacturing practices (CGMPs) and other regulatory requirements. This compliance is happening despite the challenges created by temporary plant shutdowns, the need for social distancing, and reduced on-site staff at a time of increasing production demands, complex supply chain challenges, and existing product shortages, according to Waddington. “It’s not uncommon for facilities to be operating with at least 30% less staff and key support functions, including QA, working remotely. Both companies and regulators are having to make some tough choices,” he says.

Fortunately, because API manufacturing is different from many other types of manufacturing, the need to exercise social distancing in these situations does not affect the nature of most processes, according to Jeff Ross, director of environmental health and safety for Cambrex Charles City.

“Outside of the need for social distancing, Cambrex was an early adopter in implementing screening protocols for anyone entering the site. Today, employees are required to undertake a daily temperature check in addition to answering a series of health questions. Any visitors to the site must also go through the same process and need to complete a formal questionnaire,” Ross says. Cambrex also performs job hazard analyses for all operational areas and makes recommendations on a variety of different elements in the typical workday, such as room capacities, the necessary frequency of sanitization, and the maximum size of any essential gathering.

Employee safety is always a priority for Thermo Fisher Scientific, and since the start of the COVID-19 pandemic the company has focused on protecting their health and safety while continuing to serve the needs of its customers, according to Vice President of Drug Substance Quality,Ben Gerlach. “Manufacturing safe APIs for medicines that can improve or save the lives of patients is both a large responsibility and a privilege. During the COVID-19 pandemic, we have continued to ensure the safety, efficacy, quality, and availability of the APIs we manufacture through a globally coordinated response, comprehensive site preparedness, employee training and communication, and robust business continuity planning,” he comments.

Thermo Fisher Scientific manufacturing sites have specifically established increased hygiene protocols and tightened visitor guidelines. Stringent preventative measures developed in line with guidance from the World Health Organization, US Centers for Disease Control and Prevention, and local government agencies include restricting employee travel, encouraging remote work, enforcing social distancing, and requiring employees to wear masks at all times, according to Gerlach. For those employees who are on-site, the company keeps contact logbooks, takes employees’ temperatures regularly, and employs a two-shift system for teams in the laboratories and on the manufacturing floor to accommodate social distancing.

“As a result of the support, flexibility, and discipline of our colleagues and supply chain partners, as well as the IT infrastructure available, all Thermo Fisher API manufacturing sites have remained operational since the start of the pandemic with continued GMP compliance,” Gerlach remarks.

Maintaining close communication with suppliers

Key to ongoing provision of API to pharma customers is effective management of the supply chain, including assurance that materials continue to meet the high-quality standards of the pharma industry. Prior to the COVID-19 pandemic, many API manufacturers made use of international industry conferences to meet with their vendors and customers, from raw material producers to contract research organizations, and contract development and manufacturing partners. Travel restrictions and the prohibition of large gatherings, both designed to limit spread of the SARS-CoV-2 virus, have forced API producers to find other means of keeping track of the supply chain.

FDA Takes Calculated Approach to Auditing During COVID-19

Despite being unable to attend major industry conferences in-person, representatives of Thermo Fisher Scientific have joined events virtually and maintained close communication with supply-chain partners to ensure there is no change in quality or availability of raw material, according to Gerlach. In addition, the company’s regional teams continue to closely monitor the COVID-19 situation, particularly in Asia, Europe, and North America, where most of its qualified suppliers are located. “We also continue to closely track our purchase orders and have put a major focus on regional governmental restrictions that could affect manufacturing and shipping and the timely availability of raw materials and critical equipment so there is no lapse in our ability to help customers bring important medicines to market as fast as possible,” Gerlach says.

Before the pandemic ever emerged, Cambrex had prepared for various emergencies and crisis situations by undertaking strategic logistics planning and implementing response processes, according to Ross. “Over the past several months, we have been working strategically to expand the supply chain globally by evaluating suppliers across the globe, including those in the [European Union] EU or US. Expanding our footprint and ensuring supply chain redundancy has enabled us to minimize the risk of supply chain interruptions and work with partners efficiently,” he explains.

Because of the circumstances connected with COVID-19, Ross also stresses that it is extremely important to frequently engage with supply chain partners to ensure that Cambrex understands the impact of the pandemic on their businesses and any potential downstream effects on Cambrex’s unit operations that might ensue. “Video conferencing and more frequent communications have been important for our continued visibility into the supply chain,” he asserts.

Effective communication, which Waddington says involves listening more and speaking only when there is something valuable to say, has enabled NSF International to successfully transition from a training, consultancy, and auditing service provider that operated primarily face-to-face with clients to one that can now provide true virtual and blended learning, remote audits, and consultancy. “We believe we have achieved a truly remarkable transition in such a short time frame, as have many of our pharma industry clients,” he states.

Leveraging digital tools and technologies

That rapid transition has been made possible by leveraging a wide range of digital tools and technologies in new ways and to a much greater extent than API manufacturers and their suppliers and customers were previously accustomed to. The most obvious change, according to Waddington, is the reliance on digital meeting platforms. “We have seen a significant increase in the need and willingness for more regular video calls and sharing of documents and information through secure file handling platforms. Participants can often feel self-conscious to begin with, but soon adapt and get to grips with presenting, using whiteboards, interacting breakout rooms etc.,” he observes.

As part its digital transformation strategy, Thermo Fisher had already implemented digital tools to support many of its GMP processes, and many of these systems have proven to be highly beneficial to ensuring continued API quality, according to Gerlach. As an example, he points to the company’s SampleManager Laboratory Information Management System, which helps drive productivity, ensure compliance, streamline processes, and improve organizational efficiency.

Thermo Fisher also uses Documentum (OpenText) to store GxP documentation and manage the creation, amendment, approval, use, and retention of all documents. “This system provides traceability, ensuring data integrity and compliance to good documentation practices to meet our regulatory standards,” Gerlach notes. The company also uses tools to manage quality events and support training and virtual communication and systems for electronic process control and data analysis. Cutting-edge camera and augmented reality (AR)/mixed reality technology is also leveraged to provide safe, virtual access to Thermo Fisher facilities.

Cambrex has also invested heavily in recent years in information technology platforms and advanced technologies that have enabled the company to maintain its current quality systems while allowing remote working for staff and facilitation of virtual collaboration with internal and external stakeholders, according to Chuck Walker, director of regulatory compliance at Cambrex’s Charles City facility.

Examples include live broadcasting from Cambrex’s manufacturing sites and clients being able to remotely visit its facilities, have instant interaction with subject matter experts, and undertake live-virtual audits. “When lockdown conditions were implemented at our multiple sites, we saw immediate results from these investments in that our employees were able to operate as usual from remote locations; client visits became virtual; and we were still able to undertake internal and external audits,” Walker observes.

In fact, from an auditing perspective, NSF International has witnessed a major shift with companies allowing the use of camera technology within facilities to share images, according to Waddington. “This approach is a real game-changer as it transitions from a virtual ‘desktop’ audit to a true interactive remote audit, allowing the auditor to view operations live and assess effective implementation of the PQS including remotely observing facility design, hygiene, and even operator behaviors,” he explains.

Such digital tools have also been invaluable for regulatory agencies during a period when most onsite inspections have been halted due to the COVID-19 pandemic. Many agencies have historically conducted some form of remote risk-based review or “desktop” assessment, so in some respects their current approach is an extension of that process, according to Waddington. One additional challenge that regulatory authorities have had to face, though, is to ensure the processes they are following have legal standing in line with legislation in place in their respective countries. “A number of agencies, including the [United Kingdom’s Medicines and Healthcare products Agency] UK MHRA, have been successfully conducting very detailed remote inspections of facilities and have been able to follow up on for-cause audits and ensure remediation programs are progressing in line with company commitments,” he says.

The use of AR technology, Gerlach adds, enables Thermo Fisher to provide regulatory agencies unprecedented access to its facilities without them needing to be physically present. “Auditors can navigate through the facilities and perform factory acceptance tests. Remote assist provides the means to facilitate support both internally and externally from anywhere in the world,” he says. “Limiting onsite visits helps protect both employees and visitors without impeding operations or impacting quality,” Gerlach continues. “All of these solutions are made possible with training from the augmented execution team and tremendous collaboration from our sites, vendors, clients and regulatory agencies,” he concludes.

Cambrex deployed virtual live tour technologies throughout its facilities when lockdown and restricted access conditions became applicable. “These technologies have enabled both client audits and regulatory audits to continue,” Walker says. “Although we have not had any direct regulatory requests during this period at our Charles City [Iowa] facilities, many of our other sites in different locations have successfully undertaken virtual audits, and we are fully prepared for live virtual audits if needed here at Charles City,” he notes.

In fact, Walker believes that the API industry in the United States is innately equipped to manage the COVID-19 pandemic given the governing force behind employee protections with US Occupational Safety and Health Administration’s industrial standards. “Because safety is already so deeply engrained in our daily operations, along with engineering controls, we have been able to operate confidently knowing we are protecting our employees and product simultaneously,” he asserts.

API manufacturers have also invested in expanding capacity for specialized intermediates and APIs in recent years, which has also contributed to the ability of contract service providers to meet growing demand during the pandemic. Thermo Fisher, for instance, invested more than $800 million to increase capacity and meet rising demand for biologics, cell and gene therapies, and drug products. “These global and strategic investments have ensured that lack of capabilities, capacity, or supply is never a reason medicines are delayed in reaching patients,” Gerlach asserts. “We continue to protect our colleagues on the manufacturing floor and in our testing laboratories and warehouses by adhering to strict safety measures and requirements. At the same time, we remain flexible, creative, and vigilant to ensure API quality and supply as we continue to work to bring medicines to market as fast as possible for customers and the patients they serve,” he concludes.

As horrible as the COVID-19 pandemic has been and continues to be, it, like all crises, has presented opportunities for improvement as well. “If there is a silver lining to the current situation, it will lie with those employees who stepped forward for their colleagues and found creative ways to get things done. Or it may lie in the cross-training of employees for new or expanded roles,” Waddington states. For instance, he points out that key decisions around product quality may be delegated closer to the unit operation, which should result in efficiency gains.

Pharmaceutical Technology
Vol. 44, No. 9
September 2020
Pages: 22­-27

When referring to this article, please cite it as C. Challener, “Tracking API Quality During a Pandemic,” 

Risk-based decision-making is impacting all aspects of manufacturing quality from raw material supply to facility inspections. 

Tracking API Quality During a Pandemic

Although inspections are critical, according to US Food and Drug Administration Commissioner Stephen M. Hahn, they are one part of a robust and multi-pronged approach to overseeing the safety and quality of FDA-regulated products. “Safety and quality must be part of the daily routine at a firm for their products to be high quality and reliably suitable for the US consumer,” he explained in previous press statements from the FDA press office.

Under normal circumstances, the agency uses risk-based models to identify firms for inspection. FDA prioritizes for inspection facilities deemed as higher-risk based on specific, defined criteria. For drug and device inspections, these criteria can include inherent product risk. To supplement inspections, FDA also uses a number of other tools, including denying entry of unsafe products into the United States; physical examinations and/or product sampling at US borders; reviewing a firm’s previous compliance history; using information sharing from foreign governments as part of mutual recognition and confidentiality agreements; and requesting records “in advance of or in lieu of” on-site drug inspections.

Furthermore, FDA will conduct inspections when a potential risk to public health is detected, and the agency has remained in contact with domestic and foreign regulatory counterparts to identify emerging risks in the medical products and food supply systems, according to an FDA spokesperson. “When we suspended routine operations, mission critical inspections were conducted for products deemed as mission critical drugs because of reasons including medical necessity, drugs for which there is a shortage, and pre-approval inspections for novel drugs or drugs related to the potential treatment of COVID-19,” says the spokesperson.

Both for-cause and pre-approval inspections can be deemed mission critical. They are identified on a case-by-case basis by the agency and conducted with appropriate safety measures in place.

Where routine domestic and foreign surveillance inspections have been postponed during the COVID-19 pandemic, FDA has used and implemented additional alternative approaches and records reviews, including, among other things, when appropriate evaluating records in lieu of conducting certain onsite inspections on an interim basis when travel is not permissible, according to an FDA spokesperson. The agency’s labs also continue to analyze high-priority samples.

“The resumption of prioritized domestic surveillance inspections has been an important area of focus for us,” the FDA spokesperson observes. As of July 10, 2020, FDA was working toward the goal of restarting routine on-site domestic inspections during the week of July 20. Resuming prioritized domestic inspections is, however, dependent on the data about the virus’ trajectory in a given state and locality and the rules and guidelines that are put in place by state and local governments, according to whom. “In order to move to the next phase, we must see downward trends in new cases of COVID-19 and hospitalizations in a given area,” noted Hahn in an FDA statement.

Preparation for restarting on-site prioritized domestic inspections involves using the tools available while considering other factors including the operational status of the facility, the ability for the appropriate investigator to travel, evolving local, state, and federal requirements, and updates to Centers for Disease Control (CDC) guidance. “We are using a newly developed risk assessment system to help it, and individual states make informed risk-based decisions on when and where to resume prioritized domestic surveillance inspections,” says the FDA spokesperson.

In addition, for the foreseeable future, prioritized domestic inspections will be pre-announced to FDA-regulated businesses to help assure the safety of the investigator and the firm’s employees. This approach will provide for the “safest possible environment to accomplish our regulatory activities while also ensuring the appropriate staff are on-site to assist FDA staff with inspection activities,” Hahn says.

FDA relies on risk assessments, border inspections, and compliance histories in place of routine audits during the COVID-19 pandemic.