Jennifer Markarian is a contributing editor for 

Jennifer Markarian

Continuous processes for production of antibiotics, including downstream filtration and drying processes, can improve both productivity and quality, says Detlef Steidl, senior sales director of process technology at BHS-Sonthofen, which manufactures filtration and drying equipment. Steidl notes that the company has seen successful transitions from batch filters (including agitated Nutsche filters as well as centrifuges) to rotary pressure filters. 

 spoke with Steidl about some of the benefits and challenges of moving to continuous processing.

 What do you see as the trends in continuous production of pharmaceuticals, particularly for antibiotics?

 As pharmaceutical companies move their production from traditional batch to continuous manufacturing processes, they benefit from higher throughput, significant savings, and greater yield. Particularly in the production of antibiotics, we often see that manufacturers reach the limits of their existing production processes when they want to increase their capacities. We have seen cases where the introduction of continuous filtration and drying processes increased production in the order of 150%, with a fraction of the investment costs of the previous [batch] manufacturing process.

Semi-synthetic antibiotics traditionally meet the conditions for continuous processing. These products are high in demand, have an average filtration rate, and they are relatively fast to dry. Because they are sensitive to strong forces, they benefit from the gentle treatment in continuous dryers.

 What are the limitations or challenges in filtration/drying that need to be addressed to allow continuous production to occur?

 Product characteristics must meet continuous requirements. In addition, the demand of the product must be high enough to make continuous production economically attractive. If only a few kilograms of a certain API are required per year, then investing into a continuous process is not economical. At least for a couple of months [of a year], the continuous process should be in use, preferably 24/7.

Furthermore, product behavior during filtration and drying must allow for rapid processing. In filtration, the product must build a filter cake in usable height (3–5 mm) within seconds or a maximum of three minutes. The same is true for drying. The drying process should not take too long to allow for a continuous process to be set up. Product behavior should also be stable, within a limited range of fluctuations. This [stability] can be achieved more easily in fully continuous processes.

A fully continuous process from reaction and separation to drying is preferred; it allows the reactor to be operated continuously if possible. If fully continuous is not feasible, then switching from reactor A to B and back requires detailed analysis and good engineering controls. However, if the reaction is batchwise, but several batches are alternately fed into the downstream process, then a ‘semi-continuous’ process [with continuous downstream processing] still makes a lot of sense.

In some cases, manufacturers still stick to batch dryers because the drying time is quite long, the operation requires very low vacuum, and overall capacity is not too big. Here, filtration takes place over a period of six to 12 hours until the dryer is full. The filtration process is then stopped until the dryer has done its job for a couple of hours, allowing the process to benefit from the continuous thin cake filtration with an alternating (on/off) operation.

 What are the equipment differences for filtration and for drying that are different for continuous vs batch?

 In traditional batch production, each production step involves an autonomous batch process. The overall production batch is produced in independent steps and sequences. A typical batch filtration technique is Nutsche filtration, which may use pressure or vacuum in a closed vessel. The subsequent separation and cleaning in the Nutsche filter require several manual actions, such as taking samples, analyzing them in the lab, and switching the washing method. Some amount of active ingredient is lost in the Nutsche filter, caused by the turbid flow stage at the beginning of filtration and remainder at discharge.

A fully continuous separator, such as the rotary pressure filter, has a smaller filter surface. The equipment reduces cake thickness, which results in lower cake resistance. Thus, the filtration pressure can be lowered, which allows the process to be optimized to ensure high performance over the long term. Another major difference is that online monitoring allows the operator to quickly optimize the quantity of washing agent.

A consequence of the nature of continuous processing is that the quality parameters will always be within certain limits and be constantly monitored. Quality control is carried out reliably for the entire production, compared to batch operations that rely on sampling methods with the corresponding risks.

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For certain APIs, including semi-synthetic antibiotics, continuous filtration and drying improves productivity and quality.

Considering Continuous Filtration and Drying

Continuous manufacturing for oral solid-dosage (OSD) drugs continues to grow in acceptance as early adopters and equipment manufacturers refine their equipment and processes. With six small-molecule OSD drugs approved using continuous manufacturing—including both new products and existing products made in a batch process and now made in a continuous process—the precedent has been set for other companies to follow. By manufacturing in a new way, processors hope to reap benefits, such as faster development, a smaller equipment footprint, greater flexibility in manufacturing scale, tighter process control, and the potential for real-time release. The advanced process control with continuous monitoring used in continuous processes allows more consistent quality, which reduces waste and lowers operating costs.

“CM practitioners will need to have a more advanced level of process understanding to apply advanced quality measurement and control strategies. However, if carried out successfully, the payoff will be a flexible and robust drug supply chain that can be ramped up quickly in time of health crisis,” notes Professor Johannes Khinast, head of the Institute for Process and Particle Engineering in the Research Center Pharmaceutical Engineering (RCPE) at the Graz University of Technology in Austria.

“CM is a tremendous opportunity to advance drugs to the market at a much faster pace than traditional batch manufacturing and [enable] enhanced product quality based on enhanced process understanding and a richer data environment,” agrees Jose Luis Santos, head of Drug Product Continuous Manufacturing at contract development and manufacturing organization (CDMO) Hovione.

A challenge for continuous manufacturing is that the material handling and feeding into the process is critical, and there are two primary concerns: some of the APIs and excipients are poorly flowing powders and feeding very low levels of API can be difficult.

“We need to significantly increase the consideration of process interconnection and materials aspects when designing and operating a continuous processing facility,” says Khinast. “The unpredictability of in-process material behaviour is tough, since small changes in the formulation can have significant effects on the rheology, stickiness, segregation tendency, chargeability and other parameters.”

Accurate and consistent feeding is a challenge, along with low-rate feeding and containment designs for high potency ingredients, agrees Sharon Nowak, business development manager at Coperion K-Tron USA. “High accuracy loss-in-weight feeders are at the heart of most continuous processes. As the pharmaceutical industry implements these systems, more and more robust designs in weighing technologies, loss-in-weight feeder controls, modularity in design, and also overall cleanability are being demanded,” she explains. Nowak points out that the importance of the refill system to the loss-in-weight feeders is crucial, but sometimes overlooked, by process designers. “It is imperative that the feeder technology and refill system chosen are designed to include not only optimal performance, but also integrated to ensure the highest accuracy and consistency levels in feeder mass flow output,” she cautions.

“The primary challenge with poorly flowing powders is inconsistent filling of the screw pitch,” adds Sarang Oka, process development engineer at Hovione. “Vendors have experimented with various agitator and screw geometries to improve screw filling, and these have shown promising results. Some powders, such as certain grades of silica with very low bulk density and substantial electrostatic adhesion tendency, however, continue to pose a challenge. Another trick in the book is coprocessing the poorly flowing powder with a flow aid prior to introducing the powder to a feeder.”

Pretreating the API can be a solution if changing the feeder design doesn’t work, says Doug Hausner, senior manager, Continuous Manufacturing Business Development, Pharma Services, Thermo Fisher Scientific. “Silication is the most prevalent and easiest pretreatment, but there are a number of options and companies are coming to market with solutions,” he notes.

Although feeders have been designed to feed low levels of APIs, there is a limit. “There is a physical lower limit below which signal-to-noise ratios even for the most sophisticated load cells becomes too low for effective gravimetric control, and this handicaps our ability to feed below a certain flowrate,” says Oka. “A management strategy has been to preblend (in batch) the ingredient with low weight fraction in the formulation with another ingredient, and then feed the preblend at the combined, higher feedrate.”

Development, tech transfer, and digital twins

In theory, CM processes should not require scale-up; instead of larger equipment, the line can be run for a longer time. CM thus offers the potential for faster development and easier tech transfer, but practitioners are still working on achieving these benefits. 

Because development is conducted in the same equipment and the same scale, there is potential for faster development cycles, agrees Santos. He suggests, however, that development in CM is currently slowed by a steep learning curve at most companies.

Currently, tech transfer is often conducted between units that are similar or identical in size and other characteristics, notes Oka. “One can be very confident that experiments performed, and results obtained on a standalone loss-in-weight feeder will translate well when an identical feeder is used to feed the same material in the integrated process train,” says Oka. “The challenge arises when development is performed on equipment that is different from commercial equipment. We still do not have correlations that help us transfer processes between dissimilar pieces of equipment or process trains. Recommended practice for organizations who wish to build multiple lines is to develop identical lines, if there is desire to transfer products between lines.”

Digital twins are proving to be a valuable tool for development of continuous processes. These computer models of a process allow process developers to run experiments 

, allowing a greater number of experiments to be run more quickly and a better process understanding to be developed before evaluating process conditions on the actual equipment.

“People are pushing in the direction of digital twins to limit development time, because the software/control is often the rate limiting step in getting a system up and running, not the process development in a chemistry, manufacturing, and controls sense,” says Hausner. Digital twins also allow users to demonstrate the process on different production lines, such as when transferring to a different facility, he notes.

Running experiments off-line is particularly important for CM, because the process of cleaning between products is time-consuming. “Tools that help us minimize the use of the rig are incredibly important to us [because of the time for cleaning.] These tools could be very sophisticated models or simple tools based on engineering correlations that predict the performance of the product in the rig,” says Oka.

Digital twins have been commonly used to run 

 residence time distribution (RTD) experiments, says Oka. “These experiments can be done either at the unit operation level or at the full process train level. Thorough characterization of the RTD enables one to track evolution of disturbance through the rig, a crucial element of today’s control schemes. The underlying models, if well calibrated, also enable the practitioner to ‘dial-in’ and test a desirable RTD.” Other uses of digital twins include understanding the impact of material properties and process parameters on process performance and eventually product quality.

RCPE’s particle-simulation based approach is a digital twin of CM processes, developed in collaboration with pharmaceutical companies and equipment suppliers. “We believe that such digital twins are crucial for the future of continuous manufacturing, as this technology allows us to better process and visualize real-time data to enhance our ability to predict and control the process dynamics,” says Khinast. “Specifically, we can use digital twins to monitor and predict critical quality attributes and key performance indicators throughout the process line, while simultaneously feeding data back to optimize the process output in terms of quality and yield. … Digital twins have the potential to make continuous manufacturing faster, cheaper, and less error-prone.”

Khinast says that RCPE’s digital twin allows development of key processes, such as continuous powder blending, based on material properties that can be measured with small amounts of material. “Because this 

 approach is based on the fundamental physics, it is far more efficient, compared to the traditional trial-and-error approach, when you need to transfer the product and process to a different set of equipment,” he explains.

Simulations and modeling are also commonly used to identify bottlenecks and eliminate inefficiency in processes, explains Dave DiProspero, director of Pharmaceutical Process Technology at CRB. “A continuous manufacturer’s success, survival, and profitability depends heavily on process efficiency. During the times when equipment is being maintained, cleaned, turned over or idle work in progress awaiting upstream processes, efficiency is being reduced and profits are being lost,” says DiProspero. Modeling can be used to find efficiencies in areas such as personnel movement, travel distances from operation to warehouse, process loading and unloading times, and quality control holds. “Wherever and whenever a step in the process can provide for a time reduction, operational improvements are achieved,” he says.

Another aspect of facility design is the need for maximizing flexibility and capability to handle different products on the CM line. “One of the best practices for modern OSD facility design to address flow is to incorporate uniflow operations, with minimal path crossing or back tracking,” says DiProspero. “Ideally, process flow should run in a linear motion from raw materials in, to final drug product out. Placing the weigh/dispense unit operation close to the warehouse, with direct access, and combining unit operations (e.g., granulation/drying and blending/milling) are common today.”

In addition to optimizing the equipment and facilities, manufacturers need to develop the workforce for operating CM processes. Such teams are different from those that typically support batch solid dose manufacturing, says Santos. “Now the skill set should comprise a strong background as well on process modeling, automation, and control. PAT [process analytical technology] is now a mandatory role in the teams. The quality teams should either adjust themselves to embrace a new paradigm, or new focused teams should be put together,” he explains.

Training is becoming more available, compared to in the past when most had to figure things out for themselves, says Hausner. The United States Pharmacopeia, for example, is offering training and is also considering developing standards for CM. The International Society for Pharmaceutical Engineering (ISPE) is also discussing standards as related to standard capabilities and connectivity technology to allow systems integration, reports Hausner.

To read the full interview with experts at Hovione, go to 

www.pharmtech.com/view/gaining-experience-in-continuous-manufacturing

Early adopters and equipment manufacturers refine their equipment and processes, paving the way for broader use. 

Solid-Dose Continuous Manufacturing Presses On 

Continuous manufacturing (CM) of oral solid dosage drugs has benefits that include faster development, a smaller equipment footprint, greater flexibility in manufacturing scale, tighter process control (and, thus, improved quality), and the potential for real-time release. Contract development and manufacturing organization (CDMO) Hovione partnered with Vertex in 2016 to expand Hovione’s facility in East Windsor, NJ, with continuous manufacturing equipment to produce Vertex products. 

 spoke with CM team members at Hovione: Alexandra Adao, head of Quality Assurance Continuous Manufacturing; Sarang Oka, process development engineer; and Jose Luis Santos, head of Drug Product Continuous Manufacturing about their experiences with implementing CM.

 As CM processes for solid-dosage drugs are being commercialized, what benefits are being realized? What challenges are arising?

 CM is a tremendous opportunity to advance drugs to the market at a much faster pace than traditional batch manufacturing, and additionally enabling enhanced product quality based on enhanced process understanding and a richer data environment.

Investment is significant, not just in terms of the equipment itself, but also the software for integration, which should include a strong [process analytical technology] (PAT) framework; the facility to host the equipment; and all the utilities associated.

The teams to be put together may be much different from the standard teams that typically support batch solid dose manufacturing. Now the skill-set should comprise a strong background as well on process modeling, automation and control. PAT is now a mandatory role in the teams. The quality teams should either adjust themselves to embrace a new paradigm, or new focused teams should be put together.

Development is more difficult, and requires more sophisticated process understanding, including process modeling. Currently it’s probably not as rapid as batch development, given the steep learning curve for most companies. It is likely that development takes more time than batch for similar development phases, but it shows a clear potential to be much faster than batch in the full cycle of development of a drug, since development is conducted always in the same equipment and same scale.

Even if our experience is still limited, the numbers we have currently at Hovione in terms of equipment occupancy already surpass those from our typical batch processes. So, there is a significant opportunity to make much better use of the assets in continuous as compared to batch manufacturing.

 What are some of the challenges for feeding materials into the system, and what are some of the best practices that have been implemented?

 Two challenges in feeding that plagued the technology in its early days continue to persist at their core, namely, feeding at very low flowrates and feeding of poorly flowing powders that exhibit substantial electrostatic adhesion. Although substantial progress has been made in how the challenges are managed, there has been very little transformative change in technology of powder feeding. Loss in weight (LIW) screw feeding continues to be the dominant feeding technology. For example, a few years ago, an academic group prototyped the use of a salt-shaker type feeder for feeding at very low flowrates. The technology showed only limited success, and thus, in absence of any transformative digression from LIW screw feeding, we continue to be constrained by physical limitations of screw feeders.

As previously mentioned, we have, however, made substantial progress in how we manage the challenge when feeding poorly flowing powders or feeding at low flowrates. The primary challenge with poorly flowing powders is inconsistent filling of the screw pitch. Vendors have experimented with various agitator and screw geometries to improve screw filling, and these have shown promising results. Some powders, such as certain grades of silica with very low bulk density and substantial electrostatic adhesion tendency, however, continue to pose a challenge. Another trick in the book is coprocessing the poorly flowing powder with a flow aid prior to introducing the powder to a feeder. For example, poorly flowing active ingredients are preblended with silica to improve their flow properties prior to being fed via screw feeders. In terms of excipients, progress has been made to design and develop excipients that are well suited for processing in continuous manufacturing lines and don’t suffer from the aforementioned challenges.

In the case of feeding at low flowrates, we are largely constrained by physical limitations of the hardware. There is a physical lower limit below which signal-to-noise ratios even for the most sophisticated load cells becomes too low for effective gravimetric control, and this handicaps our ability to feed below a certain flowrate. A management strategy has been to preblend (in batch) the ingredient with low weight fraction in the formulation with another ingredient, and then feed the preblend at the combined, higher feedrate.

 What are some best practices for technical transfer or scale-up that are unique to or particularly important for CM processes?

 These are many advantages when developing products for continuous processes. Development is performed at scale, eliminating the need for performing rigorous scale-up studies as would be the case for batch processing. One can be very confident that experiments performed and results obtained on a standalone loss-in-weight feeder will translate well when an identical feeder is used to feed the same material in the integrated process train. Tech transfer is often performed between very similar (in size and other characteristics) or identical units. The challenge arises when development is performed on equipment that is different from commercial equipment. We still do not have correlations that help us transfer process between dissimilar pieces of equipment or process trains. Recommended practice for organizations who wish to build multiple lines is to develop identical lines, if there is desire to transfer products between lines.

Interestingly, since several unit operations in the batch paradigm are intrinsically continuous (such as roller compaction or tableting), practitioners have been able to rely on their current development practices built over decades of development knowledge. For example, the use of compaction models and compaction simulators to develop roller compaction or tableting processes in batch manufacturing have been applied to developing these unit operations for continuous processes. Practitioners have been able to directly transfer such best practices developed for the batch world and apply them to developing continuous processes. Of course, this is not possible in cases where the unit operation is different from a batch process, such as powder blending, and completely novel development frameworks have had to be built for these.

 How are process models/digital twins being used in CM process development/process control? What are the next steps for the near future?

 Serious effort is being made in the development of digital twins for continuous manufacturing process trains and individual unit operations, with the underlying modeling framework ranging from discrete element method (DEM) based, population balance models, or other empirical and semi-empirical approaches. A very popular application of digital twins has been to perform in-silico residence time distribution (RTD) experiments. These experiments can be done either at the unit operation level or at the full process train level. Thorough characterization of the RTD enables one to track evolution of disturbance through the rig, which is a crucial element of today’s control schemes. The underlying models, if well calibrated, also enable the practitioner to ‘dial-in’ and test a desirable RTD, all performed from the comfort of one’s desk. Applications also include understanding the impact of material properties and process parameters on process performance and eventually product quality. Some digital twins even predict product performance, that is, the performance of the drug within the body.

It is also important to mention the drivers for these efforts. The primary driver continues to remain circumventing the use of valuable early stage API. However, practitioners of the technology are beginning to realize that most CM rigs have large turnaround times for cleaning. Introducing the material into the rig for experimentation and ‘dirtying’ the rig is associated with the cost of the follow-up cleaning. This limitation is especially important to us, as a CMO, where this translates to a substantial opportunity cost. Tools that help us minimize the use of the rig are thus incredibly important to us. These could be very sophisticated models or simple tools based on engineering correlations that predict the performance of the product in the rig.

 Is real-time release happening? What roadblocks remain?

 Hovione has already introduced all the requirements to enable real-time release testing in the quality systems. There are some companies that have already successfully implemented it, and we are confident that we have in place all the conditions to also perform its implementation. 

There are some technically relevant aspects that enable the implementation of real-time release testing, namely the online and inline PAT capabilities and the design of automation control systems (e.g., equipment monitoring, material tracking). An appropriate control strategy that combines both capabilities is a key element for an adequate implementation of the real-time release in CM. At Hovione, the referred capabilities are already in place and system qualification was performed, taking also into consideration the requirements for real-time release testing.

An example of a potential challenge in the implementation of real-time release is dissolution testing. In order to enable real-time release, the use of model-based prediction of dissolution performance based on process parameters and critical quality attributes (CQAs) will be required, and consequently, an adequate model maintenance procedure needs to be in place. The model maintenance requires a parallel testing program to test the methods against the respective laboratory/regulatory methods. Therefore, in addition to the significant effort associated with the verification of the models during implementation, there is also an important effort associated with the model lifecycle.

As a CMO, we have been preparing ourselves to be able to accommodate this type of release, and we agree on its benefits, as it can provide an increase of quality assurance and reduce release time, with an overall benefit for the patients. 

Experts at Hovione describe progress being made in understanding how to optimize continuous processes for oral solid-dosage drug products. 

Gaining Experience in Continuous Manufacturing

As the biopharmaceutical industry races ahead with development of vaccines and therapeutics to address the COVID-19 pandemic, experts have acknowledged that building up adequate capacity for fill/finish and ensuring the supply of materials for primary packaging containers are crucial requirements. In an unprecedented compression of manufacturing timelines and with significant investment from government and non-profit sources, commercial fill/finish manufacturing capacity is being built at-risk, while drug development and clinical trials are ongoing.

“A vaccine will only be effective if we can make and distribute adequate supply,” John Shiver, senior vice-president of Vaccines Global R&D at Sanofi pointed out in a March 23, 2020 post (1). He expressed confidence that industry is up to the task, saying, “If we can develop a safe and effective vaccine, the global pharmaceutical industry has the capacity to make and deliver it. [Sanofi] has the established capacity and infrastructure to make up to 600 million doses in two existing facilities based in New York and Pennsylvania, without compromising the supply of vaccines for other illnesses, including influenza. Other companies have similar capacity.” Furthermore, he noted, “Fighting an emerging pandemic is an enormous undertaking requiring the entire pharmaceutical ‘ecosystem’ to come together at pace and at a scale that are both extraordinary.”

Contract development and manufacturing organizations (CDMOs) are crucial components of this ecosystem for handling the expected surge of capacity needed for vaccines and therapeutics to treat COVID-19.

Over the past few months, CDMO Catalent, for example, has announced manufacturing agreements with COVID-19 vaccine candidate developers including Johnson & Johnson’s Janssen (2), Moderna (3), and AstraZeneca (4) to provide fill/finish capabilities. Catalent says it is working with more than 40 customers on COVID-related antivirals, vaccines, diagnostics, and treatments for symptoms and effects of COVID-19 (5). At the Catalent Biologics business unit’s facility in Bloomington, IN, the company reported that the scale-up in production would include the use of two new high-speed machines, including an Optima vial filling line and a Dividella NeoTOP 1604 top-load cartoner (2). The company is rapidly scaling segregated manufacturing capacity at the Bloomington facility to support dedicated production of Johnson & Johnson’s investigational vaccine candidate and plans to hire approximately 300 additional employees “to meet operational readiness and 24x7 manufacturing schedules by January 2021” (2).

The Bloomington facility is also being prepared to provide vial filling and packaging capacity for Moderna’s mRNA-based COVID-19 vaccine candidate (mRNA-1273). Barrier isolator technology will be used for filling. The capacity and the staff for commercial-scale production expect to produce an initial 100 million doses of the vaccine candidate for the US market starting in the third quarter of 2020, and the companies are discussing fill/finish capacity for continued production of hundreds of millions of additional doses (3).

Catalent Biologics facility in Anagni, Italy is being prepared for commercial-scale vial filling and packaging for AstraZeneca and the University of Oxford’s adenovirus vector based COVID-19 vaccine candidate, AZD1222. The facility will be able to supply hundreds of millions of doses of the vaccine candidate from August 2020, and potentially through to March 2022 should the product be approved by regulatory agencies, Catalent reported (4).

One of the funding sources for COVID-19 countermeasures is the US government, which is building a network of manufacturing partnerships through programs including Operation Warp Speed, which is a partnership among components of the Department of Defense (DoD) and the Department of Health and Human Services (HHS), including the Centers for Disease Control and Prevention (CDC), FDA, the National Institutes of Health (NIH), and the Biomedical Advanced Research and Development Authority (BARDA) (6). BARDA, for example, awarded more than $49 million to ThermoFisher Scientific to expand its sterile injectables capacity for fill/finish of vaccines in vials (7). HHS, in addition to contracts with Johnson & Johnson, AstraZeneca, and Moderna, in June 2020 contracted with Emergent BioSolutions for manufacturing capacity, including an investment of approximately $85.5 million for the rapid expansion of the company’s viral and non-viral CDMO fill/finish capacity for vaccine and therapeutic manufacturing (8).

“Emergent has a long, successful history of working with the US government to develop, manufacture, and deliver safe and effective medical countermeasures for public health. BARDA has been an excellent partner, across all levels from leadership to the project and technical teams with whom we work closely,” says Dino Muzzin, senior vice-president of manufacturing operations at Emergent BioSolutions. “As partners on a team, we work collaboratively to monitor, evaluate, and progress projects and help remove barriers that slow down the directive of Operation Warp Speed.” Muzzin notes that BARDA has worked to secure the supply of primary packaging components, including vials.

Through Operation Warp Speed, the US government has invested in US domestic capacity for glass vials, with $204 million going to Corning to expand capacity for its Valor Glass vials, and for two more unconventional container types—$143 million to SiO2 Materials Science to increase capacity to produce the company’s glass-coated plastic containers and a $138 million contract with ApiJect to produce prefilled syringes using the blow-fill-seal process for plastic containers (6).

In addition to planning for vaccine production, fill/finish capacity is being built up for therapeutics, and CDMOs again play a key role. Ajinomoto Bio-Pharma Services, for example, signed a manufacturing agreement with Humanigen for fill/finish of lenzilumab, which is in Phase III clinical trials in adult, hospitalized patients with COVID-19 to prevent or treat cytokine storms (9). Aji Bio-Pharma will perform fill/finish of the monoclonal antibody at its San Diego, CA facility. Programs related to the pandemic are currently being prioritized over other programs, with appropriate consideration to existing commercial supply agreements, notes Dustin Campbell, associate director of commercial operations at Ajinomoto Bio-Pharma Services.

As development speeds ahead, CDMOs are working to ensure quality by considering how to work within the shortened timelines, ensure the most efficient tech transfers, train staff, and source raw materials and single-use components.

“The most significant challenge in responding to the pandemic is making sure we’re proactive with how we plan, resource, and execute programs with our customers, rather than reactive to the larger challenges they are facing with supply chain and general development,” says Campbell. “From a business perspective, our customers are expecting quick turnaround times to shorten the CDMO selection process in order to advance COVID specific therapies, but also to make up for lost time being seen in supply chain delays. Similarly, the tech-transfer and preparation process for fills is being tightened with customers racing to get treatments into the clinic. Clinical timelines in general are usually very fast, and the expectation is the CDMO can adjust to meet the changing demands of the customer’s program.”

Campbell notes that a unique aspect of the pandemic is that the influx of government funding for sponsored programs is increasing the overall demand for capacity, which increases the pressure on CDMOs to provide a flexible service that can meet the expectations of customers and the public. In response to this changing landscape, he says, the company introduced its new Ajility platform to minimize the time to clinic. Launched on June 30, 2020, the platform is designed for novel therapeutics or vaccines and existing drug products with a new indication that can be used in COVID-19 trials, FDA Emergency Use Authorizations (EUA), or other programs (10). The company explained that the platform’s goal is to guide clients through decisions, such as choosing components, excipients, and method qualifications, with the aim of minimizing variables during tech transfer, manufacturing, and shipping processes (10).

“The team worked through every step of the manufacturing process in defining this service offering,” says Campbell. He does not currently see any supply problems for fill/finish and packaging, noting that the company already had a strong vendor supply chain in place. Flexible production is key. “The main change we have made to our operations to support the AJILITY program have allowed flexible capacity to meet demand. With increased business coming as programs increase in number, we expect these changes can support the demand that may be placed on these pieces of equipment,” says Campbell.

Planning ahead for fill/finish includes having options for filling formats and considering primary packaging supply.

“Emergent is currently working with four innovators for their COVID-19 vaccine candidates, and each client has a slightly different filling format. We continue to evaluate options as the clients’ process information is defined,” says Muzzin. “Worldwide shortages can create long lead times on single-use materials and containers like glass vials, which make the logistical planning difficult and very important. While we need to leave enough time to source these materials, deciding too early may require us to make significant assumptions of what a product will need. Alternatively, decisions that are delayed until there is enough information to be sure about what materials are needed may result in extra costs associated with expedited delivery. COVID-19 may be a new indication, but material sourcing is a universal complication of the manufacturing process, and we continue to work with our sourcing and industry partners to plan ahead and prepare appropriately to minimize the risk of delays associated with container sourcing.”

Given the fast pace of development and the expected speed of scale up, tech transfer—from innovator to the CDMO and from smaller to larger scale—is a particularly critical step. An added challenge is that processes are still being developed while manufacturing capacity is being prepared.

“Many activities, from development to tech transfer, are being done in parallel, which takes significantly more coordination and communication to ensure that both the innovator and CDMO can stay in lock-step,” notes Muzzin. “Processes for the drug product are still being developed, so as they become more defined, we need to shift our resources to adapt. A significantly positive outcome from this approach is how this leads to a higher degree of transparency and willingness to assume ‘positive intent’ in all interactions, which builds and improves trust faster, and drives us toward the desired successful outcome. At each stage there is a high degree of collaboration and coordination. We are doing this in new ways—from acquiring and delivering the equipment, to configuring and testing the equipment, and helping ensure processes will be ready for CGMP [current good manufacturing practice] manufacture all while working in new ways and at an unprecedented, accelerated pace. We maintain the same level of safety and attention to detail in these processes as always.”

The Operation Warp Speed plan calls for manufacturing and fill/finish to be prepared to be used “for whatever vaccine is eventually successful, if possible” (6). Potential shifts as development progresses will pose challenges for tech transfer.

“When we talk about switching lines, we have to remember this is not only about changing hardware. It is about the transfer of process know-how to ensure that the process runs effectively and in a repeatable fashion. The ability to do more parallel technical transfer activities is the key to rapidly moving through different vaccines and being ready to meet each client’s needs,” notes Muzzin.

Emergent’s Baltimore Bayview facility is designated as a Center for Innovation in Advanced Development and Manufacturing (CIADM) by HHS, is designed to be flexible to be able to manufacture product in large quantities during public health emergencies, explains Muzzin. The CIADM has four independent suites, and each allows products or customers to move in and out quickly, he notes.

“As with any tech transfer and scale-up, a thorough assessment by pharmaceutical development experts is required, including a comparison of equipment, related process adaptions, gap assessment, and overall risk assessment,” adds Hanns-Christian Mahler, head of Drug Product Services at Lonza, which is producing the active ingredient for Moderna’s COVID-19 vaccine. “Depending on the level of change, it may be required to elaborate further on testing [critical] quality attributes to ensure there is no relevant change in the product quality, safety, and efficacy profile due to this change.”

Analytical method transfers are typically rate-limiting steps for tech transfer when bringing a new product or process into a facility, notes Campbell. “Especially with early-stage, novel therapeutics, there are often gaps between the state of the methods for in-process control and product analysis and what is suitable for CGMP operations. Likewise, with the formulation details, often these early programs have been performed on a benchtop with inadequate attention having been paid to the scale and process characterization needed to ensure a successful CGMP operation. A clinical to commercial program typically involves fewer unknowns but includes long lead-time activities that may or may not propose a risk to a customer’s timeline depending on the quality of the process characterization activities that the customer and CDMO-focused on during clinical development.”

Designing early-stage programs appropriately can reduce problems in late-stage development and facilitate getting from clinical to commercial scale, concludes Campbell.

1. Sanofi, “Sanofi Mobilizes to Develop a Vaccine against COVID-19,” 

, March 23, 2020.
2. Catalent, “Catalent Signs Agreement with Johnson & Johnson to be US Manufacturing Partner for Lead COVID-19 Vaccine Candidate,” Press Release, April 29, 2020.
3. Catalent, “Moderna and Catalent Announce Collaboration for Fill-Finish Manufacturing of Moderna’s COVID-19 Vaccine Candidate,” Press Release, June 25, 2020.
4. Catalent, “Catalent Signs Agreement with AstraZeneca to Manufacture COVID-19 Vaccine Candidate,” Press Release, June 15, 2020.
5. Catalent, “Catalent COVID-19 Response,” 

, accessed July 9, 2020.
6. HHS, “Fact Sheet: Explaining Operation Warp Speed,” hhs.gov, June 16, 2020.
7. HHS, “Pharmaceutical Manufacturing in America,” 

, June 12, 2020.
8. HHS, “HHS Adds $628 Million to Contract with Emergent BioSolutions to Secure CDMO Manufacturing Capacity for Operation Warp Speed,” Press Release, June 1, 2020.
9. Aji Bio-Pharma, “Ajinomoto Bio-Pharma Services Signs Manufacturing Agreement with Humanigen for Lenzilumab, Currently in FDA-Approved Phase III Study for COVID-19,” Press Release, May 27, 2020.
10. Aji Bio-Pharma, “Ajinomoto Bio-Pharma Services Introduces AJILITY Fast Track Platform for Drug Product Manufacturing,” Press Release, June 30, 2020.


Supplement: Outsourcing Resources
August 2020
Pages: s15–s17

When referring to this article, please cite it as J. Markarian, “All Hands on Deck for Fill/Finish of Vaccines and Therapeutics," 

Pharmaceutical Technology Outsourcing Resources

Outsourcing partners provide capacity and tech transfer expertise in the pharmaceutical industry response to the COVID-19 pandemic.

All Hands on Deck for Fill/Finish of Vaccines and Therapeutics 

The implementation of single-use systems (SUS) for biopharmaceutical manufacturing as an alternative to or in combination with traditional stainless-steel equipment offers advantages. In a fully disposable or hybrid facility, however, because pieces of equipment (e.g., reactors, transfer tubing, holding vessels) are now consumables, the supply to the manufacturing facility is more complex. The demand for customized systems and the overall growth of demand for SUS add to the pressure to improve supply.

Biologics and Sterile Drug Manufacturing 2019

	When referring to this article, please cite it as J. Markarian, “Supply Chain Challenges for Single-Use Systems," 

Biologics and Sterile Drug Manufacturing 

Suppliers address the complexity of supplying disposable components for single-use systems to the global biopharmaceutical manufacturing industry.

Supply Chain Challenges for Single-Use Systems

	The implementation of single-use systems (SUS) for biopharmaceutical manufacturing as an alternative to or in combination with traditional stainless-steel equipment offers advantages such as reduced capital cost, faster facility construction, and more flexible and efficient manufacturing (1). In a fully disposable or hybrid facility, however, because pieces of equipment (e.g., reactors, transfer tubing, holding vessels) are now consumables, the supply to the manufacturing facility is more complex. The demand for customized systems and the overall growth of demand for SUS add to the pressure to improve supply.

	Most SUS are currently made in the United States and the European Union, but suppliers are exploring manufacturing of SUS components in Asia to serve the region’s growing biopharma market more efficiently. In September 2018, MilliporeSigma announced its first Mobius single-use manufacturing facility in Wuxi, China would begin production in 2019 (2), and in November 2018, GE Healthcare announced a collaboration with Chinese healthcare technology supplier Wego Pharmaceutical to produce single-use consumables in Weihai, China using GE’s Fortem platform film (3). Shorter lead times are one potential benefit. Local production could also reduce the environmental impact of shipping components over long distances (4).

spoke with Andrew Bulpin, head of Process Solutions at MilliporeSigma; Jeff Carter, strategic project leader at GE Healthcare Life Sciences; Eric Isberg, director of Life Sciences at Entegris; and Helene Pora, vice-president of Technical Communication and Regulatory Strategy at Pall about some of the issues facing the industry as companies look to SUS for biopharmaceutical manufacturing.

 What are some of the challenges with supplying single-use systems and components globally today?

Single-use supply chains are complex and dynamic. The large number of raw materials makes forecasting demand more difficult and requires robust materials management, supplier quality management, quality control, and business continuity planning to ensure continuity of supply. Common materials (e.g., silicone) are used across many vendors, which can create single points of failure within the supply chain for both the single-use supplier, as well as the end-users of their products.

	The key is to adopt a comprehensive, ‘risk-smart’ approach to supply continuity and control. It is important that suppliers proactively identify the potential risks and minimize the probability and impact of supply disruptions through effective demand planning/forecasting, capacity planning, business continuity planning, change control management, disaster recovery planning, supply-chain mapping, and continuous improvement. At MilliporeSigma, a cross-functional team of subject matter experts assess risks related to demand volatility/forecast accuracy, manufacturing capacity, process and equipment, sole/single-sourced raw materials, facilities (e.g., water, utilities, power, information technology/systems), and more. Risks above a certain risk priority number are mitigated and monitored. Business continuity plans are revisited on a regular basis, and risk mitigation activities are updated continually.

 One area of concern is availability of customization. Large suppliers tend to focus on systems with larger quantity production, leaving short-run, highly custom systems to small boutique suppliers. Consolidation of the single-use suppliers has exacerbated this issue.

 Sourcing and lead times have long been challenges for both suppliers and consumers, with some of the key pain points including lead times and an ever-changing and advancing industry. 

	One of the most critical challenges is that biopharma is a high-risk industry. Although there have been a multitude of advances in the industry, the fact remains that the end products being made with SUS consumables are being used in humans and can mean life or death for a patient or a patient population. Even at the clinical trial manufacturing phase, a full understanding of how the process will scale is needed. Particularly in cases where high customization can be called for, the supply chain becomes more complicated and impacts the lead time.

	Another challenge is just-in-time (JIT) delivery and customization. Warehousing requirements for larger spaces helps to solve storage and availability issues for off-the-shelf consumables but does not address the JIT approach or customized needs many consumers require for their process consumables. 

	A third challenge is that as suppliers (and the industry) evolve, product ratings, design, or supply chain sources may change, and it is critical to keep users informed. Transparency is a necessity, yet changes can impact existing processes and lead times. 

	As an industry, and through supplier associations like BPSA [Bio-Process Systems Alliance] and BPOG [BioPhorum Operations Group], we are working to overcome these challenges. There is a greater focus than ever on creating realistic supply-chain mapping models that address the global nature of today’s market. And a deeper importance is being placed on forecasting by end users so that the supplier and consumer can work together more effectively.

 Issues include logistics (including time to clear customs as goods move across borders, which can counter the speed element of the single-use value proposition) and managing complaints or investigations on product that is overseas. Geographical distances and language barriers can make general communication and relationship building challenging.

What are the challenges/potential benefits of manufacturing SUS locally in Asia?

Proximity to a large and rapidly growing customer base does allow us to step up our service level to our Chinese customers. One practical example is the efficiency of working in native language and local time zone, particularly for configured and customized single-use systems. Developing manufacturing operations in China to complement our existing single-use manufacturing network provides an added capability in how we consider and structure contingency plans to maintain business continuity even under challenging circumstances. 

	GE Healthcare published a peer-reviewed single-use system lifecycle analysis (4). The results of this analysis showed that single-use consumables provide a better choice from the environmental impact perspective vs. the clean and re-use paradigm. The more variable aspects of the single-use lifecycle analysis and some of the more environmentally impactful elements of the value chain were the distribution of what are often large volume, low bulk-density products across various distances and transportation modes. Based on this study, localized manufacturing should have a reduced environmental impact affect; of course, there are however, diminishing returns based on manufacturing facility capacity and plant efficiency. 

 With the establishment of manufacturing capacity and capabilities in China, we can reduce our product lead times and help our customers bring new products to market faster. In addition to shorter lead times, end-users can carry less inventory and have an enhanced level of supply security, with the ability to source their assemblies from multiple manufacturing sites.

	All manufacturing sites should be working under the umbrella of a single, global quality system, and customers need to qualify the new site so that they have the ability and flexibility to receive assemblies from multiple sites.

 Over the past decade, [biopharmaceutical manufacturing] has become an increasingly global industry. With SUS, the supply chain is complicated because, regardless of the location of manufacturing, the components are often coming from different areas of the globe. Although a lot of companies are considering moving production to other locations, with Asia having particular interest, questions remain. Most critically, expertise has to be there, and an often-overlooked consideration is shipping. What will the logistics look like, and how will that impact lead times? The country that any product is manufactured in will have its own resources and regulations, which will affect the ability to industrialize production. In addition to the considerations mentioned, what is really comes down to is manufacturing in locations that have the right balance between flexibility and supply. 

	2, MilliporeSigma, “MilliporeSigma to Open China’s First Mobius Single-use Manufacturing Facility in Wuxi,” Press Release, Sept. 12, 2018.

	3. GE Healthcare Life Sciences, “GE Healthcare Starts to Manufacture Single-Use Consumables in China through Collaboration with Wego,” Press Release, Nov. 7, 2018.

	4. GE Healthcare, “Single-use and Sustainability,” www.gelifesciences.com/en/us/solutions/bioprocessing/knowledge-center/single-use-and-sustainability, accessed Jan. 2, 2019.

Suppliers address complex supply chains for global biopharmaceutical manufacturing using disposable components.