Jennifer Markarian is manufacturing editor of Pharmaceutical Technology.

Jennifer Markarian

Pharmaceutical manufacturing is inching towards implementing more efficient and sustainable processes, including continuous manufacturing (CM) of solid-dosage drugs. Advantages of CM include the potential for faster development, easier technical transfer, and more efficient and flexible commercial production with tighter process control. Although early adopters have realized benefits, and suppliers continue to improve the equipment and systems used in CM (1), some barriers to broader industry adoption remain. A collaborative effort between industry, regulators, academia, and other stakeholders is driving slow progress toward overcoming these hurdles.

The success of the cooperation between government and the private sector to rapidly develop and build capacity for vaccines and treatments to combat the COVID-19 pandemic is an example of what is possible, in the normally slow-acting and risk-averse pharmaceutical sector, say industry experts. They hope to see a similar boost to the uptake of advanced manufacturing technologies, such as CM.

One positive sign is greater acceptance of public-private partnerships by FDA and the US Congress, due to the successes demonstrated during the pandemic response, said Jennifer Luray vice-president of strategy and communications at Research!America, during a panel discussion hosted by the US Pharmacopeia Convention (USP) (2). This openness may help partnerships seeking government funding.

Another factor demonstrated during the pandemic was that the alignment of regulators and industry on the need for speed-to-market acted to lower the barrier to using new technologies. The challenge during “normal” times is to continue this agreement.

“Regulators and industry are aligned in their desire to create safe and effective medicines, but there is often a misalignment because industry is also concerned about the risks to development costs and speed-to-market,” said Kelley Rogers, technical program director for Biosciences within the Material Measurements Laboratory at the National Institute for Standards and Technology (NIST), during the USP discussion (2). If government can do more to take into account these business concerns, it will help “de-risk” adoption of new technologies.

“Adoption of CM can be accelerated considerably if policy makers introduce financial incentives and regulatory incentives,” suggests Moheb Nasr, principal at Nasr Pharma Regulatory Consulting and 

Editorial Advisory Board member. These could include tax breaks, expedited approval, or exclusivity periods, for example, Nasr and his colleagues suggested in a 2019 article (3).

Generic-drug manufacturers recognize the need to innovate, but justifying the cost of investing in CM is even more challenging for them, said Lisa Parks, vice-president of Sciences and Regulatory Affairs at the Association for Accessible Medicines (2). “For any company to make a business case regardless of whether they are an innovator or generic, they need to assess the technology to gauge the appropriateness and value add of the investment,” she explains. “They need to consider whether the technology has the capability to lower manufacturing cost or meaningfully increase quality. We’ve heard that CM can increase quality by tightening specifications, but we need to better understand how this actually affects quality. We need to be asking: Does adopting CM for a particular product improve the clinical outcome for the patient in terms of safety or efficacy? Does the adoption of CM create unintended barriers for generic entry?”
Other barriers mentioned frequently in relation to CM are regulatory uncertainty and potential differences between regional authorities. The draft version of the International Council for Harmonisation (ICH) Q13 guidance on continuous manufacturing published in July 2021 (4) helps alleviate some of this concern by providing a harmonized guideline supported by the regulatory members of ICH, which include FDA, the European Medicines Agency (EMA), and many others.

“Many health authorities are very supportive of CM, but many do not have much experience and their requirements are not always clear,” says Lawrence De Belder, executive consultant at Pharmatech Associates, a USP company. “This uncertainty is a hurdle because companies are concerned that, while a product made with CM might be approved by most countries globally, there might be a few countries that would require additional data or process changes. ICH Q13 is a good step in the right direction with an agreement or suggestion on a number of aspects, but it is not yet a full harmonization.”

Dennis Hall, vice-president of manufacturing services at USP, said that one of USP's goals is to help develop more regulatory clarity by exploring the possibility of developing standards for CM (2). First, however, USP is working with manufacturers to develop methods specific to products made in the CM environment. In addition, Pharmatech Associates, acquired by USP in 2021 (5), is helping industry to evaluate how they might use CM. USP can help fill the gap that exists in access to knowledge, experience, and laboratory capabilities for PAT model development and process development, adds De Belder.

“Implementing advanced manufacturing [including CM] is knowledge intensive. To make this happen, we need to make knowledge and technology available at a low entry cost,” said Fernando Muzzio, distinguished professor of chemical and biochemical engineering at Rutgers University and 

Investment cost for CM equipment is currently a barrier to wider use of CM in the industry, partly because, in some business cases, CM equipment is competing with batch equipment that is already in place, adds De Belder. In addition, equipment needs to be more flexible. “If you could buy a CM line for one product knowing that you could adapt it easily for other products in the future, it would lower the investment cost,” he explains.

Although some advances in modularity and integration have been made (1), more of these features in equipment designs are crucial for allowing greater flexibility in production “Having interchangeable unit operations would be helpful, so that if something changes in the future, a manufacturer can more easily make a change. To make this easier, equipment designs need to be modular and interfaces need to be standardized,” says De Belder.

“Production systems that are more modular and flexible to implement than currently available offerings from vendors would be attractive,” agrees Gregory Connelly, senior director at Vertex. “Such systems should be able to leverage the processing benefits that CM affords (i.e., blending at small scale to ensure robust blend uniformity), while being easily adaptable to various pharmaceutical profiles, such as dose, tablet weight, product demand, and also material tracking requirements.”

Early adopters of CM are reaping benefits and, at the same time, continuing to improve CM processes and operating procedures. Vertex, for example, has three approved products made using CM technology, with the first approved by FDA in 2015. “The biggest benefit we have realized for our portfolio is the ability to advance more quickly through late-stage development,” says Connelly. To provide more space for development, the company is considering expanding its CM capabilities with additional platforms that can offer more modularity and flexibility for both development work and commercial production. For now, the company is using one qualified line for production that will soon be joined by a second line at a contract manufacturer. One of the challenges has been the effort required to convert a CM line from one product to another. Vertex has reduced this change-of-line burden through use of a digital tool that guides operators through the complex process of disassembly and cleaning. “Programs such as Tulip], which, among other capabilities, provides a platform for organizing video clips showing proper assembly/disassembly procedures, are a huge advance over paper-based standard operating procedures [SOPs] or even digital versions of static documents,” says Connelly.

Innovation in process analytical technology (PAT) tools and growing experience in how they are best used are also key to improving CM processes. “In the early years of CM development, we thought to use PAT to measure as much as possible, sometimes even with redundant measurements,” says De Belder. “In process development, using a lot of PAT is beneficial for helping you understand the process. In commercial manufacturing today, however, PAT is being used more judiciously, because it is resource-intensive to create and maintain PAT models. Manufacturers are performing risk analyses to see where PAT is really needed on commercial lines for the process control strategy.”

“Some PAT systems are more suited to a development environment, where the goal is to gain process understanding and knowledge about the product, but those systems may not be robust enough for routine deployment on a commercial process,” adds Connelly. “In general, we aim to implement PAT at points where the material is undergoing some change, in order to best monitor the quality of the product and the state of the process. Soft sensors, equipment controls, and process models certainly offer additional ways to maintain a desired state of control for a CM process.”

The same data used for process understanding and for process control can also be harnessed for real-time release, which relies on process data, rather than end-product testing, to assure critical quality attributes (CQAs).

Harnessing real-time data will allow manufacturers to get closer to fully realizing the benefits promised by CM, says Doug Hausner, senior manager of Continuous Manufacturing, Pharma Services, Thermo Fisher Scientific. “If you’re still using traditional analytical testing, it can be a limiting factor in turn-around times and per-batch/campaign savings that are important benefits of using CM. Traditional analytical is still critical in development, but manufacturers need to consider PAT, at-line testing, and data analytics for real-time process control and real-time release during Phase 3 as they approach commercial launch,” says Hausner. Thermo Fisher is expanding its oral solid dose CM capabilities at its Greenville, NC manufacturing site, and the contract development and manufacturing organization is currently supporting a number of products through clinical trial manufacturing using CM processes and preparing for commercial manufacturing upon market approval.

“Real-time release could leverage the data already being collected and save time,” agrees Nasr. “Using real-time release testing, however, doesn’t necessarily mean no end-product testing at all. It is up to the manufacturer to decide which quality attributes, if any, will be tested at the end of the process [when they submit a regulatory filing].”

De Belder agrees that there may be a business case for real-time release of some CQAs, but not always for all. “Dissolution, for example, is difficult because it cannot be measured directly in-line. Some companies have achieved real-time release using a surrogate method that has been proven to be directly related to dissolution, but this is not available for every product and requires significant effort to develop and maintain models,” he explains. “Other CQAs, such as product identification, can be directly measured inline, so the business case for these is easier to make.” 

Equipment and instrument suppliers are developing new ways to measure CQAs. Pharma Technology Inc., for example, introduced equipment designed for CM, for in-line tablet inspection that measures mass and content uniformity of every tablet at rates up to 120,000 tablets per hour and rejects out-of-specification tablets. A multi-point near infrared spatially resolved spectroscopy (NIR-SRS) probe predicts the API fraction (i.e., content uniformity) in each tablet. NIR-SRS allows high-speed measurement in production environments. A patented three-dimensional microwave resonant sensor measures individual tablet mass. An embedded, automated 4-P tablet tester uses conventional sampling to measure weight, thickness, hardness, and diameter of a sample of tablets at-line, and it serves to automatically calibrate the on-line weight measurement. The real-time data can be used to control a continuous mixer or tablet press, for example. Pharma Technology conducted experiments with Novartis that demonstrated the capability of the inspection strategy as a step toward real-time release (7).

Another PAT tool in development uses ultrasonic technology to measure physical properties of tablets in-line, as an alternative to off-line, destructive testing. Pharmacoustics Technologies, a start-up company founded by Clarkson University researcher and professor Çetin Çetinkaya, received a National Science Foundation Small Business Technology Transfer grant in 2021 to commercialize the patented technology in pharmaceutical manufacturing and development for continuous manufacturing and real-time release applications. 

“In oral solid dosage drug production, ultrasonic PAT can rapidly measure microstructural viscoelasticity and porosity, which can be related to CQAs of tensile strength and dissolution,” explains Cetinkaya. “It can be measured continuously, in real-time, and can be used to provide feedback for process control and data for quality assurance for real-time release.”

End-to-end CM for small-molecule drugs, which starts with raw materials to make APIs and continues directly to the final dosage form (e.g., solid-dose, liquid, parenteral), offers benefits but also some extra challenges compared to CM processes that begin with the API as a starting material. Two companies working on end-to-end manufacturing are Novartis, which has a facility in Switzerland, and US-company Continuus Pharmaceuticals, which is building a facility with its integrated continuous manufacturing (ICM) platform.

Advantages of an end-to-end integrated process include bringing manufacturing closer to “on demand,” which is useful for personalized medicines and supply-chain challenges. The ability to manufacture APIs in the same location as drug products could alleviate some of the problems with the current API supply chain. There is also the potential to streamline regulatory requirements for filing and process validation, says Nasr, who serves as senior regulatory advisor to the Continuus ICM Factory Advisory Team that was formed in 2021. “A fully integrated process means you don’t need to isolate the API,” he explains. “You do need to assure the quality of the API, but you don’t need separate stability testing and documentation or batch release of the API, which offers considerable savings of time and resources without diminishing quality.”

Real-time release is likely to be used, to some extent, with an integrated process, because the data needed for drug product release is being generated for process monitoring and control, suggests Nasr. Other advantages of an end-to-end process include streamlined warehousing and reduced equipment footprints via modular and intensified technologies, says Nasr. He adds that challenges include a lack of experience (in industry and regulatory bodies) and, as of yet, lack of regulatory precedence. On the technical side, process developers need to account for potential differences in output from drug substance unit operations and feed-rates into drug product unit operations. Innovative approaches to operational procedures, including equipment maintenance and cleaning and cleaning validation protocols, need to be developed, says Nasr.

“For example, it is costly and time-consuming to take the whole line apart to clean. Another approach could be to have cleaned equipment ready to ‘plug in’,” suggests Nasr. “Good manufacturing practice (GMP) requirements don’t change, but there could be different ways to achieve GMP. There is an opportunity for equipment suppliers to develop more ‘plug and play’ equipment or to find creative solutions for cleaning parts and filters, for example.”

Equipment reliability is key to long process runs. Bayan Takizawa, chief business officer at Continuus Pharmaceuticals, says that the company is designing more robust versions of its prototype unit operations, which will soon be tested at its facilities.

Sensors for PAT tools, including liquid-level sensors and Raman spectroscopy probes, need to have lengthy reliability as well, adds Bethany Silva, industry manager, Life Science, Endress+Hauser USA. “In batch manufacturing, you can perform maintenance and calibration of sensors during equipment downtime. In CM, there is no routine shutdown,” says Silva. Endress+Hauser uses in-line verifications to make sure sensors are working as installed while the process is running. “These in-line ‘health checks’ are called ‘verifications’ rather than ‘calibrations’ because a calibration requires a NIST [US National Institute of Standards and Technology] reference. In developing our tools, we have followed ICH Q13 and FDA’s guidance for CM, which provide specific guidance for controls and measurement,” Silva explains. She adds that new SOPs, replacing the SOPs used in batch processes, need to be written for these extended calibration intervals in CM.

Adoption of advanced manufacturing technologies could gain momentum by riding the current wave of business and government support for innovation that delivers medicines where and when they are needed. Reducing investment cost and other barriers, along with improving equipment technology, could make CM more attractive to a wider range of manufacturers.

USP, “Advanced Manufacturing Technology Panel Discussion,” at the virtual USP Convention Exchange Series: A Resilient Global Supply Chain (Feb. 25, 2022).

Continuous Manufacturing of Drug Substances and Drug Products

USP, “USP Acquires Pharmatech Associates, Inc. to Expand Services that Help Ensure the Quality of Medicines,” Press Release, July 7, 2021.

M. Rivers and C. Spivey, “Securing Manufacturing Independence Through Reshoring Facilities to USA,” 

Jennifer Markarian is manufacturing editor for 

When referring to this article, please cite it as J. Markarian, “Breaking Through Barriers to Continuous Manufacturing,” 

Articles

Collaboration and new tools aid efforts to implement new processing technologies for small-molecule drug product manufacturing.

Breaking Through Barriers to Continuous Manufacturing

Blow-fill-seal (BFS) equipment has been widely used for many years in aseptic fill/finish of small-molecule and biologic liquid formulations, including nebulizer solutions for respiratory delivery and ophthalmic sterile solutions packaged as unit-doses. A key advantage of the process is that it is a closed, automated system—a plastic container is formed within the equipment, filled with sterile solution, and closed, with limited human intervention. Although concerns about process temperatures caused hesitancy with some manufacturers of temperature-sensitive biologic drug products, understanding and control of these issues has significantly increased. As a result, more manufacturers are considering BFS as an option for fill/finish of vaccines and other biologic drug products, including large-volume and small-volume parenteral injectable drug products.

In addition to being an efficient, closed aseptic system, another benefit of the BFS process is the ability to handle unique or complex containers that can be designed for a specific need. For example, GlaxoSmithKline’s (GSK) oral rotavirus vaccine in unit-dose BFS containers was designed in collaboration with global health organization PATH and used for the first time in February 2020 in an immunization program in Myanmar (1). The container is formed as five single doses in a connected pack of tubes that can be separated for individual oral delivery. The container was designed to be less bulky than conventional vaccine squeeze tubes, which makes it easier to transport and store and reduces cold-chain costs.

“The container in a BFS process can be designed to be functional for delivery to the patient,” says Andy Goll, president of Weiler Engineering, Inc., which designs and supplies BFS equipment as well as using the equipment for fill/finish as a contract development and manufacturing organization (CDMO). “For oral delivery to young children, for example, the GSK rotavirus vaccine container was designed with a longer, narrow tube for the opening so that it would fit well inside the child’s cheek. Containers for injectable vaccines can be designed to fit to a separate needle hub.”

“Some of the benefits of BFS aseptic packaging include limited human intervention on the filling line, efficient production of unit-dose containers at high volumes, ability to rapidly scale production for surge capacity, and a consolidated materials supply chain that helps decrease reliance on external sources,” says Josh Myers, senior director, Supply Chain, ApiJect.

“Single-dose containers reduce the wastage found in multi-dose glass formats commonly used with vaccines,” adds Tim Kram, managing director at BFS equipment manufacturer Rommelag Engineering. “BFS systems are compatible with disposable filling systems, which minimize product loss during filling.” The most significant benefit, says Kram, is having a fully automated system, which reduces risks in the aseptic process.

BFS reduces the risk of microbial and foreign particulate contamination when compared to traditional glass vial fill/finish processes, adds Waiken Wong, manager of Development Engineering at CDMO Woodstock Sterile Solutions.

In the BFS process, the plastic raw material is melted, extruded into a cylindrical tube (called a parison), and formed into a container by blowing sterile air or nitrogen into the tube to force the plastic into the shape of the mold. Cooling of the container begins within seconds after it is formed, because the mold is chilled. The drug solution is then filled into the just-formed plastic container while still inside the mold, and the container is sealed. The form, fill, and seal steps typically take less than 15 seconds.

“Essentially, you have to manage process parameters to cool the container before the drug product contacts the internal surface,” explains Goll. “There are multiple ways to control the container temperature by controlling the cooling and blowing process. Not having to worry about heat degrading a vaccine is a game-changer in the ability to use BFS.”

Polymers typically used in BFS containers are low-density polyethylene (LDPE), high-density polyethylene (HDPE), and polypropylene (PP). “LDPE is typically used for containers for large-molecule drugs or vaccines, because it can be extruded at a lower temperature than HDPE or PP. A lower processing temperature makes it easier to obtain an appropriate surface temperature for filling,” explains Goll. PP would be used for drugs that require terminal sterilization, as it can withstand higher temperatures during the terminal sterilization process.

Goll says that interest in BFS for fill/finish is rising as manufacturers recognize its potential, particularly for the flexibility of the types of containers that can be filled. Weiler is performing feasibility studies for potential users who want to switch from a conventionally filled glass container to a BFS plastic container. The first step, he explains, is to check compatibility of the drug product and the container, including evaluating the extractables and leachables and product stability, typically using accelerated stability studies. Next, the container shape, including its opening, closure, and any separate adapters, is designed and a mold is made for the specific container shape. In the subsequent engineering design phase, the equipment and the process are optimized for the product. An advantage of the Weiler carriage (i.e., shuttle) system is the flexibility to easily change the mold size or shape, although it is not as high speed as a rotary BFS equipment setup, says Goll.

“Biomolecules can have some affinity for olefinic [LDPE, HDPE, and PP] materials, so stability studies are needed to ensure adsorption or absorption effects don’t impact therapeutic dose or activity levels,” adds Wong. Effects from gas and water vapor permeation through the walls of BFS containers may also need to be assessed in a stability program. Both standalone and comparative stability studies with glass are needed to demonstrate that plastic is an acceptable alternative.

“Many of the challenges a drug product developer faces when considering BFS are the same for traditional filling lines, such as glass vials,” adds Myers. “What is most important to remember, regardless of filling process, is that careful evaluation and grasp of the key parameters and process characteristics will allow for appropriate selection and risk mitigation.”

Temperature is one aspect that includes not only temperatures during filling, but also in mixing prior to filling and in post-filling activities. All materials that the drug product will come into contact with should be reviewed, along with cleaning procedures and transportation and storage of raw materials and finished products, says Myers. Modes of sterilization, heat mitigation, and protecting oxygen and light sensitive drugs all need to be considered. For plastic containers, foil wraps are often used to reduce exposure to UV light and oxygen and to reduce any potential vapor loss, adds Myers.

Kram adds that there are two primary methods to keep the product cool while using BFS technology. “The first does the most work, keeping the product at a low temperature (e.g., 2–5 °C) while in the batch holding tank, and controlling the temperature from the tank to the point of fill. By prechilling the product the final temperature can be kept in an acceptable range,” he explains. The second method is through container design.

Woodstock Sterile Solutions, which is the new name of the former Catalent BFS CDMO business that was acquired by a private investment firm in 2021 (2), was granted a US patent for a new, “cold” BFS process (3) that builds on its 50-year experience with using BFS for filling respiratory, ophthalmic, topical, otic, and oral drugs. The new process is designed to minimize the impact of temperature on thermally sensitive molecules.

“Our cold system comprises a combination of optimized process parameters that together reduce the exposure of the drug product to potentially detrimental temperatures,” explains Wong. “These parameters are from points throughout the manufacturing process, from the bulk product in the holding tank to the final sealing of the BFS container. The goal is to optimize the conditions to provide the best level of control.”

Wong says that the process has been evaluated for filling a monoclonal antibody and in exploratory studies for vaccines. He says that multiple programs, ranging from early- to late-stage clinical, are using the process. 

As BFS expands into more biologic drug products and vaccines, the opportunity is opening up for new delivery systems. Packaging an injectable product with a BFS process in a plastic ampoule is not new. What is new, however, is ApiJect’s prefilled injector that connects an intramuscular needle hub to a BFS single-dose container. In this case, the fit of the needle hub onto the container to make the complete drug delivery system must also be considered, says Myers. When filling an injectable drug product, there may be additional requirements for the biosafety level of the environment and visual inspection, adds Myers.

The prefilled injector technology in development by ApiJect is designed to be a cost-effective drug delivery system to manufacture and be lightweight for lower transportation costs. The single-dose format has advantages for safety, sterility, and low waste, which are especially important in low-resource, developing regions (4). While the drug delivery system was developed prior to the COVID-19 pandemic, the concept of being able to produce prefilled syringes on demand was seen as a potential solution to the concerns about possible vaccine container shortages in the midst of the pandemic in 2020, and the US Department of Defense awarded a contract to ApiJect to expand US production capability of up to 45 million doses per month in Biosafety Level 2 cleanrooms at The Ritedose Corporation in Columbia, SC (5). Although the emergency fill/finish capability in the United States was prepared in 2020, it did not end up being used for COVID-19 vaccine filling as the device has not been cleared by FDA. The technology, however, is available for drug manufacturers to evaluate.

Today, ApiJect continues to have operation capacity for development and commercial work at The Ritedose facility. In addition, in December 2021, French CDMO Fareva and ApiJect announced a 10-year licensing agreement to install BFS production lines with the capacity to fill/finish 500 million doses per year of vaccines and other large-molecule injectable drugs with ApiJect’s technology (6). BFS machines from Rommelag in Germany will be installed in Biosafety Level 2 cleanrooms. Fareva and ApiJect plan to produce validation batches in 2022. This type of “distributed fill/finish” capability aims to strengthen local supply chains.

PATH, “Myanamar’s Rotavirus Vaccine Campaign First to Use New Delivery Technology,” defeatdd.org, Mar. 12, 2020.

SK Capital, “SK Capital Closes Acquisition of Catalent’s Blow-Fill-Seal Sterile CDMO Business and Changes Name to Woodstock Sterile Solutions,” Press Release, March 31, 2021.

Woodstock Sterile Solutions, “Woodstock Sterile Solutions Granted US Patent for Cold Blow-Fill-Seal Packaging System and Process,” Press Release, Dec. 9, 2021.

ApiJect, “A New Way to Inject and Track Vaccines that Can Reach Everyone” dcvmn.org (2019).

DOD, “DOD Awards $138 Million Contract Enabling Prefilled Syringes for Future COVID-19 Vaccine,” Press Release, May 12, 2020.

Fareva, “Fareva and ApiJect Sign a Licensing Agreement to Create a France-based 500M Unit Annual Capacity for Single-vDose Prefilled Vaccine Injections,” Press Release, Dec. 9, 2021.

Jennifer Markarian is Manufacturing Editor for 


Vol. 46, No. 4
April 2022
Pages: 33–34,57

When referring to this article, please cite it as J. Markarian, “Considering Blow-Fill-Seal for Biologic Drugs,”

The continuous, aseptic fill/finish process is finding use in vaccines and biologic drugs. 

Considering Blow-Fill-Seal for Biologic Drugs

Continuous manufacturing for biopharmaceutical drugs offers the potential for similar advantages to those that can be obtained by continuous processing of small-molecule drugs, including higher efficiency and flexibility of scale. At Sweden’s AdBIOPRO (the Competence Centre for Advanced BioProduction by Continuous Processing), researchers from Lund University and KTH Royal Institute of Technology aim to advance understanding of continuous bioprocessing to support industry efforts.

To this end, AdBIOPRO researchers conducted a scale-up project at the Testa Center in Uppsala, Sweden, which is a pilot-scale test center that is an initiative between the Swedish government and life sciences company Cytiva. The group demonstrated that it is possible to run a large-scale, automated continuous bioprocess in which a cell culture operated in perfusion mode directly and automatically connects to a continuous purification process, says Veronique Chotteau, professor at KTH Royal Institute of Technology and head of AdBIOPRO. 

 spoke with Chotteau about the group’s proof-of-concept work and the key components that are needed to run a fully continuous bioprocess that connects both upstream and downstream processing in one workflow.

 Can you tell us more about the collaboration between the research groups at KTH and Lund University?

 My group at KTH is a leader in high cell-density perfusion for the production of glycoproteins. We develop methods and approaches for the development of these processes, push the limits, and identify the boundaries. Professor Bernt Nilsson's research group at Lund University is leading in modeling of continuous purification processes aiming at optimization and automation of these systems. Professor Sophia Hober is a well-recognized expert in protein engineering; her group has developed a new ligand for a new type of protein A, ZCa, that eliminates the need for very low pH for the detachment of the antibody from the protein A.

So, we are responsible for the perfusion culture; Bernt’s group for the design, realisation and automation of the continuous purification; and Sophia’s group for the new type of protein A used in the capture step. We have developed our respective parts and then put everything together thanks to four PhD students from the respective groups.

The next steps are to continue to apply this acquired knowledge for other glycoproteins, which could potentially be more challenging; to apply more process analytical technology (PAT); and to increase the level of automation. We plan to apply this successful concept of gathering multi-disciplinary expertise in close collaboration for other types of modalities, such as viral vectors for gene therapy.

Challenges for connecting upstream and downstream

 What are the technical challenges in creating a fully continuous process?

 Building both purification and production in one workflow was complicated. The system is a continuous cell culture, operated in perfusion mode, that is directly and automatically connected to a continuous purification process consisting of three chromatography steps and a virus reduction step, where the continuous purification process is also completely automated. The whole process runs completely unattended from late afternoon to morning. The whole system had to be optimized and automated, while ensuring robustness.

The culture was pushed to a very high cell density of 100 x 10

 cells/mL. [In this situation], small deficiencies in the feeding and aeration strategy, among other things, can rapidly lead to failure.

Classical purification processes are operated in batch mode, with each step performed batch-wise; material is stored and buffer may be changed between the different steps. In a continuous process, however, these steps are now connected automatically; the flow between the steps has to be well designed, and buffer changes have to be avoided. To achieve this, a mathematical model of the process is used for optimization, and it can also be used for process control. Furthermore, the purification process has to be robust against the variations of the cell culture process, the material harvested from the bioreactor, and the variations in the chromatography steps.

With a conventional protein A matrix, a very low pH (i.e., around 3 pH), can cause aggregation of the antibody. This aggregation represents a safety risk (because antibody aggregates are impurities, potentially triggering an immune reaction in the patient if they are present in the drug product) and a burden for the downstream steps, which need to remove these formed aggregates, thus causing a reduced yield. The new matrix ZCa has a ligand based on calcium; the presence or absence of the ligand switches the antibody-binding ability of ZCa at mild pH. In the capture step, this switch is used first to bind the antibody, then to release it. Since low pH does not need to be used, the amount of aggregates is close to zero. Since it is not necessary to remove the aggregates, the yield is very high. The potential of this matrix was demonstrated in this project at pilot scale during 300 cycles.

 What is the importance of automation in continuous bioprocessing?

 Without automation, a continuous process is not possible. A well-realized automation of a continuous purification process actually provides higher yields compared to a batch process because no material is lost. We had a yield of 90% for a purification process containing three chromatography steps and a virus reduction step. This high yield was due to the automated continuous purification process, the efficient design, and the new ligand of protein A that eliminated aggregation.

Even before perfusion became popular for robust molecules such as antibodies, this mode of operation was already being used for labile proteins, such as therapeutic enzymes. The automatic renewal of cell culture medium provided in perfusion culture is highly beneficial for the cells and the product of interest, which is constantly removed from the bioreactor and separated from any proteolytic action and other deterioration. Nowadays, many antibody-derived molecules, such as bi-specific antibodies, are in biopharma drug development pipelines. These new therapeutic drugs are more challenging to manufacture than traditional antibodies, and a perfusion operation can answer that challenge. In contrast with fed-batch, where the quality profile varies with time, perfusion culture has demonstrated a stable product quality profile over time at steady-state conditions. However, other researchers have reported that the product quality profile can sometimes have a drift with time. The implementation of PAT combined with automation could possibly counteract this drift.

 What are some of the uses of PAT in continuous bioprocessing?

 We could have advantageously included more PAT [in the scale-up project]. PAT could be a tool to tune the quality profile, for instance, or to improve the robustness of the continuous process with the help of feedback control. We have recently developed monitoring of antibody glycosylation with a Raman probe for perfusion processing. Based on this development, we plan to demonstrate a proof-of-concept involving feedback control of glycosylation using our newly developed feeding strategy. In collaboration with other KTH scientists, analytical chemists, and microfluidics experts within the European Union project, iConsensus, we are also working on miniaturized measurements of the antibody charge variant and the quantification of the host cell proteins (HCPs). PAT of charge-variant detection will be a precious tool to implement, since this quality attribute can also vary in the bioreactor. We are also looking at in-line sensors for the measurement of antibody titer, which will be helpful to further improve purification robustness by feedback control. Finally, HCP quantification during the purification process can be instrumental for the optimization of the process, its robustness, and on-line performance monitoring of the equipment.

 What is the role of single-use technologies in your process?

 Single-use equipment has allowed us to quickly mount a completely new setting at pilot-scale of a complex system of upstream processing equipment connected to downstream processing equipment, including the seed bioreactor. This set-up has taken only a couple of days; stainless-steel equipment would have required a longer time and less flexibility in the set-up. A real advantage is to be able to do whatever you want, in particular for the connections, and to also have the flexibility to easily do modifications. Using stainless-steel equipment, all the modifications would have to be somehow planned from the beginning, which is very difficult for an R&D experiment. All the tube connections are also rapidly done with single-use equipment, while this is much slower and complex with stainless steel. Another feature is that the risk of contamination of the culture is almost none. Having run a sophisticated perfusion culture in stainless-steel equipment at pilot-scale, I can tell you that this reduced risk is really important. 

Flexible and efficient methods are needed for biopharmaceutical manufacturing. 

Demonstrating a Fully Continuous Bioprocess

Ongoing trends in the biopharmaceutical industry, such as faster speed-to-market and more efficient manufacturing, continue to drive development and use of single-use technologies, which are key components of flexible and modular processing systems. Compared to multi-use stainless-steel equipment systems, single-use systems (SUS) help capacity-constrained biopharmaceutical manufacturers use their existing space efficiently (1). SUS are well established in upstream processes and fluid handling; advances are being made in downstream processing operations, such as purification, filtration and separation, as well. 

 spoke with Stuart Tindal, PhD, product manager Separations, Sartorius, about new technologies and how Sartorius is addressing supply-chain limitations and other challenges.

 What are the advantages of using SUS vs. reusable systems in downstream processes in particular?

 There are significant benefits of single-use vs. reusable systems in downstream processes. First, SUS provide a low-risk method for quick turnarounds between batches and products. And, because they eliminate cleaning and sterilization validation efforts and are used where bioburden and cross-contamination risks are highest, they are useful for clinical and low-volume, high-titer production. Secondly, customers are seeking efficient processes, and process intensification (with SUS as a part of that) leads to higher productivities, higher yields/recovery, less effort, less risk of failure, or less cost. It is these business and technical pain points that enhance the applicability and utilization of SUS in this area. Sartorius has seen those outcomes specifically with regards to next-generation treatments like mRNA [messenger RNA], cell/gene therapy for vaccines, and personalized medicine. Third, SUS contribute to the continuing desire for sustainability, which is driving single-use strategies to be accountable through fabrication, use, and disposal. Sartorius has a dedicated function focusing on strong collaboration between drug producers and material suppliers to achieve sustainability success and define suitable metrics.

 Have you added any new technologies for single-use downstream equipment for clinical/commercial manufacturing in the past year?

 Sartorius has launched the third-generation Flexact Modular, a single-use automation platform that addresses an automation need in the current good manufacturing practice (CGMP) clinical/commercial market. This platform improves the efficiencies from manual single-use processing steps and reduces the risk of process deviations that are attributed to human error or failure in system communication protocols and connection to other digital infrastructures. Flexact Modular focuses on the normal flow filtration and fluid management batch process steps. In these downstream processing areas, product concentrations and volumes increase the ergonomic challenges for operator handling. The larger the scale, the stronger the need is for automation to reduce the total time and effort.

We are also addressing a specific downstream processing pain point of packed-bed column usage. Even with pre-packed options, the operation, handling, validation, and storage is a risk-heavy part of purification. The combination of a high-capacity affinity capture membrane and an optimized chromatography system, however, achieves productivity that can exceed packed-bed capture. Currently, the technology is available in smaller-scale multi-use, with clinical- and production-scale SUS coming soon. The combination of SUS and membrane technology promises to revolutionize the chromatography space, particularly for clinical manufacture. It’s a challenge to design a system to optimize the process—with faster valve switching times, low hold-up volumes, and appropriate flowrates. Our philosophy is that as far as possible, our SUS and multi-use systems are equal partners, particularly in terms of chromatography performance and quality of instrumentation.

 Are supply-chain constraints a challenge for downstream single-use equipment? If so, what are the pinch points and what are some of the best practices for dealing with these?

 Industry wide, there have been supply-chain challenges because of COVID-19 and the continued ‘warp-speed’ need to support customers with assembling new solutions and equipment. Sartorius has been growing rapidly for decades; we were fortunate to identify many of these supply-chain pinch points pre-pandemic and thus were in the process of further sourcing and establishing supply mitigation strategies.

Supply-chain challenges have taught customers and suppliers that the route to a more robust supply chain is standardization. Standardization, within and between product lines, across different facilities, and eventually industry wide, results in more agility to increase production rates while also better balancing lead times against shelf life when considering inventory policies. Standardization also allows us to better protect supply chains by providing significant leverage to implement effective dual/multi sourcing of components.

 What are some other challenges for SUS in downstream processes, and what are the best practices you suggest for handling these challenges?

 There are several challenges in downstream processes including:

Process closure: Ensuring no unwanted contaminants enter the process

Containment and preventing leaks: Ensuring nothing unwanted gets out of the process and poses a threat to the operator or requires decontamination of the cleanroom

Detecting failures in integrity: Including ‘holes’ in or out of the consumable (in the film, connection point, weld) or through an in-process barrier (filter membrane or packed column) where the ‘holes’ are too big and may impact the integrity performance capability.

Self-contained consumables with diverse aseptic connections and disconnections can help ensure that the process is closed and contained. Integrity testing equipment can be used to test filters and SUS. Other commonly overlooked challenges often encountered in later stages are those around freezing, storage, transport, and thaw of bulk drug substance. These include the sensitivity of biologics to cryo-preservation and thawing, complexities and costs involved in the supply chain, limitations in scalability and safety, and addressing the environmental challenges posed around the refrigerant usage during the storage and shipping process. Sartorius has addressed these challenges with scalable and robust freeze and thaw solutions comprising systems and consumables. Our freeze and thaw portfolio includes plate freezing platforms providing fast freeze and thaw rates for sensitive molecules, preventing cryoconcentration effects while monitoring critical process parameters.

Logistic processes should be qualified and use standard practices for transportation of frozen materials. Our platforms include shipping solutions that are validated with common transportation methods for frozen materials according to International Safe Transit Association and ASTM-recognized standards.

PharmTech interviewed Sartorius about SUS innovations and trends.

 Single-Use Systems in Downstream Processes

Amorphous solid dispersions (ASDs) are increasingly used to address the need to enhance bioavailability of poorly soluble APIs. Contract development and manufacturing organizations (CDMOs) that have amassed knowledge and experience in this specialty area play a key role in the pharmaceutical industry by providing the capabilities of developing and manufacturing ASDs.

“The pipeline of poorly-soluble drugs continues to grow, and ASDs remain the best-in-class platform to address poorly-soluble drugs,” says Filipe Neves, strategic business senior director at Hovione. He says that spray drying has been proven as a technology for the current good manufacturing practice (CGMP) manufacture of ASDs and that pharmaceutical companies have gained confidence in the technology and its reliability. Spray drying is becoming widely accepted and is seeing a year-on-year increase in adoption, reports Neves.

“Today’s APIs are increasingly insoluble, and that can pose serious problems for formulators looking to manage the bioavailability of their formulations,” says Lieven Van Vooren, scientific director, Ardena, a Belgian-headquartered CDMO that acquired Spain-based Idifarma and its spray-drying capabilities in Sept. 2021.

“The formulation of an ASD is increasingly being recognized as one of the more reliable and efficient strategies for optimizing the solubility and dissolution characteristics of low aqueous solubility compounds,” Van Vooren explains.

“The increased development of biologic-based drugs has also fueled demand for spray drying as an alternative for the manufacturing and processing of biologics, instead of the more traditional liquid or lyophilized solid forms,” addsWilliam Wei Lim Chin, manager, global scientific affairs, Catalent. He says that additional growth in spray drying comes from the increased consideration of spray-dried intermediate powders for both local and systemic inhalation delivery of biologics.

Spray drying and hot-melt extrusion (HME) are the two most widely used technologies for CGMP manufacturing of ASDs. In spray drying, the API and excipient are dissolved in a common solvent, which is then evaporated to form ASD particles. In HME, the API is dissolved and dispersed in the molten, polymeric excipient, which is then cooled to form ASDs. An advantage of HME is that it doesn’t require the use of solvents and the additional drying step. HME has some constraints, however, particularly for thermally sensitive APIs.

“The constraints of the HME process are that both the drug and the matrix must be miscible and compatible at the temperature at which the process takes place. In addition, the components must maintain this miscibility during the cooling stage,” says Van Vooren. “Another major limitation of HME is the stability of the drug at the high temperatures at which this process is performed. On the contrary, in the case of spray drying, the evaporation process is instantaneous and therefore suitable for thermosensitive products. In addition, the control of the physical properties of the spray-dried product allows manufacturers to obtain a particle size and morphology suitable not only to meet the dissolution goals, but also to obtain density and flow characteristics that facilitate the downstream processing.”

In HME, homogeneity may be more sensitive to process parameters (such as temperature) and equipment parameters, explains Neves. He adds that spray drying is, in general, more suitable for early clinical stages because formulations can be developed and produced with minimal amounts of API.

New tools, however, may be able to address the challenge of API volume at early stages.

“There is currently a significant focus on creating advanced development tools for both spray drying and HME that allow for fast, de-risked development of ASDs using minimal quantities of API,” says Chin. “When the API is compatible with both the thermal and shear stresses of extrusion, HME offers a robust manufacturing process without the use of large volumes of solvents.”

Selecting HME or spray drying can depend on many factors, including the stage of drug development program, time, and cost, Chin concludes. Both HME and spray drying can be used in continuous solid dosage processing.

“Spray drying is a continuous manufacturing (CM) technology,” says Neves. “It offers a remarkable control over the properties of the manufactured powders, with significant downstream advantages. With adequate process development, spray drying can enable ASD formulations that are directly compressible, thus bypassing the need for granulation prior to tableting. When accomplished, this will enable much simpler CM equipment trains and processes, benefiting overall operational efficiency, speed, and conformity.”

Scaling up from development to commercial-scale spray drying present challenges related to the spray-dried bulk powder properties.

“Changes in process conditions, due to the different configuration and dimensions of the spray dryer from development to commercial scale, have a major impact on the critical quality attributes of the spray dried powder, especially on the particle size, its distribution, and residual solvent content,” says Chin. “To understand the impact of these process changes, thermodynamic and kinetic modeling techniques, supported by engineering modifications as well as exploratory laboratory work, have emerged to support a rapid and successful scale-up of spray drying processes.”

The downstream processing method should be considered in scale-up, says Neves. For example, directly compressible powders for tableting may require specific combinations of particle size and bulk density. Inhalation delivery would require different criteria, such as composite powders of small particle size, controlled within narrow ranges, explain Neves. He notes that streamlined scale-up relies on a thorough process understanding, which can be aided with advanced formulation and process modeling tools.

Formulation of ASDs involves screening APIs, excipients, and other ingredients to determine the optimal combination. The Hovione Intelligent PROprietary Screening methodology for ASDs (ASD-HIPROS) was launched in January 2021 and is offered from the company’s Lisbon, Portugal, R&D center (1).

“The service aims at developing ASDs formulations with maximum stability and performance by eliminating inviable candidates, thus saving the time and investment needed to bring the drug to the patient,” says Neves. He explains that this proprietary process can assess up to 24 formulation prototypes in six weeks, requiring as little as five grams of API.

 computational screening based on the API properties (to determine most suited polymers, surfactants, and drug loads), spray drying experimental prototyping of the most promising formulations, and analytical testing and solid-state characterization (to confirm proper dissolution in bio-relevant media as well as stability under stress conditions),” says Neves.

Van Vooren adds that in scale-up, the large number of process parameters and product characteristics add to the complexity of the spray drying process. He explains that defining a design space where the process is controlled is key.

“Approaches such as quality by design, which employs tools such as design of experiments, allow us to identify from early stages the risks related to the formulation and manufacturing process that can potentially impact product quality and, consequently, to be able to guide studies to mitigate such risks,” says Van Vooren.

Van Vooren adds that differences between laboratory and industrial-scale equipment can cause variations in evaporation rate, particle trajectory, residence time, and other factors.

“It is highly recommended to also consider the finished dosage form manufacturing requirements and technologies, since integrating the spray drying process and the finished dosage manufacturing in a single facility reduces risks and timelines, and simplifies the supply chain for the product,” concludes Van Vooren.

CDMOs have been adding capacity for both development and commercial scales to meet the expected demand for spray drying.

In November 2021, Hovione announced that the company would add commercial spray-drying capacity and equipment as part of its expansion at its facilities in the United States, Ireland, and Portugal (2). At the US facility in NJ, the company is constructing a new building and will have additional commercial spray drying capacity online by 2023. New commercial spray dryers are also slated for the Cork, Ireland and Lisbon, Portugal facilities.

Catalent acquired the manufacturing and packaging operations of Acorda Therapeutics, Inc. in January 2021, including a 90,000-ft2 CGMP facility in Chelsea, Mass. with spray drying capacity that provides Catalent with significant commercial-scale capacity for new customer programs. Catalent said that the Chelsea facility will act as a global center of excellence within the Catalent network for spray-dried dispersion and dry powder encapsulation and packaging (3).

Catalent also announced a manufacturing collaboration with clinical-stage pharmaceutical company DisperSol Technologies in August 2021 (4). DisperSol’s clinical products are made using its proprietary KinetiSol ASD platform. As part of the collaboration, DisperSol transferred its technology by setting up its proprietary equipment in a dedicated suite in Catalent’s Somerset, NJ facility. Catalent is providing staff for development, scale-up, and commercial-stage KinetiSol production.

Spray drying is suited to ASDs but is also finding use in other fields, such as microencapsulation, nanotechnology, and vaccines, according to Van Vooren. “Spray-drying stands out as an accessible, repeatable, and scalable process that offers developers a cost-effective way to improve the solubility and bioavailability of their formulations,” Van Vooren concludes. 

Hovione, “Hovione Launches ASD-HIPROS,” Press Release, Jan. 12, 2021.

Hovione, “Hovione Invests $170 million in New Capacity and Capabilities,” Press Release, Nov. 11, 2021.

Catalent, “Catalent Agrees to Acquire Dry Powder Inhaler Spray Drying, Capsule Manufacturing, and Packaging Capabilities from Acorda Therapeutics,” Press Release, Jan. 13, 2021.

Catalent, “DisperSol and Catalent Collaborate to Establish KinetiSol Technology Manufacturing Hub for DisperSol Pharmaceutical Pipeline,” Press Release, Aug. 2, 2021.

 Supplement: Bio/Pharma Outsourcing Innovation
2022 
February 2022 
Pages: s22–s24,s29

When referring to this article, please cite it as J. Markarian, “Spray Drying Finds Growing Use for ASDs,” 

CDMOs offer expertise and capacity for spray drying.

Spray Drying Finds Growing Use for ASDs

Digitalization is taking hold in many areas of the pharmaceutical industry. 

 spoke with Marcus Michel, CEO of ACG Engineering, about digitalization in pharmaceutical manufacturing equipment and ACG’s own digital transformation journey.

 What trends do you see currently in use of digitalization/Industry 4.0 technologies for the equipment you supply to bio/pharma manufacturers?

 Industry 4.0, or the ‘digital revolution’, is gaining momentum within the pharmaceutical industry. In particular, Big Data, artificial intelligence, cloud computing, continuous connectivity, and advanced analytics through the Industrial Internet of Things (IIoT) are being utilized by pharma and biopharma manufacturers to deal with issues, such as rising complexities, costs, remote connectivity, and regulations. Smart factories managed with data analytics and machine learning will lower pharmaceutical manufacturing costs, improve quality, and reduce capacity constraints. Ongoing advances in predictive analytics are enabling manufacturers to draw on vast pools of data, including information on resource consumption, machine performance, and storage conditions on shop floors to troubleshoot problems, optimize processes, and boost productivity.

With forward-thinking pharmaceutical companies expediting their plans for digital transformation following the COVID-19 pandemic, a few trends indicate the early stages of adoption of Industry 4.0 in the pharmaceutical manufacturing sector. These trends include smart connected machines and factories; the leap from a reactive to a proactive framework using data analytics; augmented and virtual reality (AR/VR) services, including remote machine maintenance, remote factory acceptance testing, and even installation and commissioning; additive manufacturing; process unit design; digital twin systems; and personalized medicine and the correct use of big data.

ACG began its digital transformation journey in 2017 with four broad objectives: 1) to use emerging digital technologies to transform manufacturing operations, 2) to enhance customer experience, 3) to build smart products and services, and 4) to create new business models. Reducing machine breakdowns and enhancing overall equipment effectiveness in capsule manufacturing were the key business drivers. While the current focus is on transforming operations, ACG is expanding into building smart connected products and services, developing customer experiences, and creating digital-led business models.

 What do you see as the biggest obstacles to the implementation of these technologies?

 The major challenges experienced by the pharmaceutical industry during this digital revolution are:

Integrating new information technology (IT) systems and updating existing systems

To completely capitalize on the potential of the IIoT, pharmaceutical manufacturers need to invest in an IIoT infrastructure that has the capacity to handle their high level of requirements. As data and network security are of paramount importance, manufacturers must also be prepared to integrate existing protocols with the latest security solutions. There must be a check on the data that is flowing out of the plants to the Cloud servers. Manufacturing shop floors typically house a wide variety of equipment and associated software, some of which are legacy systems and no longer enjoy vendor warranty. Therefore, IIoT relevant upgrades are crucial. However, these upgrades can be costly. Additionally, the workforce needs to be trained, upskilled, and educated on the importance of these technological advancements, as they are an integral part of this digital transformation.

 What do you see as needs in workforce training or changing the business and work culture to adapt to these new technologies?

 Building, deploying, and adopting Industry 4.0 initiatives requires a wide variety of technology and domain capabilities. Active collaboration with the original equipment manufacturers, continuous improvement cells, and hands-on training sessions will help in developing the required skill sets. Pharmaceutical manufacturers will have to work on developing a few core competencies, as well as flexibility, to be in the driver’s seat for successful adoption and implementation of digitalization and the technologies of the future. These competencies include:

 Industry 4.0 needs existing systems to be updated and, in some cases, entirely new IT infrastructure setups. Legacy systems are workhorses, but not high on data security, cybersecurity, and flexible communication protocols. Companies need tailored risk management systems, in addition to a strategy for cybersecurity across the organization and value chain.

 Digitalization increases the need for companies to develop new skills at an individual associate level, as well as at an organizational level. To shorten the skill development timeline, recruiting a digitally acquainted workforce and virtual training through AR/VR applications are measures being adopted by companies. This is important in terms of improving quality since we are dealing with pharmaceutical products.

 As horizontal integration will create transparency and flexibility across process chains—from procurement to production and maintenance—vertical networking opens doors to collaborate with customers and [original equipment manufacturers] to build new business models for product-based customized solutions and remote aftermarket services. Remote condition monitoring, data analytics, and sharing insights across the value chain will open avenues for different business models.

 Flexibility for adaptation will be different for different segments in an organization. R&D, services, warehousing, and production have great potential to adapt and benefit from this shift to new technologies. However, the business rules and set process standards make it difficult for warehousing, administration, and sales to transform.

 What do you see as the future in adoption of digitalization technologies in bio/pharma manufacturing?

 The Fourth Industrial Revolution is beginning to flourish within the pharmaceutical sector, which was reluctant to change before COVID-19 hit the world. Due to the pandemic, companies have realized the need for digitalization and are now focusing on a complete adoption of digital technologies. What does Industry 4.0 mean for the pharmaceutical industry? It means increased connectivity, higher productivity, simplification, and transparency in compliance, as well as consolidation and analysis of production information to optimally respond to manufacturing issues as they emerge.

Although there are challenges to be addressed, the digital transformation of equipment has begun. 