Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

3d printer with injector nozzle | Image Credit: ©phonlamaiphoto- stock.adobe.com

Advances in equipment and control systems for three-dimensional printing (3DP) are creating new opportunities to use this alternative manufacturing method for solid dosage drugs. Printers—which are available in good manufacturing practice (GMP) versions—use various additive manufacturing methods to build layer upon layer, which allows precise placement of multiple ingredients within a dose. This customization offers advantages for modified and controlled release, personalized medicine, and point-of-care manufacturing, such as in hospital pharmacies.

“3DP’s material placement turns geometry into a dosing parameter,” explains Sharon Flank, CEO of technology company InfraTrac. “It can use layer thickness, shape, and differential material properties to create complex versions of controlled-release particles.” For example, 3DP can create “upstairs and downstairs layers for a polypill of two or more APIs, or an outer layer and multiple inner layers for precision control of release. Shape manipulation can control release in a way no tablet will ever do,” Flank says. Although 3DP is not as fast as conventional tableting, it can be used to meet the needs of a smaller target patient population that was previously underserved. Custom modifications can be quickly performed via software that controls material placement, compared to conventional tableting that would require tooling changes, Flank explains.

Using 3DP, dosage shapes can go beyond tablets, Flank adds. InfraTrac is working with Stephen Hoag’s Applied Pharmaceutics Lab at the University of Maryland School of Pharmacy on extrusion-based 3DP techniques to create orodispersible films, such as a pediatric rifapentine dose to treat tuberculosis. Outside of oral dosage, the researchers are designing long-acting implants with internal compartments for subdoses.

One example of using 3DP to meet a patient need is Aprecia’s levetiracetam, a high-drug load, rapidly disintegrating design for patients with difficulty swallowing that was approved by FDA in 2015. Made using the company’s 3D-printed ZipDose technology, it was the first drug to be approved using 3DP. It is made with an open-bed, binder-jetting method. More recently, Aprecia has developed its Z-Form 3DP platform integrated with process analytical technology (PAT) that prints doses directly in their primary packaging. The company worked with Battelle to develop the new technology platform for the development and production of dosage forms with a range of functionalities, including the ability to 3D print customized tablets or those with multiple APIs (1).

Triastek is using its Melt Extrusion Deposition (MED) 3DP process for microstructured drug delivery platforms that it has designed for modified release, colon targeting, gastric retention, solubility enhancement, and for improving oral bioavailability of peptides. The company has five drug products in clinical development (in the United States, China, or both) that use these platforms, including its most recent, a 3D-printed drug product designed for extended release and absorption of drugs in the upper gastrointestinal tract that received investigational new drug (IND) clearance from FDA in early 2024 (2).

In July 2024, Triastek announced a collaboration with BioNTech to develop oral delivery forms of RNA therapeutics using 3DP. The researchers aim to use multilayer and multi-compartment tablet designs to minimize degradation in the gastrointestinal tract and deliver the dose to where it can be absorbed optimally (3).

In addition to serving smaller patient populations, the flexible, small volumes enabled by 3D printing are useful in formulation development and clinical manufacturing.

“In clinical and preclinical trial supply, a nimble, small-scale production system could save a lot of time and therefore money,” says Flank. “Whether the final doses are produced via 3DP or conventionally, it is clearly helpful to be able to test several different formulations in a single day or even hour.”

Triastek is working with Boehringer Ingelheim to quickly create multiple prototypes of a new chemical entity and examine dose designs and drug release behavior using its 3DP technology (4). The company says its formulation-by-design approach can accelerate early drug development.

Small 3D printers can be useful for point-of-care manufacturing in a hospital pharmacy or potentially for remote locations, such as battlefields or space travel. A GMP-ready printer from FABRX, the M3DIMAKER, is now available with either one or three printheads and with printhead attachments for different extrusion printing methods—fused deposition modeling, semi-solid extrusion, and direct powder extrusion (DPE).

“We are working with hospitals and healthcare providers to implement our 3D-printing solutions directly into clinical settings, allowing for on-site production of personalized medications,” says Alvaro Goyanes, director and co-founder of FABRX. The United Kingdom-based company also launched a US-based company, FABRX US, in 2024, and is working with InfraTrac and Hoag’s lab on PAT for quality control.

The researchers, funded by the National Institute of Standards and Technology (NIST) through a Small Business Innovation Research program, are working on a predictive model that uses a near infrared (NIR) spectrometer incorporated into the drug printer, in this case the FABRX M3DIMAKER2, says Flank. The lab initially used a Viavi MicroNIR spectrometer and is also testing a Sentronic instrument. “Preliminary results show how NIR can validate and even quantitate API, detect out-of-specification moisture, and reject certain mis-printed doses,” reports Flank. “A robust model should facilitate point-of-care customization by creating pass/fail quality parameters that allow the pharmacist to manage doses and flavorings while delivering GMP product.”

“Integrating PAT and advanced testing capabilities into our machines addresses a critical need for real-time quality control and assurance in 3D-printed pharmaceuticals,” adds Goyanes. “This integration ensures that every product meets stringent quality standards, enhancing the reliability and safety of the medications produced.”

Goyanes points out that the development of effective cleaning protocols for printheads is essential to maintain equipment performance and prevent cross-contamination. FABRX introduced a new DPE printhead cleaner in July 2024 to improve the cleaning process. The company continues to work on technologies to meet other user needs it has identified, including development of modular and scalable 3D printing systems that can be easily adapted to different production volumes and requirements, Goyanes says.

Another technology designed for 3D-printing of personalized medicine in compounding pharmacies is the Pharma Kit from CurifyLabs. The platform includes GMP-manufactured excipient bases (called Pharma Inks); a desktop-sized automated Pharma Printer; software containing a library of validated formulae of Pharma Inks with APIs that guides the user; and integrated, automated quality control tools.

“Our goal was to modernize and bring automation to compounding and hospital pharmacies to make safer products and save time,” says Niklas Sandler, founder and CTO at CurifyLabs.

The developers automated as much of the workflow as possible, including weighing, mixing, dispensing, and packaging, explains Sandler. The built-in quality control tools include NIR to test blend homogeneity and a weigh scale to measure every tablet. The library of premanufactured excipient bases that have been optimized for the printing process and the formulations that have been validated are crucial to the system, says Sandler.

“We did all the validation work up front so that it would be easy and quick for pharmacists to follow the validated process. The technology can be used to produce a wide range of dosage forms, such as tablets and suppositories, and to dispense liquids accurately. The Pharma Kit is used in several markets in Europe,” Sandler adds.

“Both Europe and North America are witnessing a growing adoption of 3D printing in the pharmaceutical industry,” Goyanes suggests. In 2023, Goyanes and others launched the Pharmaceutical 3D Printing Initiative, an international consortium to facilitate collaboration between academic institutions, healthcare providers, regulatory agencies, and industry players. Other partnerships with universities and hospitals aim to train the next generation of scientists and engineers in 3D printing technologies. “These collaborations are crucial for advancing the field and ensuring that our solutions are continually evolving to meet the dynamic needs of the healthcare industry,” Goyanes concludes.

Aprecia. Aprecia and Battelle Are Impacting the Pharmaceutical Industry Through 3D Printing Innovation. Press Release, Nov. 15, 2023.

Triastek. Triastek’s 3D Printed Gastric Retention Product T22 Receives FDA Clearance of IND Application. Press Release, Jan. 31, 2024.

Triastek. Triastek Announces Research Collaboration and Platform Technology License Agreement with BioNTech to Advance 3D Printed Oral RNA Therapeutics. Press Release, July 23, 2024.

Triastek. Triastek Announces Collaboration with Boehringer Ingelheim to Advance and Accelerate Research and Development of Innovative Pharmaceutical Products with MED 3D Printing Technology. Press Release, March 17, 2023.

Jennifer Markarian is a contributing editor to 


Vol. 48, No. 10
October 2024
Pages: 22–23

When referring to this article, please cite it as Markarian, J. Exploring 3D Printing for Solid Dosage Drugs. 

Articles

As a GMP manufacturing method, 3D printing offers benefits for modified release and personalized dosages. 

Exploring 3D Printing for Solid Dosage Drugs

an automated production line manufacturing glossy luxury cosmetic packaging filled with amber liquid in a spotlessly clean and modern factory. generative AI | Image credit: © yj - stock.adobe.com

The range of applications for twin-screw extruders as pharmaceutical manufacturing equipment—either as a stand-alone, continuous unit operation or integrated into a continuous manufacturing line—is growing. Hot-melt extrusion (HME), which involves melting and mixing polymeric excipients with APIs in a twin-screw extruder to produce an amorphous solid dispersion, is used commercially in multiple applications, including drug-loaded devices or as a solvent-free alternative to spray drying. Twin-screw granulation (TSG) uses a twin-screw extruder to make granules using dry granulation, wet granulation followed by drying either continuously or in a separate fluid-bed batch process, or melt granulation using a highly viscous binder.TSG was used in early powder-to-tablet continuous manufacturing lines, and commercial use continues to grow. Although direct compression can be used for some formulas in continuous manufacturing lines, TSG is important for others where direct compression isn’t suitable.

“In recent years, TSG processes have been advancing rapidly, particularly towards continuous manufacturing processes becoming standard in the pharmaceutical industry because of the potential benefits TSG offers,” says Hemlata Patil, senior manager for hot melt extrusion technology at Catalent. “Consequently, a thorough understanding of the impact of formulation and process variables on granule quality has become crucial.”

Researchers continue to create new process analytical technology (PAT) for TSG that provides process insight and helps advance the science needed for product and process development using quality by design (QbD). QbD techniques will be especially helpful because the modular design of twin-screw extruders widens the range of possible variables.

“TSG and HME technologies provide a lot of promise for formulations, such as controlled release or poorly soluble drugs,” says Doug Hausner, senior manager of business development for continuous manufacturing at Thermo Fisher Scientific. “There is a large knowledge base in twin-screw granulation, but there is also a large design space. There are many options for screw configuration in the equipment, along with other input variables such as liquid-to-solid ratio. Process design requires know-how as well as statistical analysis for optimization.”

This knowledge is important for both individual and integrated operations. Hausner adds that while Thermo does not currently use TSG or HME in its integrated continuous process for final dosage forms, the continuous manufacturing team provides expertise in feeding and PAT for individual TSG and HME operations. “A multi-step continuous process will require a good stand-alone development activity on the TSG or HME step,” Hausner says.

Patil points out that Catalent can use TSG to create granules with various profiles, such as immediate release, sustained release, delayed release, and taste masking. Twin-screw dry granulation (TSDG) is effective for moisture-sensitive materials and useful for APIs that are not suitable for roller compaction, such as molecules that require higher shear for mixing and agglomeration, she adds. “In addition, TSDG has a unique application for APIs with needle-shaped crystal habit, which have low flow rate and bulk density. These poor physical and mechanical properties make them difficult to process via conventional methods such as roller compaction and slugging. The kneading action of the twin-screw extruder enhances consolidation of powders with needle-shaped API, resulting in better flow and compressibility. For high drug-loading products, this process yields superior granule quality and bulk density.”

TSG is beneficial for both high- and low-dose APIs. “In low-dose products, it is feasible to increase the uniformity by forming granules and preventing demixing,” explains Robin Meier, scientific director at equipment maker L.B. Bohle. In high-dose APIs, TSG offers the ability to improve compressibility. Meier says that a stable and compressible granule can be formed with minimal amounts of binder, in the range of 5%. He reports that compressible granules could be produced with all APIs tested so far on the company’s equipment, once a suitable binder was identified, depending on API solubility, particle size distribution, and partition coefficient.

To build the knowledge base regarding the behavior of materials in twin-screw extrusion equipment, Leistritz Extrusion Technology formed a consortium in 2019 of pharma companies, the University of Texas at Austin, and McMaster University.

“Equipment variables include the ratio of the outer diameter of the screw to the inner diameter, the length-to-diameter ratio, and the screw design,” says Stephen Post, product manager for Life Sciences at Leistritz. “We’re working on gaining more knowledge of the fundamental behaviors of materials and equipment, and we’re looking for trends in material behavior that can be extrapolated to similar formulations.”

For example, consortium researchers have investigated how screw design affects particle size distribution (PSD). Researchers are also performing scale-up experiments to replicate the PSD obtained from an 18-mm diameter screw on a 27-mm diameter screw. Although some drug manufacturers may choose to scale-out by using multiple 18-mm extruders, there are advantages to using a larger extruder to scale-up, such as lower facility footprint and lower utilities cost, explains Post. Better scale-up data are needed, he says.

“We are also developing material-sparing methodologies to assess the feasibility of TSG using various screening tools without running the twin-screw extruder” says Feng Zhang, associate professor in the College of Pharmacy at the University of Texas. “One of the key challenges in TSG is the process-induced chemical degradation and physicochemical transformation during processing.We have developed an in-depth understanding of how these undesired changes can be inhibited via rational selection of formulation composition and process design.”

PAT is being used in TSG processes to measure critical parameters in real-time. Moisture content and PSD, for example, are critical quality attributes (CQAs) of the intermediate product that affect CQAs of the final product.

Near-infrared (NIR) PAT has been evaluated to replace time-consuming loss-on-drying measurements to quantify moisture content in granules, says Patil. “NIR analysis allows for the adjustment of process parameters in real-time, resulting in significantly less material waste and improved process optimization within a shorter timeframe, even during the same extrusion run,” she says.

For PSD, direct imaging is well established, but other PAT types are also being investigated.

“The discrete nature of moving particles makes it harder to understand what’s going on in the machine, because standard monitoring techniques like pressure and temperature monitoring are unreliable as indicators of deviating product specifications,” says Michael Thompson, associate dean and professor of Chemical Engineering at McMaster University, whose research group has studied twin-screw granulation for more than a decade. He adds that while batch granulation often produces a Gaussian PSD, twin-screw granulation typically has a bimodal PSD, which makes real-time analysis even more important. Thompson’s lab has developed an inline particle size analysis PAT using acoustic emissions (AE). The researchers created a digital signal filter to ensure that particles of any size would be represented (1). Next, they created a filter that would also account for inelastic forces by training an artificial intelligence model with an elastoplastic (Walton-Braun) contact force model and a dataset of acoustic emission spectra collected from a broad range of granulated pharmaceutical formulations. The prediction error was as low as 2%, demonstrating its applicability to monitoring particle size distributions in continuous twin-screw granulation (2).“I see the existing optical [imaging] methods and this acoustic method as complementary approaches to particle size analysis,” concludes Thompson. “Both have their strengths and weaknesses in a dusty production environment like the exit chute of a twin-screw granulator.”

In a continuous granulation and drying set-up, such as L.B. Bohle’s QbCon 1, Meier indicates it is most meaningful to measure the residual moisture after the drying process (rather than after granulation) to be able to control and feedback the dryer process parameters. “In this case, we usually apply NIR or microwave resonance measurements. The latter allows univariate calibration,” he says. In the granulation step, Meier explains that solid feeding rate and liquid feeding rate are the crucial parameters used to control mean granule size. He suggests that controlling these rates is more reliable than a method that measures in-line PSD and adjusts liquid addition. Meier reports that the QbCon 1 equipment, as part of a complete continuous manufacturing line, was recently delivered to a large German pharma company for clinical supply of new entities. This line is designed for small-scale throughputs up to 4 kg/h and is capable of handling APIs in occupational exposure band 5.

Twin-screw extrusion aids complex formulation

Researchers at Rutgers University are using a twin-screw extruder as a hot-melt coater and granulator in a unique, patent-pending solution to the ongoing challenge of manufacturing drug products with high doses of poorly soluble APIs. “Poorly soluble drugs are poorly soluble because they dissolve less, but this also is often because they are hydrophobic; they are difficult to wet and so they dissolve more slowly,” says Fernando Muzzio, distinguished professor of Chemical and Biochemical Engineering at Rutgers University. “We solved this problem by using a twin- screw extruder to coat the drug substance particles with a surfactant, which improves solubility. The particles are mixed with a low-melting point surfactant and fed into a twin-screw extruder operating at a temperature low enough to avoid decomposing the API but high enough to partially melt the surfactant and allow it to coat the API particles. The resulting granules flow and compress well, allowing us to make a high-dose (approximately 80% API), immediate release tablet.”

Muzzio says that this twin-screw granulation process is potentially less expensive to operate than more complex processes for high-dose, poorly soluble APIs, such as HME, nanomilling, or spray drying. The innovation is a result of understanding what happens to materials when their surface is modified, combined with an understanding of the twin-screw granulation process that allows accurate control of mechanical and thermal variables, says Muzzio.

Abdulhussain, H.A. and Thompson, M.R. Predicting the Particle Size Distribution in Twin Screw Granulation through Acoustic Emissions. 

Jennifer Markarian is manufacturing reporter for 

Volume 47, No.10
October 2023
Pages 24-27

When referring to this article, please cite it as Markarian, J. Considering Advances In Twin-Screw Extrusion for Solid-Dosage Drugs. 

Twin-screw granulation process insight is growing as researchers employ new analytical technologies and investigate new ways to use the equipment.

Considering Advances in Twin-Screw Extrusion for Solid-Dosage 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.

This article was previously published online at PharmTech.com on March 2, 2022.

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.

Read this article in the Trends in Manufacturing ebook. 

Demonstrating a Fully Continuous Bioprocess

Jennifer Markarian was previously manufacturing editor and is currently manufacturing reporter for 

When referring to this article, please cite it as J. Markarian, " Demonstrating a Fully Continuous Bioprocess," 

Pharmaceutical Technology's Trends in Manufacturing

Flexible and efficient methods are needed for biopharmaceutical manufacturing. 

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,” 

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

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.