Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

Traditionally, compounding facilities—also called 503B outsourcing facilities in the United States in reference to the section of the US regulation under which they are registered (1)—have conducted drug manufacturing operations manually; “on demand” production of a wide range of drugs needed by hospitals and pharmacies as well as drugs on FDA’s drug shortages list did not lend itself to automation in the way that longer-run, scheduled production did. Robotic automation technologies available today, however, offer benefits of greater efficiency and higher quality even for small volumes.

“Robotics offer several significant advantages for aseptic compounding. Most notable is that the greatest source of contamination, the person, is removed from the process,” says Chris Smalley, an independent compounding pharmacist advisor. “There is a robust traceability to what is performed, including volume, drug barcode scan and more, and it does not matter what hour or day of the week the robot operates,” explains Smalley. He notes that, in some cases, a robot is set up to operate on its own overnight (i.e., “lights-out” manufacturing), and the completed products are unloaded and checked the next day.

“Minimizing risks associated with aseptic processing is crucial when working with compounding systems,” agrees Randy Fraatz, vice-president of North American Operations at Steriline, which produces aseptic manufacturing equipment. “The primary benefit of robotics and automation in general is safety, coming from the reduction of human-related mistakes in the entire process.” Other benefits, says Fraatz, include the accuracy, efficiency, and reliability that result from automation. “If errors are reduced, process reliability and quality improve,” he explains. 

Despite these advantages, uptake of robotics is slow, and many 503B outsourcing facilities continue to have technicians working in laminar flow hoods or biological safety cabinets to handle beakers and flasks for solution compounding and fill vials manually using syringes, notes Smalley. He points out that some large teaching hospitals have adopted robotics for large-volume parenterals and for oncologic compounding and filling. “Smaller hospitals that focus on a specialty, such as orthopedics or oncology, appear to be the second wave,” Smalley adds.

An early example of a hospital compounding facility that adopted automation was the overall winner of the International Society for Pharmaceutical Engineering (ISPE) Facility of the Year Awards in 2019 (2). The Kantonsapotheke Zurich (KAZ) supplies oral, dermal, and parenteral formulations to the Canton of Zurich hospital system under current good manufacturing practice (CGMP) conditions. Exyte, the engineering firm for the project, said in the award announcement: “This facility raised the bar for quality performance to CGMP levels, which had never been done before in a hospital compounding facility” (2).

Although robotic systems have many advantages, one of the challenges is designing and programming for flexible operations. Since it takes time to set up the systems to manage different material combinations, speed can be limited. “For a compounding combination that requires a lot of flexibility, such as handling a wide range of materials to prepare one compound, the system will need more time to process materials,” says Fraatz. “In many cases, humans are typically able to handle different types of materials and combinations faster than robotics, but contamination risks are higher.” He explains that planning ahead is important for using robotics, so that the right tools, equipment, and programming instructions are ready for a specific process.

“The user requirements need to be clearly and completely defined,” agrees Smalley. “Robotics can only work with the tools that they are constructed with, for instance vacuum-assisted suction cups, pincers, barcode scanners, syringe operators, and the like. Additionally, they can only perform tasks that were included in their programming. Refitting and reprogramming can be problematic.”

Another challenge is the need to have barcodes that can be identified by the automated system. “Not all vials have barcodes, and new products or new brands of generic drugs result in barcodes not in the robot’s database. Software updates are constantly needed,” notes Smalley.

New developments are focusing on improving software and improving material handling. “Changes are being made to software to enable the robot to operate more smoothly and efficiently, as well as to make the user interface more intuitive. For material handling, some robotics manufacturers are focusing on loading cells, while others are looking at the ‘hands,’ as it were, trying to make the way the robot grasps items more securely without the danger of breaking the item,” reports Smalley.

A best practice for robotics users is periodic service by the equipment manufacturer that includes maintenance and adjustment, as well as software updates to address operational and security needs, notes Smalley.

“Routine maintenance and attention are absolutely required for robotic automation in the compounding space,” agrees Fraatz. In his experience, various hospitals tend to be familiar with using high-tech equipment such as robotics (as in some surgical settings), but the overall compounding industry is not yet as aware of how process automation can be used in compounding environments.

In particular, integrating robotics inside isolators is a relatively new technology for the compounding environment, says Fraatz. “True isolators have become very common in the pharmaceutical processing industry, and are the safest containment solution available for the compounding market as well,” he says. “From a best practice perspective, compounding organizations need to evaluate and adjust their quality risk management philosophy, including process and validation protocols for this type of automation. Evaluating [the use of isolators and robotics] is a multi-department effort, as there are also facility considerations in terms of what they may need, concerning cleanroom design or availability of utilities, for example.” Fraatz notes that it is also important to evaluate the process flow, including how materials are introduced to the compounding environment and handled after compounding. He points out that robotic equipment can be designed to be compatible with cleanroom conditions. “Cleanroom conditions require easy to clean tools, low particulate generation, and equipment designed to respect the clean airflow required,” notes Fraatz. 

A pharmaceutical manufacturing company adopting cutting-edge robotic technology for its CGMP 503B operations is Nephron Pharmaceuticals in South Carolina. The company, which specializes in producing generic respiratory medications using a fully automated process with blow-fill-seal (BFS) technology, launched its division for sterile compounded drugs in 2017 and began with manual operations, in which pharmacy technicians worked inside laminar-flow hoods to fill parenteral solutions coming from sterile filtration into intravenous (IV) bags or syringes. Now, Nephron is moving to robotic systems inside of the laminar-flow hood to perform these fill/finish operations. The company worked with the University of South Carolina (UofSC) and Clemson University in two separate projects to custom design robots for this application. In April 2021, Nephron validated the UofSC system and began commercial production, says Lou Kennedy, CEO of Nephron. A second robot is already being built, and more are planned. “We’re producing drugs on FDA’s drug shortages list, and this 503B space is growing,” she says. Robotic systems will improve productivity, reduce the burden of repetitive physical work for operators, and provide better accuracy and precision. Future projects will seek to increase speed of the robots to obtain higher throughput.

In addition to being used in commercial production at Nephron, Kennedy would like to see the robotic systems licensed to hospital compounding facilities. “What I love about both the Clemson and UofSC projects is that as we collaborate with both undergraduate and graduate students, we’re helping develop future industry employees,” says Kennedy.

Although a common fear is that robots will eliminate people’s jobs, Kennedy says this concern is unfounded. “Robotics is not eliminating people; it’s teaching people to have new skills to operate automation,” she notes. “Operators need to learn how to service the robot and work with it, to solve a jam or replenish components, for example. Operators are also needed for quality functions.”

Kennedy notes that Nephron sees a need for more pharmacy technicians, and the company works closely with local schools to help develop the future workforce. For example, Nephron built a sterile compounding lab on the nearby UofSC campus that is used to train pharmacy students at the university as well as two-year students from the local technical college in using robotics in sterile compounding.

Both developing an understanding of how robotics works and specific training with the equipment and its functions are key, adds Fraatz. “It is a new approach, which means trust needs to be gained, starting from education and understanding, so people can appreciate the purpose of robotic automation. Once they believe in the purpose, they can grow their familiarity and comfort with it.”

1. FDA, “Information for Outsourcing Facilities,” 

2. Exyte, “ISPE’s 2019 Facility of the Year Award for Operational Excellence & Facility of the Year Overall Award won by partners Exyte and Kantonsapotheke Zurich,” Press Release, Oct. 30, 2019.

Articles

Sterile manufacturing of small batches, in facilities including hospital compounding pharmacies and 503b outsourcing facilities, benefits from automation.

Robotic Automation Boosts Efficiency and Quality in Drug Compounding

When running manufacturing equipment continuously, rather than in batch mode, operators should consider what cleaning practices need to be adjusted. FDA’s draft guidance for continuous manufacturing of small-molecule, solid oral drug products notes time between equipment cleanings can depend on a variety of factors, such as running time or amount of product (1).

When considering equipment running continuously, cleaning might be automated with clean-in-place (CIP) elements or involve full disassembly with manual cleaning, say Paul Lopolito, senior manager, and Beth Kroeger, senior manager, in Technical Services at STERIS. “Using cleaning agents or cleaning tools requires a cleaning validation to demonstrate removal of these elements to acceptable limits. The calculation of accepted limits may utilize traditional uniform carry-over models or non-uniform residue or stratified residue models,” say Lopolito and Kroeger. These models are used because residue can become concentrated as it moves through the connected equipment (2). Other considerations with continuous manufacturing are addressing microbial issues and process intermediate degradant residue. “These residues may present a cross-contamination risk to the next lot or batch of product. If these hazards exist, then it is warranted to perform the appropriate level of cleaning and cleaning validation to mitigate the risk,” they conclude.

Most lines for continuous manufacturing of solid-dosage drugs today are cleaned in a “clean-out-of-place” mode, but a complete CIP solution would improve cleaning turnaround times, notes José Luís Santos, director of Hovione’s Continuous Tableting Center of Excellence, who suggests that end-users would need to work closely with equipment vendors to develop such a system for a full process train. Hovione’s contract development and manufacturing facility in New Jersey has been running continuous solid-dosage drug manufacturing equipment for a few years and working to streamline the manual cleaning process.

“The magnitude of the task of changing over a continuous manufacturing rig from one product to the next is very large,” explains Santos. “From a unit operation standpoint, there are no major differences from batch equipment, and in most cases the equipment is exactly the same at the unit operation level. The differences between continuous and batch have to do with the transition sections in between [the integrated] unit operations. Depending on the actual setup of the continuous rig, these transitions can be comprised of large pipe sections, in some cases with pass-through connections between floors. Also, such transitions might comprise large number of PAT instruments to measure, for example, powder level or quality attributes of the material being processed. Thus, continuous rigs have additional parts to be cleaned. If the continuous manufacturing line is entirely ‘clean-out-of-place,’ the extra equipment also poses the added challenge of keeping track of many equipment components of all different sizes as they move through the cleaning operation and subsequent reassembly; the learning curve associated with these operations may be much longer than comparable operations of individual batch manufacturing units.”

Santos notes that, “While in batch, each unit operation is operated independently, in separate rooms, and typically staggered in time; in continuous, the full set of equipment is used during manufacturing, typically with higher asset utilization. Hence, from a planning standpoint, the cleaning of continuous rigs requires significantly more resources, effort, and cleaning capacity (e.g., additional wash rooms and footprint for parts staging and storage) to address the full set of equipment without impacting productivity of the area or overall equipment effectiveness (OEE).”

A cleaning best practice applied at Hovione was to allocate enough resources to address the manual cleaning process—including a large team of operators and enough space to do the cleaning—and then to optimize with shop-floor operational excellence tools, says Santos. “In our experience, the use of Lean [management tools] brought not just the acceleration of the operation, but also an increase of the comfort levels of the team members involved with the cleaning. An otherwise huge challenge could be decomposed into smaller, more manageable, blocks of work, with a clear visibility of how the work was progressing during each day of the operation,” he explains.

Another best practice is to maintain control of the organization of equipment components from disassembly through assembly. “For example, use specific bins to contain disassembled components from specific (predefined) sections of the line so that those components, which make up those specific line segments, stay together throughout the cleaning process. Organization is critical to reduce lost and mixed-up equipment components among thousands of such components,” Santos explains.

In biopharmaceutical manufacturing, process intensification can change the way the equipment is used and thus affects cleaning methods. Beth Kroeger and Paul Lopolito, senior managers for Technical Services at STERIS, shared some points to consider in an interview with Pharmaceutical Technology. 

Click to read: “Considerations for Cleaning Biopharmaceutical Process Equipment”.

Process analytical technology (PAT) sensors in the equipment are a crucial part of continuous manufacturing systems, but, in some cases, such as near infrared (NIR) probes, they may be fragile and require special handling during assembly and disassembly, notes Santos. He adds that it is important to use the PAT vendor’s procedures for proper cleaning and maintenance. “Having additional instruments to address concurrently with cleaning of the manufacturing equipment is logistically quite demanding, requiring close communication and planning in order to keep operations running efficiently. Developing and controlling standard procedures with the right level of details and mistake-proofing become even more critical in the context of preventing damage to such sensitive components during handling and cleaning.”

“When cleaning equipment with internal sensors, consideration should be given to the material of construction to ensure compatibility with the chosen cleaning agent. Typical substrates may include glass, titanium, or polymeric material,” note Lopolito and Kroeger. If using a CIP cleaning method, they recommend working with the PAT vendor to check compatibility to determine if there will be any impact to the sensors through chemical exposure, high-pressure steam, foaming, build-up of residue on the probes, or through any interaction of materials.

Another concern with sensors in a CIP process is determining how well the cleaning and rinse solution flows in and around the sensor and whether there is a significant change in the flow dynamics through the piping. “Coverage testing can be confirmed using riboflavin, and flow dynamics can be assessed through computer modelling, Reynold’s number calculations, or inspection with a borescope,” they explain.

It may be possible to use the existing PAT (which measures process variables when the process is running) to also monitor a CIP cleaning process, says Lopolito. “An example would be an ultraviolet (UV) or Fourier Transform Infrared (FTIR) spectroscopy sensor (to monitor drug active) that can also be used to detect trace levels of cleaning agent in rinse water and stop the rinse process when a target limit is achieved within a specified time,” he explains.

FTIR is also being investigated as an approach to cleaning verification, using a handheld instrument to detect and quantify surface contamination (3).

One of the challenges for manual cleaning is the difficulty of standardizing across a wide range of equipment components with different degrees of product exposure or adhesion, notes Santos. “New technologies such as handheld FTIR can certainly bring a level of simplicity to this process, either in terms of an in-process control to determine the endpoint of cleaning of a component or to eliminate dependence on analytical samples altogether,” he concurs.

Draft Guidance for Industry, Quality Considerations for Continuous Manufacturing

3. C. McSweeney et al., “New Approaches to Cleaning Verification for Pharmaceutical Manufacturing Using Handheld Mid-IR,” Presentation at IFPAC (online, March 2021).


Vol. 45, No. 6
June 2021
Pages: 30–32, 42

When referring to this article, please cite it as J. Markarian, “Cleaning Continuous Manufacturing Equipment ,” 

Consider best practices for manual or clean-in-place procedures.

Cleaning Continuous Manufacturing Equipment 

 (Sept. 10, 2020).
2. Exyte, “ISPE’s 2019 Facility of the Year Award for Operational Excellence & Facility of the Year Overall Award won by partners Exyte and Kantonsapotheke Zurich,” Press Release, Oct. 30, 2019.

When referring to this article, please cite it as J. Markarian, “Considering Robotics for Drug Compounding,” 

Automation offers benefits for sterile manufacturing in 503B outsourcing facilities. 

Considering Robotics for Drug Compounding

In biopharmaceutical manufacturing, process intensification can change the way the equipment is used and thus affects cleaning methods. “Process intensification continues to influence trends, such as higher-titers in bioreactors, greater binding capacity in resins, improvements in upstream clarification, and other advances in technology and equipment design,” notes Beth Kroeger, senior manager for Technical Services at STERIS. Manufacturers that take advantage of these technology advances, however, should also consider how cleaning can be affected. Kroeger and Paul Lopolito, senior manager for Technical Services at STERIS, shared some points to consider in an interview with 

 How have changes in biopharmaceutical equipment use affected cleaning requirements?

 One area we see a change to equipment design, as a result of process intensification advances, is in the use of inline conditioning skids and inline dilution where buffers are prepared from buffer concentrates. Use of buffer concentrates meets an obvious need to mitigate the amount of storage space required for several large volume tanks and bags. However, the use of buffer concentrates along with the increase in throughput lead to a change in how buffer tanks should be cleaned and maintained. In the past, based on solubility of buffers, water has been suitable for cleaning buffer tanks. This industry practice was confirmed during a benchmarking session at a CIP [clean-in-place] Technology and Industry Summit where 90% of the participants indicated water was used to clean some part of the process, with buffer tanks listed as the predominant equipment cleaned in this manner (1,2). This method, however, is no longer applicable with the shift to in-line dilution and the manufacture of concentrated buffer solutions. We have seen several issues stemming from manufacture of buffer concentrates, ranging from faster development of air-liquid interface rings to issues with micro-pitting and rouge formation. It is important to bear in mind the types of solutions prepared in these tanks if a site is considering implementing these types of bioprocess skids and to incorporate a robust cleaning and routine passivation and derouging step in the cleaning process to properly maintain the tanks.

Similarly, perfusion systems used for process intensification allow for higher-titers, cell debris, and media constituents to remain in the bioreactor a longer time than fed-batch systems, and the increased amounts of anti-foam agents added could make cleaning the bioreactor more difficult. This [challenge] is most pronounced at the air-liquid interface of the bioreactor, baffles, air sparger, and agitator shaft. 

Can data analytics be used to identify when cleaning is needed in continuous processes?

 Predictive maintenance can be applied to any type of situation, whether the maintenance events are mechanical or, in this case, cleaning equipment used for continuous processing. Predictive modeling leverages data obtained between equipment cleaning processes to better predict cleaning frequencies, preventing failures due to residue buildup, loss of passive surface characteristics, or microbial contamination. Testing may include measurement of conductivity by trending drift in conductivity results; total organic content; bioburden; in-line ultraviolet spectroscopy measurements; and bacterial endotoxin testing. In addition to determining equipment cleaning frequencies based on data, routine stainless-steel maintenance frequencies could also be determined based on iron-monitoring testing, non-viable particulate monitoring, and surface passivation testing. The concept of predictive modeling within laboratory test methods has been useful in modifying routine cleaning procedures to mitigate risk or fine-tune preventive maintenance activities. About six years ago, we worked with one biopharmaceutical company that monitored a solution hold time in tanks, and, after a preset time, the tank was passivated with an acid detergent to prevent micro-pitting and untimely corrective action activities. Another biopharma site confirmed that final acid rinse temperature was not sufficient to maintain the corrosion resistant passive layer and that increasing the temperature and lowering the concentration would prevent the micro-pitting and unscheduled equipment downtime (3).

1. Benchmarking Sessions at the Seventh Annual CIP Technology & Industry Benchmarking Summit (Longmont, Colo., April 2013).

2. P. Lopolito, et al. “Cleaning Buffer Preparation Tank Air-Liquid Interface Rings,” 

3. E. Rivera, P. Lopolito, and D. Hadziselimovic, 

When referring to this article, please cite it as J. Markarian, “Considerations for Cleaning Biopharmaceutical Process Equipment,” 

Process intensification in continuous biopharmaceutical processing can change the way the equipment is used and thus affect cleaning methods.

Considerations for Cleaning Biopharmaceutical Process Equipment

The sudden, compulsory move to remote work during the COVID-19 pandemic pushed many into greater use of a wide range of digital tools, including companies in the slow-to-change, highly regulated pharmaceutical manufacturing industry. In addition, continuing advances in connectivity and the availability of increasingly user-friendly technology reduced barriers to implementation. As a result, more companies are successfully using digitalization tools.

Digital tools that have been proving their worth in the past year include augmented reality (AR) and virtual reality (VR) systems for activities such as training, collaborative engineering design sessions, and factory acceptance testing of new equipment.

“During facility design, it’s been really helpful to use tools such as virtual reality and 3D modeling so all parties can review a design together in a collaborative manner, yet remotely,” notes Yvonne Duckworth, automation engineer at CRB. “As another example, we had a client who had a skid at a vendor site but couldn’t travel there to perform factory acceptance testing due to travel restrictions. We were able to provide them with the augmented reality technology to conduct testing remotely, which was very effective. It’s a great way to accommodate travel restrictions and still do thorough acceptance testing.”

In addition to using these types of tools, pharma manufacturing companies in the past five years have been moving toward a greater level of digital maturity, from manufacturing facilities that have “islands of automation” to connected plants with high levels of automation and beyond. “The level of connectivity we have now is allowing plants to look at concepts such as predictive analytics,” says Duckworth.

Companies are also employing digital tools to conduct audits of their suppliers or contract partners remotely, due to travel restrictions. Although many had to learn as they went and address problems as they arose, their experience has led to development of some best practices for these new methods. By employing best practices and available technologies, remote audits can be effective, says Peter Miller, principal partner at Dynamic Compliance Solutions.

The Parenteral Drug Association (PDA) formed a 27-member, international Remote Audits and Inspections Task Force that seeks to help members prepare for and perform remote inspections and audits (1). The task force held a workshop in early April and plans to publish “Points to Consider” documents. 

In April 2021, FDA published a guidance for industry that explains how FDA may use interactive and virtual tools, during the ongoing COVID-19 public health emergency, for what the agency is calling remote interactive evaluations of facilities (2). Although these are not official FDA inspections, the agency says it will consider many of its usual inspections as possible candidates for remote interactive evaluations (3). A report released by FDA on May 5, 2021 provided an overview of inspections and evaluations using alternative tools conducted during the COVID-19 pandemic in 2020 and 2021, and outlined plans for moving forward (4). FDA said it plans a multi-year modernization effort to its regulatory oversight role that will support innovation, including remote approaches (5).

 will be hosting interviews with pharmaceutical industry experts in digitalization in an online Technology Forum on May 25, 2021: 

 Speakers will include Peter Miller and representatives from Merck to share best practices and experiences in remote audits; Yvonne Duckworth to discuss trends and best practices in digital tools for facility design and operation; experts from Stress Engineering to discuss simulation and digital twins; and consultants from McKinsey to provide another view of digitalization in pharma manufacturing. 

1. PDA, “Remote Audits and Inspections May Be Here to Stay: PDA’s Task Force Aims to Help,” Press Release, Apr. 27, 2021.

Guidance for Industry, Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities during the COVID-19 Public Health Emergency

3. FDA, “FDA Provides Guidance on Remote Interactive Evaluations for Oversight of Drug Facilities During COVID-19,” Press Release, Apr. 14, 2021.

Resiliency Roadmap for FDA Inspectional Oversight

5. FDA, “Coronavirus (COVID-19) Update: FDA Outlines Inspection and Assessment Activities During Pandemic, Roadmap for Future State of Operations,” Press Release, May 5, 2021.



Technology advances and pandemic environment drive increased use of automation and digital tools. 

Trends in Digitalization of Pharma Manufacturing 

Pharmaceutical manufacturers use a wide range of technologies, such as tablet coating, fixed-dosage combination drug products, multiparticulates, and orally disintegrating tablets (ODT), to make it easier for different patient populations to take their medicines. “Addressing barriers to adherence, such as pill burden, dosing frequency, and ease of administration, are necessary to ensure treatment success for many therapies and indications,” says Chris Gilmore, CEO of Aprecia Pharmaceuticals.

Aprecia has applied its three-dimensional printing (3DP) manufacturing technology to create an orally disintegrating dosage form for patient populations that have difficulty swallowing conventional tablets or capsules. Gilmore says that conventional ODT formulations are limited by dose load, taste, and disintegration time, and that Aprecia’s ZipDose technology overcomes these limitations. “The majority of available ODT formulations contain less than 50 mg of active ingredient due to overall product weight limitations,” notes Gilmore. “These limitations also hinder the ability to add other inactive ingredients to improve mouth-feel and taste.” Gilmore says that Spritam (levetiracetam tablets), the first commercial application of the ZipDose technology, can achieve higher dose strengths—approved strengths range from 250 mg up to 1000 mg tablets. “In standard tablets, such dose strengths would be among the largest tablets or capsules and still need to be swallowed wholly intact. For example, the size of the most commonly dispensed 1000 mg tablet is 23 mm by 10 mm. The length exceeds the maximum size recommended by the FDA for generic tablets. For perspective, this tablet has a length as long as a nickel’s diameter. But in ZipDose tablets, these strengths can be achieved in tablets that fully disintegrate in the mouth with a sip of water before swallowing, eliminating the impact of tablet size on swallowing,” he says.

The technology could also be used to combine multiple drugs to reduce pill count. In addition, notes Gilmore, Aprecia has begun working with various clients to extend ZipDose technology to payloads having modified-release particles, which could have various benefits, such as enabling lower frequency of dosing for certain medicines.

In February 2021, Glatt and Aprecia announced a collaboration to combine Glatt’s multiparticulate technologies, produced using its fluidized bed technology, with Aprecia’s 3DP manufacturing systems. “We see interesting opportunities in the field of ODTs and multiparticulate systems,” says Philippe Tschopp, head of business development at Glatt Pharmaceutical Services. He notes that multi-unit pellet system (MUPS) formulas are rarely used in ODTs, but that this use would open up the ability to address swallowing issues. “Incorporating multiparticulates in 3DP tablets gives the opportunity to have a fast dissolving ‘transport agent’ with the full flexibility of multiparticulates in dosing and dose combinations, with controlled-release profiles by functional coating of the multiparticulates.” Another benefit of combining 3DP and multiparticulates is enabling a flexible dosing regimen to adapt to patients’ needs without manipulation by the patient or caregiver, suggests Tschopp.

“Use of multiparticulates allows us to expand the range of drug delivery options from the final dosage form in order to include modified release functionality. It addresses formulation design in modular fashion, by providing certain functionality at the particle level and providing additional functionality at the finished dosage form level,” adds Thomas West, vice-president of pharmaceutical development at Aprecia.

A unique aspect of 3DP manufacturing is that it eliminates the mechanical stress on the tablets due to the compressive forces needed in conventional tablet production. In Aprecia’s patented binder-jetting 3DP manufacturing system, tablets are built layer by layer—this process of adding layers to create a product is why 3DP is also called “additive manufacturing” in some industries.

“Incorporation of multiparticulates into 3DP tablets overcomes the issue of traditional MUPS tablets as there are no compression forces applied to the film coated pellets that could deform and destroy the functional coatings and therefore alter the release profiles,” explains Tschopp. 

“Avoiding mechanical stresses on the multiparticulates helps protect the multiparticulate integrity until it reaches the patient and reduces the risk of dose dumping for modified-release dosage forms,” agrees West. “The biggest challenge of multiparticulates in tableting is the act of compaction, which initially causes localized friction (heat) and then deformation or fragmentation of the pellets or coating. Cracks or other imperfections in the pellets on the surface can alter the dissolution profile, making it challenging to have a batch-to-batch consistency.”

Another novel benefit of 3DP is blend consistency. When feeding multiparticulates and excipients into a conventional tableting press, there is a tendency for demixing, says Tschopp. The system for feeding multiparticulates into the 3DP process is more controllable; it is important to have consistent quality of the pellet population, but Tschopp says this is achievable. He says that pellets should be consistent in size and, depending on the dosing device, in weight or bulk density. Tschopp explains that pelletization equipment, such as Wurster technology or Glatt’s micropelletizing technology (MicroPX), can produce a narrow particle size distribution, a smooth surface area and, if needed, small particle sizes.

In Aprecia’s additive manufacturing process where the tablets are built layer by layer, this method of tablet forming provides a greater degree of localized control than in conventional tablet presses, adds West. “For example, the design of a 3DP tablet can include regions of greater or lesser binding based upon the regional density of liquid droplets. Since a 3DP tablet is built layer by layer, the regional droplet density may be tailored within each 2D ‘slice’ of the tablet design,” he explains. The primary considerations for this manufacturing platform are material uniformity (i.e., avoiding segregation) and wetting and drying in the open-bed process. “Multiparticulates are larger and generally flow better than finer powders, but there are fewer excipient options for size-matching in blends. The material should be amenable to water-alcohol exposure for short periods and drying at 40–60 °C,” West notes.

Recirculation is another parameter to be tested during process design. “Open-bed systems collect and refeed the unprinted powder, so the potential impact of these conditions must be evaluated through repetitive exposure with the scaled batch size in mind,” says West.

Although much of Aprecia’s commercial work has used dry powder blends, West says the company has now proven the capability of incorporating granulated APIs and functionally coated particles, such as drug-layered beads, at small scale on the commercially available open-bed platform. Gilmore adds that Glatt and Aprecia’s joint projects are underway, and multiparticulate ZipDose demonstrator tablets will be available in the coming months.

Aprecia is also developing a patent-pending printing platform in which tablets are formed, using binder jetting directly in a blister-package cavity, rather than free-standing on the open bed. This platform further expands the capability of what types of materials can be used in 3DP manufacturing, because the wetting and drying requirements are less stringent than in the open-bed system, and desegregation is less of a concern. This process also eliminates recirculation. “The in-cavity systems do not have recirculated powder, providing better precision in dosing the multiparticulates in measured amounts,” reports West.

“In the in-cavity platform, we’re looking at a wider range of material inputs and the ability to incorporate both single and multi-material inputs in a single dosage form,” West adds. For example, the in-cavity printing system can use two powder blends as inputs. “This multipowder approach can allow separate addition of a multiparticulate payload and of the other excipients used to build the product. Direct wetting of the payload can be avoided in some instances,” he says.

“We are also working on a new product design that allows for dry, ambient filling of virtually any payload into a rapidly disintegrating unit. That approach yields true minimum process stress for payloads such as multiparticulates, because it avoids direct wetting, vapor exposure, and oven exposure,” notes West. This product design is achieved using open bed 3DP with certain downstream modifications. Aprecia expects to disclose more about it later this year.

Although Aprecia is looking at these alternative 3DP systems and designs, the company continues to enhance its open-bed binder-jetting process. A collaboration with the non-profit research group, Battelle, announced in December 2020, will focus on formulation and production breakthroughs in the binder-jetting process design for pharmaceutical applications, says Jae Yoo, senior vice-president and chief technology officer at Aprecia Pharmaceuticals. “[This work will seek to] expand formulation capabilities, reduce formulation time, streamline supply chains, reduce stability risks and requirements, increase production throughput, eliminate production waste, and enhance flexibility,” says Yoo.

The objective of all these novel manufacturing technology combinations is to enable formulators to design better products and expand the possibilities for patient-focused dosage forms, concludes Gilmore.

Jennifer Markarian is manufacturing editor at 

When referring to this article, please cite it as J. Markarian, “Combining Multiparticulates and 3DP for Patient-Centric Dosage Forms,” 

Aprecia and Glatt investigate manufacturing technologies to widen the formulation design space for oral delivery.