Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

Equipment and advanced manufacturing approaches to meet the evolving needs for solid-dosage drugs include continuous manufacturing, containment strategies, Industry 4.0 tools, and techniques for optimizing solid dosage form manufacturing. “Equipment Trends in Advanced Solid-Dosage Drug Manufacturing” was part of a keynote series at INTERPHEX 2021 on Oct. 19, 2021.

The session was moderated by Jennifer Markarian, manufacturing editor, 

Pharmaceutical Technology, Pharmaceutical Technology Europe,

 In this video, Jennifer interviewed Dave DiProspero, Director Pharmaceutical Process Technology, CRB.

In the interview, Dave shared what he sees as key trends in manufacturing of oral solid dosage (OSD) drug forms. He gave his perspective on continuous manufacturing processes and containment equipment for OSD drugs.

This video is part 1 of 5. The other speakers in this session were:

Part 2: Johannes Khinast, Institute for Process and Particle Engineering in the Research Center Pharmaceutical Engineering (RCPE) at the Graz University of Technology in Austria. 

Part 3: Fernando Muzzio, PhD, Distinguished Professor of Chemical and Biochemical Engineering at Rutgers University. 

Part 4: Sharon Nowak, Business Development Manager, Coperion K-Tron USA Food & Pharmaceutical Industries. 

Part 5: Gernot Warnke, Head of R&D, JRS Pharma.

Watch other videos in this keynote series:

Advances in Molecule Characterization and Biomanufacturing for Emerging Therapies

Serialization on a Global Scale: Deep Dive into the US DSCSA & EU FMD

Articles

Dave DiProspero, director of Pharmaceutical Process Technology at CRB, spoke about equipment trends in solid-dosage drug manufacturing.

Equipment Trends in Advanced Solid-Dosage Drug Manufacturing: INTERPHEX Keynote Part 1

Drug shortages have been an ongoing challenge that FDA and pharmaceutical manufacturers have been struggling to mitigate. The COVID-19 pandemic exacerbated the problem, with shutdowns and global trade disruptions combined with sudden demand for critical drug products. FDA’s report on drug shortages for calendar year 2020, however, says that the US government and manufacturers worked together to prevent 199 shortages (1). The Agency said that the requirements for early notification helped reduce problems (1).

Supply challenges in 2020 were global in nature, says Vincent Colicchio, vice-president, Supply Chain and External Manufacturing, at generic drug supplier Dr. Reddy's Laboratories. Consistent supply of APIs and some of the key starting materials for manufacturing APIs were particularly challenging for many pharma companies during the pandemic, he notes. Having adequate staffing for manufacturing operations, laboratories, and facility maintenance has been a challenge as well. 

 spoke with Colicchio about best practices regarding supply chain and workforce training and retention.

 From your perspective, what are the important aspects to preventing drug shortages?

 One key priority of the supply chain is to minimize drug shortages by procuring a higher volume of raw materials and packaging components to ensure that you always have sufficient safety stock to produce the required finished dosage form inventory. The recommendation—especially after applying the lessons learned from operating during the pandemic—is to procure three to four months of supply for APIs, critical excipients, and other key raw materials and packaging materials that carry long lead times. It is also important for the API manufacturers to have sufficient supplies of key starting materials to produce APIs on time for your supply. In addition, pharma companies will look toward producing sufficient finished dosage form products with two to four months of inventory on hand at their warehouse or 3PL [third-party logistics provider]. With key products, that inventory level may increase to three to four months on hand. And that is notable because, while other companies may be experiencing drug shortages, with a sufficient finished goods inventory, you will be able to not only serve your core business needs, but also strive towards fulfilling the incremental demand of any select product that is experiencing a drug shortage. 

Pharma manufacturers also need to maintain sufficient production capacity to produce the required inventory of finished dosage drug products. Production equipment must be maintained and be ready for continuous operation. The quality control (QC) unit needs to also ensure that the on-site and contract laboratories (if utilized) will have sufficient analytical equipment and capacity to meet the increased level of production output from the site. The QC unit requires the proper number of analysts and materials available at all times.

In addition, the regulatory affairs group needs to continue to track drug product shortages on the FDA website and to be in continuous communication with their FDA contacts to evaluate if there are any product shortages coming up on the horizon. Based on the FDA request, timely notification from regulatory affairs to the supply chain management unit is then required to determine which products need to be shipped to the market.

 Do you see any concerns in the pharmaceutical industry for having enough trained employees, in the QC lab or elsewhere? What are some best practices in ensuring that existing or new employees have the skills they need?

 Having enough trained QC personnel was a challenge even before the pandemic. It’s essential to ensure that the QC units are staffed with a sufficient workforce to test the normal production demand as well as being able to take on spikes in demand. In addition, there is a current shortage of skilled production operators. Pharma companies need to train operators to be proficient on the shop floor with the latest equipment and technologies. Traditional oral solid-dosage drug manufacturing requires conventional skill sets, but sterile injectable, transdermal, and inhalation drugs are more difficult to manufacture drug products due to the more complex production technologies. These types of products are produced with complicated equipment and require different kinds of skill sets.

Other challenges include recruiting and retaining capable facilities engineers and maintenance staff that are able to maintain the facilities, utilities, production equipment, and the grounds. There is a significant amount of competition for engineers and maintenance staff. The competition comes from other pharma companies as well as the growth of e-commerce businesses and the establishment of fulfillment centers.

It is important that you have a strong workforce that is well trained and can maintain the care of the facility for the current state as well as to position it for future growth. Workforce training is a dynamic requirement that impacts several groups to support or perform generic drug manufacturing, including manufacturing operations as well as cross-functional groups that play key roles, including packaging, engineering, technical services, maintenance, metrology, facilities, quality assurance, quality control, warehouse, distribution, etc.

Training in current good manufacturing practices (CGMP) is fundamental for all pharma manufacturing, including generic drug manufacturing. Other key training elements are in good documentation practices and in adherence to standard operating procedures (SOPs). Steadfast adherence to the SOPs and batch records will ensure consistency in execution of the manufacturing processes to ensure the patient’s safety and avoid product recalls in the market. Other workforce training areas include safety, health, and environmental training. We want to ensure that people are performing their jobs in a safe environment, and that they are always going to operate where they are free from potential injury or any physical stress that is created from the environment that they work in. Other items would be training in Drug Enforcement Administration (DEA) [protocols] for controlled substance production, materials management, and inventory control. There are specific procedures and restrictions in doing business with controlled substance products. In addition, it is particularly important that warehouse and logistics teams can warehouse and transport products utilizing proper warehousing procedures and good distribution practices to fulfill their responsibilities in the supply chain operation.

 What do you see as challenges in maintaining and improving facilities?

 One key challenge in maintaining and improving production facilities and processes is allocating the necessary level of capital expenditure investment for new or upgraded facilities and new production/process/analytical/utility equipment. A critical requirement is to consider the perspective of short-term and long-term benefits in addition to the return on investment. The investment should support the current operation along with meeting the strategic growth plans over the long term. Investments would also include maintaining the upkeep of the facilities and production areas. These investments need to be targeted to ensure that CGMP compliance requirements are always being met, productivity goals are achieved, and the production site is operating towards a sustainable basis with the growth framework in place. In addition, these investments should ideally help the site remain ‘audit-ready’ at all times.

Process changes would require collaboration between R&D, technical services, production, engineering, quality assurance, regulatory affairs, operations, safety, etc. to review and implement any changes to the process and production equipment or the introduction of new pharma manufacturing technologies. The key concern is making effective changes to the production process to ensure a tangible benefit to business.

 Do you see tangible benefits for digitalization in generic drug manufacturing?

 Yes, we have invested in digitalization for the overall business, particularly for integrated business planning systems. We aim to integrate supply data with business and operations systems to have ‘one version of the truth’ in place for demand forecasting and supply planning. From there we can digitize sales and operations planning, which offers benefits for long-term planning and capacity planning. Integrated digital systems are powerful in all aspects of supply and finance, and they can drive manufacturing activities, which can help prevent drug shortages. Ideally, we can identify potential supply gaps and plan to improve product supply to meet the needs of our customers and improve patient access for our products. Data analytics systems can also help improve process efficiency and operational agility.

www.fda.gov/drugs/drug-safety-and-availability/drug-shortages

Jennifer Markarian is manufacturing editor at 


Vol. 45, No. 11
November 2021
Pages: 30–32

When referring to this article, please cite it as J. Markarian, “Meeting Supply and Training Challenges,”

Best practices help mitigate generic drug shortages.

Meeting Supply and Training Challenges 

Cellectis, an international, clinical-stage gene editing company, recently opened a manufacturing facility in Raleigh, NC. The new, 82,000-ft

 good manufacturing practice (GMP) facility is purpose-built for manufacturing allogeneic, universal chimeric antigen receptor T-cell (UCART) immunotherapies for oncology. UCART products are manufactured using the T-cells of a healthy donor to make off-the-shelf and ready-to-use gene-edited CAR T-cells. T-cells from one donor, used in one manufacturing batch of UCART, can make hundreds of doses of product, the company reports. 

 GMP facility in Paris, France was opened in 2020 and makes clinical and commercial critical starting materials including plasma DNA, messenger RNA (mRNA), and viral vectors that are used in UCART manufacturing. The two facilities give the company end-to-end in-house manufacturing capabilities for GMP manufacturing of all critical starting materials and cell products for clinical studies and, eventually, commercial distribution. 

The newly opened facility in Raleigh, NC, includes ambient GMP warehousing and cold-storage space, cryogenic storage for incoming white blood cells and for final products, manufacturing spaces, quality control laboratories, utility and maintenance areas, and office areas. Two UCART manufacturing suites each hold a custom designed, four-chamber isolator that encloses all parts of the manufacturing process, including Cellectis’ proprietary electroporation system that enables its TALEN gene editing technology.

“The manufacturing process includes manual steps that operators perform through glove ports in the isolators, which create a Grade A environment,” explains Steve Doares, senior vice-president of US manufacturing and Raleigh site head at Cellectis. “UCART processing can’t use in-process or terminal filter sterilization, so we must maintain an aseptic state from beginning to end. Rather than putting the process equipment inside biosafety cabinets, we chose to completely enclose them in isolators to give the best possible assurance of product quality for the patient.”

A separate filling suite contains a single-chamber isolator with a robotic filling system. Vials are filled, inspected, labeled, and frozen under highly controlled conditions. Doares notes that the manufacturing process uses single-use systems, which he says are most suitable for the scale of this process.

“Having control over the entire development, manufacturing, and production process helps eliminate setbacks in the product development timeline that could hinder delivery of medicines to patients, which is an issue biotech companies have struggled with during the COVID-19 pandemic,” notes Doares.

A new GMP facility in Raleigh, NC, and a starting materials facility in Paris, France, give Cellectis end-to-end, in-house manufacturing capacity for its UCART product candidates.  

Cellectis Opens GMP Manufacturing Facility

In inhalation drug delivery, various milling and micronization processes have been used to manufacture particles for dry powder inhaler (DPI) and metered dose inhaler (MDI) drug–device combination products. The trend today, however, is an increasing use of engineered particles, such as those made by spray drying for DPI applications. 

 spoke with Carolyn Berg, vice-president, Inhalation and Carla Vozone, vice-president, Inhalation Strategy, Innovation, and Partnerships, at Catalent; Robin Heath, head of new product innovation and commercial management, and Peter Hirst, commercial vice-president, at Recipharm; and Sandy Munro, senior vice-president, pharmaceutical development, at Vectura. These contract development and manufacturing organization (CDMO) experts shared their perspective on trends and considerations for choosing and designing a drug delivery device.

Pharmaceutical Technology’s October 2021 APIs, Excipients, and Manufacturing eBook

Considerations for DPIs and MDIs in Inhalation Drug Delivery

APIs, Excipients, and Manufacturing eBook 

When referring to this article, please cite it as J. Markarian, “Considerations for DPIs and MDIs in Inhalation Drug Delivery,” 

Pharmaceutical Technology APIs, Excipients, and Manufacturing

Experts share best practices in designing, manufacturing, and scaling up dry powder inhaler and metered dose inhaler drug–device combination products for inhalation drug delivery. 

An ongoing engineering challenge for aseptic drug manufacturing is to reduce the risk of contamination as much as possible. As it is well known that human operators are the biggest source of contamination in a cleanroom, a growing consensus is that automated systems that eliminate human intervention are the future of aseptic processing. Pharmaceutical industry experts point to the successful use of both conventional and robotic automation in other industries, such as semiconductor manufacturing and aseptic food processing, as well as in pharmaceutical packaging and warehousing, as a sign that the pharma industry should overcome its reluctance to change. This shift has begun in fill/finish processes and is moving further upstream into other aseptic manufacturing steps. Robotic technology, in particular, is finding use in drug compounding (1) and in closed, gloveless isolators.

While conventional automation is suited for larger volume operations with simple motion and few changes, robotic automation technology designed for cleanrooms offers the ability to perform different types of operations and handle multiple formats, such as vials and syringes. Robots, which can perform the repetitive tasks otherwise handled by human operators, enable the move to closed systems that can operate without human intervention.

“Over the past 30 years, the equipment evolution has been from open and manual, [to] isolated and manual, then isolated and automated, and [now] closed and automated. In the next 5–10 years, more robotic solutions will come into the pharma production world throughout all segments, driven by new regulations, more personalized medicine, and more flexible machines,” predicts Rudolf Michael Weiss, global head of pharma robotics at Stäubli Robotics.

Regulatory authorities have expressed support for automation technologies as a means to limit aseptic interventions, notes Laura Moody, North American product manager at machine builder Syntegon Pharma Technology, pointing to as far back as FDA’s 2004 aseptic processing guidance (2) and to recent conferences. “Even as recently as the 2021 International Society for Pharmaceutical Engineering Aseptic Conference, the reduction in risk to the drug product through the use of automation and robotics was reiterated by FDA representatives,” says Moody. She says that acceptance by regulatory authorities and pharmaceutical manufacturers is helping drive innovations in robotics.

Operating multiple-product filling lines in accordance with the European Union’s draft Annex 1 (3) can be achieved with various technologies. One method is to use restricted access barrier systems (RABS) with fully automated, hydrogen peroxide decontamination of the entire cleanroom prior to each batch, says Arno Schroff, director of site and plant development at contract development and manufacturing organization, Vetter. Closed isolators are another increasingly important solution. “Our long-term vision is shifting from a human-centered production towards a fully automatic process with robotic equipment to further reduce possible risk to the product,” he notes.

“The biggest news from the past year is that FDA and Health Canada have approved commercial products made using gloveless robotic isolators. Several of our customers have achieved this milestone,” says John Harmer, head of sales and marketing, aseptic filling, at Cytiva, which acquired Vanrx, a manufacturer of robotic aseptic filling machines, in February 2021. “The industry has moved beyond ‘Will they work?’ to ‘Where else can we use them?’. Our prediction is that robotics will play an increasing role in manufacturing personalized medicines including mRNA, peptides, bacteriophages, CRISPR-Cas9, and other genomic therapies.”

Compared to conventional RABS or isolator-based filling systems, gloveless robotic isolators eliminate human intervention. “The sources of interventions have to be designed out and built around the capabilities of robotics,” says Harmer. “Because these systems are standardized, they can cut a year off the typical process of building filling capacity. Robotics handle vials, syringes, and cartridges the same way within presterilized tubs, so flexibility is built in for the small-volume, high-value drugs that currently fill biopharmaceutical pipelines.”

Syntegon’s new robotic fill/finish system, the Versynta FFP [Flexible Filling Platform], was introduced in mid-2021 and is designed for small batches of up to 3600 containers (vials, syringes, or cartridges) per hour. The company’s microBatch system, currently in development with Vetter, is an automated production cell with a gloveless isolator designed for even smaller batches of 120–500 containers per hour, says Moody. She notes that this system is currently in the detailed design phase and is expected to be launched in 2022.

Both solutions use robotics: while Versynta FFP uses a four-axis robot, developed by Syntegon, to transfer containers from one station to the next without glass-to-glass contact, Versynta microBatch is a fully automated production cell. It is designed for flexibility in the types of containers and closures that can be processed. “It allows for the container and closure of a drug product to be dictated by the needs of the drug and usage of the patient, not the limitations of the fill/finish machine,” comments Moody.

The gloveless isolator also eliminates the need for glove testing and glove management; features integrating air management, so that the isolator does not need a technical ceiling or interfaces to the building; and the design is standardized to allow quick delivery and validation, notes Moody.

Schroff adds that an automated de-bagging system for presterilized packaging components eliminates human intervention to prevent contamination of materials entering the isolator. Automated line set-up, monitoring, and fill-weigh checks for process control are other benefits, he notes.

The flexibility and rapid changeover required for fill/finish of small-batch parenteral drug products is better met by robotics than by traditional automation, agrees Joe Hoff, CEO of robotics manufacturer AST. Efficient cleaning, reliable sterilization, and high overall equipment effectiveness are other drivers for growth in demand of these systems, he adds. “The biggest challenges engineers face when designing isolated fill lines are fitting the design into a small, enclosed space; achieving good operator ergonomics; and ensuring all systems and penetrations are leak-tight and properly designed for cleanability and [hydrogen peroxide] sterilization,” says Hoff.

Although some may still hold the misconception that robotics can’t be used in cleanrooms because moving parts may generate non-viable particulates, this concern has already been resolved, suppliers say. Robotic suppliers point out that robots for pharmaceutical cleanrooms have a hygienic design for low particulate generation and resistance to standard cleaning chemicals. They can also be designed to be resistant to hydrogen peroxide so they can withstand frequent decontamination.

Another aspect of design is planning for changing parts and performing maintenance. Xavier Gómez Garcia, lyophilization portfolio manager at pharma equipment and engineering supplier Telstar, points out that haptic interfaces allow users to remotely manipulate a robot. “Some of these devices allow the user to also feel the weight of the real object, even without physically touching it. The precision is extremely high. [Systems could have a] built-in feature to change format parts and do basic maintenance through telematic [remotely operated] haptic devices, without the need of glove ports or operators near the process zone,” suggests Garcia.

Software for improving robotic motion continues to be improved. “The robot is embedded into the [information technology (IT)] structure of the machine, and new software features like tele-manipulation, remote joystick fault intervention, and [motion controls such as] anti-sloshing movements, for example, need to be developed,” says Weiss. He notes that Stäubli is currently developing specific pharma software features suited to robotics inside isolators.

In addition to lowering the risk of contamination, robots increase predictability. Compared to robots, humans can have difficulty being consistent with repetitive tasks requiring precision and accuracy, suggests Toni Manzano, cofounder and CSO of Aizon, a pharma/biopharma software as a service provider and co-chair of the Parenteral Drug Association’s first Robotics and Automation conference held in April 2021.

While people need to be trained and periodically retrained—and it can be challenging to duplicate a process in multiple locations—robots are trained once and have the same precision no matter what the time, day, or location, adds Martin Düblin, managing director of consultancy One One Eleven GmbH and co-chair of the PDA conference with Manzano. High levels of standardization across multiple facilities simplifies operation and inspection.

Another benefit of robotics is easier qualification, says Alex Armengol, international senior sales director for SP i-Dositecno fill-finish products and SP Industries’ global leadership team member. He explains that a performance qualification protocol tests whether the aseptic manufacturing procedures are adequate to prevent contamination during actual drug production—via process simulations or media fills using a sterile microbiological growth medium—and replicate organism detection and counting (RODAC) surface-contact testing. Robots will require less RODAC testing because of their controlled movement. “The behavior and movement of personnel is difficult to control. Everyone behaves differently and often randomly,” explains Armengol. “The methodical and controlled movement of robots within the aseptic processing area are key to providing a predictable quality environment. [In addition,] one robot can typically cover many critical areas within the aseptic processing space.”

IT systems are increasingly intertwined with operational technology systems in modern manufacturing systems; control signals are sent to the machine, and the machine sends data to higher-level systems, such as supervisory control and data acquisition systems. In addition to machine data, data from process analytical technology (PAT) tools, used in automated systems, can improve quality and efficiency. In-process control (IPC) check-weighing in an automated filling system is one example, notes Armengol. Conventionally, check-weighing was a destructive test, but using the PAT tool of IPC, each container is weighed and no product is lost. “In this method, [empty] containers are placed on an in-process balance or load system, and the exact amount of product is dispensed and checked against the specification. Over a period of time, if the controller senses any changes to the fill weight, the system will adjust the pump appropriately,” he explains. Additionally, artificial intelligence (AI) algorithms can use data to predict machine behavior and potential failure points, adds Armengol. AI can identify process deviations, and decisions can be made in real time to reject or accept products.

These data can also be used by process experts. For example, Harmer says, “If the filling system contributes to a consistent stream of data about a customer’s manufacturing process, we have better evidence to optimize processes or improve drug product quality.”

Today’s machines are highly integrated into IT systems for sharing data such as batch records or for allowing remote viewing of machine performance or remote maintenance, but machines in the future will advance into intelligent feedback and even predictive maintenance, suggests Hoff.

Using AI in “smart” systems, set up to make decisions based on input from the process and algorithms derived from process knowledge, will increasingly play a role in automation systems.

“Smart systems, understood as the interaction between machines and AI, are able to repeat tasks consistently and, if they are well trained, make the right decisions in a systematic way,” explains Manzano.

A concern about how regulatory authorities will accept critical decisions being made by automated systems rather than human operators is creating hesitancy in pharma manufacturing. Other regulated industries, as diverse as banking and food manufacturing, have adopted fully automated mechanisms managed by AI, notes Manzano. One example of AI being adopted in pharma manufacturing is smart systems for feeding raw materials. He says that questions such as: “How do I proceed if a lot of raw material is finished in the middle of the mixing operation? Can I add a lot of the same substance from another supplier?” are examples of unusual situation that can be properly managed by AI connected to an automated system.

Handling of these types of questions would need to be validated, adds Düblin, who notes that a lack of experience by regulatory authorities is currently a limitation. Internal company inspectors also need to gain experience and confidence in smart systems.

Another area that has been tested and found to be successful is automated inspection of pharmaceutical finished products, managed by AI.

“AI has demonstrated a high value and a consistent response in complex tasks, including defect identification, deviation detection, multivariable control, and chained actions based on different scenarios, for example,” says Manzano. Good data that are digital and not managed in silos, but rather collected via the Internet of Things and managed via cloud technologies, are crucial for accurate AI results, he cautions.

“The way forward is to consider the whole process; digitalization yields the data needed to train robots or automated systems,” agrees Düblin.

Training is an essential aspect of good manufacturing practices (GMP) in the pharmaceutical industry. “Training and retraining are one of the foundational core activities that regulatory agencies often review during inspections to ensure that ongoing training is provided to key personnel so that they can demonstrate process knowledge and their ability to adhere to routine standard operating procedures,” notes Armengol. Control systems for robotics are complex systems, and training is crucial for operating and maintaining these systems. “Automation and control are key to successful implementation of robotics, including the understanding of the mechanics and electronics involved in making the robots function as intended,” says Armengol. “Key to the training is the interface between the machine and the operator, known as the human machine interface or graphical user interface.”

Armengol suggests that hands-on training is critical for these systems. SP i-Dositecno is currently installing a modular robotic filling line and isolation system at the National Institute for Bioprocessing Research and Training (NIBRT) in Dublin, Ireland, which will be used in NIBRT’s aseptic biopharmaceutical fill/finish training.

Harmer points out that for automated systems, operators do not need to be trained in aseptic technique, as they do in conventional systems. Instead, training focuses on the workcell’s integration of robotics and the closed isolator. “In Cytiva’s training, users learn how the aseptic process automation works, how to create recipe-driven processes for specific drug products, and how the machine controls risk at each stage of the aseptic filling process,” he explains.

He adds that standardization of gloveless isolators means that improvements developed by one user can be made available for other users. “Cytiva’s aseptic filling business has an active user group that collaborates on training, regulatory strategies, and environmental monitoring approaches. This group suggests design and software improvements, which can be implemented during preventative maintenance of the filling machine,” he explains. 

Despite the benefits of automation and the inevitable use of automation in facilities of the future, there are multiple barriers to upgrading existing facilities with new, automated lines, including the need to revalidate and the initial investment cost. Armengol notes that for small- and some medium-size companies, this cost barrier may be difficult to overcome.

Although industries such as semiconductors had a strong business case to automate because of their narrow profit margins, biopharma, with its higher profit margins, has less incentive to change, suggests Manzano. On the other hand, says Düblin, recalls and batch losses are costly, so a business case for automation can be made.

“Roadblocks to modernizing a fill/finish cleanroom are regulatory, cost, capacity, and time,” agrees Hoff. “Unless a facility has an unused or available fill suite they can expand into while maintaining their existing fill suite, it is unlikely they have the time or capacity to shut down a validated and qualified process to modernize.”

In addition, the design of existing facilities and equipment may not be conducive to automation. “Retrofitting within an existing machine is usually difficult due to the lack of space and freedom of movement for the robot,” notes Moody. One option is to automate the secondary processes, such as the supply of packaging materials, around the existing machine, she suggests.

Autonomous mobile robots and automatic guided vehicles for transporting materials are an example of automation that can be applied to existing processes, agrees Weiss.

Another challenge is the reluctance to replace humans with robots. The lockdown restrictions of the COVID-19 pandemic that created worker shortages have made the consistent availability of robots more appealing, but the concept of this change in work still creates hesitancy. Although it is true that implementing automation will eliminate certain types of jobs, it will create some others that need different skills, says Düblin. Not wanting to change operators’ jobs shouldn’t override the benefits brought by digitalization and automation. “It is the responsibility of enterprises to adapt,” he asserts.

Despite some barriers to use, the advantages of and continued improvement in robotic automation will drive continued implementation in aseptic processing, experts agree.

“To date, the strength of robots is primarily in performing repetitive tasks, and [robots] have so far been less suitable for constantly changing ones. But a lot is happening in this area right now,” says Moody. “The limits will continue to shift due to new technologies such as AI and reduced costs for robotic solutions. Going forward, we will be able to equip all areas needed for the operation of a filling machine with robotics. Examples of future robot applications include upgrading the filling path or inserting and changing sediment plates for microbiological monitoring.”

“Robots will become mainstream [in pharma manufacturing] within the next few years because of enhanced flexibility, repeatability, and precision,” adds Armengol.

Garcia suggests that the pending publication of Annex I is driving demand for plant retrofits. “New regulations are clearly accelerating the change in the pharmaceutical industry, encouraging both drug companies and equipment manufacturers to embrace new technologies that can minimize the risk of contamination for the final product. Annex I is pushing the industry towards automatization, [particularly] in critical processing zones, including all the operations in primary packaging, filling, and capping, [which generally have] freeze dryers in between,” says Garcia. He notes that new, automated loading and unloading modules for freeze dryers and autonomous filling and capping stations that incorporate PAT tools are being used.

“In the past 25 years, primary packaging lines have evolved from dozens of manual operations, typically through glove ports, to fully automated lines. Until now, automation has been quite rigid to fulfill high production volumes in centralized manufacturing plants,” notes Garcia. The growing need for sterile manufacturing of smaller batches, however, is driving growth of more flexible robotic automation. “In my opinion, companies with centralized factories will work together with new and flexible plants where GMP robots will play a crucial role. Local manufacturing hubs with an agile supply chain will be a vital asset,” he predicts.

Sterile Drug Products Produced by Aseptic Processing–Current Good Manufacturing Practice Guidance for Industry

Draft Revision to Annex 1, Manufacture of Sterile Medicinal Products

Jennifer Markarian is manufacturing editor of 


Vol. 45, No. 10
October 2021
Pages: 16–21

When referring to this article, please cite it as J. Markarian, “Automating Aseptic Manufacturing,” 

Conventional and robotic automation inside closed systems reduces risk. 

Automating Aseptic Manufacturing

Continuous manufacturing (CM) has the potential to create higher quality drug substances and drug products, with greater flexibility in batch size and with a smaller facility footprint. The definition of what pharmaceutical manufacturers and regulators consider a “continuous process” is broad. The International Council for Harmonisation (ICH) Q13 draft guidance, which was released for public consultation July 27, 2021, gives examples of three concepts of CM: a combination or hybrid approach in which some unit operations run in batch mode while others are connected and run in a continuous manner; a process that makes either a drug substance or a drug product, with all unit operations integrated and running continuously; and an approach that connects both drug substance and drug product, in an end-to-end continuous process (1). The industry is making advances in all these methods, even the fully end-to-end system, with Continuus Pharmaceuticals receiving US-government funding in January 2021 to bring the company’s Integrated Continuous Manufacturing technology to commercial scale (2).

Processes that are integrated to run continuously, from powder to tablet, have now been running commercially for more than five years, with the first oral solid-dosage drug made using continuous processing approved by FDA in 2015 (3). Since then, drug manufacturers, equipment suppliers, contract development and manufacturing organizations (CDMOs), and consortiums of industry and academia have continued to innovate solutions to challenges such as equipment cleanability and better control of raw material feeders.

Commercially available CM equipment lines include entire systems as well as specific unit operations. GEA, for example, announced in June 2020 that it is making its well-established ConsiGma portfolio of CM equipment more accessible by allowing integration with third-party equipment and by defining ConsiGma 4.0 modules for individual unit operations (4). Standardized “off-the-shelf” elements also make CM equipment more affordable for a wider range of users.

Modular CM equipment is available from multiple suppliers. Glatt’s MODCOS modular platform offers continuous processing beginning with powder feeding of API and excipients through coated tablets, with the addition of the Driam continuous Driaconti-T system for tablet coating added in 2018 (5).

L.B. Bohle offers CM equipment for a range of unit operations, including direct compression equipment, the QbCon WG continuous wet granulator and dryer, and a fully continuous (from powder to coated tablet) QbCon plant.

“Continuous wet granulation, drying, and milling equipment is already producing marketed products in Germany,” reports Robin Meier, manager of scientific operations at L.B. Bohle GmbH. “We also currently have a complete [powder to coated tablet] system being built right now, with factory acceptance testing planned for 2022.”

Meier suggests that, especially for companies with limited personnel resources, adopting a wet granulation process, from powder to milled granules, can be a good starting point for using CM and can be used to demonstrate the benefits of CM to stakeholders. “[Wet granulation] is easily controllable; it can be adopted quickly from already existing high-shear granulation processes and formulations, and [the company] can generate their first experience in continuous production.”

For example, Meier says that Bohle worked closely with a large German manufacturer of generic drug products to adapt a high-shear batch granulation process to continuous wet granulation and drying. The manufacturer was able to make product for the market within a few months after factory acceptance testing, says Meier. 

When a CM process is up and running, in-line quality control measurements and process control systems with feedback loops can reduce the amount of out-of-specification product and improve quality. Training operators to understand the differences between batch and CM operation is one challenge. “One has to get used to the fact that most quality control of intermediate is running in-line or at-line, and that stopping a running CM line should be [avoided]. Sometimes it is better to discharge a few-hundred grams of product, [rather than] an intermediate stop of the whole line,” notes Meier.

How materials are fed into the process is another significant difference between batch and continuous processes. In CM, loss-in-weight twin-screw feeders can be used to accurately dose raw materials as a continuous feedstream. “In a loss-in-weight feeder, the amount of weight lost is measured by means of a scale and sent back to the controller, which adjusts the speed of the screws to maintain a constant mass flow output,” explains Sharon Nowak, business development manager at Coperion K-Tron for Food & Pharmaceutical Industries.

Feeder designs are engineered to fit a process. “Since a variety of screw configurations exist that can also affect the amount of material per revolution of the screw, a variety of residence time distribution (RTD) models have been developed to look at overall feeder configuration (e.g., hopper size, type of screw, and screw speed) in order to predict the flow properties of different materials within the feeder and properly size the feeder,” says Nowak.

“The accuracy of feed is very much dependent upon screw fill,” continues Nowak. “Therefore, it is imperative that the material not only flow within the feeder hopper but also be entrained by the screws,” she explains. A challenge, however, is that some APIs and excipients do not flow easily and can be held up in the feed hopper. Developments in more flowable or coprocessed ingredients are one way to relieve flow issues, and equipment solutions are another.

Coperion K-Tron’s “smart” vibration device, the ActiFlow, monitors the loss-in-weight signal on the feeder controller; if there is an interruption in material flow, a vibration device is activated on the feed hopper to restart flow. “More importantly, this device is tied directly into the feeder’s control system and learns at what point in the process the material tends to bridge (due to changes in the feeder screw speed or feed factors). The ActiFlow proactively starts before the problem even occurs, and then it backs off on the vibration when the loss-in-weight signal is back in specification,” explains Nowak.

Equipment providers continue to improve digital load cell and feeder controls technology. For example, Coperion K-Tron’s newest load cells, combined with the company’s new KCM-III controller, have increased resolution to allow faster reaction time, which improves accuracy, especially at low feed rates and during setpoint changes or after a refill, says Nowak. “The refill reaction time is critical to maintaining overall accuracy in the continuous process,” she notes. The newest version of the controller also increases processing power and data storage capacity. These features are important for traceability and for tracking data trends. In the future, Nowak says, accelerometers could be used within the control system to accurately measure vibration and effects on feeder output, thus further increasing accuracy of control systems.

Another consideration for CM feeders is that users need equipment for very small feed rates, in the range of 10–100 g/h, as well as feeders designed for feed rates higher than 25–50 kg/h, says Nowak. “Coperion K-Tron has developed specific modular design feeders to handle a wider range of feed rate profiles. The use of specialty servo motors, for example, has widened the screw speed ranges available, with much higher turndowns, thus eliminating the requirements for changing gearboxes when higher or lower rate ranges are required.”

While this design allows higher rate ranges without a gearbox change, Nowak notes that the company’s QT model of feeders also uses a modular design, which is another advance that can facilitate quick changeovers in equipment. The overall designs, which include an option for quick roll-out frames on rails, have improved accessibility, added versatility, and minimized downtime, says Nowak.

“The QT model was specifically designed because of polling many of our key customers who were currently working in continuous processing, including continuous direct compression, continuous extrusion and granulation, and continuous coating,” says Nowak. “The new QT includes interchangeable modules that can be completely removed from the feeder motor/gearbox to change from one model to another. This allows the operator to easily remove everything in contact with the product in a few seconds and replace with either a new module or a different feeder model.” 

Quick-change designs are also helpful for improving cleanability, which is a key area targeted for improvement by those involved in CM. Nowak says that Coperion KTron’s new designs have improved connections upstream and downstream of the feeder; fewer parts make assembly easier and faster. “Turntables and rails allow the feeder to be rolled back and turned 90 degrees from the feeder ‘cluster’, thus making access to change-out screws or perform other maintenance much easier,” says Nowak. “The feeder is also automatically pitched 2 degrees for drainage to allow for quick wash-in-place operations.”

Integration is another challenge for continuous processes, particularly when connecting equipment from different original equipment manufacturers (OEMs) for different pieces. “Many end users wish to remain with their existing, known unit technology,” says Nowak, so communication between the unit operations is key. Nowak notes that, increasingly, OEMs and drug manufacturers are using OPC-UA as a common language. To make sure communication is clear and that the required parameters can be transmitted, Coperion K-Tron has partnered with several continuous systems integrators, such as Continua Process Systems, to ensure that communication and data collection of the complete process is seamless, says Nowak. The company’s KCM-III controller is equipped with communication cards and options for multiple protocols (e.g., Ethernet, Modbus, OPC-UA) so communication and integration into the overall process is maintained, she notes.

Another area where innovations are expected to continue is in process analytical technology (PAT) tools. Newer and better sensors that are faster and more precise are driving evolution in PAT, said Fernando Muzzio, in an interview with 

 (6). PAT is a crucial part of enabling in-line process control in continuous manufacturing, and companies are working on further developments in using PAT for quality control, including real-time release. Process modeling is a key part of developing real-time quality control, said Muzzio. For example, residence time distribution models are being explored for use in predicting content uniformity in the final blend and finished product as a function of measured perturbations of ingredients coming into the line.

Partnerships between industry, automation solutions providers, and academia will help the ongoing progress in PAT, added Bikash Chatterjee, CEO of Pharmatech Associates, a USP company, in an interview with 

 (6). “We are in an asymptotic rise in terms of our ability to understand what’s happening in our processes. We need to now extend that out of the lab and put it on the shop floor, so that we are making product that we know is consistently good. That’s going to benefit everyone, not just patients but manufacturers as well,” said Chatterjee.

Innovations, such as these equipment improvements along with developments in control systems and materials, will assist solid-dosage drug manufacturers—from branded to over-the-counter and generic drugs—as they move ahead with adoption of continuous processes.

Continuous Manufacturing of Drug Substances and Drug Products Q13, Draft Version,

Building Up End-to-End Continuous Manufacturing

Vertex Pharmaceuticals, “FDA Approves Orkambi,” Press Release, July 2, 2015.

GEA Aims to Expand Access to Continuous Manufacturing with ConsiGma 4.0

Glatt, “Glatt and Driam Decided to Cooperate,” Press Release, June 30, 2018.

PharmTech Editors, “Advanced Solid-Dosage Drug Manufacturing with Continuous Processing Approaches,” Virtual Technology Forum (Sept. 15, 2021).

Jennifer Markarian is manufacturing editor at


Vol. 45, No. 10
October 2021
Pages: 34–37

When referring to this article, please cite it as J. Markarian, “Adopting Continuous Manufacturing for Solid-Dose Drug Products,” 

Evolving equipment designs meet the unique needs of continuous processing techniques.