 Anniversary issue, which will be published in July, the editors interviewed industry experts about the biggest changes the industry has seen in the past 40 years and what they foresee for the future. The trend toward specialized medicines focused on smaller patient populations is leading to smaller production batches and a greater need for flexibility in manufacturing equipment and systems, says Bernd Stauss, senior vice-president of Pharmaceutical Production/Engineering at Vetter Pharma-Fertigung. The increase in highly potent drugs is another driver for equipment advances, notes Christian Treitel, director, Business Development Pharma, Bosch Packaging Technology.

 spoke with Stauss and Treitel about developments in parenteral manufacturing and fill/finish.

 What have been the most significant changes in parenteral pharmaceutical manufacturing and fill/finish in the past 40 years?

 In the past 40 years, we have seen significant increases in automation and the use of barrier systems like restricted access barrier systems (RABS), closed RABS, and isolators. More complex processes can be managed, product quality has improved, and operating costs have been reduced. A wider variety of packaging styles-ready-to-fill syringes and, recently, vials and cartridges-and flexible machine platforms offer pharmaceutical manufacturers the flexibility for different products and requirements. Pharmaceutical manufacturers also more often require 100% in-process checkweighing to prevent product loss of expensive drugs.

 The primary development in parenteral pharmaceutical manufacturing we have experienced over the past 40 years has been the continuous improvement in the quality of the drug manufacturing process. This has had an impact on the entire bio/pharmaceutical industry supply chain. Over this time period, automation grew rapidly and continues to do so today. At Vetter, for example, the use of robots in the production process had already begun by the 1990s.

	From a technological aspect, single-use technology is an emerging trend in the fill-and-finish segment, primarily in the early phases of a drug-development project. A large part of the industry, however, does not believe that single-use equipment will replace stainless-steel technology as a whole. Nevertheless, single-use technology offers a valuable option within special fields of the production process. In our experience, both technologies have their individual pros and cons.

	Today, we see two specific leading cleanroom technologies on the market: RABS technology and isolators. RABS achieves the sterility assurance level (SAL) required by regulatory authorities and allows for rapid product changeover along with high safety. To better meet future industry trends in quality, safety, and flexibility, combining the advantages of both isolator and RABS technology appears to have promising potential for a contract development and manufacturing organization like Vetter. An improved RABS concept, called Vetter CleanRoom Technology (V-CRT), achieves fast and fully-automated decontamination of the cleanroom using hydrogen peroxide.

 What trends or new developments do you foresee for the near future?

 One of the primary developments we see is the increase in the overall complexity of individual drug substances which, in turn, affects all parties along the supply chain that are involved in the handling and processing of these substances. Expectations for quality are high, with customers demanding a significant level of oversight.

	Patients are asking for innovative drug-delivery systems that fit better with the ‘mobile lifestyle’ of today. Having access to those systems supports their individual acceptance and compliance. Large areas of the developed world are experiencing growth in aged populations, which has resulted in an increase of associated diseases. As they can often be treated in private settings, there has been an impact on the homecare sector, thus creating a need for appropriate devices, such as pens and autoinjectors. Finally, we have experienced an increase in topics such as digitalization.

 In order to further reduce or avoid human interventions, there will be fully automated production lines with the use of robotics. Connected industry solutions will bring more intelligence into production. These technologies will help achieve higher productivity, safety, and efficiency.

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The need for flexibility and higher quality are driving advances in parenteral manufacturing and fill/finish equipment. 

Looking at Trends in Parenteral Manufacturing

	The population of robots working on parenteral fill/finish lines is increasing rapidly. The expansion mirrors growth in biotech products, particularly self-injected therapies, which require autoinjectors that can deliver a safe, effective, and consistent experience. Robotic systems excel at maintaining aseptic conditions and protecting operators from toxic substances. In fact, Comecer Group has offered robot-equipped systems to handle radiopharmaceuticals for more than a decade.

	Robots not only provide precise, consistent handling, but also offer a high level of flexibility so systems can accommodate a wider range of containers and components with minimal or no change parts. “Flexibility is crucial for high-value, relatively low-volume products,” says Eric Petz, senior marketing manager at Vanrx Pharmasystems. “Batches are smaller, so you can’t have long changeover and startup times,” he explains.

	Robots also can reduce or eliminate glass-to-glass and glass-to-metal contact, which are major causes of container failure. But the most important benefit robots provide is improved quality due to minimization or elimination of human intervention, the biggest source of product contamination. To prevent contamination, regulatory agencies worldwide are looking for less human intervention, and original equipment manufacturers (OEMs) are working on ways to remove operators from the process. “It’s all about risk mitigation,” says Simon Cote, principal engineer, Technical Customer Support at West Pharmaceutical Services. In fact, “I would be highly surprised if the industry doesn’t incorporate more robots,” he says.

	West Pharmaceutical Services is adding a robotic system to its equipment lineup with the purchase of a dual-robot, customized KCP 5060 Flexible Filling system from Bausch + Stroebel Machine Co. The base model, which was shown at INTERPHEX 2017, features cleanroom-compatible robots that reach upward to perform their tasks. Mounting the robots below the containers maintains sterile laminar air flow across product-contact surfaces, protecting product from potential contamination. Capable of handling vials, cartridges, or syringes in bulk or nested format, the system is equipped with four processing stations to perform filling, closing, sealing, and inspection. The system is compatible with vaporized hydrogen peroxide (VHP) for decontamination of the work area including the robots. The compact machine, which occupies less than 14 feet of linear space, operates at speeds up to 1200 units per hour, a rate particularly well-suited for self-therapy products. Container size ranges include vials from 16–52 mm in diameter with heights up to 94.5 mm, syringes from 0.5–20 mL, and cartridges from 6–14 mm in diameter with heights from 40–90 mm. 

	Biotech products have been a driving force behind robot-equipped fill/finish systems. When the founders of Vanrx Pharmasystems couldn’t find a filler for small volumes with sufficient flexibility, they studied automation. Inspired by the use of robotics in the semiconductor industry, they began designing a robotic fill/finish system from the ground up. The resulting machine needs no glove ports, relies on ready-to-use containers and closures, and eliminates aluminum crimp caps, a common source of particulate contamination. “There’s no intervention the robots can’t perform,” explains Petz. “All sources of jams have been eliminated,” he adds.

	Because containers never leave the nest, there’s no potentially damaging container-to-container contact. Press-fit closures, also supplied in nests, streamline the capping and lyophilization process. In addition, Petz says, “Conventional [parenteral] filling lines are generally custom-designed. This one is standard and scalable.” Designed to be deployed worldwide, the standardized system simplifies validation and standard operating procedures. Scalability shortens time to market and maximizes the patent protection period for brand owners.  

	The Vanrx system performs filling and closing with nested groups of containers and closures. An operator loads nests into the carousel and closes the door. At the conclusion of a vapor hydrogen peroxide sterilization treatment, the chamber is aerated, and Tyvek lidstock is removed from the nests. Containers are filled and closed and shuttled back to the carousel.

	Vanrx has installed systems at two contract manufacturing organizations, Singota Solutions and AB BioTechnologies. “Two more systems will be installed in the United States this year,” reports Petz. He predicts, “It’s a technology that is going to be widely adopted. We’re seeing a wide uptake.”

	Lines from Luciano Packaging Technologies also demonstrate the advantages robots can bring to fill/finish operations. In one example, robots transfer product and load preformed pouches. “The ability to manipulate and transfer uniquely and/or irregularly shaped syringe products … significantly decreases the complexity of the mechanism required for manipulations like inverting, placing, and spacing … while maintaining a high degree of orientation and control,” says Larry Luciano, president of Luciano Packaging. “The robots also provide the ability to re-direct product into alternate paths.”  

	Other OEMs, including M&O Perry Industries, ESS Technologies, Marchesini Group, and MG America, offer robotic fill/finish systems. The NSF nested syringe filler from M&O Perry Industries features a Yamaha robot. Capable of filling powders, liquids, or powders and liquids, the system also can handle vials. The robot controls powder filling and achieves speeds up to 40 units per minute. Higher speeds are possible by adding fill needles.

	The Model SF20 TaskMate robotic aseptic syringe filling and capping system from ESS Technologies integrates a FANUC robotic cell with an OEM-supplied restricted access barrier system. A FANUC LR200iD clean class robot receives syringes from a flexible feeder and uses vision and a mechanical gripper to pick the syringe and place it on the filling station. The second FANUC LR Mate 200iD robot picks a cap from the tray and places it into the torque station. A servo-driven pick-and-place unit transfers the syringe from the fill station to the torque station. Capped syringes descend a divided chute to a discharge/reject bin. Fills range from 50 µL–60 mL at speeds up to 15 syringes per minute. The machine also can handle vials and various cap styles. Changeover generally can be accomplished in less than 15 minutes.

Marchesini’s Extrafill syringe filling and stoppering machine features a robotic de-lidding station, monobloc design, and two tub opening and syringe filling/stoppering stations. Up to three more stoppering stations can be added to boost output to 12,000 syringes per hour. Dosing range is 0.1–50 mL.  

	The Steriline RVFCM50 filling and capping machine, supplied in the US by MG America, handles vial sizes from 2 mL–100 mL without changing format parts. Rated at up to 3000 vials per hour, the system can be integrated with an RA-V4 rotary vial washer, ST2 CCS depyrogenation tunnel, and EDM-C external decontaminating machine.  

	Robotic inspection and packaging systems

	Beyond the fill/finish operation, robotics play a role in inspection and secondary packaging of parenteral products. Robotic inspection systems can overcome problems with limited floor space. “A typical, commercially available manual inspection line for two operators that includes automatic de-nesting and re-nesting is a linear line using three machines for the primary operations and is in the order of 40 feet long,” explains Luciano. “The LPT robot cell [HPI-30M nested syringe inspection machine] is only 10 feet long because the robot is able to perform multiple operations-de-nesting, syringe presentation for flange inspection/rejection, and labeling path transfer or re-nesting. In this case, the robot is picking five syringes from the Hypak that supports a matrix of 10 staggered rows of 10 syringes per row. And since there is extra spacing between each tub, there are four different pick positions and 12 different re-nesting positions, so you can see how the programmable flexibility of the robot (in combination with a servo-indexing Hypak conveyor) is helpful in reducing mechanical complexity.” If higher speeds are needed, manual inspection can be replaced by automated vision systems, and a second robot can be added for discharging.

	An example of a robot-equipped line for secondary packaging functions was shown by Marchesini Group at CIPM Qingdao (April 19–21, 2017, Qingdao, China). The customizable line integrates a deep-draw FBZ 320 thermoformer with a continuous-motion BA 400 Argento cartoner (see Figure 1). Operating at up to 240 cartons per minute, the system thermoforms trays, loads syringes and vials, and cartons filled trays. A centerpiece of the thermoformer is a four-axis Robomaster system. Positioned between the forming and sealing stations, it picks syringes or vials and places them into trays. Infeed options include plug-in belts and vibrating tables.

	Many robot providers offer cleanroom models compatible with hydrogen peroxide sterilization for parenteral fill/finish applications. When designing robotic equipment, the first consideration is whether a robot is the best option. “You don’t want to use robots where simple mechanics could accomplish the task,” says Massimiliano Cesarini, global sales manager, Isolation Technology Division at Comecer.

	A primary consideration when specifying a robotic fill/finish system is speed. “Robot lines are typically slower,” says Gregor Deutschle, business development manager at Schott North America. Batch size is another consideration. Shorter runs mean more frequent changeover. “Robots eliminate a lot of change parts and star wheels,” notes Deutschle.

	Robots also replace traditional container handling mechanisms. “Eliminating turntables and infeed belts definitely helps reduce glass-to-glass contact,” he adds. As a result, robots can provide gentler handling and may be especially well-suited for polymer containers, which scratch easily.

	End-of-arm tooling (grippers or end effectors) must be carefully designed to optimize handling. Factors to consider include weight, which directly impacts speed, and arrangement of pneumatic and vacuum lines and sensor wires so performance is not impacted by movement of the arm. The end effector also must handle the product without marring or other damage. Vacuum is a common choice, but may not work with all surface areas and product orientations. Nevertheless, “Vacuum is usually the gentlest,” says Luciano. However, vacuum may not provide enough support for the container(s). In that case, a rigid guide may need to be added.  

	Finally, programmability must be considered. Many of today’s robots do not rely on proprietary programming languages, but can be easily programmed from a library of functions or by simply moving the arm through the path it needs to take.   

	When referring to this article, please cite it as H. Forcinio, " Robots Package Parenteral Products," 

Robotic fill/finish systems reduce human intervention, improve flexibility, and allow more gentle handling of containers.

Robots Package Parenteral Products

	With the November 2017 deadline for the Drug Supply Chain Security Act (DSCSA) looming, US pharmaceutical manufacturers, contract manufacturing organizations, and contract packaging organizations are getting their serialization solutions ready and validated. Few, however, are as concerned with what happens next. While widespread track-and-trace adoption will help mitigate many longstanding problems-counterfeiting, supply chain security, pinpointing recalls-it will create issues well beyond the immediate hassles of infrastructure investment, implementation, and validation. Most prominent is loss in production line efficiency. As manufacturers continue to outfit and upgrade packaging machinery to comply with regulations, the extra steps in serialization (and aggregation) will bring an unwelcome 5–10% reduction in overall equipment effectiveness (OEE), as experienced by early adopter countries such as Turkey. Some companies have seen decreases of 20–30%.

	The good news is that with serialization incorporation, any process causing an initial slowdown can produce data that, when properly interpreted, can reveal a roadmap to restoring OEE to pre-track and trace levels, or even higher. Data generated by serialization compliance can be parlayed into guideposts for improving production practices. The metrics are there for the mining, allowing manufacturers to track and trace their operations along with their pharmaceutical products with exceptional granularity.

	Serialization implementation and the data mining it affords are the first vital steps toward transforming pharma production facilities into digital factories whose foundations are built on web-enabled and data-driven technologies. Its advantages touch every aspect of manufacturing, including enterprise-wide resource allocation, asset tagging, and real-time inventory and personnel tracking.

	Tomorrow’s digital factories can use a three-tiered digital transformation process to successfully deliver the promise of smart manufacturing, or Industry 4.0. The race is on for manufacturers to optimize production practices by navigating from data to dashboards to decisions. In doing so, they will apply mined information toward comprehensive yet digestible operational feedback that, in turn, leads to logical adjustments for improved production practices. The three “D”s of this process are described as follows:

 Unique unit-level serial numbers for enhanced supply-chain product visibility are only the beginning. Emerging Internet of Things technologies, such as wireless sensors and gateways, offer opportunities to enhance datasets collected by traditional "transaction-based" systems such as enterprise-resource planning, manufacturing execution systems, and warehouse management systems. Additional environmental and location-based data can tremendously enrich previously untapped metrics with unprecedented granularity.  

. Dashboards convert raw data into actionable insights through business and management platforms, made available to personnel throughout an organization depending on their specific roles. For example, managers could access live dashboards showing all production lines, and view preconfigured reports showcasing exceptions, trends, and downtimes in detail. Undesirable situations can be addressed faster and more effectively. Conversely, optimum outcomes are identified so that ideal conditions can be replicated. 

. Data and dashboards are used for critical resourcing and prioritization decisions. For example, scheduling work orders on shop floors using real-time data and historical trends can significantly improve resource utilization and overtime/waste reduction, while increasing capacity and throughput. 

	Replacing manual or paper-based tracking with a digital tracking system improves operational visibility and allows identification of procedure-driven activities that show significant variability in duration so that managers can identify areas for improvement. Such systems can also help allocate personnel more efficiently, in real time. More fundamental performance improvement can use digital tracking of shop floor activities to create a more robust scheduling process. Digital tracking can thus improve management of operations.

	Evren Ozkaya, PhD, is founder and CEO of Supply Chain Wizard, LLC, www.supplychainwizard.com.

igital tracking of overall equipment effectiveness can improve efficiency.

Countering the Loss in Efficiency Caused by Mandated Serialization Compliance

	Twin-screw extruders, long used by the plastics industry for continuous mixing of polymer compounds, are now also well established as continuous mixing equipment for polymeric excipients and APIs. GMP materials of construction, easily cleanable designs, and equipment for contained feeding of high potency ingredients are all commercially available. Pharmaceutical applications for twin-screw extrusion, as well as practical information for setup, cleaning, and validation, were discussed at the Leistritz Pharmaceutical Extrusion Seminar (June 7–8, 2017, Clinton, NJ).

	An important use of pharmaceutical hot-melt extrusion (HME) is the bioavailability enhancement of poorly-water soluble APIs. In HME, twin-screw extruders are used to dissolve and mix the poorly water-soluble, hydrophobic APIs (typically below their melting temperature) in water-soluble, hydrophilic excipients (typically 50–100 ËC above their glass transition temperature) to create “amorphous solid solutions” that have increased bioavailability relative to their crystalline counterparts. One challenge is that the amorphous forms should remain stable (i.e., not revert to crystalline form) at ambient temperature, typically for a two-year shelf-life, noted Nicolas Ioannidis, research engineer at the Polymer Processing Institute, in a presentation at the seminar.

	Twin-screw extrusion can also be used to continuously mix APIs with excipients so that the mixture can be formed into a drug delivery device, such as a contraceptive ring or an implantable rod for long-acting, controlled release and local drug delivery. Merck, for example, is investigating an implantable rod to deliver an antiretroviral HIV treatment. In oral form, repeat administration or large tablets would be required, but an implant could improve patient compliance, explained Seth Forster, scientist at Merck Research Laboratories, in a presentation at the seminar. The API-excipient mixtures for such products could be either amorphous solid dispersions or, if API solubility is not a concern, dispersions of a crystalline API in the polymer. “Extrusion is an elegant way to make a complex structure,” concluded Forster.     

	Foster Delivery Science opened a new cGMP manufacturing facility in 2015 that is dedicated to using twin-screw extrusion to make polymer blends for various drug delivery dosage forms, including drug-delivery implants, and is seeing growing use in these areas, noted Tony Listro, vice-president of Foster Delivery Science. At the seminar, he described a direct extrusion process for a drug-eluting dental implant for local drug delivery, in which the API and excipient are mixed and then formed into a monofilament, all within one process. In another example, he described how drug products mixed on a twin-screw extruder can be formed into a film for transdermal delivery.

	“The evolution of twin-screw extrusion for continuous mixing applications is analog to what happened 50 years ago in the plastics and food industries,” explained Charlie Martin, president and general manager at Leistritz, which hosted the seminar. “This technology has been well proven for decades in a 24-hour-per-day industrial setting making many of the most sophisticated products we use every day. The next stage of development for pharmaceutical applications will be downsizing and applying existing extrusion technologies for multifunctional and specialty dosage forms.”

At an industry seminar hosted by Leistritz Extrusion, experts explained the use of extrusion equipment to mix polymeric excipients with APIs for solubility enhancement and for multifunctional and specialty dosage forms, including implants. 


Equipment and Processing Report-06-21-2017

Looking at Trends in Parenteral Manufacturing

Robots Package Parenteral Products

Countering the Loss in Efficiency Caused by Mandated Serialization Compliance

Twin-Screw Extruders Serve the Pharma Industry