	Digitalization and Industry 4.0 tools are being employed to improve pharmaceutical equipment and systems. An example of this is Optima Packaging’s Comprehensive Scientific Process Engineering (CSPE) approach to project planning for its fill/finish systems, which uses simulation for mock-up, engineering design, and design review to speed the design process. Three-dimensional models can be experienced using virtual reality to collect input from users early in the design process. The company opened a new facility, the CSPE Center, at its Schwaebisch Hall, Germany site in July 2019 that gives the company space to build, test, and commission multi-story, turnkey, fill/finish facilities. 

spoke withJan Deininger, editor at OPTIMA Packaging Group, about the company’s approach to equipment and process design.

What are some of the parameters you might consider in the design phase? 

During the design phase, strength calculations, flow simulations, and determination of the resonance values of individual components support the developers. First, air flow and simulations of vaporized hydrogen peroxide flow support a flow-optimized machine design. In addition, designers use simulation to optimize the line layout, considering factors such as accessibility. Simulation can also be used for preliminary tests, such as setting the stopper. 

	The CSPE approach minimizes the risks associated with large plant construction projects by conducting a thorough analysis even prior to the design stage. If potential risks based on reliable data gained from comparable earlier projects are identified, they can be proactively countered.

What are some best practices you use for factory acceptance testing (FAT) and site acceptance testing (SAT)? 

The CSPE Center is designed so that the entire system-consisting of isolator and filling and closing machine-is brought together in Schwaebisch Hall and can be fully tested and approved on the supplier site under conditions that are as realistic as possible. In the past, in projects without integrated FAT (iFAT), the separately pre-tested plant parts were not combined until they reach the customer’s site. With iFAT, the system components are optimally coordinated as an overall system, which allows reliable performance of qualification work that is similar to the later SAT of the overall system at its destination. The only deviations that might arise later result from special features of the cleanroom environment on the customer’s premises. The systematic exploitation of digital engineering in combination with iFAT significantly reduces the overall project duration. 

	The entire system is tested before it goes to the customer. This means we carry out smoke studies, leak tests, SCADA [supervisory control and data acquisition] tests, and alarm tests. Also included are interface tests and filling tests under production conditions, sometimes with original or placebo product of the customer. Line safety tests and cycle development also take place. In general, everything can be tested that is later required in installation qualification, operational qualification, and even in performance qualification. By doing this, risks of unexpected delays at the customer site can be reduced to a minimum, and the time to market is reduced as well. 

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Optima Packaging explains its approach to process design. 

Using Simulation to Optimize Fill/Finish Equipment

	Systems-based Pharmaceutics (SbP) uses a systems engineering approach and calibrated, mechanistic models to design optimally formulated pharmaceutical or biopharmaceutical products. These models-sometimes called digital twins-are crucial to digitalization, both for product and process design and for manufacturing. 

	The Systems-based Pharmaceutics Alliance (SbPA), a pre-competitive association, was founded in 2013 to develop integrated digital design techniques to improve efficiency by simultaneously designing the product and the process. The group consists of solution provider Process Systems Enterprise (PSE) and five major pharmaceutical companies. The SbPA developed modeling tools based on mechanistic models and verified by experiments, and the tools, such as PSE’s gPROMS Formulated Products modeling platform, are now being applied. As presenters noted, SbPA shows how a precompetitive alliance can achieve more than can be accomplished by an individual company. The group is actively collaborating and working to advance the technology. “Our focus now is establishing workflows, finding gaps that still need solutions, and capturing outcomes,” says Dana Barrasso, PSE’s technical lead for the SbPA. 

	In digital design, used for R&D and for technology transfer, models are used to run “what-if” scenarios. Models are also used for a statistical evaluation technique called global systems analysis (GSA). “GSA allows developers to explore the whole design space and see how disturbances of the system affect critical quality attributes as a probability distribution,” explained Barrasso (1). 

	Although the focus of models to date has been primarily for digital design, over the next few years, models will be used for digital operations, predicted Barrasso (1). Models will be used, for example, to replace the full-plant experiments that have been needed to create model-predictive control and to test control systems, as well as to train operators.

	One of the SbPA’s goals is to transform the development process to modeling and simulation said Bob Yule, GSK, in a presentation at PSE’s modeling forum (2). The benefits of simulation are reduced experimentation (along with reduced labor and materials) and greater exploration of the process space, he explained.  In turn, this will allow more robustness in manufacturing, enhance finding simpler processes, and eventually permit the use of real-time monitoring and maybe even real-time control. One of the challenges in implementing modeling and simulation is the infrastructure needed. Although the platform (the model) is available, both subject matter experts in modeling and acceptance of this new way of doing development are needed, said Yule. A traditional design of experiments (DoE) model involves a scoping DoE, a factor-screening DoE, and a statistical model, then identification of critical process parameters (CPPs) and ranges, followed by verification in the lab. The new way of process development, however, is to create a flow model and then perform an 

DoE to identify CPPs. This method cuts process design time in half, said Yule, but to make it the new way of working, industry inertia must be overcome. It also takes time to build a “critical mass” of people who are capable of modeling. Yule said that at GSK, the most progress in modeling has been made in drug substance and projects are underway in drug product. The company is currently evaluating biopharma modeling in its partnership with Innovate UK. 

	Although SbP is now well established in small-molecule development and production, with several off-the-shelf libraries that can be used in modeling tools, modeling of biopharmaceutical processing is an emerging area. PSE received seed funding in 2018 from Innovate UK to explore how small-molecule SbP could be translated to large-molecule SbP. Initial work showed that existing methods and models are directly applicable to develop bioprocess modeling, and PSE is preparing to release new modeling software, gPROMS FormulatedProducts for Biologics. 

	Several posters at the conference highlighted academic and industry work in modeling cell culture. For example, researchers at the University of Massachusetts Lowell worked on a model in collaboration with PSE and the NSF Advanced Mammalian Biomanufacturing Innovation Center (AMBIC), which includes academic members from UMass Lowell, Johns Hopkins University, Clemson University, the University of Maryland, and the University of Delaware. The project developed a model for viral growth and created a flowsheet model for continuous production of viral vaccines that can be used to optimize the continuous process (3). Another project at UMass Lowell used modeling to optimize the media components that impact cell growth (4). 

	Researchers at Rutgers, the State University of New Jersey, presented FDA-funded research on using process analytical technology (PAT) to measure cell growth in continuous upstream monoclonal antibody production using Chinese Hamster Ovary mammalian cells (5). The group is also developing a mechanistic model of the bioreactor, which it will validate with the experimental PAT data. The researchers plan to connect the model of the bioreactor with downstream process models using flowsheet models, such as PSE’s gPROMS.

	1. D. Barrasso, “Applications of digital twins in continuous drug product manufacturing,” Presentation at Advanced Process Modeling Forum USA (Tarrytown, NY, Sept. 10, 2019).

	2. B. Yule, “The Challenges of Implementing System Modeling in Pharmaceutical Process Development,” Presentation at Advanced Process Modeling Forum USA (Tarrytown, NY, Sept. 10, 2019).

	3. C. Morris, et al., “In-silico Platform Based on Flowsheet Modeling for Continous Viral Vaccine Production,” Poster at Advanced Process Modeling Forum USA (Tarrytown, NY, Sept. 10, 2019).

	4. Galbraith, H. Liu, S. Yoon, “Media Formulation Optimization Based on Multi-Scale Modeling of Heterogeneity in Mammalian Cell Culture Process,” Poster at Advanced Process Modeling Forum USA (Tarrytown, NY, Sept. 10, 2019).

	5. O. Yang et al., “Continuous Upstream Biopharmaceuticals Manufacturing,” Poster at Advanced Process Modeling Forum USA (Tarrytown, NY, Sept. 10, 2019).

Systems-based pharmaceutics case studies, challenges, and new uses were discussed at PSE’s Advanced Process Modeling Forum.

Process Modeling Tools Find Use in Bio/Pharma R&D and Manufacturing

	The focus on specialized medicines and biologics has led to more small-batch production in aseptic manufacturing, which calls for flexible machinery and faster changeovers. Flexible and repeatable filling are more crucial as companies focus on targeted therapies for smaller populations. Nearly 50% of pharmaceutical and medical device companies have begun to replace legacy equipment with automated systems, according to PMMI’s 2017 report The Evolution of Automation (1).  

	The report also found that two out of five pharmaceutical and medical device manufacturers do not operate legacy equipment and can point to operating fully automated equipment in the future. Additionally, the majority (62%) of pharmaceutical and medical device companies predict spending more on capital equipment over the next two years, with smaller batch runs being a main driver. Expanding varieties of drug types and dosage forms, higher standards for quality and precision, and pressure to reduce development times are all factors fueling demand for greater speed in aseptic operations. Fully automated processes can go a long way to overcome these challenges. 

	In aseptic processing, people are the primary source of contamination because aseptic filling requires close coordination and involves complex interactions between the operator, sterilized products, the fill/ finish equipment system, and the cleanroom. Handling of sterile liquids in the pharmaceutical industry traditionally relies on consistent techniques that have not advanced much over the past 100 years. Innovation, such as near-zero particle generating designs and complete tolerance to biodecontamination cycles with gaseous hydrogen peroxide, are making automated lines easier to integrate.

	The rise of costly biologics has pressured downstream fill/finish operations to ensure the highest levels of safety, quality, and cost efficiency. Automation at the fill/finish stage reduces the risk of contamination, and pharmaceutical processers are adopting systems that lead to as few human interactions as possible. By eliminating operator intervention, automated aseptic filling systems can reduce contamination potential and improve manufacturing efficiency. Traditional, one-axis automation works well for high-speed processes, but multi-axis robotic arms offer repeatability with the flexibility to easily change the process or the type of container being filled.

	Operators can easily reprogram today’s robotic systems for changes after setup without the help of a programming specialist. Some platforms are recipe-driven, and an operator inputs the recipe information-such as the type of container and volume to be dispensed-through a touchscreen interface. 

	The use of nested components, such as vials, syringes, cartridges, stoppers, and caps, simplifies material flow within aseptic systems. The nested components configuration eliminates machinery and tooling used in traditional systems, cutting back on sources of particulates and contamination. Newly developed products, increasingly smaller batches, more highly potent products, and the need for flexible and efficient vial and syringe filling solutions are leading to constant demand to make the freeze-drying process fast, safer and more cost-effective, particularly regarding changeovers, driving demand for nested vials. 

	Robotics systems create streamlined decks for nested vials that are easier to clean than traditional automated systems. The use of pre-sterilized, disposable product contact path materials (e.g., bags, tubing, sterile connections) reduces material cross-contamination and speeds product changeovers by eliminating extensive system cleaning.

	At PMMI’s Healthcare Packaging Expo (Sept. 23–25, 2019, Las Vegas), Groninger exhibited semi- and fully automated filling solutions for nested syringes, vials and cartridges that can process up to 400 objects per minute with 100% in-process control. The systems are flexible for multiple formats. 

	Another exhibitor, AWS Bio-Pharma Technologies, manufactures linear-style fillers that can process syringes, cartridges, and nested vials from one to 30 mm in diameter at speeds of up to 2000 units per minute. The RNFM series of filling systems are available in three models with various output options and production speeds to suit the needs of manufacturers of any size. 

	Another common use of robots in aseptic processing is to replace highly repeatable production processes. Robotic systems are agile and can switch quickly between vial, syringe, and cartridge formats, reducing the number of electro-mechanical components that complicate the machine’s interior. This also speeds up decontamination cycles.

	With the use of cobots-collaborative robots that can work in proximity to humans with fewer concerns for injury due to their ability to sense obstacles-glove-boxes can be located next to the robot so that the operator can intervene in the isolator without stopping the production process. Robots also allow the design of gloveless isolators. A gloveless isolator is completely closed, removing batch contamination risks caused by mouse holes, conveyors, glass-to-glass contact, or sortation bowls and minimizing particle generation. Gloveless isolators make particle counts as low as ISO 2 levels possible, and their simple design allows for complete and consistent clean-in-place and vapor-phase hydrogen peroxide decontamination. 

	Vanrx Pharmasystems makes technologically advanced aseptic filling solutions that use robotics, machine vision, and gloveless isolator technologies to automate the packaging of injectable drugs into vials, syringes, and cartridges. The Vanrx gloveless isolator can run without need for human intervention. The workcell’s design eliminates sources of particle generation, such as aluminum crimp caps, and single-use consumables prevent cross-contamination. By eliminating glass-to-glass contact and reducing manufacturing complexity, the gloveless isolator reduces risk of product loss or recall. 

	Innovations in robotics can help manufacturers of aseptic drug products ensure that their products meet the long list of inspection criteria for pharmaceutical products and packaging. Aseptic products must be scanned for moving and deposited particles, fibers, and splinters. Packages must be inspected for defects including spots, cracks on the side walls or base, and defects in caps and seals. 

	Antares Vision, which exhibited at the Healthcare Expo, provides automated vision inspection machines for complete verification of pharmaceutical products in the production process. Antares Vision offers standalone or inline automatic machines for tablet and capsule inspection with accuracy up to 50 μm. The company’s Visual Rotating Inspectors can inspect a wide range of glass or plastic medical containers for liquids, powder, or lyophilized drugs. 

	Today’s robotic inspection systems can deliver small batches of reproducible inspection results without human intervention. Brevetti C.E.A. delivers automatic inspection systems for syringes, vials, ampoules, and cartridges. The company’s A1 Human-like Inspection Machine combines the advantages of motion and optics flexibility with the stability of inspection results. 

Automated fill/finish and inspection equipment displayed at the 2019 Healthcare Packaging Expo improves quality and efficiency.

Equipment and Processing Report-10-16-2019

Using Simulation to Optimize Fill/Finish Equipment

Process Modeling Tools Find Use in Bio/Pharma R&D and Manufacturing

Automation on Display at Healthcare Packaging Expo