	Biopharmaceutical manufacturing companies have an opportunity to participate in the latest industrial revolution, which is being called Industry 4.0. In this digitalized paradigm, machines collect process and product data and communicate with other machines via the Industrial Internet of Things (IIoT).  Using artificial intelligence (AI) or machine learning, machines can even use these data to improve processes without human intervention, although how to use AI in a regulated, GMP-compliant space is yet to be resolved. In fact, in many cases, the bio/pharma industry is still transitioning from manual systems to automation (i.e., “Industry 3.0”) (1).  Next-generation technologies are already providing more data that, along with advanced analytics and modeling technologies, can help increase process understanding and be used for advanced process control and efficiency improvements. 

	One of the hallmarks of Industry 4.0 is “big data” collected by equipment sensors and process analytical technologies (PAT). These manufacturing data can be used to analyze what is happening in a process and why, to predict what will happen in response to given changes, and-using simulation algorithms-to optimize processes, explained Lennart Eriksson and Chris McCready of Sartorius Stedim Data Analytics (2). Eriksson calls this higher level of simulation and optimization “prescriptive data analytics.” Others call it process modeling, and some give the name “digital twin” to a process model that is a virtual copy of the actual process. Modeling has become more sophisticated, enabling process designers to run virtual experiments and gain a greater understanding of their process before actually running it. 

	Digital twins are also being used to predict maintenance and downtime more accurately; plan for process improvements, such as the replacement of components; and prepare alternative plans in case of malfunctions or disturbances, all without interrupting manufacturing, explains Billy Sisk, Life Sciences industry leader at Rockwell Automation. 

	Sanofi, for example, is bringing digital transformation to its biopharmaceutical manufacturing facilities. Each of the company’s digital plants will have a digital twin connected directly to the sensors and data in the physical plant. “The data flows to these digital twins, giving managers a real-time view into the plant’s operation. Simulation on the model provides the level of manufacturing modularity and future flexibility required to support personalized medicine,” Sanofi said in an October 2017 press release (3). At its Geel, Belgium biologics manufacturing facility, sensors generate more than one billion data points in every manufacturing cycle. “By analyzing this data, potential deviations can be spotted and swiftly corrected. Yield is improved with adaptive process control strategies, and downtime is reduced by optimizing maintenance activities and shifting to predictive maintenance, based on equipment monitoring, which will increase overall output,” reported the company.

New technologies that allow better process control are improving efficiency and reducing waste in biopharma manufacturing by automating tasks or assisting operators to improve manual task handling. GE Healthcare’s XDUO, for example, is a new “smart” mixer for buffer solutions that continuously measures pH and performs automatic titration using acid and base pumps. This solution creates tighter control and saves a significant amount of time compared to manual titration, notes the company. 

The use of PAT to measure critical quality attributes in real-time is well-established in upstream bioprocessing, but more research is needed to apply it to downstream development and manufacturing (4). Work is underway: multi-attribute methods (MAM) that use mass spectrometry as PAT, for example, are being developed in cooperation with FDA’s Emerging Technology Team (4,5).

	As biopharmaceutical manufacturers transition to Industry 4.0, they should consider the requirements for changes to processing equipment, such as the automation of bioprocessing skids, and increased data security. 

The moveable, skid-mounted biopharmaceutical manufacturing equipment in use today has different requirements for automation than fixed equipment. Fixed equipment typically uses a distributed control system (DCS). Stand-alone skids, however, typically use programmable logic controllers (PLCs), which work well for isolated equipment but are more complex to integrate into supervisory systems, such as a DCS or a manufacturing execution system (MES), explains Bob Lenich, Global Life Sciences director at Emerson. To solve this problem, Emerson’s new DeltaV PK Controller is a DCS controller for skids that are self-contained, like a PLC, but can be more easily plugged into a plant-floor automation system, such as Emerson’s Delta V DCS (for coordinated operations in real-time with alarming, automated closed loop control, an integrated user interface, and historical data collectionthat a DCS provides) or into a MES (for stand-alone pieces of equipment that only need limited direction on what to produce). 

	“In the near future, we anticipate that there will be more of two types of skids: mobile and movable skids, with the difference being that mobile skids are moved much more frequently,” says Lenich. “What’s missing today is a tracking mechanism to identify the physical locations of mobile and movable skids. Many of our customers are interested in using [radio-frequency identification] RFID tags as a potential solution for mobile skids because they need constant tracking. In contrast, moveable skids are repositioned less frequently, and most end users would be fine with something simpler like a barcode or QR code that doesn’t require constant tracking.”

	The use of skids and super-skids with single-use (i.e., disposable) components presents additional automation challenges, notes Torsten Winkler, lead of the Life Sciences Center of Excellence in EMEA for Honeywell Process Solutions. “It is important to identify single-use equipment and, more importantly, that all are connected properly. Automation systems can continuously monitor when skids are connected, but there are additional challenges with identifying the disposable parts,” says Winkler. 

	Single-use facilities and skid-based equipment require a significant amount of manual set-up to connect all the equipment pieces. Producing a batch in a single-use bioreactor, for example, might require up to 900 individual connections, and any mistakes can cause the batch to fail, notes Sisk. Graphical aids can help operators visualize the instructions, and equipment recognition and verification systems can be integrated into the control platform to track and confirm equipment placement. For example, the control system could be set up to require the operator to scan a barcode on a disposable part, which would become part of the batch record.

With the increasing connectivity of systems communicating over the IIoT, data security has become even more important. Systems must use modern protocols that have adequate security. Another best practice is to segregate non-GMP business data from GMP process data using an “industrial demilitarized zone” in information technology systems, note experts. Mobile connection, such as having access to process data on mobile phones or tablets, is an issue manufacturers must consider. The technology is available, but it must be managed to maintain data security. 

	“Organizations have adopted ‘safety cultures’ for years, but now they need security cultures,” says Lenich. Just as a safety culture uses various programs to make the importance of safety visible to everyone in the organization, a security culture would similarly highlight that security is everyone’s responsibility and make security best practices a regular part of day-to-day priorities, he explains.

	2.    L. Eriksson and C. McCready, 

	3.    Sanofi, “The Digital Plant: From Collaborative Robots to Virtual Reality,” Press Release, Oct. 24, 2017.

	5.    R. Deshpande, “Progressive Technologies to Realize the Vision of Advanced Biomanufacturing,” presentation at IFPAC 2018 (North Bethesda, MD, 2018).

Articles

Feature

Modern technologies, including Industry 4.0 and the Industrial Internet of Things, offer opportunities to increase biopharmaceutical manufacturing efficiency.

Industry 4.0 in Biopharmaceutical Manufacturing

	The global market for child-resistant (CR) packaging is projected to grow 4% per year through 2023, according to a report from Market Research Future (1). In the United States, CR packaging requirements have been a fact of life since 1970, when Congress passed the Poison Prevention Packaging Act (PPPA) to protect children from accidental poisoning. 

	Over the years, the Consumer Product Safety Commission, the federal agency that crafts PPPA-related regulations, has expanded the list of products that must meet requirements for what the PPPA calls “special” packaging (CR and adult-friendly). Recent pharmaceutical additions include products containing imidazolines (2). Despite being required for nearly 50 years, CR packaging continues to evolve, and the expanding market for cannabis-based products has helped spur a new round of development efforts. 

	Nonetheless, missteps still occur. The absence of an effective CR feature is a frequent cause of recalls. At least three recalls involving products containing lidocaine have occurred since mid-2017: 56,000 4-oz jars of Synodrin Lidocaine Maximum Strength Pain Relieving Cream in November 2017 (3); 74,000 2-oz tubes of Well at Walgreens Pain and Itch Relief Cream in January 2018 (4); and 500,000 1-oz tubes of Maximum Strength Bacitraycin Plus Ointment with Lidocaine in March 2018 (5). At the time of the recalls, no injuries had been reported. 

	CR features can be incorporated in rigid or flexible packaging. Several sources supply flexible packaging with a CR zipper track and slider, including ProAmpac and Presto Products (2). For rigid packaging, the family of CR closures continues to expand. One recent addition is a 63 mm-diameter, wide-mouth closure from Mold-Rite Plastics (6).  

	But the highest level of activity appears to be occurring in CR “wallet” packs for blister cards. A major advantage of a CR wallet pack is increased print area for information or illustrations compared to similar size bottles. Wallet packs also can eliminate the need for CR blister structures, which typically require peeling away a paper layer before the dose can be pushed through the lidstock. This type of blister card can be difficult to open, especially for seniors. 

One wallet upgrade that improves ease of opening for seniors, the Locked4Kids 2.0 pack, achieved a 100% first-try opening rate without any previous instruction to the testers. Before the redesign, only 93% of seniors could open the pack on the first try, reports Janet Schultze, director of Business Development at Locked4Kids. The patient or caregiver gains access to the blister card by pushing in smaller tabs to unlock “hooks” and pulling out the tray. Like its predecessor, a tear-resistant film laminate prevents children from accessing medication by biting or tearing the package. An end flap sealed with full adhesive coverage can’t be picked open, and a tab on the manufacturer’s joint tears before the pack opens. As a result, the Locked4Kids 2.0 pack has achieved an F=1 status, which is the strictest rating. 

	Four out of 11 patents on the Medlock EZ wallet design, developed by Colbert Packaging, cover CR features. The design can accommodate a calenderized blister and meets the requirements for an F=1 rating. The first commercial adoption of the Medlock wallet pack is vitaPearl Prenatal MultiVitamin with DHA [docosahexaenoic acid, a type of omega-3 fatty acid]. 

Another CR wallet with an F=1 rating, the EcoSlide-OTC pack from Keystone Folding Box, targets over-the-counter (OTC) products packaged in blisters. It relies on the same reclosable locking mechanism as its enhanced, easier-to-activate Ecoslide-RX 3.0 package for clinical trial material and commercial prescription products. True to its name, the Ecoslide-OTC pack consists of 100% recyclable paperboard and separates easily from the internal blister for recycling. The blister goes in the trash, but represents a significant source reduction compared to a bottle. “Millennials are continuously seeking attractive, alternative, eco-friendly packaging, while the growing senior population is looking for solutions that are easier to open. Ecoslide-OTC addresses all of these challenges,” explained Ward Smith, director of Marketing and Business Development at Keystone Folding Box, in a press release (7).

	Machinery builders haven’t stood still either. To empty CR blister cards that need to be reworked, the laser-equipped RPB Bauer CP50 deblistering machine from Prodieco slices the lidstock around the perimeter of each pocket and then bends the card to eject the solid doses. The unit can empty up to 65 cards/min and offers an infinitely adjustable format range from 40 x 55 mm to 145 x 130 mm. 

	1. Market Research Future, “Global Child Resistance Packaging Market Is Predicted to Grow at Approximately 4% by 2023,” 

www.marketresearchfuture.com/press-release/child-resistance-packaging-market

Child-Resistant Packaging Meets Regulations and Consumer Needs

Pharmaceutical Technology Equipment and Processing Report 

	3. US Consumer Product Safety Commission, “Natural Solutions for Life Recalls Synodrin Pain Relieving Cream Due to Failure to Meet Child Resistant Closure Requirement,” Press Release, Nov. 30, 2017. 

	4. US Consumer Product Safety Commission, “Walgreens Pain and Itch Relief Cream Recalled by Natureplex Due to Failure to Meet Child Resistant Closure Requirement,” Press Release, Jan. 30, 2018. 

	5. US Consumer Product Safety Commission, “First Aid Research Recalls Maximum Strength Bacitraycin Plus Ointment with Lidocaine Due to Failure to Meet Child Resistant Closure Requirement,” Press Release, March 7, 2018. 

	6. PMMI Media Group, “Latest Child-Resistant-and Senior Friendly-Closures,” Email, Mar. 7, 2018. 

	7. Keystone Folding Box, “Keystone Folding Box Co. Launches Ecoslide-OTC: A Compact, Child-Resistant Paperboard Package for Medication in Blisters,” Press Release, Aug. 9, 2017. 

Pharmaceutical packaging designs evolve to protect children, while maximizing access for seniors. 

Equipment and Processing Report-07-18-2018

Industry 4.0 in Biopharmaceutical Manufacturing

Child-Resistant Packaging Demand Grows