	Product protection took many forms at this year’s INTERPHEX (April 17–19, 2018, Javits Center, New York, NY). Innovations in fill/finish systems included robotic systems to minimize human intervention. In solid-dosage drug packaging, several companies exhibited desiccants and other technologies for extending shelf-life.

	Two fill/finish systems captured 2018 INTERPHEX Exhibitor Awards. The Best in Show Award recognized the Microcell vial filler from Vanrx Pharmasystems. The completely robotic aseptic filling machine, built within gloveless isolators, performs repeatable and precise fills for drug development, early clinical trial supplies, and manufacturing of autologous cell therapies, gene therapies, immuno-oncology products, and other personalized medicines. 

	A system for ready-to-use vials, cartridges, and syringes, the FlexPro50 from groninger USA, earned the Biotech Innovation Award. This modular, manual, or automated filling and closing system minimizes human intervention. Additional flexibility is provided by exchangeable trolleys for handling vials in trays or in bulk. A direct injection system cuts decontamination cycle time in half. 

	Another notable fill/finish system, the FSM machine from Colanar, fills, stoppers, and caps nested vials and can be configured with single or dual stations, which are rated at 30 vials/min each. Compatible with single-use bags, filters, tubing sets, and filling needles, the unit offers multiple pump options and positions the control cabinet in the base. With installation of change parts, the machine can handle syringes, cartridges, and micro-vials.

	The Genisys 10-20 filling and closing machine from AST also handles nested vials, syringes, or cartridges. Integrated nozzles provide inert gas purging before and after filling and during the stoppering process. In-process fill-weight verification ensures accurate fills. Options include laminar airflow hood, restricted access barrier system, or isolator. 

	Italy’s Steriline, which offers a broad range of fill/finish equipment, isolators, and accessories, displayed the RTDS2 robotic tub decontaminating system. Installed as a standalone unit or between debagging and filling, the pulsed light sterilizer achieves a 6-log reduction and can decontaminate two tubs/min. It’s currently in the validation phase. 

	With many bagged products in short supply since September 2017, when Hurricane Maria caused severe damage to the infrastructure and manufacturing capacity of Puerto Rico, interest is high in equipment like the 525-526 aseptic bag filling and closing machine from Bausch Advanced Technologies. The flexible carousel system handles various bag types and fill volumes from 5 mL to 5000 mL. A tube-clamping mechanism on the robot-equipped unit prevents particle penetration into the bag. Options include gassing before, during, and after filling; radio frequency, ultrasonic, or heat sealing; and camera inspection. 

	Matrix and line-scan cameras on the Innoscan system from Stevenato Group Engineering Systems confirm syringe plunger position and orientation and check for particle contamination. Handling by four delta robots ensures no glass-to-glass contact even at the system’s maximum speed of more than 600 syringes/min. Integrated high-voltage leak detection identifies any faulty syringes.

	Micro-current, high-voltage leak detection locates openings as small as 5 microns in vials, syringes, and containers for protein products and water for injection. The lower voltage prevents damage to product or container and generates such a small amount of ozone that no ozone filter is needed. Capable of checking one tray (160 syringes) in less than three minutes, the online E-Scan 665 tester from PTI–Packaging Technologies & Inspection relies on a six-axis robot to pick each row, place it in the test position, and return good product to the nest and faulty product to a reject tray. An off-line system, the E-Scan 655 model, also is available. 

	Extending shelf-life for solid-dosage drugs

	Desiccants, oxygen absorbers, and other scavenging technologies are shrinking in size or being integrated into packaging materials. Desiccare offers a narrow pouch containing molecular sieve, carbon, silica gel, or 50/50 silica gel/carbon moisture absorbers plus equipment to automate its dispensing into 30-cc or 60-cc bottles or stick packs. 

	A compressed, solid-form design from Multiform Technologies eliminates the pouch or high-density polyethylene canister needed to contain traditional loose-fill desiccant. In addition to providing source reduction, the solid form packs two grams of capacity into the size of a conventional one-gram moisture controller. Currently available in white and one-, two-, or three-gram capacities, color could be added to maximize visibility. 

	For products that require a specific humidity, RH Stabilizers from Clariant Healthcare Packaging maintain equilibrium relative humidity levels from 10–30% inside the package. Applications include dry powder inhalers and soft gelatin capsules. Options include packet, canister, or stopper form. 

	A moisture absorber is built into a multi-dose dry powder inhaler (DPI) designed by CSP Technologies in conjunction with Simplified Solutions Sweden. In the smaller, 12-mm-wide XHaler unit,  the desiccant is mixed into the polymer material used to make the DPI device. Currently undergoing validation, the XHaler DPI depends on a patented, no-piercing technique to open the seal covering the dose to be inhaled. Eliminating piercing prevents generation of product-contaminating debris. The opening method also ensures the dose is fully loaded before the user inhales. 

	Hallie Forcinio is the Packaging Editor for 

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Innovations in fill/finish equipment and in solid-dosage moisture-control packaging technologies were on display at INTERPHEX 2018.  

Maximizing Quality in Pharmaceutical Packaging

	Now that global regulators have approved four oral solid-dosage drugs that were made using continuous processes-two from Vertex (in 2015 and 2018), one from Janssen (in 2016), and one from Eli Lilly (in 2017)-equipment manufacturers and early adopters are working to resolve engineering challenges that may be hindering more widespread use of continuous manufacturing (CM). Equipment cleaning and configuration is one such challenge; so is operator training. At a roundtable hosted by 

at INTERPHEX in April 2018, panelists discussed efforts within the industry. 

	Equipment manufacturers are adapting to requirements that have been identified by early adopters. First there was the need to make equipment such as mixers and extruders smaller. Then came the need to automate them. The emphasis now is on simplifying changeover and cleaning, said Sharon Nowak, global business development manager at Coperion-K Tron.

	Coperion KTron, for example, introduced the next-generation of it pharmaceutical loss-in-weight feeder with a smaller modular design that allows easier change-out of feeders and hoppers for greater flexibility and easier cleaning (1).  

	Improving changeover speed will take some effort, given the industry’s trend to process multiple products on the same equipment and to integrate equipment from different vendors on the same line.  “There can be upwards of 1000 individual parts in a continuous processing train as well as a couple hundred tri-clamps-associated gaskets, which makes cleaning and turnover a lengthy process,” noted Dave DiProspero, associate and director of pharmaceutical process technology at CRB.

	The need to disassemble, swab, clean, and reassemble the equipment is a time-consuming and complex process, noted Jose Luis Santos, head of operations for drug product continuous manufacturing at Hovione, a contract manufacturer that is partnering with Vertex. Although cleaning is currently done manually, automated clean-in-place (CIP) systems could be considered for future designs. “In addition to the equipment, rooms need to be cleaned. CIP could enable greater efficiency,” commented Santos. 

	At Vertex’ facility in Boston, however, the company chose not to use CIP because of issues and cost associated with wastewater at that location.  Vertex is, instead, considering an automated washer that will reduce cleaning time dramatically, David Nadig noted in a presentation at IFPAC (2). 

	Like other companies that have adopted continuous processes, Hovione is now measuring the time required for each activity and the sequence of operations within continuous, in an effort to reduce the overall time required and to determine the optimal staffing requirements, said Santos. 

	“Companies are going through each stage to identify bottlenecks and areas where they can reduce the amount of time required,” said Doug Hausner, associate director for Industrial Relations and Business Development with the Engineering Research Center for Structured Organic Particulate Systems located at Rutgers University. “As a result, cleaning is becoming part of the initial equipment design stage for continuous processing.”

	In addition, he noted, ergonomics is becoming a more important design factor.  For example, Eli Lilly optimized placement of feeders in its continuous processing suite, and placed them on tracks and turntables to cut down cleaning, maintenance, and changeover time.

	Human resources and training will be crucial. Currently, processes are typically run by PhD-level engineers, but eventually will need to be run by process engineers and trained operators. Despite a great level of automation in continuous manufacturing rigs, operator intervention and close monitoring are key for success. “You can’t have someone running the process from a control room. You need the process engineer on the floor, giving close attention to several different unit operations at the same time,” said Santos.

	It will also be important to change the approach to standard operating procedures (SOPs), which, today, can run in the thousands of pages for each unit operation.  “You want to digest this information so that it can be used in the field, for example, with checklists highlighting the most important steps to take,” said Santos. Then, if a user is not familiar with the process, they can be referred back to the relevant SOP, without carrying tomes of paper. Technology such as making SOPs available via human-machine interfaces or mobile devices could be used to get information to the operator at the right place and time. 

	Despite these challenges and others, those involved with CM implementation say that the opportunity for benefits of a flexible, efficient process that offers greater speed of development, scaleup, and tech transfer and can run under a high level of control is well worth the effort. Panelists see continuous manufacturing becoming increasingly important for orphan drugs and rare disease therapies, as well as for generics.  “We’re working with a number of generic-drug companies on business cases…it is my belief that once cleaning and some of these other hurdles are cleared, more companies will put continuous processes in their facilities,” said Nowak.

New Compact and Modular Pharmaceutical Feeder Design at Interphex 2018,

	2.  D. Nadig, “Industrialization of Continuous Manufacturing,” Presentation at IFPAC, (Arlington, VA, Feb. 2018).

As more continuous processes move toward commercialization, users and equipment vendors are working to speed changeovers and address other needs.

Equipment and Processing Report-05-16-2018

Maximizing Quality in Pharmaceutical Packaging

Addressing Continuous Manufacturing’s Growing Pains