	Aseptic processing is as important as ever, and new aseptic product areas, such as personalized medicine and combination products, are growing, noted James Agalloco, president of Agalloco & Associates and member of the editorial advisory board of 

in a presentation at INTERPHEX 2019 (1). Technology is changing rapidly, and equipment manufacturers have introduced new technologies for closed systems, including isolators and single-use disposable systems for product transfer and fill/finish. 

	Despite the advantages of systems that remove operator intervention, such as gloveless isolators with robotic handling of ready-to-fill components, not all users are ready to adopt these new technologies, said Agalloco. Concerns about costs, regulatory response, and potential project delays are reasons for hesitation. “Like it or not, however, closed systems are the future of aseptic processing,” concluded Agalloco. 

	One option for closed processing is restricted access barrier systems (RABS). RABS are a relatively easy upgrade to implement in existing cleanroom facilities and may have a lower capital expense than isolators, but are more expensive to operate. “RABS are most useful as an upgrade of an existing facility, because the investment can be staged over a period of years, and a portion of the existing infrastructure and utility systems can be reused without modification. Long term, however, I don’t think RABS have much of a future,” says Agalloco.

	Isolators are an increasingly popular solution, agreed equipment vendors at INTERPHEX, where several new systems were on display. According to Randy Fraatz, vice-president of North American Operations at Steriline North America, the increase in use of isolators is driven by the need to reduce contamination risk and increase worker safety, and by encouragement from regulatory bodies to use technology such as isolators. While 25 years ago there may have been only a few isolator installations, today 80% or more of Steriline’s projects are isolator based, with only a few RABS or traditional cleanroom installations, says Fraatz. 

	Another trend is the increasing use of robotics, rather than traditional automation, especially for material handling within a closed system but also for handling components at the front-end and at the discharge, adds Fraatz. Robotics are more efficient and flexible, and they reduce the number of parts needed inside a closed system, which increases cleanliness. While traditional automation is still best for high-speed applications (e.g., greater than 300 vials/minute), robotics are beneficial for the flexibility in handling multiple container sizes and for reducing reject rates, which is more crucial in high-cost goods such as personalized medicines, comments Fraatz. 

	Olivier Cremoux, business development manager for North America, Robotics at Stäubli, agrees that there is growing demand from machine makers for robotics because robots allow a reduced footprint and lower particle generation with increased flexibility. Stäubli's Stericlean robots, including the TX2 collaborative six-axis robots and the four-axis TS2 SCARA robots, are designed to be compatible with hydrogen peroxide sterilization so that they can be used inside a closed system, explains Cremoux.

	Steriline’s Robotic Vial Filling Machine (RVFM), designed for filling inside an isolator using bulk primary packaging, uses one or two robotic arms made by Stäubli to move the vials within the machine. The machine is designed to detect missing stoppers or caps and to allow repeated operations to correct the missing piece within the process so that the problem container can be fixed rather than rejected (2). While the RVFM handles bulk containers, the company’s robotic nest filling machine is designed for filling ready-to-use nested containers inside a RABS or isolator.

	Fraatz sees interest in the industry in continuing to go further in removing possible contamination sources, such as designing isolators with fewer glove ports, and eventually gloveless isolators.

	Vanrx Pharmasystems’ SA25 Aseptic Filling Workcell is a gloveless isolator technology in use today. In 2018, for example, Fujifilm Diosynth Biotechnologies reported that it had invested in the workcell to expand its gene therapy and viral vaccine fill/finish capabilities in support of late-phase candidates and commercial supply at Fujifilm’s Flexible Biomanufacturing Facility in College Station, Texas (3). The systems from Vanrx use robotic arms for repeatable filling that is also flexible for producing smaller batches and using different container formats (4). 

	Fedegari displayed a prototype of its multi-process system that contains sterilization, washing, and fill/finish, all within an isolator. The system uses a seven-axis robot, constructed completely from stainless steel, for handling containers inside the isolator. Fedegari’s proprietary Thema4 software, used for the robotic control system, provides complete audit trails and data integrity. 

	Other closed fill/finish systems at INTERPHEX included AST’s GENiSYS R robotic filling and closing machine; NJM’s Dara NFL/2-RDL aseptic filling and closing machine for ready-to-use, nested vials; and groninger’s Integra aseptic filling machine with an integrated isolator using SKANFOG decontamination (5). SKAN’s SKANFOG Spectra Modular Aseptic Processing and Sterility Testing Isolator System was awarded “Best in Show” at INTERPHEX 2019 (6). The system allows faster transfer into an isolator and faster isolator decontamination cycles, said the company. 

	Watson-Marlow Fluid Technology Group displayed its new Flexicon FPC60 peristaltic fill/finish modules that are built to fit a small footprint. The modules-which include vial infeed, filling, stoppering, capping, auto-reject, gas purging, and product outfeed-are designed for users to create their own filling system for small-batch applications. Machine guarding is standard, and integration of laminar airflow, restricted-access barrier systems, or isolators are also available. According to the company, the entire FPC60 fluid path has been developed for single-use, which simplifies cleaning validation and facilitates changeover between liquid types (7).

	Several systems for decontamination of closed aseptic systems or cleanrooms were on display at INTERPHEX. The DECOpulse Biodecontamination System from Optima Pharma/Metall+Plasticreceived an INTERPHEX Exhibitor Award for its system that uses atomization to produce vapor-phase hydrogen peroxide. The approach provides faster decontamination, improved safety because of reduced outgassing, and shorter decontamination cycles, says Dena Flamm, business development manager at Optima Pharma. The patented system’s atomization-driven evaporation creates droplets of a defined size that evaporate quickly, which results in a more homogeneous and faster distribution of hydrogen peroxide, says Flamm. Another benefit is that the technique, which doesn’t require additional heating to evaporate the liquid, prevents unintended decomposition of hydrogen peroxide. Optima offers the DECOpulse system for all its isolators as a turnkey filling solution.

	TOMI Environmental Solutions displayed its SteraMist binary ionization technology (BIT), a patented two-step process that creates ionized hydrogen peroxide (iHP). The process, originally developed in a program with the US Defense Advanced Research Projects Agency, uses a lower percentage hydrogen peroxide compared to other systems. The company installed SteraMist systems in four cleanroom cGMP suites in a new Pfizer facility in Chesterfield, MO, TOMI announced in an April 10, 2019 press release. The Chesterfield facility, at approximately 295,000 ft

, houses Pfizer’s BioTherapeutics Pharmaceutical Sciences R&D group. This SteraMist iHP Custom Build-In System uses 20 ceiling-mounted SteraMist applicators connected to dual-generator control cabinets, programmed to run one or all applicators simultaneously, which will be used on a daily basis to ensure total disinfection and decontamination, reported TOMI (8).

	1.    J. Agalloco, “Aseptic Processing 2019: Trends and Challenges,” Presentation at INTERPHEX (NYC, 2019).

	2.    Steriline, “New Technologies and Customization, Steriline is Following the Innovation Path to Meet Pharma Customers’ Needs,” Press Release, April 2, 2019.

	3.    Fujifilm, “Fujifilm Announces the Expansion of Its Fill Finish Services to Include Late Phase And Commercial Production Of Gene Therapies And Viral Vaccines to Become an End-to-End Solutions Provider,” Press Release, May 23, 2018.

Robotics Solve Aseptic Filling Challenges

	6.    SKAN, “Award Winner at INTERPHEX New York,” Press Release, April 5, 2019.

	7.    Watson Marlow Fluid Technology Group, “Uniquely Configurable Flexicon FPC60 Fill/Finish System Offers Production Flexibility,” Press Release, Jan. 10, 2019.

	8.    Tomi Environmental Systems, “TOMI Environmental Solutions, Inc. Implements SteraMist Into Pfizer, Chesterfield, MO,” Press Release, April 10, 2019.

Articles

Feature

Closed systems for aseptic fill and finish were featured at INTERPHEX 2019.

Aseptic Processing Innovations on Display

	Demand for contract packaging is strong. Driving forces for outsourcing include the growing number of virtual pharmaceutical companies, plant consolidation, global emerging markets, the need to maximize internal resources, and the rise in biopharmaceutical products, which prompts more companies to turn to contract packagers to label and kit products. Another influence on growth is the expanding number of rare and orphan drug indications. These often high-valueproducts can be difficult to manufacture and frequently require customized packaging and temperature-controlled handling. 

	“From a high-level perspective, outsourcing to contract packagers allows pharma companies to do what they do best: develop and market drugs,” says Joe Luke, vice-president of sales and marketing for Reed-Lane, which offers blister packaging, bottling, pouching, and vial filling as well as secondary labeling, cartoning, card sealing, and kitting of vials and syringes. He explains, “A contract packager is usually more nimble and quicker to react than most pharma companies when it comes to packaging launches or changes.”

	With ever-evolving and increasing regulatory requirements, “outsourcing to a specialist contract packaging organization is often seen as the safest and most reliable, as well as cost- and time-efficient, way to proceed,” adds Phil DiGiacomo, senior vice-president of sales and marketing at PCI Pharma Services, a global provider of packaging services for commercial medicines as well as drug development, scalable drug manufacture, clinical trial packaging, and labeling, storage, and distribution. 

	“Brand owners are increasingly looking for full-service suppliers that are able to support them throughout the entire product lifecycle-from formulation development to compounding and filling through to packaging and delivery,” reports Shaun Gaus, president and CEO of Precise Packaging, a specialist in over-the-counter liquids and aerosols. He predicts this contract packaging market trend will continue into the foreseeable future “as it provides a variety of benefits including operational advantages and cost savings.”

	Brand owner focus on core competencies prompts demand for collaborative partnerships and a range of turnkey services potentially starting with product development and continuing through testing, clinical production/samples, pilot production, sourcing of material/components, and full-scaleproduction. “Sonic Packaging has continued to add expertise to its production management team and develop stronger ties with materials suppliers to co-develop new technologies that will add value and give brand owners a competitive edge,” says Howard Thau, president of Sonic Packaging, a cGMP-compliant supplier of turnkey packaging solutions in product development, package design, sourcing, manufacturing, and sampling, specializing in single-use, metered-dose, and applicator devices. 

	Outsourcing givesbrand owners access to the expertise and know-how of seasoned product manufacturing and packaging experts. Gaus says, “Contract manufacturing also reduces the costs of products by providing brand owners with access to flexible skilled labor, bulk purchasing costs, etc.while reducing errors. The result is a lower-priced finished product, which can ultimately increase sales and improve margins.” 

	Luke agrees, noting, “Based on the size of the package, volumes ordered, and packaging configuration, contract packagers can find cost and production efficiencies that in-house packaging may not have been able to find.” 

	Outsourcing not only can lower costs, increase sales, and improve margins, but also streamline the entire production process, by providing “one main contact point for manufacturing, sourcing of all components, scheduling, testing, and shipping of finishing goods,” concludes Thau. 

	With demand increasing for a broader range of services, contract packagers are expanding capabilities and infrastructure. For example, Pharma Tech Industries has boosted capacity and speed with the startupof a Medisealline capable of producing more than 300 sachets/min. “The Medisealline supports both client growth within the market category as well as recentand projected business [demand],” reports Tu T. Tran, vice-president of sales and marketing for Pharma Tech Industries. “Such assets are an extension of our customers, facilitating turnkey, high-speed efficiency, which fulfills cost-of-goods-sold metrics without the need to incur millions of dollars in capital expense.” 

	Aphena Pharma Solutions has expanded US Drug Enforcement Administration (DEA) operations and storage and added powder filling and inhaler capacity. “We’ve invested millions of dollars in order to provide our customer base with one of the broadest ranges of packaging formats in the industry,” said Eric Allen, vice-president of sales and marketing at Aphena, in a press release. Since 2016, the company has expanded both the CII vault capacity and the DEA-licensed CIII-CV cage at itsliquid and semisolids division in Easton, Maryland, to hold more than 85 pallets of active products. The Easton liquid and semisolid plant now includesmore than 12 custom packaging lines with additional blending equipment and capacity already on the drawing board for 2019 (1). 

	Aphena’s solid-dose division in Cookeville, Tennessee, has almost doubled in size to more than 135,000 ft

, adding packaging lines and increasing CII capacity to more than 110 pallets for blisters, bottles, carding, or kit packaging. Finally,Aphena has invested millions of dollars in serialization capabilities and to prepare for serialization data exchange (1). 

	“Investments at PCI Pharma Services have included the acquisition of new sites to support clients both globally and at a more local level, expansions of existing sites in terms of size and scale of overall physical footprint, and general line capacity extensions, as well as innovative technologies plus highly specialized cold chain, ultra-coldchain, and controlled substance capabilities,” reports DiGiacomo. In addition, he says, “We have also undertaken selective strategic alliances including an exclusive collaboration agreement with CSP Technologiesfor US clinical trials and stability testing utilizing Activ-Blisterpackaging solutions, which help protect and promote speed-to-market for pharmaceutical and medical device products with heightened susceptibility to moisture and gases, especially oxygen.”

	Contract packagers are well-prepared for serialization requirements. With at least 80 serialization lines across its global network of facilities, PCI Pharma Services delivers serialized medicines with integrated overt and covert anticounterfeitingprotection featuresand can meet current and upcoming requirements internationally. “It’s been a long journey,” noted Brad Payne, PCI’s senior vice-president of Global Operations. “The industry still has a ways to go in coalescing around a truly common standard, but PCI has been able to leverage an adaptable solution that allows us to meet the requirements of established markets as well as those countries which are still in flux with shifting or developing standards” (2). 

	Serialization is just one of the upgrades at Reed-Lane, which recently equipped several bottling lines for full aggregation. “We knew that in order to continue servicing existing customers and to grow our business, we would need to make the necessary investment in serialization,” says Luke. “From our conversations with our customers and serialization partners, we decided to install aggregation capabilities right away, instead of waiting until 2023, when it will be required.” 

	Reed-Lane also has installed a new secondary vial and syringe labeling and kitting suite and a fully validated cold-chain storage unit. “With the growth of the biologicmarket, we’ve seen a continued rise in the demand for cold-chain storage,” reports Luke. 

	Many contract packaging organizations specialize in certainproduct or packaging formats. At Precise Packaging, a specialist in over-the-counter liquids and aerosols, a new aerosol production line has boosted capacity. The company also recently opened an 18,000-ft

contract manufacturing facility with a high-speed liquid filling line and automated shrink bundler. Plans for 2019 include improvements to bulk storage and compounding areas to improve batching capabilities and capacities.

	Halo Pharma specializes in topical products. With topical centers of excellence at its Whippany, NJ, and Mirabel, Quebec, Canada, facilities, Halo Pharma helps pharmaceutical companies develop and manufacture compliant, high-quality gels, creams, lotions, and sterile and non-sterile ointments. “Halo covers the full breadth of equipment, technologies, skills, and expertise when it comes to taking a topical drug product from formulation to market,” said Lee Karras, CEO of Halo Pharma, in a press release. “Our manufacturing and packaging facilities are co-located for a seamlesstransition to commercial supply; we handle the bioequivalence (IVRT [

release testing]), chemistry, and microbiology testing that are essential for today’s dermatological markets” (3). The company offers packaging that includes tubes, jars, and bottles in various sizes, including trial or sample sizes.

	Thermo Fisher Scientific is investing $150 million in its Pharma Services business to increase capacity for sterile liquid and lyophilized product development and commercial manufacturing. New aseptic filling lines and isolator technology will be installed in Monza and Ferentino, Italy, and Greenville, North Carolina. Projects are expected to be completed before mid-2021 (4). 

	1.    Aphena Pharma Solutions, “Aphena Continues on a Path of Growth,” Press Release, Sept. 25, 2018.  

	2.    PCI Pharma Services, “PCI Pharma Services Celebrates Significant Milestone–80 Serialization Installations across Global Supply Network,” Press Release, Oct. 29, 2018.

	3.    Halo Pharma, “Halo Pharma Simplifies Topical Drug Product Development and Manufacturing,” Press Release, April 12, 2018. 

	4.    Thermo Fisher Scientific, “Thermo Fisher Scientific to Invest $150 Million to Expand Pharma Services Capabilities,” Press Release, March 18, 2019. 

Contract packagers expand operations and services to accommodate growing need. 

Equipment and Processing Report-04-17-2019

Aseptic Processing Innovations on Display

Contract Packaging Grows