Unit Operations / Automation & Control / cGMPs / QRM Process

Soaring Innovation, Grounded Goals

Readers recognize tools that break new ground but promise to improve efficiency

By Paul Thomas, Senior Editor

What is innovation? It’s one of those circuitous philosophical questions that can be debated endlessly. Whether the word conjures images of Steve Jobs or Thomas Edison, innovation is happening every day in the pharmaceutical industry.  Patients’ lives depend upon your innovations.  But how innovative are the tools that are being introduced to help you do your jobs every day? 

This article briefly highlights some of the new products that you, the readers of our magazine, have found to be most innovative. One key requirement for consideration was that a nominated technology must have been formally introduced to the market after January 1, 2010.

Each nominated technology has been put under the scrutiny of members of our editorial advisory board and other industry experts, who have helped us separate wheat from chaff. We received over 50 nominations to start with, and with the help of advisors have whittled them down to those listed below.

This is not an all-inclusive list. If you feel there’s a technology out there that deserves notice, let us know. Here are our reader-nominated 2012 honorees:

Microbiology
Microbiology is an area of drug manufacturing that has seen rapid innovation in recent years, led by the proliferation of rapid microbiological methods (RMM). Processes for tracking and identifying microbes that used to take weeks can now be done in days. Not surprisingly, many new technologies are joining the RMM bandwagon, making it harder and harder to decipher which are truly innovative.

Even the experts we consulted were not in full consensus, and yet here are the nominated technologies they see as difference-making:

BioTrakBioTrak Real-time Viable Particle Counter (TSI, Inc.): “This is truly innovative as it counts viables, non-viables and collects the viable organisms for subculture,” says one of our experts. It’s this ability to collect the counted viable organisms that distinguishes the BioTrak, the expert says. Another concurred that what separates this technology is the cell capture filter.

On paper, says another microbiologist, real-time viable particle counting has great potential. In practice, he says, “issues relating to the discrimination between ‘live’ and ‘dead’ cells needs to be ironed out (non-microbiological fluorescent particles).” Another issue is how detection by the instrument relates to colony forming units and how this, in turn, relates to regulatory guidance. So while the technology is promising, he says, “some of the philosophical questions in relation to regulations require careful discussion.”

A technology that our experts like is the PLEX-ID Molecular System from Ibis Biosciences (now part of Abbott). PLEX-ID has been around for a few years, but is just gaining market penetration in the U.S. and was only recently introduced into the European market. “The ability to detect multiple microorganisms moves the art of microbial identification forward and can deliver significant time savings, moving past the need to obtain a single culture,” says one of our experts. “The sample throughput and time-to-result features (of up to 250 samples per day) is impressive and would fit the needs of most busy laboratories. Furthermore, the size of the database is comprehensive and should match most applications.”

Finally, one of our experts nominated Pall’s GeneDisc Rapid Microbiology System, and others concurred. The GeneDisc uses polymerase chain reaction (PCR) technology and consists of three steps: a DNA Extractor for sample prep, a disposable Plate for assays, and a Cycler which performs the qPCR assay and automatically records results (without operator intervention).

“This technology is new and innovative,” says one micro expert. “The automation of the system is the real advance.” The GeneDisc is well-suited for a Microbial Limits Test. “The advantage is the speed and the accuracy, whereby specific pathogens can be targeted and detected,” another expert says.

Analytical and Monitoring Devices
With the encouragement of process analytical technologies (PAT) by FDA and other regulatory bodies, technologies that manufacturers have been tinkering with for decades came in vogue. “We’ve been doing PAT for years,” is a common refrain. But only recently has it been given its due respect by pharma’s higher-ups. As such, there’s been a wave of new PAT and related technologies of late.

imMixOne is the ImMix Micromixing Hyperspectral Imager from Middleton Research. Hyperspectral imaging (HSI) is the combination of spectroscopy and digital imaging. A hyperspectral image contains many spectra, one for each individual point on the sample’s surface, providing details about the spatial distribution of materials in a sample. It is particularly well-suited to analyzing solid drug such as films, blends, and tablets, either on-line during manufacturing or in lab formulation development. The ImMix can be a tremendous help for product development, says one of our consulted experts.

Another Innovations honoree is the Eyecon 3D Particle Characterizer from Innopharma Labs. The Eyecon is a real-time 3D imager developed specifically for pharma applications such as milling, granulation, and spheronization. Information on particle shape and surface topography is included in automatically generated batch reports and size distribution histograms. Whether for real-time or archival info, one of our advisors noted, this product provides an excellent 3-D presentation of data.

picospinAnother favorite of our review panel in this category was the picoSpin-45 miniature NMR Spectrometer, from picoSpin of Boulder, Colorado. For research or manufacturing, only 20 microliters of sample fluid is needed to obtain a spectrum. The company bills the product as “100 times smaller and 10 times less expensive than any previous NMR spectrometer.” While we can’t verify this statement, our experts agree that represents a capability leap compared with existing technology.nanoram

Also noteworthy is the NanoRam Handheld Spectrometer, from B&W Tek. The NanoRam is not the first product in this space, but readers and reviewers praised its data quality and stability.

The FlowIR Continuous Flow Chemistry Analyzer, from Mettler Toledo, is an FTIR instrument for monitoring of continuous flow chemistry, making it an important technology in the expanding world of continuous manufacturing. The small size of the device allows it to be placed anywhere within the continuous reactor setup, the company says. While FTIR is nothing new, our experts say that the FlowIR is a step up in technology and a truly useful new product (having been introduced in 2011).

The AquaLab Water Activity Meter 4TE, from Decagon, was singled out for its innovation in helping pinpoint water activity for API hydrolysis, crystallization, moisture migration and caking/clumping of powders. 

Drug Delivery
The ENHANZE Drug Delivery Technology, from Halozyme, was nominated by a reader from Merck. ENHANZE is designed to improve subcutaneous delivery of injectable biologics, it uses the enzyme recombinant human hyaluronidase (rHuPH20), which temporarily degrades hyaluronan, which lies just beneath the outside surface of human skin. The temporary degradation provides a window for the improved subcutaneous delivery of MAbs and other large-molecule therapies.

Tableting and Chromatography
FetteIntroduced in Europe in late 2011 and in the U.S this spring, Fette Compacting’s FE55 Tablet Press PHOTO was singled out as being noteworthy by readers and reviewers, oparticularly for its level of automation. Fette claims that the machine allows for production of more than 90% of all types of tablets without additional investment. Inside the cube—comprised of FDA-certified high-performance polymer panels, offering access from all sides—are three pressing units that can compress 1- and 2-layer tablets as well as nongranular powder. Its “Fill-o-Matic” system has far fewer mechanical parts and fills dies without redirecting the material over several wheels as in the past.

Closely related to tableting is tablet coating.  Nominated, and given high marks for its potential to add efficiency to tablet film coating operations, Sentient’s Spectrablend is a prebSentientlended dry dispersion for tablet film coating. A polyethylene glycol-free alternative to traditional polyvinyl alchohol formulas, the coating has been designed to allow for faster dispersion times, and, thus improved production rates.It also reduces moisture uptake in final tablets, while offering comparable dissolution rates.

In the separations technology area, ChiralPak Immobilized Polysaccharide-Based CSPs (chiral stationary phases), from Chiral Technologies, were nominated.  Although the technology was introduced several years ago, a new line was added last year to improve chiral separations. “For a prep chromatographer like myself, these phases allow me to use a wider variety of solvent combinations to perform the separation,” says one of our readers from Bristol-Myers Squibb, who noted significant efficiency improvements for some processes.

Bioprocessing
Sartorius Stedim Biotech and G-Con Manufacturing, recently introduced FlexMoSys, an all-in-one “mobile facility” that includes a GMP-ready cleanroom and biopharma process train. The unit is not the first mobile cleanroom on the market, but perhaps the most sophisticated and ambitious. Inside the pod is an end-to-end single-use cell culture upstream process, including disposable bioreactor, cell culture unit, bag system, touch-panel controller, and more—an entire “presterilized and interconnected” fluid path. “The mobile bioprocessing unit was developed using suggestions from people who manufacture drugs,” said Barry Holtz, president and cofounder of G-Con.

3M uprightOne of the key trends in depth filtration is recent years has been scalability and simplicity. While not the first stackable, single-use depth filtration product on the market, the Zeta Plus Encapsulated Multi-Round System (Model #16EZC5) (3M Purification) which readers and reviewers alike praised for its automation and ease of use.

Packaging & Anticounterfeiting
In a market where solutions are proliferating daily, readers and reviewers praised two packaging security technologies:  InfraTrac’s SmartWrap, commercialized two years ago, and SignaKey, introduced last year by Nosco and SignaKey.  SmartWrap is coded polymer film for shrinkwrap, neckbands, blister packs, bottle sleeves and ingredient packaging.  It uses a patented dose fingerprinting solution that allows materials to be tagged by varying the amount of active ingredient.  SignaKey, meanwhile, is a covert or overt mark that consists of 256 equally-sized elemental spaces stacked in a square so that 16 elements are found on each side.  No marks are ever the same and the mark contains a number that allows users to access any item’s pedigree, easily, using a smart phone.  It now includes GS1-compatible data.

A machine vision system was also named as a finalist:  TriTronic’s Ultrasonic Clear Label Sensor, introduced this year, is designed to ensure correct printer setup so that clear labels on syringes will be properly positioned and read, every time.

Facility Equipment and Software
In the equipment calibration area, readers and reviewers nominated the Calibration Excellence Solution (CES), introduced this year by Emerson Process Management and Beamex. The solution combines Emerson’s AMS asset management suite, including its “Intelligent Device Manager,” with Beamex’s CMX calibration software and associated Calibrators (including the new portable MC6 calibrator—see below), and the AMS Suite Calibration Connector. CES has been tried and tested within the past few years in, for example, GSK’s Cork, Ireland, facility, replacing a mostly manual legacy method.

“We used to have a mostly paper-based calibration process,” Don Brady, GSK Cork automation engineer, told Control magazine recently. “We’re trying to achieve calibration efficiencies by using condition monitoring to reduce our total number of calibrations and then performing the remaining calibrations in a timely and efficient manner,” Brady said. “This means synchronizing instrument data between the calibration management system and the asset management system; using documenting calibrators; optimizing scheduling of planned periodic calibrations; and removing paper from the calibration process.”

While recognizing the full solution, the Beamex MC6 Field Calibrator also received an Innovations nomination—and indeed, one of our rating experts felt that calibrator on its own is deserving of notice. The MC6 offers calibration capabilities for pressure, temperature and various electrical signals, and contains a full fieldbus communicator for HART, FOUNDATION Fieldbus and Profibus PA instruments.

Other calibration products were also nominated, including Prime Technologies’ ProCal direct hosted cloud solution for calibration, which received top scores for innovativeness from reviewer experts in process control.
Given the importance of fluid control in any pharmaceutical plant, it was no surprise to find that several readers nominated products connected with valve maintenance and control.  A traditional dilemma with weld-end ball valves for pharma and other processes has been that the welding process can damage valve seat materials, while the cost of adding pipe welding to valve ends in many cases exceeds the overall cost of the valves. One solution has been to remove the seat materials during welding and then to later reassemble, which has its obvious drawbacks such as expended time and labor.

flotiteFlo-Tite Valves & Controls out of Lumberton, N.C., has introduced a line of 3-Piece Multi-Choice Weld-in-Place Ball Valves this year. The valves have integrated extended end caps with heat sink rings with a series of “radiator-type” grooves cast into the outside diameter of the valves. The design means an increased surface area, allowing more heat to dissipate during welding thus protecting the valve seat materials from harm. One pharma customer recently standardized on Flo-Tite valves, realized the benefits of the Weld-in-Place option, and insisted that its contractors be educated on the product as well. One of Flo-Tite’s field reps shares the story of a contractor who began using the product to save time and rework and, in his words, “make it home for dinner.”

Festo’s MPA/CPV bulkhead mountable pneumatic pilot valves were also nominated by readers, and praised by reviewers.

The valves and networked I/O platforms can reduce the cost of installation by 30-40%, compared to traditional networked systems, which typically are located inside a cabinet and routed externally via bulkhead connectors.  Both MPA and CPV valve termals allow for direct bulkhead mount, eliminating the need for bulkhead connectors, and all tubing and connections inside the cabinet.  Its I/O system is available to allow for connection on the same backplane, allowing direct connection to most controllers and DCS systems.

Designed to monitor equipment and building infrastructure, Yokogawa’s M1115NL wireless I/O transmitter received high marks from readers and reviewers.  Said one user, “Using this system to replace a wired solution, we could monitor temperatures, compressor usage and door status on around 80 critical freezers, where the wired system allowed temperature monitoring only.” 

Software and IT Solutions
Also new and noteworthy from Emerson Process Management is its Batch Analytics Solution. The solution will be commercially released as part of the company’s 2013 DeltaV version 12.3 release, and yet has been through field trials at several customers, one application being for fermentation control at DSM-Martek in Kingstree, South Carolina. The site used the multivariate data analysis capabilities of the solution to analyze and adjust tuning settings for temperature and dissolved oxygen, and to better define critical quality parameters by, for example, understanding inoculation conditions and DO levels.

UMetricsSIMCA-Batch On-Line (SBOL) data analysis and modeling software from MKS Umetrics recently received a major upgrade in its version 3.4. We include it here as an Innovations honoree since, with its continued improvement, it has become a key tool within several manufacturers Quality by Design efforts. SIMCA-Batch On-Line gets batch data from the process at regular intervals, through different supported interfaces (e.g., OPC, Oracle, SQL) or files, and presents the multivariate results for easy analysis and process control.

Novartis in particular has been vocal about how SBOL has been integral to its QbD efforts, citing benefits including enhanced on-line multivariate statistical control (MSPC), analysis of process variability, early (and on-line) fault detection, and design space verification, all leading to Real Time Release (RTR) of product.

AspenTech’s aspenONE Supply Chain software has long been used by various manufacturers for planning and scheduling needs. Within the past year, however, it’s undergone a major revamp. A redesigned user interface makes it easier for planners and schedulers to navigate complicated supply chains and access information that triggers quick responses to unexpected market conditions. The new interface also features an updated planning board that cuts down on scheduling time and is easy even for novice planners to use.

AspenTech was also nominated for its Aspen InfoPlus.21 Mobile app, designed to give anyone within an organization access to real-time and historical plant data (from the Aspen InfoPlus.21 database, part of the aspenONE Production Management and Execution solution). Users can tailor the app to get key KPI data, trending, analysis of performance data, and so forth. “With IP.21 Mobile, the location of critical operations personnel is no longer an impediment to problem solving,” says Rajeev Joshi, senior product manager.

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