Continuous manufacturing promises more efficient production than batch manufacturing, with smaller-footprint equipment that can more flexibly produce small or large volumes with fewer scale-up difficulties and the potential for tighter control. Process development in continuous manufacturing is more efficient too; with a short residence time, the effects of changing process variables can be evaluated quickly. Other industries (e.g., food, chemicals, plastics) use continuous manufacturing, and it is taking hold in both solid-dosage and biopharmaceutical production. 

 has been tracking trends in continuous processes for solid dosage manufacturing, such as 

process analytical technology for implementation of closed-loop process control

continuous granulation and hot-melt extrusion

. On Tuesday morning, March 18, at INTERPHEX 2014 in New York City, 

will host several experts on Innovation Stage 2 (located on the 

 in the INTERPHEX Connects Networking Area) who will highlight developments in continuous solid-dosage processing. From 10:30-11:15 am, two presentations will focus on 

, a continuous process that is being used to improve the solubility of poorly-soluble drugs and create innovative dosage forms. Gain insight from hot-melt extrusion expert Charlie Martin, president of 

, who will explain twin-screw extrusion theories, as well as give practical tips and share recent test results, and hear Tony Listro, managing director of 

, share his experience in extrusion and shaping technologies for combination drug-device products. From 11:15 am-12 pm, gain a broad view of 

Engineering Research Center for Structured Organic Particulate Systems

 at Rutgers, the State University of New Jersey, and learn the latest is enabling integrated system control from Pamela Bruen Docherty, Life Sciences industry manager at 

focuses on the biopharmaceutical industry, which is under pressure to improve downstream processing (i.e., purification and separation) to keep up with upstream processes, and is exploring the potential of the higher efficiency of continuous processing, such as 

. On Wednesday, March 19 from 1:30–2:15 pm, experts will discuss 

continuous manufacturing for biologic drugs

. John-Bonham Carter, vice-president of business development at 

, will discuss trends and challenges in continuous biomanufacturing, and Stéphanie Dubois, Cell Culture lab manager and applications specialist at 

 will describe continuous cell-culture platforms and the  challenges addressed by alternative technologies.

 Another aspect of improved efficiency is the use of new facility designs. As reported in the 

, biopharmaceutical manufacturing is experiencing a shift to flexible, multiproduct facilities, which can be enhanced with single-use and modular technologies. From 2:15–3 pm on Wednesday, March 19, experts will share the latest trends in 

modular biopharmaceutical manufacturing systems

 and Modular Partners, will discuss standardized modular facility solutions, and Parrish Galliher, Founder and CTO of 

Xcellerex, a GE Life Sciences Healthcare 

company, will explain how to rapidly enable flexible biomanufacturing in a new or existing facility. 

Articles

Production Trends

Experts will examine continuous processing in solid-dosage and biopharmaceutical production.

Continuous Manufacturing Discussions at the INTERPHEX Innovation Stage

New injection-delivery systems, such as auto-injectors, recombinant syringes, and retractable needles, have introduced new challenges to package validation and product development, particularly for container closures. These delivery systems may have multiple closure points and more complex manufacturing processes with increased opportunities to introduce manufacturing related defects. For complex delivery systems, the final system is an orchestra of the individual components working together. Each component coming in contact with the critical product path must be validated to provide a reliable sterile barrier. With additional fitment contact points comes greater risk that one of the fitments will contribute to a container-closure integrity (CCI) failure. Taking a clear approach to developing the methods used to validate and assure CCI early in the process is crucial in providing a solid platform for product launch.  


  CCI is defined as the ability of a package to prevent ingress of microorganisms, chemicals, and environmental contaminants and to retain the contents of the package, thus ensuring the product meets physiochemical and microbiological specifications. CCIT is focused on detection of leaks in the sterile barrier of a package. A maximum allowable leakage limit must also be defined, because most package types demonstrate at least miniscule gaseous leakage, in addition to permeation, even when optimally designed and assembled.   

CCIT is a growing regulatory concern for all packages, and new, complex delivery systems introduce unique challenges. Before a CCIT method can be established, the sterile barrier for each package format must be defined.  Although a package may have several seals, a single barrier should be identified as the sterile barrier.  For a glass vial, this barrier includes the rubber stopper and glass body of the vial. The crimp contributes to the barrier but is not a portion of the sterile barrier field. 

 Certain component fitments may have multiple closure points as the sterile barrier, such as the ribs on the plunger of a prefilled syringe. One closure point is in contact with the product.  The outer closure point is in contact with the non-sterile environment.  The space between the ribs represents a unique no-man’s land of sterility.  If one is breached, what does this mean in terms of CCI?  Is the barrier breached? A syringe tip presents similar controversy, with a complex sterile barrier mechanism that includes the needle shield and syringe-tip cap. One contact point protects the sterility of the product, and the second contact point provides a sterile barrier to the delivery contact point (e.g., needle or nozzle).  Integrity of the overall system can be determined to assure there is no leakage of the closure system. Between the closure points, however, there is often space that must remain sterile and free from contamination by outside contaminants and from the product itself.  Interclosure sterile space must be challenged for sterility, and few tests exist to challenge the integrity of this space on a final assembled component.  When designing a delivery system, designing multiple sterile barrier closure points seems logical in an effort to reduce the risk of a breach of the sterile barrier. The multiple closure points, however, can present challenges that are both difficult to test and manage. Ultimately, for each package format, a clearly designed and defined sterile barrier is an important step in establishing CCI.  

This article was excerpted from an article that will be published in the April issue of 

Oliver Stauffer is vice-president and COO and Heinz Wolf is general manager at 

Troubleshooting

New injection-delivery systems with multiple closure points pose challenges for container closure integrity testing.

Defining the Sterile Barrier of Complex Drug Delivery Systems

Many exhibitors at INTERPHEX, held Mar. 18-20, 2014 at the Javits Center in New York, plan to showcase packaging innovations. 

 INTERPHEX marks the North American debut of the 

 labeling system from Schreiner MediPharm. This diverse portfolio of overt, covert, and machine-readable security technologies provides multiple levels of protection against counterfeiting. Overt options include complex holograms with custom artwork, two- and three-dimensional effects, dynamic structures, and micro/nano text; ShiftSecure color-shifting ink; and thermo-reactive print, which changes colors at a certain temperature. Covert features include combinations of luminescence and digital watermark, which are visible under ultraviolet light. Invisible, machine-readable LaserSecure and Laser HighSecure security pigments can be integrated into any graphic element. For more stringent requirements, the two-step DNA-Secure with red luminescence authenticates product using a handheld reader and DNA laboratory analysis. KeySecure encrypts data in human-readable text, barcode, or DataMatrix code for authentication by phone or internet. A plug-and-play system expedites implementation and simplifies integration with information technology. 

. A 266-Panel Outsert from Platinum Press offers an expanded number of panels to provide more space for product information and instructions and eliminate the need for piggybacked outserts or “twinserts.” Despite the number of panels, the 266-Fold Outsert measures approximately 20% thinner than traditional outserts. Easier to handle both manually and mechanically, the more compact printed piece increases production speeds while reducing production, storage, and shipping costs. Platinum Press also plans to show a carton with integrated insert. A window on the carton makes the insert visible for quality assurance inspection. Merging two packaging components increases line speeds and cuts costs. 

 Compliance-prompting packaging will be displayed by several members of the Healthcare Compliance Packaging Council (HCPC): Aphena Pharma Solutions Inc., Constantia Flexibles, Howell Packaging, IMA Life North America Inc., Platinum Press, Pharma Packaging Solutions, Uhlmann Packaging Systems, and Winpak Heat Seal Packaging Inc. HCPC executive director, Walt Berghahn, will give a presentation at INTERPHEX, “Improve Patient Adherence with Compliance-Prompting Packaging.” Berghahn will provide data showing improved patient adherence with compliance-prompting packaging, offer an overview of successful pharmaceutical compliance-prompting packaging, and discuss trends in smart adherence packaging. 

 The 2060 Unipac Tube Filling System from Romaco North America is a high-speed, modular machine, equipped with a 12-station turret, which handles aluminum and polyethylene laminate tubes as well as various closure shapes. The unit features an easy-to-replace upper head, quick size-changeover, and a lightweight, easy-to-disassemble dosing pump. A high-capacity, ergonomic tube loader requires no changeover and is easily accessible at the side of the machine. Options include a servo-driven dosing pump and diving nozzle.

Filamatic plans to display its economically priced Econofil System and its versatile AdaptaFil Benchtop Filler. Capable of filling with accuracy of at least 0.5%, the two-head, piston-pump-equipped Econofil System reaches speeds of 60 containers per minute. If desired, the piston pump may be replaced with a peristaltic pump. The semiautomatic AdaptaFil Benchtop Filler is equipped with a touch-screen operator interface and accommodates a piston, peristaltic, gear, or lobe pump on the same base. With the multiple pump options, the unit can fill a range of products, volumes (milliliters to gallons), and viscosities (aqueous to viscous). 

 Domino Amjet will show one of its print/apply labelers integrated with Omega Design’s Intelli-Pac Manual Case Aggregation System for serialized cartons or bottles. Featuring an ergonomic design and stainless-steel construction, the machine handles loose or bundled bottles and cartons and is configurable for manual or semiautomatic operation. The system also allows seamless integration to layer-aggregation technology, case-label printer, operator touch-screen, data-management system, case-loading table, and handheld scanner. Other capabilities include unit-to-bundle data syncing, case-to-pallet data syncing, and case-forming and case-taping capabilities. 

. The web-based Proofware suite from Global Vision consists of tools to inspect text, artwork, spelling, Braille, and barcodes. The Proofware suite also enables e-signature, annotation, call-outs, stamps, measurement, and color inspection. Deployed on an on-premise server or private cloud server, the web-based system offers instant access to everyone involved in the development and use of brand copy and artwork. As a result, it enhances the level of collaboration among teams within and outside a brand owner’s organization. Other features include report management tools, the ability to run multiple inspections with the same set of files, and easy integration with artwork, document, and product lifecycle-management systems. 

Hallie Forcinio is Pharmaceutical Technology's packaging editor, 

Packaging

Displays will include new products for anticounterfeiting, labeling, and compliance packaging and new equipment for filling, aggregating, and quality control.

INTERPHEX Features Packaging Innovations

Crane’s DEPA DH next-generation double air-operated diaphragm pump has a newly designed pump chamber, center design, manifold, and free-flow-path technology. The pump features flexible multi-port connections; a customized manifold design improves ball-valve guidance, increases functionality, and provides up to 25 different installation options. Cast feet integrated in the center block housing enable maintenance in place that, compared to the previous model, can reduce downtime by up to 25% and decrease the number of required parts by 30%. The block-mounted pump and air chambers provide a safe and well-defined diaphragm clamping mechanism. The diaphragm is fixed to its specifications to provide consistent lifetime wear and tear and eliminate overstretching of the pump. A new flow design with free-flow-path technology can accommodate particle sizes up to 25 mm, increase the scope of applications, and reduce the total cost of ownership through enhanced efficiency. 

The DEPA DH next-generation double air-operated diaphragm pump from Crane features a new design.

Crane Introduces Next-Generation Diaphragm Pump

SCHOTT expanded its range of TopPac prefillable polymer syringes (PFS) to include a 20-mL format that can be used in combination with syringe pumps in infusion therapy. Prefillable syringes significantly reduce the risk of medication errors compared to manual transfer of a drug from a primary container to a disposable syringe. This accuracy is crucial for infusion therapy, in which common medications (e.g., pain medications, anesthetics, and cardiovascular medications) have a narrow safety margin. TopPac PFS are compatible with various syringe pumps, and the exact outer diameter enables automated recognition by the syringe pumps. The syringes are also compatible with intravenous devices (e.g., needleless luer access devices). TopPac PFS’ optimized siliconization ensures consistent gliding forces for smooth drug application and also reduces the interaction of silicone with the drug throughout its shelf life. 

Schott's 20-mL TopPac prefillable polymer syringe simplifies the infusion-therapy preparation process.

Equipment and Processing Report-03-17-2014

Continuous Manufacturing Discussions at the INTERPHEX Innovation Stage

Defining the Sterile Barrier of Complex Drug Delivery Systems

INTERPHEX Features Packaging Innovations

Crane Introduces Next-Generation Diaphragm Pump

SCHOTT Introduces Prefillable Polymer Syringe for Infusion Therapy Devices