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February 2013 Editor's Picks: Products from Schenck AccuRate and Eriez

Serialization, the application of a unique item-level code that provides traceability and serves as the backbone of pedigree records, depends on integrated hardware and software plus data collection and access up and down the supply chain. With pedigree requirements in place or pending in several parts of the world and less than 24 months before the California E-pedigree Law begins to take effect on Jan. 1, 2015, it seems prudent for any current packaging-line equipment purchases to be serialization-ready so, when implementation time comes, the transition is as seamless as possible. The California law applies only to prescription drugs sold in the state. Unless and until FDA writes national regulations, however, industry observers predict the California law will serve as the 

 United States standard because it will easier to serialize all prescription products rather than segregating and serializing product destined for California. 

Fortunately, it’s not that difficult to find machines that are serialization-ready. One checkweigher integrates printing of unique codes and verification with the weighing function. A single operator interface controls all action from one screen to simplify operation. Capable of weighing up to 550 packs per minute with an accuracy of ±50mg at 3 sigma, the checkweigher is compatible with a variety of coders and vision systems, giving brand owners the flexibility to specify their favorite models. Adjustable side belts maintain control of the bottle or carton moving through the machine to ensure correct positioning during marking and verification. Two reject systems, one working with the vision system and one linked to the scale, ensure only properly coded and filled packs continue down the line (Versa RxV Checkweigher, Thermo Fisher Scientific).

A label applicator applies serialized single, dual, or wraparound labels at rates up to 200 bottles per minute. An onboard, ultraviolet-inkjet printer prints two-dimensional barcodes on the labels and an integrated vision system verifies code quality and correctness. An Ethernet connection delivers serialized code data to e-pedigree software. The labeler also handles labels equipped with radio frequency identification (RFID) tags and can be configured to apply labels to round, square, or oval containers ranging from 1 to 14 in. (25 to 356 mm) high and 5/8 to 7 in. (16 to 178 mm) in diameter. Integration with shrink bundler, print-apply labeler, and case packer results in a serialization-ready line. Options include hot-stamp or thermal-transfer coders, barcode readers, and missing label detectors (Model 130 Bronco Labeler from NJM Packaging and TrackSafe hardware and software from Optel Vision). 

A coding equipment supplier provides hardware, software, and services, including serialization-ready inkjet printers, laser coders, and line controllers. The line controller operates the code marking systems, cameras, reject mechanisms, and other external devices on the packaging line and helps aggregate codes for item, multipack, and case levels of packaging. For maximum flexibility, the line controller and software work with a variety of printers and cameras. The software also accommodates rework by deactivating the code on a rejected product and assigning a new code after rework (IMprints Track & Trace Solution, Videojet). 

Another provider of serialization hardware and software supplies all necessary packaging line modules. The first module applies a unique, alphanumeric or two-dimensional DataMatrix code to primary containers, which proceed through a bundler. Codes on containers in the bundle are aggregated and bundles are labeled. Bundles are loaded into cases and aggregated, and cases are labeled. Cases are palletized, and pallets are aggregated (DataMatrix Station XMV bottle/carton marking or Bottle Serialization Station, Advanced Bundle Station, Shipping Case Station, Pallet Aggregation Station, Pilot Device Manager, Pilot Line Manager and Pilot Site Manager software from Mettler Toledo). For less automated lines, a standalone system, equipped with a scanner and printing equipment, provides a location for code marking and aggregation of codes on primary packages, bundles, cases, and/or pallets (Manual Aggregation Station, Mettler Toledo). 

Hallie Forcinio is Pharmaceutical Technology's packaging editor, 

Packaging

Equipment purchased today for the packaging line should be serialization-ready in preparation for upcoming requirements.

Be Prepared for Serialization

This article addresses energy management in biopharmaceutical facilities, but much of the advice is applicable to any pharmaceutical facility.  The article is excerpted from a series of primers with training experts from the National Institute for Bioprocessing Research and Training (NIBRT) published in 

. NIBRT provides training, educational, and research solutions for the international bioprocessing industry in state-of-the-art facilities located in South Dublin. It is based on an innovative collaboration between University College Dublin, Trinity College Dublin, Dublin City University, and the Institute of Technology Sligo. Michael Lacey is plant manager at NIBRT and is responsible for facility, equipment maintenance, and support services to the plant’s core business of bioprocessing, training, and research.

PharmTech: In terms of specific facility operations, can you address the common needs for energy management in biopharmaceutical manufacturing? Also, what key things should companies look for when planning for these systems?

Lacey: Energy management is becoming increasingly important across the industry given the strong green agenda worldwide and the need to reduce carbon footprint. There is also a very strong need to reduce cost base, and energy cost is a major portion of the operation cost of most pharmaceutical plants. Companies fall into a number of categories in terms of how they manage energy. For example, there are companies who manage energy very well according to national and international standards. They dedicate resources to energy management, and these resources make a big difference to operating cost. There are other companies who engage in energy projects and do quite well in terms of saving money, but perhaps, don’t manage energy in a structured way. And then there are those companies who do not address energy issues at all.

Overall, energy must be factored into plant design and construction. It’s particularly relevant to those who are looking at inward investment in new plant construction. New plant construction provides an opportunity to get energy management right. The problem that the industry faces in designing a plant is that it must comply with cGMPs and must be validated. Requirements for energy usage reduction can sometimes conflict with cGMPs, for example in relation to air changes, but I am convinced based on my experience that designers, production teams, quality teams, and engineering teams can work together to deliver an energy-efficient plant that is also GMP compliant.

PharmTech: What other factors are at play with energy systems and cost?

Lacey: There are many opportunities to make gains in terms of the building, such as good insulation and draft-proofing, use of solar gains, natural lighting, intelligent lighting, compressed air usage, an optimum strategy for HVAC (heating, ventilation, and air conditioning), and use of alternative energy sources. HVAC systems are major energy users, because of the requirement to make air changes in rooms and to condition the air. Air changes represent scope for cost savings. For example, if you have a Grade B room with a national requirement of 20–30 air changes per hour, the air change rate should be critically reviewed to suit the operation. At building design stage, room sizing (i.e., volume) should also be optimized. Thus, the air moved and conditioned can be minimized and so minimize energy usage. Most HVAC systems in pharmaceutical processing applications are “once-through.” However, the use of recirculation systems should be adopted where possible as these are less expensive to run. Finally, room temperature control is key to optimizing energy usage. Room temperatures should be selected to suit the process and/or occupants.

Lighting is an appreciable proportion of a plant’s energy usage. High-frequency fluorescent systems allow for dimmable lighting, so facilities can use dimmers to control the lighting in a way that it reacts to ambient light level. If a building has natural light, the fluorescent lighting levels can be dimmed accordingly. Lighting in public areas should react to presence and ambient natural light. “Intelligent lighting systems” should be considered.

Air compressors represent another area of opportunity for cost savings. Companies should analyze their air usage, and maybe use two or more smaller compressors rather than a single larger one. They should have variable-speed drives (VSDs) to allow maximum flexibility of response to demand. Most importantly, plant managers should ensure air leaks are repaired, as leaks can represent up to 30% of compressed air generation, and contribute significantly to energy wastage. In a medium size plant of 10,000 square meters, it can cost something like €60,000–70,000 (approximately $78,000–$91,000) per year to run a compressor.

Lastly, it’s important to train staff about energy management. People use energy, and if they are taught good habits (e.g., turning off lights and monitors), then money can be saved.

PharmTech: You mentioned using two smaller air compressors instead of one larger unit. What benefit does this provide?

Lacey: As I mentioned, an air demand analysis needs to be done before that decision is made. Your air compressor supplier can do this for you. This improves response and “scalability” between air demand and compressor running. One plant I worked with had a single, large compressor supplying the entire factory, and had a fixed-speed drive. The problem with this is that the motor either runs 100% or is off completely. This means that a large motor has to stop and start in response to changes in demand and this is not energy-efficient. A smaller unit fitted with a VSD can respond more flexibly. Using two smaller compressors also means that you have a backup in case one unit fails.

Troubleshooting

A Q&A with Michael Lacey, plant manager at the National Institute for Bioprocessing Research and Training.

Energy Management in Bio/pharmaceutical Facilities

Continuous solid-dosage manufacturing that uses quality by design (QbD) for process set-up and process analytical technology (PAT) for continuous, real-time process control is a vision that is starting to become a reality. In the past year, research at university-based consortiums has been transferred to the pharmaceutical industry. 

Researchers at Rutgers, the State University of New Jersey, in the Engineering Research Center for Structured Organic Particulate Systems (

), successfully connected traditional unit operations to form a continuous direct compaction tableting process. C-SOPS, based on the Rutgers University campus and in partnership with Purdue University, The New Jersey Institute of Technology, and The University of Puerto Rico at Mayagüez, brings together a cross-disciplinary group of engineers, scientists, and industry leaders from academia, pharmaceutical manufacturers, and equipment manufacturers. C-SOPS has been investigating continuous manufacturing concepts since 2006 and has worked on both the fundamental science and commercialization of advanced pharmaceutical manufacturing. In 2012, C-SOPS collaborated with Janssen to develop a direct compaction line using continuous manufacturing principles. The continuous direct-compaction line replaces the traditional multistage batch process by integrating feeders, mills, blenders, and a tablet press into a single continuous process. C-SOPS researchers built a full-scale production line at Rutgers to test concepts and define a design space. Janssen is now constructing a line based on that design, which is hoped to be operational in 2014.

In developing the line, C-SOPS researchers defined parameters and performed design-space experiments to evaluate the effect of parameter changes. “Because the process is continuous, we were able to measure parameter-change effects in nearly real-time; we performed a full set of design experiments with dozens of conditions, in hours rather than days to weeks, and used a fraction of the API needed for batch processing,” explains Douglas Hausner, associate director for industrial relations and business development at C-SOPS.

A major challenge in developing continuous manufacturing is process control. “Control systems must be integrated with PAT using closed loop control and process management in order to fully implement QbD and completely control the system,” says Hausner. C-SOPS continues to work on process control integration within its production-scale Continuous Pharmaceutical Advanced Manufacturing Laboratory (CpAML).  At this facility, process-control hardware and software from various vendors are used with existing and emerging PAT in a production-scale pharmaceutical manufacturing facility. The environment allows research to be performed in an industrially realistic environment.

The Novartis–MIT Center for Continuous Manufacturing (

), based at the Massachusetts Institute of Technology (MIT), used a different approach to develop an API-to-coated tablet continuous manufacturing prototype. The Novartis–MIT CCM started the beginning of a 10-year partnership in late 2007 and completed its prototype, end-to-end continuous manufacturing line, which begins with forming the API and ends in coated tablets, in late 2011. The system was put together entirely from scratch and is completely new to drug manufacturing. In 2012, CCM completed its work of fully integrating a control system that automates the process as a whole by using mathematical models.  CCM researchers also published work in continuous reactive crystallization, which is integrated directly into the end-to-end process (1). MIT researchers are now focused on translating various technologies for transfer to Novartis, says Bernhardt Trout, director of the center and chemical engineering professor at MIT. Novartis has set up its own unit to implement continuous manufacturing on the pilot and ultimately to full-production scales and is planning to implement continuous manufacturing technologies across its entire portfolio, once testing at the upcoming pilot plant is successful. 

Production Trends

Engineering groups at Rutgers and MIT constructed solid-dosage continuous manufacturing lines and transferred the technology to pharmaceutical industry partners.

Equipment and Processing Report-02-20-2013

February 2013 Editor's Picks: Products from Schenck AccuRate and Eriez

Be Prepared for Serialization

Energy Management in Bio/pharmaceutical Facilities

University Research Centers Transfer Continuous Manufacturing Technology to Industry