Manufacturing execution systems (MES) are now considered a proven technology for bio/pharmaceutical manufacturing, and companies are moving forward with more fully implementing MES to accomplish their manufacturing operation-management tasks. The goal is to move beyond merely collecting data for electronic batch records (EBR) and to use MES in a holistic manner, enabling integration with the process automation layer, laboratory information management systems (LIMS), and enterprise resource planning (ERP) systems. 

“MES fills the gaps by introducing near real-time data exchange, work instructions, and true integration across all steps of the complex manufacturing process,” explained Gloria Gadea-Lopez, associate director of manufacturing systems at Shire, in a presentation at MES 2013, the 8th Annual Forum on Manufacturing Execution Systems, held in Philadelphia, PA, Aug.13–14, 2013. MES are a crucial link in product lifecycle management (PLM), which is an all-encompassing approach to manage information from product design through manufacturing and beyond to the end-of-life stage, added Gadea-Lopez.

The common terminology brought about by two International Society of Automation (ISA) standards, S88 (for process control) (1) and S95 (for integrating enterprise and control systems) (2), has been crucial for the advancement of MES in PLM. The S88 standard sets out a vision for designing the production process from the first R&D stage all the way to commercial production, said Baha Korkmaz, senior vice-president of operations at Enterprise System Partners, in an MES 2013 presentation. The standard sets out models for activities, procedures/processes, and equipment (i.e., physical model). Modeling the process separately from the equipment provides flexibility because recipes can be developed without equipment constraints, explained Korkmaz. Korkmaz said that process mapping (as defined in S88 and S95) is a crucial part of applying MES early in product development and later in clinical and commercial manufacturing. 

Conference participants noted that companies do support this vision of using MES in PLM, but implementing it at the process-development level can be difficult. One challenge is multiple automation and data-collection systems in different manufacturing locations. Another challenge is that, although the technology exists, the necessary application software are only beginning to emerge and are not necessarily ready to go "out of the box" for process development. 

MES vendors, several of which displayed their products at the conference, are working on developing such software solutions. Werum, for example, recently introduced a preconfigured package for its PAS-X system that is a standard software product with all major requirements available in prepackaged content modules and GMP-compliant templates, said Marc Puich, senior vice-president of sales and program management, Werum Software & Systems America, in a company newsletter. 


  While S88 and 95 standards eased communication between systems and helped users implement MES, the next step is to implement data analytics tools and standards that will ease data transfer and allow greater use of data collected by MES, noted Gadea-Lopez in an interview with 

EBR data (e.g., process parameters, material information, and event time stamps) have been buried within MES datastores and not readily available for actionable use, noted Krishna Venkataraman, director of product and technology at POMS, an MES-solutions provider, in a presentation. MES vendors are beginning to develop solutions for extracting data (i.e., data mining) and making it available for various groups (e.g., quality control, engineering, scheduling) to view in the appropriate context and more quickly respond.    

MES have value beyond EBR, pointed out other panelists. MES, for example, can be used for business intelligence (BI) data mining. These data can then be used for activities such as measuring key process indicators (KPIs) and monitoring exceptions in quality control.  

Although MES have already brought operational improvements to pharmaceutical companies, these systems offer even greater potential if used as part of an integrated system that enables comprehensive visualization of process and product data. Vendors are dedicated to developing new tools, and users are working to unlock this potential in their organizations.  

ISA95 Manufacturing Enterprise Systems Standards and User Resources

, 3rd Edition (Research Triangle Park, NC, 2011). 

Articles

Production Trends

Presenters at the 8th Annual Forum on Manufacturing Execution Systems (MES) discuss how a vision and common terminology help companies implement MES globally.

Standards Promote Successful Use of Manufacturing Execution Systems

Software enables faster optimization and improved plant safety for manufacturing process.     

Aspen Techology’s latest release of its flagship software, aspenONE V8.3, includes new functionality in the Aspen HYSYS process simulation software that allows process engineers to size pressure safety valves (PSV) as an integral part of the overall process design. This feature allows calculation of necessary safety valve sizing specifications, including relief loads and orifice size. Process data can be used to analyze multiple overpressure scenarios, and a documentation-builder tool creates data and summary sheets. Another new feature, silent-install deployment, speeds software deployment.

A feeder’s disposable feed hopper shortens cleaning time and reduces cross-contamination.     

The Schenck AccuRate AP-300 PureFeed feeder is designed for quick and easy disassembly, a dual-arm agitation system for maximizing material handling versatility, and an FDA-compliant feed hopper that is disposable and recyclable. The disposable feed hopper allows shorter cleaning cycles and virtually no chance of cross-contamination when moving from one material to another. The PureFeed AP-300 is available in volumetric and gravimetric configurations for pharmaceutical and nutraceutical applications with feed rates from 0.5 to approximately 150 kg/h. 

Featured products from Pharmaceutical Technology's monthly newsletter, Equipment & Processing Report

September 2013 Editor's Picks: Products from AspenTech and Schenck

The rapid uptake of single-use vessels for use in bioprocessing applications has made assuring integrity that much more crucial. Although major failures in the seams or large punctures in a vessel should be visible to the naked eye, the real problem lies in the potential presence of microscopic holes. These smaller imperfections are often undetected and can cause not only leaks, but also the ingress of microbial or other contaminants into the vessel, thus ruining the entire batch. It is crucial that each vessel is tested, prior to use, to assure that there are no holes or leaks in either the vessel’s walls, seals, or—importantly—the joints and seals between the valves and tubings that enter and leave the vessel. 
  
For many years, the only nondestructive technique available for detecting leaks was the pressure-decay method, which can typically identify holes that are 250 µm (for a 200-L vessel) or 500 µm (for a 1000-L vessel) and is reasonably effective when used on small vessels. In testing larger vessels, however, the accuracy level exponentially decreases because the vessels’ lack of rigidity means they can relax, therefore continually changing the pressure within the vessel. This can be overcome, to a certain extent, by constraining the vessel between two plates as it is pressurized. Holding the vessel in this manner makes it less likely to relax, which results in a more steady pressure hold and, hence, a greater sensitivity to any loss in pressure. In some instances, using this additional constraint method, defects down to 100 µm can be detected in a 200-L vessel, which is a significant improvement from standard pressure-decay testing limits of approximately 250 µm, but still risks allowing smaller defects to go undetected. 


Studies coordinated by ATMI found that microbes proved to be unable to penetrate a vessel defect of 10 µm or smaller, and ATMI developed a solution that can measure defects as small as 10 µm using helium tracer gas (HIT, ATMI). Unlike the pressure-decay method that measures pressure loss in a vessel, this method measures the amount of tracer gas leaking through a defect. Although helium was well established in leak-testing protocols in the automotive, aerospace, and vacuum industries, ATMI’s method was the first use of helium in integrity testing of flexible vessels used in the  bioprocessing industry.

To carry out HIT testing, the vessel is placed inside a well-sealed, rigid chamber and connected to a helium inlet valve. The seals ensure no air or other gas can enter or leave while the test is in progress. All the air is then pulled from the chamber with a vacuum until there is a negligible amount of helium in the chamber. A predetermined amount of helium is injected into the vessel. If there are no defects in the vessel, the helium will remain inside it. If there are any defects (e.g., holes or splits), the vacuum will cause helium to escape from the vessel into the chamber. If this happens, the helium is detected using mass spectrometry; the amount of helium detected correlates precisely to defect size. 

Detection limits of HIT, however, are not the only advantage over the constrained-plate method. In the real world, a single-use vessel is not just a vessel with a single inlet. It will have a number of different inlet ports, all attached to connectors and tubes, particularly if it is being used as a bioreactor instead of a product-storage container. These ports and connectors are the most vulnerable part of the vessel in terms of leaks, holes, and other defects. To run a constrained-plate pressure-decay test, however, all of these ports and inlets must be removed from the vessel before it can be placed between the plates. Therefore, not only does the constrained pressure-decay method offer lower sensitivity, it also omits testing of the ports and inlets that have shown to be most likely to fail. In contrast, the HIT method allows a fully assembled vessel to be tested. The entire vessel, including the tubing sets, is placed inside the test chamber. If end connectors have porous membranes on the tube ends, the outlets  are blocked using a plug or sealing mechanism to allow testing of the joints between the tube and end connector. 

In addition to being offered for the preshipping validation of vessels and manifolds manufactured by ATMI, HIT technology is now available to end-users for testing in their own facilities of single-use systems from any supplier. On-site testing enables processors to verify the integrity of vessels at the point-of-use, immediately prior to use, giving a further failsafe to ensure that expensive batches of biopharmaceutical products are not spoiled by microbial contamination or lost through a leak. HIT testing can currently be applied to vessels up to 200 L, with plans to extend this to 2000 L.

Vishwas Pethe is a R&D scientist, vpethe@atmi.com, and Alex Terentiev, PhD, is R&D and engineering director, both at ATMI LifeSciences.

Troubleshooting

Helium integrity testing offers advantages over pressure-decay testing for biopharmaceutical single-use vessels.

Helium Integrity Testing of Single-Use Vessels

The counterfeit drug problem shows no signs of disappearing. In fact, since January 2012, FDA has issued warnings about fake Adderall (dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate), Avastin (bevacizumab) and Altuzan (bevacizumab) (1-3). Fortunately, even as counterfeit products are discovered in marketplaces worldwide, drugmakers have added weapons to their anticounterfeiting arsenal. 

 One way to authenticate product involves a syringe label with overt and covert security features. These features include a security printing-image and a 23-digit, encrypted KeySecure code overprinted with a removable scratch field (see Figure 1). The KeySecure technology from Schreiner Medipharm is already commercial in China where Q-Med AB adopted it in 2012 to protect prefilled syringes of its Restylane gel (an injectable hyaluronic-acid-based product). 

“Our customers rely on a product that has been subjected to years of research and testing,” said Lars Carlson, head of purchasing at Q-Med, a Galderma division (4). “This makes it all the more important for us to prevent [customers] from suffering undesirable side effects and health problems by counterfeit products.”  

For further quality assurance and documentation, a barcode referencing the security code is integrated into the label. In addition, a customized adhesive and security slits in the substrate make it impossible to remove the label without destroying it. 

To authenticate the product, the doctor or therapist exposes the encrypted code by scratching off the overprinted ink with a coin or fingernail, dialing the phone number on the label, and entering the security code on the phone’s keypad or touch screen. Confirmation of authenticity is almost immediate. “The KeySecure tracing system allows products to be tracked anywhere in the world…web-based queries are possible too,” said Gene Dul, president of Schreiner MediPharm US (4). The telephonic code queries not only authenticate product, but also provide Q-Med with data about user behavior and alerts about potential threats, such as a rising number of false codes received from a particular region. 

Another authentication technology applies microparticle barcodes to solid dosage forms using inert silicon dioxide, which is a commonly used excipient with GRAS (generally recognized as safe) status from FDA. Invisible to the eye, the barcode, developed by TruTag Technologies, is readable via a Portable Authentication Reader, also from TruTag. The scannability enables both verification and product tracking at the dosage level and can reveal product information such as dosage strength, batch number, site of manufacture, and expiration date.

Another barcode technology combines widely used logistic symbols, such as a two-dimensional GS1-DataMatrix or QR code, with polymorphic, nonmathematical technology from Six Degrees Counterfeit Prevention. Common readers and SmartPhones read the hybrid barcode to obtain item identity, serial number, lot number, and expiration date. The encryption technology is impervious to cryptanalysis and other attacks and enables authentication without referring to a database. Since the code can only be authenticated once, any copies on counterfeit product would raise an alert. In addition, the unique encryption prevents counterfeiters from reverse engineering the algorithm and producing new codes. “Six Degrees Counterfeit Prevention will enable mass serialization for the pharmaceutical, biotech, and medical device industries; ensure brand protection and prevent counterfeiting, providing end-to-end e-pedigree, recall control, and ensure hack-proof security for all data without requiring special hardware or readers,” said Reid Graves, senior pharmaceutical advisor at Six Degrees (5). 

Other labeling technologies also can thwart counterfeiting. Thinfilm Memory electronic labels from Thin Film Electronics ASA provide an electronic signature that is virtually impossible to replicate. A handheld reader tests the label and verifies the product’s authenticity. Customized signals can be dedicated to a specific product line or manufacturer. On the packaging line, the Thinfilm Memory labels handle just like conventional labels. 

Randomly placed micro- and nano-particles create a unique fingerprint on tamper-evident labels applied to product packaging. The nonClonableID technology from Bilcare Research (see Figure 2) cannot be copied and provides instant authentication, as well as secure track-and-trace and e-pedigree data. Authentication occurs in seconds through a commercially available reader that checks a scanned fingerprint against an online database. Confirmation information also can be sent to a SmartPhone.

FDA, “FDA warns consumers about counterfeit version of Teva’s Adderall,” Press Release, May 29, 2012. 

FDA, “Avastin (bevacizumab): Counterfeit Product - FDA Issues Letters to 19 Medical Practices,” Safety Alerts for Human Medical Products, Feb. 14, 2012.  

FDA, “Altuzan (bevacizumab): Counterfeit Product - Contains no Active Ingredient,” Safety Alerts for Human Medical Products, April 3, 2012.

Schreiner MediPharm, "Q-Med and Schreiner MediPharm Partner to Secure Medical-cosmetic Products in China through Telephonic Authentication," Press Release, June 13, 2013. 

Six Degrees Counterfeit Prevention, "Six Degrees Counterfeit Prevention Announces Release of Revolutionary Hybrid Barcode," Press Release, Oct. 4, 2012. 

Hallie Forcinio is Pharmaceutical Technology's packaging editor, 

Packaging

New weapons in the anticounterfeiting arsenal include authentication and labeling technologies.

Equipment and Processing Report-09-18-2013

Standards Promote Successful Use of Manufacturing Execution Systems

September 2013 Editor's Picks: Products from AspenTech and Schenck

Helium Integrity Testing of Single-Use Vessels

New Tools Fight Counterfeiting