News. Pharmaceutical Preparations. In the Crosshairs Supply Chains in Pharma Production. Industrial Weighing & Product Inspection

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1 Pharmaceutical Preparations Industrial Weighing & Product Inspection 20 News In the Crosshairs Supply Chains in Pharma Production New regulations regarding traceability and serialization aim to protect consumers and facilitate fast and efficient reactions to drug-quality issues and fraud. Production processes that use data integration, compliant software and marking and control systems better manage the challenges presented by the new regulations. Supply chains in pharmaceutical production are becoming increasingly complex. According to Chemical Engineering News, more companies are outsourcing production steps to contract manufacturers to improve profitability. At the other end of the supply chain, counterfeit medicine poses a risk to patients. In 2012, the World Health organization estimated that counterfeit medicine composes 1 percent of sales in western countries and up to 10 percent in emerging countries. To reduce the risk to consumers, regulatory agencies address fraud with their guidelines. Combatting fraud also is enforced by audits that focus on data integrity and batch tracking. Let s explore the three hot spots, or places within the supply chain, where tracking and tracing is critical to comply with the new or enforced guidelines. Hot Spot 1: Raw materials GMP Guidelines state, the supply chain for each active substance must be established back to the manufacturer of the active substance starting materials. This should be documented and must be kept current. That applies to suppliers of raw materials and contract manufacturers and service companies. Scales often are data-entry points throughout production and can help to improve efficiency of such processes.

2 Compliant Supply Chains Hot Spot 2: Data integrity Production and analytical data, such as weight values, batch numbers, user IDs, time stamps and critical parameters, need to be collected, verified and stored to document each production step. Access rights to computerized systems need to be clearly identified. CFR Part 11 compliant software ensures full traceability of data management for quality critical steps, such as data collection software, formulation or statistical process-control software. Hot Spot 3: Serialization The U.S. Drug Supply Chain Security Act and the E.U. Directive on Falsified Medicinal Products 2011/62/EU both require drug packages to carry unique serial numbers to track the drug as it moves throughout the supply chain. If something is wrong with the drug, officials can use the unique number to trace its path back to the source of the problem. Each entity in the supply chain, from the original manufacturer to the end distributor, is supposed to keep track of the product coming into and out of its possession. That requires the installation and use of new systems for packaging, but also new operating procedures. Managing those challenges effectively will reduce audit-related problems and improve customer confidence in pharmaceuticals. Serialization White Paper For more information about the latest requirements for product traceability and an outlook on the changing regulatory landscape. Download the White Paper: Simplified Track & Trace Getting Started with Serialization FDA With serialization high on their to-do list, many pharmaceutical companies are uncomfortable with the thought of implementation. New hardware and software solutions can simplify the process and eliminate potential challenges. ERP Corporate Hospital & Drug Store Publisher / Production Mettler-Toledo GmbH Industrial Division Heuwinkelstrasse CH-8606 Nänikon Switzerland Manufacturer / CMO Serialization: Traceability models in the US. Third Party Logistics Wholesaler = Product flow = Data flow In the U.S., serialization will be required beginning in 2017 on both folded cartons and shipping cases. The requirements of EU Directive 2011/62 will be enforced beginning in To ensure that all systems are implemented by key dates, companies should start thinking about serialization now to avoid the laborious task of re-labelling or even repackaging old stock. The new XMV-TE system from METTLER TOLEDO contains a marking system which prints a unique serial number on cartons for end-to-end traceability. A tamper-evidence module is also included that uses a safety seal to provide protection against tampering. The system corresponds exactly to the specifications of Directive 2011/62/ EU. The product sealing is compliant with the relevant CEN standard Enhanced software solution PCE Line Manager Direct serialization software from METTLER TOLEDO has been created to network individual stations easily and directly with manufacturers IT systems. PCE Line Manager Direct connects the serialization system to manufacturers existing MES, ERP and cloud solutions. The software uses an open XML interface for integration. This enables the movement of order data from the inventory system to software. The system logs all details in reports for implementation. Once a serialization order is complete, the data is sent back via FTP upload or stored in a pre-defined directory. Flexible and scalable The software can be upgraded at any time. For example, if entering new markets, it is possible to add new coding scenarios as required. It can also be upgraded for aggregation purposes or to control entire lines. Subject to technical changes 09/2016 Mettler-Toledo GmbH 2 METTLER TOLEDO Pharmaceutical Preparations News 20 METTLER TOLEDO Pharmaceutical Preparations News 20 3

3 Laboratory Data Integrity Data Integrity and Automation Enable a Culture of Quality The QA management system at Novartis has clear objectives: efficiency, compliance and traceability with complete data integrity. Their ChemOps site in Brazil set the goal of ensuring data integrity and simplifying analytical processes. With the help of LabX software validated for multiple instruments, their goal has been achieved. Novartis is a well-known global leader in health care with their headquarters located in Basel, Switzerland. The company has around 135,000 employees in 140 countries worldwide. In Brazil, Novartis has over 3,000 employees in 4 different locations. One of these operations, ChemOps in Resende, produces a wide range of active pharmaceutical ingredients (API) and their intermediates used in the production of therapeutic drugs. Intermediates of the Diovan compound are the main product of the site today. The Culture of Quality project ChemOps in Resende is part of the Novartis Culture of Quality project. The major objective of the project is to ensure data integrity, i.e. records of analytical results that cannot be manipulated by the user. This project led to various actions in their analytical sector. A wide selection of METTLER TOLEDO instruments are involved in quality control analysis at the Resende site with the latest installations being an MP90 melting point instrument and an RM40 refractometer. Both are fully validated in compliance with 21 CFR Part 11 through LabX, a software solution that controls most of the instruments, automates the analysis and manages the data. The key goal of this installation was to improve the reliability and tracking of analytical results through enhanced automation which, in turn, improves product quality. Manager and operator satisfaction Novartis QC lab manager Silvio Toledo already feels the benefits of the LabX soft- ware system, Thanks to integrating the MP90 and RM40 instruments with LabX, the reliability and traceability of analytical results has increased significantly. The improved automation of the system has contributed to the increased quality of our analytical results and reports. In 2012, ChemOps Resende achieved the largest number of batches analyzed by full time employees out of all the ChemOps Novartis sites. Several Novartis employees have now had hands-on experience with the validated LabX system. These operators are highly satisfied as, The user interface is intuitive and easy to use. There is an excellent task fields tool where we can add relevant warnings if necessary. Another great feature is the option to make calibration compulsory if necessary. This greatly facilitates the daily laboratory routine, reduces paperwork and fulfills 21 CFR part 11. The practicality of an integrated system run by a single software is fantastic. It not only helps with our daily analyses but also when searching for results in the audit trail. Novartis Resende have now added to the instruments already managed by LabX Left: OneClick to your desired method Right: Melting Point sample capillaries and have connected a larger number of balances to this data-management system. Thanks to METTLER TOLEDO s LabX software system, ChemOps Resende gets consistently high quality results with simplified workflows and increased efficiency. Another positive step achieved towards Novartis Culture of Quality. 4 METTLER TOLEDO Pharmaceutical Preparations News 20 METTLER TOLEDO Pharmaceutical Preparations News 20 5

4 I can transfer the knowledge of one sensor to another with just a click. Intelligent Sensor Management Sensors That Learn Give You the Most Reliable Diagnostics To maximize product quality and yield, you need to know if your sensors are performing correctly. That is why we have always made diagnostics the main focus of Intelligent Sensor Management (ISM ). And with our new version of ISM we offer a world s first sensors that actually learn from your processes to give you unequalled diagnostics performance. Breakthrough innovation Since its launch in 2006, ISM technology has gone on to help hundreds of companies across the world increase process reliability, reduce maintenance costs and simplify sensor handling. One of the central features of ISM is its diagnostic algorithms that predict when sensor maintenance, cleaning or replacement will be required. With our new, advanced algorithms we provide a breakthrough innovation sensors that actually learn from and adapt to processes. This gives you exceptionally reliable diagnostics that are specific for every single process. No more guesswork ISM sensor diagnostics do not give you raw data that has to be interpreted: they provide easy-to-read tools that tell operators what needs to be done and when, to keep sensors and your processes running reliably. Sensor diagnostics mean you can confidently plan maintenance for when it is actually needed neither late which can damage production, nor early when it is not required. Keep your processes in the lead There is a huge variation in processes found across manufacturing, so the latest ISM sensors actually adapt to the conditions they operate in. As a consequence, ISM diagnostics represent each and every process more accurately than ever before. This enables you to further optimize maintenance and calibration procedures to get the most out of your resources. Diagnostics speed saves time Exchanging sensors can lead to risk exposure as a measurement point is taken offline, so a fast ramp-up and getting back to reliable operation is key. To always ensure your sensors are up and running quickly, the new algorithms provide accurate diagnostics in only 24 hours. They not only learn they teach In some applications the process conditions mean that it can take some time for algorithms to stabilize and give you precise diagnostics data. have already been used in an application. For example, when a ph probe is removed from a process and is connected to our 21 CFR part 11-ready isense software, information on the conditions of that particular process can be stored as an application profile. This profile can then be transferred into a different ph sensor. When this second sensor is installed in the same process, because it carries the knowledge of its predecessor, it does not need time to acclimatize. And if conditions in the process alter, the sensor diagnostics adjust themselves appropriately. Sensor maintenance exactly when it is needed Now diagnostics are accurate as soon as a sensor is installed and you can be sure you are conducting maintenance when it is necessary. Which means that you can be certain your sensors are always performing at their best. Beyond Plug and Measure With the application profile database on isense and the ability to calibrate ISM sensors away from the process, you can build a stock of ready-to-go application specific sensors. Now you can replace a sensor at the measurement point in seconds, without having to adjust the transmitter. For today s processes and tomorrow s The new advanced diagnostics and other ISM developments, such as a mobile app that provides a quick sensor check on the go, mean that ISM will remain the leading technology in analytical measurement. Request a free demo: We have solved this by giving ISM sensors the ability to learn from other sensors that 6 METTLER TOLEDO Pharmaceutical Preparations News 20 METTLER TOLEDO Pharmaceutical Preparations News 20 7

5 Checkweighing & Serialization Weighing, Printing, Verification, Sealing Four Technologies, One Inspection Solution An independent company based in Germany manufacturers and supplies liquid, semi-solid and solid pharmaceutical products. New inspection technology has enabled the company to check package contents, print serialization data, verify codes and apply tamper-evident seals. Krewel Meuselbach GmbH is a mid-sized, independent pharmaceuticals manufacturer with a presence in more than 20 countries. The company has facilities in Eitorf and Gehren, Germany and produces a wide range of pain relief and cold & flu products. Comprehensive quality program The company recently installed compact XS2 MV TE systems on a thermoforming line as part of a comprehensive quality-control program. The systems are also helping to combat instances of product counterfeiting and falsification. The XS2 MV TE combines precise weighing, marking, sealing and verification with global requirements for traceability and the prevention of product falsification, addressing the needs of new and upcoming regulations in Europe and the US. Key for international business The installation is especially important for pharmaceutical manufacturers like Krewel Meuselbach, which produces goods in line with EU Directive 2011/62/EU and the GMP standard, and markets its products internationally. The XS2 MV TE system has proven to be a reliable solution that meets our requirements when it comes to safety markings and tamper-evident seals, says Hilmar Höhne, head of the Technical Department for Krewel Meuselbach. It integrates perfectly into our existing production environments, he says. The XS2 MV TE features a reliable weighing unit with a track-and-trace component and a tamper-evident labeler. The weighing unit ensures that pharmaceutical packaging is complete by checking the weight of the product. If any of the contents are missing, the product is automatically removed from the production line by means of an air jet. Once a data-matrix code and plain text have been printed on the carton, a camera checks the printing and rejects products that fail to meet Krewel Meuselbach s quality requirements. Tamper-Evident seal A tamper-evident seal on the packaging protects the product against adulteration. Self-adhesive sealing labels are attached to both tab openings of the packaging. Sensors then check whether the seal has been correctly applied and confirm the carton is securely sealed. The seals provide security, ensuring consumers can easily see if the seal has been tampered with. By 2018 at the latest, prescription pharmaceuticals and individual over-thecounter medications will need to be protected against falsification and clearly identifiable Höhne says. We are already meeting these requirements. The XS2 MV TE optimizes production efficiency. The system provides complete carton-handling through the use of product guidance systems, product transfer units, labelling systems, tamper-evident labelers and inspection cameras. Together, those solutions ensure a reliable product flow, a clear print image and a correctly placed seal. Software completes the package Krewel Meuselbach also uses PCE Line Manager Direct serialization software to process the 20 different packaging formats used by the company, as well as job information and product data. It also generates and stores the printed codes, serial numbers and image information. In addition, PCE Site Manager Software is utilized to ensure comprehensive production-line management, providing all information about the process, such as output, product and packaging quality, and coding. PCE Site Manager is connected directly to the Krewel Meuselbach production database and provides those responsible for quality management with valuable information from multiple production lines at both production sites when necessary. The Importance of Serialization Why is it necessary? How can it be simplified? What hardware and software solutions are available? For more in-depth information download our track and trace solutions guide 8 METTLER TOLEDO Pharmaceutical Preparations News 20 METTLER TOLEDO Pharmaceutical Preparations News 20 9

6 Filling in Hazardous Area Case Study Compliant, Start to Finish Traceable Filling and Reporting An Indian pharmaceutical company needed to secure safe data printing from scales in hazardous filling areas. A customized intrinsically safe weighing solution ensures worker safety while providing traceable recordkeeping, resulting in better productivity and more time for value-added activities. A pharmaceutical company* based in India develops, produces and sells raw materials, intermediates and APIs for anti-infectives and other therapies. This includes handling of potentially explosive materials. Workers prepare those substances for shipment in hazardous areas classified as ATEX Zone 1/21 and Zone 2/22. Inefficient manual documentation Before shipping, operators must capture the weight of each outgoing container. Room 1 ATEX Zone 2/22 IND560xx 30kg Platform Room 2 ATEX Zone 1/21 They keep one report for internal records and send a copy with dispatched material. While effective, there was one problem with this method. Because of the nature of the hazardous-area handling, all records were completed by hand. Those handwritten logs then had to be entered into spreadsheets after the shift. This process not only came with a risk of human error, it also took a significant amount of time that operators could have put to use completing other value-added tasks. Manual filling machine Room 3 ATEX Zone 2/22 A complex process The company s process necessitated the use of three rooms, which added complexity. In room 1, which is classified Zone 2/22, empty containers are weighed and placed on a conveyor belt. The belt moves the containers to room 2 a Zone 1/21 hazardous area where they are filled to a 20 kilogram capacity. Finally, filled containers are conveyed to another Zone 2/22 area, room 3, where they are weighed again. Could company management find IND780xx 30kg Platform Pictured is a fill line with IND560xx and IND780xx hazardous-area weighing terminals and a safe-area printer, according to customer requirements. Room 4 Safe Area Printer a cost-effective way to bring electronic recordkeeping and traceable report printing to this multi-step, paper-based process? In a word, yes. Integrated documentation The solution, which involved report generation directly from intrinsically-safe scales, came from METTLER TOLEDO India representative Deepak Pal. While the three-room process remains unchanged, today the new equipment configuration for the fill line (Figure 1) includes: A PBA430 platform with 30 kilogram capacity and IND560 weighing terminal are installed in room 1, where the attending operator tares empty containers. The scale is connected to an IND780 weighing terminal with another PBA430 weighing platform in room 3 via RS485 cabling. Here the attending operator obtains and accepts the net weight after automated filling in room 2. Data from both scales is stored in the IND780 terminal. Printouts are generated in a nearby safe area via an Epson printer connected via RS232 cabling. Easy customization While both IND560 and IND780 provide a high degree of programming flexibility on their own, TaskExpert has been an important factor in the success of the new system. As a graphical programming environment, TaskExpert made it easy for the company to customize its application. Operators created special user interface features to simplify interactions with terminal functions and more intuitively manage databases all without learning special programming languages. Safe and compliant processing With the intrinsically safe nature of the new set-up, the operation adheres to hazardous-area standards, keeping workers safe. With the new scales and reporting capabilities, the operation also maintains airtight traceability. All product details, batch numbers, processing date/time and tare/gross weight are catalogued for internal quality control and client recordkeeping. A consultative service approach with Pal and other METTLER TOLEDO representatives working alongside the company s process experts has helped ensure that management has a solution they feel confident about. In addition, the company is saving two man hours per day on operations plus the added savings from eliminated operating and documentation errors. Company management was able to secure the budget, and the equipment they chose will provide returns many times over in the coming years, Pal says. * Company name excluded for confidentiality reasons. 10 METTLER TOLEDO Pharmaceutical Preparations News 20 METTLER TOLEDO Pharmaceutical Preparations News 20 11

7 Are You Testing Enough? Or Too Much? ISO9001 requires that weighing equipment must be calibrated and verified at defined intervals. But how those tests should be done or how often is not specified. Our GWP Verification service provides testing recommendations based on your process requirements. Minimize risks and reduce costs Optimize your routine testing to ensure consistent weighing results. Save costs by eliminating unnecessary tests. Assure traceable documentation including testing procedures and frequencies. Improve Your Scale Testing For more information Mettler-Toledo GmbH Industrial Division CH-8606 Nänikon, Switzerland Local contact: MTSI