The time is now Pharmaceutical companies are teaming up with universities to overcome technological

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1 Pharmaceutical Preparations Industrial Weighing & Product Inspection 21 News Continuous Manufacturing From Vision to Reality For many years, continuous manufacturing in the pharmaceutical industry has been a promising yet seemingly unattainable vision. However, years of development and recent technical innovations have resulted in the first approved continuous production lines, turning the vision into reality. In April 2016, the U.S. Food and Drug Administration approved the first switch from batch to continuous manufacturing of tablets at Janssen, a global pharmaceutical manufacturer owned by Johnson & Johnson. That step illustrates the growing momentum of continuous manufacturing across the industry. Changing manufacturing paradigm In light of changing market requirements and with recent support from regulatory bodies, manufacturers are increasingly willing to invest in the benefits that continuous processes can deliver, including: Easier and faster scale-up Small, flexible production facilities Real-time process quality control The time is now Pharmaceutical companies are teaming up with universities to overcome technological challenges. Equipment suppliers are developing innovative solutions to close the gaps in the production process and support manufacturers in implementing continuous solutions from start to finish. For example, accurate dosing and mixing of powders is a critical process step in continuous production of oral solid dosage (see interview on page 2). At the end of the line, fully automated contamination-detection and product-inspection systems ensure only flawless produces enter the market.

2 Continuous Manufacturing A Leap in Process Efficiency Expert Advice: Continuous Solids Dosing Continuous manufacturing of oral solid dosage (OSD) forms provides significant efficiency and quality benefits but it can also pose substantial process-development challenges. Dr. Ralf Weinekötter, an expert on continuous dosing and mixing, provides insights on the capabilities and limitations of such systems. How does a tablet manufacturer benefit from a continuous approach? A tablet press can be considered a continuous system already. However, the tablet mixture has historically been prepared in a batch mode. Making the entire process continuous provides significant efficiency gains and contributes to better product quality. What is the role of dosing and mixing in this process? The continuous dosing-mixing module is an essential element of continuous OSD production. It typically consists of gravimetric feeders for APIs and excipients, as well as a mixing module that feeds directly into the tablet press, granulator or extruder. Such a system requires much less floor space and substantially reduces development and validation time because scale-up is no longer needed. Current systems can process between 50 grams and 250 kilograms per hour. What needs to be considered when switching to a continuous process? Product quality is substantially determined by the accuracy and consistency of upstream gravimetric dosing processes. Any error will result in a deviation from target quality. Additionally, mix homoge- Dr. Ralf Weinekötter General Manager, Gericke AG, Switzerland Dr. Weinekötter studied Chemical Engineering at University Karlsruhe, Germany and ENSIC Nancy, France. He was awarded his Ph.D. at the ETH-Zürich, Switzerland on the topic of Continuous mixing of fine solids. Weinekötter is a respected author of articles, papers and books, including Mixing of Solids, published by Springer Verlag, Germany. Publisher / Production Mettler-Toledo GmbH Industrial Division Heuwinkelstrasse CH-8606 Nänikon Switzerland Subject to technical changes 02/2017 Mettler-Toledo GmbH 2 METTLER TOLEDO Pharmaceutical Preparations News 21

3 neity is influenced by mixing chamber and paddle design, rotational frequency (shear rate) and residence time distribution. Continuous processes have a reduced segregation risk compared to batch mixers because the product is directly fed into the next process without the use of intermediate bins with a high segregation risk. Material properties can also pose challenges. Cohesive materials, for example, require extensive engineering to ensure accurate dosing and mixing. Why is weighing technology a critical part of continuous dosing systems? Dosing of micro-components, such as APIs, requires a level of accuracy that only can be achieved with gravimetric dosing feeders. Other technologies for powder dosing, such as flow meters, are significantly less accurate. What are important specifications for weighing sensors in these systems? Precise feeding requires advanced weighing, optimal design of the screw feeder and a sophisticated controller that analyzes weighing-sensor data and selects the optimal settings to ensure a constant feed rate. The weighing sensor must combine high accuracy with a large capacity. The capacity is essential because the sensor has to carry the screw feeder with the feed hopper, which contains the dosing material. Not many weighing technology companies, apart from METTLER TOLEDO, can provide sensors that master this challenge of high capacity with pristine accuracy. In addition, the weighing sensor must provide a high measurement update rate and fast transmission of weighing data to the controller. This is necessary to accurately control the screw feeder and ensure constant material throughput. Are continuous processes the future of pharma preparation? Continuous processes provide significant benefits in terms of efficiency, quality and process safety. We have reached a point where suitable systems are available to help companies transition to the continuous method, and we believe the coming years will generate many more exciting developments. Key Benefits: Continuous Solids Processing Better quality: Easy integration with downstream processes, such as tablet compression, reduces segregation risk. Improved efficiency: Continuous manufacturing is an automated process with integrated sophisticated online measuring devices and control technologies to ensure accurate formulations. Faster time to market: Scale-up from lab to pilot to production is no longer necessary. Extending the operating time of the pilot module to reach normal production output is sufficient. Less space: A continuous dosing-mixing-module s footprint is just 2 x 2 x 2 meters. Continuous gravimetric dosing and mixing system for OSD production with percent accuracy. METTLER TOLEDO Pharmaceutical Preparations News 21 3

4 Serialization Time is Running Out Serialization Legislative Changes Imminent Serialization is becoming a strict requirement worldwide. To do business in key global markets, pharmaceutical manufacturers must comply with new and up-and-coming legislation. Is your business ready? The global threat from counterfeit medicines is well documented. New regulations to be implemented in the coming years will apply short-term pressure on manufacturers to meet compliance needs, but will ultimately make life safer for the consumer. New regulations imminent The introduction of new regulations in North America, Europe and Asia will help address the threat of counterfeit drugs throughout the supply chain by making serialization mandatory. The regulations will optimize the traceability of products, support the identification of counterfeit products in the supply chain by retailers and the authorities, ensure consumer safety and protect the integrity of pharmaceutical manufacturers brands. North American deadline close In the United States, beginning in November 2017, the Drug Supply Chain Security Act (DSCSA) requires that specific information be provided on product packaging. By 2023, the DSCSA will require complete interconnectivity, meaning shared ownership of data between all supplychain partners, allowing for full real-time traceability of pharmaceutical products back to their origins. European deadline in sight The European Union has adopted the use of serialization to prevent counterfeit drugs with the introduction of the Falsified Medicines Directive (FMD). Serial- ization aimed at pharmaceutical manufacturers, including amended package design requirements, will come into effect in Changes in Asia China s Food and Drug Administration has mandated that all pharmaceutical products require serialization and compliance reporting. The South Korean Ministry of Food and Drug Safety now requires serialization and serialized product reporting for all pharmaceutical products. In India, serialization is currently only required for exported products, although draft regulations indicate that may change. Time is running out The implementation of serialization solutions within the pharmaceutical packaging line is no longer optional. Time is running out for manufacturers to ensure compliance with new regulations. The legislative landscape varies from region to region. Individual printing and verification of serialization codes 4 METTLER TOLEDO Pharmaceutical Preparations News 21

5 Serialization technology The family of serialization solutions from METTLER TOLEDO includes marking and verification system components as well as checkweighing functionality, mechanical transfer units and automatic rejection devices. They can be combined into one inspection unit. The systems lay the foundation for tracking and tracing products via serial numbers. That enables downstream devices and systems to closely monitor packages throughout the supply chain, meeting regulatory trackand-trace requirements. Software completes the package PLM Direct serialization software from METTLER TOLEDO PCE has been created to network individual stations easily and directly with manufacturers IT systems. PLM Direct connects the serialization system to manufacturers existing MES, ERP and cloud solutions. 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. It s not too late there is still time to implement a serialization program White Paper Trust METTLER TOLEDO to show you the way Serialization of Pharmaceuticals A Key to Success for the Pharma Industry For more information about the latest requirements for product traceability and an outlook on the changing regulatory landscape, download the white paper. METTLER TOLEDO Pharmaceutical Preparations News 21 5

6 Bioburden Analyzer New! Real-Time Bioburden Analyzer Continuous, On-line, Accurate Measuring microbial levels in Purified Waters has almost exclusively depended on timeconsuming and error-prone culture-based lab measurements. Now, the 7 000RMS offers accurate, continuous, on-line determination of microbial contamination. Lab measurements are slow and costly The real-time monitoring of the conductivity and Total Organic Carbon level of Purified Water and Water for Injection is well-established and widely used. But for another vital pharmaceutical waters measurement, microbial counts, it is the traditional lab measurement of cell culture growth in an agar media that dominates. This method is not only time-consuming and retrospective, it regularly results in the costly investigation of false-positive results. Further, due to the high number of points-of-use (POU) in an average production facility, a single POU may only be tested a few times in a month. This can make the identification and remediation of microbial issues a significant challenge. Industry requirement for on-line analyzers The pharmaceutical industry therefore requires real-time monitoring to provide instant notification of microbial excursions. In 2013, in recognition of this, a group of seven leading pharmaceutical companies formed the Online Water Bioburden Analyzer (OWBA) workgroup. The OWBA believes that pharmaceutical companies can benefit from an on-line 7000RMS bioburden analyzer 6 METTLER TOLEDO Pharmaceutical Preparations News 21

7 microbial analyzer in a number of ways, including: 1. Lower costs through a reduction in labor due to less sampling, and reduced conventional testing and materials. 2. Fewer investigations of, and improved responsiveness to, microbial excursions. 3. Greater process understanding and product safety through real-time monitoring. Spectroscopic measurement technique Laser-induced fluorescence (LIF) is a bioburden measurement technique that can meet industry needs. All microorganisms contain metabolites which are used to regulate organism growth and development. These metabolites fluoresce when exposed to light of certain wavelengths. LIF is a highly sensitive technique that exploits this phenomenon to detect microbes. Accurate, real-time bioburden data METTLER TOLEDO Thorntonʼs 7000RMS is a new on-line analyzer for real-time measurement of bioburden in pharmaceutical water systems. It uses LIF to instantly and continuously measure microbial levels and also determines contamination from inert particles that can come from diaphragms, filters, etc. The accuracy of the analyzerʼs measurements results in a significant reduction in false-positive results. And unlike other microbial analyzers, the 7000RMS does not use any dyes or reagents and has no moving parts. It is therefore very easy to operate and maintain. The analyzerʼs touchscreen interface displays the readings for microbes and inert particles. Alarms can be set for alert, action and specification limits. The 7000RMS offers SCADA connectivity with ModBus TCP, multiple analog outputs and is Wi-Fi capable. Improved product quality at a lower cost The advanced LIF technology employed in the 7000RMS analyzer can provide continuous and accurate data on bioburden contamination throughout a water system. Assurance of in-specification microbial levels and real-time identification of excursions leads to improved product quality, greater process understanding, risk reduction and lower operating costs. METTLER TOLEDO Pharmaceutical Preparations News 21 7

8 Process Verification Passing the Audit Risk-Based Process Verification Do you have an informed response when an auditor asks, Why are you using this weight to calibrate the scale? Klosterfrau Healthcare Group always has a competent answer regarding their routine balance testing and weighing processes, making it easier for them to pass audits in the highly regulated pharmaceutical industry. For more than 200 years, the Germanbased company Klosterfrau Healthcare Group has been developing, manufacturing and selling pharmaceutical products. Its portfolio combines traditional remedies with modern drug therapies and encompasses more than 30 brands and nearly 220 over-the-counter products. At its Berlin site, the company runs stateof-the-art production lines. Scales and balances, whether in quality control or production, are an integral part of the process. Every piece of weighing equipment in use must be regularly calibrated and qualified to ensure regulatory compliance. The compliance challenge The challenge for Claudia Brostmeyer, Head Quality Control at the Berlin site, is to ensure that all workplaces with their variety of processes and responsibilities calibrate and qualify weighing equipment according to stringent Good Manufacturing Practice and Good Laboratory Practice standards. Running a compliant weighing station is more complex than it may seem. In addition to making sure that a scale or balance is suitable for the application, sound documentation must prove that suitability to auditors. Operators also must be trained according to valid standard operating procedures to ensure periodic equipment testing, calibration and qualification is done accurately. When Brostmeyer learned about Good Weighing Practice (GWP ) Verification from METTLER TOLEDO, she immediately recognized that this approach would make her life easier. GWP is a wellthought-out and accepted concept that provides a scientific basis for our weighing equipment verification needs, she says. Risk-based process assurance After METTLER TOLEDO conducted a GWP Verification assessment at Klosterfrau s Berlin site, Brostmeyer received a risk-based assessment and testing recommendations for each scale and balance. What I like about the verification document is that it clearly states whether the equipment is suitable for the given pro- 8 METTLER TOLEDO Pharmaceutical Preparations News 21

9 cess. It also provides recommendations on which tests should be conducted at which intervals with which test weights, says Brostmeyer. That makes it easy for me to instruct operators and maintenance personnel on appropriate testing procedures. Shortly after METTLER TOLEDO verified the weighing equipment, a production audit put the new process to the test, leaving no questions unanswered. GWP Verification ISO 9001 and GMP regulations require that weighing equipment be calibrated and verified at defined intervals, but how those tests should be done or how often is not specified. GWP Verification provides testing recommendations based on your process requirements. It will help you: Optimize your routine testing to ensure consistent weighing results. Save costs by eliminating unnecessary tests. Provide traceable documentation, including testing procedures and frequencies. METTLER TOLEDO Pharmaceutical Preparations News 21 9

10 Checkweighing & Metal Detection Compliant and Complete Inspection Technologies Support Standards When exporting pharmaceutical products globally, the list of standards and guidelines that must be met can be daunting. However, a Spanish manufacturer uses multiple inspection technologies to ensure its products are complete, contaminant-free and compliant with all applicable regulations. Spanish pharmaceutical company Cinfa relies on the latest metal-detection and checkweighing technology from METTLER TOLEDO. Detecting metal contamination The company has installed Tablex-PRO metal detectors, which reliably inspect every tablet and detect metal contaminants less than 0.3 millimeters in diameter. Metal contaminants can find their way into products through machine wear and tear. That can happen for example when pills and tablets are pressed. support requirements of FDA 21 CFR part 11, we are now able to capture electronic signatures and track user access. No missing blisters or leaflets Cinfa also needs to ensure that the correct number of blister packs is contained in each carton and that all cartons contain a patient information leaflet. Checkweighing is a highly effective tool to do that when used in conjunction with a well-designed quality-control program. By installing checkweighers specifically designed for pharmaceutical production, Cinfa is able to confirm that all products are checked for completeness. That helps to ensure patient safety and maintains their credibility as a premium manufacturer. The checkweighers also provide transparency in the production process for Cinfa. The checkweighers deliver realtime data on access management so that we can fully trace all system changes, says Torres. We needed a highly sensitive metaldetection system that detects all metals and meets the exacting standards of our industry, says Oscar Torres, Cinfa engineering manager. The metal detectors were smoothly integrated with our tablet de-dusters and other production-line equipment. With the dedicated software, we are in total control of our processes. To Checkweighers ensure cartons contain the correct number of blisters and an information leaflet. 10 METTLER TOLEDO Pharmaceutical Preparations News 21

11 jamming. Using a transversal adjustment option, cartons are automatically re-centered, which leads to optimal positioning of products on the weighing conveyor. The checkweighers are modular in construction, which allows for future adaptations to meet new requirements, such as pharmaceutical serialization and anti-counterfeiting measures. How to Enhance Process Safety in the Pharmaceutical Industry Using Checkweighing White Paper Advanced features Effective handling of the products at high speeds is critical to process efficiency. The checkweighers enhanced software and mechanical features support the detection of open flaps and misaligned packages to protect downstream equipment and avoid Enhancing Process Safety Checkweighing in the Pharmaceutical Industry Contents 1 Cinfa is currently retrofitting some of its production lines with a marking and vision solution from METTLER TOLEDO, which will help the company comply with new guidelines against counterfeiting. Introduction 2 Dynamic Checkweighing in Today s Pharma Market 3 Enhancing Process Safety and Process Management 4 Effective Product Handling to Maintain Process Safety 5 Advantages of Integrated Pharma Solutions 6 Factors to Consider When Choosing a Solution Partner Read more in-depth information about maximizing process safety in our white paper. Tablex-PRO metal detectors ensure all tablets and capsules are metal-free. METTLER TOLEDO Pharmaceutical Preparations News 21 11

12 No Surprises Real-time Equipment Monitoring Don t wait for Industry 4.0 to happen. Start monitoring the performance of your weighing equipment today with InTouch SM Remote Services. Connected scales send proactive alerts that enable you to immediately respond to performance issues. Increase uptime and ensure consistent measurement quality. Alarm Alarm I'm OK Pharma Workflow Event I'm OK I'm OK Alarm I'm OK I'm OK Event I'm OK Efficient Equipment Management Real-time equipment status information Fact-based timing of preventive maintenance activities Improved Performance Control On-going monitoring of measuring performance Periodic asset status reports to optimize processes Security without Compromise ISO certification User authentication and access control No changes to existing IT or security infrastructure For more information about Real-time Equipment Monitoring visit: For more Information Mettler-Toledo, LLC 1900 Polaris Parkway Columbus, OH Mettler-Toledo Hi-Speed 5 Barr Road Ithaca, NY Mettler-Toledo Safeline 6005 Benjamin Road Tampa, FL Mettler-Toledo CI-Vision 2640 White Oak Circle, Unit A Aurora, IL Mettler-Toledo, Inc Argentia Road, Unit 6 Mississauga, Ontario L5N 8G6 Local contact: