PyroSense PAT for WFI By Ken Nichols and Maribeth Donovan Janke

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1 LALreview LAL REVIEW: PUBLISHED BY LONZA 2008 Issue 1 EDITOR S COLUMN With our first issue of the new year, we would like to introduce you to the PyroSense on-line endotoxin detection system. The PyroSense system represents an innovative solution to the problem of relying upon retrospective endotoxin testing results for high purity water systems. High purity water is an important raw material. The PyroSense system allows you to schedule the testing of your water system so that the results are ready when you want them. Your Production team will be able to know the state of the system before the water is used. The lead article about PyroSense was written in collaboration with Ken Nichols, R&D Scientist for the Rapid Testing Systems Unit of Lonza. PyroSense was developed with the FDA s PAT or Process Analytical Technology Initiative in mind. In addition, it fits within the scope of several ICH Guidances. Brett Beardmore, Regulatory Affairs Associate, has written an accompanying article to explain the goals of these quality initiatives. His article includes several references for additional information. Maribeth D. Janke, Ph.D. Sr. Product Manager PyroSense PAT for WFI By Ken Nichols and Maribeth Donovan Janke The FDA s Process Analytical Technology Initiative (PAT) is aimed at improving the quality assurance for products that are manufactured by the pharmaceutical and medical devices industries. The PyroSense on-line system addresses this initiative by automatically monitoring gram-negative bacterial endotoxin levels in Water For Injection (WFI) and high purity water systems. Water is a critical raw material. In addition to it being a component in final products, water is also used in cleaning processes. Knowing that the water used in production has met the endotoxin specification prior to its use reduces the risk to final products and leads to quality by design. Automated On-Line Endotoxin Testing The PyroSense instrument is designed to be mounted near the water loop of high purity water systems. Water is diverted to the instrument and flows out to a drain. The robot uncaps reagent vials, prepares the 3-point endotoxin standard curve, collects a water sample from the water loop, prepares the positive product control (PPC), and runs a fluorescent endpoint endotoxin detection test. In keeping with the spirit of the PAT, the PyroSense system moves the endotoxin test from the lab bench to the water loop. The PyroSense System The PyroSense system includes the PyroSense instrument, a Reagent Cartridge and WinKQCL V3.1 endotoxin detection software. The system can be programmed to perform from 1 up to 12 automated assays per day. The schedule is determined by 1 LALreview

2 PyroSense PAT for WFI the end-user. The system will run both Initial Qualification (IQ) and Routine Tests. When a new lot of reagents is introduced, the software will indicate that an IQ test must be run before routine testing can begin. The reagents and plastic accessories needed for the endotoxin test are found in the disposable Reagent Cartridge. The Reagent Cartridge includes tips, 96-well plates, the recombinant Factor C assay reagents of PyroGene, and a liquid endotoxin standard. With Lonza s proprietary liquid endotoxin standard, no vortexing is required. The 0.05 EU/ml to 5.0 EU/ml standard curve is sufficient to monitor high purity water systems. The cartridge also includes a water trough for sampling the water. Water continuously flows into the instrument, through the trough and out to the drain. PyroSense Reagent Cartridge contains all components needed to run the endotoxin detection assay. Loading a Reagent Cartridge is easy. The Instrument Front Panel allows the user to interact directly with the machine. The intuitive menu screens prompt the user for input as necessary. When a new cartridge is needed, the onboard firmware instructs the user to open the drawer, remove the used cartridge, and place the new cartridge in the instrument. When the drawer is closed, the system is ready for testing. Behind the closed door is the workhorse of the system, the PyroSense robot. When a test is initiated, the robot will begin removing caps from the various reagent vials in the Reagent Cartridge. Caps have specific parking places within the cartridge. The robot also picks up a tip, confirms it is attached and then moves reagents or takes a water sample from the built-in trough. After the water blank, endotoxin standards, water sample and PPC, all in duplicate, are placed on the 96-well plate, the recombinant Factor C reagents are added. Then, the robotic head takes the first fluorescent reading. An hour later, the second reading is taken. Software collects the raw data, calculates the standard curve and sample and PPC results. Monitoring Ease with WinKQCL The firmware on board the PyroSense instrument can be used to schedule the tests and analyze the data. The instrument is designed to be connected to a network containing WinKQCL software via a BUS converter. This is the same WinKQCL software that customers have relied upon for years to run and analyze endotoxin detection assays that utilize a microplate reader. Version 3.1 software contains the PyroSense module. The PyroSense module allows the analyst to initiate a test or setup a routine testing schedule directly from the office or lab. The WinKQCL software will retrieve the assay results and generate a results report. If a water sample result fails to meet the userdefined specification, WinKQCL software The PyroSense robot with a tip attached. can be set to automatically initiate a retest. Additional Features There are relays on the instrument that allow the user to connect to a lab monitoring system. This allows for facility-specific PyroSense notifications where the user can be made aware of 2 sample states (Alert and Action) and 2 instrument states (Service and Fault). The PyroSense hardware features a syringe pump for liquid handling. Chambers underneath the Reagent Cartridge keep the 96-well plates warm at 37ºC ± 1ºC and the assay reagents cool at 5º C ± 3ºC. The PyroSense instrument is UL listed for Canada and USA and bears a CE mark for Europe. Worldwide Support Bringing the PyroSense system into your LALreview 2

3 facility is more involved than installing a microplate reader on the lab bench. Our international team of highly trained service engineers will work directly with your facilities and engineering personnel to determine the appropriate location for the PyroSense instrument and assure that the proper electrical, plumbing and network connections are in place. Lonza engineers will perform the Installation, Operation and Performance Qualification (IOPQ) procedures on the instrument. This includes confirming that the robot is properly calibrated. Routine Preventive Maintenance service is also available from Lonza. Our team of engineers will service your instrument in place to minimize the effects of maintenance on your testing schedule. The technical support you rely on from Lonza will continue to be there after installation. Service engineers will train personnel to handle Reagent Cartridges as well as train the QC staff on the software to run the instrument. Once trained, your in-house PyroSense team will be ready to run the instrument as soon as the IOPQ documents are signed. In addition, Technical Service teams are available by phone and to answer your testing questions. Quality by Design Made Easy The PyroSense system was designed to help you meet the FDA s PAT initiative. The system is on-line and needs minimal interaction once installed. A QC analyst or supervisor can set the testing schedule from their lab or office. Anyone properly trained can unload and load a Reagent Cartridge. Lot numbers for the cartridge components are easily and quickly entered with the barcode scanner. If you run only one test a day, no one will need to touch the instrument for 24 days. During this time, the testing on your water system will continue automatically. The PyroSense system provides a completely valid endotoxin test. All of the expected components of an endotoxin test are included: a negative control, standards for each log of the curve, the sample, and the Positive Product Control. With WinKQCL software, results reports will be similar in appearance to other endotoxin test results reports and include electronic signatures. The PyroSense system offers something that no other endotoxin detection system can provide: 24 hours a day, 7 days a week monitoring of your water system. The endotoxin results on your high purity water system can be available to your Production Departments BEFORE the water is used to clean tanks or vials, or included in the formulated product. Knowing the quality of your water before you use it provides you with the confidence that you are building quality into the final product. Controlling variation in the production process leads to a quality product. Technologies that allow an organization to monitor the status of an important raw material, such as high purity water, in a timely manner will allow the organization to build quality into any final product that contains or uses that water in the manufacturing process. The PyroSense on-line endotoxin detection system offers a PAT solution to the problem of production delays and product discards due to the retrospective nature of current laboratory endotoxin detection testing methods. For more information on PyroSense, call your local Lonza representative or distributor or visit the Endotoxin and Microbial Detection section at and click on PyroSense. The sensible way to test your water: Water flows continuously through the trough built into the Reagent Cartridge. Moves in-process water testing from the lab bench to the water loop Labor-saving, robust robotic system Reduces risk by providing endotoxin results prior to production Allows for greater process control of your water system 3 LALreview

4 The PyroSense Starter System contains everything you need to get your system up and running. Ordering Information: Name Description Part No. PyroSense Starter System Instrument, WinKQCL software, 4 Reagent Cartridges, BUS converter Data Station for PyroSense Processor, Monitor, Printer PyroSense Additional Unit Instrument alone PyroSense Qualification Manual Installation, Operation and Performance Qualification Manual for PyroSense Reagent Cartridge Enough supplies for 24 tests U WinKQCL V3.1 Software Endotoxin detection software with PyroSense module WinKQCL V3.1 Software License Additional license for networked systems with multiple computers Endotoxin Detection Systems Qualification Manual Installation, Operation and Performance Qualification Manual for WinKQCL V ICH and the PAT Initiative By Brett Beardmore To help ensure the safety and efficacy of medicines, laws and rules were enacted to reduce the risk of harm to the public. As individual countries developed regulatory agencies for controlling medicine, it became apparent that a global harmonization effort was needed to allow for uniformity and consistency for the development of medicine. The International Committee of Harmonization (ICH) is a team effort involving both Regulators and Industry as equal partners in the discussions of the testing procedures required to help ensure safety, quality and efficacy of medicines. The ICH is composed of the European Union (EU), Japan and the United States (US). Specifically, the groups include the European Commission, the European Federation of Pharmaceutical Industries Association (EFPIA), the Ministry of Health, Labor and Welfare (MHLW), the Japan Pharmaceutical Manufacturer s Association (JPMA), the US Food and Drug Administration (FDA) and the Pharmaceutical Research and Manufacturers of America (PhRMA). In addition, there are ICH Observers that have one seat on the steering committee, which is non-voting, but acts as a link with non-ich countries and regions. Observers include the World Health Organization (WHO), the European Free Trade Area (EFTA) and Health Canada. The purpose of the ICH is to harmonize regulations, while reducing delays in getting drugs to the market and to decrease the burden on pharmaceutical companies. The ICH topics are divided into four major categories: Safety, Efficacy, Multidisciplinary, and Quality. Quality topics are those related to chemical and pharmaceutical quality assurance. The FDA has worked with the ICH to develop and issue guidance documents specifically to address proper quality systems in the medical field: Pharmaceutical Development (Q8), Quality Risk Management (Q9), and Pharmaceutical Quality System (Q10). The three guidance documents describe an effective quality management system to ensure proper quality controls for the entire life cycle of the product. The aim of the Pharmaceutical Development Guidance (Q8) is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. 1 The more knowledge gained about the process parameters and the product ca- 4 LALreview

5 pabilities, the more flexible the regulatory approaches may be. One specific technology that has emerged from the industry is Process Analytical Technology (PAT). PAT is not about the amount of information gained, but the quality of the information and what it means about the product. The PAT concept also supports the concept of Continuous Process Verification, where the manufacturing process performance is constantly monitored, evaluated and controlled. Both PAT and the Continuous Process Verification concepts allow the user to monitor process parameters with real time results. The Quality Risk Management Guidance (Q9) places emphasis on the idea that a proper Risk Management System will allow for the safest and most effective drug product. It is important to note that the Risk Management System should not focus entirely on the product, but on any venture associated with the overall company goal(s). The level/quality of the Risk Management System should directly correlate to the level of risk associated with the product. Proper risk assessment involves risk identification, risk analysis, and risk evaluation. 2 Any Risk Management System should be constantly identifying, analyzing, and reducing the potential for risk. The Pharmaceutical Quality System (Q10) is the third piece outlining an overall effective quality management system. Three main objectives for the Pharmaceutical Quality System are to achieve product realization, establish/maintain a state of control and facilitate continual improvement. 3 These objectives, along with proper product development and essential risk management, will help ensure a safe and effective product without wasted regulatory efforts. Proper leadership/management is essential for a company to meet these objectives, which means active involvement, continual allocation of finances, and availability of resources to pull from. Proper management will allow for effective teams to achieve the main objectives for the Pharmaceutical Quality System. Both Regulators and Industry agree that quality should be built into the manufacturing process by design; it should not be tested into the product. In addition, quality should be a part of the entire life cycle of the product, starting at the development phase. PAT is a system for designing, analyzing and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality. 4 The goal of PAT is to use scientific means to gain information about the product at each stage in its production. The quality of a product can be monitored during the production process with the use of in-, on- or at-line devices that measure for the presence of key attributes or absence of contaminants. For instance, an in-line TOC instrument can provide information on the current amount of total organic compounds in a water supply prior to that water being used in a production process. Another example would be monitoring for product consistency while it is still in the blender. Some companies are using NIR technology to determine when the blending of their formulation is complete while the product is in the blender. This allows them to know that the formulation of the product is consistent before they move the powder to the next step in the tablet production process. The ICH and the FDA encourage industry to use emerging concepts and techniques. The 2004 FDA guidance on PAT describes the concepts behind PAT to assist industry with utilizing PAT. 5 The FDA has set up PAT review boards and inspection teams to help the industry with the transition into this technology. In addition, presentations, lecture series and other resources can be found on the FDA website regarding the PAT framework. Using PAT during the start of product development will streamline the process, minimize risk and potentially lead to minimizing the amount of regulatory burdens placed on the pharmaceutical company. References: 1. FDA/CBER resources page. Food and Drug Administration Web site. Available at: Q8 Pharmaceutical Development. 2. FDA/CDER resources page. Food and Drug Administration Web site. Available at: Q9 Quality Risk Management. 3. FDA/CBER resources page. Food and Drug Administration Web site. Available at: Q10 Pharmaceutical Quality System. 4. FDA/CDER resources page. Food and Drug Administration Web site. Available at: Process Analytical Technology (PAT) Initiative. 5. FDA/CDER resources page. Food and Drug Administration Web site. Available at: PAT - A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. 5 LALreview

6 Lonza Walkersville, Inc Biggs Ford Road, Walkersville, MD Sales & Customer Service North America Customer Service: Technical Service: Online Ordering: Europe Customer Service: 32 (0) Technical Service: 32 (0) or Online Ordering: International Contact your local Lonza Distributor Customer Service: , ext Fax: International Offices Australia Austria Belgium 32 (0) Brasil Denmark France 33 (0) Germany India Italy The Netherlands Spain Switzerland United Kingdom Lonza Walkersville, Inc. Walkersville, MD Unless otherwise noted, all trademarks herein are marks of the Lonza Group or its affiliates. Copyright 2008, Lonza Walkersville, Inc. All rights reserved. A-LAL , 01/08 6 LALreview