Giving a Classic Manufacturing Process a Modern Facelift
Upgrading Processes And Environmental Controls Pose Unique Challenges
By Tobi Limke, Don Kupka, Robert Schulteis, Alan Doty & Joe Montalto
Millipore Corporation
Abstract
Biomanufacturing facilities face the challenge of upgrading process and environmental controls without altering the properties of the final product. Such "like-for-like" upgrades are critical for end-users, who rely on manufacturers to provide consistent products to maintain their own product specifications. The process of enhancing controls while maintaining final product specifications requires detailed knowledge of both the manufacturing process and the final product. In this article, we describe a case study of the modernization of a plant that produces a classic life science product, bovine serum albumin (BSA); address the challenges and resolutions met during the upgrade process; and provide suggestions for managing such a project.
Background
Bovine serum albumin (BSA) is widely used in the biopharmaceutical, diagnostics, and veterinary industries. Albumin is a multi-use protein used to stabilize and protect enzymes, antibodies and antigens; block non-specific binding; reversibly bind and carry ligands; enhance the antigen-antibody reaction; and to facilitate monoclonal antibody production. Although widely used, albumin is not a commodity, and different manufacturing methods yield products that often cannot be used interchangeably. For this reason, manufacturers utilize several different treatment regimens to meet specific use requirements, which vary depending on the industry and application.
Albumin production, as with any manufacturing methodology, is a tightly controlled process, where even minor variations during critical steps can significantly alter the characteristics of the final product. Albumin can be produced using a variety of methodologies, including cold ethanol fractionation and heat shock. Millipore's Kankakee, IL, manufacturing site uses a combination of heat shock and cold-solvent partitioning of albumin. The purification process starts with the heat shocking of bovine serum or plasma. A precipitate of contaminating proteins is formed during the heat shock and the purified albumin is recovered in the supernatant liquid. The purified albumin is contacted with cold-solvent and recovered in the precipitate. The rehydrated precipitate can be further processed by ion-exchange chromatography and acid-charcoal treatment. Depending upon its application, the albumin can be polymerized or remain in monomeric form.
Millipore's albumin manufacturing site has been producing and supplying albumin for over 50 years. The facility is ISO 9001:2000 certified and operates in consideration of Good Manufacturing Processes (GMP). The Kankakee plant is dedicated to the manufacture of Probumin BSA and other products derived from bovine serum or plasma. The Kankakee site has large scale processing equipment capable of meeting market demands for BSA and other serum derived proteins. Both powdered and liquid forms of BSA are available; features include low levels of endotoxin, fatty acid, IgG and metal ions.
In 2006, the decision was made to perform a multi-million dollar upgrade to the Kankakee plant. Modernization included installation of new, state-of-the-art-control and processing equipment, with the goal of enhancing control over product quality while maintaining the existing proprietary, fully validated processes. The Kankakee facility was tasked with modernizing the albumin production facility while maintaining in-kind processes. The goal was to substitute critical equipment "like-for-like" with modern equivalents of the exact same configuration and processing characteristics, so as to not change the characteristics of the final product. At the same time, the plant modernization provided the opportunity to enhance process controls for critical processing steps, such as temperature and pH.
Along the way, there were three central issues we faced with this modernization: 1) defining "similar" processes to maintain like-for-like substitutions; 2) compiling a comprehensive upgrade and validation plan to ensure completion in a controlled, timely manner; and 3) implement enhanced environmental controls and workflow improvements without altering the manufacturing process itself.
Maintaining "like-for-like" during equipment exchanges
The first challenge was defining "similar" manufacturing processes so that like-for-like equipment exchanges were possible. For albumin manufacturing, one of the critical factors that must be controlled is temperature. The BSA manufacturing process harnesses thermal energy to cause separation of proteins not protected from heat denaturation, thus an in-depth understanding of the thermal characteristics of our process was critical.
For the modernization, we were required to maintain similar heat distribution and temperature changes in a controlled manner throughout the reaction vessel. However, we first had to determine the "normal" heat distribution patterns in the old equipment. To achieve consistent temperature during the equipment change, the temperature ramp up and hold were mapped prior to the equipment change, and the temperature profile was duplicated with the new system. Computer aided thermal mapping models were constructed for each of the many validated processes needed to manufacture specialized grades of BSA and other proteins. Using these templates and the known heating and cooling capabilities of the various components of the reaction chamber, we were able to closely mimic these patterns using the new equipment. By utilizing computer driven control and heating/cooling solutions better designed for their purposes we are able to assure that optimal conditions will be achieved in every manufacturing run and produce a heat shock, solvent precipitated albumin that meets pre-renovation results. More importantly, we achieved our goal of installing new equipment with similar heating characteristics to the older equipment.
Project planning
The second important issue we faced was devising a comprehensive upgrade and validation plan to ensure completion in a controlled, timely manner. To this end we followed a Comprehensive Master Validation Plan which included all major systems. Throughout, we relied upon the quality and document control functions to facilitate ongoing manufacturing as well as the switch over to the new manufacturing and control systems. Working under an ISO13485 quality system, the need for comprehensive manufacturing batch records, validated and double checked run sheets, bills of material and in process quality checks are embedded in our processes. All these had to be renewed and revised for use with the new equipment, and full traceability of equipment and processes maintained. No equipment or process change was implemented until and unless it had been fully validated and cleared for use. Following this detailed plan enabled us to complete the project close to the projected deadline.
Implementing enhanced environmental controls and workflow improvements
The upgrade provided us with the opportunity to redesign manufacturing space to enhance environmental controls. Air conditioning and ventilation patterns were studied and optimized and, where needed, high efficiency air filtration was installed or upgraded. Floors and walls in processing areas were upgraded to seamless or other easy to clean surfaces. Environmental health and safety experts were consulted and large capacity drains leading to retention and recovery systems installed in key areas, ventilation was upgraded, and security enhanced by implementing key card entry access to all manufacturing, warehousing, quality and records areas. Through these and other measures, water usage at the plant is significantly lower, lessening environmental impact and helping to control utility costs.
In addition to improving environmental controls, we also installed modern means of monitoring and adjusting the manufacturing process during a run. The addition of computer-driven programs provides more comprehensive and better quality data on our manufacturing processes than ever before. Real time data acquisition and computerized tracking and trending of key parameters means that we can intervene by spotting abnormal trends and failing or fouled equipment early, before expensive and time consuming reworks or even shutdowns are required. Manual controls have been replaced with computer actuated valves and gates enhancing the consistency of manufacturing. In combination with the workflow improvements, these changes have increased the plant's productivity and provided greater flexibility in responding to increased demand.
Success Achieved
The key to this project's success was strongly related to defining our criteria for success. For this project, our definition of success was determined by verifying the heat shock process met the final temperature objective, the temperature ramping, heat distribution uniformity and, of course, the solvent recovered albumin had to meet historical results. The solvent precipitated albumin was tested and results indicated outcomes that met pre-renovation criteria. Establishing the Comprehensive Master Validation Plan allowed us to define our success criteria prior to project initiation. In the end, the data provided evidence that our renovated albumin manufacturing system produces a heat shock, solvent recovered albumin that meets pre-renovation metrics.
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