Multiple Products in a Monoclonal Antibody S88.01 Batch Plant

Presented at the World Batch Forum North American Conference Chicago, IL May 16-19, 2004 900 Fox Valley Drive, Suite 204 Longwood, FL 32779-2552 +1.407.774.0207 Fax: +1.407.774.6751 E-mail: info@wbf.org www.wbf.org Multiple Products in a Monoclonal Antibody S88.01 Batch Plant Mahasti Kheradmand Automation Supervisor Genentech 1000 New Horizons Way Vacaville, CA 95688 United States Phone 707-454-1000 Fax 707-454-1011 mkheradm@gene.com John O Connell Automation Supervisor Genentech 1000 New Horizons Way Vacaville, CA 95688 United States Phone 707-454-1000 Fax 707-454-1011 johno@gene.com KEY WORDS S88, Biotechnology, Monoclonal Antibody ABSTRACT The most successful biotech companies have multiple products approved for market and must make the use of existing manufacturing capacity to produce them. Often times this requires rapid changeover from one product to the next. This paper addresses the challenges with bringing new products into an existing S88.01 facility and the challenges involved in maintaining the standard as well as implementing a change in an operating plant with a minimum of downtime. It was found that the S88 concept is enormously helpful in implementing changes within the equipment capability but that challenges arise when the equipment capability must be changed also. The recommendation is to standardize the manufacturing process and build the necessary capability into the plant upfront to avoid costly downtime during product changeover. Copyright 2004 World Batch Forum. All rights reserved. Page 1

PAPER Introduction The S88 batch standards have been a tremendous benefit to the pharmaceutical industry. The standardized approach in the design of process equipment and control system software has dramatically reduced the effort required to design, construct and validate a batch manufacturing facility. With the increased number of marketed products, the market leaders in biotechnology are approaching the limits of their in-house manufacturing capacity. The net result is that existing plants are being required to produce multiple products and to switch as quickly as possible between production campaigns. For those companies fortunate enough to have newly approved products, there is an additional demand to quickly introduce the manufacture of new products into existing facilities. This paper explores some of the major aspects related to bringing a new manufacturing process on-line in an existing multi-product monoclonal antibody facility already automated to the S88 standard. Some thoughts on future directions for easing these difficulties in new plants are also offered. Process Background The typical monoclonal antibody facility includes a fermentation train that ranges from laboratory scale fermenters in the 10 to 20L scale to large scale cell culture vessels in the range of 10,000 to 20,000 liters. The cell culture vessels are held under controlled conditions of level, ph, agitation and dissolved oxygen in order to provide the optimal conditions for production of the molecule of interest by genetically engineered organisms. The facilities will also include a harvest system that is used to clarify the cell culture fluid as it is removed from large scale cell culture vessels at the end of a batch. The clarified harvest is typically further processed in a product recovery suite that includes one or more chromatography steps and final product formulation via ultrafiltration. Chromatography is used to purify the product by separating it under carefully controlled conditions from the clarified harvest. Both the cell culture and protein areas are serviced by preparation and storage tanks that provide and store growth media for the cell culture vessels and buffer solutions for the chromatography and ultrafiltration units. Most Changes Happen in Product Recovery Most of the changes from product to product occur in the recovery area as this is where the manufacturing process for monoclonal antibodies is most variable. It is very rare that major equipment changes need to be made in cell culture since this portion of the process has been somewhat standardized across the industry. The process variation can take the form of new production steps such as replacement of a chromatography step with a filtration step, new capability requirements such as inline dilution as part of a chromatography step or increased yield. Variations in yield can render the existing recovery process equipment to small or too large for the intended purpose. New process steps Copyright 2004 World Batch Forum. All rights reserved. Page 2

or equipment capabilities may require modification of existing recovery equipment. Both of these types of process changes may require plant downtime between products as both the equipment and the associated software will need to be modified and fully tested before the next production campaign can begin. Production campaign changeovers are usually much less trouble in the cell culture area. Since it is rare that new steps or capabilities need to be added, most new products can be introduce with recipe level changes only. This dramatically reduces the time spent defining requirements and developing software in cell culture as compared to recovery. As more products are added to the facility it becomes more difficult to make changes The complexity of a multi-product monoclonal anti-body plant tends to increase over time. For a single product plant only one set of conditions needs to be considered for every phase or control module that is added or changed in the plant. In a plant that supports six different products, the impact on each of these processes must be considered for every change. The level of design effort is increased as the changes become more complex and as the functional requirements differ between products. Piping and control schemes that would be relatively straight forward for a single product become more involved as the process requirements for each of the various products is built into the design. The net result is that as more capability and flexibility is added to the plant the design and implementation cycles will lengthen since any changes must preserve existing functionality while meeting the requirements of the new product. The overhead required to maintain the master recipes for all the products in a plant will increase with the number of products. The overhead required to maintain a library of master recipes increases with the number of supported products. All products have a particular set of processing requirements defined in their set of master recipes. As the number of products supported by a particular plant increases the number of master recipes associated with the plant also increases. Process model changes for any new product may invalidate existing master recipes requiring them to be revised before they are used again extending the project schedule. Depending on the complexity of the changes and the level of testing required, it may even take longer to revise the existing product recipes than it did to develop recipes for the new product or process. A large library of master recipes also tends to increase the time required to make routine changes to the plant. For a facility that supports multiple products it becomes more difficult to assess the impact of a particular change on all of the recipes. For example a recent project to introduce a new product required the development or modification of over 171 recipes 95 of which were existing product recipes. In addition, a process improvement change that is common for all products will require multiple edits in order to implement the change since each product will have its own set of master recipes. Copyright 2004 World Batch Forum. All rights reserved. Page 3

In the absence of general recipe, transferring a process from one site to the next can be very time consuming. For organizations that have multiple sites, transferring processes between facilities can be extremely challenging. This is particularly true if the two facilities have different control systems, equipment capabilities and/or business systems. In particular, process transfer between paper based and paperless facilities is very labor intensive without general or site recipes. In the absence of an enterprise wide information structure such as that defined by S88, it is necessary to convert the words and steps from paper based operator instructions to recipes, phase logic and control modules. An exhaustive verification is required to ensure that the critical process parameters and steps have been correctly coded into the recipes. For a complex process transfer, this verification can add several weeks to the design effort and require many hours of cross functional team meetings. Adopting the common data structure of a general recipe would speed this process up tremendously by quickly allowing the identification of the critical steps, equipment capabilities, process parameters and material requirements. Implementation of the S88 standard for general and site recipes requires an enterprise wide commitment and there may be some institutional resistance to expend the time and capital required to implement the concept. It would however be worth the investment since it can reduce the time it takes to move a production process between sites and as a result makes the manufacturing capacity of the organization more responsive and flexible. Planning is Essential for a Smooth Product Transfer It is essential that monoclonal antibody manufacturing firms adopt a plan to manage process to process variability if they are to maximize on the capability of existing facilities. Since it would be prohibitively expensive to build a plant that can run all of the current manufacturing processes for monoclonal antibodies most manufacturing plants can support a limited subset of these processes. Information about the existing manufacturing capabilities must be communicated to the process development staff. Often times the process developers have choices in the methods they select to manufacture and purify a new molecule. If they are aware of downstream constraints they are more likely to develop a method that will fit within the existing capabilities. At the very least they will be able to provide advance warning when changes will be required for an existing facility. The process development scientist must communicate the required manufacturing capabilities of the process equipment early in the process transfer effort. This is most conveniently done in a user requirements specification that forms the basis for both the process and control system design. Having well defined user requirements up front allows the project team to quickly assess whether a manufacturing site has the necessary capability to run a process or to determine what changes will be needed to support the new product. Planning for product to product process variation will allow the organization to more rapidly respond to required changes and maximize the use of existing manufacturing capacity. Minimizing Downtime Copyright 2004 World Batch Forum. All rights reserved. Page 4

Keeping plant downtime to a minimum is mandatory during a campaign changeover. Downtime in a manufacturing facility is never a good thing and since most monoclonal antibody plants run on a 24/7 basis it is also difficult to schedule. A successful product changeover with minimum downtime requires careful planning. Sufficient lead time should be allowed to get the requirements documents revised and to develop and test most of the software changes in an offline environment. Since downtime comes at such a premium, early involvement and training of persons performing debug is a must. Adequate staffing should be provided across all disciplines to allow around the clock coverage during the plant shutdown for all installation, debug and validation activities. Although detailed planning is a required, the project team must also be flexible enough to take advantage of opportunities to complete tasks ahead of schedule when debug and testing efforts go well in order to compensate for the time lost when they do not go as expected. The S88 standard is both a help and hindrance in the effort to minimize plant downtimes during campaign changeovers. The modular software structure of a S88 plant allows changeover lead times to be reduced because software objects such as phases and control modules that are used in multiple units can be modified and tested once in an offline environment and then copied to where they are used. For example, in a recent project over 31 control module instances had to be added to the configuration but since the control modules were designed to be portable between multiple units only 1 new control module had to be created. This reduced the level of effort required for software engineering of control modules by at least two orders of magnitude since there was no need to specify, develop and test the existing control modules that were being re-used. For product changeovers that do not require unit level changes, software development is limited to the creation of new master recipes. Designing software to the S88 standard reduces the downtime required to change from product to product by allowing the same code to be used on multiple units and multiple products with simple recipe parameter changes. The S88 standard can become a hindrance when adherence to the standard will require extra effort. For example it may be much quicker to solve a problem found during debug by modifying a control module on a single unit so that it is no longer portable to other similar units. In almost every case it is best to make the extra effort to comply with the standard since non-standard code will make plant harder to maintain in the long-term. Stay on Top of Change Control An important factor in minimizing plant downtime is managing the change control process. After requirements definition, most of the hours in a software development effort are spent developing and executing test plans. Doing this work correctly is essential for project success. Executing the change control process poorly by not following good documentation procedures, making unauthorized changes or taking short cuts on testing will increase the number of hours required to complete a project. In a regulated industry if the software development and testing is not done under proper change control it Copyright 2004 World Batch Forum. All rights reserved. Page 5

will normally take the involvement of department management and quality assurance to justify the deviation from the process. In some cases repeating the work may also be required and in all cases it will take much longer to correct an error than to follow the correct procedures.. Doing it right the first time is definitely worth the effort in the final quality of the software and the overall productivity of the project. Before a large implementation project begins it is best to get prepared to work under the change control system. The following steps will go a long when in getting your team ready: Review the change control process and streamline it where possible prior to the start of software development Refresh the team members understanding by conducting change control and configuration management training. Put an administrative assistant on the project to assist with managing and organizing the large volume of paper associated with software testing. Have a written configuration management plan and all the necessary tools in place to manage the software objects through development, testing and implementation. Review and close out tests and testing deviations as soon as possible following test execution. Doing this rapidly will allow testing issues to be documented and dealt with while the events are fresh in the memory of the parties involved. Applying Lessons Learned To A New Facility Designing a new facility presents the opportunity to avoid building in the limitations inherent in older concepts. With the pace of technological change in Monoclonal antibody manufacturing a new facility must have the ability to deal with increase yields and process changes by providing a scalable and flexible plant. This is especially true in the recovery area which is so sensitive to yield improvements and the area with the greatest product to product process variability. Consideration should be given to technologies such as buffer concentrates that increase the capacity of processing suites and the use of skid mounted recovery equipment that can be changed out quickly for a product change over. To help build in the required capabilities a user requirements specification should be developed for each process unit. The user requirement should specify the equipment capabilities that will be required to support all the products that the plant is intended to produce not just the product that the plant will begin to manufacture immediately after start-up. The process development staff needs to be fully engaged with engineering and manufacturing in the requirements development process because they are most fully aware of the manufacturing processes being considered for all the products in the pipeline. Involving them in the requirements definition also makes them aware of what the new plant will be capable of and having this document available will allow them to make more informed choices as they design the process for future products. Finally there should be a formal risk assessment considering the impact of emerging technologies as related to cell culture yield improvements and protein recovery operations. Asking the what if questions up front can allow some level of risk mitigation to be built into the plant and reduce costly downtime and changes over the life time of the plant as new technologies are employed. Copyright 2004 World Batch Forum. All rights reserved. Page 6

What s Ahead in Monoclonal Antibody Manufacturing? According to the BIO Editor s and Reporter s Guide 2003-2004 published by the Biotechnology Industry Organization there were 35 new Biotech drugs and vaccines approved for market in 2002 and there are more than 370 new Biotech drugs in clinical trials. It has also been speculated that the current industry standard yield for a CHO based monoclonal antibody cell culture process may triple from 1 g/l to 3 g/l and this will require continued innovation in the product recovery technology downstream of cell culture (Gottshalk). Plants designed for the 1 g/l scale will be challenged to take full benefit of these yield improvements and new facilities must be both scalable and flexible to accommodate product to product yield changes and evolving technology. With the large number of products in the pipeline, those monoclonal antibody manufacturing firms that can deal best with multiple products, fast product changeovers, improved yields and evolving technology will have a key advantage over their competitors. Copyright 2004 World Batch Forum. All rights reserved. Page 7

Sources Cited Biotechnology Industry Association. Bio Editor s and Reporter s Guide 2003-2004, June 2003, 02 Mar 2004 < http://www.bio.org/er/biotechguide.pdf> Gottshalk, Uwe. Biotech Manufacturing is Coming of Age. Bioprocess International April 10, 2003 02 Mar 2004 <http://www.bioprocessintl.com/> Copyright 2004 World Batch Forum. All rights reserved. Page 8