White Papers

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  • Batch Manufacturing in the Biopharmaceutical Environment

    The operations and manufacture of biopharmaceuticals is a complex process combining the capabilities of multiple systems that extend the boundaries of batch processing. The Manufacturing Execution System (MES) receives information from the Enterprise Resource Planning (ERP) system and creates the necessary production orders, maintains material tracking/genealogy and coordinates key manual activities. The automated batch control system sequences the phases, controls the devices and captures the necessary history. These systems come together in the operation of Biopharmaceutical production plants, which require a very specific architecture that leverages standard batch products that are tightly integrated with MES capabilities. This is driven by the upstream and downstream processing specifications of such plants, the detailed compliance requirements and the benefits achieved in maximizing automated functionality. This paper explores the unique requirements of batch manufacturing in the biopharmaceutical environment.

    Torsten Winkler, WBF
    06/23/2008
  • Communication Through B2MML – Is That Possible?

    Many of you have certainly heard about the ISA S95 standard, and you know that it treats the subject of how Enterprise/business systems should be integrated with manufacturing and control systems You might also be aware that of B2MML (Business to Manufacturing Markup Language), a set of XML schemas corresponding to the S95 object models, is intended to be used for data exchange between a business system and a manufacturing system. This paper describes experiences of using the B2MML schemas in real applications. What happens if the Business system does not export the data in a format compliant with the schemas? What about reliability for the data being exchanged? Were extensions or restrictions needed on the schemas? Which are the reasons for choosing to use B2MML? Is it practically possible to communicate using B2MML? Benefits, difficulties, compromises, challenges etc of using the B2MML schemas in practical applications will be described in the paper.

    Heike Schumacher, Charlotta Johnsson, WBF
    06/23/2008
  • Coriolis Mass Flow Meters in Batching Applications – The Good, the Bad and the Ugly

    Coriolis mass flowmeters are the most accurate of the industrial flow measurement technologies, and the only flowmeter that claims to measure true liquid mass flow directly. They are widely used in both continuous and batch processes. They are often used in batch processes as a less-expensive alternative to load cell weighing systems (the good). As with any other flow metering technology, Coriolis has its own application “watch outs,” including a requirement that the flowmeter be totally and completely full of non-aerated liquid during the measurement.

    James R. Reizner, WBF
    06/23/2008
  • Functions Need to be Considered for Batch Material Transfer Controls

    Batch processes depend heavily on the speed and repeatability with which each material transfer is completed for every recipe executed. Each and every transfer generally requires precise cut-off control over the valves, screw feeders or pumps, as those transfers directly impact the annual profitability of a manufacturing facility. Therefore it is very important to have a cost-effective material transfer control system that consistently improves process quality and throughput while reducing raw material waste and operating costs. This paper presents some main factors to impact speed and accuracy of batch material transfers. In addition to functions to reach the goals of speed and accuracy for batch material transfers, many other either must-have, should-have or beneficial functions are explained. Where those functions should be built? Some considerations are presented to answer the question in this paper.

    Charlie Fu, WBF
    06/23/2008
  • Implementing B2MML with SAP

    The Procter & Gamble MES organization is implementing B2MML with SAP. When starting, we found several obstacles including; Lack of examples of B2MML; No desire from the SAP company to pursue a B2MML interface; Our lack of XML skills; Missing automatic interfaces in SAP. Several factors in our favor included: Support for B2MML at management level in our Information Exchange, Material Movement/Warehouse, SAP Production Execution, and MES organizations; we could use an existing SAP Business Connector infrastructure; our key MES vendor was actively developing a B2MML interface; The WBF XML working group was willing to exchange information.

    David Cornell, WBF
    06/23/2008
  • Model Predictive Control of Batch Temperature

    Control modules used for critical phases of reactor operation such as heating, cooling and reacting can be optimized using advanced process control technology to reduce batch cycle time. Temperature control of batch reactors is difficult for conventional proportional-Integral-Derivative (PID) controllers due to the open loop instability of these processes coupled with the long time delays and large time constants. These dynamics are present on various reactor designs involving heating or cooling with jackets, internal coils, or recirculation loops through external heat exchangers. Model Predictive Control (MPC) provides an alternative to PID for use in these control modules to dramatically improve temperature set point tracking, improve product consistency, and reduce batch cycle time. This paper describes the design of an MPC controller that is built to specifically handle the dynamics found on batch reactors as well as the large process disturbances that occur due to exothermic reactions. The results of an application example will be discussed.

    Bill Gough, Sava Kovac, Lynne DeVito, David Quick, WBF
    06/23/2008
  • Multiple Products in a Monoclonal Antibody S88.01 Batch Plant

    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.

    Mahasti Kheradmand, John O’Connell, WBF
    06/23/2008
  • Production Performance Ratings

    Key Performance Indicators (KPIs) are used in batch processing industries as measurements of production performance. Their use is one element in the current trend of real-time performance management. A single KPI used as the primary measurement of production can cause other dimensions of production performance lose importance. When multiple KPIs are used to measure a batch’s production performance it can be difficult to reconcile differences between them for individual batches or for groups of batches. KPIs based upon meeting a target, or specification, measure absolute performance yet do not provide relative information regarding how a batch performed against its peers. The peer comparisons are important for monitoring variability of production performance, which is a critical factor in documenting ROI.

    David Emerson, WBF
    06/23/2008
  • Retrofit of an Existing Process Cell with S88

    Retrofitting a working process cell that must manufacture medicine using the S88 standard presents unique challenges. Engineering solutions are not simply driven by cost-benefit analyses when working in a GMP environment. Gathering true user requirements for a system that has been in use for 10 years is not nearly as simple as one would expect and educating developers, management, and engineering technicians on the effective implementation of the standard in a design that is user-friendly requires more time than engineering the solution. Configuration management and revision control of nearly 70 modules in the development process while working with multiple vendors requires careful planning and a defined set of processes before starting the project. The business realizes many benefits from the delivered flexible system, but there is a price in ongoing documentation management.

    Brian N. DeHaan, WBF
    06/23/2008
  • S88: The Good, The Bad and The Ugly!!

    As S88 becomes widely adopted within the batch industries operating companies are increasingly looking for reliable transfer of recipes between systems from different vendors. This makes sense for industry as operator companies seek to use best in class components to reduce design and implementation times as well as integrate effectively with existing systems. However, whilst the standard is now well proven for implementation of projects within a vendor's suite of tools, it is far less common to find real transfer of recipes between systems from different vendors.

    Alistair Gillanders, WBF
    06/23/2008
  • Transfer Lines As Units In An S88 Framework

    Traditional process models typically view a transfer line between Units either as a physical extension of the batching vessel or as a shared equipment module. The valves in the transfer line are then convenient places to establish the boundary of the upstream or downstream Unit.

    Todd A. Brun, WBF
    06/23/2008
  • Application of S88 Model in the Control of Continuous Distillation Facilities

    A recipe control of a continuous distillation plant was a challenge in its design, simulation, validation and successful exploitation. The plant was used for solvent recovery in an Active Pharmaceutical Ingredients Production Facility (API). Following S88 models, which were used as tools in structuring a specific process cell, which had several trains with batch operating units, it was decided to apply and extend the same approach on the continuous processes as well.

    Franjo Kralj, WBF
    06/23/2008
  • Applying MPC to a Batch Process

    The application of Model Predictive Control (MPC) is often considered for multi-variable continuous processes. However, the benefit of applying MPC to a batch process can often be just as significant as a continuous process. In this presentation we will show how MPC is being applied in a pharmaceutical manufacturing facility for the control of one cut of a batch distillation column. The primary benefit of using MPC is to reduce batch cycle time. The performance that can be achieve with MPC vs. traditional techniques for this application will be examined.

    Noel Pérez, Dan Lorenzo, WBF
    06/23/2008
  • Automated Batch Scheduling and MES Integration Using a Hierarchical Based, Batch Control Software Architecture

    After years of advancement in the batch control industry--particularly within the area of standardization using S-88 and S-95--today’s automated batch control systems offer end users many features which have enabled improvements in product quality, reduced cycle time, and overall return on investment. However, the area of automated batch scheduling and MES integration has to date gone largely untapped on a relative basis when comparing features incorporated into the actual control system. In general, the problem of batch scheduling and MES integration has been left to customized, one-off solutions developed on a site-by-site basis (due to both plant variability and lack of support in the underlying control system). This paper will address recently developed technologies that begin to incorporate the batch scheduling and integration layers into the control system itself, while still maintaining the flexibility required for customization of the already present hierarchical architecture. Along with a description of the solution, real world case studies will be discussed, including both results and lessons learned.

    Nathan Pettus, Dieter Wolf, WBF
    06/23/2008
  • Automating the Manufacture of Highly Energetic Organics using the S88 Model

    The manufacture of highly energetic organics consists of three distinct and physically separated process steps. The steps are Reaction, Filtration and Crystallization. Due to the reactive nature of the products produced each step is performed in separate and isolated manufacturing areas. In 2000, a project was initiated to automate the complete production of the manufacturing process and to install state-of-the-art automation in all three of the manufacturing steps. The effort was completed in late 2001 and has been in use for almost six months at the time of this paper. One of the most visible signs of success of the new system has been the reduction of off-specification products from 15-20% to less than 2% of the batches produced. This paper addresses some of the lessons learned, trials, tribulations, and issues involved in bringing batch automation to a process that has been traditionally handled manually. Some of the issues revolve around process measurements, control problems, replacing human action with computer actions, and resistance to change. The paper will discuss how S88 concepts were applied in the manufacture of highly energetic organics.

    John Arnold, Dennis Brandl, WBF
    06/23/2008
  • Batch XML Interfacing

    The ability to share information between batch control systems and Manufacturing Execution Systems (MES) or Enterprise Resource Planning (ERP) systems has become a critical parameter in adapting to the expanded requirements for agile manufacturing. Traditionally, batch data and execution control has been the domain of control engineers. MES and ERP Systems have lived in the information technology environment with data exchanged manually with the plant floor. This increases the chance of data entry errors and slows down access to process information needed for effective scheduling, material tracking, reporting and decision-making.

    Pamela Mars, WBF
    06/23/2008
  • Centralized System Approach For Part 11 Compliancy

    The paper presents a case study on how the world’s largest pharmaceutical tablets manufacturing site achieved 21 CFR Part 11 compliancy on their manufacturing equipment by using a central information system. The paper shows the development of User Requirements Specification and Information System Design. It shows the Information Systems Implementation and how the project organized to be able to work with a large number of machines and against a tight time schedule. The technical solutions to fulfill the 21 CFR Part 11 requirements was the primary goal of the project but it also gives an added value to AstraZeneca since the system can and will be used for production optimizations and planning purpose.

    Per Westerberg, Göran Eriksson, WBF
    06/23/2008
  • Definition and Format of Recipes for the Packaging of Consumer Packaged Goods

    The S88 standard has delivered significant cost savings benefits to the batch industry worldwide. This has been achieved through standard terminology and models as well as inherent reusability of recipes and equipment phases. The PackML subteam of the OMAC (Open Modular Architecture Controls) Packaging Working Group is a diverse group of end users, technology suppliers and packaging machine OEM’s (Original Equipment Manufacturers) committed to the development of industry guidelines which will deliver Plug-and-Pack functionality. Their objective is to significantly simplify the integration of packing machinery from different OEM’s, built using control system hardware and software from various technology providers. PackML’s work has used the state model within S88.01 as one of its foundations. It has further been discovered that there is significant potential to nhance and transfer models, terminology and principles used in batch manufacturing into the discrete world of packaging. The process, physical and procedural models, which appear in S88.01, have direct analogues in the packaging domain. It is also possible to design, in general terms, a recipe which defines both batch and discrete components of a consumer product. The principal advantage to be gained from this approach is the ability to more rapidly deploy and roll out product definition, in a consistent format, to many global manufacturing facilities. This is essential for those global Consumer Packaged Goods (CPG) companies who are committed to ensuring consistency and quality of their products irrespective of where they are manufactured.

    Andrew McDonald, WBF
    06/23/2008
  • General to Master Recipe Transformation, Capturing Best Engineering Practices in Recipe Generation

    This paper discusses various strategies and methods that may be used to convert equipment independent general and site recipes, as defined in the ISA-88 Part 3 draft standard, into equipment specific master recipes, as defined in ISA-88 Part 1. The methods described have been used in multiple companies and examples of use are included in the paper. These methods allowed the companies to gain economic advantages from general recipes, reducing the engineering time and cost for new product deployment. General recipe transformation can use each site’s best engineering practices in the transformation process. This results in more consistent master recipes, fewer trial batches, and improved multi-site product consistency. The methods for general recipe transformation can be performed manually, semi-automated, or completely automated. Automation requires strict conformance to the ISA-88 Part 3 procedure definitions models. The relationship between the models and the transformation strategies is covered in the paper.

    Dennis Brandl, WBF
    06/23/2008
  • How New Technologies Can Improve Compliance

    While U.S. drug products are of high quality, there has been an increasing trend towards manufacturing problems, resulting in recalls, disruption of operations and drug shortages. Companies are missing billions of dollars of potential additional revenue, and necessary medications are sometimes unavailable to the public. By enforcing 21 CFR Part 11 and introducing additional new quality-related initiatives, the FDA is signaling a need for better compliance to ensure consistency and safety. The industry wants to comply, but many manufacturers lack the necessary capabilities, or are unaware that new technologies are available to meet the beefed-up regulatory demands and still operate efficiently and profitably.

    Justin O. Neway, Ph.D., WBF
    06/23/2008
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