Emerson Process Experts

Interphex2008, the Pharmaceutical and Biotech manufacturing conference is going on this week in Philadelphia. Before Emerson's Terry Blevins and Mike Boudreau left, they passed along the presentation they are giving on Thursday, March 27. It's entitled, Application of PAT in Product Development. They are joined by University of Texas at Austin PhD graduate student, Yang Zhang and Broadley-James' Trish Benton. Here's an excerpt from the abstract:

The Process Analytical Technology, PAT, initiative encourages innovation in pharmaceutical development, manufacturing, and quality assurance to enhance understanding and control of the manufacturing process. The challenge for many manufactures is to identify how best to address the opportunities that PAT offers. Broadley James, Emerson Process Management, and the University of Texas are working together to examine and quantify the potential to reduce cycle time and out-of-spec product through the use of high fidelity, dynamic simulation and multivariate analytics. The objective of this work is to show that the impact of PAT can be maximized through the integration of these tools during product development (PD).

In the presentation, Terry begins by discussing the U.S. Food and Drug Administrations' PAT initiative, which has a framework that identifies some of the tools they discuss in the presentation. These include:

• Multivariate data acquisition and analysis tools
• Process and endpoint monitoring and control tools
• Continuous improvement and knowledge management tools

Terry describes on-line process analytics including fault detection and quality parameter prediction. Tools for detection of abnormal operations vary for measured and unmeasured disturbances. For measured disturbances, principal component analysis (PCA) captures contributions that can be associated with process measurements. Deviations may be quantified using Hotelling's T-square statistic.

The residual space that is not captured by the principal component score space reflects changes in unmeasured disturbances that can impact operations. These deviations can be measured with the Q statistic, squared prediction error (SPE).

For the quality parameter estimation, detection of deviations is addressed using projection to latent structures (PLS).

Armed with these statistical tools, Mike shows how the basis for bioreactor process modeling. In the book Mike coauthored with Greg McMillan, New Directions in Bioprocess Modeling and Control, they present a first principal bacterial model that was developed for fungal, bacterial, and mammalian cell processes. The intent of the process model is to more quickly evaluate input step techniques and control strategies in the PD stage.

The BioProcess International magazine article, PAT Tools for Accelerated Process Development and Improvement describes this collaborative effort between Emerson and Broadley-James technologists and University of Texas researchers along with how these tools can accelerate life science manufacturers' PD phase.

Tags: bioprocess modeling | Interphex | process analytical technology | PAT | multivariate analytics | first principal model |

March 25, 2008 in Analyzers, in Control Strategies, in Life Sciences, in Simulation | Comments (0)

Continuous manufacturing processes have long benefited from the application of advanced process control (APC) in their processes to improve upon their regulatory control. Batch manufacturing processes have recently been able to take advantage of these technologies. I received an email the other from Lou Heavner, part of Emerson's Advanced Applied Technologies team. We've featured Lou's work here a few times in the past.

I'll summarize a few of these applications with the hopes that it might spark some ideas for application in your batch manufacturing process.

A manufacturer of sweeteners was having scheduling problems caused by the unpredictability of batch cycle times. End of batch could vary between six and twelve-plus hours. The operators could determine when end of batch was reached but not predict when this would occur. The APC consultants worked with this manufacturer to apply neural network technology as an inferential estimator to predict the end of batch time. The model can successfully predict the end of batch plus or minus ten minutes up to four hours before the completion of the batch. Scheduling downstream equipment is more manageable given these accurate predictions.

A second example Lou mentioned was again around batch cycle time, but in this case poor distillation control, which resulted in longer batches. Model Predictive Control was used in this pharmaceutical manufacturing process to control the batch distillation, specifically the reflux. Distillation time was reduced with the overall batch cycle time reduced by more than three hours per batch on average. The net effect of this improved control performance was a five-plus percent increase in production capacity. The quality of the product produced was also improved.

A third example is in a specialty chemical manufacturer's semi-continuous fluid bed hydrogenation reactor. In this process, cold solids are added to the top batch-wise based on level in the vertical reactor. Heated feedstock (gases) enters the bottom to provide the fluidizing medium and heat to drive the reaction. The reactor was a bottleneck, limited by temperature control and high temperature constraint. Adding model predictive control around the reactor provided more stable temperature control. The controller reduced temperature variability and allowed target to be moved closer to constraint limit with fewer high-temperature trips.

I thought these were great examples of advanced control technologies combined with people like Lou with process and APC application knowledge that are solving process problems and improving process efficiency. Perhaps these ideas will spark some ideas for improvement in your operations.

Tags: batch manufacturing | APC | advanced control | advanced process control | neural network | batch cycle time | MPC | model predictive control | batch distillation | hydrogenation reactor |

March 7, 2008 in Distillation Column, in Food & Beverage, in Life Sciences, in Process Optimization | Comments (0)

In the upcoming March issue of BioProcess International magazine, there is a great article by Emerson's Greg McMillan and Michael Boudreau, Broadley-James' Trish Benton, and the University of Texas at Austin's Yang Zang. The article, PAT Tools for Accelerated Process Development and Improvement, describes the collaborative effort between Emerson, Broadley-James, and UT, "…to examine and quantify the potential for faster optimization of batch operating points, process design, and cycle times." The specific objective of this collaboration:

…is to show that the impact of PAT can be maximized through the integration of dynamic simulation and multivariate analytics in a laboratory-optimized control system during product development.

Greg and Michael are putting many of the ideas they described in their book, New Directions in Bioprocess Modeling and Control: Maximizing Process Analytical Technology Benefits, into practice.

The authors outline the challenge for the 400 biotechnology medicines currently in development, which require overlapping and iterative stages for process development and commercialization. These stages include:

…cell line selection and development, media optimization, process conditions optimization and verification, scale-up, project definition, and plant design.

This team is working on beta tests using this new dynamic model and on-line data analytics and wants to make the results fully public to promote wide use and to advance these concepts and methodologies.

If you're like me and not in the biotechnology field, much of the article may get a little deep. I did glean a few tidbits you might find useful. By creating a dynamic model, one of the big benefits to the team is the ability to speed up the model by up to 1000 times real-time. Whether you're simulating the growth of mammalian cell lines or have another slow process, this can really help reduce trial and error time.

Another key is that the model, configuration, and tools can run in the "virtual plant" PC environment or can be downloaded to the automation system. With proper scale up factors:

…the embedded tools go readily from bench-top bioreactors to pilot plants and eventually industrial-scale bioreactors.

With the recognition by the FDA that quality cannot be tested into products, which led to the creation of the Process Analytical Technology (PAT) initiative, the authors discuss the role of analytics in their efforts.

Principal component analysis (PCA) and projection to latent structures (PLS) are two multivariate analysis techniques that can help analyze continuous and batch process operations. The authors' beta test is focusing on the on-line use of these analytical techniques where PLS detects deviations in quality parameters and PCA detects abnormal operations from measured and unmeasured disturbances.

Given the importance of new product development for pharmaceutical and biotechnology manufacturers, anything to reduce the overall development time and build in quality monitoring as prescribed in PAT should be a welcome addition.

Tags: bioprocess | biotechnology | pharmaceutical manufacturing | process analytical technology | PAT | multivariate analytics |

February 20, 2008 in Abnormal Situation Prevention, in Life Sciences, in Simulation, in Variability Management | Comments (0)

While in Asia last week, I had the opportunity to catch a presentation by Bob Lenich, Director of Emerson's Data Management Services. With the announcement last year of Emerson's acquisition of Decision Management International and the Compliance Suite manufacturing execution system software, Bob has been busy integrating the organizations.

The Compliance Suite software is being used by many process manufacturers, especially in highly regulated industries such as Life Sciences—Pharmaceutical and Biotech manufacturers. The starting point for applying manufacturing execution system software is the data model defined by the ISA-95 (S95) standard. The S95 standard describes the architecture of information flow between the plant floor, the automation system, the manufacturing execution level and the enterprise resource planning levels. Getting these workflow activities and the flow of information between them right is what defines highly efficient, customer-responsive manufacturers.

Bob described the place to start as understand the challenges of improving quality, improving throughput and/or increasing process availability/uptime as a few examples of what can drive process manufacturers to look at improving the flow of information around the organization. You have to understand the problems and needs in order to improve things.

As an example, in the area of quality, typical issues are to reduce deviations. These can be caused by ensuring the right material is available to add at the right time or eliminating manual error in calculations. Also, much time and effort currently spent just doing all the paperwork and paper work tracking required to meet today's regulatory needs. Converting from paper to paperless systems can eliminate all of these problems

In addition to eliminating problems, reducing these deviations also improves throughput by reducing batch variability, reducing batch cycle time and reducing the overall batch release time as there aren't as many problems to address.

Solving these problems requires addressing a mixture of automated and manual processes. Bob noted that the best way to address these issues should begin with a look at the current workflow, to understand where efficiencies can be gained.

The workflow should look at equipment, people, materials, documents and existing information to develop the business justifications and information architecture to address the areas of inefficiencies. Once a good benchmark is established, improvements can be made and the results quantified.

There many opportunities to do this and Compliance Suite is a great tool to use for enforcing these changes. Bob stressed that these changes are typically strategic in nature for the process manufacturer and require the upfront planning and design work to focus the efforts to the areas of greatest efficiency gains and continuing to prioritize the areas of improved data management and flow over time.

Tags: ISA-95 | s95 | manufacturing execution system | MES | manufactuting workflow | material management | batch cycle time | batch variability |

January 22, 2008 in Data Management, in Enterprise Integration, in Life Sciences | Comments (0)

As he announces yet another eBook now available, ModelingAndControl.com's Greg McMillan continues to share his control expertise with the world.

Greg describes the book Biochemical Measurement and Control:

When Monsanto was making the transition to a life science company, I had the opportunity to work on fermenter measurement and control for various genetically engineered products. Important opportunities identified then such as the application of mass spectrometers, dissolved carbon dioxide probes, and inferential measurements of metabolic processes have come to fruition today opening the door to more advanced process analysis and control techniques. Additionally the applications gave me a chance to apply my expertise in pH measurement and control in new ways and dig into the practical aspects of dissolved oxygen measurement and control.

As he goes on to mention, the progression of technology and new thinking prompted an updated version, New Directions in Bioprocess Modeling and Control: Maximizing Process Analytical Technology Benefits published by ISA in 2006. This book:

…provides an updated view and details on new tools for batch modeling, analysis, and control. This ISA book includes the development of neural network inferential measurements of dryer moisture by Washington University in Saint Louis and my first principle dynamic fermentor models for the National Corn to Ethanol Research Center. The book concludes with an excellent review of new technology for batch analytics by the University of Texas.

As I had mentioned in an earlier post, Greg has chosen to make many of his works available as free eBooks once the copyrights are returned to him. So, for the next many years, the Bioprocess book is available for purchase from the ISA folks or in the DeltaV Bookstore, along with many other great books we've discovered along the way.

We live in great times where many with expertise make it freely available. If this expertise happens to intersect with our interests and we have some bandwidth to absorb it, we're but a mere Google search (or whatever your favorite search engine happens to be) away. It just wasn't this easy way back when!

Tags: biochemical | bioprocess | life science | Greg McMillan |

October 26, 2007 in Education, in Life Sciences, in Measurement | Comments (2)

Pharmaceutical Technology magazine published an interesting article by Emerson's Bob Lenich and Christie Deitz. The article, A Look at 30 Years of Change in Pharmaceutical Automation, recounts the changes affecting Life Science manufacturers from the late 1970s though today. I joined the world of process automation in the early 80s as a summer systems engineering intern in offshore oil and gas production and this article brought back some memories of the amazing changes we've seen.

I'll highlight some items from the article to see if it generates any nostalgic thoughts for you.

Although the distributed control system came along in the mid-70s, Bob and Christie note that most life science companies used pneumatic and single-loop electronic controllers. Data was collected manually or with circular and strip charts.

With growing U.S. Food and Drug Administration (FDA) regulations through the late 70s and early 80s, the DCS began to be seen by life science manufacturers as a tool to help comply.

Batch-based automation systems, the first one being the PROVOX system, came out in the early-to-mid 80s to help with sequencing, failure handling, parallel unit operations, and the creation of recipes.

Just a few years before I recall a little collaborative effort between IBM and Microsoft being introduced to the market (wow a 4.77MHz CPU!) This would have some impact in our industry in the following decade as commercially available technologies (COTS) were incorporated.

Toward the later part of the 80s and into the 90s, standards began to play a larger role. ISA-88 (S88), a batch automation standard was important to life science manufacturers. The digital busses including Foundation fieldbus were developing, and Microsoft operating systems began to make their appearance in systems like the DeltaV system. For communications, the OLE for Process Control (OPC) standard became the way to connect Microsoft-based clients and servers—a big improvement over earlier generation DDE communications technologies.

Automation systems became increasingly modular with class-based configurations. These technologies would help the trend toward more modular construction techniques that brought production on-line quicker compared with prior construction and engineering methods.

Regulations continued to advance to try to address concerns around system, production and data management through the balance of the 90s. Efforts began on the ISA-95 (S95) standard to better define the integration of enterprise and control systems.

These regulations had a positive impact in building competency around data security, record security, lot tracking, and overall batch management. The downside was that it placed the focus of life science manufacturers on meeting regulations rather than continually improving their manufacturing operations compared with other industries.

The FDA's Process Analytical Technologies (PAT) initiative addressed this by changing the focus from meeting regulations to improving operation. The FDA's cGMPs for the 21^st Century added in using a risk-based approach to these improvements. As part of this initiative, they encouraged the use of innovative technologies. We've addressed a number of these innovations with respect to PAT in earlier posts.

Bob and Christie closed the article with a note of how flexibility and the integration of automation with the business-level systems is becoming increasingly important as life science manufacturers move from organic-based synthesis to biologics to continue to develop vaccines and medicines to address our health needs.

Update: Thank you Eric for pointing out the error of my ways! The link to the OPC Foundation has been corrected.

Tags: life science | pharmaceutical | FDA | batch automation | S88 | S95 | OPC | process analytical technologies | PAT | cGMP |

July 25, 2007 in Education, in Life Sciences | Comments (1)

Standards play an important role in fostering technological progress—both in the willingness of consumers to adopt the technologies and suppliers in developing products to meet the standards.

In our world of process automation, standards have continued to advance from base-level digital communications protocols to higher-level data communications standards for process manufacturers. The ISA-95 (S95) or IEC/ISO 62264 family of standards as they are globally known are an example of a set of data standards for the interface between enterprise planning systems and automation systems.

I had a chance to get a preview of a whitepaper that Emerson's Shenling Yang is developing around S95 and the XML-based implementation of this standard called Business To Manufacturing Markup Language (B2MML). You may recall Shenling from an earlier post on project timelines. She is now a data integration specialist in the Life Sciences industry center.

As stated in an ISA press release this past January on B2MML improvements:

B2MML was developed by the WBF's XML Working Group to provide manufacturing companies with a freely available XML Schema implementation of the ISA-95 Enterprise - Control System Integration Standard.

You can get a sense for just how detailed and comprehensive these standards are by viewing some of the schema documents available on the World Batch Forum's B2MML web page. Beyond the common schema organized around the S95 data model, other schemas exist for equipment, extensions, maintenance, materials, personnel, process segments, product definitions, production capabilities, production performance, and production schedules. Warning, these schema documents are not light reading!

On projects requiring workflow improvements and/or paperless operations, Shenling and the team follow B2MML data definitions to be consistent with the S95 standard. Because leading enterprise resource planning (ERP) systems like SAP support B2MML, Shenling finds that it simplifies connectivity and reduces the overall engineering effort for integration between the ERP and manufacturing execution systems like Compliance Suite. Ongoing maintenance is also reduced since the information exchanged between applications follows well-defined data definitions.

An example is an order coming down from SAP in an XML-formatted document complying with the B2MML Production Performance schema. The project team used transaction templates, along with the Compliance Suite support component and the process order XML from SAP to generate the actual transaction documents to be passed from the ERP to Compliance Suite. The automated parts are handled by the DeltaV Batch system and other parts of the process like materials management, laboratory information, and proof of personnel training are sent to their respective workflow processes.

The results of these workflows and batch data from the automation system are consolidated in an electronic batch record, which is a critical piece in reducing the overall cycle time on the way to releasing the product for sale.

Update: Gary Mintchell reports on his Feed Forward blog today that the World Batch Forum has announced version 4 of the B2MML standard and some of the additions to this standard. Here's the announcement from the WBF.

Tags: ISA-95 | s95 | IEC 62264 | ISO 62264 | B2MML | World Batch Forum | WBF | Life Sciences |

July 3, 2007 in Data Management, in Interoperability, in Life Sciences, in Project Services | Comments (0)

At the recent Interphex Pharmaceutical Manufacturing Conference, Emerson's Todd Ham presented on the subject of automating fermentation. Todd acknowledged that Christie Deitz, whom we've featured in several other posts, had a large hand in the development of this presentation and work on the project discussed.

The presentation discussed a recent project done on a large-scale, multi-product biopharmaceutical complex. This project was so successful it recently won the Facility of the Year Award Winner in Project Execution. One of the keys to success was a clear design philosophy established up front. Elements of this philosophy included:

• Fully automated
• Paperless, dock-to-dock using electronic records, operator handheld devices, and barcode scanning
• Consistency for operators based on industry standards like ISA-88 (S88), ISA-95 (S95), and digital bus technologies
• Focus on fermentation as a key process area for the project

A key to success in the project was the close working relationship between the manufacturer and the Emerson Life Sciences project team on the up front requirements and design, and the subsequent module-level and integration-level testing.

The upfront design considered not only the fermentation and recovery processes, but also the full automation required for paperless operations. This design included recipe-level batch control, warehouse management, electronic signatures, and a complete electronic batch record, including the manual processes. These manufacturing processes included material management, container management, filter management and sampling.

The project team applied the S88 standard to control modules looking to identify the common modules and instances for things like motors and valves. At the S88 equipment module level, the team created project wide module templates, area specific module templates, and unique, one-time use equipment modules.

The sampling system and sparger control are examples of project-wide templates. Fermentation agitator control and dissolved oxygen control are examples of area-specific equipment modules. Transfer panels and valve assemblies are examples of unique equipment modules.

At the S88 unit level, the team designed classes and instances based on physical similarity and phases that they use such as batch media, inoculate, ferment, etc. This led to various unit classes for fermentation vessels including seed fermenters, production fermenters, and feed vessels.

From a recipe standpoint, the design grouped phases into operations, then grouped operations into unit procedures, and finally grouped unit procedures into procedures, all again following the S88 standard.

Todd shared some lessons learned from the team. With regard to the modular design approach, the team learned to keep process units the same as much as possible. With similar units, it is also important to make sure the operations are also as uniform as possible. The team cautioned about the overuse of aliases, which reference pieces of physical equipment like valves and motors, in phase logic. By not overusing aliases, but rather relying on equipment modules to handle physical differences, the phase logic could be generically written to handle multiple pieces of similar equipment like process tanks.

Other lessons learned were to plan for the extra documentation required for high levels of modularity and dock-to-dock automation. Like other members of the Life Sciences team have counseled in earlier posts, time spent upfront in planning and testing saves a lot of project backend effort.

The benefits of a complete electronic batch record vs. a paper-based process in terms of faster release of products are pretty clear. It's important to assemble the project team and begin the planning and design early to prepare for the additional effort commensurate with the increased automation required for a successful project.

Tags: ISA-88 | S88 | ISA-95 | S95 | fermentation | biopharm | electronic batch record |

May 2, 2007 in Fermentation, in Life Sciences, in Project Services | Comments (0)

From my prior post with Greg McMillan and his thoughts on PAT and Advanced Control, I neglected to mention that he will be at the Interphex 2007 Conference & Exhibition next week presenting two seminars in the Emerson booth (#2354). The seminars will be held 1:30pm on Tuesday and 10am on Thursday. He'll also be around the booth demonstrating the Virtual Plant and DeltaV InSight.

In case you will be there at Interphex2007, I'd be remiss in not mentioning two other Emerson presenters featured here at the Emerson Process Experts blog.

Todd Ham is co-presenting with Genentech's Todd Edgington a session entitled Automating Fermentation on Tuesday from 9-10am.

Mark Coughran is presenting a session entitled Practical Control of Batch Reactors also on Tuesday from 3:15 to 4:15.

I'll work to get my hands on these presentations to recap them for you in future blog posts.

Tags: process analytical technology | PAT | FDA | Interphex | Interphex2007 |

April 20, 2007 in Life Sciences | Comments (0)

Recently I discovered in my PAT RSS persistent search feed an article in Pharmaceutical Processing magazine entitled, PAT Solutions-Eight advanced process control technologies worth considering. This article was written by Rick Rys, President, at R2 Controls, and Janice Abel, Director, Global Pharmaceutical and Biotech Industries, at Invensys.

Since ModelingAndControl.com's Greg McMillan recently co-authored a book New Directions in Bioprocess Modeling and Control-Maximizing Process Analytical Technology Benefits and recently had an article published entitled Maximizing PAT Benefits from Bioprocess Modeling and Control in the November 2006 issue of Pharmaceutical Technology IT Innovations, I had to ask for his thoughts.

Greg sent me a great email which I'll pass along with my edits to insert hyperlinks:

---

The DeltaV systems offers the advanced control technologies mentioned in the PAT article, such as synthetic analyzers, feedforward and predictive control, dead time compensation, and model predictive control in its standard integrated graphical configuration studio that uses Fieldbus function blocks. The synthetic analyzers not only include online regression models such as Neural Networks but also embedded first principal models. Furthermore, innovative analytics, control systems, and models can be prototyped faster than real time in a virtual plant on a desktop or laptop PC anywhere. The virtual plant uses an exact duplicate rather than an emulation or simulation of the control system in the control room. Advanced technologies in the virtual plant can be developed and tested from the high speed play back of historical data from existing systems used to automate bench top fermentors. This includes a new adaptive control technology that identifies process dynamics and indicates the relative improvement possible from better control. The high speed virtual experimentation capability of the virtual plant is a key feature and may be the only way to provide enough historical data particularly on "what if' scenarios since a fermentor batch for most new bioprocesses takes 14-17 days.

The same virtual plant can be used for education of operations and technical support by the dynamic restore and high speed playback of instructive periods of operation.

The technologies can be connected to the bench top system for evaluation, verification, and adaptation of models early on in the commercialization process.

The uses and advantages of the synergistic environment of the virtual plant are explored in the book New Directions in Bioprocess Modeling and Control, the article "Maximizing PAT Benefits from Bioprocess Modeling and Control" in the November 2006 issue of Pharmaceutical Technology IT Innovations, and in the lectures on the Control Insights website. The important practical implications of the extremely slow one direction integrating response of biomass and product concentration on modeling and control are also discussed in the book, article, and website and on the companion Modeling and Control blog site.

The integration and knowledge management of a diversity of technologies in DeltaV addresses the essence of the PAT initiative as expressed in the following statements by the FDA:

Process Analytical Technology:

• It is important to note that the term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner.

Process Analytical Technology Tools:

• Multivariate data acquisition and analysis tools
• Process and endpoint monitoring and control tools
• Continuous improvement and knowledge management tools
• An appropriate combination of some, or all, of these tools may be applicable to a single-unit operation, or to an entire manufacturing process and its quality assurance.

---

Tags: process analytical technology | PAT | FDA | virtual plant | bioprocess | modeling | advanced control |

April 19, 2007 in Control Strategies, in Fermentation, in Life Sciences | Comments (0)

In an earlier post, I mentioned seeing a draft article by Emerson's Terry Blevins and James Beall on performance monitoring and the Process Analytical Technologies (PAT) initiative.

The article, Monitoring and Control Tools for Implementing PAT, has now been published in Pharmaceutical Technology magazine.

Terry and James do a great job in summarizing the common problems process monitoring can detect. These include problems where the control is limited, information from the field transmitters is bad or uncertain, loop modes are incorrect, or there is high variability associate with the loop.

You can do process monitoring with an application that runs either on top of the existing automation system or embedded within it as I discussed in an earlier post on DeltaV InSight.

Here's a few tips gleaned from the article which I'll paraphrase:

• Make sure the performance monitoring application understands the operating states of the batch process avoid false indications or failed measurements
• Where you are using smart field devices like Foundation fieldbus, HART, or others include the status which accompanies the measurement so that performance calculations are based on valid information
• Check the operating modes of the loops versus their design as a basic measurement of control performance.
• Having a model to compare the actual running process against can help spot the largest areas of variability to focus improvement efforts.

Terry and James wrap up their article nicely pointing out that the Food and Drug Administration's PAT initiative has opened up the opportunity to use these performance monitoring tools to improve the operations of their processes. The timing is great with newer technologies coming along to simplify the performance monitoring process.

Tags: process analytical technology | PAT | FDA | performance monitoring | variability |

April 3, 2007 in Foundation Fieldbus, in Life Sciences, in Variability Management | Comments (0)

As reported in my DeltaV News RSS feed, Emerson's Michalle Adkins and Dawn Marruchella have written a great piece in the AIChE's Chemical Engineering Progress Magazine entitled, Ask the Experts - Avoiding the Pains of Systems Integration.

In it, they recognize some of the issues process manufacturers have faced with manufacturing execution system (MES) integration projects and they share their expertise about how to reduce concerns about integrating existing batch process and achievable business benefits.

Their initial guidance is to analyze the integration needs and current business processes and develop a solution weighing the costs and risks against the sought benefits.

Functionality can overlap in both the MES and control system. If your control system has well integrated batch capabilities, Michalle and Dawn recommend using it to manage recipe execution and historical data collection around the batch. This reduces the complexity of the integration between the MES and control system and helps simplify the requirements for the MES. Then ease of MES and DCS integration and specifically capturing the information required for the electronic batch record would be the focus of the integration efforts.

Also, as mentioned in prior posts, they recommend that the solution have:

Support for web services, a service-oriented architecture, and the use of XML schemas, such as ISA-S95's business-to-manufacturing markup language (B2MML)…

Their final recommendation is to review successful implementations to understand not only the software and integration, but also the experience of the project team who implemented the solution.

The benefits for these efforts must accomplish the highly sought after business objectives. If these objectives are to reduce the cycle time for product release, you can incorporate much of the current after-the-fact documentation into the running batch process. Examples cited include:

• Manual setup, cleaning, and maintenance activities
• Review and approval processes for master and batch documents
• On-line data validity checks, electronic signatures, and completed calculations
• Exception-based reporting tailored for intended audience

By executing these tasks during the production of the batch, process manufacturers can increase their right-first-time metrics and shorten the post-batch approval cycle time. The article cites other achievable benefits based on the identified business objectives such as reducing deviations, significantly decreasing manual data entries, and eliminating paper log books.

Tags: manufacturing execution system | MES | system integration | ISA-95 | S95 | B2MML | cycle time |

March 23, 2007 in Data Management, in Enterprise Integration, in Life Sciences | Comments (0)

The growing conversation on the Food and Drug Administration's Process Analytical Technology (PAT) initiative continues. My persistent RSS search on PAT pointed to another great article, this time in Pharmaceutical Technology magazine. The article, The Five Steps to Starting PAT by Jacob Cook, discusses simplifying the process of getting started with a PAT initiative.

The five steps discussed were:

• Pick simple.
• Understand all the details and nuances.
• Evaluate the instrumentation you already have, and the information you can easily collect.
• Understand the appropriate intervals for collecting that data.
• Evaluate the tools available for reading and synchronizing the data.

Just last week we discussed the benefits of applying a structured approach to a PAT initiative to improve opportunities for initial success.

I passed this article by Christie Deitz, whom you may recall from earlier posts on PAT and ISA-88 (S88) projects. Like most initiatives, Christie believes having good data (step 3) is very important. The Life Sciences industry project teams use DeltaV Batch which integrates in a single location the data required for this analysis. This data includes: alarming, continuous and batch history, operator actions and other events. Having this information organized together around batches and campaigns can help identify PAT opportunities.

Where manufacturing execution systems (MES) like Compliance Suite are also used, exception-based reporting can also help with this process of analyzing the data. We discussed using XSL style sheets to do these reports in an earlier post. An example of this exception-based reporting is showing the batch reviewers only the alarm data that occurred during any particular batch run or campaign.

Christie also points out that where manufacturers have already implemented PAT analyzers, they can make decisions in electronic work instructions (EWIs) based on the analyzers' real-time data values to help verify its correct operation. For example, if a PAT analyzer is not reading the expected value based on other operating data, the work instruction can be to have the operator take a manual sample against which to compare the analyzer data value.

Whether you "pick simply" as a starting point or apply a structured methodology to assess the best opportunities to begin, analyzing your existing data is extremely important. The analysis process is less manually intensive when this data is either centralized or logically organized together in some manner to help better identify these opportunities.

Tags: Process Analytical Technology | PAT | Life Sciences | Pharmaceutical | Biotech | electronic work instructions |

March 12, 2007 in Analyzers, in Life Sciences | Comments (0)

In a recent Pharmaceutical Processing magazine article, PAT Searches for its Identity, author Bikash Chatterjee discusses the seemingly slow pace of Process Analytical Technology (PAT) implementations. The article states:

What the FDA has provided is a bold chance for our industry—long mired in historical inefficiencies and product failure—to reinvent and improve existing processes for superior cycle-time, consistency and yield.

Given the change in regulatory climate the article questions why we haven't seen a glut of PAT applications to help achieve better operational results. The author points to challenges in the details to implement. Also the traditional emphasis on product and compliance orientation needs to shift as the article states:

…toward an understanding of critical processes to achieve the significant PAT benefits that have worked so well in other sectors.

Given the complexity of this undertaking the author suggests going forward with an approach like Six Sigma as an operational excellence project management framework.

I caught up with Michalle Adkins, a consultant in Emerson's Life Sciences Industry Center, whom you may recall from an earlier post on five strategies for mitigating project risk. She agrees with the author that a PAT initiative should be managed as part of an overall Operational Excellence program. This is because more structure and process can be provided to the initiative.

Michalle believes that by using the Six Sigma methodology, the right tools can be applied at the right time for evaluating, managing, and implementing PAT projects.  The Six Sigma structure of define, measure, analyze, improve, control provides the structure for managing the PAT initiative. 

It's interesting to note that some of the same tools in the Six Sigma toolbox are already inherently part of PAT such as design of experiments (DOE), statistical process analysis, and methods development. These are all very much related in terms of the types of statistical tools that are used.

Given that the PAT guidelines are still relatively new, pharmaceutical and biotech manufacturers are recognizing that the proven Six Sigma tools along with the analytical tools already used for methods development can help organize the PAT process and move these initiatives forward. It will be interesting to see how these PAT implementations begin to accelerate in the coming years as structured methodologies are applied.

Tags: Process Analytical Technology | PAT | Pharmaceutical | Biotech | Life Sciences | operational excellence | six sigma |

March 6, 2007 in Life Sciences, in Process Optimization, in Regulatory Compliance | Comments (0)

In an earlier post I discussed common transactions between enterprise, manufacturing execution, and control systems. At the heart of this exchange of information is Extensible Markup Language (XML) to pass types of data between systems in a standard, text-based way.

For instance, if you subscribe to this blog's RSS feed, it means you have an RSS reader which translates the XML data in the RSS feed and displays it in a readable format.

Another example is our Google search appliance that crawls the Emerson Process Management website to help you find things faster. The search results are in XML with eXtensible Stylesheet Language (XSL) to make the returned search results readable. Also, the latest version of Microsoft's Office (Office 2007) switched from saving data in a binary format to an XML format.

The uses for XML extend far beyond these examples and include the work being done with OPC Unified Architecture standard and many more.

I caught up with Dave Marschall who is an integration consultant in our Life Sciences industry center. He shared with me how he and his team were using the XSL/XSLT stylesheets in the process of creating custom electronic batch reports which contain information from the enterprise planning systems, manufacturing execution systems and control systems. XML is commonly used to store this batch report data from these various systems.

The XSL/XSLT stylesheets allowed the team to create different renditions or views of the same XML data. A production view might include process operations events and alarms, operator comments, equipment usage statistics etc. A quality assurance/quality control view might contain material usage, lot history, expirations, environmental data, laboratory data requests/results, etc.

Dave described a recent project where the addition of Quality Specifications data allowed the customer to add intelligence to these views of information. Instead of just displaying the data in a tabular format, the XSL/XLST stylesheets could perform comparisons between actual results versus the specifications, and change the color or highlighting of any discrepancies.

This change of colors was used to help the process manufacturer quickly scan dozens of pages of report data and identify areas of concern like out-of-spec conditions. The logic also triggered additional batch details where these abnormal conditions occurred to assist in the review process. The net effect of embedding this intelligence into the batch end report was quicker reviews of the batch which meant quicker release of the final product.

By using a text-based standard XML and XSL/XSLT approach, the solution can be well documented and more easily changed over time to meet the changing needs of the process manufacturer.

Update: Welcome readers of Gary Mintchell's Feed forward blog! Also, it was interesting timing to get a ControlGlobal.com email this morning discussing The ABCs of XML, Parts 1, 2 & 3.

Tags: XML | XSL | XSLT | manufacturing execution system | electronic batch record | production reports | quality reports | batch analysis |

February 26, 2007 in Enterprise Integration, in Life Sciences | Comments (7)

My colleague, Deb Franke, who was instrumental in getting this Emerson Process Experts blog going nearly a year ago, pointed me to an excellent article in Biopharm International magazine.

The article, ON-LINE PROCESS CONTROL: Automating the Control of Process-Scale Purification Columns Using On-Line Liquid Chromatography describes how Lilly used liquid chromatography to measure product purity in near real-time. This is an example of how pharmaceutical and biotech manufacturers are using the guidance from the FDA's Process Analytical Technologies (PAT) initiative to improve their operations. I'll warn you that this article is pretty technical and suited best for those Chemical Engineers among us.

I ran this article by our Life Sciences industry experts to see if they were involved in this or any similar efforts. Lead engineer Brian Crandall, whom you may recall from an earlier post, sent me a note back how his team had recently completed a project for a biotech manufacturer. They wanted an integrated way for their operators to interact with the chromatography columns with the goal of achieving process repeatability and more quantifiable product quality.

Brian and his team developed a solution based upon the ISA S88 modular standard. The major pieces of equipment used on the chromatography skid including dilution control, feed pumps, columns and valve arrays were grouped into processing categories to provide the operators a way to efficiently operate this skid. They can start new operations, hold ones that are currently running, and respond to abnormal processing conditions to take corrective action before quality is impacted.

Also critical was collecting the data from the chromatographs to do analysis around product optical density trends and equipment performance metrics. The DeltaV Batch automation system was also integrated with manufacturing execution system (MES) software to provide material genealogy with the manual and automated process information. This genealogy record included the materials transferred into and out of the chromatography skid. The solution for this information integration was based upon the ISA S95 information standard between enterprise and control systems.

To tie this information back to the business objectives of repeatability and improved quality, Brian and the team created a final batch report that displays the complete product history through the chromatography process. As stated on the PAT site:

The goal of PAT is to understand and control the manufacturing process, which is consistent with our current drug quality system: quality cannot be tested into products; it should be built-in or should be by design.

This design, integration and implementation work by Brian and team sounds exactly like what this goal is meant to achieve.

Update: Welcome Wall Street Journal readers!

Tags: FDA | Process Analytical Technology | PAT | Life Sciences | Pharmaceutical | Biotech | chromatography | MES | ISA-95 | ISA-88 |

February 5, 2007 in Chromatography, in Life Sciences | Comments (2) | Trackback (0)

Pharmaceutical Technology Europe has a recent article entitled, Artificial intelligence the key to process understanding. It discusses the opportunity to enhance the FDA's Process Analytical Technologies (PAT) initiative using artificial intelligence based tools like neural networks, fuzzy logic and genetic algorithms. I shared this article with Greg McMillan who has been quite immersed with advanced control as it applies to bioprocesses.

I received this response which I'll share in total (I've inserted some context-sensitive hyperlinks to his work on Process Control Insights):

There are opportunities to improve plant performance in the front end of the process where most of the product qualities are set by the use of online process models, batch analytics, and Model Predictive Control (MPC). Online process models based on first principals offer a significant source of knowledge discovery for both the process and the control system. The models are part of a virtual plant that enables virtual experimentation for the exploration of "what if scenarios".

This is important for the next steps of implementing online batch analytics and MPC. Since fermentation batches take days to weeks to complete and the cost of wasted batches is considerable, the virtual plant can provide data on various degrees of adverse operating conditions that would be infeasible to obtain from the actual plant in terms of time and cost.

The virtual plant facilitates the development of techniques for the proper unfolding and alignment of batch data and more advanced analysis techniques such as super model based Principal Component Analysis. Neural networks can be employed to provide reaction rates when information on the kinetics is insufficient.

Fuzzy logic rules can be formularized and tested for a wide variety of scenarios. Inferential measurements can be developed for viable mass growth rates and product formation rates to fill in the blanks between lab measurements for MPC applications to improve batch consistency and yield and to reduce batch cycle time.

In summary, the virtual plant offers a synergistic environment for the application of online batch analytics, artificial intelligence, and advanced control. These opportunities and others are discussed in the book New Directions in Bioprocess Modeling and Control published and in the lectures on the Process Control Insights website.

Tags: FDA | Process Analytical Technology | PAT | model predictive control | MPC | neural network | fuzzy logic | bioprocess | life sciences |

January 31, 2007 in Fermentation, in Life Sciences, in Process Optimization, in Simulation | Comments (0) | Trackback (0)

I caught a sneak preview of draft article that ModelingAndControl.com's Terry Blevins who collaborated with James Beall whom you may recall from earlier posts.

The draft explores the initial steps Pharmaceutical and Biotech manufacturers should consider when preparing to implement the U.S. Food and Drug Administration's Process Analytical Technology (PAT) initiative. For those unfamiliar with the PAT guidelines, they were established to encourage innovation in development and implementation of manufacturing processes to improve product quality. The existing regulation designed to achieve quality through rigorous design and documentation actually served to discourage improvements due to the time-consuming nature of the revalidation of any changes.

Terry and James offer some guidance on some initial steps that Life Sciences manufacturers can take. Since most of their manufacturing processes are batch-based, it can be trickier to apply some of the advanced process control technologies more often found in continuous processes found in the chemical, petrochemical, and oil and gas industries. They recommend starting by looking at ongoing performance monitoring. This software has typically layered on top of the automation systems but has begun to become embedded in the automation system. DeltaV Insight is a good example of this type of performance monitoring software embedded in the DeltaV system. This performance monitoring can be keyed to the phases within the running batch to account for the changing process conditions. The dynamics of the process are learned as changes in the process are made.

Terry points out that these performance monitoring tools can help manufacturers spot issues like excessive process variability which can have direct impact on product quality. Other conditions this software can help detect include control-limited conditions, bad/unreliable data coming from intelligent field devices, and control loops operating in modes other than those intended. All of these conditions can contribute to quality issues in the final product.

He notes that the ability of intelligent field devices to provide status of the goodness of the data is a key part of performance monitoring so that the control strategies, history collection, and analytical tools have a clear picture of what is really happening in the process.

I look forward to seeing the finished article!

Tags: process analytical technology | PAT | pharmaceutical | biotech | life sciences | FDA | performance monitoring |

January 9, 2007 in Life Sciences, in Process Optimization, in Variability Management | Comments (0) | Trackback (0)

While thumbing through the November/December issue of Pharmaceutical Manufacturing magazine, I came across a great article, Getting the Most from Coriolis Flowmeters in Pharmaceutical Processes, co-written by Vince Salupo of Eli Lilly and Franki Parson of Emerson Process Management's Micro Motion division. It's a great article for discussing the advantages and disadvantages of bent-tube vs. straight-tube meters depending on the requirements of the application. If you are already well-versed in Coriolis flow technology, this may all be too basic for you. If you're like me and not as well-versed, the article is worth a read because it makes the complex understandable.

Coriolis meters provide mass flow and density measurements, and are available in both bent-tube and straight-tube design. The article discusses the two types of designs and their advantages specifically in Life Sciences applications. The bent-tube meters have better accuracy and turndown. The straight-tube meters offer improved drainability which is something critical for pharmaceutical and biotech manufacturing processes which have clean-in-place operations to clean and sterilize the process piping between batches. The choice for of Coriolis design most suitable really is based on the application. If accuracy and repeatability are the overriding concern, the bent-tube technology is recommended. If raw material contamination within a batch or between batches is the key concern, the straight-tube flowmeters are recommended.

Another reason for the popularity of Coriolis flowmeters in Life Sciences manufacturing applications is their non-intrusiveness into the process. There are no fluids or moving parts that can cause problems on failure. Only the inside of the flow tubes touch the process.

The article further explores specific challenges found in Life Science applications like API synthesis and purification, formulation, and high purity water and what you should consider in selecting bent-tube versus straight-tube Coriolis meters for these unique applications.

I hope others considering their options in these types of applications found the Pharmaceutical Manufacturing article as clear and succinct as I did.

Tags: Coriolis | flowmeter | straight tube | bent tube | Life Sciences | Pharmaceutical | Biotech | drainability | clean in place |

January 5, 2007 in Life Sciences, in Measurement | Comments (0) | Trackback (0)

Todd Ham and Dan Lorenzo from Emerson’s Life Sciences Industry center presented a workshop entitled, Large Project Execution. The focus is on sharing best practices for successfully executing large projects.

They define a large project as 10 or more engineers with more that 5000 engineering hours. The project schedule is typically measured in years and tends to have high visibility with upper management.

Far and away the most important aspect to success is the team leadership. Team leaders should possess technical expertise, managerial competence, and the ability to attend to problems early. Many different styles of leader can be successful, but setting upfront expectations is critical. Dan cites a balanced leader that is knowledgeable, but non ego driven, is willing to make and stand behind tough decisions, knows when to defer to the team, and provides an environment for the team to explore new ideas. This leadership style gives the project its best chance of success.

The next important step is to create a common message to breakdown the project complexities, to provide a clear, cross-functional set of objectives, and to help everyone understand their roles in achieving these objectives. Todd made it clear this is not “rah-rah” motivational sayings on wall posters, but rather a clear vision such as a world-class biotech facility.

The makeup of the team is very important. Most teams have a mix of experience and inexperience and personalities. It’s important the leadership be engaged, reinforce the common message and direction, and deal with people issues head-on and early. Build a team with a balance of skills and personality.

Project indicators that things are going well include new ideas being suggested, measured progress being made, and people on the project generally seem happy. On the flip side, indicators that things are not going well include people acting differently in the presence of team leadership, the leadership being unaware of major issues, and people hoarding information and knowledge. It boils down to reinforcing practices that are yielding good results.

Finally measure and monitor what makes sense for the project. Items that are measured will get better. Too many metrics can do more harm than good and not move the project forward toward the intended objectives.

Tags: project execution | project management | leadership | life sciences |

October 5, 2006 in Emerson Exchange, in Life Sciences, in Project Services | Comments (0) | Trackback (0)

At the recent conference, Implementing Manufacturing Execution Systems in the Pharmaceutical and Biotech Industry, Emerson Senior Vice President John Gardner presented with DMI International’s Bob Schiros a paper on Integrated Recipe Authoring on the first day of the conference. John is the general manager for the Life Sciences, Food and Beverage, Pulp & Paper, Energy, Metals and Mining industry organizations.

The thrust of their presentation is that manufacturers need to integrate their existing "functional islands". Today people want to get information easier, but that's just the tip of the iceberg. Integrating and simplifying the management of documents, personnel qualifications, equipment and material, work activity, automation, various plant floor systems, etc. is where the real operational benefits occur.

John stresses the place to begin is to analyze the causes of deviations in these areas. Eliminating these deviations provides the potential operational improvements at the heart of your business case for change. These areas of opportunities should be broken into manageable phases.

Gaining executive sponsorship for the changes is critical since people and processes are likely impacted, and organizational inertia tends to resist changes.

For pharmaceutical and biotech manufacturers, the opportunity comes in reducing the cost of goods manufactured. John stresses the place to begin is to analyze your current functional operations and the causes of deviations in these areas. This will lead to better inventory and yield management, lower regulatory compliance costs, and reduced product release times. John stresses the place to begin is to analyze your current functional operations and the causes of deviations in these areas. Focusing on eliminating these deviations is the most immediate potential improvement and that's at the heart of your business case for change. These areas should then be broken into manageable phases.

John believes the key is to start with the low hanging fruit which is to have a structured integrated recipe authoring process. The process starts by disassembling the recipe into its components: personnel, materials, equipment, data, and documents. These components are optimized and a database of reusable objects is created. Now the recipe can be reassembled with the optimized components and made available for execution of the batch with its associated electronic batch record.

The Emerson Life Sciences industry experts use the manufacturing execution system (MES) software product, Compliance Suite, as a platform to help manufacturers achieve this structured approach.

The presentation highlights measurable results which have been achieved including 40-70% reduction in batch record complexity, 30-50% reduction in product release cycle times, 20-40% reduction in documentation authoring and approval cycle times, and up to 40% reduction in errors, omissions and deviations of operational data.

Tags: manufacturing execution system | MES | recipe management | electronic batch record | pharmaceutical | biotech |

August 23, 2006 in Data Management, in Life Sciences, in Process Optimization | Comments (0) | Trackback (0)

Pharmaceutical Manufacturing magazine’s On Pharma blog had an interesting post last week entitled Silencing Pharma’s cGMP high priesthood. The post pointedly asks:

We all know that cGMPs are essential to safety. But has the industry gone too far with them? Has pharma, in effect, created a high priesthood of cGMP that stymies creativity, and even common sense?

This post references a Pharmaceutical Manufacturing editorial by Emil Ciurczak who makes the argument:

But, in some cases, cGMPs: have become laws to follow without question. Just as many religious people may not really know why they perform certain ceremonies, many scientists today don’t know why they do many things. Ask them and you may hear an answer very close to "It is written!"

I ran this by Christie Deitz, a senior principal engineer in our Life Sciences organization that you may recall from an earlier post on executing S88 projects. Christie believes that this viewpoint has many subscribers and has some elements of truth to it.

She reminded me that this is on of the key drivers for the Process Analytical Technologies (PAT) initiative from the Food and Drug Administration. PAT, a risk-based regulatory framework, is one of the initiatives in the FDA’s GMPs for the 21^st Century program.

The intent behind this initiative is to break down some of the barriers preventing pharmaceutical manufacturers from using current technologies to improve the quality of the products manufactured. An added benefit is that these technologies can also reduce the cost of manufacturing through improved cycle times and other process efficiencies. One example where this has happened is Baxter’s use of model predictive control to improve solvent recovery.

Another example where today’s technologies can help maintain high quality is Talecris Biotherapeutics’ use of smart devices and digital bus technologies like Foundation Fieldbus to monitor on-line analyzers and generate “GMP critical alarms” in real-time for anything out of tolerance.

While there is some truth to the statement in the On Pharma blog, many in the industry, including the FDA, are working to change the “cGMP high priesthood” mentality. And, many Life Science manufacturers are beginning to take advantage of the risk-based regulatory framework and are using current technologies to improve their manufacturing quality and improve their overall operational performance.

Tags: pharmaceutical | Life Sciences | Process Analytical Technology | PAT | cGMP |

July 19, 2006 in Life Sciences | Comments (0) | Trackback (0)

An interesting paper was presented recently at the Honeywell User Group (HUG) meeting as captured by Pharmaceutical Manufacturing magazine's On Pharma blog. The post, Abbott dispels MES myths (Notes from HUG II) is interesting for the $1.3 Million USD estimated annual savings from applying Manufacturing Execution System (MES) software.

Why I make particular note of this project is that it was accomplished with the help of Emerson Life Sciences expertise in deliverying ANSI/ISA-95 (S95) solutions.

I caught up with Principal Engineer, Josh Gangl in our Life Sciences / Food and Beverage industry organization who was involved in this project. The selected MES software, POMSnet, was integrated by Josh and the team with the plant's DeltaV Batch system.

As the On Pharma post notes:

For Abbott, the MES was a critical aspect of its pursuit of an integrated and paperless environment.

Josh described the challenge as connecting to manual processing pieces like manual operator instructions and procedures, executing weigh and dispense operations, and other non-automated procedures. These were connected with the continuous, batch, alarm, event, and operator actions performed in the DeltaV system to create an electronic batch record. In addition, batch definition and scheduling was done in the MES layer and integrated with the DeltaV system via campaigns.

As Abbott's David Kircher noted in the On Pharma post:

The customizations we did were related to integrations and custom reports, but everything else was out of the box.

This helped minimize the complexity of the integration effort yet still provide savings from reduced documented exceptions, reduced incorrect operator actions, and reduced documentation errors which contributed to the annual savings realized from the project.