Life Sciences

In an earlier post I mentioned how Emerson's Shenling Yang had taken an assignment in Shanghai, China. She's bringing her expertise in operations management and the Syncade software gained while executing projects as a member of the Life Sciences industry team. Shenling had some thoughts on the FDA Globalization Act of 2009 and its impact on pharmaceutical and biotech manufacturers across the globe.

The Formulary web site sums up the act:

The Globalization Act expands FDA's authority to inspect foreign plants, to block questionable imports, and to crack down on those who fail to comply. Regulatory "parity" is sought to ensure that lax oversight is not luring manufacturers from the United States to Asia. All registered manufacturers and importers--including generic drugmakers--will have to pay new user fees to support the broader oversight program, and manufacturers will ensure the integrity of product supply chains through electronic pedigrees. FDA also would gain the power to detain, recall, or destroy unsafe, adulterated, or misbranded goods. The act gives the agency added authority to subpoena records and to impose criminal penalties for drug counterfeiting.

The web site continues:

Ironically, legislation that increases FDA inspections of foreign drugmakers may reopen the door to drug importing. A group of leading senators is sponsoring a bill to allow nationwide reimportation of prescription drugs, claiming that the program would save $50 billion over 10 years. All of the imports would have to come from FDA-approved manufacturing plants in Canada, Europe, Australia, New Zealand, and Japan--a policy that assumes more frequent inspections and a viable pedigree system.

Shenling provided her views on the legislation's impact on Asia:

It will impose higher costs on the Asia Pharma industry, because of its stringent quality compliance requirements, particularly the new requirements to secure entire supply chains. On the other hand, it might also help raise Asia Pharma industry's competitiveness on the global stage.

The Act may encourage Asia exporters to follow a more structured approach towards securing supply chain and higher quality standards. Hence, it might reduce the cases of non-compliance. Considering the growing export markets, maintaining the quality standards required for these exports might help Asia Pharma companies grow revenues to offset the costs of this legislation.

Shenling described how the ISA95 information model with automation like the DeltaV system and Syncade operations management can help with compliance.

One of the important aspects of the operations management is quality and compliance. By using the latest technology and adhering to the ISA95 standard, Syncade smart operations management suite integrates smart real-time, plant-floor data with your business processes. Through data and workflow management, Syncade suite reduces non-value added activities and variability. By identifying and correcting problems during the manufacturing process instead of post-process, this streamlined workflow improves the product quality and regulatory compliance.

DeltaV Batch uses the ISA88 standard, which helps batch process manufacturers to define a single recipe in a single engineering environment. It reduces time and cost during the documentation, implementation, and validation phases of a project, and enables manufacturers to quickly produce a quality end product.

Thanks for your perspectives on this legislation and its impact on pharmaceutical and biotech manufacturers, Shenling.

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I caught up the other day with Emerson's Shenling Yang, who is a senior project execution engineer in the Life Sciences and Food & Beverage (LSFB) industry group. You may recall Shenling from earlier posts.

She shared two pieces of news with me. The first is that the Critical Data Backup application developed by the LSFB team, and used for protection of DeltaV automation system configuration and critical process data, has been extended to the Syncade operations management software. Shenling has been working on a project with a pharmaceutical manufacturer implementing this application.

In one of the earlier posts with Shenling, Backing Up and Recovering Critical Control System Data, the goal of a biotech manufacturer was total recovery from a system failure in hours instead of weeks. For highly regulated industries, the scenario described was:

...the dreaded 3 am phone call from the plant with the news that production has stopped, people standing around and it's up to you to do something. Choice one is to go to the plant, to rebuild the automation system configuration, to revalidate the process, to lose a bioreactor batch that may have been running for up to 100 days, and then to hopefully resume production within a few weeks.

The Critical Data Backup application was the solution:

...to meet the 21CFR Part 11 compliance for backup, recovery and preservation of electronic records. It's a part of the overall disaster recovery plan, which includes files, spare on-site server hardware, physical separation of equipment and networks, and always-available support personnel on-site.

With the ISA95 Enterprise-Control System Integration standard, this critical backup need extends to level 3. The Critical Data Backup covers some of the Syncade Suite modules including: Document Control & Archiving, Security & Audit, Equipment Tracking, Batch Production Record, Recipe Authoring, Training and Development, and Manufacturing Information Portal. The backup extends beyond the operational and configuration data to include backup reports, style sheets, and behaviors.

I did mention there were two pieces of news. The second is that Shenling is moving to Shanghai to work with the Emerson Asia Pacific marketing team. She's promised to help me discover and tell stories of all the great work being done by our experts in China. I look forward to being able to broaden out the view of these Emerson experts around the world.

Safe travels and best of success in your new assignment, Shenling! And, make sure to show this post around to everyone that we've promised our readers some good stories.

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I'd like to welcome a new voice, Emerson's Alan Babbitt, to the blogosphere. Alan and team's purpose with this new blog, The Emerson Global Life Sciences Blog, is:

...to provide insight into the Life Sciences Industry from a number of perspectives. We will provide periodic updates on industry trends that include commentary on the state of the Life Sciences marketplace. Of particular interest is the current state of the economy and how we are all affected by change that is in our midst. Our blog will also speak to the value and importance of how the Emerson Team solves business problems at the automation and operations layers of the S95 context model. Readers will benefit from the many years of hands-on experience our team has realized, working with some of the largest pharmaceutical and biotechnology firms in our industry.

Beyond the initial welcome post, his second post looks at the Capital Contraction occurring and its impact on the Life Sciences industry. Alan writes:

Only 1 Biotech firm went public in 2008 and predictions are the Initial Public Offering (IPO) space will continue to be a tough year in 2009. The guess is there will be very few IPOs completed in 2009 and they will be the companies that have proven revenue growth coupled with limited risk. Gone are the IPOs with large technology or regulatory risk. Additionally, venture backed companies looking for more rounds of development capital will be questioning their outlook.

Much like the ModelingAndControl.com blog, I have subscribed to Alan and the Life Sciences team's blog and look forward to sharing some of their thoughts here at Emerson Process Experts.

If you have interests in the Life Sciences industry, the ISA88 and ISA95 models of information management, or industry perspectives of current global economic conditions, you'll want to subscribe too.

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Every industry has its special jargon that is like a secret handshake. If you're an insider, you can quickly spot the outsiders based upon their understanding of your industry's jargon and acronyms. For instance, my background was in the offshore oil and gas business back in the mid '80s. We had jargon like pigging (to clean out pipes) and Christmas trees (fittings and valves on the top of well casing which control the well production rate) to name a few.

My friends in Emerson's Life Sciences/Food & Beverage industry center are insiders in their industry jargon. What sparked this rambling opening was when I read a piece in the Asia Food Journal, Tackling CIP Automation with S88. Written by Emerson's Christie Deitz and Yogesh Rathi, they did a great job, right from the start, defining CIP for us outsiders:

Clean-in-place (CIP) is a method of cleaning vessels and lines without disassembling them. It involves delivering solutions of chemical detergents and rinses at specified flow rates and temperatures. Typically, a CIP skid creates the cleaning solutions and routes them to a user skid that requires cleaning.

According to Christie and Yogesh, CIP began in the 1950s as a manual operation. Over time, this process has been largely automated by most food & beverage, pharmaceutical and cosmetic manufacturers. The authors note that many common challenges exist whether CIP is performed manually or automatically. They include:

• Performing similar actions (acid wash, alkali wash) in an efficient way
• Managing CIP timing of available resources like process skids, and supply/return piping paths
• Minimizing CIP time cycle
• Managing distribution headers or transfer panels to process resources requiring cleaning
• For processes with portable CIP skids used in multi-product facilities, providing local control and easy point-of-use connects

Christie and Yogesh describe how the ISA88 (often referred to as S88) standard and terminology for batch control are applied to CIP processes to address these common challenges. The ISA88 model is comprised of both a physical and procedural model.

On the physical model side, one recommendation was to make the distribution headers and/or transfer panels into equipment modules that are independent of the CIP skid and the equipment it connects to in order to clean and sterilize. The path can be managed as a resource, which allows CIP skids to operate in a similar fashion.

The authors pointed out that the physical model helps to drive the procedural model. They wrote:

The sequences that operate the CIP skid equipment become phases on the CIP skid unit, and the sequences that operate on the user skid become phases on the user skid unit. Similar sequences can be modularized or made into reusable, flexible phases. The differences are handled with recipe parameters.

A final key point is that the ISA88 procedural model can be optimized to run phases in parallel to reduce the overall CIP cycle time for processes with fixed CIP skids. Their example:

...while circulating the pre-rinse solution from one of the vessels on the CIP skid to the user, the other vessel on the CIP skid can prepare the acid rinse solution.

Read the article for specific examples of physical and procedural models for fixed and portable CIP skids.

Understanding the jargon around batch processes begins with understanding the ISA88 terminology. Finding and reading articles like this is a good start as is the ISA website's ISA88 page.

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Recently, one of my RSS feeds alerted me to a new Micro Motion 2400S transmitter packaged in stainless steel for the ELITE Coriolis flow and density meter line. This 316L stainless steel packaging is:

Rated to IP66 and IP67, the corrosion resistant stainless steel housing is ideal for applications where instruments are subjected to regular caustic wash-downs, which are typically found in the food, beverage and life science industries. The 316L construction is also ideally suited for marine and offshore environments.

I caught up with Emerson's John Martin, a Food & Beverage industry manager for the Micro Motion family of products. I wanted to get the story behind the design of this product.

For those that have never been inside a food & beverage or pharmaceutical manufacturing process, John shared how you'll be struck by the bright, shiny silver look you see around the process. Hygienic standards are paramount in these industries and a mild caustic (e.g. sodium hydroxide) is often used to wash down the processing equipment. Standard painted-aluminum transmitter housings do not do well in this caustic environment. This new 316L stainless steel housing allows the transmitter to be integrally mounted with the Coriolis meter and provides a local display at the measurement point for the operations personnel.

John noted that normally, transmitters with aluminum and painted-aluminum housings had to be mounted remotely, in stainless steel enclosures or control rooms, to avoid the corrosive environment. This installation method meant more engineering and installation costs.

This 2400S transmitter supports DeviceNet and Profibus DP communications. These are common digital bus communication protocols used by PLCs and other automation systems like Emerson's DeltaV system. Across two wires, these transmitters communicate process and diagnostic information back to the controllers. From the press release:

The result is that one instrument can provide flow, density and temperature measurements, eliminating the need for multiple sensors and the wiring/configuration costs associated with them. In addition, digital communications unlock instrument diagnostic information, such as drive gain, meter verification and other alarms.

John also shared with me that other industries like offshore oil and gas and other marine environments have corrosive environments caused by saltwater and salt in the air, making them good candidates for this stainless steel transmitter housing.

I do know from my days back as an engineer working on offshore Gulf of Mexico oil and gas platforms, that we put the instruments with painted aluminum housing inside 316 stainless steel junction boxes to protect them from the corrosive, salt-air environment. This packaging option might have reduced the size/number of junction boxes required.

Update: I just saw a Twitter "tweet" from @timalosi who reminds me:

there is more to hygenic than stainless. draining is much more important. the Housing is just for looks

Tim, point taken and all in 140 characters or less!

Twice here at Emerson Process Experts, I've featured the work of Shenling Yang. The first was in her role as member of the DeltaV technology team and the second as an integration specialist in the Life Sciences industry center. Shenling shared with me a presentation she is developing with a biotech manufacturer for the Emerson Exchange on backing up and recovering critical process data. This is a huge requirement for regulated industries like pharmaceutical and biotech manufacturers.

The scenario they will present is the dreaded 3 am phone call from the plant with the news that production has stopped, people standing around and it's up to you to do something. Choice one is to go to the plant, to rebuild the automation system configuration, to revalidate the process, to lose a bioreactor batch that may have been running for up to 100 days, and then to hopefully resume production within a few weeks. To give you a sense of the value of saving a batch, it's important to note that the medications being produced in these bioreactors save lives and any loss of a batch means a delay for a patient who needs this medication.

Choice two is to load the data backed up from the critical data backup application, have the operator restart the plant, verify normal operations and save the running batch in the bioreactor. Obviously, choice two was the way to go. It is vital to protect and recover control system data because human error or system failure can wipe out years of work, experience, plant operations information and process records.

The U.S. Food and Drug Administration (FDA) regulates and requires fully validated backup and restoration solutions for critical data. With the FDA's 21CFR Part 11 electronic record provisions include the accurate and ready retrieval of control system information through the record retention period. The FDA's 21CFR Part 210 & 211 good manufacturing practices (GMP) require this retention period be at least one year after the expiration date of the batch.

The goal established by this biotech manufacturer was to be able to recover and be back up and running 100% with minimal loss in three hours or less. They were looking for something with minimal customization that would automatically back up the configuration and version control databases without any operator intervention. The solution was to use the Critical Data Backup application (CDBA) developed by the data management services team to meet the 21CFR Part 11 compliance for backup, recovery and preservation of electronic records. It's a part of the overall disaster recovery plan, which includes files, spare on-site server hardware, physical separation of equipment and networks, and always-available support personnel on-site and at their Emerson local business partner location.

The backup system includes a server, tape carousel and gigabit network to link multiple DeltaV systems and transfer large files quickly, safely and efficiently. This application help formalize the backup process which was not as diligent or documented as it should have been.

Like anyone who administers a server or even backs up the family PCs can attest, you don't know how good it will work until you have to use it. The day came when this site lost two hard drives in a RAID array. They were able to put a new server in the rack, transfer data using CDBA, do a warm batch restart and be back up in an hour with no loss to the batch.

This sounds like a great presentation to catch if you need a way to formalize your system backup and recovery effort.

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.

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.

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.

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.

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!

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.

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.

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.

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.

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 Modeling and Control.com blog. 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.

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.

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.