Some revolutions are violent and disruptive. Some revolutions are quiet and consistent. Process analytical technology (PAT) is certainly disruptive, but its adoption has been quiet and relegated to isolated pockets within the industry. As with any revolution, the skepticism abounds on whether this new way of doing things will stick. Simply put—is it worth the risk to change? 

The pharmaceutical industry enjoys both the world's highest profit margins and intense FDA scrutiny. High margins blunt the economic incentives for continuous process improvement; heavy regulation stifles technical change. As a result, the pharmaceutical industry has fallen behind other automation communities. 

And so, ironically, this science-based industry does not apply anything close to current science to its manufacturing side. Process analyzers have played a role in chemical manufacturing for more than 60 years. PAT offers the chance to help close this gap with our manufacturing counterparts. 

This past fall, a KPMG analyst reported that 72% of drug recalls are a result of manufacturing defects. Public safety issues aside, manufacturing missteps on this scale impose a huge business drain—even before the costs of potential litigation. 

To encourage progress, FDA initiated "Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach," which defined PAT as:  

				"Systems for analysis and control of manufacturing processes based on timely measurements, during processing, of critical quality parameters and performance attributes of raw and in-process materials and processes to assure acceptable end product quality at the completion of the process."			

It is an exciting time to be involved in pharmaceutical manufacturing. At the same time, the proliferation of off-the-shelf PAT options makes it tough to know where to start. So, what is a PAT novice to do? Start small—very small. Tackling easily understood processes can make implementing PAT much more manageable.  

Watching timely measurements show up live can be strangely satisfying. Whether you're plugging directly into a programmable logic controller (PLC) or dipping into a SCADA (supervisory control and data acquisition) system, seeing what happens in near-real-time is very powerful. This applies even if the process is already well understood. Building a knowledge foundation with PAT builds momentum and excitement for the next bigger and more complicated processes out there.  

The trick is to begin with the right process. Here's how to get started: 					

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.

The options for PAT can be overwhelming: A number of technologies already can provide amazing information in real time. For example, near-infrared (NIR) spectrometry can provide almost instant quality assessment for identification of raw materials, provide an analysis of complex mixtures or process byproducts, or sniff out counterfeits. The technique is fast and can be configured to require little operator skill or sample preparation.  

Integrating NIR into a production line is not a plug-and-play exercise, however. It demands time, resources, and knowledge. Still, NIR's robust reputation can tempt PAT novices into selecting it as a first PAT solution. Resist the temptation. 

Let's step back for a second and consider other areas of pharmaceutical manufacturing. Take water, the foundation of any pharmaceutical manufacturing process. If a pharma company has periodic problems with its water-for-injection (WFI) system, it can foul up a number of subprocesses. Moreover, WFI production can carry high capital and operating costs. Finally, WFI production is usually well understood. A well understood, critical process with demonstrable influence on the bottom line: WFI can be the perfect jumping off point for PAT. 

Assume that a team is ready to begin delving into PAT and needs to get budgetary approval to begin investigating. They have astutely picked a simple WFI process to show upper management where the money can be saved. 

Now, this is where the real work of process analytical technology lies. A careful distinction must be made between tools that help provide a window into the process on the one hand and truly understanding the causes and effects of deviations on the other. Technology can help provide the former, but only hard work and scientific awareness can provide the latter. 

For the WFI process, the PAT team might begin by investigating what values are acceptable for parameters such as flow rate and temperature. The team might, for example, investigate velocity characteristics of the water flow in order to understand which flow rates prevent or slow microbial growth. The PAT team can then begin developing worst- and best-case scenarios for production, developing a solid hypothesis against which to compare manufacturing. 

This example hints at the importance of understanding the crucial parameters to achieving quality. CQAs are the underpinnings of PAT. Understanding what the absolute acceptable ranges for a given process are is paramount. From that foundation, the appropriate technology can be selected, installed, and used to bring real-time results and control (see Figure 1). 

 Figure 1: Relationship of critical quality attributes to time and work.			

Too often, pharma companies start the process backwards. They install the analytical technology to measure the process before they completely understand what needs to be monitored. The end result is typically no change in controlling end-product variation and no better understanding of what is influencing the process. A lot of money can go down the drain for no gain, along with the possibility of doing bigger PAT projects. 

Back to our WFI example: the entire PAT team could begin by correlating flow rates with bacterial growth, determining minimum velocities, and cross-referencing this data with industry standard guidelines. Next, the PAT team would gather a statistically significant data set from the production environment. These data can then be compared with the industry standards and expermimentally derived acceptable limits. The flow rate is now associated with CQAs to compare with what has happened in production. The next task for the WFI process team is to focus on the temperature readings and apply the same methodology. 

How do you know when you have understood the process? These are the typical indicators:  					

You can explain the variability from batch to batch.

You can reliably predict whether a run will be good or bad from the in-process data.

You have accounted for and understood all of the factors that can alter quality.

As mentioned previously, WFI is a good practice for first-time PAT because its success can often tie back to bottom-line results. Remember, the PAT team is usually under fairly intense scrutiny. If they can improve product quality and prevent rejects through something as simple as water, it can turn the political tide in their favor. 

Another basic process to consider is building monitoring systems. Observing ambient temperatures may not be exciting, but it does give the PAT team invaluable experience on getting a system up and on-line. These are almost always stable processes, so variations can be explained and understood with modest investigative effort. Similarly, stand-alone equipment like autoclaves or glass washers can be rewarding for working with PAT on a micro scale (see Figure 2). 

Figure 2: Screen shot of critical quality attributes for an autoclave.			

At this point, a chicken and egg paradox emerges. Teams are starting to hypothesize about the parameters that influence end-product quality, but they don't want to invest in dynamic analytical technology until they have a firmer grasp of what to measure. But how do they measure the process to begin with? Unfortunately, there are no easy answers. Typically, process and automation engineers do the best they can with the available static measuring tools, in conjunction with the appropriate data-mining techniques, to get a picture of what has occurred within the process. 

With the proliferation of SCADA systems at manufacturing sites, grabbing data is usually not a problem. Depending on the age of the plant, however, some stand-alone machines may not be writing their information to a central database. These situations can present a big roadblock to bringing the entire process up and running with PAT. Some currently available software solutions may be able to capture previously unrecorded data and synchronize it into the analyzing process. 

How invasive must these tools be? The less invasive the better. Given the huge investment in an enterprise resource planning (ERP) solution, the challenge lies in working with the existing systems. The ideal method is to work with management execution systems (MES) and pick a tool that can make decisions on the quality of the process as it is coming into the database. This is where those infamous CQAs for that process are critical to help evaluate the status. A PAT team will develop a profound appreciation for real-time analytical tools and software after going through this exercise. 

Referring back to the WFI team: the goal is to tie all this process understanding together to make a real difference in either end quality or direct savings. For example, if temperature readings are all over the place, chances are that the process is squandering significant energy. The PAT team can determine exactly where in the process this energy drain occurs and suggest, for example, monitoring distillate transfer to a storage vessel much more carefully in real time. But the data sampling rate must be frequent enough to provide this information. This is where the hard work of understanding the process and developing the CQAs really pays off. A WFI process monitor would not need to collect data with anywhere near the frequency of an NIR probe evaluating active ingredient in tablets coming off press. For each process, developers can pick a sampling interval that provides enough information to be useful, but doesn't gobble up server space and irritate the IT administrators (see Figure 3). 

Figure 3: Screen shot of water-for-injection chart in real time.			

In picking a PAT solution, remember the varying facets of process analytical technology. From sensors and hardware to software, the return on investment can vary significantly. Ideally, a tool can not only provide an immediate positive influence on the bottom line, but also grow along with the PAT team as it gains expertise and understanding. Here are a few criteria to evaluate when evaluating a potential solution: 					

How invasive is this going to be with our existing systems?

How quickly will we recoup our investment?

What are the costs and risks of validation?

Remember, pick a simple process and intimately understand all of its nuances. This will show what should be measured. And that, in turn, will show the way to the most appropriate process analytical technology and most beneficial instrumentation. 

This is where the hard work is. When the instruments are connected and the real-time data start coming in, that's where the fun starts. It gets even better when a team can show how it achieved business goals through research findings and process understanding. Be sure to document the findings and show what the solution can save in terms of energy costs over the next six months, one year, and five years. Chances are these can be staggering figures. 

The momentum gained can be used to tackle even bigger and more complex processes. Pointing to quality improvement and cost savings provides the platform for budgetary growth for future PAT projects. The PAT team suddenly gets a lot more interest and respect. Respect is the catalyst for starting off any revolution, and little by little, process analytical technology will bring pharmaceutical manufacturing up to speed with other automated industries. Just don't be afraid to plant the seeds of revolution. 

 is the marketing manager at Novinity Software, 895 Technology Blvd., Suite 202, Bozeman, MT 59718, tel. 206.347.1020, 

Articles

Implementing process analytical technology principles can be a challenging task. This article presents a straightforward approach.

The Five Steps to Starting PAT

The use of robotic automation in pharmaceutical production processes continues to grow. Tighter control of manufacturing processes and increased regulatory testing requirements drive the need for automation. Well thought-out automation offers extensive benefits including high-throughput, robust, 24-hour manufacturing and testing; real-time process monitoring; reactive control; high-volume data gathering; and low data variability. In addition, automation gives pharmaceutical companies more information about the characteristics of its products, and its manufacturing and testing processes than ever before. As a consequence, a wealth of high-integrity data are available. 

In a highly commercial market, any automation requires a solid business case to justify its implementation. The most common business justifications include cost benefits, increased data integrity, increased reliability, increased throughput, and harmonized manufacturing and testing benefits. The tried-and-tested approach of using cost benefits awarded by a reduction in headcount is not always enough to demonstrate the need for automation.  

data integrity and reliability) can hold the key. Increased data integrity results in reduced process variability and, therefore, avoids the need to reject or retest batches. Because the cost of typical pharmaceutical batches can be extremely expensive, only a small reduction in the number of reject batches can justify automation. Increased operation reliability and robustness also can decrease time to market and increase shelf life, which further justify the implementation of automation.  

A broad look at the global pharmaceutical market indicates that automation is not only essential for the future success and growth of manufacturing and testing operations, but also for the harmonization of automation across manufacturing facilities worldwide. But, many pharmaceutical companies have encountered problems with ensuring consistent manufacturing and testing processes at sites worldwide because of variations in regional standards.  

Good automation can help. Developing solutions suitable for global multisite implementation ensures that consistent, controlled methods are used during manufacturing and testing. The technology should function in an identical manner across all worldwide locations.  

Figure 1: The steps required to develop an automation process include requirements gathering, user requirements specification development, concept design, and proof-of-concept activities.			

Although this task sounds simple, many automation providers struggle to enforce the necessary development and commercial-build controls required to provide this assurance. Unlike many other industries, the pharmaceutical industry requires the development of novel, innovative technology followed by the quality-controlled supply of low-volume commercial roll-out units that are identical to the first. Thus, an ensured pedigree is required.  

This requirement is atypical for many automation providers and thus, the needs of the pharmaceutical industry are not widely understood in this respect. Some suppliers focus on the one-off development of bespoke automation, whereas most others focus on large-volume product supply. Therefore, the pharmaceutical industry relies on a small number of specialist suppliers to meet its specific demands. 

The first step in the development of automated manufacturing and testing processes is to gather and analyze the requirements and needs of the pharmaceutical end user. Good automated manufacturing practice (GAMP) guidelines (1) provides clear information about the contents of the user requirements specification (URS).  

Figure 2: Commercial roll-out objectives: first implementation performance assessment, enhancement program, design "lock down," and roll out.			

Typically, the pharmaceutical end user provides the URS to the automation provider to define the detailed requirements for automation. Nonetheless, it is beneficial to involve the automation provider during the development of the URS. A good automation provider will help the pharmaceutical end user to document its objectives and needs, bring global sites together, and promote the detailed thinking necessary to ensure the resulting solutions meet the end user's needs for the future. 

Once the URS is determined, the automation provider will begin the development of the automated solution. Because of the complex nature of drug manufacturing and testing, it is essential that the automation provider keeps the pharmaceutical end user fully involved during the early stages of the development lifecycle. The automation provider must avoid the temptation to jump into a detailed design too soon in the lifecycle. An early concept design exercise is essential.  

Using modern three dimensional-modeling techniques, it is now possible to demonstrate in great detail how an automated solution will look and how it will operate in a short timescale. This tool can help explain the operating philosophy to nonengineering end users. Involving the pharmaceutical end user and soliciting the client's early comments on the proposed solution can greatly improve the long-term rewards. 

Novel, innovative designs often require the development of new techniques. Using formal project management techniques (

 Prince2, Projects Process Limited, Bucks, UK) encourages the automation provider to identify such areas during early risk assessment and to identify measures to mitigate the risk. Proof-of-concept (PoC) equipment is a good way of removing technical risk from a development project. It also provides the pharmaceutical end user with a technical assurance of success at a very early stage of the development lifecycle before significant spending occurs.  

PoC equipment must be well thought out. Its purpose is risk reduction. It should demonstrate the success of core automation elements before full development and manufacture. Its success is heavily dependent on setting clear guidelines and targets for the PoC exercise. The purpose of testing, the acceptance criteria, and the contingency planning to correct any deficiencies encountered must be clearly defined before the PoC exercise commences.  

It is essential that the automation provider keeps the pharmaceutical end user fully involved and aware of PoC equipment testing. The pharmaceutical end user must be comfortable with the PoC equipment and its performance before allowing the automation provider to develop and manufacture the solution. PoC equipment should be cost effective and designed for its intended purpose. It is for short-term use only. 

ISPE's GAMP guidelines provide a useful model for the development of the first implementation. The guidelines ensure that requirements are traceable from the URS onwards. Traceability is demonstrated to the functional specification (FS), the factory acceptance test (FAT) documents, and site-acceptance test (SAT) documents. It is usually possible to ensure that the automation provider's documentation, particularly FAT and SAT documents, cover installation qualification (IQ) and operational qualification (OQ) requirements, thus simplifying and reducing the demands placed on the pharmaceutical end user (1).  

Cost model for the early development of automation

It is useful to treat the cost model for the first implementation differently from that of repeat-build commercial units. During the development of the first implementation, the design is not fixed and it is likely that the automation provider may propose better ways of doing things or that the pharmaceutical end user may change its requirements. One common cause for a change in requirements is the parallel development of new drugs and drug delivery devices. Often, the drug development program will be evolving at the same time as the automated solution. A change in this program will directly affect the automated solution.  

The pharmaceutical end user must preplan for this eventuality with effective finance planning. Otherwise, the quality and performance of the resulting automated solution may suffer. The timing and interaction between the development of drugs, drug delivery devices, and automated solutions hold the key to a successful automation program. An effective collaboration will allow automated solutions to form part of method registrations and pave the way for effective qualification.  

The first implementation of robotic automation is typically installed at a lead site. At this location, the performance qualification (PQ) is completed and the benefits of the technology are measured over a defined time period. Often, a program of enhancements is implemented under change control to maximize the benefits of the automated solution. This is the pharmaceutical end user's first opportunity to use the robotic automation and measure its performance. The success of the first implementation and the benefits awarded is the usual trigger for commercial roll-out of technology to global sites. At this stage, the business case is clearly measurable against actual performance and funding is normally a simple process. Automation costs are clear and well-defined. 

The commercial roll-out of technology to global sites realizes the benefits of automation on a large scale. The objectives of commercial roll-out are to implement a consistent, well-controlled means of product manufacturing and testing, independent of location. The drug product developed or tested at any location must meet an assured level of quality control.  

Before committing to commercial roll-out, it is essential that the automation provider locks down the design of the automated solution. A thorough documentation package should be available upon the completion of the first implementation and should be used as the basis of lock down.  

For example, the automation provider should review the design of the automated solution during the design of the first implementation considering factors such as component supply lifetimes, calibration techniques, set-up techniques, local standards, and regulatory requirements. When the first implementation is in place and operational, the provider should repeat the review exercise. Then, it would critically assess the design of the automated solution and ensure that, where possible, any roll-out issues and risks are eliminated. This process effectively "future proofs" the solution. Each commercial unit must have the necessary controls to set the performance to be equivalent to the first implementation. The benefits of global roll-outs are reduced significantly if equivalence cannot be achieved. 

The skillset required to manufacture commercial-build units differs from that of novel, innovative design. In this case, quality control and consistency of manufacture are the keys. A dedicated team committed solely to commercial-build and roll-out offers an effective means to meet the increasing demands of pharmaceutical companies. Such a team would take over control of the automated solution and lock down the design and testing protocols once the first implementation is in place and operating effectively. 

Harmonization challenges and regulatory standards

The quest for global harmonization of drug manufacturing and testing is complicated by the introduction of local standards and regulatory requirements. It is not unusual for a pharmaceutical company to have different operating procedures at various sites to comply with regional standards and regulatory requirements. It also is important to note the legal differences associated with the sale of equipment into different geographical regions.  

Within Europe, the automation provider should operate to European directives supported by harmonized engineering standards. Equipment can be presumed to comply with the relevant directive if it is designed and manufactured in accordance with a harmonized standard. The result is the "CE mark" generally accepted across Europe. Typical directives relevant to robotic automation include the machinery directive, the low-voltage directive, the electromagnetic compatibility (EMC) directive, and the ATEX directive.			

In the United States, the CE mark is not recognized and, in many municipalities, a UL assessment or "UL listing" is required. This requirement is met by submitting a product for testing and safety certification. The "field assessment" approach works best for robotic automation in which the inspection can take place at the end user's site. Using Europe and the United States as examples, it is clear that the automation provider must offer slightly modified equipment that accommodates different regional requirements. The automation provider must recognize the local requirements of the individual sites and the legal and regulatory standards imposed.  

But, the automation provider must also ensure that these differences are transparent to the operation of the automated solution. The automated solution must function in the same manner and produce the same results, regardless of regional differences. Formal testing and qualification must demonstrate that these results are achieved. Focusing on the functional requirements of each component of the automated solution enables the automation provider to develop testing and qualification documentation that demonstrates equivalent operation of core components, regardless of the technical differences in implementation.  

Harmonizing automated solutions across low- and high- volume sites

One common misconception blocking the introduction of harmonized automated solutions is that harmonized solutions cannot be implemented if the manufacturing or testing capacity of sites varies dramatically.  

This is not the case. Automation providers can offer scalable solutions that allow lower-cost implementations to be delivered to low-volume sites. These solutions are achieved by identifying the core components that affect the manufacturing and testing process. Designing these core components to be scalable across platforms means that automation providers can offer a range of solutions that all operate according to harmonized standards.  

For example, a typical dry-powder inhaler may require a consistent, harmonized means of actuation to release a controlled dose. The automation component that performs the actuation function can be delivered in either a low-throughput work-station solution in which the user loads a single inhaler one at a time or a high-throughput solution in which the user loads hundreds of inhalers at the same time and leaves the system to operate unattended. Through proper testing, the automation provider can prove that the robotics for handling the inhaler and placing it in the actuation unit do not alter the results data. Rather, data can be demonstrated to be the same as the low-throughput workstation. By making the core components scalable, the methods are identical and the manufacturing and testing are consistent, regardless of site capacity. 

When identifying an automation provider, pharmaceutical companies should look for industry experience, coupled with ISO 9001 and TickIT accreditation. TickIT is an accredited quality system certification scheme and is extremely important given the complex nature of software development for real-time automated equipment. Regular audits conducted in accordance with GAMP guidelines also can offer a level of assurance to pharmaceutical companies embarking on automation projects. A good supplier will welcome the audit as a means of demonstrating its commitment to quality. The importance of data and data integrity means that the automation provider must have knowledge about and experience with 21 

 Part 11 requirements. This guideline covers the use of electronic records and electronic signatures. Given the vast amounts of data that an automated solution can provide, using paper records is not a viable approach. The use of electronic records and signatures are necessary. 

Automation providers will offer on-going support for the automated solutions they provide. Preventative maintenance is important to ensure continued reliable operation. Nonetheless, it is also necessary to consider "acceptable downtime" in case of equipment failure. This helps the automation provider to suggest the correct level of spares holding for the automated solution and the correct call-out response time. 

Spares holding can be optimized to meet global multisite needs. It should not be necessary to hold a full set of spares at each local site. Instead, cost savings should be considered a result of the common technology used. It is an important strategic decision to know the proper level and location of spares. 

A call-out response to equipment failure is another strategic decision. The cost of maintenance services is likely to increase exponentially as the requested call-out response time decreases. It may be worth investigating the possibility of local site staff to undertake simple maintenance tasks to remove the need for rapid call-out response. Local staff can be trained by the automation provider to perform basic maintenance functions. 

Once commercial roll-out is completed and site operations are on-going, companies tend to allow local changes to be implemented. The automation provider often is contacted by individual sites to undertake enhancement work on a single site basis. Although this is a cost-effective means of meeting the needs of the single site, it destroys efforts to achieve the long-term harmonization that was needed in the first place. The automation provider will offer a means of change control for the client's global installations. But without the end user's support, the provider cannot prevent local changes. Changes must be controlled and rolled out to all sites. This process increases the cost of changes, but it also ensures the benefits of harmonization to be realized. 

Several problematic issues are associated with the development and installation of automated drug manufacturing and testing processes. The author addresses how vendors can overcome these factors to deliver robust automation across multiple sites.

Commercial Product Supply of Robotic Automation to the Pharmaceutical Industry

The goal of the US Food and Drug Administration's process analytical technology (PAT) initiative is to encourage pharmaceutical manufacturers to improve their operations to reduce the cost of pharmaceuticals. Before the PAT initiative, there was not much emphasis on changing ongoing pharmaceutical operations—repeatability, not innovation, was the order of the day.  

Now that the regulatory climate has changed, how can pharmaceutical manufacturers look to achieve results? Today's automation systems can be an excellent place to begin. Technology is now available to automatically evaluate measurement and control performance and point directly to those areas where improvements are possible. Reduction in process variability is one of the key areas that can be influenced by this effort. Imagine the impact on costs if production cycle times can be reduced or a few rejected, out-of-specification lots of material can be avoided by improving operations to ensure that all manufactured goods are made right the first time.  

The pharmaceutical industry often has been reluctant to introduce change into their manufacturing processes because of perceived regulatory complications. From a manufacturer's perspective, the regulatory process has been rigid and unfavorable to the introduction of innovation. Process changes are managed by time-consuming regulatory submission. Thus, many manufacturing procedures traditionally were treated as being unchangeable.  

Realizing the impact this has on manufacturing efficiency and innovation, FDA established the PAT initiative to encourage the voluntary development and implementation of innovative pharmaceutical development, manufacturing, and quality assurance. As part of this framework, an innovative approach has been developed for helping the pharmaceutical industry address regulatory issues and questions. This new approach is discussed in 

A Guidance for Industry, PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance.

 The agency's usual regulatory scrutiny has been tailored to meet the needs of PAT-based innovations that promote continuous improvement and improve manufacturing while maintaining or improving the current level of product quality. 

The primary goal of PAT is to enhance understanding and control the manufacturing process to ensure final product quality. The concepts addressed by PAT are applicable to all manufacturing situations. Nonetheless, the gains in quality, safety, and efficiency will vary depending on the process. In general, these gains are anticipated to come from:  					

reducing production cycle times by using measurements and control;

preventing rejects, scrap, and reprocessing;

improving operator safety and reducing human error;

improving efficiency and managing variability.

There are many current and new automation tools that can effectively facilitate process understanding and achieve continuous improvement.  The PAT framework defines the following tool categories: 					

multivariate data acquisition and analysis tools;

modern process analyzers and process analytical chemistry tools;

process and endpoint monitoring and control tools;

continuous improvement and knowledge management tools.

As defined in the PAT framework, 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. The challenge for many manufacturers is to identify how best to address the opportunities that PAT offers. This article focuses on the first steps that may be taken to improve operation through process monitoring and control tools. Often these tools are available in your existing automation system or may be easily added to the system.  

Conventional pharmaceutical manufacturing is generally accomplished using batch processes with laboratory testing conducted on collected samples to evaluate quality. Also, most pharmaceutical processes are based on time-defined end points. The role of the automation control system is to control all critical quality attributes to insure consistent quality of the end product. Thus, as outlined in the PAT framework, process controls play an important part in the design of the manufacturing process and in the validation process. In such batch applications, however, the control system itself may face many challenges that affect how closely the control parameters may be maintained and how quickly the control system can respond to process changes throughout the batch cycle. 

One of the greatest challenges in the design and commissioning of a batch-control system is the wide range of operating conditions the control system must undergo during the batch cycle.  

For example, consider the control issues associated with a typical bioreactor shown in Figure 1. During the batch cycle, the feed flow, reagent, and oxygen demand may vary by as much as two orders of magnitude, making it difficult or impossible for typical control devices to continuously maintain desired operating conditions. Also, operation over such a wide range may exceed sensor measurement limits for key operating parameters. When analytical measurements are used in the process, there also is an opportunity for drift in the measurement due to coating or faults in the sensor elements. Poor performance of these measurement and control devices usually contributes to variability in the process operation and deviation in key product quality parameters. Thus, often one of the first basic steps that should be taken in addressing PAT is to implement ongoing performance monitoring of measurement and control.  

Figure 1: Batch process example: bioreactor.			

Performance monitoring of measurement and control is not necessarily a difficult undertaking and can deliver immediate results. The process understanding that monitoring provides may lead to early detection of problems. This can permit action to head off these issues before they impact key operational parameters that could lead to a failure of the products to meet specification. Moreover, the information provided by such a performance monitoring system lays the foundation for identifying areas for improvement in measurement and control.  

Continuous learning through data collection and analysis of measurement and control performance over the life cycle of a product is important. This analysis process can provide insights that contribute to justifying proposals for postapproval changes. As recognized in the PAT framework, information technology systems that support knowledge acquisition are valuable for the manufacturer and also can facilitate scientific communication with the agency. During the past 10 years, a variety of manufacturers have developed process monitoring applications that may be layered onto an existing control system. Also, in some modern control systems, this capability is actually embedded within the control system. When this capability is embedded in the control system, then usually you will find that the initial setup and ongoing maintenance of the monitoring system can be made much easier. Embedding monitoring within the automation system facilitates configuration and implementation; eliminating the difficult integration normally needed by layered systems.  

There are many differences in the ways measurement and control performance monitoring can be implemented. Many of today's commercially available products were designed primarily to monitor continuous process. For typical pharmaceutical batch processes, it is critical that the performance monitoring application take into account the operating state of the process. Without this capability, the monitoring system will provide many false indications of failed measurement when the process is off-line or is an alternate phase of operation such as a sterilization or cleaning cycle.  

Figure 2: Typical diagnostic signal from a Foundation fieldbus device.			

There are key differences in the ability to judge the health of the devices monitoring and controlling a process based on the technology embedded within those devices. When using a traditional analog transmitter for a process measurement, the determination of the health of the measurement must be made on the basis of a transmitter signal value; that is, whether the value is outside the normal measurement range. When digital transmitters are used, then the device performs self diagnostics and can provide a clear indication of the health of the measurement. For example, the health of the measurement made with a Foundation fieldbus device is communicated as a status that accompanies the measurement value, as illustrated in Figure 2. The status indications of measurement quality are categorized as follows: 					

Good: The measurement value may be used for control calculations and actions.

Uncertain: The quality of the value is less than normal, but the value may still be useful.

				The measurement status also contains information indicating whether the measurement is limited and the reason for the quality being "Uncertain" or "Bad."			

In addition to monitoring quality, some measure of variability is usually provided. Typically, variability may be expressed in statistical terms such as the measured standard deviation. 

The proper design of the control system's user interface is key to being able to quickly identify problem areas. When the monitoring application is embedded in the control system, it is possible to make this information available at all operator and engineering stations. Typically, an overview of the process measurement and control performance will provide insights to the measurements and control loops that have incorrect mode, high variability, limited operation, or a value with bad or uncertain quality. It is also possible to look at how these problems have been occurring over time. Using options in the analysis tools, users may evaluate performance for the current operation within a selected period of time that may span multiple batches. For example, by selecting a single measurement or control loop of interest, it is possible to easily "drill down" into more detail to obtain information about the identified problem. An example of this type of navigation is shown in Figure 3.  

Figure 3: A simple three-step process allows users to find the origin of process problems using modern data analysis tools such as DeltaV InSight.			

A basic measurement of control performance is the percent of time the feedback control loop actually runs its designed mode of operation without reaching limits on its range of control. In batch operations, the mode parameter associated with feedback control loops will typically switch between automatic and manual modes in various phases of a batch. The performance-monitoring system must compare the actual mode of operation to the design mode of operation to account for this switch. The performance-monitoring system also should identify when a control loop is not operating properly because its range of control has become limited.  

Another common measurement of control performance is process variability and the ability of the control system to maintain a desired operating condition and compensate for unexpected disturbances. Statistics on control loop error, such as standard deviation, and a control-performance index that benchmarks actual 

 ideal operation are typical measures of control performance. Unfortunately, these statistical methods often require some knowledge of the process and may only provide a relative measure of performance.  

One of the most significant developments in process monitoring is the ability of some of these packages, such as DeltaV InSight, to automatically identify the process dynamic and gain during normal plant operation. Changes in the process are automatically reflected in the process model that is derived by this package. Thus, it is possible to accurately predict absolute control improvements without the need for the configuration and maintenance that is associated with a traditional control-performance index. The expected improvement in control is expressed as a "tuning index."  

Once a process model is identified, then it may be used within the monitoring system for other functions. For example, based on the process model it is possible to automatically provide the best tuning needed to achieve the performance improvement, as shown in Figure 4.  

Figure 4: Automation-system tuning parameters can be automatically determined based on process conditions, permitting optimal control system performance to be achieved.			

Automation system tuning may be suboptimal as a result of simple changes in process dynamics. It is most often impractical to manually retune systems based on day-to-day conditions. This can lead to increased variability in process performance. Through the application of best tuning determined by process modeling software, however, it is possible in many cases to quickly address this source of high variability in a control loop.  

As process models are identified during a batch, great insight into the process can be obtained by observing changes in the model throughout the batch. By comparing identified process models and recommended tuning identified during batches where various products are made with the same equipment, then the effect of these products on control becomes apparent. Also, by comparing the models developed for the same product but using different equipment, one can determine the effect of vessel size and other equipment differences on the process response and gain.   

Today's process modeling tools can facilitate the analysis of process models. For example, it is possible to store the hundreds of process models identified for each loop that have been automatically captured and saved in a database. Tools allow the user to easily analyze changes in a process model and to determine the cause of these changes (

 product grade, feed concentration, time in batch). An example of the interface used for model analysis is shown in Figure 5.  

Figure 5: A representative database of derived process models typical of a process modeling tool.			

By implementing process monitoring, it is possible to quickly identify problem areas in the process that could influence final-product quality or production rate. Industry surveys have shown that without the capability of these new performance monitoring tools, many of these problems may go undetected until they influence production or product quality. On a recent PAT project to implement model predictive control on batch distillation at a major pharmaceutical facility, more than half of the control loops had problems that contributed to increased variability. The action that should be taken to correct such problems depends highly on the process instrumentation and the process design. Some common problems that may be detected through process monitoring are listed in the sidebar, "Common problems."  

One of the more challenging areas to troubleshoot is to determine the source of high variability in a control loop. If the monitoring system supports model identification and provides recommended tuning, then this information may be used to determine whether the tuning is correct for the current operating conditions and whether this changes during the batch or with varying operating conditions. If the process conditions continuously change, it may be advantageous to continually adapt tuning parameters based on tuning calculations during various stages of the batch cycle. By providing best operation at all points, it is often possible to reduce process variation and provide quicker response to setpoint changes. Such improvements can often have a direct effect on final product quality. 

Some monitoring systems also can identify problems with control devices such as control valve actuators. When the process variation is caused by poor actuator performance, then there may be an opportunity to achieve greater performance with the installation of a digital actuator. For example, a digital HART-based actuator system may be retrofitted on an existing valve and work directly with a controller providing a standard 4-20 mA output. On a new installation, a Foundation Fieldbus digital actuator may be used to achieve the best performance. An example of the control performance improvement provided by a high-performance digital actuator system is shown in Figure 6.  

Innovations in process analysis and control offer significant opportunities for improving pharmaceutical manufacturing operations

Monitoring and Control Tools for Implementing PAT

Increasing competitive pressures have forced manufacturers to demand greater flexibility from production facilities. Production managers are being challenged to achieve the seemingly incompatible objectives of increasing output and reducing the risk of regulatory noncompliance while implementing cost-reduction initiatives. These pressures are driving the evolution of interoperability between distributed-control systems and enterprise-planning and information systems. 

The deployment of modern process-automation solutions enables pharmaceutical manufacturers to increase production output and reduce manufacturing costs while ensuring and documenting regulatory compliance. This article will introduce the reader to current trends and possible applications of process-automation strategies for world-class pharmaceutical manufacturing.  

The most basic application of process automation is at the individual machine level. Process machinery used in the manufacture of pharmaceuticals may be installed with a programmable logic controller (PLC) embedded as part of the unit. Typically, this PLC also includes a basic panel display unit that provides limited operator information and interaction. The manufacturing transformation of the pharmaceutical material progresses from machine to machine with manual intervention by the operator. In this simplest scenario, the process automation is local to an individual machine and performs the sequencing and control of the specific process-equipment function. The coordination of equipment and production-record documentation are manual activities.  

Figure 1: Batch-management software such as "System 800xA Production Management" provides the batch-context of material processing by providing markers to enable the automatic retrieval of the measured process values during batch processing.			

A more commonly used approach to process automation is through the use of a process-control system. Other terms used to describe this method include process-control system (PCS), process-automation system, distributed-control system, open-control system, or supervisory control and data-acquisition system. A 

 typically includes multiple controllers, each responsible for one or more pieces of process equipment with one or more operator stations that enable the monitoring and control of the connected process equipment. New process-control systems such as ABB's "System 800xA Extended Automation" integrate plant systems and functions to include more than traditional process control. For example, such systems integrate production management, safety, smart instrumentation, smart drives and motor control, information management, asset optimization, documentation, and other areas into a single operations-and-engineering environment. This combination improves both the control and visibility of the production process. 

The PCS also can be leveraged to provide programmed sequencing of the material through the production equipment. Most material processing in pharmaceutical manufacturing is done on a batch-by-batch basis. Batch-management software coordinates the manufacturing sequence as the material progresses through the processing equipment. A batch manager (or batch supervisor) promotes consistency throughout the manufacturing process. It ensures that each batch of material is sequenced in the same way and is not subject to subtle differences resulting from the working style of various operators or shift teams.  

Figure 2: ABBs "Industrial IT Enterprise Connectivity" provides a framework for connecting enterprise resource planning systems such as SAP, Oracle, and PeopleSoft with process-control systems.			

Deploying batch-management software also brings additional benefits to the manufacturing suites. It allows batch sequences to be programmed to monitor key measured process variables as processing step endpoints (commonly referred to as transitions) and immediately begin the subsequent processing steps. This software also removes some of the variability of the human element and should result in a more optimized processing time and lead to improved production throughput. 

Increase product yield while maintaining batch consistency

Manufacturing plants with multiple production lines and those capable of processing several products use batch-management software to maximize product output. The material processing sequence equipment requirements, target process parameters, and the quantity and types of material to be used are all specified in a master recipe. A master recipe should exist for each type of material produced. A batch manager simultaneously supervises and sequences multiple instances of the same product master recipe (commonly referred to as a control recipe) on different production lines or a mix of different products across the production lines. 

Batch traceability: meeting regulatory documentation requirements

The PCS system also can be used to fulfill production-recording requirements as specified by regulatory bodies such as the US Food and Drug Administration. Most systems include a continuous historian function, which provides a mechanism to sample and store measured process values on a regular, fixed interval. These historian functions supply data to be used as part of the production record. For example, they might document that a vessel temperature was within an allowable limit or confirm that the air pressure in a cleanroom-rated area was maintained above the minimum specified parameter. 

In most cases, the record-keeping requirements to document fully each batch of material produced are more extensive than the simple examples described previously. A batch-production record (BPR) typically is created for each specific batch of material produced. In simple terms, the BPR includes all of the information about the processing of the batch that could have an effect on the final quality of the material produced. This record likely will include the specified master-recipe parameters, (

 target-process values and material ingredients to be added), the main processing steps and the results of their actual performance, and key process measured values that directly affect product quality. 

Many of the regulations that specify the production record-keeping requirements were in effect before the widespread use of process-control systems in this sector. Pharmaceutical manufacturers implemented standard operating procedures (SOPs) to prepare and use manual BPRs required to fulfill the applicable regulations that governed the materials produced within the facility. Several of these facilities still use these manual-based SOPs to meet record-keeping requirements. 

Electronic batch records streamline regulatory compliance

As facilities modernize, or as new production capacity comes on-line, electronic solutions for batch-production recordkeeping are becoming more mainstream. Regulatory agencies, especially FDA, have been actively working with industry to encourage the use of newer technologies to fulfill regulatory requirements. The PCS batch-management software, working in conjunction with the historian functions, can facilitate the maintenance of the BPRs electronically. As described previously, the basic PCS historian functions are designed to acquire and record measured process values at fixed intervals. The production-recording requirements, however, typically must record a process value during a specific step in the production sequence. Batch-management software provides the "batch context" of the material processing by providing "markers" for the batch to enable the automatic retrieval of the measured process values during the specific batch-processing duration. 

Integrated batch and historian functionality: how it really works

A simple example can illustrate why batch and historian integration is useful. For example, a batch reactor includes a temperature probe and associated transmitter among its various process-control instruments. The PCS historian function is configured to acquire and record the value of the reactor temperature every 30 seconds. The typical batch recipe processes the material in the reactor for 90 minutes. Therefore, the BPR must include a trend of the reactor temperature, but only for the time during which the batch material is processed in that specific reactor. A properly configured PCS batch-management history strategy will associate the reactor temperature measured value with the portions of the batch recipe that are associated with the reactor. This eliminates the task of manually associating the batch-recipe processing times with the continuous historian trend data. 

The batch-management software also transfers information to the BPR, including recipe parameter values, master-recipe version number, and the actual processing steps performed during that recipe's execution (control-recipe instance). The batch master recipe also may include specific processing steps that do not necessarily result in actual process-control actions on the equipment. These processing steps may include calculations performed within the batch-management software to confirm a quality-related attribute of the work-in-process material or the explicit recording of a total quantity of material added for inclusion in the batch-production record. 

The PCS batch-management and historian functions can create a significant portion of the BPR. Depending upon the manufacturing methodology, it could even create the entire BPR. In some instances, all of the processing activities are not under the direct control of the integrated process-control system. There may be one or more manual processing activities, in-process sampling for quality evaluations, or processing in equipment that is not integrated into the PCS. The batch master recipe and the PCS can be developed to account for these activities to collect a complete electronic BPR. Leading-edge solutions access and integrate information from disparate systems and equipment from all parts of the process to create a complete batch history. 

The master recipe includes processing steps to facilitate operating personnel's execution of manual processing activities. The batch-management software configures recipe steps that present context-based electronic work instructions to guide the operator through and facilitate the recording of the performance of manual processing activities. These work instructions also can be configured to accept operator keyboard input, including authentication actions that represent an electronic signature. Essentially all of the manual processing steps that were previously executed by means of an SOP and a manual batch record can be performed and recorded within the PCS. This functionality provides the possibility of using handheld barcode scanners for material or equipment confirmation and usage recording, which was not an option for a manually completed SOP or batch record. 

As previously discussed, process machinery used in the manufacture of pharmaceuticals may be installed with a PLC embedded as part of the unit. The PLC, however, may not be a controller type native to the integrated PCS that controls the majority of the processing equipment. It is quite likely that the PLC can be connected to the PCS so that measured values can be acquired and supervisory commands can be transmitted to the PLC. In this manner, the batch-management software of the PCS also can include recipe steps for processing activities in the PLC-based equipment. The ability to acquire measured values enables these activities to be included in the consolidated BPR. 

Industry standards foster a common approach among automation suppliers and manufacturers that deploy this technology. The ISA-88–IEC 61512 "Batch Control" standard defines common models, terminology, and data structures for batch control, batch recipes, and BPRs. 

Why are various companies looking to deploy these types of solutions in the manufacturing environment? 

 These solutions can drive consistency throughout the manufacturing process. 

 The solution also can document the successful completion of manufacturing activities as required by company policy and regulatory agencies. 

Increased throughput with higher quality.

 Increased production quantities are one of the tangible financial results that can be realized by reducing the processing time and minimizing the production of out-of-specification material. 

Reduced production delays, rework, and scrap.

 Using a batch manager to sequence the processing steps automatically helps eliminate processing delays while waiting for human intervention. Consistent processing should reduce the time spent on adjustments and reprocessing of out-of-specification material, leaving more time available for first-run product. 

 Electronic BPRs typically reduce the amount of time required to review, approve, and release the finished product. 

These solutions do not bring benefits in the full-scale commercial production environment alone. Using these solutions in a clinical-manufacturing or in a process-development and scale-up facility can add value and improve the bottom line. More complete electronic recording of clinical or scale-up production batches can facilitate more comprehensive analysis of the process, thus leading to quicker process improvement and optimization opportunities. It also may be possible to transfer significant portions of the PCS configuration and batch master recipes to the production environment, thereby enabling the faster introduction of new products into commercial production. 

Some developing trends in additional applications of process automation in pharmaceutical manufacturing will provide more opportunities to improve efficiency. Facility and building automation, integration with business-level systems, and adoption of process analytical technology (PAT) are affecting how PCS is deployed. 

Certain manufacturing facilities use the PCS for facility or building automation instead of a commercial-facility or building-automation system in critical process areas where the environmental conditions have an effect on product quality. In some processes, the environmental conditions (

 temperature, humidity, cleanliness) may have a significant effect on product quality and must be tightly controlled. These environmental conditions also must be collected, reported, and recorded as part of the BPR and are part of the quality criteria evaluated in the product-release decision. 

Manufacturers that have adopted this approach have been motivated by various considerations. One factor is the ease of inclusion of these critical quality data in the consolidated BPR. Another is the ability to leverage the computer-system validation effort that must be undertaken for the process-control system. 

The leading companies in this market sector are connecting the enterprise-level business systems (enterprise resource planning systems such as SAP, Oracle, and PeopleSoft) with the process-control systems. The deployment of the business-level systems has been completed in many companies, and now the focus has shifted to the systems and processes that consume and supply the information from these systems. A leading industry-analyst firm, ARC Advisory Group, recommends "a focus on work processes, connecting plant systems to business systems, and providing real-time access to information for better decisions. These are the keys to better performance" (1). A typical application includes transferring production-order information with material type and desired quantity to the PCS. The PCS subsequently would supply the enterprise resource-planning system with key information about the actual quantity produced associated with the production order. Similar to the batch-control standards, industry standards also have been developed in this area. ISA-95–IEC 62264 describes enterprise- and control-system integration. ABB's "Industrial IT Enterprise Connectivity," for example, provides a framework for deploying these integration scenarios. 

FDA launched an initiative in August 2002 entitled "Pharmaceutical CGMP for the 21st Century: A Risk Based Approach." The agency issued subsequent guidance on the use of PAT in September 2004. A main goal of using PAT is to enhance the understanding and control of the manufacturing process. FDA hopes to promote innovative pharmaceutical development, manufacturing, and quality-assurance techniques. Some early adopters now use PAT in on-line process-control applications for manufacturing. As pharmaceutical and biotechnology manufacturers look to update, enhance, or introduce process-automation solutions, the ability of a PCS platform to implement or support process-control strategies that leverage PAT is an absolute must. 

A wide variety of automation options exists for plant managers, manufacturing managers, and others responsible for the production of pharmaceutical products to consider. A spectrum of automation possibilities is available, from minimal through fully automated. It is important to carefully review the possible solutions available for the type of facility, the products produced there, and the overall goals that are desired or required by the management team. 

The options, while giving a possible set of tangible benefits, have an associated cost. It is critical to evaluate carefully the likely costs of deployment against the target goals and the possible benefits resulting from the deployment of the solution. No two facilities or enterprises are alike. Typical benefits available may include a reduction in manufacturing cost because of the more efficient use of existing plant assets or the elimination of personnel, the elimination of costly errors resulting from data discrepancies between unconnected systems, a reduction in finished-goods inventory because of an expedited product-release process, or a reduction in the probability of noncompliance. 

 is a product line manager at ABB Inc., 29801 Euclid Ave., Wickliffe, OH 44092, tel. 440.585.8180, fax 440.585.7071, 

 1. G. Gorbach, "Why Manufacturers Are Investing in Plant Floor IT Systems," 

How can manufacturers improve efficiency and increase production while maintaining regulatory compliance? Process-automation solutions are one method.

Pharmaceutical Technology-03-01-2007

The Five Steps to Starting PAT

Commercial Product Supply of Robotic Automation to the Pharmaceutical Industry

Monitoring and Control Tools for Implementing PAT

Technologies to Improve Batch-Production Profitability, Consistency, and Traceability