Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

	Orally inhaled and nasal drug products (OINDPs) are formulated as either solutions, suspensions, or dry powders that are delivered using devices such as nebulizers, metered dose inhalers (MDIs), or dry powder inhalers (DPIs). One of the critical quality attributes of an inhaled drug product is the amount and size of foreign particles in the product. “Foreign particles-including glass, stainless steel, or different types of polymers-can come from any step in the manufacturing process or from the source materials,” notes John Bak, PhD, principal scientist at PPD Laboratories’ GMP Lab. Manufacturers must develop appropriate tests to identify and measure these particles so that they can be eliminated or maintained below a certain level. 

 spoke with Bak to learn best practices for developing these tests.

 guidance documents are used to develop appropriate tests for foreign particulate matter in inhaled products?

 Current guidance documents that are available include:

 <5> Inhalation and Nasal Drug products–General Information and Product Quality Tests (1)

Nasal Spray and Inhalation Solution, Suspension and Spray Drug Products-Chemistry, Manufacturing and Controls Documentation

Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products

	Although the requirement to do particulate matter testing is included in these documents, no techniques or guidelines for specifications are given. It is up to the applicant to develop and justify the choices made.

 <788> Particulate Matter in Injections (4) and its specifications are specifically for parenteral products and are not appropriate for OINDPs. The testing procedures can be used to help develop an appropriate test, but not the specifications.

 provide little guidance, there have been some position papers published to fill the gap. Two papers by Blanchard et al., ‘Foreign Particles Testing in Orally Inhaled and Nasal Drug Products’ (5) and ‘Best Practices for Managing Quality and Safety of Foreign Particles in Orally Inhaled and Nasal Drug Products, and an Evaluation of Clinical Relevance’ (6), describe the types of tests that can be done and a rational means of setting product specifications specifically for OINDPs.

	The means of setting specifications proposed in the paper (5) is to use the US Environmental Protection Agency National Ambient Air Quality Standards (NAAQS) for particles with < 10 µm aerodynamic diameters. A small percentage (1–5%) of the allowable exposure is suggested for the maximum daily exposure due to the use of the product.

	The first article (5) also has a survey of the commonly used techniques for testing for particulate contamination along with each technique’s strengths and weaknesses.

What factors should be considered when deciding upon a testing strategy?

 Based upon the recommendations of these two articles (5,6) and our experience, when looking at a strategy to test a product under development, the device used for delivery (e.g., nebulizer, MDI, or DPI), the location of action (e.g., nasal or pulmonary), the state of the formulated drug (e.g., solution, suspension, or dry powder), and the testing strategy (e.g., delivered dose or extracted formulated drug product procedures), all impact choices that are made as far as the technologies used, the test method validation strategies applied, the robustness of the resulting procedure, and the cost of the ongoing testing for stability and release.

	The first step in putting together the strategy is to harvest the particles from the drug product, drug substance, excipients, and delivery devices and analyze them using microscopic techniques that allow chemical identification, such as Fourier Transform infrared (FTIR) microscopy, Raman microscopy, and scanning electron microscopy with energy dispersive X-ray probe (SEM/EDX), to elucidate what the common contaminants are and identify their sources so they can be eliminated or reduced in the manufacturing process. In addition, a toxicological assessment can be performed to ensure that no particularly harmful materials are present. Special consideration is given to the < 10 µm particles because they are respirable and therefore present the highest risk from exposure.

	Understanding the particulate profile and having it be reasonably stable from lot-to-lot demonstrates control of the manufacturing process with respect to particulate contamination in the drug product. When this level of understanding is established, the use of faster and less-expensive techniques to monitor the level of particulate contamination is warranted. Light obscuration is the most common technique used for monitoring.

What are the considerations for choosing to collect and analyze particles using the delivered-dose technique or analyzing the drug product extracted from the device or container?

 The delivered-dose technique sounds better because it simulates the actual exposure the patient receives. These techniques, however, tend to be difficult to implement because of their poor precision, which requires higher-skilled analysts and thereby increases the cost of testing. In addition, the incidence of atypical and out-of-specification result investigations is increased with the associated delays. If a justification can be made to use material extracted from the device or container, the routine testing for stability and release is typically more robust and trouble-free.

	Delivered-dose techniques for particulates often can be created by modifying methodology used in delivered-dose uniformity testing. A sufficient amount of material is collected, and then any solid drug substance or solid excipients are dissolved using an appropriate particle-free solvent. If no other solids are present, a compatible suspending solvent is added instead. The solvent is then well mixed to suspend the captured particulate contamination and tested by light obscuration or other techniques. This approach allows the use of the same or similar devices that analytical teams are used to working with, for instance, those described in 

 <601> Inhalation and Nasal Drug Products: Aerosols, Sprays, and Powders

 <1601> Products for Nebulization-Characterization Tests (8).

	When extraction techniques are used, the testing is usually simplified. For nebulizers, the blow-filled vials are opened and the liquid pooled. The pool is then tested by light obscuration or another technique. For DPIs, the powder is extracted as appropriate. For instance, blister strips are cut open and the powder pooled. The powder is then dissolved in an appropriate solvent. The remaining particulate matter is then suspended in the solution and it is tested. For MDIs, the material is extracted by cutting open the frozen can or by dispensing into a container that catches the drug product. If needed, any solid excipients or drug substance is then dissolved in a particle-free solvent. The resulting solution has the particulates suspended and is then tested.

	Light obscuration typically is preferred for analyzing the resulting test solutions. If visible light microscopy is used, the solutions are filtered, and the remaining particulate contamination is counted. The magnification should be set high enough that the < 10 µm particles are clearly visible. Techniques based on 

 <788> often undercount particles in the 2–5 µm range because at 100x magnification specified in 

 <788> (4), these particles are difficult to see against the background of a filter membrane. Light obscuration testing, on the other hand, has good sensitivity to particles in the 2–5 µm range.

What are the most significant challenges in developing appropriate tests for foreign particulate matter?

 Typically, the most challenging part of developing the testing is to find a solvent that dissolves the drug substance and the excipients at the same time, while minimizing interfering artifacts like microbubbles. The second most significant challenge is cleaning the equipment in a particle-free environment to control laboratory contamination of the samples.

What is typically required for validating these analytical methods?

 We typically recommend that the < 10 µm particles be validated as a quantitative impurity test, since they present the highest risk because they are respirable. The range of analysis is demonstrated from the limit of quantitation to 120% of the product specification along with any demonstrations of method robustness indicated from the method development. The ≥ 10 µm and ≥ 25 µm particles also can be validated in the same manner, or be shown to have impurity-limits compliance, because they present less risk and are monitored more from a product quality standpoint than a safety risk.

 40 Supplement 2 <5> Inhalation and Nasal Drug products

General Information and Product Quality Tests (2017).

Nasal Spray and Inhalation Solution, Suspension and Spray Drug Product-Chemistry, Manufacturing and Controls Documentation

 40 Supplement 2 <788> Particulate Matter in Injections (2017)

 40 Supplement 2 <1601> Products for Nebulization-Characterization Tests (2017).

Articles

The delivery device and drug form should be considered when choosing a test method for identifying and measuring particulates.

Best Practices for Testing Foreign Particulate Matter in Inhaled Products

	Self-driving vehicles and robots that pull items from shelves and deliver them to another location in a manufacturing facility or warehouse are not just science fiction anymore-these technologies and others are already being used for automated movement of materials and finished goods in various industries, including the pharmaceutical industry. Efficiency is a primary driving force for this type of automation, which increases accuracy and reduces labor costs. 

In the pharma manufacturing “facility of the future”-and in some facilities already today-automated systems will move raw materials or semi-finished goods from the warehouse to the production line or between departments, and they may also move finished goods from the line to the warehouse. Autonomous mobile robots (AMRs) have an intelligent navigation system with built-in sensors, cameras, and software that allows them to “identify their surroundings and take the most efficient route to their destinations, safely avoiding obstacles and people,” says Ed Mullen, vice-president of sales for North America at Denmark-based Mobile Industrial Robots (MiR). These collaborative robots can improve productivity and efficiency, and return on investment is typically less than a year, says Mullen.

	Transporting goods in and out of cleanrooms with AMRs offers time savings, because employees have to change gowning when moving in and out of cleanrooms. Transporting materials from the warehouse to production departments using AMRs also becomes more efficient. AMRs allow “warehouse employees to stage materials, load the robot with material for multiple departments, and send it on missions to deliver the material automatically in real time,” explains Mullen. Automated guided vehicles (AGVs) can similarly be used for transport and may run faster, but these require physically mounted guides, such as magnetic stripes or rails, and so are not as flexible for facility layouts that may change, he adds. “The trend to collaborative automation in warehouses as well as production was in its very early stage five years ago, but because of technology innovations, it is booming now. We will see an even greater tendency to use collaborative robots in the coming years,” predicts Mullen. “Warehouse automation is an obvious target for cost savings, and we see that more companies request mobile robots like ours because they can take over the internal transportation, and skilled employees can be redeployed for more valuable tasks than just moving parts from A to B.”

	In warehouses for finished pharmaceutical goods, putaway and retrieval, as well as functions such as case picking, can be automated. Technologies available include storage/retrieval machines (S/RMs), which replace work conventionally done by standard fork-trucks, and gantry or articulating-arm robots for case picking activities, which are generally combined with conveyance and sortation equipment, explains Dan Labell, president of Westfalia Technologies.

	If a company wants to consider automation, they should first evaluate the business case, considering labor savings goals, worker safety, and regulatory compliance, notes Jeff Christensen, vice-president of product at Seegrid. Automating the putaway process can be a first step towards a “smart” warehouse. “Companies can set up a pilot program that includes self-driving pallet trucks that replace manual forklift moves from dock to storage,” suggests Christensen. “Companies can also tie in small bin automated storage systems that carry items along conveyor belts from the sorting area to picking. Once these applications are tested, companies can expand their automation footprint by integrating software systems and increasing the number of self-driving vehicles on site.”

	Sophisticated warehouse management systems (WMS) support the movement towards more fully automated warehouses. For warehouses of finished pharmaceutical goods, such as those delivering to pharmacies and hospitals, the near future will see “more emphasis on software integrations to connect data across systems, manage inventory, and improve performance. These systems will include the WMS and software associated with smart machines, such as self-driving vehicles,” predicts Christensen.

	Cost-savings and better data tracking justify automation

	Automation can be justified for high-volume products, but it can also make sense for lower case volumes of high-value products with special cold-storage conditions (e.g., blood plasma), notes Labell. In general, warehouses have been densified to enable growth and reduce construction costs, and the savings in real estate and construction can often pay for a majority of the automation costs, he adds.

	Automated movement in warehouses of finished pharmaceutical goods will be needed to better track product and product serialization/lots and capture this information for everything leaving the pharma warehouse, says Brian Hudock, vice-president at Tompkins International. “The ability to scan product at the sellable level through multiple tracking devices and 100% data capture is important,” he adds.

	Another driver for automation is the need to efficiently handle smaller shipments to support digital shipments. So far, says Hudock, US pharma companies have taken a limited approach to automation and have instead used third-party logistics (3PL) partners to handle distribution of smaller orders, such as those going directly to physicians, clinics, or home care. “Because most 3PL’s want longer contracts to invest in automation, the result has been mechanization for efficiency at best. The US distribution market, however, is on the verge of a major evolution as digital disruptors are entering the equation and are about to create a new channel in the form of increased direct-to-patient/home-care provider shipments,” predicts Hudock. He anticipates that Amazon and others will create changes in the supply chain that will justify automation at both manufacturers and 3PL partners.

Automation systems, vehicles, and robots improve efficiency of transporting materials and finished goods in pharmaceutical warehouses. 

Smart Warehouses: Automating Transport in Pharmaceutical Manufacturing and Supply

Single-use systems for biopharmaceutical manufacturing offer advantages such as flexibility, reduced capital cost, and reduced water use. Single-use (i.e., disposable) components are available for the entire process, from storage containers to bioreactors, filtration, and fluid handling systems. Designing a facility and operations for fully disposable systems requires different considerations compared to traditional stainless-steel systems, however. 

 spoke with Andrew Bulpin, head of Process Solutions at MilliporeSigma, which provides single-use systems (SUS), and Gene Yoshioka, senior director of manufacturing at Avid Bioservices, a contract development and manufacturing organization (CDMO) that built a fully single-use biomanufacturing suite in California in 2016. Avid Bioservices’ cGMP facility manufactures commercial and clinical biologics, and in 2017, the company added multiple 2000-L Mobius single-use bioreactors. Bulpin and Yoshioka shared some best practices for single-use facility design and operations.

What are the most significant concerns when designing a fully disposable biopharma process?

With fully disposable processes, detailed thought needs to be put into how process solutions (i.e., media and buffers) are transferred from one point to another. Containers used for single-use solution storage are limited by size and must be placed in relatively close proximity to the process as compared with traditional fixed tank stainless-steel systems. As a result, fluid management-the transport of hundreds to thousands of liters of solutions to a process-becomes a labor-intensive exercise. The payoff is enhanced flexibility, as a single-use plant does not necessitate the extensive equipment infrastructure and plumbing required by a plant with fixed equipment.  

	Another major difference when dealing with disposable technologies is the shift to relying heavily on raw material procurement and design. In a traditional stainless-steel plant, the focus is on equipment as the driving force for operations. Equipment still plays a big role in disposable plants, but the main systems are the single-use consumables. For example, a stainless-steel bioreactor is the workhorse in traditional plants, with fixed product-contacting surfaces, whereas in disposable plants, the product-contacting bioreactor bag is a material. This difference shifts the focus more toward procurement and acceptance of consumables. In addition, when developing a process, bag and tubing assembly designs need to be thought through to manage a balance between ensuring that assemblies serve their function and minimizing the number of different designs required to complete a process. As a CDMO, managing different assemblies across multiple processes is crucial in reducing consumable costs and warehouse storage requirements. And especially with consumables having a finite shelf-life and long lead times, managing inventories efficiently is a challenge.

 The biggest concern when designing a fully disposable biopharma process is ensuring that the fluid contact materials of construction are compatible with the process and will not adversely impact the drug product. When sourcing materials from multiple suppliers, end users must ensure that all materials meet their quality requirements and can be interconnected as needed to run the process.

	One of the challenges with operating a fully disposable biopharma process is supply security. With traditional stainless-steel manufacturing, the number of consumables needed to run a process is limited to cell culture media, process chemicals, resins, and filter elements. Additionally, production plans are primarily driven by turnaround time, or the time it takes to clean and sterilize vessels between batches. With single-use, the number of consumables needed to run the process significantly increases, which makes the supply chain, especially procurement and inventory management, much more complex.

 What are some of the concerns with testing and validating incoming single-use systems?

While regulations governing single-use processing have yet to be published, industry guidance and best practice recommends users confirm that SUS do not affect the quality, efficacy, or safety of the drug product. One of the biggest challenges end users face is the cost associated with qualifying SUS. Due to the number of different components that make up single-use systems and the variety of different materials of construction of those components, a large amount of testing is required to ensure compatibility with process streams and conditions, and no adverse impact to product quality, efficacy, or patient safety. It benefits users to leverage similar designs where possible and generate a list of preferred components that have been previously validated to minimize additional testing. Users should partner with suppliers that provide robust documentation packages, which will increase the speed and decrease the cost associated with qualification.

	Prior to implementing a new SUS, users should confirm that the fluid contact materials of construction are compatible with process streams and conditions and that extractables and leachables levels will not be harmful to patients. Most SUS suppliers provide this type of data and support product-specific testing. It’s also very important to ensure that the SUS performs as intended during processing. This testing is executed by the user as part of a performance qualification.

	Once a system is qualified, users perform inspections on incoming lots and may perform leak testing, depending on the criticality of the operation in which the system will be used. The ongoing testing strategy should be determined based on a risk assessment. Evaluation of a new SUS is based on the material of construction and functionality of the system. A risk assessment should be performed to determine if additional testing is required, based on the supplier’s documentation package and historical qualification and use of similar systems by the user.

 Testing and validating hardware of single-use systems is no different from the expectations for stainless-steel systems. There are usually less components to deal with in single-use systems, but the general approach is the same. Where the difference lies is with qualification of the single-use bags and assemblies, which not only includes testing of components, but is also highly dependent on qualification of the vendor itself. Much of the quality of single-use bags and assemblies is determined in the manufacturing and testing process at the vendor site. Users of single-use systems need to ensure that their vendors have appropriate controls in place to ensure quality of product during their manufacturing process and that they hold their component vendors to the same level of scrutiny for quality. Vendors are now working on testing methods that users can implement for testing large-scale bags just prior to use, which will significantly reduce the risk.

 What best practices can be used for facility layout?

 Our facility layout is designed such that tanks of buffers, media, and solutions are stored outside of the core production suites. Transfer lines are fed through the walls via transfer panels to reduce the need to move tanks in and out of the processing area. This design also allows for organization of transfer lines, as each port is identified to minimize opportunity for confusion. The segregation of bulk liquids to a supply corridor outside the upstream and downstream process spaces reduces material and personnel traffic into critical areas, reduces equipment congestion in the suites, and facilitates unidirectional process flow, thus improving control and functional operability.

The type of production and manufacturing process should be defined to build the right facility for the right use. For example, will the facility produce small molecules or biologics? Will production be at clinical-scale or commercial-scale? Will the facility be multi-product or product dedicated? Are there plans for future expansion? The facility should have properly sized areas for equipment, people, and storage, and the layout must prevent cross-contamination. As part of the process design, and as a best practice, users should layout the floor plan, using actual equipment dimensions. This layout can be done simply by using tape on the floor. This practice allows operators to provide input to material flows and efficiency, while also providing engineering with the information they need to best design the single-use assemblies that will be used in the process. The next step is to create prototypes of the designs and repeat the exercise, which will help identify the required design changes to the assemblies; identify where supporting brackets, tubing tracks, or organizational systems are needed; and assist with operator training.

	One of the biggest concerns with single-use processing is that it is still very manual. Smart design, detailed standard operating procedures, operator training, and clear communication between production planning and procurement are vital to success and staying on schedule. Systems should be designed in such a way that they are effectively ‘plug and play’.


	Vol. 42, No. 2
	February 2018
	Pages: 54–55

	When referring to this article, please cite it as J. Markarian, "Designing a Single-Use Biopharmaceutical Process," 

Layout and supply details must be considered when implementing a fully disposable biopharmaceutical manufacturing process.

Designing a Single-Use Biopharmaceutical Process

	New tools, such as smart glasses and systems that monitor equipment remotely, can improve pharmaceutical manufacturing operations by making daily tasks and training functions safer and easier. 

	Smart glasses-eyeglasses or goggles with augmented reality (AR) technology-are available commercially and are being used in the pharmaceutical industry. One use of smart glasses is operator training. “Operators can work with a digital version of the equipment that behaves exactly like the physical equipment,” notes Billy Sisk, Life Sciences Industry manager for EMEA at Rockwell Automation. “Machinery can be virtually disassembled into its components in front of the trainee’s eyes with AR glasses. Operators can then better understand how equipment functions instead of looking at the real unit, the insides of which are normally covered by a hood when the machine is up and running.”

	Technology company Apprentice, which has a GMP-compliant augmented reality platform for bio/pharma manufacturing and R&D, introduced the 3.0 version of its trio of augmented reality modules and announced that it had received $2.5 million in venture funding, in a Dec. 7, 2017 press release. According to Apprentice, the three modules of its platform run on smart glasses, such as Microsoft HoloLens, Google Glass 2.0, Epson Moverio BT350, ODG R9, and the Vuzix M300. The Tandem module is a telepresence tool that allows remote viewers to see whatever the glasses’ wearer is viewing. The Manuals module is a hands-free aid that overlays text, images, or video onto an operator’s field of view so the operator can access a standard operating procedure or batch record, for example, during a work process or for training. The BioCapture module collects laboratory and manufacturing data, while an operator is performing a task, using augmented reality and computer vision. The latest version of the three modules has an updated user interface, an improved workflow, and additions to the computer vision and machine learning components.

	“We don’t just augment reality; we augment human ability,” Angelo Stracquatanio, CEO and co-founder of Apprentice said in the press release. “We are changing the way humans interact with intelligent technology.”

	Another enabling technology is the industrial Internet of Things (IIoT), which uses sensors connected to the Internet to send data from equipment on the plant floor to remote monitors for analysis, viewing, and decision making. Operators, engineers, and other personnel can have access to real-time process data without being at the equipment or inside the cleanroom, for example. With appropriate security measures, equipment manufacturers or personnel outside a company can be given access via the IIoT to look at data for a specific concern. The data from IIoT-connected equipment can be analyzed to gauge equipment health and determine when maintenance is needed. Data can also be used for troubleshooting and for optimizing manufacturing processes. 

	The IIoT also allows creation of a “digital twin,” which refers to a virtual representation of a physical entity, such as a bioreactor. “The use of a digital twin helps with the analysis, simulation, and control of real-world conditions, as well as potential changes and improvements in the manufacturing process,” says Sisk. Simulation can be used to experiment with process changes without interrupting manufacturing.

	With more connections to the Internet, security is a concern that must be addressed. Connectivity and integration are also challenges. “Communication between equipment from different suppliers will become more important,” notes Sisk. “Pre-Internet assets lack the connectivity of newer pieces of equipment. However, these legacy devices still have years of remaining value if linked to the cloud, enabling data to be analyzed and revealing actionable insights that provide real benefits.”

	1. Apprentice.io, “NJ Startup Raises $2.5M for Industrial Augmented Reality Platform,” Press Release, Dec. 7, 2017.

The Industrial Internet of Things and new tools such as smart glasses can improve training and daily tasks for pharmaceutical manufacturing operations.

Smart Tools Enhance Work on the Plant Floor

The Industrial Internet of Things (IIoT) involves connecting “things” (i.e., equipment) through the Internet. “Smart” equipment uses sensors to provide data for improving a process or monitoring equipment health, for example.

	“The IIoT brings new options to the table for collecting data from the process and sending it to manufacturing execution systems and distributed control systems (DCS),” explains Greg Newman, vice-president of Marketing at Parsec Automation Corp. “IIoT devices on the plant floor are being used to reduce the investment in infrastructure and setup time for simple data collection tasks, such as production counters, temperature measurement, and equipment state. IIoT devices can also more easily enable sending these data off-site to remote data-capture software.”

	Manufacturing companies from different industries are relying on data analytics, with data collected by the IIoT, to solve problems related to unscheduled downtime, a survey conducted in 2016 by Honeywell found (1). Although pharma manufacturing is different from other manufacturing sectors in its focus on regulatory compliance and in the types of equipment being used, the ultimate aim to prevent downtime and improve reliability still applies. “Manufacturers want to produce high quality products, and they don’t want to lose batches. Monitoring equipment and process data is crucial to achieve this goal,” notes Matthias Maaz, director of Pharma and Specialty Chemicals, Honeywell Process Solution.

	“Predictive maintenance might be the killer app for IIoT,” says Petter Mörée, industry principal for Life Science, Food and Beverage, Chemical at software supplier OSIsoft. Mörée reports that one pharma company using remote monitoring of real-time data had reduced unplanned downtime at a facility because it could more closely monitor conditions such as temperature and humidity, and calibrate systems more accurately.

	“Continuously collecting real-time data from the operating equipment and machines, and then analyzing these data to harness and deliver actionable insights related to asset utilization will help with failure prediction and can improve uptime in all the machines across the plant,” says Billy Sisk, Life Sciences Industry manager for EMEA at Rockwell Automation. He says that although predictive maintenance isn’t a new concept, more data can now be captured, and the cost of computing and data storage is now lower. “One of the key values of scalable analytics is the ability to leverage all the data gathered from the shop-floor equipment and analyze it to improve plant and asset performance. For instance, pharmaceutical producers can monitor performance at an equipment or system level, and track what assets are failing more frequently or are degrading. This information can be used to develop a comprehensive maintenance and predictive asset-management program.”

	Troubleshooting is also enhanced. For example, reports Sisk, a biopharmaceutical company that was upgrading to new purification skids added monitoring of the skids’ variable frequency drives (VFDs). “The VFD fault codes are reported to the programmable logic controller (PLC) and collected in a data historian. The company said using such monitoring saved a day’s worth of troubleshooting in just the first week. The new skids also support workers who want remote access from the office or another location, which provides the ability to begin troubleshooting in mere minutes.”

	Another example of an IIoT-enabled device is the i-ALERT2 Bluetooth Smart monitor from ITT. The monitor tracks pump vibration, temperature, and run-time hours, and the data are sent wirelessly to cloud storage for analysis of equipment health. Guidance can then be sent to the operators to schedule regular maintenance, and the system can alert operators of problems so they can take action to prevent equipment failure.

	Equipment performance is directly affected by process performance, and overall production reliability is intertwined with overall equipment effectiveness (OEE), says Edwin van Dijk, vice-president of Marketing at TrendMiner, a company offering self-service industrial analytics software. He says that “contextualizing asset performance with process data” is crucial, and that a better understanding of the connection of the equipment and process will enable improved reliability and control of product quality and efficiency.

	Manufacturing process data tied to the process (i.e., time-series data) are valuable when presented graphically to subject-matter experts, says van Dijk. He explains that process engineers can use the advanced analytics software to search the historian for similar behavior in the past and graphically overlay the performance patterns. “In correlation with behavior of other tags, these comparisons may indicate root causes for anomalies,” says van Dijk. “On the other hand, in case of good behavior, the patterns of multiple periods of preferred behavior can be combined into golden fingerprints for batch or continuous production. Actual production can then be monitored against the golden fingerprint, even remotely.”

	Smaller batches, such as those used in personalized medicine, can be more difficult to optimize for process efficiency and reliability. Analyzing the data collected through the IIoT, however, enables optimization. “Data analytics by subject matter experts thus becomes more important, and they need tools to quickly analyze, monitor, and predict process and asset performance,” says van Dijk.

	The IIoT allows producers to more accurately monitor production, which enables personalized batches, adds Mörée. Consistency and reliability are crucial for reducing product losses no matter what the batch size is. Using data analysis to catch problems early, or even prevent them, will be one of the major trends over the next several years, says Mörée. He reports that one of OSIsoft’s biopharma users is using IIoT technology to monitor and correct deviations in a fermentation process to reduce the inherent variability in the process. “In a traditional production environment, you may not be aware of deviations until two days into the process. This manufacturer expects to triple its yields by better monitoring,” reports Mörée.

	Modular, “plug-and-play” equipment is increasingly being used, and bio/pharma manufacturing that uses skid-mounted, moveable, and modular equipment can particularly benefit from IIoT solutions, adds Chris Morse, technical solution consultant at Honeywell Process Solutions. “With the IIoT, you can connect a piece of mobile equipment and the system automatically identifies the equipment and knows information such as its cleanliness status. The IIoT simplifies configuration and prevents connection errors.”

	The IIoT can optimize manufacturing processes that use single-use equipment, which require equipment tracking, flow-path verification, material tracking, and hygienic status tracking, says Sisk. In the facility of the future, he envisions that “workers will move assets such as mobile mixing tanks and smart totes into and out of production areas. A modern DCS can coordinate this movement, including verifying the right asset is in the right place, executing production processes, releasing equipment modules, and disabling display information after a process is complete. Mobile tablets or screens on wheels will be able to go with operators as they follow production from one process area to another.”

	The IIoT is built around sending data from the plant floor to “remote” locations, whether these locations are a few feet away in the facility control room or many miles away at a location where specialists can analyze the data. Pharma manufacturers are typically leery of the concept of remote monitoring, says Maaz, because they don’t want equipment manufacturers to have direct access to their DCS and to sensitive data. “Remote,” however, could also mean that a pharma manufacturer’s engineers have a secured line of information from the process at their desktop or mobile device, or that the maintenance person outside of the cleanroom can have access to data at the same time as the operator inside of the cleanroom, explains Maaz. “The ‘mobile operator’ can be in the area but not directly at the equipment monitor. They can carry a mobile human-machine interface (HMI) that can alert them when a disturbance may have occurred,” he adds.

	“Decision making in pharma manufacturing is not just by the operator,” says Maaz. “The operator, quality assurance personnel, management, and regulatory compliance personnel also want access to data. An IIoT platform is flexible and enables everyone to be involved in complex decisions.” In addition to data access, data configuration is important. For the operators, for example, the HMI should present information “in a way that they can use it, so they can react to a disturbance, for example, or be reminded what process step is coming up next so they can prepare for it,” explains Maaz.

	It can also be valuable for remote access to be given to an equipment manufacturer to look at a specific issue. This access, which could be enabled and then disabled again, would be limited to specific instances under high security, adds Morse.

	Another potential use of remote monitoring is that pharma companies may be able to use IIoT technology to remotely monitor and track production at a contract manufacturing organization, enabling them to ensure data integrity and optimize production at different sites, says Mörée.

	Securing IIoT devices is a significant concern. “There are many facets, including isolating the interference that a rough data collection device could cause, to the overall network exposure as the devices are opened up to the public internet,” notes Newman. Although the ability for remotely located software solutions, either in the cloud or in central private data centers, is a significant potential benefit for pharma manufacturing, the biggest barriers to using such solutions, Newman says, are “reliable remote connections and network infrastructure, as well as organizational maturity in setting up risk-acceptable security around the implementations.”

	Additional connections can create more potential entrance points for threats, adds Sisk. “Pharma producers should adopt a defense-in-depth security approach, which deploys multiple layers of protection, assuming that any one protection point can and likely will be defeated. Some security measures that pharma producers should use as part of a defense-in-depth strategy include anomaly-detection software, AAA [authentication, authorization, and accounting] software, and an industrial ‘demilitarized zone’.”

	A survey sponsored by Honeywell found that industrial companies, in general, are lacking in their adoption of cyber-security measures. “To take advantage of the tremendous benefits of industrial digital transformation and IIoT, companies must improve their cyber-security defenses and adapt to the heightened threat landscape now,” said Jeff Zindel, vice-president and general manager, Honeywell Industrial Cyber Security, in a press release (2).

	1. Honeywell, “Survey Finds Manufacturing Executives Will Prioritize Big Data Investments to Solve Problems,” Press Release, Sept. 13, 2016.
	2. Honeywell, “Honeywell Survey Shows Low Adoption of Industrial Cyber Security Measures,” Press Release, Dec. 6, 2017.


	Vol. 42, No. 1
	January 2018
	Pages: 40–43

	When referring to this article, please cite it as J. Markarian, "Pharma Equipment Gets Smart," 

	Jennifer Markarian is manufacturing editor for 

The Industrial Internet of Things can be used in the bio/pharmaceutical industry to monitor equipment health, optimize processes, and enable modular facilities.

Pharma Equipment Gets Smart

Environmental sustainability is a growing concern in many manufacturing industries, and the pharma industry is no exception. Facilities and operations that are designed to conserve resources, such as energy and water, can improve a company’s “green” image as well as reduce its manufacturing costs. Although there are some instances where GMP requirements may not be the most energy or water-conserving mode of operation, it is possible to attain both GMP compliance and efficiency, say experts (1, 2). Big Pharma companies have already made progress toward reducing water, energy, and waste, thus improving carbon footprint (3, 4).

	Drinking water, a crucial input to pharma manufacturing, is expected to become an increasingly limited resource, which means its cost will rise (2). Careful use, including repurposing discharge water from pharma processes for other uses (e.g., cooling towers or building sanitation systems) would help address this problem (2). Discharge of polluted water from some API manufacturing facilities, particularly effluents that could cause antimicrobial resistance, is also a growing concern that is beginning to be addressed (5).

	Although different types of pharmaceutical manufacturing processes use energy in different amounts, HVAC (heating, ventilation, and air conditioning) systems, used to control the air quality of the process environment, consume more energy than any other system across all types of manufacturing. In API manufacturing, for example, HVAC may account for 35–40% of manufacturing site energy use, and in drug product manufacturing, HVAC may account for 60–75%, says Keith Beattie, Life Science lead at EECO

, a UK-based energy efficiency consultancy. “Optimizing other utilities, such as installing a more energy-efficient chiller or implementing control strategies, can improve efficiency by a few percent, but improving HVAC is the quickest return on investment,” he adds.

	There are some straightforward methods for reducing HVAC energy use, often using existing systems and reengineering or optimizing them. “The first step is to minimize the quantity of air used,” suggests Beattie. “Cleanrooms often use higher air change rates than required to meet their classification, and reducing air flow by even a small amount can result in significant savings.” A second step is to minimize the energy going into conditioning of the air. Systems can be set back or even switched off when not needed, and widening the set points for temperature and humidity can allow the system to run more efficiently. Conditioning more efficiently-using high-efficiency motors and fans, for example-also creates energy savings. Finally, says Beattie, companies should maintain their systems by monitoring, optimizing, and not neglecting mechanical maintenance.

 has developed an innovative approach to make cleanroom operations even more efficient using a control system that maintains a fixed air quality level (i.e., particulate count) by varying air flow rates, rather than the traditional method of fixed air change rate. The company has been able to reduce energy consumption by nearly 70% using this method of model predictive control in the company’s test facility, which is representative of a commercial cleanroom, says Beattie. He reports that this energy savings using the adaptive, demand-based system is measured from an already energy-efficient baseline traditional system. “Our adaptive system analyzes the data from particle counters in real time and uses these data to control the air change rate. From a compliance point of view, we are controlling the contamination level and we have data on the real performance of the cleanroom. This control system can thus assure quality and improve efficiency.” How to validate such a system is a question that needs to be answered, because the current validation methods were based on traditional methods, notes Beattie.

	Single-use systems impact in biopharma manufacturing

	In biopharma manufacturing, single-use systems are considered beneficial for various reasons, including significantly reducing the water use required for cleaning of traditional stainless-steel systems. Another benefit is that, because they are closed systems, single-use systems can operate in a cleanroom with a lower grade classification, which corresponds to operational savings (6).

	To better understand the factors affecting the sustainability of a biopharmaceutical facility, the M+W engineering construction company conducted a lifecycle assessment (LCA) on a facility model. LCA is standard methodology used to evaluate environmental impact of a product, process, or service (or in this case, a facility), explains David Estapé, technology manager for Life Sciences in the Global Business Unit, Life Sciences & Chemicals, of M+W Group. An LCA can look at different environmental impact categories; this study considered climate change impact (i.e., carbon footprint in carbon dioxide equivalents). An LCA from “cradle to grave” takes into account not just the facility operation, but all materials and resources from construction to demolition of a facility. Facility operation, however, is the largest contribution to carbon footprint, the study confirmed (7). 

	Using a software program designed to evaluate LCA via mass and energy balances, M+W looked at process, building, and utility systems for a generic monoclonal antibody production process using single-use systems and modular construction for a manufacturing facility located in China.

	The study concluded (7) that transportation of the building modules (by ship) had a small percent of the total environmental impact of the facility (only 1%). The building systems (particularly HVAC) had a significant impact that varied by facility output (28–38%). Surprisingly, the production and disposal of single-use components accounted for only 9–11% of the total impact, while transportation of the consumables to the facility site accounted for 25–30% of the total. “The waste generated by consumables has been raised as a possible concern for single-use systems, but we found that waste was, in reality, a relatively small component. For a facility located at a long distance from the single-use system source, air transportation of the consumables was the biggest impact,” reports Estapé. Optimizing the supply chain for consumables is thus important. “Facility location is significant for transportation as well as for the ‘greenness’ of the energy source used in the LCA,” he adds.

	“Sustainability of facility design is increasingly important, and programs like LEED [the United States Green Building Council’s Leadership in Energy and Environmental Design] certification are desired,” notes Estapé. “It is necessary, however, to understand what exactly contributes to the environmental impact for a particular facility, given its location and all aspects of its operation, not only factors such as energy-efficient lighting and HVAC. We can design the best facility but not truly solve the problem, if the majority of the impact is outside the facility, in transportation, for example. Looking at the LCA is crucial to addressing the real impacts.”

	1.     PharmTech, “Energy Management in Bio/pharmaceutical Facilities,” (Feb. 20, 2013), 

www.pharmtech.com/energy-management-biopharmaceutical-facilities

 .
	2.     J. Markarian, “Considering Water Use in Pharma Manufacturing,” (Oct. 18, 2017), 

www.pharmtech.com/considering-water-use-pharma-manufacturing

,” (Jan. 20, 2016).
	5.     S. Milmo, 

 (2017).
	7.     D. Estape, “Sustainable Facilities: Global Environment Impact of a Biopharmaceutical Facility,” presentation at 2017 ISPE Annual Meeting & Expo (San Diego, Oct. 30, 2017). 


	Vol. 41, No. 12
	December 2017
	Pages: 48–49

	When referring to this article, please cite it as J. Markarian, "Designing Sustainable Pharma Facilities," 

	Jennifer Markarian is manufacturing editor for 

Optimizing water and HVAC systems can reduce resource use in all pharma facilities, and, for biopharma manufacturing, the supply chain of consumables should be evaluated.  