	Process modeling is becoming established as a method to design and optimize pharmaceutical processes using data from process analytical technology (PAT). Modeling software can be implemented to monitor the process and increase process understanding and, if desired, to control the process.

	A process control model takes process data inputs, such as temperature and flow rate, from traditional sensors, as well as spectral and other data from PAT, and calculates a predicted output. In an open loop, process operators evaluate this predicted data and decide whether a change to the process is necessary. In closed-loop, advanced process control (APC), a process controller uses the model to make changes automatically, to keep the process in specification.

	One use of process modeling and control is to evaluate the quality characteristics of incoming raw materials and determine how these characteristics will affect the final product. "A raw material could be within specification, yet result in an out-of-specification end product," notes Jakob Mohr Christensen, general manager at MKS Umetrics. "The modeling software can be used to determine how process parameters could be changed to account for variability in a raw material or, in some cases, to identify whether a given material should not be used at all. The software can be used to build quality control charts for the materials that go into the process."

	Modeling software can be used to meet various goals, including improving the quality or economics of a product, or determining a design space. To build a process model, users identify the relevant variables and extract representative data, either from the existing process or, if the process is new, from designed experiments, explains Chris McCready, principal engineer at MKS Umetrics

 With Umetrics’ offline SIMCA modeling software, users refine the model by analyzing data and reviewing it with process experts to compare the model to existing process knowledge. Next, they verify the model on the system using SIMCAonline software, while the process is running, and the controller is commissioned to monitor and/or control the process.

	Currently, most of the pharmaceutical clients who use Umetrics' SIMCA-online process modeling software use an open-loop mode. "This 'advised future' mode is typically the first step of applying process control models to a pharmaceutical process, but the software can also be programmed to allow closed-loop control," explains McCready. "Although APC is a mature technology, a challenge is in applying these methods to pharmaceutical processes where the regulatory environment was written for release of batches. A few companies are building continuous processes with advanced control, while others are waiting to see."


	Umetrics SIMCA modeling software uses finite impulse response (FIR) modeling to handle "data lagging," which is how the state of the process at a given time point is influenced by what was happening in the process at an earlier time. "Some variables have longer lag times than others," explains Lennart Eriksson, senior principal scientist and lecturer at MKS Umetrics. "The most appropriate lag sequence must be identified by testing each case as part of the overall process of refining the process model." FIR modeling in a continuous process can be compared to the method of "data unfolding" in a batch process, explained McCready in a presentation at IFPAC. The Umetrics software can be configured to either batch or continuous or even hybrids of the two. For example, in a biopharmaceutical perfusion process, the software is used to monitor the initial cell growth, which is a batch process, and then to monitor and control the steady-state, continuous perfusion process. 


	The topic of control systems for continuous processing will be discussed on the 

 (New York City) on Tuesday, April 21. Doug Hausner, Associate Director for Industrial Relations and Business Development at the Engineering Research Center for Structured Organic Particulate Systems, Rutgers University, will present "Meeting Regulatory Expectations for Continuous Processing Sensing and Control," and will review technology and regulatory expectations for implementing next-generation continuous processes in solid-dosage pharmaceutical manufacturing.

	To hear Chris McCready explain the steps of implementing process control software, tune in to 

Articles

Production Trends

Use of modeling software can help improve process understanding, and can be used in open- or closed-loop control.

How Modeling Software Can Help Process Development

	Regulations addressing good manufacturing practices (GMPs) are a set of principles that are promulgated and enforced internationally by regional and national agencies. Within GMPs, the design of the physical plant is always addressed. One principal that is central to GMP design is ease of cleaning. For example, the European Union guidelines to good manufacturing practice states that in production areas, “interior surfaces (walls, floors, and ceilings) should be smooth, free from cracks and open joints, and should not shed particulate matter and should permit easy and effective cleaning and, if necessary, disinfection” (1). To illustrate and appreciate how cleaning impacts the design of a facility, this article will look at the selection and specification of a range of divergent products used in the construction of GMP manufacturing rooms. These products include high-speed roll-up doors, sprinkler heads, epoxy paints, and exposed pipe supports.
	
	


	High-speed roll-up doors have become a practical solution for openings that are required to accommodate the movement of materials and equipment. These doors are complex devices with a host of components and moving parts including motors and drivetrains. They are far from the ideal flush, smooth-surfaced mechanisms that are desired in a GMP production area. As an example, the tracks that hold the fabric, because of their configuration, are difficult to clean. For pharmaceutical-grade doors, these tracks, along with other hard-to-clean surfaces, are typically shrouded by stainless-steel covers that present an easily cleanable surface.
	
	The single largest and the most prominent component of a high-speed roll-up door is the fabric. In GMP environments, frequent and regular washing occurs with harsh, usually caustic, cleaning agents. To withstand constant washing, the fabric must be non-porous and compatible with the cleaning chemicals. Manufacturers usually provide several fabric options, and an appropriate fabric must be selected. Perhaps the most important feature of a roll-up door is the door’s ability to maintain room pressurization. In the past, these doors were not pressure tested and presented many problems when installed. Special and deliberate attention must be given to the design of high-speed roll-up doors if they are to be used in GMP production areas. Only doors with published test data can be relied upon to provide the sealing necessary to maintain room pressure.
	
	Besides proper selection of the product and its options, the details of the door’s installation is also important. Roll-up doors require an independent control box that is rather large and bulky. Where to locate this device, how to mount it, and concealing the wiring to the door within the walls cannot be overlooked. Due to this cabling, the controllers can be located remotely. One option is to place the control panel in the ceiling. Ceilings at this type of door, however, are usually high and hard to access. If a gypsum wallboard ceiling is necessary, then an airtight access door is also required and must be large enough to provide access. An alternative is to mount the controller on a wall near the door. If this option is selected, the panel should be placed on the “less clean” side of the door and installed in a manner that minimizes horizontal surfaces that require cleaning.
	
	


	Automatic fire sprinkler systems are devices that are virtually ubiquitous throughout every pharmaceutical facility; however, no sprinkler heads have been developed exclusively for GMP applications. Instead, standard models are used, and again, cleaning is an important consideration in their selection. In addressing this issue, there are two schools of thought. First, and perhaps the most common today, is the use of concealed, flush-mounted heads. The second approach is to use a common, pendent-type head installed with an extended escutcheon.
	
	Concealed heads present a visually clean appearance due to the near-flush condition they provide. These heads are actually recessed and a cover is installed that sits nearly flat against the ceiling. When the ceiling and cover are the same color, they present a near monolithic surface plane. In the event of a fire, the cover releases and falls to the floor, and the head activates. When cleaning the ceiling, only the cover is touched, leaving the sensitive head undisturbed. The criticism of this approach is that the recess and the head is not cleaned, and cleaning residue can build up between the cover and the ceiling.

	The alternative is to use conventional pendent heads but with an extended escutcheon. This was standard practice before concealed heads became commonplace. The reasoning behind the selection of an extended escutcheon is that it is easy to clean. The conical shape of an extended escutcheon results in the head being well below the plane of the ceiling. This configuration provides excellent access and visibility. The prominence of the head means it is easy to see and avoid. In addition, the visibility and range of movement about the head results in excellent access. It is this access to all sides that makes cleaning easy. The argument against this installation is Murphy’s Law; anything that can go wrong, will go wrong. In other words, if the heads are exposed, eventually they will be hit and the resulting water discharge is not worth the risk.
	
	


	The concern with paints in a GMP facility is that coatings that are usually used for interior construction will deteriorate if exposed to cleaning chemicals. Flaking and peeling paint is an obvious source of particulate, but an even worse scenario occurs when moisture gets behind the paint and promotes mold growth. Therefore the painting of walls, doors, and ceilings in GMP facilities needs deliberate consideration. Cleaning with harsh cleaning agents is a frequent activity, and conventional paints are not acceptable. In the construction industry, epoxy paints are specialty products commonly found in heavy industrial settings. If properly specified, however, they are a practical, relatively inexpensive solution for GMP production areas.
	
	Traditionally, epoxies have been solvent based. These products are extremely durable, but shortcomings include difficulty in working with them and the release of large quantities of volatile organic compounds (VOCs). Although acceptable when constructing a new facility, VOC release is not acceptable when the facility is already occupied. The fumes from solvent-based epoxies are substantial and hard to contain to the construction area. Complaints from plant personnel and increased sick leave are to be expected. Therefore, when working in an existing facility, a water-based product is the coating of choice. These paints are generally easy to work with and have substantially lower VOC content. Not all water-based epoxies are durable enough for a pharmaceutical application. One-component epoxies should be avoided. They are easy and fast to work with, but have the least chemical resistivity and likely will fail after a period of time exposed to a regular cleaning routine. A two-part, waterborne epoxy system should be sought out. Two-component epoxies cure by both solvent evaporation and chemical reaction. When the two components are combined, a cross-linking chemical reaction occurs, and the coating obtains a greater resistant to chemical exposure.
	
	


	Products for the support of piping and conduit have been available in the mechanical and electrical trades for many decades. However, the cleaning criteria integral to a GMP space renders conventional supports unacceptable. Personnel engaged in the design, maintenance, and operation of process systems understand this and rely on sanitary supports to provide easily cleanable conditions. Although these specialty products are readily available, they are not widely known and specified outside the process community. In addition, these supports are expensive relative to conventional alternatives.
	
	Many of the utilities that serve process equipment are provided by the base building systems. When base building systems enter a process room and the materials and fittings become exposed, their specifications need to change to allow for cleanability. Hangers and supports get little attention as part of base building systems, and they can easily be overlooked once they enter the process space. It is important to ensure that sanitary supports are used universally in GMP areas.
	
	These special products are available from several manufactures. They are specifically designed to minimize the accumulation of contaminants and are easily cleaned. Besides the housing that secures the piping, a rod is required to support and fasten the assembly to the ceiling, wall, or floor. In base building systems, this is typically achieved with a fully threaded rod. In a GMP environment, however, the threads are problematic because they collect contaminates. To address this issue, sanitary-hanger manufacturers provide rods and stanchions that eliminate the exposed threads.
	
	


	The previous examples illustrate how, when designing and constructing a facility, the simple statements used to describe GMP requirements must be carefully considered. GMP principles, such as “easy and effective cleaning,” are expressed in minimal terms, but the implications are significant. The specification of materials and products for pharmaceutical production areas require specialized knowledge and experience that goes beyond conventional construction. Even when using materials found in typical construction, GMPs often require special applications  to achieve appropriate GMP room design.
	
	

Volume 4: Good manufacturing practice (GMP) Guidelines

,  “Part 1, Chapter 3: Premises and Equipment,” 

ec.europa.eu/health/files/eudralex/vol-4/pdfs-en/cap3_en.pdf


	Eric Bohn is partner at Jacobs Wyper Architects, 1232 Chancellor St., Philadelphia, PA 19107,  tel: 215.985.0400, 

 When referring to this article, please cite it as E. Bohn, “Considering GMPs In Room Design,” 

Troubleshooting

Cleanability is crucial when choosing components for GMP manufacturing areas.

Designing GMP Manufacturing Areas

	A growing global middle class, longer supply chains, and the launch of new, innovative healthcare products are putting more complex demands on the pharmaceutical industry’s high-stakes logistics environment. Factors such as new, temperature-sensitive biologics, increasing cold-chain regulations, and growing cost pressures require pharmaceutical executives to reconsider how they prioritize (cold) supply-chain decisions. Strategies such as breaking down silos, implementing a proactive intervention strategy, and refining best practices can help businesses not only protect cold-chain products, but also bottom lines and customer relationships.
	
	


	Four industry factors are increasing the stakes and the need for cold chain reinvention.
	
	

 Growth in volume of specialized products such as biologics that demand a cold chain environment and growth of demand for these products in emerging markets are impacting the cold chain. Worldwide, revenues from biologics, which accounted for 12% of all drug sales in 2005, are expected to grow to 23% by 2017 (1). Specialty drug spending in the United States is expected to quadruple from $87.1 billion in 2012 to $401.7 billion in 2020 (2). More global clinical trials are requiring stricter temperature regulations, further driving the need for innovative cold chains.
	
	Not only are there more complex products, but the challenges of transporting them farther distances are getting more complicated. As companies expand to new geographic regions, they must keep temperature-sensitive products safe and compliant for longer journeys--often when in-market infrastructure is lacking and temperature fluctuations during transportation are extreme.
	
	According to the 2014 UPS Pain in the (Supply) Chain survey, which surveys healthcare logistics decision makers on their top supply chain pain points and opportunities, 65% of global executives have used logistics and distribution partnerships to overcome challenges accessing global markets and new customer bases (2). Increasingly, healthcare companies are collaborating with third parties to address challenges from global market access to regulatory compliance and product protection.
	
	

 Increasing and more complex regulations globally, especially when factoring in additional categories of temperature requirements, such as controlled room temperature (CRT), make regulatory compliance a top pain point among healthcare executives. For the third consecutive year, UPS’s survey respondents cited regulatory compliance as the top supply chain issue. And 66% said the complicated regulatory environment was a top challenge to global expansion (2).  Senior logistics executives polled by UPS reported an extremely low rate of success in addressing the challenge of regulatory compliance. Only 12% reported they were satisfied with their companies’ performance in this area (2).
	
	

 Cold chain supply is becoming a riskier business. Factors ranging from longer supply chains and more sensitive products to limited infrastructure and extreme weather conditions are driving risk. At the same time, many healthcare executives don’t prioritize risk management in their supply chains. Only 26% of healthcare executives view supply-chain interruption as a top concern, according to the UPS survey (2). In the past five years, however, unexpected events, such as the 2011 Brazil flooding and earthquakes in China, have taken a toll on healthcare supply chains, particularly in the Asia-Pacific and Latin American regions.
	
	Companies should put a sharper focus on contingency planning. Risk mitigation plans must look at factors such as whether companies have the protection methods in place for getting clinical trials shipments to far-flung regions, if they have factored CRT into their broader temperature-sensitive product protection plans, whether they have the right packaging and transportation solutions for all types of products, and if they have a means to intervene when temperature-sensitive shipments go off course.
	
	

 The recovering global economy and increasing number of generic products coming to market elevate industry cost pressures. Fifteen years ago, when the industry was largely producing branded high-value products, the cost of cold-chain monitoring and transportation services weren’t as much of a factor. Recently, between the patent cliff and the recession, cost has become a crucial part of the cold-chain discussion. Companies must work with their third-party logistics providers and other partners to determine how to keep cold chain costs down.
	
	Even with cost-management concerns beginning to wane, regulatory reform and changing reimbursement models will keep cost at the forefront of supply chain issues. On the other hand, less concern may indicate executives are finding innovative ways to address cost management. But will these cost-saving measures produce long-term gains?
	
	Furthermore, as cost pressures are causing earlier patient discharges, new models of care are emerging. The home healthcare market is expected to grow to $27 billion in 2016 (2), presenting an incredible opportunity but also a new set of supply-chain challenges. As evolving and new distribution models present challenges to the cold chain, the time to act is now.  
	
	


	Reinvention is already happening in many areas. The pressure is on for healthcare companies to deliver on expectations of efficiency, safety, and customization. Focusing on several key areas will help healthcare companies adapt to emerging trends.
	
	

 Overcoming silos within companies-and across the broader healthcare industry-can lead to greater innovation and efficiency in the cold chain and may ultimately lead to cost savings. Collaboration across divisions and tapping into industry expertise are crucial. In the past, companies have taken the traditional route of cost cutting, looking to procurement to identify ways to find savings across various areas of the supply chain. While this approach has generated some short-term gains, it is risky in the long-term because the need for integration and collaboration among all supply-chain parties is critical. The procurement approach alone can break some crucial links that make up the cold supply chain or may cause companies to overlook some opportunities for creativity and improvement that can be gained from a more integrated approach. It’s vital to look at the supply chain as a whole, evaluating needs and opportunities from end to end, to identify strategic opportunities for efficiency.

 The question is: what level of risk are companies willing to accept, and can you mitigate that risk? Technology has advanced to allow for real-time monitoring of shipments. But if a company cannot act upon the insights that data and technology reveal, it’s worthless. Alarmingly, just 25% of a typical company’s end-to-end supply chain is being assessed in any way for risk (3). Pharmaceutical companies have opportunities to implement product protection measures or contingency planning.

	For example, proactive monitoring, intervention, and risk-management solutions cover products the value of the product and protects shippers against unforeseen delays, including weather-related issues. Intervention capabilities range from rerouting shipments that could go off course to re-icing shipments in danger of going outside their temperature range.
	
	

 Companies can leverage existing best practices, whether in packaging, product development, or transportation and apply them to healthcare products. Companies should consider a cold supply chain the same way they look at new product development-as an area that needs continual focus, research, and innovation-and investigate new innovations in temperature-sensitive packaging, transportation, and warehousing. Creative solutions for CRT transportation have emerged over the past 24 months, impacting both small-package transportation and freight forwarding. One example is an increased use of phase-change materials (PCM) in small-package passive packaging solutions. A growing range of PCMs can ensure temperature ranges that are increasingly precise for extended transit times. In the air-freight world, another innovation combines the use of active reefers (i.e., refrigerated containers) on the ground legs of transportation with pallet covers, customized thermal profiles, and electronic data loggers.


	Where is the cold chain going? In the past, companies operated in silos by using several packaging vendors and procurement models to cut costs. The key to future success is integrating the knowledge of cold chain with the entire network, including packaging and intervention capabilities, and implementing holistic plans that allow for actual intervention, rather than just monitoring. Most importantly, companies should look at reinvention as an opportunity. This approach will better equip businesses for success in a high-stakes cold-chain marketplace.
	
	


	1. EvaluatePharma, “World Preview 2013, Outlook to 2018: Returning to Growth,” June 2013.
	2. UPS, “Seventh Annual Pain in the (Supply) Chain Survey,” www.pressroom.ups.com/pressroom/staticfiles/pdf/fact_sheets/UPS-PITC-Executive-Summary-North-America.pdf, accessed Jan. 5, 2015.
	3. J. P. Dittmann, “Managing Risk in the Global Supply Chain: A Report by the Supply Chain Management Faculty at the University of Tennessee, Summer 2014,” www.upscapital.com/ManagingRiskInTheGlobalSupplyChain.pdf , accessed Jan. 5, 2015. 


	Dirk Van Peteghem is marketing vice-president, healthcare logistics, UPS and Wanis Kabbaj is marketing director, healthcare strategy, UPS, waniskabbaj@ups.com. 

When referring to this article, please cite as D. Van Peteghem and W. Kabbaj, “Reinventing the Cold Chain in a High-Stakes Market,” 

Packaging

Market changes are driving pharmaceutical companies to consider new ways to mitigate risk in the cold chain.

Equipment and Processing Report-03-25-2015

How Modeling Software Can Help Process Development

Designing GMP Manufacturing Areas

Considering Cold Chain Needs