Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

Formulating drugs for hot-melt extrusion (HME) was one of the topics at the Pharmaceutical Extrusion Seminar organized by Leistritz near the company’s US headquarters in New Jersey in June. Several of the speakers noted the growing problem of poorly soluble drugs in the drug development pipeline and the need for efficient production methods for improving solubility. While other options, such as spray drying, are available, HME is attractive because it does not require solvents and is a continuous process, which brings advantages of efficiency, flexibility, and process control. 

HME has been used in the pharmaceutical industry since the late 1980s, but because of its growing acceptance and use, the past five years have seen increasing application of fundamental research and understanding of HME to pharmaceutical formulations, notes Charlie Martin, president of Leistritz. This year’s Pharmaceutical Extrusion Seminar (PES) was the 8th annual, and the experience of attendees has significantly increased in the past five years, says Martin. In the first few years of the PES, only 10–20% of attendees had any extrusion experience, but now 80–90% do. In addition, many companies now have research to present. 

One area of research is the use of supercritical carbon dioxide (CO

) in HME for foaming and as a fugitive plasticizer (i.e., a material that acts as a plasticizer or processing aid during the process but does not remain in the final product). Supercritical CO

 reduces the glass transition temperature of polymeric excipients and acts as a molecular lubricant to reduce melt viscosity. Processing temperatures can be reduced by as much as 20 

C, which can be important if the API has low thermal stability, noted Graciela Terife, senior scientist for Pharmaceutical Sciences at Merck, in a presentation. 

Identifying an appropriate polymer to use as an excipient in HME was also discussed at the seminar. Requirements for polymers include high thermal stability, appropriate glass transition temperature and melt viscosity, no toxicity, and, perhaps most challenging, solubility with the target drug, explained Shaukat Ali, technical sales manager at BASF.  He explained that a screening test in which the API and polymer are mixed in a solvent and dried onto a film can be used to evaluate compatibility. Suppliers have done this work with many excipient-API combinations; BASF, for example, has published an 

In the HME process, high temperatures and shear combined with intermolecular interactions (e.g., ionic, hydrogen bonds, and polar forces) between API and polymers breaks up a crystal lattice of poorly soluble actives; the amorphous active is then stabilized within the polymer matrix, explained Firouz Asagarzadeh, director of technical services at Evonik, in a presentation. Miscibility of drug substances in polymers plays a crucial role in formation of solid solutions and stabilization of the amorphous structures. Polymer selection should be based upon structure of the active and polymers. To select appropriate polymers, Evonik has developed a miscibility and process estimation package called MemFis (Melt Extrusion Modeling and Formulation Information System). MemFis calculations do not require use of any active, and using MemFis minimizes screening experiments.

HME also lends itself to direct production of combination products, in which a drug is loaded into a device that can be shaped or molded as part of the extrusion process. HME is being used, for example, to produce fibers loaded with drugs that are injected for local delivery (e.g., ocular drugs), sutures containing drugs for dental applications, and catheters containing drugs or antimicrobials, explained Tony Listro, managing director of Foster Delivery Science.   

Although HME is still a cutting-edge technology, experience and understanding are growing and development continues, as evidenced by the presentations at the seminar. 

Articles

Presenters at a pharmaceutical extrusion seminar discussed formulating drugs produced using hot-melt extrusion.

Hot-Melt Extrusion Progress Continues

	Upcoming requirements in the US and around the world for serialization and track and trace of pharmaceuticals were a focus of the Pharmapack conference held in Philadelphia, PA earlier this week. Momentum toward implementing these technologies across packaging lines is building as deadlines, including California’s requirements in 2015 and others around the world, approach. After listening to several presentations and a panel discussion, the message I heard loud and clear was that time is of the essence and that packagers should prepare for serialization now.

	Some companies have delayed working on serialization because US federal track-and-trace legislation is not yet in place, although a vote could come this summer. Regulations in California and other countries, however, are approaching deadlines for implementation. Many companies are moving forward despite federal delays, said panelists.

	Others may have delayed programs because of the lack of harmony in requirements from various countries. Packagers should not wait for globally harmonized standards, however, before deciding what to implement, warned Peter Schmitt, managing associate at Montesino, in his presentation, “Finding a common denominator in the (dis)harmonized global serialization standards.” He suggested that, instead, companies should adopt flexible labeling, printing, and vision systems that can be adapted for different regulations in different countries. Regulations are a work in progress and might still change, but he advocated setting up a scalable and configurable (rather than customized) serialization system now and being prepared to grow it quickly. Requirements for such a system would include high resolution and high bandwidth to handle large amounts of data.

	Panelists pointed out that benefits of serialization go beyond complying with regulations. One of these benefits is the hidden business opportunity to take logistics to the next level. Pharmaceutical companies could gain the benefits found by other industries, such as consumer electronics, automotive, and apparel, that implemented unit-level serialization long ago.  For example, serialization could improve supply-chain collaboration on processes such as returns. Schmitt pointed out that the data obtained by serialization systems can be mined to find patterns in the packaging process, which would allow problem solving as well as potentially lowering packaging cost and aiding new packaging development. Panelists agreed, however, that the biggest benefit, which should also be the biggest driver for use, is the increased patient safety that would result from improved supply-chain integrity and security. “Does patient safety need a business case?” someone asked.

	For further commentary on the pending US federal track-and-trace legislation, read an article in the June issue of 

Congress Considers Legislation to Secure Drug Supply Chain

Upcoming requirements in the US and around the world for serialization and track and trace of pharmaceuticals were a focus of the Pharmapack conference held in Philadelphia, PA earlier this week.

Prepare for Serialization Now

Model-predictive design—used to define, predict, and control a process—is well established in many industries and is beginning to take hold in pharmaceutical process-development and manufacturing. Modeling offers a way to improve process understanding and control and to speed development. In response to this trend, software tools that have improved capabilities and increased user-friendliness are being designed to meet the needs of pharmaceutical-industry users. Although modeling is relatively established in API-production processes, modeling of solid-dosage processes is less mature; software tools for modeling solids behavior are at the cutting edge. A wide range of tools can be used to model solids behavior, including computational fluid dynamics, population-balance models, and discrete-element modeling (DEM).

DEM discretizes a granular domain into elements and computes the interaction forces between the elements, which results in a detailed description of solid material movement, explains Richard LaRoche, PhD, vice-president of Engineering at DEM Solutions. DEM is being used to model solid-dosage unit operations including mixing, coating, powder feeding, granulation, and compaction. "A well-calibrated model can provide useful process information that is difficult or impossible to measure experimentally. For example, simulation and analysis can show shear inside a mixer, real-time forces in a tablet coater, segregation within a feed frame, and change in flow properties as the material is mixed or operated upon by devices (e.g., mills)," says LaRoche. DEM Solutions recently made available a searchable 

 containing over 3000 abstracts of papers involving DEM modeling, including many topics relevant to pharmaceutical solid-dose production. 

As with any new tool, there are challenges in adapting DEM to the needs of the pharmaceutical industry. One challenge is for the industry to better accept modeling in general and to understand the power, scalability, and adaptability of DEM, says LaRoche, who adds that he does see, however, an increasing acceptance of DEM-based modeling methods within the pharmaceutical industry. 

Another challenge is that modeling has traditionally been the tool of chemical engineers rather than chemists (who make up a large segment of the pharmaceutical industry). New modeling software interfaces, however, are more straightforward and incorporate online training that is designed to make the software more user-friendly for a wider range of users, notes Jonathan Kadane, director of product marketing for Pharmaceuticals/Life Sciences at AspenTech. Other improvements include a special search tool in the software that allows users to efficiently find and access models and data and a feature that allows users to identify ways to change designs to reduce energy or capital cost. Most recently, the company added a web-based user interface for its aspenONE software, which empowers more users to work with the software without specialized training using touch-enabled devices (i.e., through simple touch and swipe gestures on a tablet).   

For further discussion on modeling that includes additional comments from AspenTech and DEM Solutions as well as input from other modeling software providers, such as Accelrys and CD-adapco, and pharmaceutical industry members, see "

Using Model-Predictive Design in Solid-Dosage Manufacturing Processes

Model-Predictive Design, Control, and Optimization

,” written by members of the Engineering Research Center for Structured Organic Particulate Systems at Rutgers, the State University of New Jersey, which describes application of model-predictive methods and a continuous process-control framework to a continuous tablet-manufacturing process.  

Model-predictive design is applied to solid-dosage processes.

Developments in Pharmaceutical Process Modeling

ALENGO/GETTY IMAGES; DAN WARDUsing model-predictive design to define, predict, and control a process is well-established in many industries, and is beginning to take hold in pharmaceutical process development and manufacturing. Modeling software helps developers to model unit operations and, in some cases, an entire continuous process. 

Model-predictive design includes a hierarchy of different approaches, explains Bernhardt Trout, PhD, director of the Novartis–Massachusetts Institute of Technology (MIT) Center for Continuous Manufacturing (CCM) and professor in the Department of Chemical Engineering at MIT. The most basic approach is the use of linear univariate models (e.g., parameterized from a linear design of experiments). A more complex approach is multivariate analysis, followed by mechanistic modeling; the ultimate approach is analysis of  first principles (e.g., conservation of mass and energy).			

The pharmaceutical industry needs to move beyond statistical models, says Fernando Muzzio, PhD, director of the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS) and professor in the Department of Chemical and Biochemical Engineering at Rutgers University. "Models based on first principles allow you to achieve a greater level of understanding and thus extrapolate outside of the area defined by the statistical models," explains Muzzio, who further discusses modeling tools in an article in this issue (see "Model-Predictive Design, Control, and Optimization").

Generating the level of knowledge necessary to build a model, whether it be statistically or mechanistically based, helps to speed development and mitigate risks during product development, scale-up, and commercial manufacture, adds Howard Stamato, associate director in the Portfolio Enabling Technology Group of Drug Product Science and Technology at Bristol-Myers Squibb. He adds that in those cases where the model can be used in closed-loop control, there are significant advantages for both efficiency and quality of the final product. 

Much progress has already been made in employing models in the pharmaceutical industry, driven in part by advances in process analytical technology (PAT). "Advances in computing power and analytical methods, including PAT, have broadened what can feasibly be measured and subsequently modeled," says Stamato. "These advances allow models to be built with reasonable resource commitments and much higher accuracy than previously possible," he adds. In the solid-dosage drug-product manufacturing arena, modeling work has been performed, for example, in scale-up of fluidized-bed processing using computational fluid dynamics (CFD) (1) and in tablet coating using  mechanistic models (2) and discrete element modeling (DEM) (3).  

Models for continuous, plant-wide solid-dosage processes have also been developed (4–5). The Novartis–MIT CCM, for example, constructed a functioning prototype of an end-to-end continuous manufacturing line that forms coated tablets directly from API and, in late 2012, finished integrating the process with a control system that used models to simulate the entire process. Models for the individual unit operations are described by first principles, such as material balances, energy balances, and chemical kinetics, notes Richard Braatz, the Edwin R. Gilliland Professor of Chemical Engineering at MIT. "An advantage of first-principles models is that you can build a predictive model with less data. Statistical models tend to have poor extrapolation outside of the data range," explains Braatz. MIT used modeling software to connect the individual units and then tuned the process controllers by running simulations of the process as a whole. "Without a model of the process, we would not have been able to complete the project in an appropriate time because it would have taken too much trial and error to tune the controllers," says Braatz, who notes that when starting up a continuous process it is desirable to quickly reach steady-state operations to avoid producing out-of-specification material. 

Modeling software tools are available to perform various computer-aided engineering tasks in development and manufacturing in various process industries, including pharmaceutical manufacturing. Models and modeling software are well established in API-production operations, such as solvent selection, crystallization, and separation, for both batch and continuous manufacturing processes, comments Jonathan Kadane, director of industry marketing for Pharmaceuticals/Life Sciences at AspenTech. Modeling for solid-dosage pharmaceutical processes is less mature. Bristol-Myers Squibb's Stamato comments,  "The behavior of solids from a surface energy, flow, and compaction perspective is still difficult to characterize.  Better understanding of the behavior of solids would help to build more computationally manageable and accurate models." AspenTech's solids-modeling capabilities, acquired through SolidSim in 2012, model specific, solids-handling unit operations (e.g., screens, dryers, and cyclones). Although this technology is, to date, primarily targeted for chemical process industries, the early-users group includes pharmaceutical companies, notes Kadane.   

Modeling software can be used in all stages of pharmaceutical production, from R&D through to quality control and manufacturing, notes Michael Doyle, principal scientist and marketing director, Materials Science Segment, at software-provider Accelrys. Process designers can use software to understand excipient–API interactions or optimize mixer speeds, for example. Process-centric software captures numeric inputs about the process (e.g., formulation data, PAT sensor data) and feeds this into predictive models that allow process developers to evaluate "what if" questions, explains Doyle.   

CFD software can be used to model common operations, such as scaling up a mixing tank, and for more complex operations, such as three-dimensional modeling of a fluidized bed (e.g., tablet coater), explains Kristian Debus, director of Life Science at CD-adapco.  

Some particle flow can be modeled with CFD alone, but to capture more detail about particle behavior (i.e., how particles interact with each other, the surrounding walls and equipment parts, and air flow), developers use discrete element modeling (DEM) software. "DEM tracks the interaction between every particle in a numerically efficient manner, modeling contact forces and energy transfer due to collision and heat transfer between particles," explains Debus. DEM has been used extensively to model mixing and coating, and there is now increased interest in using DEM for granulation and compaction, says Richard LaRoche, PhD, vice-president of Engineering at DEM Solutions.     

Another type of CFD is multiphase fluid flow (e.g., volume-of-fluid method). This method can range in complexity from nonmixing to phase mixing, which allows modeling of suspensions, for example. Models can also be done in steady state or in real time (i.e., transient state). As complexity increases, so does the computation time and expense. When choosing how to model a process, companies must balance the accuracy needed with the computational expense that will incur.  

In the past, computational capabilities have limited applications to laboratory and pilot scales, says DEM Solutions' LaRoche. This work, however, can be used to help devise scale up-rules for process engineers. The company recently added the capability of running DEM on large, high-performance computing and shared-memory systems, which will enable production-scale modeling.  

Another type of software uses flow-sheet modeling to describe individual unit operations and provide mechanisms for exchanging data between these unit operations. This method combines techniques, such as DEM, CFD, and population balance modeling, and can be used, for example, in solid-dosage process development to predict what type of process (i.e., wet granulation, dry granulation, or roller compaction) should be targeted or to predict how upstream API properties affect downstream tablet production (6),  adds Douglas Hausner, associate director for industrial relations and business development at C-SOPS. 

An increasing use of modeling in the pharmaceutical industry is being driven both by the FDA mandate to better control the manufacturing process using quality by design and PAT and by the imperative of reducing drug-product development costs and speeding the development process, explains Doyle. A greater focus on efficiency, agrees Kadane, will push the industry toward more process modeling. Modeling the process first, before running experiments, saves time and money because simulated experiments are faster and cheaper than laboratory or pilot-plant experiments. In reality, however, model development and experimental development are run in parallel and correlated with each other, adds Debus. When used together, the process is better understood and error is reduced.  

The ultimate goal is to use predictive models to interpret, understand, and control the pharmaceutical process, adds Doyle. Achieving this state would improve consistency and reduce out-of-specification product.  

The real power of modeling software for the pharmaceutical industry, says Debus, is in modeling an entire continuous manufacturing process, including three-dimensional models (e.g., multi-phase fluid flow, DEM) of the unit operations and one-dimensional models (e.g., fluid flow through a pipe) of the transfer from one unit to another. Modeling the process as a whole allows advanced process control, in which a parameter change in one unit operation is accounted for in other parts of the process as it affects other unit operations.   

Most big pharma companies are using CFD, mostly at a basic level, and smaller pharma companies are just getting started with CFD, comments Debus. Process industries (such as chemical), manufacturing industries (such as automotive), and industries in which flow and particle interaction are crucial (such as aerospace and nuclear), have advanced the use of modeling. The task at hand in the pharmaceutical industry is for all parties (i.e., software and equipment vendors, pharmaceutical producers, and academia) to work together using and improving these tools to better understand pharmaceutical processes. 

 4.  B. Benyahia, R. Lakerveld, and P. Barton, 

 6. M. Sen, et al., Intl J. Pharm. 445 (1-2) 29-38 (2013). 

How is the pharmaceutical industry using model-predictive design? 

Models and modeling software gain a foothold in solid-dosage manufacturing process design.

At the INTERPHEX show last month in New York City, several conference sessions focused on quality by design (QbD). One of these was a panel discussion sponsored by 

, “Lessons Learned: Successes and Challenges in Implementing Quality by Design.” Panelists agreed that QbD approaches have proven to offer benefits to industry, although it was clear that there is more work to be done in implementing QbD.

Panelist Dr. John Lepore, senior director of Chemical Process Development and Commercialization for Global Pharmaceutical Commercialization at Merck, noted that a benefit of QbD is increased process understanding, which results in higher quality at a lower cost. He emphasized that QbD encompasses both customer needs and business requirements, because a science- and risk-based approach results in a high level of assurance that patient needs will be met. 

A second panel member, Dr. Chris Moreton, partner at FinnBrit Consulting, discussed how QbD methods can be used to incorporate excipient variability into a design of experiments. He explained that samples at the extremes of specification are most often not available and that there are other ways to attain the necessary understanding.  

Panelist Jonathon Thompson, senior manager of Compliance Services Consulting at Invensys Operations Management, discussed using process analytical technology (PAT) and inferential sensing (i.e., simple measures, such as pressure and temperature, correlated to parameters) to obtain real-time data. He also discussed using advanced process control (APC) of manufacturing processes. APC is a dynamic optimization of the process either via an open loop (i.e., engineers make a decision to adjust the process) or closed loop (i.e., the control system automatically makes changes directly to the process).  Dynamic optimization is a cultural change, noted Thompson, but has the potential to improve reliability and consistency and to reduce release time. 

Real-time release (RTR) is ready to be implemented and is, in fact, already being used, agreed the panelists.  Challenges for RTR include controlling risk (a factor to which regulators are particularly attuned) and managing analysis failures. Parallel testing early in manufacture can be used to verify RTR. 

Going forward, Lepore noted a need for improved global harmonization of regulatory expectations. Actions toward more consistent interpretation and application of International Conference for Harmonization (ICH) guidelines and greater collaboration involving industry and regulators would form important first steps. He also suggested that industry members need to share more real examples to continue to drive alignment and understanding. 

Other conference sessions at INTERPHEX did present examples of using QbD. Dr. Carl Anderson from Duquesne University, for example, presented an example of how cycle time was significantly improved using PAT. Richard Creekmore from AstraZeneca discussed improving process robustness and gave examples of risk assessments. 

Examples of applying QbD were also the focus of a recent webcast, "

A Pragmatic Application of QbD: Turning Theory into Tangible Success

 earlier this month with experts from Patheon.  The complimentary, on-demand webcast can be accessed 

Making the effort to apply new methods to pharmaceutical processing will bring benefits.

Experts at INTERPHEX Discuss Quality by Design

The conference schedule at INTERPHEX 2013 covered a wide range of topics, including facility and process design. 

interviewed Craig Sandstrom, director of process engineering at Fluor; Par Almhem, president of ModWave and Modular Partners; and Jeff Odum, director of operations at IPS–Integrated Project Services, to gain their perspectives on  trends in facility and process design.  

Modularization has been used by other industries for decades and, over the past few years, has been more accepted by the bio/pharmaceutical industry. Modularization is fast becoming an essential component of bio/pharmaceutical facility design. Use of modularization is growing because it meets the industry needs for reduced cost, accelerated construction schedules, and quality construction.  

 What are some of the considerations for using modularization? 

Typically people have certain cost, schedule, and quality goals for their projects. Early on in a project, an effort is undertaken to look  at the site and region where the facility will be constructed and also the facility design itself to determine what opportunities exist to address these cost, schedule, and quality issues. 

Some of the local or regional issues include labor availability, labor rates, and associated logistics, such as what the site has in terms of being able to get people and materials to the site. Limitations in this area may drive a desire to try to move some of those activities offsite. 

In addition, there is a desire to accelerate schedules. People want to make decisions and capital commitments as late as possible to save money and also to meet product demand, which causes project schedules to be increasingly compressed. One of the ways to address compressed schedules is via modularization. Modularization allows you to parallel path many of your activities, such as process-piping and equipment construction, and in parallel with some of the activities that take place to erect the building shell. 

Finally, there are quality issues. Some places that you may want to build may not have quality labor resources available, or the weather or site conditions may be prohibitive. Moving the construction offsite allows you to do your construction in a better-controlled environment with higher-skilled labor. 

 What is involved in standardization of modular unit operations? 

 A module, in itself, is intended to be standardized. A module has a defined function with defined inputs and outputs. Once you identify a part of the process as a clear function with a clear input and output, you can design and build that as one unit. You can combine these units in different ways to create a variety of systems from a limited number of building blocks, which are the module units or unit operations. One example is a mixing skid, with the mixing system and controls all in one module. 

 What types of modules are used in pharmaceutical production? 

 One common type is the building module, in which  all the architectural features, equipment, and piping are preinstalled. Another commonly used concept is the tank-array module, which may include several different process-unit operations in one module. There are many other varieties of modules. In piping-specific modules, for example, you modularize just the equipment, such as a pipe rack or a large cluster of instrumentation. 

 What do you see as the future of modular manufacturing? 

 I see modularization as an essential component of almost all facility designs. We see it now, and we see the trend continuing in the future.  

One driver is that as facilities increasingly move to more remote locations, such as in Asia or South America where local trades aren't as mature as they are in the US and Europe, there's a desire to modularize to get the hygienic components of the facility designed and fabricated in a controlled-quality location. 

Modularization doesn't actually change the manufacturing itself; it's more about how you manufacture. Modules will be used as the building blocks for more and more processes simply because it's a more efficient way of building a process function, or indeed building almost anything. Nobody would  consider building a software system any other way than using modules (or objects as they are called in software), for example. We will see more and more modular systems and modular pieces in pharmaceutical and biotechnology facilities and processes. 

Implementing single-use systems in traditional stainless-steel facilities

 What are some of the advantages of implementing single-use systems? 

 Advantages include reduction of cleaning costs via the decrease in the size or elimination of costly clean-in-place (CIP) systems because you are now getting away from fixed stainless steel equipment. Along that same line, there can be a reduction in floor space because equipment is smaller and easier to move in equipment modules. Work is being done to consider how the implementation of single-use systems can reduce the amount of classified space that you must maintain during your manufacturing operations, via validation of system closure. Perhaps the biggest advantage of single-use systems is flexibility, especially if you are looking at the issues related to process changes in early-stage development.   

Many developments in the biopharmaceutical industry have added to the challenges of designing, building, and operating the traditional manufacturing facilities that we've used over the past three decades.  As our insights into product requirements and product characterization increase, the critical path for the development of  many new products is now shifting to the process development stage, and manufacturing timelines are being condensed. Speed and flexibility are thus becoming crucial to many of our clients.  

Future manufacturing systems must be agile enough to deliver on this flexibility with regards to a wider variety of product types and in a shorter timeframe. Single-use systems can provide a means to allow for this increased flexibility and a focus on speed to market, even if you are dealing with a stainless steel-based facility. 

  Who should consider implementing at least some single-use systems? 

 Implementing single-use technology must be driven by the product and process attributes, the need for flexibility, and an understanding of the critical process parameters. Any number of manufacturing organizations could benefit from the implementation of single-use technology.  

One group that I think is going to see a significant benefit is contract manufacturers. Because their business model is driven by both speed and flexibility, single-use technology could provide some distinct advantages in terms of their ability to adapt to new processes based on not only new clients but existing clients. Single-use technology gives them the flexibility to change their platform technology rather rapidly and probably with a lower cost. Lower need for classified space would also decrease capital expenditures.   

Other business models would also benefit from this type of technology. Organizations that are focused on process development, such as research-driven organizations that do high-level development work, would benefit. Manufacturers focused on pandemic response would benefit from the ability to adapt very rapidly. Flexibility and adaptability are crucial. 

Another group that could benefit from single-use technology, in a way that perhaps they haven't started to look at in depth, is the academic institutions, which  are being squeezed by their ability to fund capital expenditures for facility infrastructure. Any manufacturing organization should really explore the potential advantages of this type of technology.   

 What are some of the unique challenges of implementing single-use systems, particularly when you have an existing stainless-steel facility? 

We work with a number of clients who have a stainless steel-based platform and are creating what we refer to as hybrid facilities. Three challenges stand out. First is a real understanding of the process definition and description. Although this may seem obvious, we have found that companies sometimes have a knowledge gap, especially from a developmental standpoint, on exactly how a specific process-unit operation may or may not be impacted by going to this technology.  

The second challenge is looking at flows. Single-use systems are very flexible and modular in their approach from an equipment standpoint, and the ability to move components in and out of a particular space creates some logistical issues. As a part of that, there also needs to be a close investigation of accessibility. When your scenario includes a fixed stainless-steel asset that resides in a particular manufacturing suite—maybe due to size or maybe due to a future need—the ability for operators to access equipment and perform their day-to-day operations is extremely important. 

The third challenge is process support.  When you are dealing with single-use systems, you are now going to also deal with many single-use components that are absolutely necessary in order for each process unit operation to be executed and work the way it's supposed to. Tube sets, for example, are needed to connect components and allow the process to occur. Instruments, such as those to measure flow or temperature, must be integrated into the system. The design and development of these support items becomes a complex effort because there are a lot of parts and pieces that are going to have to be put together. Some companies get outside vendors to do this for them.  Others have chosen to do some of it internally, but it's very different from designing a fixed piece of stainless-steel pipe in a building to run from point A to point B.  Because of the fact that you're dealing with tubing, you  have issues with regards to accessibility and logistics. Where do these hang? How do you support them?  How do you make sure that they do not get damaged, or stepped on, or run over during the movement of equipment? 

Wrapping around all these issues is the idea of closure. One of the things that we pay very close attention to is the idea of looking at system-closure analysis to make sure that, as all these components are designed, we are doing everything that is necessary to, first and foremost, protect the product from any potential contamination source and, in doing so, making sure that the system components are designed properly so that this closure can be validated. 

Single-use technology is not without its challenges, but these are challenges that are being addressed to create systems that are efficient and bring a much higher utilization to a facility.  

Pharmaceutical Technology spoke with INTERPHEX 2013 conference-session presenters to gain insight on trends in facility and process design.