Unit Operations

On Shire, Single-Use and Simplicity

CRB’s Eric Unrau talks about what worked at Shire Lexington, and what limitations need to be overcome for single-use systems.

By Paul Thomas, Senior Editor

Drug manufacturing facilities of the future will need to be a lot smarter and flexible than those today. They will be “smaller, more nimble, more flexible, more responsive to evolving processes and changing purposes,” says Eric Unrau, Director of International Operations for CRB Consulting Engineers. “This makes for overall reduced project investment, and faster project schedules for new facilities. The operational costs are lower, with a reduced environmental impact versus a more traditional process and facility. When done correctly, it is lower risk from a product quality and patient perspective and also a regulatory perspective.”

Single-use equipment and systems will be a major facilitator of such facilities, Unrau acknowledges. But they won’t be the be-all and end-all. They need to be put into context. We speak with Unrau about his company’s work with single-use, including Shire’s recent award-winning facility in Lexington, Massachusetts, and ask him to clarify what factors might limit the adoption of single-use.

PhM: First, a general question: When you think of the “facility of the future,” what do you think of primarily? How might your vision differ from that of others?

E.U.: In general, the thought is around a process which leverages the best of current compliance thinking, operating philosophy, closed system designs and new technology in a way that allows for the facility that houses it to be simplified. What we call the “FutureFacility” will have risks clearly identified and adequately mitigated. Equipment will be used most efficiently with emphasis on value-added operations. Cleaning and sanitization operations (value negative) and idle time (value = 0) will be minimized. Net water utilization will be minimized by reducing waste. Bioprocessing will be more streamlined and more continuous than traditional batch processes seen yesterday.

The FutureFacility will be smaller, more nimble, more flexible, more responsive to evolving processes and changing purposes. This makes for overall reduced project investment, and faster project schedules for new facilities. The operational costs are lower, with a reduced environmental impact versus a more traditional process and facility. When done correctly it is lower risk from a product quality and patient perspective and also a regulatory perspective.

A number of companies, on both the consulting and manufacturing sides, are interested in these concepts and many have similar goals of reduced cost and schedule. One of the things which makes our vision different is our holistic approach in designing the facility. We focus on the particular project needs and listen to our client’s requirements, and then leverage numerous technologies, business drivers, design, quality, maintenance, safety, environmental and operations initiatives to incorporate all those aspects into the project.  The end result is a facility that can be more flexible, affordable, and faster to bring up and operate.

PhM: You’re an advocate of fully closed processes. Why exactly? What are some benefits of fully closed processing that many people might not realize?

Shire LexingtonE.U.: Simply put, closed processing protects the product from the room environment. If that is true, then this allows the facility requirements to be dramatically reduced in terms of product protection—in other words, the facility is a non-impact system (as defined in ISPE’s Baseline Guide). As the facility is no longer protecting the product, it can be simplified—better, faster, cheaper—and not just one of these, but all three. Process closure is safer and cheaper. Benefits can be numerous and depend specifically on the technology, product and project requirements. However, in general they can be: reduced risk of product contamination, reduced project cost and schedule, improved operations, and reduced operational costs. There are many others, but that is a start.

PhM: Shire’s Lexington facility has received attention and accolades for, among other things, housing the first commercial 2,000-Liter bioreactor. In your mind, what is truly groundbreaking about the Lexington facility that will be imitated in years to come?

E.U.: This was a great project and one that CRB was excited to be a part of. Shire pushed the envelope by implementing single-use systems in evolutionary, pioneering ways. In addition to setting the vision of a groundbreaking facility, Shire also had a number of other goals in the project, leveraging complementary areas of scope on the project such as design and construction of the facility vs. design and fabrication of the equipment is one area. Early occupancy of the building was achieved through close collaboration of design, vendor, quality and construction teams. This allowed for early procurement of single-use systems, early commissioning of those systems at the vendor’s site, and even improved operator training prior to equipment coming to the site. There are other areas specific to the project which were highly beneficial to Shire in areas that are client confidential.

PhM: That Shire project was also a case study in how a commercialization timeline can be squeezed. CRB believes that timelines can be reduced significantly on average—what is this based upon?

E.U.: Experience! Despite needing to develop new technologies, the Shire project timelines were enviable compared to most traditional bioprocessing facility design projects. Schedule reduction on a project, and specifically focus on the ability to compress project schedule is nothing new. The differences in this particular case came from a few different sources. Closed processing, which allows for a simpler facility, means there is less to design, less to install, less to start-up and commission. All of this together leads to savings in time and money. Single-use systems can offer expeditious timelines for equipment procurement as well as the potential offsite commissioning and operator training, depending upon the systems and vendors used.

How this compares to a typical project without closed processing and single-use systems depends on a number of factors. However, for a typical biotech process, these factors can reduce a project timeline by up to 40%, and in some more extreme cases even beyond that number.

PhM: Single-use systems are synonymous with the drug manufacturing facility of the future. Among the various concerns expressed regarding disposables (scale limitations, disposal, etc.), which do you think is most significant and could truly limit their adoption?

E.U.: Single-use systems are an excellent tool in the toolbox of the future facility owner and operator.  Certainly, the rapid adoption and growth of single-use systems in the marketplace in terms of solutions and options available to manufacturers today is a sure sign of their capabilities and advantages.  However, each project and facility needs to be designed specifically around the product and patient needs. In many cases, this does not lend itself to single-use systems. And remember, closed processing can be achieved in both traditional stainless steel equipment and systems, as well as in single-use systems; therefore, it is not always a default to use single-use systems today or tomorrow. Some of the limiting factors for single use systems are (in no particular order):

  • Scale: Some processes require larger scale production and single use systems become cumbersome and costly at large scale, or are entirely unavailable at the required scale.
  • Cost: Some operations are more cost effective over time in fixed vessels than in single-use systems; proper evaluations need to be done for each case. 
  • Supply Chain: Today and potentially tomorrow in some locations overseas, supply chain and ability to get single-use consumables is an issue, especially from multiple suppliers.
  • Production Technology: Certain production technologies, both upstream and downstream in the biotech side, can limit single-use system application—for example, microbial fermentation; other areas include processes with higher volumes of solvent processing or other potential explosivity issues which require traditional stainless vessels.  
  • Reliability: Failure rates of 0.4% are still being reported. 
  • Product Compatibility: Some processes and constituents are not compatible with certain plastics used in the manufacture of single-use components. These can be very specific to the process.
  • Standardization: Few standards exist in terms of platforms for consumables; the industry is working on this and will hopefully develop a solid platform in the future for all manufacturers to follow. This is under development now at ASME BPE and BPSA. Further, standardization will mitigate many of the risks discussed above especially supply chain.

There are of course other areas that could limit their adoption, but these are some of the current prevalent ones. One item to note is the increased interest in single-use systems outside of biotech API production, such as in fill/finish applications, which offers an area of continued growth for more single-use applications. 

PhM: Closed systems and disposables lend themselves to “sustainable” facilities. Where will the most significant green benefits be found in future facilities? What areas might manufacturers be overlooking at present?

E.U.: There are a lot of potential areas, some of which are reduction in water (probably the most advertised and best known area), reuse of existing facilities, reduced energy consumption now and as technologies continue to improve, reduced chemical use for cleaning and sanitization, reduced land requirements, increased operator efficiencies due to improved working environments (reduced gowning requirements, more natural lighting, etc.), etc. Closed systems and reduced environmental constraints clearly reduce capital cost of a facility and ongoing HVAC/energy costs but significant savings can come from reduced labor requirements, where some clients report up to 30% labor time wasted for gowning-degowning activities.

Most manufacturers look to their particular needs on a project and are not trying to overlook any particular area. However, we have found that many times there are project drivers, corporate standards or other “internal inertia” that steers projects away from some areas. Those vary widely depending upon the client and location, but some of the areas where projects are driven to non-ideal solutions are around use or non-use of single-use systems, acceptance that closed systems are closed and allow a lower room classification, architectural finishes and systems, operational segregation requirements and operational philosophies, and of course new technologies. 

PhM: As you have noted, the “c” in cGMP is constantly changing. Therefore, how do you best future-proof a facility from a regulatory standpoint?

E.U.: There is likely no way to completely “future-proof” a facility and design from a regulatory standpoint. However, you can improve the defensibility of a facility by defining your process and completing and documenting a risk assessment on the process and operation. Those areas that require mitigation are documented and executed to show how the final process and facility reduces overall risk and improves product quality, efficacy, and patient safety.

Traditional facilities have very little “re-sale” or “re-purpose” value because they are so compartmentalized and specialized. The FutureFacility is essentially a high-quality warehouse ballroom that could easily be re-purposed for other applications. By rendering a process environment “non-impact” and demonstrating adequate mitigation of any risk to process, product or patient, the FutureFacility (or more importantly, the process within) achieves an optimal state. Even the best cleanroom conditions and operating procedures will fail at mitigating all process contamination risks from the environment or more importantly from the personnel within the environment. Verifiable/validatable closure of a process DOES mitigate this risk.

The ISPE Baseline Guides and other guideline documents describe methods to design and implement projects to help owners and manufacturers mitigate their regulatory risks.

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