Disposable Technologies Implementation: Understanding and Managing Risks

As disposable technologies supplant stainless steel in our biomanufacturing facilities, there are some important implications over and above the design and cost issues. The key difference is that as we move to disposable technologies, we become more dependent on suppliers. The more customized and unique the product, the more dependent we are. One might argue that this situation is no different from that of sterilizing filters, but this ignores the differences in the maturity of the technologies and the extent of their usage within manufacturing. With sterile filters, we are dealing with a mature technology and established suppliers who have been working with users for more than 20 years, all of which has led to the development of procurement strategies that minimize dependencies and establish a robust supply chain. In contrast, in the disposable technologies arena we have relatively new technologies that are making significant inroads into manufacturing, replacing large swathes of reusable equipment. The key features of the current disposable market are:

Andrew Sinclair

• a large number of suppliers offering a wide range of technologies

• rapid and changing development of technologies

• no clear market leaders with offerings in all areas of disposable technologies

• no standardization across the range of products between suppliers.

Miriam Monge

As a result, the challenges we face as an industry are first to understand the risks, then to critically evaluate them and develop coherent risk mitigation strategies. At Biopharm Services, through years working on a variety of projects we have developed a formal approach to risk identification and management (Table 1). This article focuses primarily on supply chain issues, because these concerns are often ignored at the beginning of a project. It is important to take supply chain issues into account early, however, because decisions made in the engineering phase of a project can have major impact on the facility's future operations. Some common examples of bad practice include:

Table 1. Risk management for disposables implementation

• Specifying a technology from a specific supplier and writing that into all the specifications and validation documentation, which makes future change difficult.

• Not developing design practices that minimize the number of unique items and not basing designs on common components. This leads to a lot of stock items and causes problems in supply, warehousing, and cost management.

• Not evaluating the suppliers of the disposable technologies on the basis of their ability to provide long-term service, support, and quality operations for the consumables.

This list is not exhaustive; it is intended to illustrate the need for a more integrated approach between engineering, procurement, and operations, focusing on both hardware and the consumables. We would argue that this is vital for new investments integrating disposables.

Figure 1 illustrates this point, which was covered in a great more detail at a recent conference.¹ The key to this approach is to get these three groups—operations, engineering, and procurement— together as part of an integrated working team. The role of the operations group is to identify requirements, assess the operability issues associated with disposables, and define the overall cost and schedule targets. To do this, they need to understand risks, including supply chain and quality risks, and be prepared to compromise where necessary. For the engineering group, the key point is not just identifying the best technology that is fit for purpose but to design in a way that includes the consumable components and considers the entire lifecycle. In addition to considering the usual requirements of cost, time, and quality, they must ensure that designs support procurement goals. The other key team that needs to be involved in the engineering project early on is procurement. While the technical evaluations are being carried out, the procurement group should be developing the supplier strategy by understanding supply chain risk and making sure that the engineering design minimizes supplier dependencies. Through this approach it is possible to integrate procurement's lifecycle responsibilities with the capital project.

Figure 1. In the design of a new facility, an integrated approach is needed that includes the engineering, procurement, and operations groups, focusing on both hardware and the consumables.

We have highlighted some factors to consider as the technology and supplier base rapidly develops in this fast evolving area. Of course, there is a lot more to the subject in terms of the implementation of these approaches. At the project level this highlights the need to consider an integrated approach early. If we take an even broader view, we should consider that as an industry we need to share our user experiences, develop best practices, and communicate our expectations to suppliers. We shall return to this theme in a later column.

TECHNOLOGY ROUNDUP

Disposables for Upstream and Downstream Applications

Mixing Systems

The mixing system in the Thermo Scientific HyClone S.U.B. (single-use bioreactor) has been used as the basis for the Thermo Scientific HyClone Single-Use Mixer (S.U.M.) platform. This product line was recently expanded to cover a wide range of upstream and downstream mixing applications in unit volumes from 200 to 1,000 L. Alternative hardware systems as well as open and closed singleuse mixing bioprocess containers (BPC) are now available.

Millipore launched the MIX500, a 500-L disposable mixing system based on levitated, magnetically driven impeller technology.

Sartorius Stedim launched the Flexel 3D Levmix System. This system uses the Levtech levitated impeller and Sartorius Stedim Biotech's Flexel 3D bag. The Levtech superconducting drive unit delivers strong torque for efficient mixing of a wide variety of solutions from process intermediates to final drug product. The system is available in sizes from 50 to 650 L.

Disposable Bioreactors

In 2008, Thermo Scientific HyClone increased the S.U.B. unit volume range from 50 to 1,000 L. The platform S.U.B. development program has also resulted in alternative sparging systems and integration of disposable non-invasive sensors to increase the range of potential applications. The installed base of over 200 units has produced a large body of experience with most of the common animal-cell platforms and an increasing range of compatible control systems supplied by Thermo Scientific HyClone's integration partners. Further developments are planned for 2009.

Single-use bioreactors from Xcellerex are fully-integrated, fully-characterized systems designed for GMP clinical and commercial production. XDR systems are available with working volumes of 200, 500, 1,000 and most recently 2,000 L. XDR has been proven to deliver stirred-tank performance that closely tracks and often exceeds the productivity of conventional stainless-steel systems.

The ATMI/Pierre Guérin and Artelis collaboration provides the Nucleo bioreactor. Nucleo is currently available in volumes of 20 to 200 L, and 500 L and 1,000 L volumes will become available in first half of 2009.

The Sartorius Stedim Biostat Cultibag stirred tank bioreactor is now available in a 200-L volume. A full range of volumes from 50 L to 1,000 L will be available by summer 2009. Twin 200-L systems that work with the same controller are already available. A 2 x 50-L setup or a 50-L + 200-L combination will be available in Q1 2009. Sartorius indicates that these twin systems allow for significant space savings and also reduce investment costs. The system offers disposable sensors for oxygen and pH.

Sartorius Stedim offers the possibility of twin 50 L and 200 L systems that work with the same controller. The system offers disposable sensors for oxygen and pH.

Aseptic Connectors

Millipore launched the Lynx ST 1-inch connector in May 2008, the only 1-inch steam-to-sterile connector available on the market. Sartorius has launched the OPTA SFT connector, which is available in sizes up to ¾ inch.

GE has rebranded its genderless connector as "Readymate" as part of its ready-to-process range. The connector is available in sizes up to ¾-inch in a barb format and ⅝ inch with a miniature tri-clamp.

Sampling Systems

Several of Millipore's NovaSeptum components that have been available for sampling in stainless-steel systems are now available for use in Mobius single-use solutions. These components enable accurate volume sampling of disposable systems and sterile additions to stainless-steel systems, using a single-use fluid path.

Disposables for Freezing

Sartorius Stedim launched the Celsius FFT 6L, which combines the unique design of a flexible bag with an integral protective shell. The Celsius FFT 6L is specifically designed for freezing, thawing, and long-term frozen storage of biopharmaceuticals such as process intermediates and bulk drug substance. Celsius FFT is designed for use with common chest and upright freezers.

Sensors

Sartorius Stedim has launched single-use pH sensors to be used with Flexel 3D bags. These sensors are stored in wet conditions, are calibrated on line, have a measurement range of pH levels from 2 to 11 and accuracy according to calibration of 0.1 – 0.2.

Disposables for Fill–Finish

Sartorius Stedim has launched the Biosteam port, which is mounted on an autoclave with which it is sterilized so as to enhance stopper sterility assurance. Unlike Tyvek bags, single-use gamma irradiated Biosafe bags eliminate residual humidity. They also ensure safe aseptic transfer from the autoclave onto the filling line, avoiding the need for intermediate isolators.

Bosch Packaging technology has launched the PreVAS system, which is the first ready-to-use pre-assembled, prevalidated, and presterilized dosing system with scale-up capabilities from laboratory to high-speed commercial production. PreVAS is a positive displacement rolling diaphragm pump made of polycarbonate material with all of the hoses, connectors, and filling needles assembled as one unit which is then sterilized using gamma radiation and double bagged.

According to Bosch, the advantage of PreVAS over other disposable dosing systems is the positive displacement piston pump. Positive displacement ensures dosing accuracy over time, unlike other systems that tend to change and require constant adjustment.

The next Disposables Advisor technology roundup will take a more detailed look at market offerings for disposable mixing technology. We will examine the technical features of the various technologies and ask end-users who have worked with these systems for their feedback.

Andrew Sinclair is the managing director and Miriam Monge is the vice president of marketing and disposables implementation, both at Biopharm Services, Chesham, Bucks, UK, +44 1494 793 243, disposables@biopharmservices.com Miriam is also the European chair of ISPE's Community of Practice for Disposable Technologies.

REFERENCES

1. Monge M. Production and economics of biopharmaceuticals. Bioprocess Int. Conference. 2008 SEPT. 23–26. Anaheim, CA.