Evaluating Disposable Mixing Systems

At the moment, single-use mixing systems are fast evolving. This is reflected by the extent of ongoing innovation, which is presenting potential users with difficult choices to make. In this article, we present an overview of the current offerings in this area, discuss end-user feedback, and provide the suppliers' perspective on the latest technologies.

Andrew Sinclair

The situation for mixing systems is more complex compared with the use of bags for holding liquids because mixing systems are used for processing and the duty varies depending on the application. Table 1 summarizes the key applications and disposable technologies for cell-culture available in the market today. We are certain that this situation will gradually resolve itself over the next few years as leading technologies and companies gain acceptance and market share.

Table 1. Typical mixing applications and disposable technology options for cell culture

It is, however, important in this current environment that you use a formal risk-assessment methodology to select the right mixing system on the basis of technology maturity, economics, supplier dependencies, supply chain, and validation. In our previous column published in the December 2008 issue of BioPharm International, we described an approach that we have developed and successfully implemented for many projects that use disposable systems.

Miriam Monge

Besides the technology selection methodology outlined in our last article, the following are a few key points to consider when evaluating disposable mixing systems:

• What are the benefits of moving to disposable technology as opposed to working with stainless steel mixing technologies for your given process? Can you quantify these benefits? Does moving to disposable mixing systems reduce the overall cost of goods of your process, improve operation flexibility, and product security?

• Can a given disposable mixing technology be acquired from more than one vendor? If so, is it possible to do that for both hardware and consumables?

• Does the mixing technology have solid intellectual property (IP)? It is to be noted that there are numerous patent claims in this area—the IP situation is quite complex.

• Is the technology scalable?

• Is the level of particulate generation of a given disposable mixing technology within defined limits?

• How much floor and cleanroom height does the system require? How cleanable is the hardware?

The above list is not exhaustive but it illustrates the type of factors that need to be considered when selecting disposable mixing systems.

TECHNOLOGY ROUNDUP

In the current market, there are a large number of companies offering disposable mixing systems that evolve as companies introduce new developments and extend existing ranges. In this section, we provide an overview of the leading large-scale single-use products.

ATMI Life Sciences

ATMI offers the broadest range of mixing systems with a total of five different mixing technologies in their portfolio.

The Newmix PAD drive overhead impeller mixer with the paddle enclosed in a film sleeve is suitable for a comprehensive range of applications covering all powder-to-liquid and liquid–liquid applications available in a range from 5–1,000 L.

The LevTech Levmixer (a technology that ATMI recently acquired from LevTech) is a levitating radial impeller with two impeller sizes (4.95" and 6.35"). Standard bag sizes are available from 30–1,000 L, with the 2,000 L volume available as a custom item. Jacketed tanks are available and special bags can be customized with the Newsafe powder transfer system.

The LevTech Magnetic Mixer system is a versatile mixing universal drive machine suitable for most powder-to-liquid and liquid–liquid applications. It is available in 30–1,000 L volumes. Magnetic coupling and agitation generates more particulates than the levitating technology. These particulates are within largely acceptable limits and are not an issue provided there is a subsequent sterilizing filtration step.

The Wandmixer is suitable for small-scale mixing applications in the range of 5–200 L.

The jet drive is suitable for totally contained liquid–liquid mixing applications in 50 and 200 L volumes.

Newsafe contained powder transfer bags for media and buffer preparation applications are available in capacities from 5–100 L with triclamp port sizes available from 1–8 inches. These powder-transfer bags are available in antistatic format.

Millipore

The Millipore Mobius Mix is currently available in 100, 200, and 500 L sizes. A 1,000-L system is expected to be in the market later this year. The system includes a magnetically driven impeller with magnetic levitation technology. The system has no mechanical shaft and bearings. It doesn't have particulate generation and no recalibration is required.

Sartorius Stedim Biotech

The Levmix system uses the LevTech levitated impeller licensed from ATMI (see description above) and Sartorius Stedim Biotech's Flexel 3D bag. Sartorius Stedim offers the system in both drum and cubical Palletank format. The system is available from 50–650 L for Palletank and 50–1,000 L in drum format. Heating and cooling options are available.

Flexel 3D Aseptic Mixing system uses a double recirculation loop system and peristaltic pumps for completely contained liquid–liquid mixing applications from 200–1,000 L.

Xcellerex

The Xcellerex XDM Quad Mixing system is equipped with a disposable bottom-mounted impeller. The engagement between motor and disposable impeller is by magnetic coupling, and agitation is driven through stainless-steel bearings in the impeller. The bags have an integrated three-inch triclamp port for powder addition. The system is available in 100–1,000 L sizes adapted to a square configuration container taking advantage of the natural baffling effect of this shape. Standard features also include probe sheath assemblies, floor scale or load cells, and heating and cooling options.

Thermo Scientific

The Hyclone Single-Use Mixer is currently available in 200, 500, and 1,000 L volumes. According to Jon Reid, Hyclone's EU Bioprocess market manager, Hyclone is expanding the volume range from 50 to 2,000 L and adding a docking station option, which will be available in April 2009. The Single-Use Mixer is based on the same concept as the Thermo Scientific Hyclone Single-Use bioreactor (SUB) with a single-use bioprocess container, an integrated overhead impeller, and reusable hardware. The system is available with or without a heating or cooling jacket, and has cutout sections to facilitate bag positioning and monitoring probe capability. The same hardware also can be used with open top liners for media and buffer preparation. The system sports a powder port for contained powder transfer up to 25 k in one shot into a closed bag system.

END-USER FEEDBACK

Given the many mixing technology options available and the variety of applications, it is important to get feedback from end-users. Keeping this in mind, we interviewed several end-users to see if there are some general messages that need to be addressed by the suppliers.

Technical Challenges

When considering mixing technologies, it is important to consider the application. We interviewed a German contract manufacturer who has been testing disposable mixers (5–200 L) for the last 18 months for ultra and diafiltration applications used in the GMP manufacture of a human therapeutic protein. They tested the Millipore Mobius system, the LevTech system, and the ATMI Padmix system. The LevTech system was not retained because of the startup time. "If an operator accidentally switched the system off, we would lose an hour's production time," said the manufacturer. Although the ATMI Padmix system provided robust mixing, it was not retained because of the room height required to fit in the paddle for a 200-L system. The system that best fitted their requirements was the Millipore Mobius because it "works efficiently, is virtually particle free, is not cumbersome, and takes less than five minutes to set up."

Another end-user selected the ATMI Padmix system for solid-liquid applications because it works efficiently for even the most difficult mixing applications. Contained powder transfer is also a nice feature of this system. According to this end-user, the drawbacks of the system are the ceiling height requirement because of the overhead impeller and certain manipulations of the paddle.

The beauty of the LevTech technology as seen by end-users is that the levitating technology ensures there is virtually no particulate generation, which makes it the technology of choice for late-stage downstream processing applications. This also makes it useful for final formulation applications in vaccine manufacturing, when a final sterilizing filtration step may not be possible. The technology is suitable for a majority of powder-to-liquid applications, although the set up time for charging the superconductors (40 minutes) is not accommodating to the fast turnaround required in media and buffer preparation.

A veterinary vaccine manufacturer tested both the Padmix and the Hyclone Single-Use Mixer for a viral inactivation step and found the ATMI Padmix very simple to use and liked the fact that it is a completely contained system. Another factor that contributed to this end-user's choice of the Padmix was that the mixer driver can be decoupled from the bag container allowing interchanging of containers. This end-user considers that disposable mixing systems have considerably matured over the last two years but durability and integrity of the bags can still be an issue.

A major US contract manufacturer tested several mixing systems for blending chromatography column loads. In this case, they chose the Xcellerex XDM Quad Mixer working at 500-L scale. The selection was based on ease of use, mixing efficiency, and the fact that it is an all disposable impeller and that the system is reasonably priced.

The last interviewee, a veterinary vaccine manufacturer in France, indicated that they had tested several disposable mixing systems since 2003 for final bulk formulation working with aluminium gel hydroxide. This was a difficult mixing application, in which the product had to be maintained in a sterile condition because there was no downstream sterilization before filling. They tested the Wave Mixer, LevTech Mixer, Stedim Flexel 3D recirculation system, Millipore's Mobius, and ATMI's Padmix. The Padmix provided robust mixing but was apparently difficult to set up and the LevTech technology was efficient but the length of start-up time was a major drawback. The company selected the Millipore Mobius Mixer because of the plug-and-play nature of the technology along with the particle-free nature of the mixing system.

Non-Technical Issues Raised

As disposable technologies start to play an active role in the process and become more integrated into manufacturing, factors such as cost, testing, and supply-chain security become as important as the technologies' capabilities. Below are some specific comments made during the interviews.

Cost. In our work with users evaluating mixing technologies, we have seen situations where the proposed mixing technologies are more expensive in terms of upfront capital costs and operating costs. This is linked to the application and the actual technology being considered. In this situation, operational and other benefits have to be identified and it may be that the stainless-steel option is the most sensible.

Testing. Testing the integrity of a system before use in critical application is an issue for both stainless-steel and disposable systems. Some companies also expressed reticence to use disposable mixing technology from any supplier for later-stage downstream processing applications such as bulk product formulation because of the current unavailability of a post-integrity test system on the disposable-bag systems themselves.

Supply chain. A concern for all users is security of supply and in the case of unique mixing systems, the single sourcing of the mixer is of concern and has to be managed. From the supplier side, ATMI appears to be addressing this concern through the outlicensing of their technologies to other suppliers such as Sartorius Stedim Biotech. The end-users have reacted favorably to this approach because it opens up avenues to obtaining the same technology from two suppliers, thereby reducing supply-chain risk.

SUPPLIER'S PERSPECTIVE

Having spoken to a number of users, we wanted to get the suppliers' perspective. ATMI has the widest range of mixing technologies currently, and therefore, we wanted to get their perspective on the market and ATMI's approach. Miriam Monge (MM) spoke with Mario Philips (MP), managing director of ATMI Packaging. The following are excerpts from the interview:

MM: What was the driver for ATMI focussing specifically on the disposable mixing market segment?

MP: The driver for ATMI focussing on disposable mixing systems came out of our Six Sigma approach that involved a voice of the customer process. A market study was carried out in 2004, to establish what the key needs of the end-users in disposables were. The clear message that came out of this study was the need for disposable mixing solutions. A Pareto analysis was subsequently carried out to establish the 10 criteria that the technology had to meet in order of their importance. The top three criteria were 1) scalability, 2) powder–solid mixing capabilities for up to a 60% solid concentration, and 3) one product contact material from small scale to large scale.

MM: What do you see as the main value-added features that we will see in mixing systems moving forward?

MP: Mixing systems are increasingly used for virus inactivation, in which pH and conductivity measurements are required. As such, reliable sensor systems are required. Currently, conventional sensor systems are used, but as the disposable sensor technology matures, this will bring added value to the end-user base.

MM: What do you see as the main barrier to entry for disposable systems? We have heard end-users voice concerns with regards to supply-chain security.

MP: As ATMI saw previously in the semiconductor industry, there is a clear need for standardization, with, for example, different suppliers working with similar film formulations. Our vision is that there is little value in the film itself—the suppliers should agree on a standard so as to facilitate contingency of supply, which is the end-users' primary concern. Customers need a dual sourcing strategy. It is the technologies themselves that bring value to the customers, not the film. The fact that each supplier has developed different film formulations represents a validation nightmare for the end-users.

MM: How do you see the level of market acceptance of disposable mixing systems? Has this evolved?

MP: This is somewhat company dependent in terms of the level of maturity of the given company working with disposable technologies. For disposable mixing systems, we do see a move away from local decision-making in many companies to a global decision-making approach. There is now certainly far more technical benchmarking of the different mixing technologies available and all the companies taking this global decision-making approach have defined that they must validate two mixing technologies.

SUMMARY

There are many disposable mixing technologies available from a range of vendor. Some of this variety is in response to the differing applications but much of it reflects the novelty of the technology in this application. It is clear from our discussions with end users that progress is being made in terms of vendors supplying effective technologies, but the total disposable mixing technology offering is relatively immature and carries with it an inherent supply-chain risk. Also, from the technical point of view, no one system is considered optimal.

A number of users have indicated that they were holding off on making decisions to move forward with disposable mixing systems because of three reasons: supply-chain insecurity, technology immaturity, and uncertainty as to whether the technology was really going to be cost effective, particularly for larger-scale media and buffer preparation applications. So the challenges remain and as the interview with Mario Phillips shows, the suppliers are listening and the eventual winners will be those that address not only the technical solutions but also the cost and supply-chain security issues.

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.