Disposables Open Up Possibilities in Facility Design

With this month's column, we are introducing a new regular section dealing with the latest developments in disposable technology and, in particular, feedback from users about these developments. In putting this together, I will be helped by my colleague Miriam Monge, a well-known figure in the disposables business; she is also European chair of ISPE's Community of Practice for Disposable technologies.

Andrew Sinclair

CHANGING MABS MARKET MAKES DISPOSABLES USE MORE FEASIBLE

Much of the current clinical pipeline is geared toward monoclonal antibodies (MAbs) and the current trend is for smaller market-volume requirements for MAbs. When linked with increasing product titers, this trend puts many new manufacturing facilities well within the reach of disposable technologies. Johannes Roebers made this point in a recent talk, noting that annual product requirements of about 500 kg/year will become the norm.¹ As disposables become more and more integrated in our manufacturing facilities, it is interesting to assess the implications for both design and project management.

Implications for Facility Design and Project Management

If we consider a typical bulk MAb facility, designed to produce 500 kg/year with a titer of around 3 g/L and product recovery to bulk of about 60%, around 8,000 L of bioreactor capacity is needed.² If processed as one batch, about 63,000 L of solutions are required for processing. At this scale, this facility is well within the comfort zone for using disposable technologies. Today, we would consider disposables for various unit operations in a plant, such as: production bioreactors (4 by 2,000 L or 8 by 1,000 L); depth filters for harvest; membrane chromatography for flow-through columns; process mixing; and product, media, and buffer hold and preparation.

Monge Miriam

So, what are the implications for facility design? One clue is given by the amount of water used for cleaning a stainless-steel facility, in which much of the complexity of facility design is driven by pipework for steam-in-place (SIP) and clean-in-place (CIP). For example, if our model 500 kg bulk MAb plant were a stainless-steel facility, 155,000 L of solutions would be required annually for cleaning. In a disposable facility, on the other hand, we can:

• remove most CIP systems, restricting their use to packaged equipment

• remove all CIP and SIP infrastructure

• remove the autoclave and wash-up areas

• remove process pipework between the unit operations by replacing it with physical movement and disposable tubing.

Figure 1 shows a development of these design concepts, published in 2004.³ The result of this level of integration is a building containing cleanrooms but little process infrastructure. The process is configured by setting up process operations in designated serviced work stations minimally equipped with power, data links, and gases. In this way, the operational space becomes flexible and easily reconfigurable. This kind of facility design has more in common with traditional manufacturing operations, focusing on optimizing material and people flows and giving serious consideration to lean approaches (e.g., reducing changeover times, inventories, and waste). In the building project, there is less emphasis on the process that will take place in it, because we have now effectively separated the process from the building. Against this backdrop, below are the key considerations when undertaking this type of a design project.

Figure 1. A disposable concept facility

1. Speed in one area affects other parts of the project. The simplicity of the building, its layout, and lack of process infrastructure allow a project that is largely based on disposables to be built more quickly than a stainless-steel facility. This means that other aspects of the project, such as process and validation activities, vendor audits, and extractables and leachables studies, must be started earlier.

2. Separating process design from building design. Process and technology are still important but they can be quickly separated from the building project. Here the emphasis is to define the mass balance and assess the available technologies for the particular applications. It is important that all effort be made to eliminate or minimize all clean utilities, CIP, and process pipework. Use of modeling tools helps in the cost–benefit assessment and the analysis of process, material, and people requirements. Where possible, develop vendor-independent disposables design specifications.

3. Plan for more manual handling. This type of facility relies more heavily on manual handling, rather than pipework, to move product and materials around the facility. Therefore, it is important that early prototypes be developed of the disposable systems that will be used and that the operations be laid out at scale to allow for ergonomic and functional evaluations to be completed before commission-ing and start up.

4. Engage the procurement team early. When a lot of disposable technologies will be used in a new facility, it is important to involve the procurement organization from the outset of the project design. The procurement team will need to carry out the vendor assessments in terms of pricing, risk, and security of supply, and ensure their requirements are effectively communicated to the engineering project team.

LATEST TECHNOLOGIES IN THE MARKET

As the industry demand for disposables increases, the suppliers are striving to add new technologies and innovations to their disposable technology offerings. Examples of most recently announced new developments include:

New offerings in large-volume bags for holding fluids:

• Pall Corporation has launched a new large-volume bag range called "Allegro" with capacities of 100, 200, and 500 L.

• The Millipore Mobius line now includes includes bags from 200 to 2,000 L. The Mobius stainless-steel totes have a patented registration plate that makes it possible to adapt the ports at the bottom of the container to work with bags from multiple suppliers. Millipore's large-volume bags (1,000 and 2,000 L), branded "EZ fold," also feature walk-away filling in which the bags unfold as they are filled.

• Sartorius Stedim Biotech has recently added a 50-L volume Palletank to its Flexel 3D range.

Single-use pH probes

New measurement and control systems greatly expand the use of disposable bags. Of particular interest is Sartorius Stedim Biotech's newest single-use pH probes, which can measure pH levels from 0 to 11 with a +/–0.1 precision.

New aseptic connectors

When configuring fluid handling systems, aseptic connectors are an enabling technology that has greatly extended the use of disposable systems. This was spearheaded by the Pall KleenPak connector,but recently many other vendors have developed their own connectors:

• Saint Gobain has recently launched its new sterile connector, the Pure Fit SC.

• GE Healthcare's Bioquate is a genderless connector that is popular with end-users.

• Millipore offers a wide range of connectors in both dry-to-dry and dry-to-wet formats, with internal diameters (IDs) up to 1 inch. The Lynx ST, for connecting to stainless steel, was recently launched in 1-inch ID format. This is a membrane-free system that facilitates integrity testing and is simple to manipulate.

In addition to making technical developments, vendors are also looking at ways to improve supply-chain security; a common approach is to achieve this through product standardization. By offering standard, off-the-shelf products, vendors are able to shorten lead times and improve the security of supply. This standardization should benefit the end-users as the industry develops generic design standards, thus making it easier for end-users to work with multiple suppliers.

REFERENCES

1. Roebers J. Future trends in biopharmaceutical manufacturing. PDA Meeting; 2008 Jun 25; Dublin, Ireland.

2. Data presented is for a typical monoclonal antibody process generated using Biopharm Services bps Biosolve process model.

3. Andrew S, Miriam M. Biomanufacturing for the 21st century: designing a concept facility based on single-use systems. BioProcess Int. 2004;Oct supplement:26–32.

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.