September 1, 2012 (Vol. 32, No. 15)

Traditional Systems Still Essential in Range of Biomanufacturing Operations

Is there such a thing as a “universal solution” in the assessment of the technological options for the biotech industry? Do single-use process components outperform systems based on conventionally designed stainless steel equipment?

Whereas single-use technology has been an established practice in laboratories for many years, its application in biotech production is now being promoted heavily, particularly for cell culture. Vendors offer single-use components as part of a comprehensive tool box extending from simple storage and shipping bags to agitated tanks/bioreactors and tube manifolds and connectors. Even selected components for downstream processing steps are being marketed.

Single-use technology permits more cost-efficient design and swifter implementation compared to conventional stainless-steel components and allows bioprocessors to minimize technological and procedural cleaning efforts. Thus, preparation times are shortened, particularly for product changeovers, but also for batch-to-batch preparation during manufacturing.

Still, implementation time cannot be reduced at any level. Comprehensive planning is also required. Sourcing of basic process skids (bag support containers and control units) must be considered and is not negligible. Starting with mid-size installations, skids for generation and loops for distribution of clean utilities, namely WFI and clean steam, must also be designed, procured, and installed. Such systems are typically based on conventional stainless steel designs for fluid integrity and construction material handling reasons.

Deployment Limits

Limits for the deployment of single-use systems are currently set at one to two cubic meters for stirred systems and two to three cubic meters for storage tanks. This is primarily due to constraints with respect to the stability of the bags and their handling. Operators must be familiar with the specific skills required for working not only with bags, but also hoses, since numerous new hose connections need to be created for each batch.

Restrictions arising from the tube diameter that result in overly long transfer and filling times also play a role (Table).

The tube diameter is determined by the connectors sealed to the bags. For many years ¾ inch was considered to be the maximum viable connector size. More recently, however, a diameter of 1 inch has been introduced.

The greater the hose diameter the more complicated the manual handling of the material becomes. A thinner wall thickness may facilitate handling due to higher plasticity but it also entails a disadvantage in that if the medium is drawn off from the container by means of a pump, this may cause the hose to contract, thus reducing the flow or even blocking the hose.

Influence of tube diameter on maximum flow volumes and transfer times

Design Approaches

Various design approaches have been evaluated with respect to partial or full replacement of conventional systems by single-use components. Potential cost savings on capital expenditure (Capex) have been estimated as follows:

  • 25–45% reduction in process equipment,
  • 37–40% reduction for piping and equipment installation,
  • 36–52% reduction in instrumentation and automation.

Savings in Capex are mainly based on absence of the need for complex piping systems required for CIP and SIP, including associated automation components. Similarly, fewer qualification and validation efforts are needed due to vendor-sterilized (gamma-radiated) bags and associated flowpaths. In contrast, other cost blocks typically arising with Capex projects (e.g., building, cleanroom, and floor and ceiling construction, HVAC and laboratory facilities) yielded lower or even negligible potential for savings.

Sourcing costs for single-use components rise substantially during regular production in line with the number of batches to be manufactured. They are even substantially higher if manufacturers use tailor-made configurations rather than the suppliers’ standard ones.

While the single-use option for systems smaller than one cubic meter often can be considered as a feasible alternative option, the situation is different if the targeted scale exceeds a few cubic meters or dedicated manufacturing facilities are envisaged. In such cases, the benefits of conventional stainless steel systems prevail.

Advantages of Alternatives

Stainless steel offers competitive advantages due to almost no volume design restrictions and to the ability to design a system according to a client’s specifications and processing requirements. Tanks with a capacity of up to 100 m³ are industry standard. Pipes are designed accordingly.

Such individual design reflects the customer’s specific requirements and provides flexibility during operation.

Proven instrumentation and automation of key process steps (e.g., sterilization and liquid transfers) ensure high process stability and improve the reproducibility of routine activities, which lead to the reliability of the operation.

With stainless steel, the range of applications is neither limited to the specific nature of the process technology itself (i.e., animal cell, yeast, or microbial) nor by their particular operation parameters, (e.g., high cell densities, high oxygen consumption, or high viscosity). Construction materials are well characterized and surface treatment is well established. Proven retention systems/emergency scenarios can be applied in the event of a leak.

Figure 1A. Table

Some of the intrinsic disadvantages of stainless steel components, namely higher investment costs and longer equipment construction and setup times, can be minimized by optimizing design and installation approaches. Such procedures rely on process-oriented project-management methods and use sophisticated software tools, such as Intergraph PDS, an intelligent computer-aided design/engineering (CAD/CAE) application for plant design, construction, and operations.

Figure 1B. Prefabrication approach for sanitary piping: bending

Construction time can be shortened by using skid or super-skid structures as well as generating piping isometrics directly from 3D-planning tools and utilizing prefabricated pipe spools from specialized and qualified centralized workshops. These efforts need to be coordinated with the logistics department to arrange for the just-in-time delivery of the spools to the construction site. These measures help shorten design and delivery times substantially, improve systems’ reliability, facilitate intercontinental data exchange, and decentralize project teams.

During pipe installation the number of weld seams is significantly lowered if bent piping is used rather than welding elbows. Bending (Figures 1A and 1B) and collaring (Figures 2A, 2B, and 2C) technology, along with advanced orbital welding techniques, permits savings of up to 40% on the piping construction and associated quality assurance costs at significantly shorter realization times.

Figure 2A. Prefabrication approach for sanitary piping: collaring

Bending is applicable up to DN 50 for pipes according to the EN ISO 1127 standard. For Imperial (OD) as well as for DIN 11850 standards, this technology is applicable up to DN 25.

For larger diameters [32

Collaring for aseptic design pipe-work is applicable for run pipe dimensions up to DN 200 in combination with collar dimensions of DN =

Figure 2B. Table

Manufacturers of stainless steel systems incorporating the approaches described in this article achieve significantly lower installation costs and accelerated completion of projects, flexibility in the design phase, systems’ operational reliability, reproducibility, and safety.

The bottom line is that no general statement can be derived on which approach is superior: single-use or stainless-steel system. The decisive criteria for which technology to select includes the expected volume requirements of the product(s) to be manufactured, the requested flexibility in case of multiproduct activities, and resultant capacity planning with associated volume constraints.

Figure 2C. Collaring

Peter Kraemer, Ph.D. ([email protected]), is responsible for directing technical projects, chemistry and biotech development, and large-scale fermentation at Sanofi. Tobias Eitel ([email protected]) is general manager, and Claudia Nachbur is former head of international sales, at BIS Industrietechnik Salzburg.

Previous articleLegalizing Medicinal Marijuana
Next articleTop 20 Pharma-Friendly Congress Members