Successful Project Management for Implementing Single-Use Bioprocessing Systems

In its early days, the biotech industry was almost entirely science driven, but it has since expanded from a laboratory environment to a sophisticated and dynamic manufacturing environment. As technological discoveries are increasingly translated into commercial products, biotech companies are realizing that they must generate a stronger return on assets.

The implications of this evolution are that production costs and capacity utilization are becoming critical success factors. In general terms, the drive for operational excellence requires initiatives that improve quality, increase throughput, and reduce waste. This translates into

• Improving asset utilization

• Improving quality by reducing deviations and sterility failures

• Improving yield and recoveries

Biotech facilities are complex and highly regulated, and the industry is on the lookout for technologies that can simplify operations, improve product security, speed up changeovers and consequently improve quality and reduce costs. For this reason, we have seen rapid adoption of single-use technologies, particularly over the last five years. Single-use technologies can play a significant role in this drive for operational excellence by offering closed, sterile, ready-to-use systems that eliminate the risk of cross contamination and the need for cleaning and cleaning validation. This enables faster turnaround and hence higher throughput.

Single-use system manufacturers have been actively expanding their range of product offerings (see sidebar). As the list of components available in disposable format increases, the vision of a single-use process train comes closer to reality. But how simple is this technology to implement and operate? How easy is it to validate? How does it compare to the well established conventional technology that the industry has been using for years? This is what this article sets out to examine.

The range of single-use products available

Project management for implementing disposables

The design and specification of process equipment and support operations typically are determined early in facility design, because these factors have a direct impact on facility architecture, utilities, air classifications, and flows of process, material, and personnel. So how do industry end-users evaluate the implementation of single-use systems for a new facility or retrofit project? Two managers with recent experience in this area give their views.

Perspective 1: Using Disposables in a New Facility

Karin Wassard, production director for Bavarian Nordic's smallpox vaccine manufacturing facility, evaluated the use of disposables for a new site.

This plant was to be used to manufacture vaccines using the MVA-BN virus, which is the largest known DNA virus and is too big to be sterile filtered. "Therefore, we needed aseptic production from A to Z—either using a completely closed process or by having all open processes in a class 100 environment," says Wassard. "We chose to create both class 10,000 and class 100 areas, and to ensure an aseptic process we also aimed to minimize the number of open manipulations." The final setup is an almost completely closed process; this design was facilitated, among other things, by extensive use of sterile single-use bags, tubes, connectors, and aseptic zone-to-zone transfer technology (Figure 1).

Figure 1. Arrival of growth media at a manufacturing site docked straight through the wall, using an aseptic transfer port.

Despite designing the process around closed systems wherever possible, Wassard decided to go for a low risk approach in construction by keeping room classifications high. This was decided due to parallel activities in closing the process and construction on site.

Bavarian Nordic worked with separate partners who handled engineering, process scale-up and optimization, and disposable systems. The final process design for the disposables implementation was carried out by Bavarian Nordic in collaboration with disposable system providers.

Wassard says that the key benefits her company saw in working with disposables on this project were:

• They were able to delay final process design as long as possible to allow more time for final process development and scale-up optimization.

• The construction project timeline was much faster because they were able to separate the process flow from the construction project.

• Reducing initial investment cost, by lowering equipment costs as well as reducing the floor space needed for processing.

• Cleaning validation was minimized, and this saved time and effort during commissioning. Also, if the facility is ever changed to a multiproduct site, cleaning and cleaning validation efforts between product runs would be reduced.

• More flexibility due to shorter change-time than with conventional technology, and no need for shut-down.

Perspective 2: Retrofitting Disposables into an Existing Facility

Adam Goldstein, director of operations at Amgen, has experience in implementing disposables into existing facilities. According to Goldstein, the most important aspect of implementing disposable systems in a facility is to assign a project manager who will:

• Define the project

• Define the process and applications where disposable systems will be used

• Discuss applications with area managers in the QA and validation groups

• Identify engineering leads for each application and for facility fit

• Determine vendor options and industry standards

• Develop a schedule and project plan for testing and other critical steps.

• Conduct a technical assessment to conduct extractables testing and a product impact evaluation

• Determine storage locations and material flows throughout the plant.

Goldstein and his team worked extensively on the validation approach to disposables. The questions they raised at the start of this analysis were:

• Where is the solution used in the process? Upstream or downstream?

• Has the solution held in the disposable system been sterile fitered or not?

• How does the solution affect the product?

• How long will the solution be in contact with the disposable system?

• What are the different plastic materials out of which the disposable system is manufactured?

• What is the ratio of the solution to the contact surface?

• What are the possible extreme conditions the solutions will be stored in?

In both Goldstein's and Wassard's cases, the industry end-users devised their own project management strategy for evaluating disposables. Some parts of the project went very smoothly; others proved more time consuming than expected (for example, connector validation by suppliers and initial operator training at Bavarian Nordic). This planning was facilitated by the fact that both companies had previous experience working with disposables. It is not surprising, therefore, that there is a growing lobby in the biotech industry for developing guidelines and standards to facilitate the implementation of disposable technology.

Guidelines for implementing disposable technologies

BioPharm Services¹ and Stedim Biosystems have developed a project management approach for implementing disposables in both new facilities and retrofit projects. This approach has been fine-tuned through experience in numerous disposable implementation projects in the United States, Europe, and Japan.

The project management approach that has been developed to ease implementation of single-use systems into new and existing facilities covers the following areas: 1) new technology risk analysis; 2) conceptual design and facility layout; 3) workflow and process optimization through process simulation; 4) economic analysis; 5) validation; and 6) supplier evaluation.

Risk analysis of new technologies

Several key questions should be asked before embarking on a project to implement a new technology such as disposables. For example, How much risk is the company prepared to take in moving away from traditional processes? How significant a role will disposables have within the project?

It is also important to ask whether the company is prepared to use only disposable technologies with which staff has experience, and whether the company is prepared to consider what the engineers recommend. And are they prepared to install technologies straight from the supplier?

It is also important to define the application and to evaluate what technologies are available for each specific process application. Then, the company should evaluate how those technologies are used, and their benefits and limitations.

A cost–benefit analysis of rival technologies also is needed. For example, technology ease of use, ease of installation, and the level of service support that the system manufacturers guarantee all must be analyzed. Technical specifications and performance data comparisons can be complicated by the fact that different suppliers do not necessarily use the same test methods.

Supplier validation packages for given technologies also must be examined and compared. (This is examined further later in the article).

Conceptual design and facility layout

A disposable process must be planned to match production requirements, bearing in mind that wide implementation of disposables can radically change the facility design. Key points to consider include:

• The degree of flexibility that the company seeks. Is the facility single-product or multi-product? What are the capacity requirements? Does expansion capacity need to be planned from the outset?

• How important is it to the company to reduce utility usage in a retrofit or process upgrade environment?

• Is the company looking to increase capacity in an existing facility?

• Are there project-specific limitations in terms of containment?

The first stage of developing a disposable concept is to understand the process characteristics and workflow constraints of the manufacturing operation. From this information, a layout is developed that takes into account the definition of room requirements; process and material flows; and cGMP compliance.

In addition, some workflow considerations are specific to disposable technology. These include logistics and manual handling considerations; process connection and aseptic transfer philosophies; and waste management.

Logistics and manual handling. In evaluating logistics and manual handling, one must consider:

• the volumes of solutions to be made up and stored, and when they are required

• floor area requirements for work in progress

• the logistics of moving the single-use systems around the facility. Unlike a fixed pipe system, which normally has a large solution makeup and storage area located away from the processing rooms, with a pipe dropping into all of the user points, disposable solutions require corridor access to each of the rooms that the utility will be serving.

Process connection and aseptic transfer philosophies. In evaluating approaches to process connections and aseptic transfer, one must consider aseptic transfers, people flows, and design and layout.

Aseptic transfer. The concept of segregation—both by space and by closed processing—is an area in which single-use systems can create new standards in operational excellence and containment (Figure 1). Alpha/beta aseptic transfer port technology, for example, can make this kind of segregation possible. This technology solves a recurring problem in bioprocessing—namely, how to transfer processing solutions aseptically—and enables totally closed disposable bioprocessing across different area grades without compromising any area. For example, the preparation and storage of voluminous media and buffer solutions can be segregated from the main process areas and fed through the wall using the disposable aseptic transfer technology.

People flow. Segregation makes it possible to have two separate teams working in the facility, one dedicated to support and the other dedicated to the process areas, thus reducing the risk of microbial contamination or the need to increase containment. This greatly simplifies operations, reduces the amount of equipment, simplifies flows of material and people, and improves final product integrity by minimizing or removing aseptic operations.

Design and layout. The segregation of process and support areas reduces the surface area of the higher classification cleanrooms, which in turn has a significant impact on overall cost of goods.

Process connections. Industry end-users tend to choose air classifications that are higher than needed when implementing disposable systems (consider the Bavarian Nordic example above).

The approach to connector technologies used in traditional and disposable systems tends to be different. Traditional bioprocess manufacturing methods have adopted an almost universal stainless steel sanitary tri-clamp fitting or stainless steel straight connectors (originally put in place as they could be flamed). Disposables manufacturers, on the other hand, have developed a wide variety of connector technologies for aseptic and nonaseptic connections, both dry and wet. This means that end-users often end up evaluating three or more technologies for different parts of their process, all of which have to be subsequently validated and operators trained.

Guidelines need to be developed to specify the qualification and validation requirements for connector technologies. A risk analysis approach also must be developed in relation to ergonomics and operator handling of each technology.

Guidelines for bioburden controlled and sterile processing. Appropriate guidelines also will facilitate single-use system selection and implementation in terms of using bioburden controlled processing, instead of sterile processing. If we look at the ISPE biotech baseline guide for biopharmaceutical manufacturing facilities,² we see that typically, low bioburden processing applies to recovery and purification operations. This means that 70–80% of single-use systems are currently being supplied for low bioburden applications, though all are systematically gamma sterilized and are often preassembled with aseptic connector technologies.

Of course, if we consider radically changing the way we design facilities, the fact that the single-use systems are gamma sterilized and offer the possibility of totally closed processing across different zones, this allows room classifications to be lowered if suitable validation is carried out. Could aseptic processing in a controlled non classified (CNC) environment become a reality?

Waste management. While some components of disposable systems, such as silicone tubing, can be recycled, many have to be incinerated. Consideration must be given to what was contained in the disposable system, what contracting company will deal with waste, and how frequently the waste will be collected.

Disposables companies have analyzed the relative quantities of water, chemicals, and electricity requirements needed for cleaning and steaming stainless steel for a given process in comparison with the kilos of plastic to be incinerated. Despite the common perception that disposables are the worst option from the environmental point of view, this is not necessarily the case. Further guidelines in the area of waste management will need to be developed by the industry standards committees.

From an economic perspective, a study was carried out to determine the relative costs of plastics incineration for a given process compared to the average costs of wastewater treatment. The costs were based on a survey of key European biopharmaceutical industry players. The total amounts of water and bag consumption were multiplied by the unit waste management costs to compute a total waste treatment cost for one campaign. On an annual basis, the incineration cost of plastics was half the cost of waste water treatment.³

Workflow and process optimization through process simulation

Process simulation can offer critical insights for developing guidelines and standards for the implementation and operation of single-use systems.

Figure 2 shows how simulation can be used to assess the impact on personnel and floor space requirements for buffer make-up strategies with single-use bag systems. The company is a multiproduct contract manufacturer. The simulation tools allowed the workflow and buffer makeup process to be optimized to suit the multiproduct production schedule. Operator levels were reduced and contingency time increased under the same storage and makeup area constraints.

Figure 2. Buffer use per day, broken down by volume. Through a simulation, the buffer makeup process and workflows were optimized for a multiproduct site using disposables.

When process simulation is used for equipment and infrastructure sizing, it often shows that using disposable technologies can have a big impact. For example, on average 70% of WFI usage in a biotech plant is for cleaning. Many engineering companies struggle to evaluate the direct impact of disposables on utility requirements and oversizing of WFI systems still occurs frequently.

Economic analysis

In a disposables implementation project, an in-depth understanding of the investment requirements, return on investment, and associated manufacturing costs is required. Implementation strategies must be compared to determine the maximum capacity required for the short term, and future expansion strategies; and to make cost comparisons of rival technologies.

Indirect expenditures related to operator training, validation, and utilities are usually much greater than direct equipment costs and are considerably more difficult to measure. Industry guidelines are clearly needed as many companies are uncertain about how to carry out an economic analysis of manufacturing options and comparative technology evaluation.

Validation

In BioPlan Associates' 2006 annual survey of biopharmaceutical manufacturing, the number one reason given for restricting the use of single-use or disposable systems was concern about leachables and extractables, with 63% of respondents expressing concern in this area (down from 68.9% in 2005).⁴

Industry end-users considering implementing a disposables manufacturing approach will evaluate various supplier validation packages. These packages usually contain physical, chemical, and functional test results for film, filter, tubing, and connector qualification. They also may contain extractables and leachables testing results. The packages are currently based on a variety of industry standards, which makes comparative evaluations of validation packages more difficult. In addition, some suppliers have more complete packages than others, so individual assessment is required. Each package should be reviewed and a risk analysis developed with respect to product-specific studies.

Other process-specific studies that need to be carried out include:

• Integrity studies

• Aseptic simulations (media fill)

• Cleaning agent compatibility for outer surface wipedown

• Process exposure compatibility tests.

So how can end-users work their way through the variety of guidelines and standards to make an evaluation? At present, many companies set up their own process or product specific tests, as we saw in the case of Amgen.

Bavarian Nordic based their analysis primarily on audits of suppliers (including film manufacturers), combined with supplier validation packages and knowledge from previous use in process development and optimization. This was all combined in a risk evaluation, which was the basis for prioritizing items for process-specific testing.

A sign of industry maturity and the drive for disposables implementation is that committees such as the Bio-Process Systems Alliance are being set up with the aim of evaluating the guidelines already in use and making recommendations for harmonizing the validation approaches proposed by disposable manufacturers.⁵

Supplier evaluation

The second most common reason industry members cite for restricting use of single-use or disposable system components was to avoid dependence on vendors—i.e., single-source issues. In the 2006 BioPlan survey, 54.5% of respondents expressed this concern, up from 34.2% in the previous year. It is not surprising, therefore, that single-use system manufacturers are being asked to supply far more detail around supply security. Further definitions in this area will no doubt be part of the guidelines set up by industry standards committees.

Take home messages

Single-use systems have a key role to play in the drive for operational excellence in biotech manufacturing. This article has set out to analyze the current status and to determine the key areas that require set up of guidelines and standards to facilitate successful project management of single-use system implementation.

Acknowledgements

The author wishes to thank Adam Goldstein of Amgen, Karine Wassard of Bavarian Nordic, and Andrew Sinclair of Biopharm Services.

Miriam Monge is a marketing director at Stedim Biosystems, Z.I. des Paluds, Ave. de Jouques, BP 1051, 13781 Aubagne Cedex, France, +33 (0)4 42 84 56 11, fax + 33 (0)4 42 84 68 70, m-monge@stedim.fr

References

1. Biopharm Services, Lancer House East Street, Chesham HP5 1DG, UK: e-mail: a.sinclair@biopharmservices.com

2. Baseline Pharmaceutical engineering guide—Pharmaceutical engineering guides for new and renovated facilities, volume 6: biopharmaceutical manufacturing facilities. ISPE, Tampa,FL.

3. Study carried out for Stedim Biosystems by Biopharm Services in 2005, involving selected client interviews across Europe on waste management programs.

4. Fourth annual report and survey of biopharmaceutical manufacturing, June 2006, Disposables and Single-use components. BioPlan Associates, Rockville, MD, June 2006.

5. Bio-Process Systems Alliance, The Society of the Plastics Industry, Inc.Washington, DC, www.bpsalliance.org.