Implementing Disposables Technology, Delivering Innovation, and Transforming an Organization

When organizations move from reusable manufacturing to single-use technologies, What are the issues the organization faces? And in the case of large multinational companies, How do you assess and deliver innovative technologies that add real value to the development and manufacturing groups? In this article, we focus on one organization's structured approach to this challenge.

Andrew Sinclair

Sanofi Pasteur is a complex organization with manufacturing and R&D sites across the world. One key technology that they are actively evaluating as a part of their innovation program is single-use technologies. We spoke to Jean-Marc Guillaume, the head of Bioprocessing Research and Development (upstream) who leads the disposables technology domain within the Sanofi Pasteur "Knowledge & Innovation for Technology Excellence" (KITE) program.

Miriam Monge

We also asked Jean-Marc to provide an example of how the KITE initiative has helped Sanofi Pasteur evaluate and implement a specific technology. His case study, prepared in collaboration with colleagues at Sanofi, follows the interview.

SANOFI'S APPROACH TO MANAGING INNOVATION

Q: You head up a disposables group that is part of the Sanofi Pasteur KITE program. What this program is about?

The KITE initiative started in 2008, and spans Sanofi Pasteur's global R&D and industrial operations groups. Its goal is to ensure the availability of innovative enabling technologies to sustain the evolution of our industrial activities and product development. The mission is to stimulate the development of innovative enabling technologies from discovery to production, to develop a robust methodology to prioritize and manage those technologies across a portfolio of opportunity, and to be an intelligence forum for new technologies. This means that our groups scan, investigate, evaluate, and recommend innovative enabling technologies and ensure their implementation.

Q: How is the program organized?

The program is sponsored by top management, who define the budget and resources assigned to the program based on group recommendations, cross-domain coherence, and alignment with company strategy. For all domains, common governance and process rules have been established. Domains of expertise or key programs to foster have been selected company wide. Disposable systems is one of the domains.

For each domain, management identifies a group of people from various functions to represent the whole company's scope of activities. The people involved are to spend 20% of their time on the program, and have specific personal objectives linked to the program. Each group has a sponsor, with the overall KITE project sponsorship being shared between the group heads of research and industrialization.

Q: In your role leading the disposable systems technology domain, what results have you seen so far?

We are already seeing the benefits of this program. It leads not only to improvements, but in some cases the outcomes of our analysis lead us to completely change the way we work to ensure that we are taking full advantage of technological advances when it makes sense to do so. A further outcome is that we are stimulating an innovative spirit and developing innovation synergies between the R&D and industrial operations groups.

Q: At what stage of your process development do you start evaluating when and where to implement disposables?

The answer here is that it really depends. Innovative technologies such as disposables can be implemented as much in early development processes as in commercial manufacturing; the difference is in the amount of effort required, notably in terms of qualification and validation. Considerable savings are achieved by doing a scan of technologies across the company and taking advantage of the KITE forum to see if common standards and solutions can be established.

Q: Traditionally, Sanofi has been very stainless-steel oriented. Why have disposables now come to the forefront?

Yes, it has taken us time to come round to the benefits of disposables. At a high level, the benefits are clear, but we believe it is always important to judge the features and benefits of disposables in relation to specific projects, to make sure we choose the best option for a specific application in an existing process. The high-level benefits that need to be verified or measured in the context of specific projects include:

• Reductions in capital expenditures and risk, by delaying spending and investing later.

• The potential to downgrade room classifications by using closed disposable systems. Such downgrades simplify gowning procedures, which offers benefits from the human perspective and in terms of productivity.

• Economic benefits. Disposables clearly offer economic benefits: We are able to downsize water systems, eliminate a lot of stainless steel, and considerably simplify the facility. But again, the level of economic benefit will depend on the specific project, the type and scale of the process, existing capacity, skills, and lifecycle costs. As part of this program, we have selected analytical tools that enable us to conduct such an economic assessment.

• Regulatory impact. The FDA is pushing the industry toward disposables because there is less risk of cross contamination, and this is of course extremely important for vaccines. Until now, we have had a policy of one building per vaccine—total segregation. If we can demonstrate that we are able to eliminate the risk of cross contamination through closed disposable systems, we could potentially have multiproduct vaccine manufacturing operations.

• The potential to gain a competitive advantage for market access through speed to market and flexibility in terms of production capacity. The need to adjust capacity is key for vaccines, because it often is difficult to judge the exact manufacturing capacity requirements for a vaccine. When there is a new product launched on the market, there is a virgin population to vaccinate. After all the people in that group have been vaccinated, supply needs will be reduced to newcomers. As a result, phasing the production volume of vaccines to avoid under- or over-supply is not always easy.

• The ability to set up a new process very quickly, as in the case of a pandemic. This was demonstrated last year with H1N1.

• In terms of specific risks related to disposables, equipment quality and procurement issues need to be assessed. A permanent element of our evaluation is our commitment for long-term supply, so we need to assess the sustainability of any new technology.

Q: Do vaccine manufacturing processes have specificities that affect the way disposables can be deployed?

Yes, they do indeed. One important point to note from the outset when talking about vaccines is that vaccines are given to healthy human beings. As a result, the regulatory requirements for vaccines are extremely stringent; the thorough guarantee of product quality comes first. Apart from that, typical issues are the requirements for decontamination and waste management of disposables when working in virally contaminated areas. Also, live viral vaccines are manufactured in a biosafety level 2 environments.

Q: What specific issues do vaccine manufacturers need to address in relation to biosafety level 2 when implementing disposables?

Disposables entering and leaving a biosafety level 2 environment need to be totally contained, so they require more outer packaging. This packaging needs to be designed in such a way that it is effective whilst not creating additional manual operations that would negate the inherent flexibility that disposables offer. Specific training and solutions in handling disposables are required in that respect. Additional packaging also means additional storage space is required.

A method we have found effective for limiting the amount of decontamination required for disposables is leaving disposable equipment in lower classification areas and using aseptic transfer ports to transfer them into the contained areas.

Another area where the implementation of disposables is not simple for vaccine manufacturers is managing the decontamination and waste of microcarriers; they must be separated from the disposable bag after use.

CASE STUDY: SINGLE-USE BIOREACTORS FOR VACCINE MANUFACTURE

Eric Calvosa, manager, cell culture and virology development; Nicolas Sève, process engineer; Jean-Marc Guillaume, head of bioprocessing upstream development, all at Sanofi Pasteur.

Sanofi Pasteur's KITE program has led to a number of key initiatives that have provided tangible benefits. In one example, we wanted to evaluate the effectiveness of scaling up a vaccine manufacturing process using disposable bioreactors.

A number of commercially significant viral vaccine processes are based on adherent mammalian cell lines. In the process examined in this case study, a Vero-based cell culture had been expanded in serum-free media and scaled up in increasingly larger stainless steel bioreactors, with the pilot scale established at 180 L. The objective was to examine the potential for driving out cost by moving this process to a fully disposable process design, starting from the seed train and expanding up to a 500-L scale disposable bioreactor.

In this evaluation, we focused on the following areas:

• the specifics of bioreactor design in relation to Vero cell amplification and productivity

• how to manage biosafety

• how to qualify disposable technologies

• what effect the implementation of disposable bioreactors would have on our facility footprint.

Outcomes

The exercise demonstrated that it is feasible to scale up the Vero cell culture in a disposable bioreactor up to 500 L using the Nucleo series of bioreactors from ATMI. Good virus yield and productivity were obtained in Nucleo 20-, 200-, and 500-L bioreactors, achieving performance comparable to that seen in the 180-L stainless steel process.

In addition, major benefits were seen when implementing a disposable process from seed to large-scale cell expansion and infection. A significant time savings was achieved for rapid cell expansion when thawing large volumes of prepared banks and seeding directly in a disposable Nucleo 20. With the disposable set up, the time from initial equipment reception to the first harvest was only four weeks, compared to more than six months for stainless steel.

Facility and Engineering Design

As part of the feasibility analysis for scaling up to a 500-L scale bioreactor, we carried out a biosafety "what if" review, covering aspects such as prevention of bag failure through the addition of safety pressure sensors on the bag and water traps on the exhaust filter, bag stress validation, and connection of a sampling line. For overall disposable bioreactor protection, the bag was installed with a retention tray placed under the bioreactor to recover any leaks or fluid in the event of bag rupture. The retention tray can be fitted with a soft wall isolator cabinet for viral production steps.

We also carried out an evaluation of the relative impact on qualification and maintenance of working with the Nucleo as opposed to the stainless steel bioreactor. We were able to demonstrate a decrease in preventative maintenance, reduced shutdown time, and higher turnover. We also compared the timeline for process design, installation, and qualification, and were able to demonstrate a very significant reduction, from 20.5 months to 6 months (Table 1).

Table 1. Comparison of the time required for equipment ordering, installation, and qualification of a 180-L stainless steel bioreactor and a 500-L single-use bioreactor. The single-use bioreactor saved 14.5 months.

In terms of overall footprint requirements in a classified area, we were able to demonstrate an equivalent footprint between the Nucleo 1000 (1,000-L) and a 200-L stainless steel bioreactor, and the footprint of the Nucleo 500 is 2.5 times smaller than the equivalent 500-L stainless steel bioreactor. In a classified area, such footprint reductions can lead to significant savings because of reduced utility requirements to maintain the space.

Economic, Environmental, and Process Robustness Evaluations

We carried out an economic analysis in which we considered factors such as the upstream and downstream process, the capital investment, utility requirements, labor time, raw materials, waste management, and maintenance. To do this, we evaluated available process modeling tools on the market and selected BioSolve, from Biopharm Services Ltd. We were able to run multiple scenarios very rapidly in BioSolve, comparing the completely stainless-steel based process (scenario 1) with the fully disposable process (scenario 2) and a third option, which was a hybrid solution involving both disposable and stainless steel equipment (scenario 3).

Economic Comparison. The results left no doubt as to which solution was the most economically attractive. Through full disposables implementation in upstream and downstream processes, we decreased the capital charge by 30% (Figure 1). The implementation of disposables for each step also meant a 90% decrease in pure water requirements and a 50% reduction in water for injection needs.

Figure 1. Cost comparison for three set ups for a bioprocess based on a bioreactor with a 1000-L working volume. Scenario 1: completely stainless-steel process; scenario 2: a fully disposable process; and scenario 3: a hybrid solution.

Environmental Impact. On the environmental impact front, we carried out an energy requirement assessment. Our evaluation showed that the disposable process (including gamma irradiation, sterilization, manufacturing of tubing, and so on) decreases energy requirements by 35 to 45% compared with a traditional stainless-steel process (Figure 2).

Figure 2. Comparison of the energy requirements for a stainless-steel process to a disposables-based process.

The question of disposable waste is more complex, particularly when you look at the available options. Recycling is not really feasible. It requires waste segregation and sometimes specific treatment. Landfill, although low cost, has a potentially high impact on the environment in terms of noise, odor, and visual aspect. Incineration without energy recovery is better than landfill; modern incinerators allow for carbon dioxide capture. We use incineration.

Process Robustness. There is improved process robustness when disposable closed systems are implemented for sampling, decontamination, and waste elimination. This improved process robustness results in better regulatory compliance and significant time and money savings. These savings apply both to existing facilities for cGMP manufacturing and for new facilities.

SUMMARY

As part of the Sanofi Pasteur Knowledge & Innovation for Technology Excellence (KITE) initiative, we have been able to demonstrate the feasibility of large-scale Vero cell culture in disposable bioreactors up to the 500-L scale. This included successful integration of the disposable process from seed to large-scale cell expansion and infection, including cell thawing and expansion directly in the disposable Nucleo 20 (a closed system for sampling, decontamination, and waste elimination) up to a 500-L working volume. Good virus yield and productivity were obtained in 20-, 200-, and 500-L scale disposable bioreactors.

By using a validated BioSolve process modeling platform, we were able to identify where significant time and money savings could be achieved by implementing disposables. Sanofi intends to continue the scale-up program and will move to disposable industrial integration wherever disposables demonstrate benefits in line with the criteria defined in the KITE program. In the future, based on KITE program criteria, Sanofi Pasteur will in some cases consider hybrid processes involving a mixture of stainless steel and disposable technologies to solve ergonomic and large equipment decontamination issues.

ACKNOWLEDGEMENTS

We would like to thank our colleagues who participated actively in the KITE disposables initiative and helped prepare the scale-up case study.

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.