Disposable bioreactors are a new technology in the biotechnology field. To evaluate potential risks associated with implementing
this new technology in future manufacturing processes, risk assessments based on the FMEA methodology were performed. The
main risk assessments performed were related to the two critical risks: assurance of supply, and biosafety, a risk specific
to viral vaccine applications. The biosafety risk assessment will be used as an example.
Biosafety is one of the main concerns of viral vaccine production, especially when biosafety level 2 and 3 viruses must be
produced at large scale. One concept of biosafety is that the equipment itself is considered the first barrier to isolate
the pathogenic micro-organism from the environment. The second barrier is the room where the equipment is located. The move
from stainless steel to disposable equipment has weakened the first barrier. The main problem in terms of biosafety is the
loss of integrity of the disposable bag leading to a leak of the viral contaminant, and potentially operator contamination.
To identify all potential root causes for the loss of integrity of the disposable bioreactor, a risk assessment was conducted.
Risks were scored according to four criteria, each scaled from 1 to 3: impact, occurrence, detection, and action response
time. A risk priority number (RPN) was calculated as the multiplication of these four criteria. Based on the associated RPN,
risks were classified as follows:
- 1 to 3 RPN: low risk
- 4 to 6 RPN from: medium risk
- >7 RPN: high risk.
Figure 7 gives a summary of the risks identified associated with their respective RPN. Based on this risk assessment, a set
of corrective actions were defined. The following gives examples of improvements made to the systems to mitigate potential
- automation, aeration, and pump stops when an overpressure is detected
- external protection was developed to avoid liquid projections in case of leak and to avoid contact with cutting objects
- a retention vessel will be part of the system skid to keep the liquid contained in case of spill
- integrity testing of the disposable bag is under development using pressure to detect bag defaults.
Implementing all of the corrective actions identified in the risk assessment will help secure the disposable system for manufacturing
Figure 7. Summary of biosafety risk assessment and associated risk priority numbers
Cost of Goods
Most of the studies performed today are in favor of disposable implementation from a cost perspective. Despite this, two scenarios
should be considered in which the effect of disposable use on cost can be significantly different.
- Introducing disposables to an existing process in an existing facility.
- Introducing disposables to a new facility.
In the first scenario (existing facility), the effect of disposables may be marginal and can sometimes even result in increased
cost of goods. The reason is that savings linked to disposable implementation are minimized because operating costs are fixed.
Costs linked to full time employees will not be affected because production teams are in place. Building depreciation and
maintenance also will be equivalent.
In the second scenario (new facility), the effect of implementing disposables can be more significant if the new facility
is designed for using disposables. In this case, the facility footprint can be significantly reduced, utility sizing and distribution
can be minimized, and production headcount can be adjusted.
At GSK Biologicals, we decided to compare two greenfield manufacturing plants for viral bulk production, one using the old
process as a reference, the other one using a similar process but implementing disposable bioreactors along with other disposable
systems for media and buffer preparations and purification intermediates. It is important to mention that the manufacturing
scheduling was changed along with disposable bioreactor implementation. This point has a major effect on costs.
The model used to make this cost calculation was developed in-house and was validated on existing marketed vaccines. The first
component of the cost analysis was establishing a bill of material analysis. Regarding the new process, 50% of the raw material
cost was linked to the medium, ~25% was linked to micro-carriers, and the disposable bioreactor represents 6% of our raw material
The output of our model shows that 35% can be saved on facility investment, and the manufacturing headcount (production and
maintenance) can be reduced by 30%. If we consider the effect on total direct cost, 25% can be saved on the cost per dose
driven by saving on building depreciation and labor. As mentioned previously, a significant amount (~50%) of the savings are
linked to the optimization of manufacturing scheduling.
We demonstrated the feasibility to achieve equivalent process performance using the right disposable bioreactor systems compared
to stainless steel bioreactors, even in the case of challenging processes, such as the one described in this article.
Additionally, cost of goods analyses show a significant savings when disposable technologies are implemented in new facilities,
along with redesigning the manufacturing schedule.
Disposable bioreactors are an attractive technology for viral vaccine production if biosafety risk can be mitigated. One major
point is that supply assurance is still a major problem because back-up supply is difficult to establish because of the specificity
of these disposable bioreactors.
Jean-François Chaubard is a director, Sandrine Dessoy and Yves Ghislain are expert scientists, Benoit Barbier and Raphael Battisti are technicians, and Pascal Gerkens, PhD, and Ludovic Peeters are associate scientists, all at Viral Industrial Bulk, GSK Biologicals, Rixensart, Belgium, firstname.lastname@example.org