Few industrial sectors face the challenges of pharmaceutical manufacturing. The necessity of stringent regulation and validation procedures are contrary to the market needs of shorter campaign runs of specialist drugs and the greater flexibility within the manufacturing environment to support them.
That necessity, though, leads to innovation; and, at the manufacturing level, it makes our industry a hotbed for Industry 4.0 technologies that can offer new solutions to old problems. And it’s the application of Industry 4.0 technology that makes the case for single-use facilities in drug manufacture more appealing than ever before.
The rise of single-use
Single-use (SU) facilities present a dramatic step away from traditional manufacturing plant. In the past, biopharmaceutical manufacturers produced in commercial-scale facilities using large stainless-steel bioreactors. Single-use facilities are far more agile in nature, focusing on the production of small batches of highly personalised medicines.
They utilise mobile equipment and disposables to allow for manufacturing to be reconfigured quickly — as often needed to meet the challenges of a highly flexible manufacturing environment. There are lower staffing requirements in these facilities owing to less maintenance, cleaning and validation.
For manufacturers, these facilities can present a number of key benefits. In terms of set up, the building has a much smaller footprint, offering heavily reduced capital costs. Apart from reduced square meterage, there is less equipment required for clean-in-place (CIP) and sterilise-in-place (SIP) procedures and generation of purified water for cleaning.
Although a large-scale, traditional, biotech greenfield facility might cost between US$500 million to $1 billion to build and get into production, a single-use alternative typically ranges from $80–200 million. The start-up time is also far lower for a single-use facility. Less equipment means, less installation work and no cleaning and/or sterilisation to qualify.
This level of efficiency also remains when the facility is up and running, with far less downtime between batches or runs. In a traditional stainless-steel reactor, you would expect to need at least two days for cleaning and sterilisation. However, a single-use reactor bag can be changed in less than four hours.
This can lead to a strong increase in throughput. The use of disposables not only drastically reduces the time and cost spent on cleaning and sterilisation, it also offers additional operational savings by using less chemicals, less water and less energy.
The challenges of single-use
There are, however, significant challenges to overcome to reap such benefits. The consumables themselves are not cheap and a lack of standardisation and regulation means that materials and hose connections vary from OEM to OEM, making the integration of systems from different vendors difficult.
At scale, the mobility of single-use equipment is an issue – when you get to 500 L capacity, it is difficult to move equipment by hand, and reconfiguring a production line relies on human input — a backwards step in automation terms that carries inherent risk as engineers try to follow paper-based instructions for the myriad connections and decisions required to configure up to 100 different pieces of equipment.
In fact, in any one batch, an operator may be required to make up to 900 individual connections; and, even if they get this 99% right, that still leaves nine errors — any one of which may cause a batch to fail. At present, operators generally follow a paper-based set of instructions detailing each of these connections with the onus on the operator to get it right.
In parallel, they need to record the SU components used in the batch, which will then become part of the batch record for regulatory purposes further down the supply chain. As these single use tubes and connectors do not lend themselves to being instrumented, it is currently impossible to verify that the operator has correctly understood and followed the work instruction.
The innovative technology solution
To guide the operator through the connection of single-use facilities, augmented reality (AR) provides the opportunity to use graphical aids to help operators visualise the work instructions required. To aid the operator, each connection point can be numerically identified and illuminated when connections are required.
Once the operator makes the connection and verifies it, the line becomes visible. Once all connections are verified, the prompt allowing the sequence to progress is enabled. Verification that tube connections are made and the recording of SU tube details can be completed either by scanning barcodes on the tubes or by manual entry; this then becomes part of the batch record.
This information can also be used as a cross-check to verify that the correct SU tubes are being used and to manage SU consumables by interfacing with the warehouse management system.
These simple tweaks to the way a manual operator works could have positive results on their error rates. However, in an effort to find a solution that could drastically reduce errors, Industry 4.0 can help further.
The latest innovation available uses both augmented reality and smart glass technology. Operators in the “facility of the future” are provided with smart glasses that use AR to overlay the single-use tubing connections in their field of vision. So, instead of looking at a work instruction and trying to determine connection points, these would now illuminate as the operator looks at the equipment through the glasses.
The software also verifies that the tubing connections are correct prior to allowing the system move to the next step.
Smart glasses also allow the operator to dynamically follow the process and interact with it using voice commands and gestures.
This substantially reduces the opportunity for error as operators can clearly see how different single-use technology should connect. The smart glass technology can also take a picture when an operator makes a connection and append this to the batch report, increasing compliance.
Integrating location-sensing technology can also allow for relevant content to be shown to operators depending on their position in the facility. This could include video training or visualisations to help them set up and operate the facility. The experience of senior operators can also be applied across a number of locations with this technology.
By using the smart glasses, there can be collaboration between junior and senior engineers or even OEM vendors operating remotely. The smart glasses can offer a clear window into what an operator is seeing and has the ability to remotely guide an operator to the correct task, offsetting some of the current skills availability challenges.
This type of technology has already been successfully operated in the airline industry, whereby maintenance expertise has struggled to meet the demands of growing global airlines. To address the sharp skills gap, the airline sector invested in augmented and virtual reality technology to help guide their technicians and engineers to find and resolve faults. This is a good example of how we can transfer an innovation from a non-pharma industry and effectively leverage that concept into single-use facilities.
Conclusion: time for a new solution
As pharmaceutical manufacturing moves away from stainless steel, fixed-in-place equipment to flexible, mobile, single-use technology, a number of challenges associated with how these facilities are operated and controlled will emerge.
As operators become more involved in the set-up of what could be frequently changing processes, it is important that we take advantage of technology to help guide the operator through the implementation and operation of such a facility and minimise the potential for error.
To achieve this, it is vital that mobile, single-use skids can be networked and communicate with each other, and with centralised process control and MES systems, and don’t operate as standalone units. Similarly, by using technology, we can build intelligence into devices such as totes and use this intelligence to track their positions and contents.
Through this networking of devices and sharing of data, we can then ensure the operator has the right information available at the right time to make the right decisions with the overall aim of ensuring that the automation concept enhances the overall objectives of the facility if the future.
As we operate in a heavily validated industry, we see how manufacturers can face huge challenges in the adoption of new technologies. However, when there is the opportunity to reduce risk, improve quality and accelerate time to market, an innovative approach that uses the very latest industry 4.0 approaches can offer an important solution.
