How industry 4.0 technologies could address some of the biggest risks in single use facilities

The growth of single use facilities

In the past decade, we’ve seen a paradigm shift in the nature of products being manufactured with a greater prevalence on:

• Large molecule drugs,
• Expansion in the number of personalized or targeted treatments, and,
• A rise in the number of treatments for orphan diseases.

This has not only been driven by clinical factors such as enhancements in cell & gene biology and more potent drugs but also by technological advances and competition.

With highly personalized treatments offering a potentially stronger return than traditional therapeutics, they are proving to be an attractive choice for Pharmaceutical R&D and manufacturing investments.

As many of these new drugs are targeted at niche markets, manufacturing needs can be met in smaller volumes which in turn is forcing biopharma companies to look at their manufacturing requirements and how best these can be satisfied in a new generation of facility. Some of these requirements include:

• Facilities that are multi product and can support more than one product at a time.
• The evaluation of disposable or single use technology versus stainless steel.
• Low volume flexibility of process equipment which leads to an evaluation of mobile process equipment versus hard piped equipment
• The reduction of the Cost of Goods from lower staffing requirements and the increased importance of flexibility from personnel.

These considerations coupled with a growing trend of locating smaller more agile facilities closer to customer markets is pushing manufactures towards facilities that make extensive use of mobile, single use equipment that can be easily reconfigured to support the manufacture of multiple products. Additionally manufacturers are looking for repeatable and scalable solutions that can be developed in one location and thereafter deployed in other locations minimizing capex and reducing time to market. This is what is known as a Facility of the Future.

There is also a growing focus on how the Internet of Things, or ‘Industry 4.0’, could further increase throughput, quality and competitiveness in the global manufacturing market.

Key benefits of single use facilities

Single use facilities present a dramatic step away from traditional manufacturing facilities. In the past, BioPharma manufacturers produced in large scale facilities, using large stainless steel bioreactors.

Single use facilities are far more agile in nature, focusing on small batch sizes of highly personalized medicine. They utilize mobile equipment and disposables to allow for manufacturing to be reconfigured quickly, as needed to meet the challenges of a highly flexible manufacturing environment. There are lower staffing requirements in these facilities due to less maintenance, less cleaning and less validation.

For manufacturers, these facilities can present a number of key benefits. In terms of set up, the facility has a much smaller building footprint so offer a heavily reduced capital costs. Apart from reduced square meterage there is less equipment specifically associated with CIP, SIP and generation of PW for cleaning. While a large scale, traditional, biotech greenfield facility might cost between $500 million to $1 billion to build and get into production, a single use facilities typically ranges from $80 million to $200 million. The startup time is also far lower for a single use facility. Less equipment means, less installation work and no cleaning & sterilization to qualify.

This level of efficiency also carries over when the facility is up and running, with far less down time between batches or runs. In a traditional stainless steel reactor, you would expect at least two days needed for cleaning and sterilization. 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 sterilization, it also offers additional operational savings by using less chemicals, less water and less energy.

What is holding back adoption?

However, these facilities do not operate without challenges. Single use technology does present cost benefits, but the consumables themselves are not cheap. They can retail from $10,000 to $25,000 per item, with a large number needed in the manufacturing process. Availability can also be a challenge, especially in the downstream area. For example, chromatography is a key area where there isn’t much availability in equipment.

The absence of standardization and regulation around SU material composition and hose connections in the disposable space. Currently, purchasing the same equipment from two different OEM vendors could leave you with two significantly different products. This can be cost prohibitive as you may be locked into a single vendor for all disposables. It also creates difficulty in the Integration of systems from different vendors into a single process train.

An additional dilemma is that of mobility. Although the equipment is mobile and on wheels, when it reached the 500 liter capacity it is difficult to move equipment by hand. While there may be more flexibility in how to arrange the single use production process, it can be a challenge to reconfigure the production line by hand in an efficient way.

The typical Single Use facility relies on the operator to correctly select and dock the right Single Use equipment and then interconnect this equipment using SU tubing. Any errors or omissions with these connections may cause the batch to fail.

Is human error now the biggest risk to facilities?

Beyond the above issues, in regards to single use facilities, there is one core challenge; the high risk for human error.

By their very nature Single Use facilities take a regressive step in terms of automation. Currently many SU facilities make use of low level of automation and are dependent on the operator following paper based instructions to walk through each step of the process - this can be onerous bearing in mind the myriad of decisions and connections that need to be made in any one batch. In a facility, there may be up to 100 different mobile equipment items in use. These must be consistently set up in the correct way to avoid issues.

As I previously mentioned operation of the Facility of the future varies greatly from a hard piped stainless steel facility. Not only because it makes extensive use of mobile equipment but also because it relies on single use tubing to connect mobile equipment.

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 9 errors – any one of which may cause a batch to fail. At present operator generally follow a paper based work instruction 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. 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.

Rockwell Automation's augmented reality solution 

It order to guide the operator through the connection of these single use tubes Rockwell Automation have developed solutions that use graphical aids to help operators visualize the work instruction . To aid the operator each connection point is numerically identified and illuminates 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 recording of SU tube details can either be by scanning barcode on the tubes or manual entry - this then becomes part of the batch record. This information could also be used as a cross checked 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 can have positive results on their error rates. However, in an effort to find a solution that could drastically reduce errors, Rockwell has been exploring how technology, in particular ‘Industry 4.0’, could help.

Rockwell’s latest innovation, developed from a partnership with PTC, utilizes both augmented reality and smart glass technology. Operators in the Facility of the Future are provided with smart glasses which use Augmented Reality 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 looked 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 would 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 visualizations to help them set up and operate the facility.

The experience of senior operators can also be utilized across a number of locations. By using the smart glass technology, there can be collaboration between junior and senior engineers or even OEM vendors operating remotely. The smart glass can offer a clear window into what an operator is seeing and has the ability to remotely guide an operator to the correct task can also be a tactic to bridge the skills gap.

This type of technology has already been successfully utilized in the airline industry, where 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 where we can see an innovation from one industry that can be effectively leveraged in single use facilities.

Time for a new solution

In conclusion as pharmaceutical manufacturing moves away from stainless steel, fixed in place equipment to flexible, mobile, single use technology a number of challenges around 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 set-up and operation of such a facility and minimize the potential for error. To achieve this it is vital that mobile single use skids can be networked and communicate with each other and centralized Process Control and MES systems and not operate as standalone units. Similarly by using technology we can build intelligence into dumb 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 manufacturers can be slower to adopt new technology. However, when there is the opportunity to reduce risk, improve quality and accelerate time to market, we are seeing a real appetite to utilize this new technology.