PAT – a dynamic approach for greater ROI

19 June 2012

Suzanne Gill speaks to a systems integrator that specialises in using techniques such as process analytical technology (PAT) to ensure that product processes remain at the highest level of efficiency. PAT requires the implementation of a more dynamic approach to manufacture, with a move away from fixed process batch manufacturing.

Traditionally, life science and many pharmaceutical processes have been validated on a three-batch principle with the product continuing to be produced to the same rigid fixed batch process, with product testing being undertaken at the end of multiple unit operations and every batch.

However, this can result in extended production cycle times and unnecessary product wastage. Any process where the raw materials have natural variability, will result in varying product quality when the same fixed control approach is employed for every batch. The introduction of the FDA guidance on PAT in 2004 encouraged a new approach embracing innovation based on sound science whilst identifying a regulatory pathway.

The FDA guidance in 2011 on process validation further promoted the need for process understanding, using PAT-based methodology to replace the traditional three-batch validation principle. PAT has, broadly, been defined by the FDA as a mechanism to design, analyse, and control processes through the measurement and control of critical quality attributes via the control of material and process parameters that affect these parameters.

Martin Gadsby is a director of Optimal Industrial Automation, a systems integrator which specialises in automating manufacturing systems for the food, chemical and life science industries to ensure that production processes remain at their highest levels of efficiency. He suggests that the use of process analytical technology (PAT) can offer some impressive cost and time savings for the manufacturer.

“PAT is all about measuring and controlling the critical quality attributes of the product” said Gadsby. “There are certain parameters within a pharmaceutical product, for example, that are critical to the efficacy of the end product. PAT allows for these product attributes to be measured and controlled in real-time, in-line or at-line. This is very different to the traditional approach of controlling process parameters in a pre-set, prescribed way.”

The technology invariably uses a variety of complex instruments which usen on destructive techniques to measure product parameters. Technologies including (but not limited to) near-infrared, mid infrared and Raman spectroscopy are used to provide spectral data which can then be run through a multi-variate analysis (MVA) process model to produce the vital data on the critical quality attribute product data. Armed with this data and together with true process understanding the process parameters can be controlled to optimise these product parameters.

Gadsby went on to explain why there is an increasing interest in PAT: “The regulations currently are driving the need for science based process understanding. The FDA requires that in the first place the critical quality attributes of a process are identified and then measured in real-time. With this capability enabled it is then possible to execute experiments to see how these attributes change when the raw material and process input parameters are changed. This gives you process understanding, or mechanistic knowledge, leading to an understanding of how to build the control model. With the control model implemented you are able, in real-time, to drive the process to optimise the critical quality attributes. PAT is all about measuring the product attributes and enabling process parameters to be changed automatically in real-time to ensure consistent quality of the end-product. Armed with your process knowledge, process (MVA) models and control models thenby using PAT it is possible to migrate your batch process into a continuous process which is able to provide orders of magnitude cost benefits.”

“The holy-grail is that, at the end of each unit operation and at the end of the batch it will not be necessary to carry out off-line quality tests because product quality has been monitored, controlled and assured throughout the process. The real-time release of product has huge financial benefits to clients in terms of significantly reduced cycle times (from weeks to hours) plus the very substantial reduction in work in progress.”

“Whilst PAT can be deployed on existing processes, the biggest gains can normally be achieved by employing PAT early on in the development stages of a new product, following it from the very beginning of its lifecycle through to full production. In this way the full benefits of PAT can be gained in all stages of development and production.”

“If you use PAT at the development stage then the scale up times can be reduced. Traditionally, the period of transition from pilot scale to full scale can be problematic. By using PAT and developing your process models, process understanding and control models early on in the product’s life cycle then the timescale for transition can be cut from many months to a few days or weeks. This is a huge benefit to clients as the financial implications of maximising the product’s patent life cannot be overstated.”

This can only be good news for the industry as whilst quality remains an extremely important reason for employing PAT, return on investment (ROI) has taken over as a key technology driver today.“PAT can offer big financial savings potential,” said Gadsby. “Successful implementation results in faster products to market, less product wastage and faster production cycle times. An often overlooked saving, however comes from the reduction in work-in-progress which can be huge.”

PAT developments
Data management is currently one of the biggest areas of PAT development. Gadsby said: “Today it is possible to co-ordinate instruments, MVA packages and control packages. Good data management is vital to ensure the huge amounts of data being gathered from multiple instruments at different rates is achieved in a timely way. It is important to have a software system that is able to synchronise all the datasets to ensure the data going into the model is valid - with all of this being carried out in a regulatory compliant way.

Another area of development is in relation to the instruments. Manufacturers are developing instruments more suitable for the production environment than just the laboratory whilst trying to manufacture them in increasingly cost-effective ways.

However, the main barrier to implementation and development of PAT is one of culture, rather than technology and a successful project will require a significant cultural change within an organisation regarding the way the product is produced. The culture is however slowly changing as it is recognised that the industry has to embrace PAT if it is to thrive.

Applying PAT
It is best to apply PAT as early as possible in the development process of a new product. This will provide the scale-up benefits mentioned previously as well as all the other quality and return on investment benefits, throughout the product’s lifecycle. It is important to engage with the regulator or engage a suitable a consultant to help do this, to ensure that the correct pathway is followed in the very beginning of the project.

It is important to accurately document the process and to use a scientific approach. “PAT should embrace continuous improvement of the process. By definition from day one the model will not be perfect,” said Gadsby. “However, it is important that, when the model is fit for purpose – when you can produce product which meets your specification – then begin to use it, to ensure you get the maximised return on investment. Models can then be optimised over time using the continuous improvement approach.”

Gadsby concludes by advising that potential PAT users first pick a project that is not overly complicated so that it can be deployed in a timely way. Although the financial gains of this initial project may only be modest it will allow you to gain vital experience of using and applying PAT. “A timely deployment will assist in gaining management approval of using PAT and gives them the confidence that the technology works. It will demonstrate to them that the technology can bring a good level of return on investment, ensuring that further investment will be available for future projects.”

In a recent project undertaken by Optimal Industrial Automation for a pharmaceutical manufacturer, the company’s synTQPAT data management system was used in combination with a third-party MVA product and a near-infrared instrument.

Through a process of building process models, and gaining process understanding the client was able to determine – in real-time – the drying phases that occurred in the drier. It was then possible, by means of the orchestrations (PAT methods) within synTQ, together with a third-party control system and the OPC connection from synTQ, to design an application that controlled the dryer parameters in-line with the stage of the process, as determined by synTQ, and to introduce real-time dryer end-point control. The system has proved to be very successful, and has delivered a short payback time, helping the company to maximise ROI.

Having started with a simple project that proved the worth of PAT, the pharmaceutical company has succeeding in gaining valuable PAT deployment experience and skills, and has proven that the technology works and can deliver very real benefits. The company now intends to optimise other aspects of its processes using PAT.

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