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Pharmaceutical Manufacturing and Packing Sourcer

The Ingredients for Business Success

Dean Chespy at Siemens Industry Automation examines PAT and the wide-ranging benefits it can harness in the pharmaceutical manufacturing process

Regulatory and competitive pressures, product diversification, social change and operational efficiencies of manufacturing processes are some of the key market drivers forcing pharmaceutical manufacturing companies to take a fresh look at how technology can deliver value to their business and help secure their long-term future. Process analytical technology (PAT) has been positioned as a critical tool to help support key objectives to meet such issues, and ultimately deliver measureable benefit in crucial areas, ranging from optimising production performance, reduced time to market and, importantly, ensuring patient safety through consistent product quality.

It is time for the pharmaceutical industry to get on the front foot and follow the example of other manufacturing industries, such as the automotive and electronics sectors, and to take action today that will help secure their tomorrow. Pharma must act, as the companies that are able to gain a better understanding and process insight will be the ones who will survive in a fast growing and competitive market.

The pharmaceutical manufacturing industry, while largely perceived by the outside world as cutting edge, lags behind other sectors when it comes to embracing the technological benefits that are available in order to drive manufacturing processes, quality control and basic process understanding. As mentioned, both the automotive and electronics sectors with their respective adoption of lean manufacturing techniques and advanced technologies have witnessed massive improvements in the operational efficiencies of their processes over a number of years.

Although the pharmaceutical industry is taking a greater interest in the ‘inefficiency’ of its operations, it is still largely behind the curve, restricted in many cases by a desire not to change its culture, incumbent legacy production systems, as well as being tied to heavily regulated processes and procedures that are in place to ensure patient safety.

Whether it is a batch or continuous manufacturing process, the pharmaceutical sector seeks the benefits of a Lean/Six Sigma manufacturing approach, but it has been slow to adopt the technology available that will help and optimise key areas such as production performance and the delivery of consistent product quality; in summary, operational excellence.

Market pressures ranging from regulatory scrutiny, global manufacturing competition, product diversification, demographic changes and economic issues are now forcing a re-assessment of what the next steps should be, in terms of how manufacturing and production solutions can help meet such demanding market drivers. Such a re-assessment is particularly applicable to major pharmaceutical manufacturers with expiring patents on the horizon that are also facing low pipelines, high development costs and the delivery of new drugs to market. It also applies to drug manufacturing companies reliant on providing generic products to the market at extremely competitive prices, and where any undue costs, because of product waste issues, energy consumption and production downtime, can severely affect the bottom line. S

ince the middle of the last decade, the US FDA – with the launch of a new cGMP initiative – set the guidelines that have provided the pharmaceutical industry the opportunity and the parameters to take a more risk-based analytical approach to its manufacturing and processing commitments, under the auspices of PAT.

In general, the industry has been slow to react to this lead and adopt the core principles of PAT, which has, at its heart, the goal of understanding product performance in process. Indeed, the following definition explains it well. ‘A process is well understood when all critical sources of variability are identified and explained; when variability in the process is managed by process controls that deliver a consistent process output; and when product quality attributes can be accurately and reliably predicted’ (1).

For companies that have adopted PAT, it has proven to be an advantageous strategic move. Manufacturers, large or small, are in a far better position to ask questions of their production processes, optimise plant efficiencies and improve product quality, thanks to the adoption of PAT. Their return on investment has been justified through an increase in plant availability and a reduction in the energy demand for the same capacity schedule. T

his has been achieved by reducing manufacturing cycle times and the reduction of cleaning/changeover cycles, which is critical to the operational efficiency of the process when producing a wide portfolio of products and short batch runs. The increase in available plant time provides the opportunity to adhere to a preventive and respond to a predictive maintenance schedule.

Businesses that have taken this on board have come to realise that implementing PAT within an integrated automated manufacturing platform has provided them with the ability to reduce waste and costs by making faster, better informed process control decisions, and being able to automatically control the process based on a real understanding of what is happening in it. In principle, getting it right first time has had a direct result in the overall increase in productivity and reduction in time-to-market.

WHAT IS PAT?

So what is PAT and how can it seek to support the key manufacturing performance objectives for pharmaceutical companies?

Within an overarching philosophy centred on ‘process understanding’, with a tool such as PAT, quality becomes an element that is designed into the manufacturing process, rather than checked afterwards. Introducing PAT has a positive effect on production costs, helps speed up decisions on the unit operation level and improves the quality and efficiency of process steps. This leads to shorter batch runs and increased quality consistency which can result in eventual real-time product release.

In accordance with the FDA’s guidelines on PAT, it is defined as ‘a system for designing, analysing and controlling manufacturing through timely measurements of critical quality and performance attributes of raw and inprocess materials and processes with the goal of ensuring final product quality’ (2).

New production methods and the ongoing demand for shorter time-tomarket are creating a need for a faster and more complete understanding of the processes involved. This increased emphasis on production efficiency also requires increased real-time process information and visualisation. PAT drives stricter control of operational conditions throughout the process as it is capable of being achieved through advanced sensor technologies and new techniques that can handle a wider range of process parameters, all linked into overall plant automation. It is also important to note that the analytical term within PAT is viewed broadly, to include chemical, physical, microbiological and mathematical and risk analysis conducted in an integrated manner.

A common mistake is to view PAT too narrowly and base its use upon current validation and quality control through a focus on, for example, a sensor and what it can measure, as opposed to the wider quest of process understanding that can help determine the choice of technology and design of the process system in question. As the FDA says, “PAT is not about just throwing in-line sensors at a production line. It is more about understanding the sources of product variability during production and controlling your processes in a flexible way to allow you always to produce a quality product” (3).

The impetus for PAT lies within an initiative that the FDA took back in 2004 based upon a realisation that regulatory barriers had inhibited pharmaceutical manufacturers from adopting state-of-the- art manufacturing practices. The modernising of the regulations was based on a new risk-based approach to manufacturing practices which sought to allow companies to implement continuous improvement with the aim of lowering production costs. The premise is that if manufacturers demonstrate that they understand their processes, they will reduce the risk of producing poor quality products. Essentially, they can now implement improvements within the boundaries of their knowledge without the need for an overbearing regulatory review.

THE BENEFITS OF PAT

While a lighter regulatory framework is beneficial, real competitive advantage is the achievable goal through PAT. Typically, therapeutic drug performance analysis cannot be evaluated online. This limits the possibility of controlling and optimising processes due to the relatively long time required for laboratory analysis prior to release. PAT closes the information gap using in-process data and data analysis tools that improve process understanding and control. This ensures quality and reduces the risk of bringing non-compliant products to the market. It is about getting it right first time, every time.

For existing production processes, PAT adoption and implementation tend to be seen in terms of reduced cost, lower inventory levels and a move towards ‘just in time’ production and supply. For new processes, the benefit of PAT is the ability to quickly develop the manufacturing process, upscale to a robust process and perform validation more easily.

EVALUATING PAT

The pharmaceutical industry is battling on many fronts: drug development pipelines are under pressure, pricing is being squeezed and generic competition is intense. To ensure that PAT implementation truly matches the goals that an individual company wishes to achieve will depend on the particular strategic vision each company has.

Nonetheless, from a clear starting point based on business objectives concerning current manufacturing processes and future strategy, PAT can fix or improve existing processes, speed new product development, reduce site to site transfer risk and times, reduce validation costs and, through the reliable quality of its products, enhance a company’s reputation. In addition, at the end of a drug’s life cycle, PAT can help prolong patent life through the development of new formulations. Most companies will seek a blend of these benefits and particular circumstances will dictate priority areas.

THE PAT TOOLBOX

The objectice of PAT is to develop process understanding. In order to identify sources of process variability, companies need to be able to integrate information ranging from raw material and intermediate measurements to processing and environmental data. There is often a mix of real-time measurements, both univariate (temperature, pressure and PH) and multivariate (NIR or other spectroscopic methods) sampled during processing, as well as static data sampled from raw materials, intermediaries and finished product.

The greatest hurdles involved in all analysis are the generation, integration, organisation and visualisation of data. PAT encourages translation from the definition of a critical product specification (usually tested afterwards in the laboratory) into critical process specifications that can define the parameters necessary to keep the process under control. A number of tools in the PAT ‘toolbox’ will contribute to this, varying from multivariate tools, process analysers, process control tools and continuous improvement and knowledge management tools, all synchronised in a real-time architecture.

The benefits of PAT for pharmaceutical manufacturers are real, measurable and tangible. Early adopters are already enjoying significant competitive advantages, but many companies, despite assessments, have yet to fully commit to the thorough understanding of their processes that PAT actively delivers. While burdened by growing market and regulatory pressures, companies are slow to adapt, perhaps as a result of legacy issues surrounding processing traditions, and as such they are being left behind when it comes to seeking solutions to the competitive, legislative and manufacturing problems they now face.

PAT supports all of these issues by delivering a position of understanding and knowledge from which strategic and tactical process performance decisions can be made, as well as seeking to optimise existing investments. At its best – part of a totally integrated automation (TIA) manufacturing platform – PAT provides the information and performance infrastructure that should sit at the very centre of any pharmaceutical manufacturing operation. It is only from such a position that the successful pharmaceutical manufacturing companies of the future will thrive. Can your company really afford not to embrace such a possibility?

References

  1. Siemens white paper – SIPAT the software heart of PAT, March 2010
  2. US FDA Guidance for Industry PAT – A framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance, September 2004
  3. Economist Intelligence Unit, Quality manufacturing: a blockbuster opportunity for pharmaceuticals, September 2005

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Dean Chespy studied electrical and electronic engineering, and has an accomplished background with over 30 years in the electronics and pharmaceutical manufacturing industries. Having held senior engineering, advanced manufacturing and project management positions, his experience specialises in the implementation and use of automated high-technology solutions and advanced production methodologies. He has a proven track record in manufacturing excellence and the continuous improvement of a production company’s bottom-line results. As Siemens UK Life Sciences Development Manager, Dean’s role involves the co-ordination of a wide range of Siemens businesses that offer a value proposition through their cross-business solutions specific to the UK pharmaceutical and life science industry.
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