Kenneth S. Kovacs

Many companies are adopting or extending PAT solutions to achieve product innovation and process improvements through engineering development and manufacturing performance. Typically, quality units Quality Assurance or Quality Control operate within budgets representing 20–30% of manufacturing costs, but industry statistics indicate that adopting PAT could reduce this figure to <5%. Simultaneously, PAT could enhance product yields, enable faster product timetomarket, and improve operational performance by increasing plant and process line key performance indicators (KPIs). 

(GEORGE DOYLE & CIARAN GRIFFIN/GETTY IMAGES) 			

Employing the PAT principle of having a scientific understanding of how critical process parameters impact product quality attributes is fundamental to drive operational excellence programmes and lower the risk, as well as cost, of manufacturing. Despite these benefits, many companies are concerned about embracing PAT solutions for all aspects of the drug life cycle because of the potential risks at the different levels:  					

Supply chain and business level — risks include excessive raw material inventory acquisition, storage or usage, throughput and product delivery time, and loss of product quality excellence. 

Programme or project activities at midmanagement level — risks revolve around organizations because new cross-functional teams must be created, which could diminish other activities and cause personal relocation or dislocation. 

Project or plant level — risks include developing new complex process development techniques, operator training and capability enhancement.

Operational excellence enables an organization to manufacture products to exact quality specifications in the shortest period of time, consume the least amount of resources possible, address regulatory requirements and satisfy customer demand. Goals will vary for each company depending on operating constraints, but referencing 'world class' benchmarks can provide insight as to what is possible. 

Business level risks may cause companies to struggle in finding the best way to utilize PAT. A company may not have a clear manufacturing technology strategy or may possess a 'wait and see' attitude regarding PAT, or adopting PAT may involve undefined expenses. Management may also consider PAT initiatives as labour reduction exercises, which are counterproductive at all levels in the organization as labour reduction in terms of rationalization or downsizing may be perceived as a large risk by personnel. Additionally, PAT can cause a paradigm shift in an unprepared business. New personal skills and capabilities may be required to support Quality by Design (QbD) for new products or building quality into the manufacture of existing important drugs.  

Organizations must be willing to make appropriate changes to benefit from utilizing PAT in any of the three areas presented by FDA:

Designing quality into the processes for existing products.

Maintaining cGMP operations throughout the manufacturing floor.

What are the risk factors at each of the operational management levels? 

Global competition, rising costs, timetomarket constraints, governmental regulations, political pressures and supply chain management are driving companies to develop new products to meet market needs, and ensure product quality and patient safety, while also increasing shareholder value. Today's businesses require: 					

Comprehensive understanding of process and product quality relationships.

Costeffective process solutions investments.

Implementing PAT programmes into process facilities can be challenging and may pose a risk to the business. Because new processes change the way operations are performed, there is an associated risk to product quality and regulatory compliance. Implementing the proposed changes may, therefore, be met with some reluctance. Additionally, each business must keep existing operations running, continue to manufacture quality products and allocate resources for future projects. By considering the risks and benefits associated with their vision for a 'desired state', a comprehensive plan can manage risk during PAT project implementation, and utilize company resources effectively and efficiently. 

With operating efficiencies increasingly dependent on 'right first time', there is a need to change the 

 in the way processes are controlled. These changes impact product life cycle management, resulting in a risk to operations and overall organization. 

PAT programmes can help companies achieve their desired state, address today's business requirements and mitigate business risks. As described in FDA guidance,

  PAT must be based on a scientific understanding of how development formulations and manufacturing process factors impact product performance and quality attributes. Understanding the relationship between these concepts is essential in applying PAT during the entire product life cycle (Figure 1). 

PAT methods should be identified that analyse parameters or variables that control critical process parameters through defined process models and produce specified product quality characteristics with continuous verification. PAT is both strategic and tactical: strategic in that it establishes plans to achieve company goals, and tactical in that it defines specific projects that are aligned with strategic plans. 

Implementation and automation solutions may be defined through an applied systems development life cycle (SDLC) that: 					

Assures organizational buyin at senior management level.

Involves multidiscipline teams, such as R&D, process engineering, quality, operations and maintenance.

Engages stateoftheart applications, including multivariate analysis, design of experiments (DoE), predictor–corrector algorithms and advanced process controls. 

Creates offline research systems for process development.

Is scalable from pilot projects to manufacturing and the enterprise. 

Integrates into online systems for process/production line control.

Is compatible with company IT infrastructure, network and data storage.

Communicates with applicable governmental agencies such as FDA and EMEA.

Continues to consider all relevant governmental agency regulations and guidance, particularly for making and reporting manufacturing changes.

Provides for continuous quality improvement in the product life cycle. 

Through multivariate analysis in R&D, a correlation between critical process parameters and product quality attributes can be established. This type of analytical approach is a basis for identifying parameters that should be controlled through scientific understanding of what factors contribute to product quality. In turn, the performance of DoE in R&D can be implemented to optimize equipment setup and operation before transferring processes to manufacturing. These activities foster an environment for producing product QbD that reduces startup time and inprocess development to drive operational excellence directly through R&D endeavours. 

This is a means for applying knowledgeable change to increase right-first-time performance indicators. Incremental process improvements to existing process automation and control systems, such as closed loop predictor–corrector algorithms, can be implemented as they are identified. This approach provides an opportunity to analyse processes and implement applicable PAT methods. 

Managing the risks associated with PAT initiatives provides a framework to drive operation excellence through a scientific understanding of critical process parameters as they relate to, and influence, product quality attributes. In addition, properly applied PAT will mitigate the risk associated with regulatory compliance and meet business objectives (Table 1). 

Table 1: Potential benefits of PAT initiatives.			

 Once a company is committed to using PAT, a programme or project must be initiated. Unfortunately, there are PAT projects that have been started without reaching their full potential as there was no real cohesive business strategy for implementing them. When executing the planning phase, the risks in the project preparation phase, as well as in future development phases, must be recognized. 

It is important to build a crossfunctional team with executive sponsorship. The executive sponsor should also be the project champion. Without the commitment and active participation of the sponsor, the project has a high risk of failing.  

The project team will need to identify the control system that will be the foundation of the process line. IT systems that can integrate the company's process systems, databases of historical data and other information generated by PAT technology should also be identified. The resulting planning, implementation and management will extend during the life of the project, and different groups will take the lead role throughout the various phases of SDLC for the product, process or both. Losing project sponsorship could lead to a lack of focus, resulting in inefficient resource or higher funding requirements. 

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Operational excellence awaits, but only if you can implement PAT successfully.