Managing the risks of PAT

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:¹

• Designing quality into new products.

• 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?

Mitigating risks

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:

• Consistent quality conformance.

• Increased manufacturing KPI performance.

• Reduced product timetomarket.

• Comprehensive understanding of process and product quality relationships.

• Dynamic product life cycle management.

• Costeffective process solutions investments.

• Ongoing regulatory compliance.

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

Knowledgeable change

PAT programmes can help companies achieve their desired state, address today's business requirements and mitigate business risks. As described in FDA guidance,¹ 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).

Figure 1

A conceptual approach

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.

• Ensures patient safety.

• 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.

• Is driven by financial justification.

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.

Continuous improvement. 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.

Savour the benefits. 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.

Programme and project risks

Risk of organizational change. 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.

It is also important that the team is empowered to work as an independent group with the backing of the sponsor. Technology selection and purchases will be needed as the project expands into a workable and promising system. The team needs to know that it can fail and pursue alternate paths if necessary.

Organizational dynamics. Implementing a PAT project may present different risks to different parts of the organization. Roles and responsibilities should be defined upfront and in detail so that everyone understands the team. This practice should continue as new members join the project.

One major issue that will be encountered is the perceived risks relating to organizational changes that could come into being as a result of project completion. A large portion of the quality organization's expenses are caused by a labcentric testing model, high workinprocess (WIP) levels and a manufacturing supply chain that is usually supply or schedule driven. By implementing PAT initiatives, the inprocess testing quality unit could be reduced by approximately 80%. This reduction presents a palpable risk to quality management, as well as the quality organization, and these concerns must be addressed quickly and decisively. Senior management may view executing PAT products as a head count reduction activity rather than enhancing operational excellence.

Implementing a manufacturing execution system (MES) or electronic batch record (EBR) technology as part of the project can reduce documentation issues that could impact the quality organization. If the project is successful, the review and approval of batches by exception adds further potential reductions. As parametric or near realtime release is an eventual goal of PAT, the quality unit may have a perceived or real higher risk unit rationalization.

Head count reduction risks can be mitigated by informing personnel that PAT is about increasing business performance and product quality. The quality unit will need to assume new responsibilities as they change roles to meet these new quality demands. Periodical briefing of all team members will assure them of their importance to the project's success. With all of the value and intellectual property (IP) contained within the team members, they should be viewed as key to the expanding business successes.

Execution risks. Highvisibility projects should have complete work breakdown structures with a detailed execution plan and schedule. These documents should be frequently updated as the project progresses. Project management is typically matrix driven, and all team members must understand how their skills and experiences fit into the overall project execution to recognize the important roles they play in project success. It should also be noted that delays can occur because of missing equipment; lack of available floor time because of operations; IT issues; and the unavailability of operators to run the production line for testing the PAT system. GMP requirements must be followed and there will typically be extra requirements for PAT installation.

Validation risks. Validating a PAT initiative may involve considerable risk. PAT initiatives often involve sophisticated systems with embedded methods and instrumentation, and multiple sensors that each have multiple methods. For example, feedforward/feedback loops could also have predictor–corrector algorithms that use advanced process control models and generate volumes of data for controls and multiple data streams. Additionally, the solution may contain historical process data, batch execution data, real-time data from sensors, and large networks with a high degree of automation. Developing the risk assessment and the associated risk scenarios is challenging.

Close communication with FDA is vital for the successful implementation of a PAT programme and may continue throughout the product life cycle. Implementation plans should be risk-based, but, where appropriate, FDA is proposing alternative implementation plans that include:

• PAT initiatives can be implemented under the facility's own quality system. cGMP inspections by the PAT team or PAT-certified Investigator can precede PAT implementation.

• A control, labelling or manufacturing changesbeingeffected (CBE) or priortoapproval supplement can be submitted to the agency prior to implementation and, if necessary, an inspection can be performed by a PAT team or PATcertified investigator before implementation.

• A comparability protocol can be submitted to the agency outlining PAT research, validation and implementation strategies and time lines. Following approval of this comparability protocol, one or a combination of the aforementioned regulatory pathways can be adopted for implementation.

Sometimes, once PAT initiatives are established, the method can be implemented into the production system without review by FDA. As part of the validation effort, the team will need to manage the change control process together with hardware and software configurations for product and processes. This can be done using integrated automation architectures, MES and electronic production records (EPR), such as EBR.

Risk assessments will be required to identify the systems and processes that need validating. Validation risks include qualifying the appropriate portions of applications, such as EPR systems, laboratory information management systems, supervisory control and data acquisition, batch recipes, and formulation systems with multivariate analyses and advanced control algorithms. The domain of all associated functions that must be validated can be large and complex, and it is advisable to begin by analysing individual functions in each domain to determine validation requirements. The risk assessment of each function will contain different risk scenarios that must be developed into qualification test protocols. This may involve creating different test methods for each aspect of the functional activity.

Applying a riskbased assessment methodology to quantify validation compliance ensures all system functions meet predetermined requirements, as well as promoting the efficient execution of the testing and verification process of related functions. This approach also ensures that risks are assessed on a comprehensive basis, with consideration given to overall risk to the patient by adopting a given PAT method.

Process development risks

One area of significant change for a PAT project that creates a number of risk elements is the role of process development. Table 2 describes some of the risks involved with the changes required for migrating from the current process development model to the desired state model.

Table 2: Changing model of process development.2

The present model represents a mature company, while the desired state model depicts a new and unique product development organization. In a process development environment, cost reductions are achieved through minor adaptations, process optimization, use of automation, investment in manufacturing and using lower cost or higher quality raw materials. Product designs are similar: a stable mature environment is present and labcentric testing is the common way for determining results.

For a new product PAT initiative, the process team could consider different delivery systems. Exploring and developing new process architectures required for new product designs necessitates a core development team comprising research, process development and quality. For a new product PAT initiative, the process development team will be making critical project decisions. Research will have to consult with process development for new process designs early in the drug development life cycle. A potential risk is the challenge to develop new skills in the development team, as well as acquiring adequate resources from different teams to maintain development schedules. Process developers will need to perform as peers with resources in product development. Figure 2 shows the changes in the organizational mix of skills necessary for a successful PAT project.

Figure 2

The new product development organization must be an integrated team of multitalented skills. Each individual will assume changing roles at different stages in the project, but the quality unit will continue to be involved for the project's duration.

Regulatory affairs

The organization's regulatory affairs will be involved with all FDA communication and the technology transfer of company IP. This interface and the information transmitted to and from FDA depends on the specifics of the PAT project. A project focused on designing quality into a product involves different activities to a project that enhances an existing product's manufacturing process. Some projects involving a new product require enhanced process control in the manufacturing process. As the project is executed, project results must be quantified, communicated and discussed with FDA, which may recommend changes.

Considerable risk is involved as regulatory affairs convey the confidence that the different organizational entities are doing their respective jobs successfully, including managing regulatory submission data for continuous improvement and the validation issues associated with enterprise rollout strategies. Regulatory affairs must closely cooperate with production and engineering as normalized batch comparisons, golden batch definition, and production data correlation and analysis have to be reported to various regulatory bodies.

Reporting requirements will change in such areas as:¹

• annual reports

• CBE0/CBE30

• prior approval supplements

• comparability protocols

• chemistry manufacturing and control supplements

• correlating clinical trial data

• integrating patient adverse drug reaction data to production

• reviewing and approving corrective and preventative action (CAPA) results.

FDA is, however, very supportive of companies participating in PAT projects. It is creating opportunities to develop less restrictive regulatory approaches to manage change when processes are well understood. This mitigates some of the risk factors that prevent organizations from becoming a strong partner in the project. When the company can gain knowledge by applying formal DoE, PAT concepts or risk management tools, presenting such knowledge can allow regulatory agencies to develop more flexible regulatory approaches. Some of these approaches facilitate risk-based regulatory decisions (reviews and inspections) within the boundaries of the knowledge described in the dossier, without the need for regulatory review. These activities can reduce endproduct testing and approach realtime release of the final product. Risk is also reduced by these compensatory approaches.

System risk

Once the strategic business approach is established and the project has begun, the risks become PATproject specific. At this point, the strategic direction of the company should be in driving PAT initiatives. Perhaps a PAT committee has selected a list of opportunities and one has been chosen for implementation. The process development challenges will begin with the involvement of research, process engineering and the quality unit throughout the development and scaleup phases of the project. Key risks associated with system implementation are data collection, management and validation.

The PAT solution usually involves offline, atline and online testing using applicationspecific sensors and instruments, automation, data storage (possibly with different data formats), system security and flexible common user interfaces. One challenge at this phase is developing pertinent critical performance parameters and critical control parameters, which are collectively considered as critical operating data (COD) targets for pilot plant operations. These performance metrics should be identified in pilot operations to have benchmark values that are achievable during scaleup. COD information will need to be included in CMC disclosures, as well as a part of the technology transfer, for process development and batch operations. Meeting these targets will mitigate scaleup risks and lead to a successful project.

Production challenges

A CAPA programme should be implemented to mitigate the risks associated with issues identified during project execution. It is a single source for continuous improvement and the resolution of project divergent situations that will have to be reported and tracked for FDA review.

Electronic configuration management tools may be needed as PAT methods may have multiple versions of automation software that is sensor specific. There is the possibility of having more than one sensor as a part of the implementation, with instrumentation included to test the sensors during operations.

Operators may use the flexible common user interface of MES to allow operator control of the process line. They will have close cooperation with automation/engineering, and all operators will participate in training and certification.

IT risks can be mitigated by considering the bigger picture of IT resources for highspeed data storage and retrieval. Data storage, needed for disparate data types, may be present in a typical installation. Process historian, streaming binary data, batch operation process data and XML data are some of the data types that will be stored in IT storage arrays. These data must be available for FDA review so mechanisms for readability have to be available. Regulatory submission and continuous improvement data may be developed from the data analysis and CAPA transaction as PAT global rollouts generate new improvements or new product lines.

One approach to risk mitigation is to use federation techniques for secure business and technology transfers. This combines business and technology practices to enable identities to span systems, networks and domains in a secure and trustworthy fashion; as a simple example, passports use this type of techniques for travel identification. Enterprises will continually extend their business processes outside their traditional boundaries to conduct PAT implementation or rollouts with regulatory agencies, partners and suppliers. These systems will need independent administration that provides strong accountability for regulatory, operations and business transactions to support international regulatory requirements.

Summary

FDA has defined its desired state for the pharmaceutical industry. PAT is a voluntary programme, but its implementation represents an important endeavour for a company — all levels of management must be made aware of changes being planned with the introduction of PAT applications. The greatest risk to success is not possessing senior management sponsorship of the projects. There needs to be a commitment at these senior levels to drive a business strategy that will support and drive PAT initiatives.

The impact of successful PAT investments will change the paradigms within the company, and generate business benefits through gains in quality and efficiency, with benefits being product and process dependent. Realtime online control and monitoring of product quality enhances management's confidence that product quality characteristics are being met during processing. In turn, this reduces the amount of product at risk of being out of specification. Additional benefits are achieved through reductions in production cycle times that result in more efficient plant utilization, with reduced energy and material usage — all basic principles for driving operational excellence.

On the plant floor, preventing or reducing rejects, scrap and reprocessing can be achieved while improving operator safety and reducing human errors. Near real-time release and increased throughput through processing improvements and managing product variability are just some of the benefits that can be achieved through implementation of PAT.

Joseph F. deSpautz is Senior Global Industry Technical Consultant in Life Sciences with Rockwell Automation (WI, USA).

Kenneth S. Kovacs is Senior Global Industry Technical Consultant in Life Sciences with Rockwell Automation.

References

FDA Guidance for Industry: PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, September 2004. www.fda.gov

G.P. Pisano, The Development Factory: Unlocking the Potential of Process Innovation (Harvard Business School Press, Boston, MA, USA,1996) pp 167.