A roadmap for PAT implementation

Process Analytical Technology (PAT) is "a system for designing, analysing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with a goal of ensuring final product quality" as defined by "Guidance for Industry: PAT - A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance".

By providing real-time measurements of relevant material and quality attributes, PAT is a fundamental piece of the process control strategy, allowing to adjust the process in a timely manner to consistently achieve predefined quality targets.

PAT works hand in hand with the Quality by Design (QbD) paradigm and plays a prominent role in the transition to Continuous Manufacturing and as an enabler of real time release. Besides, by reducing human intervention in the measurements and decision-making workflow, PAT provides data integrity.

PAT has been extensively supported by regulatory agencies and has proven its benefits in drug development and manufacturing. Yet, a wide use of PAT is still to be seen across pharma industry, with some companies struggling to embrace advanced analytics and process control. Resistance to PAT implementation is typically associated with regulatory and financial concerns, as well as with technology maturity and reliability risks and with the need of specialized technical skills.

While it may require more time and resources at first, as a learning curve for the organization as a whole, with the right engagement PAT will bring insight on the product and processes, and assist product development, technology transfer and commercial manufacturing, having a key role in the product's lifecycle.

1. Select the project to tackle

As a starting point, avoid complex products/processes. Select a simpler case that can lead to a quick win (minor implementation efforts and investment costs), create the skills and knowledge foundation on PAT and break new ground for future PAT projects, giving the organization a tangible credit on PAT benefits. Get visibility on PAT within the organization by accomplishment!

You may start at R&D to learn about the technology first and not having to deal with more complex GMP aspects, as well as equipment reliability issues. However, if you envision the shift to pilot and commercial scale, technology transfer and regulatory aspects will come into play. It will be crucial to ensure that your PAT systems are designed to operate in a fully validated state. So, it might be beneficial to initiate a communication channel with your vendor or a consultant to identify potential challenges and be better prepared for a smooth successful transition.

2. Fully engage your team and organization

Define objectives, deliverables and timelines and make it clear for the team. Teams must know their roles.

PAT requires specific expertise but also a collaborative environment within the organization. While the skills set needed for PAT depend on how mature the PAT technology is, a PAT project typically requires an interdisciplinary team with skills in both science and technology, a compliance and quality focus, but with a pragmatic mind-set in terms of operations and profitability.

Besides technical skills, the team must have the right level of authority for decision-making and/or have solid management sponsorship.

In order to cover the different aspects of a PAT implementation, along with PAT experts, the team may include chemists, persons from QC/QA, technical services, engineering, manufacturing, automation, IT, maintenance and regulatory affairs.

It might also be good to consider a project manager in the team to keep the project at the right pace and direction, and oversee potential roadblocks.

Besides internal know-how, seek for external know-how: talk with vendors, talk with other companies that already have implemented PAT. Accelerate your organization's learning curve by outsourcing specialized know-how, if required.

If appropriate, also work with regulators as this might be beneficial to get insight on regulatory intricacies and accelerate regulatory approval.

3. Get overall insight on PAT

It is important to have a general overview of key concepts of PAT before diving into the PAT project. So, learn about the regulatory framework and resources that support PAT implementation (e.g. ICH guidelines, FDA guidance, ASTM standards). This will give you a holistic perspective of the path to follow (time and resources, regulatory and business implications) and will allow establishing realistic expectations. Besides, knowing the "language" will facilitate interaction with both internal and external players.

4. Work on your PAT application

With a committed team in place and target project to implement PAT, start working on it!

Define the Analytical Target Profile (ATP; i.e. what needs to be measured by the method, the measurement performance characteristics and criteria), prepare the user requirements specification (URS) and perform an initial risk assessment (RA) to guide method development and validation phases (i.e. identify potential critical method parameters), determine required activities and specific regulatory applicability given the level of risk impact of the PAT application on product's quality (low-, medium- or high-impact application).

Note that both URS and RA are living documents that may evolve along the project as more knowledge is generated.

5. Choose the PAT solution

Carry out due diligence to select the right technology for your target process. The URS will direct the procurement of PAT tools. Some of the resources that you might need to consider are:

1. Process analytical equipment (either univariate or multivariate), including sampling/process interface, sample delivery systems.
2. Statistical software for data analysis and modelling.
3. PAT data management system to integrate analytical instrument control, perform data (and metadata) collection, data fusion and calculation functions, data trending and reporting and have interfaces to external information technology (IT) and control systems, in full GMP and regulatory compliance.
4. Automation and IT infrastructure to interface and integrate PAT machinery with existing multilevel data management and control systems (e.g. LIMS, PLC, DCS, data historian). It would be key to have a central data repository for multisite, multiline reporting.
5. A digital solution to gather all the above would constitute a powerful end-to-end tool including lifecycle management of the PAT application. In compliance with a risk-based approach for development and maintenance of analytical methods, a lifecycle management platform should ensure that a structured management workflow is available to guide the user from the initial step of design, through PQ and ongoing routine verification.

6. Set up the PAT tools and auxiliary resources needed and start developing the PAT application

This involves generating data on the process and using it to build models to meet the ATP. Different metrics can be used at this stage to evaluate models' performance and guide the selection of a preliminary model to take to the next stage - validation.

7. Validate your PAT method

In the validation stage, the method is challenged to demonstrate that its performance is suitable for the intended purpose. In some cases, this may be an element of the Performance Qualification (PQ) of your PAT system, completing its qualification.

Method validation should be risk- and science-based and appropriate to the impact level of your PAT application. Most importantly, the process of method validation must be planned and documented before execution, and will follow similar principles as described in established international guidelines for the validation of analytical methods.

8. Define the analytical control strategy for your PAT application

Concomitant with the previous steps, you should design the analytical control strategy to follow during the lifecycle of the PAT method in order to assure consistency and validity of the process method. The analytical control strategy identifies the necessary elements for ongoing monitoring and evaluation of model's performance, and includes aspects such as model monitoring and verification (namely, how to handle outliers and out-of-specification results), model maintenance (e.g. model revalidation), documentation and change control management.

9. Deployment of the PAT application to routine use

Implement the PAT method in the process, in commercial production in a cGMP compliant environment, either as a monitoring tool only or, in case of a comprehensive PAT application, integrated in the process control strategy. With PAT, CQAs can be measured automatically to enable real-time decision making in order to meet specific targets and achieve consistent quality. Besides, continuous improvement can also be pursued.

10. Lifecycle management of the PAT application

PAT should be incorporated in your organization's Quality Management System, and consider key aspects, such as assurance of data integrity, documentation and change control procedures, criticality and risk assessment periodic review, qualification and validation strategy.