FDA's New Process Validation Guidance: Industry Reaction, Questions, and Challenges - Pharmaceutical Technology

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FDA's New Process Validation Guidance: Industry Reaction, Questions, and Challenges
The authors desribe the three-stage approach to validation that is outlined in the new guidance and discuss questions surrounding implementation.


Pharmaceutical Technology
Volume 35, pp. s16-s23

Stage 1–Process Design. Process validation is an ongoing process within the product life cycle. This cycle begins at Stage 1. Here, the commercial process starts to be defined using knowledge gained through development and scale-up activities (1). Process knowledge and understanding is captured in Stage 1 to determine initial process capability and to evaluate sources of variation. Design of experiments can be used to identify and establish process-parameter relationships with quality attributes. Risk-management efforts should begin in earnest at this phase to assist in capturing the product and process knowledge and to prioritize development efforts, which can be ranked by the relative importance of the quality attributes. Process-control strategies can begin to be developed during this stage through initial understanding of the risks and sources of variation (8).

Stage 2–Process Qualification. Although the 2011 guidance document's three-stage description of validation may be new to the industry, the content and concepts within Stage 2 should be the most familiar. During this stage, the process design is confirmed as being capable of reproducible commercial manufacturing. This phase involves evaluating the facility and equipment for its fitness for use. Utility systems and equipment are verified to be built and installed properly, and operators ensure that they operate within the intended and anticipated operating ranges. The conclusion of this stage commences with the execution of a process-performance qualification (PPQ) exercise. PPQ is a significant milestone in the product life cycle. The decision to distribute product to the market will be determined by the successful completion of PPQ. The amount and usefulness of the product and process knowledge gained up to this point in the life cycle will determine the approach a company takes with its PPQ (1). The focus at this stage should not be on the number of batches needed to produce a successful PPQ run, but rather, on whether enough data has been produced and evaluated to answer two basic questions:

  • What scientific evidence is there to provide the appropriate level of assurance that the manufacturing system has been designed to consistently deliver a quality product to the market?
  • Are there systems in place to properly monitor and control that manufacturing system?

Stage 3–Continued Process Verification. Stage 3 of the 2011 guidance is the continuous-improvement phase of the process-validation life cycle. In this phase, data obtained from routine production is used to provide ongoing assurance that the process remains in the state of control. This activity is more than an annual product review; rather, this action involves using a system or multiple systems of assuring control.

Control strategies originally conceived in Stage 1 are implemented during this phase as well. Tracking and trending of data allows for the detection of special-cause variability and the reduction of inherent common-cause variability. Determination on the state of control of the processes in commercial distribution should be calculated using appropriate statistics and derived from appropriate confidence levels. These confidence levels should be based upon risk factors, experience, and attribute criticality (1).

A continuous process of evaluation

With the new life-cycle approach, process validation is no longer a one-time milestone event. Process validation should be considered a continuous process of valuation. The five steps shown in Figure 2 represent stages of validation. These steps require industry to:

  • Know the process
  • Know the variables
  • Have confidence before going into commercial manufacture
  • Create vigilance in understanding variation through monitoring and continuous improvement that the process is under control.


Figure 2: The process-validation sequence.(Figures are courtesy of authors)
Initial process understanding for a given product is most often based upon a combination of early development work on the product along with prior knowledge of the existing product and manufacturing platforms that will be used to commercialize the product. It is quite rare that a product entering the validation lif cycle will have a unique product or manufacturing platform. This initial process knowledge allows for a more robust process-design phase, which creates an enhanced understanding of the sources of variation and their impact on the product's quality attributes. Understanding the sources of variation provides confidence to go into commercial manufacture and to create an ongoing monitoring program that will track and trend data for continuous improvement.


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