FDA Process Validation Guidance


The FDA released the updated guidance for Process Validation in January 2011.  It has been almost 6-years since this guidance was released.  For those of us in the life science industry, how has this guidance changed how you perform process validation?

The stated intent of the guidance is to align process validation activities with the product life-cycle concept. This is accomplished by defining 3-stages of process validation.

Stage 1 – Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities. The goal of this stage is to design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its quality attributes.  This stage consists of two sub stages:

  • Building and capturing process knowledge and understanding
  • Establishing the strategy for process control

Stage 2 – Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing. The goal in this stage is to demonstrate that the manufacturing process is suitable for commercial manufacturing.  This stage consists of two sub stages:

  • Design of a Facility and Qualification of Utilities and Equipment
    • This stage includes validation planning document(s), establishment of system user requirements, design review/qualification, and commissioning and qualification / verification testing.
  • Process Performance Qualification
    • This stage combines the qualified facility, utilities, equipment, and trained personnel with the commercial manufacturing process, control procedures, and components to produce commercial batches. Success in this stage confirms Process Design and demonstrates performance of the commercial manufacturing process.

Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control. The goal of the third validation stage is continual assurance that the process remains in a state of control (the validated state) during commercial manufacture. This is accomplished through implementation of  systems to detect unplanned departures from the designed/ validated manufacturing process. Key elements of this stage include:

  • Definition of what data are critical to defining the stability and variation of the manufacturing process
  • Data monitoring frequency
    • Initial recommendation is to employ the same monitoring frequency as during process performance qualification
    • Frequency can be adjusted based on statistically appropriate and representative sampling.
  • Analysis of the data by a qualified person to evaluate process stability and capability

Commissioning, qualification and validation activities typically occur during stage 2.

  • Sub stage 1 activities may include development of the validation master plan, design reviews, user requirements, verification of proper system and equipment installation, commissioning and startup, followed by qualification. Qualification is defined as the sum of activities undertaken to demonstrate that utilities and equipment are suitable for their intended use and perform properly.
  • Sub stage 2, what typically was considered process validation, combines the actual facility, utilities, equipment (each now qualified), and the trained personnel with the commercial manufacturing process, control procedures, and components to produce commercial batches. A successful PPQ will confirm the process design and demonstrate that the commercial manufacturing process performs as expected.
  • There are two additional elements in the guidance that provide greater details on what is expected during the PPQ:
    • The first is PPQ Protocol, where the FDA recommends protocol content.
    • The second is PPQ execution and report where the FDA recommends when the PPQ may be executed, by whom and how, and the expectations on what should be included in the PPQ final report.

Some primary takeaways from this guidance include:

  • Validation is not a discrete event, but a continuous process of evaluation.
  • Understanding and controlling process variation is a key to process control.
  • Decisions should be based on sound scientific information, related to patient risk (i.e. 3 is not a magic number for validation lots).

At a recent USFDA/ASTM workshop one of the FDA presenters shared that the most commonly asked question to his department is how many batches were needed to validate a process.  FDA shared that one acceptable method was contained in the ASTM Standard Practice E2709-14 (referenced in the process validation guidance document).  As stated in the standard, this practice provides a general methodology for evaluating single-stage or multiple-stage acceptance procedures which involve a quality characteristic measured on a numerical scale.   The next time you are wondering how many batches do I need to run – take a look at this standard and you may be surprised!