In other words, process validation is defined as the “collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering a quality product.”

Typically, the process validation considers the most relevant and critical operating parameters of the system at the full range established and recommended by the specific product’s specifications at the intended use.

FDA Guidance for Industry: Process Validation:

General Principles and Practices

This guidance outlines the general principles and approaches that the FDA considers to be 21 appropriate elements of process validation for the manufacture of human and animal drug and 22 biological products, including active pharmaceutical ingredients (API or drug substance). For more information refer to httpss://www.fda.gov/media/71021/download

Performance Qualification (PQ) is NOT equal to Process Validation (PV).

Some people confuse performance qualification with process validation.

Performance qualification is just one activity of the whole process of validation activities required to be done by the FDA statutory and regulatory requirements for process validation.  For more information about performance qualifications, click here.

Performance Qualification (PQ) Definition

The Performance Qualification is a collection of test cases used to verify that a system behaves as expected under simulated or real-world conditions demonstrating that the process or equipment is consistent over time with the user’s requirements and functional requirement specifications.

The term “qualification” refers to activities undertaken to demonstrate that utilities and equipment are suitable for their intended use and perform properly.

During the (PQ), the process design is evaluated to determine if it is capable of a reliable and controlled commercial manufacture within specifications.  In this phase, the PQ aims to verify and document that the equipment is working with reproducible results within a specific production working range.

Instead of testing components and instruments one-by-one, PQ tests them all as a whole and overall process.  Depending on the size and complexity of the system, Performance Qualification PQ-E and PPQ can be combined in the same protocol document(s) with Installation Qualification or Operational Qualification.  But, the testing must be performed and executed in established chronological order: IQ first, OQ second, and PQ third.

The protocol must be prepared as per the FDA guideline “Process Validation: General Principles and Practices,” which officially defines the PROCESS VALIDATION into three (3) steps elements: httpss://www.fda.gov/media/71021/download

Step 1. Design of the facility and qualification of the equipment and utilities (sometimes called by the industry as PQ-E)

The PQ-E generally includes the following activities:

• Selecting utilities and equipment construction materials, operating principles, and performance characteristics based on whether they are appropriate for their specific uses.

• Verifying that utility systems and equipment are built and installed in compliance with the design specifications (e.g., built as designed with proper materials, capacity, and functions, and properly connected and calibrated).

• Verifying that utility systems and equipment operate in accordance with the process requirements in all anticipated operating ranges. This should include challenging the equipment or system functions while under load comparable to that expected during routine production. It should also include the performance of interventions, stoppage, and start-up as is expected during routine production. Operating ranges should be shown capable of being held as long as would be necessary during routine production.

Step 2. Process Performance Qualification (PPQ)

The Process Performance Qualification (PPQ) protocol is a fundamental component to demonstrate how the equipment or system achieves and run. Its purpose is to ensure ongoing product quality by documenting performance over a period of time for certain processes.

The PPQ 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 using objective measures (e.g., statistical metrics) wherever feasible and meaningful to achieve adequate assurance.

Data from laboratory and pilot studies can provide additional assurance that the commercial manufacturing process performs as expected.

PPQ will have a higher level of sampling, additional testing, and greater scrutiny of process performance than would be typical of routine commercial production.

A written protocol that specifies the manufacturing conditions, controls, testing, and expected outcomes is essential for this stage of process validation.

The PPQ protocol generally includes the following activities:

• The manufacturing conditions, including operating parameters, processing limits, and component (raw material) inputs.

• The data to be collected and when and how it will be evaluated.

• Tests to be performed (in-process, release, characterization) and acceptance criteria for each significant processing step.

• The sampling plan, including sampling points, number of samples, and the frequency of sampling for each unit operation and attribute. The number of samples should be adequate to provide sufficient statistical confidence of quality both within a batch and between batches. The confidence level selected can be based on risk analysis as it relates to the particular attribute under examination. Sampling during this stage should be more extensive than is typical during routine production.

• Criteria and process performance indicators that allow for a science- and risk-based decision about the ability of the process to consistently produce quality products. The criteria should include:

— A description of the statistical methods to be used in analyzing all collected data (e.g., statistical metrics defining both intra-batch and inter-batch variability).

— Provision for addressing deviations from expected conditions and handling of nonconforming data. Data should not be excluded from further consideration in terms of PPQ without a documented, science-based justification.

• Design of facilities and the qualification of utilities and equipment, personnel training and qualification, and verification of material sources (components and container/closures), if not previously accomplished.

• Status of the validation of analytical methods used in measuring the process, in-process materials, and the product.

• Review and approval of the protocol by appropriate departments and the quality unit.

Step 3.  – 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 a continual assurance that the process remains in a state of control (the validated state) during commercial manufacture. A system or systems for detecting unplanned departures from the process as designed is essential to accomplish this goal.

Adherence to the CGMP requirements, specifically, the collection and evaluation of information and data about the performance of the process, will allow the detection of undesired process variability. Evaluating the performance of the process identifies problems and determines whether action must be taken to correct, anticipate, and prevent problems so that the process remains in control.

An ongoing program to collect and analyze product and process data that relate to product quality must be established. The data collected should include relevant process trends and quality of incoming materials or components, in-process material, and finished products.

The data should be statistically trended and reviewed by trained personnel. The information collected should verify that the quality attributes are being appropriately controlled throughout the process.

It requires a statistician or person with adequate training in statistical process control techniques to develop the data collection plan and statistical methods and procedures used in measuring and evaluating process stability and process capability.  Procedures should describe how trending and calculations are to be performed and should guard against overreaction to individual events as well as against failure to detect unintended process variability.

Production data should be collected to evaluate process stability and capability. The quality unit should review this information. If properly carried out, these efforts can identify variability in the process and/or signal potential process improvements.