Process validation- Stage 2

Process validation

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 quality product. 

Guidance for industry process validation: General principal and Practice describes process validation activities in three stages.

• Stage 1 Process design.: This stage is based on knowledge gained through development and scale-up activities.
• Stage 2 Process Qualification.: The process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.  
• Stage 3 Continued Process Verification.: Ongoing assurance is gained during routine production that the process remains in a state of control. 

Before any batch from the process is commercially distributed for use by consumers, a manufacturer should have a high degree of assurance in the performance of the manufacturing process. The assurance should be obtained from objective information and data from Laboratory, pilot, commercial scale studies.

A successful validation depends upon information and knowledge from product and process development. The manufacturers should:

• Understand the source of variation.
• Understand the impact of variation on the process.
• Able to detect the presence and degree of variation. 

Stage 1: Process design:

Process design is the activity of defining the commercial manufacturing process that will be reflected in planned master production and control records. 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 part will be discuss in other blog)

Stage 2: Process Qualification: 

 In stage 2 of process validation, the process design is evaluated to determined if it is capable of reproducible commercial manufacture. This stage has two elements:

(1) Design of the facility and qualification of the equipment and utilities.

(2) Process performance qualification (PPQ).

 1. Design of the facility and Qualification of utilities and equipment's.

As per Part 211, subpart C of cGMP covers the proper design of a manufacturing facility is required.  It is essential that activities performed to assure proper facility design and commissioning precede PPQ. 

Qualification of Utilities and equipment includes the following activities:

• Selecting utilities and equipment construction materials, operating principles and performance characteristic 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.
• Verifying that utility systems and equipment operate in accordance with the process requirements in all anticipated operating ranges.

 2. Process Performance Qualification (PPQ)

The PPQ combines the actual facility, utilities, equipment and the trained personnel with the commercial manufacturing process, control procedure and components to produce commercial manufacturing process.

A successful PPQ will confirm the process design and demonstrate that the commercial manufacturing process performs as expected.

The critical process parameters and in-process controls studied during stage 1 shall be further evaluated to check the robustness of process during the process validation studies.

Following prerequisite for the process performance qualification and same shall be ensured before starting of process performance qualification activity:

• manufacturing facility is qualified.
• Equipment and utilities used for PPQ are qualified.
• Instruments or devices used in processing have been calibrated.
• Analytical method validation shall be available for input , in-process and finished product.
• Vendors are qualified.

 It is strongly recommend that firms employ objective measures (e.g., statistical metrics) wherever feasible and meaningful to achieve adequate assurance. In most cases, PPQ will have a higher level of sampling, additional testing, and greater scrutiny of process performance than would be typical of routine commercial production.

PPQ protocol:

A written protocol that specifies the manufacturing conditions, controls, testing, and expected outcomes is essential for this stage of PPQ. Following are the recommendations for protocol.

• The manufacturing conditions, including operating parameters, processing limits, and component (raw material) inputs.
• Sampling locations, sample size and No. of samples.  The number of samples should be adequate to provide sufficient statistical confidence of quality both within a batch and between batches.
• Sampling methods.
• A description of the statistical methods to be used in analyzing all collected data
• Provision for addressing deviations from expected conditions and handling of nonconforming data.
• Status of validation of analytical methods used for testing of input, in-process and finished goods.
• Review and approval of the protocol with appropriate department.

PPQ protocol Execution and Reports:

Execution of the PPQ protocol should not begin until the protocol has been reviewed and approved by all appropriate departments. The commercial manufacturing process and routine procedures must be followed during PPQ protocol execution. 

A report documenting and assessing adherence to the written PPQ protocol should be prepared in a timely manner after the completion of the protocol. PPQ report should include:

• Summarize data collected and analyze the data, as specified by the protocol.
• Evaluate of observations and additional data not specified in the protocol.
• Summarize and discuss all manufacturing non-conformances such as deviations, aberrant test results, or other information that has bearing on the validity of the process.
• State a clear conclusion as to whether the data indicates the process met the conditions established in the protocol and whether the process is considered to be in a state of control.
• Include all appropriate department and quality unit review and approvals.

Stage 3 Continuous process validation is not covered. This will be discuss in other blog.