What is Process Validation?
FDA Definition:
The FDA Guidelines on General Principles of Process Validation defines process validation as "establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics."
EMEA Definition:
According to EMEA, "Process validation can be defined as documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a Medical product meeting its predetermined specifications and quality attributes."
Importance of Process Validation:
There are several important reasons for validating a product and/or process:
- Manufacturers are required by law to conform to GMP regulations
- Good business dictates that a manufacturer avoid the possibility of rejected or recalled batches
- Validation helps to ensure product uniformity, reproducibility, and quality
Approach to Process Validation
For purposes of this guidance, 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. Process validation involves a series of activities taking place over the lifecycle of the product and process.
Three-Stage Lifecycle Approach:
This guidance describes process validation activities in three stages:
Stage 1 – Process Design
The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities.
Stage 2 – Process Qualification
During this stage, 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.
Types of Process Validation
Prospective Validation
- Establishing documented evidence prior to process implementation that a system does what it proposed to do based on preplanned protocols
- Normally undertaken whenever the process for a new formula (or within a new facility) must be validated before routine pharmaceutical production commences
- Often leads to transfer of the manufacturing process from the development function to production
Concurrent Validation
- Used for establishing documented evidence that a facility and processes do what they purport to do, based on information generated during actual implementation of the process
- Involves monitoring of critical processing steps and end product testing of current production, to show that the manufacturing process is in a state of control
Retrospective Validation
- Used for facilities, processes, and process controls in operation use that have not undergone a formally documented validation process
- Validation is possible using historical data to provide the necessary documentary evidence that the process is doing what it is believed to do
- Only acceptable for well-established processes and inappropriate where there have been recent changes in product composition, operating processes, or equipment
Revalidation
- Means repeating the original validation effort or any part of it, and includes investigative review of existing performance data
- Essential to maintain the validated status of the plant, equipment, manufacturing processes and computer systems
Reasons for Revalidation:
- The transfer of a product from one plant to another
- Changes to the product, the plant, the manufacturing process, the cleaning process, or other changes that could affect product quality
- The necessity of periodic checking of the validation results
- Significant (usually order of magnitude) increase or decrease in batch size
- Sequential batches that fail to meet product and process specifications
- The scope of revalidation procedures depends on the extent of the changes and the effect upon the product
Two-Phase Validation Approach for Tablets
The validation of a new or reformulated tablet product requires two phases. In phase I the development team formulates the product and general process of manufacture.
Phase I Objectives:
- Producing an optimal formula and process
- Identifying the most critical tablet characteristics and establishing specifications for the tablet
- Quantifying relationships between the critical tablet characteristics and process/formulation variables
- Establishing specifications for process/formulation variables to ensure that tablet specifications will be met
- Proposing in-process tests for critical process variables and raw materials specifications for critical formulation variables when appropriate
- Documenting above information
Phase II Objectives:
- Demonstrating that all manufacturing equipment and related systems (SOPs, equipment calibration, cleaning procedures, assays, packaging, and personnel training) have been qualified for use in the manufacture and testing of this product
- Drafting a process validation protocol before manufacture of first production lots that specifies the procedures to be validated. This protocol should be written to challenge the proposed limits on the critical process/formulation variables
- Running production/validation lots; collecting and analyzing data
- Demonstrating that all product specifications have been met in spite of the challenges presented to the process
- Documenting above information
Important Notes:
- Usually several production lots are required to complete phase II validation
- The more process/formulation variables, the more production lots will have to be used
- If the production scale validation lots pass all the required specifications for that tablet product, the lots may be used for commercial sale
Control Parameters for Tablet Manufacturing Processes
Granulation Process:
Fixed Parameters: Equipment
Variables: Mixing speed, Amount of granulation fluid, Feed rate of granulation fluid, Time load
Response Tests: Drug (API) distribution, Power consumption (Ampere/torque)
Drying and Sizing:
Fixed Parameters: FBD bowl size, Porosity of filter bags, Bowl sieve (screen)
Variables: Inlet/Exhaust air temperature, Product temperature, Drying time, Air volume, Humidity of inlet air (dew point)
Response Tests: Granules particle size distribution, LOD, Densities (Bulk density, Tapped density), Assay (for heat sensitive API)
Milling:
Fixed Parameters: Equipment (Multi-mill / Co-mill)
Variables: Screen size, Milling speed, Feed rate
Response Tests: Granules particle size distribution, Densities (Bulk density, Tapped density)
Blending:
Fixed Parameters: Equipment (Drum blender / Double cone blender / Bin blender)
Variables: Blending time, Blending speed (rpm)
Response Tests: Content uniformity (CU), Assay, Particle size distribution, Powder flow
Lubrication:
Fixed Parameters: Equipment (Drum blender / Double cone blender / Bin blender)
Variables: Blending time, Blending speed (rpm), Method of addition
Response Tests: Content uniformity (CU), Assay, Particle size distribution, Powder flow
Compression Process Validation
- Environmental Control: Check and ensure the temperature and relative humidity of the compression room is not more than 25°C and relative humidity not more than 50%.
- Equipment Cleaning: Check and ensure the compression machine is cleaned.
- Sampling Protocol: Collect 40 tablets and inspect for Appearance, weight, thickness, friability and hardness every 1 hour.
- Specifications: Tablets weight variation shall be XX mg hardness shall be (IP) kg/cm², thickness.
- Speed Variation Testing: Collect 40 tablets at high speed & slow speed i.e. by increasing the speed of the compression machine from the target speed and by reducing from the targeted speed.
- Content Uniformity Testing: Collect 10 tablets during initial, middle and end of the compression process and subject it to analysis for content uniformity and perform the assay also.
Compression Variables:
- Tablet press speed
- Compression force
- Weight and compression force
- Powder feed rate into dies
Response Tests:
- Appearance
- Tablet weight
- Thickness
- Hardness
- Friability
- Content uniformity
- Disintegration time
- Dissolution
- Assay
Coating Process Validation
- Equipment Cleaning: Check and ensure the coating pan and other equipment's are cleaned.
- Process Parameters: Check and ensure that the tablets is deducted, the speed of the coating pan inlet and exhaust air temperature, spray rate, spray type, temperature of the coating solution.
- Post-Coating Testing: After coating is completed, samples are collected for dissolution testing and weight variation.
Coating Variables:
- Spray rate
- Pan speed
- Airflow rate
- Pan loading
- Inlet temperature
- Exhaust temperature
- Spray guns assembly
Response Tests:
- Average weight
- Weight of 20 tablets
- Thickness
- Assay
- Dissolution/disintegration
- Mottling or speckling
Process Validation Protocol
A validation protocol showing how validation will be performed, including test parameters, product characteristics, production equipment, and decision points on what constitutes acceptable test results. It should include the following items:
| Component | Description |
|---|---|
| Purpose | Clear statement of what the validation aims to achieve |
| Scope | Defines the boundaries and extent of the validation study |
| Responsibilities | Roles and responsibilities of assessment team members |
| Acceptance Criteria | Predefined standards that must be met for validation to be successful |
| Critical Parameters | Identification of critical process and product parameters |
| Product Details | Complete description of the product being validated |
| Reference Documents | Documents for method of manufacturing and testing |
| Reason for Validation | Justification for conducting the validation study |
| Bill of Raw Materials | Complete list of raw materials with specifications |
| Equipment Details | Specifications and qualifications of equipment used |
| Process Flow Chart | Visual representation of the manufacturing process |
| Critical Process Stages | Identification of stages to be validated |
| Validation Batch Summary | Details of validation batches including size and number |
| Deviation Procedure | Protocol for handling deviations during validation |
| Evaluation & Conclusion | Framework for evaluating results and making recommendations |
Validation Report
At the end of the Process Validation a Validation report is need to be prepared. The tests results and conclusions of Validation Protocol documented and summarized in a process validation report. The validation report should include the following items:
Report Components:
- Aim of the validation study
- Batch No. and Batch size
- Process summary
- Verification of critical process controls
- Conclusion
- Attachments
Key Elements:
- Comprehensive documentation of all test results
- Analysis of data against acceptance criteria
- Documentation of any deviations and their investigation
- Clear conclusion on validation status
- Recommendations for routine manufacturing
- Signatures of responsible personnel
Regulatory Importance:
The validation report serves as the definitive documented evidence that the process has been validated and is capable of consistently producing products meeting predetermined specifications. This document is critical for regulatory submissions and inspections.
