To ensure the quality, consistency, and compliance of pharmaceutical products, controlled and reliable equipment, systems and processes are required. Pharmaceutical manufacturers follow three basic procedures calibration, validation, and qualification to control their operations.
While these terms are frequently confused or defined as if they were the same thing, they are not interchangeable and have separate meanings and applications in the GMP regulations. It is important to differentiate between the three to be compliant with the regulatory agencies such as the US FDA and the EMA by demonstrating compliance with the cGMP regulations.
In this article, we will clarify the definitions of each of these terms and explain their respective objectives, the significance of each term from a regulatory compliance perspective and, finally, to highlight the differences between them using real-world examples of how they are used in the pharmaceutical industry.
The easiest way to think about these terms is:
- Calibration checks that the measurement is accurate.
- Qualification checks that an instrument has been correctly installed and integrated into the process.
- Validation checks that a process will consistently produce a predetermined result.
Next, let’s know the details of each component.
This process will occur prior to the use of any piece of equipment that will be used to produce a product for either manufacturing, or conducting laboratory tests. The qualification will provide assurance of "fitness for use". Therefore, qualification is considered an essential component of the overall validation process.
1. Design Qualification (DQ) - A review of the design is done to verify that it meets user requirements and Good Manufacturing Practice (GMP) requirements.
For example: Review of the design and layout of cleanrooms or equipment designs before installation.
2. Installation Qualification (IQ) - The verification process is done to confirm that the equipment or system has been installed as required for design and specifications.
For example: The verification that a tablet press has been installed according to the manufacturer's drawings, and that the necessary utilities are connected to it.
3. Operational Qualification (OQ) - The verification process will ensure that a system or piece of equipment will operate according to its required operating limits.
For example: Testing to ensure the temperature is uniform across the entire chamber of an heating oven or to confirm that the alarm or control system for that oven is functioning correctly.
4. Performance Qualification (PQ) - This verification process will provide data to demonstrate that the equipment operates consistently during actual production conditions.
For example: A demonstration that the weight and hardness of tablets has remained the same despite running multiple batches through the equipment.
- That they operate in a consistent and reliable manner.
- That there is documented evidence of compliance to established qualifications.
Validation is used to determine not only whether the process works but whether it will work consistently and to the same degree of success every time the process is performed under the same operating conditions.
Validation addresses the question "Can the process consistently produce products of the specified quality?"
An example of a process validation would be validating a table compression process for uniformity of product weight and hardness.
2. Cleaning Validation: Cleaning Validation is the validation procedure by which the cleaning of manufacturing equipment is validated to ensure the effective reduction of product residues (contaminants) to acceptable limits.
An example of Cleaning Validation is the swabbing and rinsing of cleaned equipment.
3. Analytical Method Validation: The validation of an analytical testing method involves the determination of whether an analytical method produces accurate, precise, specific, and reproducible results.
An example of analytical method validation would be the validation of a High Performance Liquid Chromatography (HPLC) assay method.
4. Computer System Validation (CSV): CSV is the process to assure the computerized systems developed to comply with Good Manufacturing Practice (GMP) and also comply with 21 CFR Part 11 (i.e., electronic records and electronic signatures) and are reliable and consistent in operation.
An example of CSV is validating a Laboratory Information Management System (LIMS) or electronic batch record system.
5. Equipment/Utility Validation: The overlap of the qualification process and continuation of performance of an equipment/system is validated through Equipment/Utility Validation.
Examples of Equipment/Utility Validation would be validating HVAC Systems and Purified Water Systems.
Step 2: Conducting Execution Testing, where we perform tests to gather information about how the system performs, and to identify whether there have been any non-conforming activities.
Step 3: Documenting & Authorizing Results; All test results, any identified non-conformities, and the conclusions drawn from these results must be described in a Validation Report.
Step 4: Revalidation; The performance of a process will be confirmed through regular monitoring of risk or time intervals.
- Calibration provides accurate measurements from instruments or other measuring devices.
- Qualification assures that equipment and systems have been installed and operated according to manufacturer's specifications.
- Validation determines that the entire manufacturing process can produce consistent compliant products as promised.
When calibration is not done correctly the results of qualifications and validations may not be valid. Furthermore, if any of the qualifications have not been completed the validation cannot be completed.
As such Calibration, Qualification, and Validation represent a continuum of assurance beginning with the individual instruments and ending with full-scale production.
The GMP compliance process consists chiefly of three parts, Calibration, Qualification and Validation. Calibration provides the proper measure of instruments used in testing. Qualification confirms that equipment and systems are installed and running correctly. Validation validates that a process yields product of consistent quality.
By correctly designing and utilizing these three components (calibration, qualification, and validation), a manufacturer can be assured of being able to show compliance with regulatory requirements, provide for data integrity, and provide for patient safety via the production of reliable and high-quality products.
In this article, we will clarify the definitions of each of these terms and explain their respective objectives, the significance of each term from a regulatory compliance perspective and, finally, to highlight the differences between them using real-world examples of how they are used in the pharmaceutical industry.
Introduction to Calibration, Validation, and Qualification
An important aspect of a pharmaceutical quality management system is the process of calibration, validation, and qualification as a means of controlling equipment and processes throughout the life of the drug product. The three terms provide an understanding of how well an instrument's readings correlate with its ability to produce consistent and valid results consistently from start to finish.The easiest way to think about these terms is:
- Calibration checks that the measurement is accurate.
- Qualification checks that an instrument has been correctly installed and integrated into the process.
- Validation checks that a process will consistently produce a predetermined result.
Next, let’s know the details of each component.
What is Calibration?
Calibration compares the readings of an instrument against known standards that determines if the instrument produces accurate measurements within acceptable ranges. Calibration tells us that the equipment measures accurately and is performing as expected.Purpose of Calibration
The purpose of calibration is:- To verify the accuracy and precision of measuring instruments.
- To identify instrument performance deviations or drifts over a period of time.
- To ensure consistency of test/process results.
- To remain in compliance with GMP and ISO regulations.
Examples of Calibration
- Calibrating a weighing scale using defined weights.
- Calibrating a pH sensor utilizing pH buffer solutions (pH value of 4.0, 7.0 and 9.0).
- Calibrating a temperature measuring device utilizing the readings of a certified thermometer.
- Calibrating a pressure measuring device utilizing the readings of a defined dead weight tester.
Frequency of Calibration
Calibration should happen:- At defined time intervals (monthly, quarterly, annually).
- After performing repairs or completing maintenance related activities.
- After relocating the calibration instrument, and/or after an incident of shock or heavy physical stress to the instrument.
- Whenever you have uncertainty about the accuracy of the measuring instrument.
Documentation of Calibration
A confirmation of calibration should include the following elements in the Calibration Logbook/Calibration Certificate:- Identification number and serial number of the instrument under calibration.
- Traceability of Calibration Standard Reference.
- Before and After Readings - actual readings of the instrument BEFORE performing the calibration and the FINAL READING of the instrument AFTER calibration.
- Acceptance Criteria/STATUS (Pass/Fail) of the instrument being calibrated.
- Signature of an Authorized Representative and Date.
What is Qualification?
Qualification is a process by which a company documents that its equipment, systems or utilities have been designed, installed, and are operating as expected.This process will occur prior to the use of any piece of equipment that will be used to produce a product for either manufacturing, or conducting laboratory tests. The qualification will provide assurance of "fitness for use". Therefore, qualification is considered an essential component of the overall validation process.
Stages of Qualification
Generally, there are four major stages involved in the qualification process:1. Design Qualification (DQ) - A review of the design is done to verify that it meets user requirements and Good Manufacturing Practice (GMP) requirements.
For example: Review of the design and layout of cleanrooms or equipment designs before installation.
2. Installation Qualification (IQ) - The verification process is done to confirm that the equipment or system has been installed as required for design and specifications.
For example: The verification that a tablet press has been installed according to the manufacturer's drawings, and that the necessary utilities are connected to it.
3. Operational Qualification (OQ) - The verification process will ensure that a system or piece of equipment will operate according to its required operating limits.
For example: Testing to ensure the temperature is uniform across the entire chamber of an heating oven or to confirm that the alarm or control system for that oven is functioning correctly.
4. Performance Qualification (PQ) - This verification process will provide data to demonstrate that the equipment operates consistently during actual production conditions.
For example: A demonstration that the weight and hardness of tablets has remained the same despite running multiple batches through the equipment.
Why Qualification is Important
- To determine that equipment, systems or utilities are fit for GMP related production work.- That they operate in a consistent and reliable manner.
- That there is documented evidence of compliance to established qualifications.
Examples of Qualification
- All new HVAC, autoclaves and water purification systems must be qualified.
- Equipment like tablet compression machines, coating machines, filling machine, GC or HPLCs undergo IQ, OQ, and PQ before use.
- New equipment should only be qualified once, but after a major maintenance, moving or changing of equipment, the equipment will need qualification again.
What is Validation?
The process of validation is the documentation of a systematic and complete examination of whether or not the process, system, or method produces product that meets its predetermined quality standards, consistently.Validation is used to determine not only whether the process works but whether it will work consistently and to the same degree of success every time the process is performed under the same operating conditions.
Validation addresses the question "Can the process consistently produce products of the specified quality?"
Types of Validation
1. Process Validation: The procedure used to validate the entire manufacturing process for the manufacture of products that meet product specifications.An example of a process validation would be validating a table compression process for uniformity of product weight and hardness.
2. Cleaning Validation: Cleaning Validation is the validation procedure by which the cleaning of manufacturing equipment is validated to ensure the effective reduction of product residues (contaminants) to acceptable limits.
An example of Cleaning Validation is the swabbing and rinsing of cleaned equipment.
3. Analytical Method Validation: The validation of an analytical testing method involves the determination of whether an analytical method produces accurate, precise, specific, and reproducible results.
An example of analytical method validation would be the validation of a High Performance Liquid Chromatography (HPLC) assay method.
4. Computer System Validation (CSV): CSV is the process to assure the computerized systems developed to comply with Good Manufacturing Practice (GMP) and also comply with 21 CFR Part 11 (i.e., electronic records and electronic signatures) and are reliable and consistent in operation.
An example of CSV is validating a Laboratory Information Management System (LIMS) or electronic batch record system.
5. Equipment/Utility Validation: The overlap of the qualification process and continuation of performance of an equipment/system is validated through Equipment/Utility Validation.
Examples of Equipment/Utility Validation would be validating HVAC Systems and Purified Water Systems.
Validation Stages
Step 1: Creating a Validation Plan/protocol which describes why we are performing validation, who will be responsible for managing it, and what are the expected results.Step 2: Conducting Execution Testing, where we perform tests to gather information about how the system performs, and to identify whether there have been any non-conforming activities.
Step 3: Documenting & Authorizing Results; All test results, any identified non-conformities, and the conclusions drawn from these results must be described in a Validation Report.
Step 4: Revalidation; The performance of a process will be confirmed through regular monitoring of risk or time intervals.
Objectives of Validation
- To ensure consistent performance for a process.
- To reduce the possibility of variation and the risk of failure to a final product.
- To comply with government regulations and Good Manufacturing Practices.
- To create a documented record to substantiate control and reproducibility of manufacturing processes.
Relationship Among Calibration, Qualification, and Validation
Calibration, Qualification, and Validation are separate but the three combined are required for any good manufacturing practices control system.- Calibration provides accurate measurements from instruments or other measuring devices.
- Qualification assures that equipment and systems have been installed and operated according to manufacturer's specifications.
- Validation determines that the entire manufacturing process can produce consistent compliant products as promised.
When calibration is not done correctly the results of qualifications and validations may not be valid. Furthermore, if any of the qualifications have not been completed the validation cannot be completed.
As such Calibration, Qualification, and Validation represent a continuum of assurance beginning with the individual instruments and ending with full-scale production.
Common Errors and How to Avoid Them
- Assuming that Calibration, Qualification, and Validation mean the same thing
- Inadequate Documentation (missing reports, incomplete protocols or lack of traceability)
- Neglecting Requalification/Revalidation (as the system can drift over time, periodic checks will be necessary)
- Utilizing Uncalibrated Instruments (this will provide invalid results, and could trigger a regulatory citation)
- Not Taking a Risk-Based Approach (fail to rank priority of critical instruments or critical processes)
- Every pharmaceutical facility must implement a structured Validation Master Plan (VMP) to include all three above activities for compliance purposes.
The GMP compliance process consists chiefly of three parts, Calibration, Qualification and Validation. Calibration provides the proper measure of instruments used in testing. Qualification confirms that equipment and systems are installed and running correctly. Validation validates that a process yields product of consistent quality.
By correctly designing and utilizing these three components (calibration, qualification, and validation), a manufacturer can be assured of being able to show compliance with regulatory requirements, provide for data integrity, and provide for patient safety via the production of reliable and high-quality products.
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