Difference between Validation ,Qualification and Calibration in pharmaceuticals

In the world of pharmaceutical manufacturing, qualification and calibration are precision, accuracy, and consistency are paramount. To ensure the highest quality of products, manufacturers rely on three crucial processes: calibration, validation, and qualification. Despite being integral to quality assurance, these terms are often confused or used interchangeably. This article aims to clarify the differences between these three processes, shedding light on their distinct roles and importance in the pharmaceutical industry.

Flow chart of calibration ,validation and qualification process:

1. Calibration: Ensuring Accuracy in Measurements

Definition and Purpose
Calibration refers to a set of operations performed to establish the relationship between the values indicated by a measuring instrument or system and the known values of a reference standard. Essentially, calibration ensures that instruments such as thermometers, pressure gauges, and pH meters provide accurate and reliable readings. The purpose of calibration is to detect and correct any discrepancies in measurements, thereby ensuring the precision of the instruments used in manufacturing processes.

Key Aspects

• Reference Standards: Calibration always involves the use of reference standards. These are materials or instruments with a known and precise value against which the performance of the measuring device is compared.
• Specified Conditions: Calibration is conducted under controlled and specified conditions to ensure consistency and accuracy in the results.
• Acceptance Limits: Acceptance limits are predetermined for each instrument, indicating the acceptable range of deviation from the standard value. If an instrument’s readings fall outside these limits, adjustments or repairs may be necessary.

Example
Consider a balance used to weigh pharmaceutical ingredients. Calibration involves comparing the readings of this balance with the known weight of a certified standard. If the balance shows the expected results within the acceptable range, it is considered calibrated. If not, it may need to be adjusted or serviced to meet accuracy requirements.

2. Validation: Proving Consistency in Processes

Definition and Purpose
Validation is the process of providing documented evidence that a procedure, process, or method consistently leads to the expected results. In other words, validation ensures that every step of a manufacturing process works as intended and produces consistent, high-quality outcomes.

Validation is essential in pharmaceutical manufacturing because it confirms that processes such as sterilization, mixing, and tablet compression consistently produce products that meet pre-determined specifications and regulatory requirements.

Key Aspects

• Documented Evidence: Validation is a thoroughly documented process. This documentation serves as proof that the method, process, or procedure reliably produces the intended results.
• Process-Oriented: Unlike calibration, which focuses on equipment, validation focuses on the performance of processes and methods. It ensures that processes work correctly under real-world manufacturing conditions.
• Continuous Monitoring: Validation is not a one-time activity. It requires continuous monitoring to ensure that the validated process continues to perform as expected.

Example
In the manufacturing of sterile injectables, the sterilization process must be validated to ensure that it effectively eliminates all microorganisms. The validation process includes running the sterilization cycle multiple times under different conditions and proving that the process consistently achieves sterility.

3. Qualification: Ensuring Proper Installation and Functionality

Definition and Purpose
Qualification refers to the action of proving and documenting that premises, systems, and equipment are properly installed, function correctly, and deliver the expected results. Qualification is typically the initial step in the validation process. It ensures that all equipment and systems are installed and working as intended before the actual process validation begins.

Qualification is often divided into three stages:

• Installation Qualification (IQ): Verifies that equipment is installed correctly and according to the manufacturer’s specifications.
• Operational Qualification (OQ): Demonstrates that the equipment operates within the defined parameters and performs its intended function.
• Performance Qualification (PQ): Confirms that the equipment consistently performs according to the required specifications in actual production environments.

Key Aspects

• Part of Validation: Qualification is often seen as the first step of validation. Equipment must be qualified before it can be validated for use in the manufacturing process.
• Equipment and Systems: Qualification focuses on the physical premises, equipment, and systems (such as HVAC or water purification systems), ensuring that they meet the required standards.
• Documented Proof: Similar to validation, qualification is a documented process that proves the equipment or system is fit for its intended purpose.

Qualification and Calibration Example

Consider a pharmaceutical manufacturer installing a new tablet press machine. Before the machine can be used for production, it must undergo qualification. Installation Qualification (IQ) ensures that the machine is installed correctly, Operational Qualification (OQ) verifies that it functions as expected under various conditions, and Performance Qualification (PQ) proves that the machine consistently produces tablets of the required quality.

The Interconnection of Calibration, Validation, and Qualification

Though distinct in their objectives, calibration, validation, and qualification are interconnected and form the foundation of pharmaceutical quality assurance. Here’s how they relate:

• Calibration focuses on ensuring the accuracy of measuring instruments. Accurate instruments are essential for both qualification and validation, as they provide the data needed to assess performance and consistency.
• Qualification ensures that equipment and systems are correctly installed and functioning before they are used in the manufacturing process. Without qualification, process validation cannot occur, as the equipment must first be proven to work as intended.
• Validation confirms that the manufacturing process, once the equipment has been qualified and calibrated, consistently produces the desired outcomes. Validation cannot happen without first qualifying the equipment and ensuring that the instruments used are properly calibrated.

Conclusion:

While calibration, qualification, and validation may seem similar, they each play distinct roles in ensuring the quality and consistency of pharmaceutical products. Calibration ensures that instruments provide accurate measurements, qualification ensures that equipment and systems are correctly installed and operational, and validation proves that processes consistently produce the expected results. Together, these three pillars form the backbone of quality assurance in pharmaceutical manufacturing, working in unison to maintain the safety, efficacy, and reliability of the products we depend on.

Frequently asked questions (FAQ):

1. What is the difference between calibration, validation, and qualification?
   • Calibration is the process of adjusting and verifying that a measuring instrument provides accurate results by comparing its readings with known standards. Validation, on the other hand, ensures that processes consistently produce the desired outcomes. Qualification verifies that equipment and systems are installed, functioning properly, and ready for use. While calibration focuses on accuracy of measurements, validation emphasizes process consistency, and qualification ensures equipment readiness.
2. Is validation and calibration the same?
   • No, validation and calibration are not the same. Calibration ensures the accuracy of measuring devices, while validation focuses on proving that processes or methods consistently deliver expected results. Calibration is one component within the broader validation framework, but they serve different purposes.
3. Is qualification and validation the same?
   • Qualification and validation are related but distinct. Qualification is a part of the validation process that ensures equipment and systems are installed and operational as intended. Validation extends beyond qualification to ensure that processes consistently yield the expected results.
4. What are the four types of validation in pharma?
   • The four main types of validation in pharmaceuticals are:
     1. Process Validation – Ensures the manufacturing process consistently produces products that meet quality standards.
     2. Cleaning Validation – Confirms that cleaning processes remove contaminants effectively.
     3. Analytical Method Validation – Ensures that analytical methods used in testing are accurate and reliable.
     4. Computer System Validation (CSV) – Verifies that computerized systems used in pharma comply with regulatory requirements.
5. What are the three types of calibration?
   • The three types of calibration are:
     1. Mechanical Calibration – Involves adjusting physical instruments like scales and balances.
     2. Electrical Calibration – Adjusts electrical devices such as voltmeters or ammeters.
     3. Thermal Calibration – Ensures temperature-measuring instruments, such as thermocouples, provide accurate readings.
6. What is calibration and validation in pharmacy?
   • In pharmacy, calibration ensures that measuring devices like balances, thermometers, and pH meters provide accurate results. Validation ensures that manufacturing processes, equipment, and methods reliably produce the desired quality of pharmaceutical products.
7. What is the principle of calibration?
   • The principle of calibration is to compare an instrument’s readings against a known reference standard to detect and adjust any deviation. The goal is to ensure that the instrument provides accurate and reliable measurements.
8. How to do calibration and validation?
   • Calibration involves comparing the output of an instrument to a known standard and adjusting if necessary. Validation requires a documented process to confirm that methods, equipment, and systems consistently produce the expected results through repeated testing and monitoring.
9. What is Alcoa and Alcoa Plus?
   • ALCOA stands for Attributable, Legible, Contemporaneous, Original, and Accurate, which are the principles for ensuring data integrity in pharma. ALCOA Plus expands on this by adding Complete, Consistent, Enduring, and Available to further strengthen data integrity standards.
10. What is SOP in pharma?

• SOP stands for Standard Operating Procedure, a documented set of instructions that detail how to perform specific tasks or operations in pharmaceutical manufacturing to ensure consistency, quality, and compliance with regulatory requirements.

11. What are the 4 levels of validation?

• The four levels of validation are:
  1. Installation Qualification (IQ)
  2. Operational Qualification (OQ)
  3. Performance Qualification (PQ)
  4. Process Validation

12. What is the purpose of calibration?

• The purpose of calibration is to ensure that measuring instruments provide accurate and reliable results, thereby ensuring the integrity of data used in pharmaceutical manufacturing and quality control.

13. What is an example of calibration?

• An example of calibration is adjusting a laboratory balance by comparing its readings against a certified weight and making necessary adjustments to ensure the balance provides accurate weight measurements.

14. What are the 5 points of calibration?

• The 5 key points of calibration include:
  1. Reference Standard: Use of a known standard.
  2. Comparison: Compare the instrument’s readings with the standard.
  3. Adjustment: Make necessary adjustments if deviations are found.
  4. Documentation: Record the calibration process and results.
  5. Verification: Re-test to confirm accurate calibration.

15. What is CAPA in pharma?

• CAPA stands for Corrective and Preventive Action. It is a systematic approach used in pharma to address deviations or issues (corrective) and to prevent their recurrence (preventive).

16. What is BMR and BPR in pharma?

• BMR stands for Batch Manufacturing Record, which documents the manufacturing process of each batch. BPR stands for Batch Packaging Record, detailing the packaging process of a batch.

17. What is QC in pharma?

• QC stands for Quality Control. It involves the testing and verification of products to ensure they meet predefined quality standards and regulatory requirements.

18. Why calibration and validation?

• Calibration ensures the accuracy of measuring instruments, while validation ensures that processes consistently produce quality results. Together, they guarantee the precision and consistency needed to maintain high product quality in pharmaceuticals.

19. What is calibration in pharma?

• Calibration in pharma refers to adjusting and verifying the accuracy of measuring devices used in production and quality control, ensuring they provide reliable and precise measurements.

20. What are the different types of validation?

• The types of validation include:
  1. Process Validation
  2. Cleaning Validation
  3. Analytical Method Validation
  4. Computer System Validation (CSV)

21. What is validation in pharma?

• Validation in pharma refers to the process of providing documented evidence that a process, method, or system consistently produces the desired outcome under predefined conditions.

22. What is calibration in simple words?

• Calibration is the process of adjusting an instrument to ensure that it provides accurate measurements by comparing it with a known reference.

23. What is the difference between QC and validation?

• Quality Control (QC) focuses on testing products to ensure they meet quality standards, while validation ensures that the processes used to create the products consistently deliver the desired outcomes.

24. What is the difference between validation, qualification, and calibration?

• Calibration ensures measurement accuracy, qualification verifies equipment readiness, and validation ensures process consistency.

25. What is calibration according to USFDA?

• According to the USFDA, calibration is the process of comparing and adjusting the output of an instrument to ensure it provides accurate measurements based on a known standard.

26. What is calibration for QA?

• In Quality Assurance (QA), calibration ensures that all instruments used for measurements are accurate and reliable, which is critical for maintaining product quality and regulatory compliance.

27. What is the difference between a calibrator and QC?

• A calibrator is a reference standard used to adjust or verify the accuracy of instruments, while QC refers to the process of testing products to ensure they meet quality specifications.

28. What does ISO 9001 say about calibration?

• ISO 9001 emphasizes the need for regular calibration of instruments used in manufacturing and testing to ensure their accuracy and reliability.

29. What is validation also known as?

• Validation is also known as qualification when referring to equipment, or process validation when referring to manufacturing processes.

30. What is the difference between OQ and PQ validation?

• Operational Qualification (OQ) verifies that equipment operates according to its specifications, while Performance Qualification (PQ) confirms that equipment performs effectively under real-world production conditions.

Pharmaceutical process validation, qualification and calibration