According to Good Manufacturing Practice (GMP) regulations, the distinction between qualification vs validation forms the cornerstone of ensuring adherence to stringent quality and safety standards.
Before a medicine can be released to the market, it must undergo rigorous testing to meet regulatory guidelines and quality standards. Two essential processes in this testing are qualification and validation studies.
While these terms are often used interchangeably, they have distinct meanings and serve different purposes. Understanding the differences between qualification and validation is crucial for anyone in the pharmaceutical industry.
Qualification: Ensuring Fitness for Intended Purpose
Qualification is the process of verifying that a piece of equipment or a particular item is fit for its intended purpose. It focuses on ensuring that all aspects of the equipment or facility meet regulatory and operational requirements.
Qualification ensures that the equipment, instruments, and software used in the pharmaceutical industry are functioning properly and capable of producing consistent results. This process is directly linked to the equipment, rather than the overall process itself.
Applications of Qualification
Qualification is a comprehensive process applied to various elements within a manufacturing facility, encompassing:
- Equipment: Ensures the correct functioning and performance of manufacturing equipment.
- Ancillary Systems: Validates the reliability of support systems integral to the manufacturing process.
- Instruments: Verifies the accuracy and precision of measurement instruments used in production.
- Utilities: Qualifies utility systems such as water, air, and power to meet specified requirements.
Regulatory Emphasis
Regulatory authorities, such as the FDA (Food and Drug Administration) and EMA (European Medicines Agency), pay meticulous attention to the qualification processes in manufacturing facilities. The focus on qualification intensifies during regulatory inspections when approving medicines produced in a given facility. Compliance with qualification standards is a critical factor in obtaining regulatory approval for pharmaceutical products.
Key Qualification Steps: A Brief Overview
The qualification process involves several key steps to ensure the reliability and functionality of equipment, systems, and instruments. These steps include:
1. User Requirements Specification (URS)
The foundation of the qualification process lies in the User Requirements Specification (URS). In this stage, the specifications for equipment, facilities, utilities, or systems are defined. The URS serves as a reference point throughout the validation life cycle. Essential quality elements must be incorporated at this stage, and any GMP risks should be mitigated to an acceptable level.
Read our article for User Requirement Specification – URS, with a free template.
2. Design Qualification (DQ)
Following the URS, the next critical step is Design Qualification (DQ). This stage focuses on demonstrating and documenting the compliance of the design with GMP. Verifying the user requirements specification occurs during DQ, ensuring that the design aligns with the specified criteria.
3. Factory Acceptance Testing (FAT) / Site Acceptance Testing (SAT)
Before equipment is delivered, especially if it incorporates novel or complex technology, evaluation may occur at the vendor’s site (FAT). Documentation review and tests may be performed at these stages without the need for repetition on-site if functionality is not affected by transport and installation.
Additionally, Site Acceptance Testing (SAT) may supplement FAT upon receipt of equipment at the manufacturing site.
Read more about the importance of FAT and SAT for equipment validation.
4. Installation Qualification (IQ)
The Installation Qualification (IQ) phase is critical for verifying the correct installation of components, instrumentation, equipment, pipework, and services against engineering drawings and specifications. It includes calibration of instrumentation, verification of materials of construction, and the collection of supplier operating and maintenance instructions.
Table 1 – Installation Qualification Checklist
Verification Aspect | Criteria |
Correct installation of components | Verified against engineering drawings |
Calibration of instrumentation | Completed |
Materials of construction | Verified |
Supplier operating and maintenance instructions | Collected and collated |
5. Operational Qualification (OQ)
Operational Qualification (OQ) typically follows IQ but may be combined into an Installation/Operation Qualification (IOQ) for complex equipment. OQ includes tests developed from knowledge of processes, systems, and equipment to ensure the system operates as designed. It also confirms upper and lower operating limits and “worst case” conditions.
Table 2 – Operational Qualification Criteria
OQ Aspect | Criteria |
Tests for system operation as designed | Passed |
Confirmation of upper and lower operating limits | Verified |
Successful completion of OQ allows for the finalization of standard operating and cleaning procedures, operator training, and preventative maintenance requirements.
6. Performance Qualification (PQ)
Performance Qualification (PQ) typically follows successful IQ and OQ completion. While PQ often occurs separately, it may be appropriate to perform it in conjunction with OQ or Process Validation in some cases. PQ involves tests using production materials, qualified substitutes, or simulated products with equivalent behavior under normal operating conditions, including worst-case batch sizes.
Table 3 – Performance Qualification Testing
PQ Aspect | Testing Criteria |
Tests using production materials or equivalents | Frequency of sampling justified |
Operating range coverage (unless documented evidence is available) | Verified |
Validation: Consistently Delivering Quality Products
Validation, on the other hand, focuses on the overall process rather than the equipment. It is the documented act of demonstrating that a procedure, process, or activity consistently produces results that meet predetermined specifications.
Validation is a systematic approach that checks and helps processes to have expected and consistent outcomes. It involves testing and analyzing the process to ensure it meets the required specifications and quality standards.
The validation process in the pharmaceutical industry includes various activities such as process design, process verification, process confirmation, and process qualification. These activities aim to establish objective evidence that a process can consistently deliver a quality product. Validation is directly linked to the process itself, ensuring that it consistently meets regulatory guidelines and industry standards.
1. Process Validation
Process validation serves as the backbone of quality assurance, encompassing various stages of product development, modifications, transfers, and ongoing verification.
As per FDA requirements (Section 820.75 of the Quality System Regulation), process validation involves inspecting the performance of the process to obtain documented assurance that the manufacturing process meets pre-defined acceptance criteria.
Activities related to machines, systems, and equipment are referred to as “qualifications” and include design qualification (DQ), installation qualification (IQ), operational qualification (OQ), and performance qualification.
Read more about process validation in our article.
Validation Approaches
Some of the validation approaches used in the pharmaceutical industry, according to Eudralex Annex 15 – Qualification and Validation include:
Concurrent Validation
In exceptional circumstances, concurrent validation may be employed, provided it is justified, documented in the Validation Master Plan (VMP), and approved by authorized personnel. Sufficient data supporting batch uniformity and adherence to acceptance criteria should be formally documented.
Traditional Process Validation
The traditional approach involves manufacturing batches under routine conditions to confirm reproducibility. The number of batches and samples taken should align with quality risk management principles, establishing variation trends. Typically, a minimum of three consecutive batches under routine conditions constitutes validation.
Process Validation Protocol
A comprehensive process validation protocol is essential, defining critical process parameters, critical quality attributes, and associated acceptance criteria. The protocol should cover a range of elements, including process description, responsibilities, equipment lists, and analytical methods.
Continuous Process Verification
For products developed using a quality-by-design approach, continuous process verification serves as an alternative to traditional validation. A science-based control strategy for incoming materials, critical quality attributes, and critical process parameters is defined. Regular evaluation of the control strategy, using tools like Process Analytical Technology and multivariate statistical process control, ensures consistent product quality.
Hybrid Approach and Ongoing Process Verification
A hybrid approach, combining elements of traditional and continuous verification, may be adopted based on substantial product and process knowledge. This approach proves useful for validation activities post-changes or during ongoing process verification.
The ongoing process verification, applicable across all validation approaches, involves periodic monitoring, review, and documentation of process trends. Statistical tools support conclusions about process variability and capability, ensuring a state of control.
2. Validation of Test Methods
Validation should include the establishment of appropriate detection and quantification limits. These limits are crucial for determining the method’s sensitivity and its ability to detect and quantify low concentrations of analytes. This is particularly important in ensuring the method’s suitability for its intended purpose.
Read our article about analytical method validation, how it affects testing integrity and why is it important.
Microbial Testing of Products
Validation for Product-Related Testing
For microbial testing of pharmaceutical products, the testing method must undergo validation to confirm that the product itself does not interfere with the recovery of microorganisms. This is essential for maintaining the accuracy of microbial testing results and ensuring the safety and efficacy of the final product.
Microbial Testing in Clean Rooms
Validation for Clean Room Surfaces
In clean room environments, where microbial testing of surfaces is conducted, the validation of the test method is critical. The objective is to confirm that sanitizing agents used in clean rooms do not impact the recovery of microorganisms. Validating these methods ensures the reliability of data related to clean room hygiene and microbial contamination control.
3. Cleaning Validation
The primary goal of cleaning validation is to confirm the efficiency of cleaning procedures, thereby preventing cross-contamination and ensuring the production of safe and high-quality pharmaceutical products.
Visual Inspection and Acceptance Criteria
Visual checks for cleanliness are integral to the acceptance criteria for cleaning validation. However, relying solely on visual inspection is generally unacceptable. The repeated cleaning and retesting approach until acceptable residue results are obtained is not considered appropriate.
Factors Influencing Cleaning Processes
Level of Automation
Validation should consider the level of automation in the cleaning process. For automatic processes, the specified normal operating range of utilities and equipment should undergo validation.
Variable Factors Assessment
An assessment should be conducted to identify variable factors influencing cleaning effectiveness, such as operator influence and procedural details. Worst-case situations should be used as the basis for cleaning validation studies.
Limits and Risk Assessment
Carryover Limits
Limits for the carryover of product residues should be based on a toxicological evaluation. A risk assessment documenting the justification for selected limits should be conducted, considering the cumulative effect of multiple equipment items.
Therapeutic Macromolecules and Peptides
Special considerations apply to therapeutic macromolecules and peptides, which may degrade under certain conditions. In such cases, a toxicological evaluation may not be applicable.
Representative Parameters
If testing for specific product residues is not feasible, representative parameters like total organic carbon (TOC) and conductivity may be selected.
4. Validation of Computerized Systems
Validation of computerized systems is a crucial process in the pharmaceutical industry, ensuring the integrity, reliability, and compliance of these systems throughout their life cycle.
Risk-Based Approach
Validation follows a risk-based approach, requiring manufacturers to justify standards, protocols, acceptance criteria, procedures, and records based on a thorough risk assessment. This approach ensures that validation efforts are focused on areas with the highest potential impact.
Documentation and Reporting
Validation documentation includes change control records, accounting for any modifications during the process. Deviation reports are also essential to document any observed deviations during validation. Maintaining an up-to-date system inventory provides a clear overview of relevant systems and their GMP functionality.
For critical systems, a detailed system description covers physical and logical arrangements, data flows, interfaces, prerequisites, and security measures.
User Requirements Specifications
User Requirements Specifications (URS) describe required functions based on documented risk assessments and GMP impact. This documentation ensures that user requirements are traceable throughout the life cycle.
Quality Management and Supplier Assessment
The regulated user ensures that the system is developed in compliance with an appropriate quality management system. Additionally, suppliers undergo thorough assessments to guarantee reliability and compliance.
Qualification vs Validation: Key Differences
While qualification and validation are both essential processes in the pharmaceutical industry, they have distinct differences. The table below summarizes the key differences between qualification vs validation:
Importance of Qualification and Validation in the Pharmaceutical Industry
The pharmaceutical industry holds qualification and validation in high regard due to their vital roles in ensuring the production of safe and effective products. Regulatory agencies such as the FDA, EMA, WHO, and others require pharmaceutical companies to conduct qualification and validation studies to meet regulatory guidelines.
Qualification and validation processes are crucial for ensuring production efficiency and minimizing the risk of product failures. By thoroughly testing and inspecting equipment and processes, pharmaceutical companies can reduce rejections, minimize the chances of product recalls, and ultimately provide safe and effective products for consumers.
FAQ: Qualification vs Validation
Frequency depends on factors like equipment changes, process modifications, and regulatory requirements.
Non-compliance may lead to regulatory issues, product recalls, and compromised safety and efficacy.
Qualification ensures the reliability of equipment and facilities, reducing the likelihood of failures in the manufacturing process. Validation ensures that the entire production process consistently meets quality standards, minimizing the risk of producing substandard products.
Implementing both qualification and validation activities is crucial for companies in regulated industries to align with GxP regulations. Qualification ensures equipment and systems comply with specifications, while validation guarantees consistent processes and results, reinforcing the principles of Good Manufacturing Practice (GMP), Good Laboratory Practice (GLP), and Good Clinical Practice (GCP) by mitigating risks and maintaining documentation traceability.
Conclusion: Differences Between Qualification vs Validation
Qualification and validation studies are essential processes in the pharmaceutical industry that ensure the safety, efficacy, and quality of drugs. While qualification focuses on verifying the fitness of equipment and facilities, validation ensures that processes consistently deliver expected outcomes. Understanding the key differences between qualification and validation is crucial for maintaining regulatory compliance and producing safe and effective products.
By following best practices and conducting thorough qualification and validation studies, pharmaceutical companies can minimize the risk of product failures, reduce rejections, and provide consumers with reliable and high-quality drugs. The qualification and validation process, when executed effectively, contributes to the overall success and reputation of the pharmaceutical industry.