Facility qualification is an essential step at the beginning of implementation of Good Manufacturing Practices in any pharmaceutical manufacturing facility. Facility qualification provides an indirect assurance that the manufacturing site equipment, utilities and systems for manufacturing are correctly installed and operated to produce high quality products consistently.
Regulatory agencies such as USFDA and other international regulatory agencies such as European Medicines Agency (EMA) and World Health Organization (WHO) require pharmaceutical manufacturers to demonstrate facility qualification as a part of their compliance to GMP.
In this article, we will understand what facility qualifications consist of, the stages of facility qualification, how to document facility qualification and the expectations of regulatory agencies.
Additionally, in simple terms, facility qualification serves to demonstrate the alignment of “as build” equipment to the “as designed” equipment. Facility qualification is a part of total process of validation, not only for the equipment but also for utilities and processes.
Facility qualification process demonstrates that all systems determined to be critical to the manufacturing of pharmaceutical products such as HVAC systems, water distribution systems, compressed air systems and cleanroom environment meet GMP compliance requirements.
1. Regulatory Compliance: Regulatory bodies such as USFDA and WHO GMP require documentation of qualification as evidence of compliance with Good Manufacturing Practice (GMP) regulations.
2. Product Quality Assurance: The facility qualification process ensures that all aspects of the facility environment and all systems necessary for safe drug manufacturing are in place.
3. Operational Consistency: The facility qualification ensures that equipment and facilities will operate consistently under a controlled and reproducible manner.
4. Risk Mitigation: The qualification process identifies and reduces potential contamination, mix up and equipment failure issues.
5. Audit Readiness: Properly qualified facilities have established control. Therefore, there is less potential for audit observations in a qualified facility.
If a facility is not qualified, even the best facility design could result in the production of low quality products.
Validation = DQ + IQ + OQ + PQ
These four stages are applicable to both equipment and facilities. Let us now examine each of these stages in detail.
DQ has several main components:
- Review of layout, flow chart and user requirement specification (URS)
- Verification of logical separation of clean and unclean
- Verification of air pressure differential and moving men and materials
- Verification that utilities (like HVAC system, purified water system) can support the process being implemented
For example, during DQ, QA verifies that the cleanroom design confirms the ISO Class 7 and allows unidirectional flow of materials.
- Verification of the installation against the engineering drawing
- Verification of construction materials (SS, epoxy, PVC) to ensure accordance with URS
- Calibration of monitoring devices
- Verification of air filters, pressure gauges, and temperature sensors
- Verification that all utilities like power, water and compressed air are operational and connected
- Review vendor documents and certificates
IQ will confirm that all of the components have been installed and documented correctly before any operational testing occurs.
- Measuring flow velocities, pressure differential tests and monitoring temperature uniformity
- Validating the performance of HVAC systems through HEPA filter integrity test, air flow studies and emergency recovery time
- Testing alarms, interlocks and control systems
- Conducting utility performance tests for purified water system, compressed air systems and steam systems
- Document software and automation controls for performance verification
Results must demonstrate the ability to obtain consistent and reliable performance in simulated usage conditions.
- Monitoring environmental conditions in clean rooms during several different production cycles
- Developing a temperature and humidity map of storage areas
- Reviewing the flow of people and materials during active production
- Validating the repeatable nature of results from HVAC and utility systems
- Evaluating product quality in the same manner as with normal manufacturing operations.
PQ is the last step in qualifying facility operations and demonstrates ongoing performance consistency overtime.
Manufacturing and cleanroom areas: Performance of HVAC System including air classifications, particle counts and pressure differentials.
HVAC systems: Air handling units, filters, ductwork and controls for the temperature and humidity.
Water systems: Purified water system, water for injection system and water distribution loop.
Compressed air/nitrogen systems: Quality testing for oil, moisture and particulates.
Lighting and power supply: Validation of emergency lighting, sockets and voltage stability.
Storage areas: Temperature mapping of warehouse, cold storage, quarantine area etc.
Drains and piping: Verification of slope of all drains, accessibility to drains and the material used for construction for the drain piping etc.
1. After significant maintenance or modification
2. Following extended shutdowns
3. At predetermined intervals typically every two or three years.
How often to perform requalification will be determined by both risk assessment and previous performance history. For example, HVAC and water systems may require annual requalification while static sources such as clean room panels only require requalification when necessary.
WHO-GMP: The following regulatory requirements regarding facility qualification.
- Critical utilities HVAC and cleanroom systems must be qualified prior to process validation.
- Change control and requalification after a change must be controlled by a document and must be documented.
EU-GMP Annex 15: It has the following regulatory requirements regarding facility qualification.
- EU-GMP Annex 15 provides, in detail, EU GMP Qualification Stages (DQ, IQ OQ PQ).
- EU-GMP Annex 15 allows Risk Based Qualification Scope Definitions.
- EU-GMP Annex 15 requires a written Validation Master Plan (VMP) that Summarizes the Qualification Strategy.
Regulatory authorities expect that facility qualification will be completed using a systematic, documented and risk based process for all critical facilities and systems.
Download Facility Qualification Checklist
The execution of a well organized qualification program has control over the process, reduces risk and develops trust during the inspection process. Deploying a formal, structured approach to completing a facility qualification and maintaining complete, detailed documentation demonstrates both regulatory compliance and safe products.
Regulatory agencies such as USFDA and other international regulatory agencies such as European Medicines Agency (EMA) and World Health Organization (WHO) require pharmaceutical manufacturers to demonstrate facility qualification as a part of their compliance to GMP.
In this article, we will understand what facility qualifications consist of, the stages of facility qualification, how to document facility qualification and the expectations of regulatory agencies.
What is Facility Qualification
Facility qualification verifies thorough documented proofs that the manufacturing plant and its components as well as associated systems have all been installed according to the specifications and are functioning according to their intended purpose. Facility qualification confirms that pharmaceutical manufacturing facilities can consistently produce pharmaceutical products in accordance with established specifications and quality assurance standards.Additionally, in simple terms, facility qualification serves to demonstrate the alignment of “as build” equipment to the “as designed” equipment. Facility qualification is a part of total process of validation, not only for the equipment but also for utilities and processes.
Facility qualification process demonstrates that all systems determined to be critical to the manufacturing of pharmaceutical products such as HVAC systems, water distribution systems, compressed air systems and cleanroom environment meet GMP compliance requirements.
The Importance of Facility Qualification
Facility qualification is an integral part of an organization’s quality management system (QMS) rather than a simple regulation requirement. A few examples of why facility qualification is critical include:1. Regulatory Compliance: Regulatory bodies such as USFDA and WHO GMP require documentation of qualification as evidence of compliance with Good Manufacturing Practice (GMP) regulations.
2. Product Quality Assurance: The facility qualification process ensures that all aspects of the facility environment and all systems necessary for safe drug manufacturing are in place.
3. Operational Consistency: The facility qualification ensures that equipment and facilities will operate consistently under a controlled and reproducible manner.
4. Risk Mitigation: The qualification process identifies and reduces potential contamination, mix up and equipment failure issues.
5. Audit Readiness: Properly qualified facilities have established control. Therefore, there is less potential for audit observations in a qualified facility.
If a facility is not qualified, even the best facility design could result in the production of low quality products.
Relationship Between Qualification and Validation
Qualification is a part of the validation process. Whereas validation is the overall process of demonstrating that a particular system has been developed for its intended purpose. Qualification is especially concerned with facility, utility and equipment.Validation = DQ + IQ + OQ + PQ
These four stages are applicable to both equipment and facilities. Let us now examine each of these stages in detail.
Stages of Facility Qualification
1. Design Qualification (DQ)
Design qualification is the initial stage of the qualification process that verifies that the facility design meets GMP and project requirements.DQ has several main components:
- Review of layout, flow chart and user requirement specification (URS)
- Verification of logical separation of clean and unclean
- Verification of air pressure differential and moving men and materials
- Verification that utilities (like HVAC system, purified water system) can support the process being implemented
For example, during DQ, QA verifies that the cleanroom design confirms the ISO Class 7 and allows unidirectional flow of materials.
2. Installation Qualification (IQ)
Installation qualification verifies that the facility, its equipment and the utilities have been installed as per the design and the manufacturer’s specification. An IQ may consist of the following verification activities:- Verification of the installation against the engineering drawing
- Verification of construction materials (SS, epoxy, PVC) to ensure accordance with URS
- Calibration of monitoring devices
- Verification of air filters, pressure gauges, and temperature sensors
- Verification that all utilities like power, water and compressed air are operational and connected
- Review vendor documents and certificates
IQ will confirm that all of the components have been installed and documented correctly before any operational testing occurs.
3. Operational Qualification (OQ)
Operational Qualification confirms the installation of systems and their functionality within designated areas. Typical activities associated with OQ include:- Measuring flow velocities, pressure differential tests and monitoring temperature uniformity
- Validating the performance of HVAC systems through HEPA filter integrity test, air flow studies and emergency recovery time
- Testing alarms, interlocks and control systems
- Conducting utility performance tests for purified water system, compressed air systems and steam systems
- Document software and automation controls for performance verification
Results must demonstrate the ability to obtain consistent and reliable performance in simulated usage conditions.
4. Performance Qualification (PQ)
PQ confirms the performance of a facility as expected under extended manufacturing operations. Typical activities associated with a PQ include:- Monitoring environmental conditions in clean rooms during several different production cycles
- Developing a temperature and humidity map of storage areas
- Reviewing the flow of people and materials during active production
- Validating the repeatable nature of results from HVAC and utility systems
- Evaluating product quality in the same manner as with normal manufacturing operations.
PQ is the last step in qualifying facility operations and demonstrates ongoing performance consistency overtime.
Systems and Areas Included in Facility Qualification
Facilities must be qualified for:Manufacturing and cleanroom areas: Performance of HVAC System including air classifications, particle counts and pressure differentials.
HVAC systems: Air handling units, filters, ductwork and controls for the temperature and humidity.
Water systems: Purified water system, water for injection system and water distribution loop.
Compressed air/nitrogen systems: Quality testing for oil, moisture and particulates.
Lighting and power supply: Validation of emergency lighting, sockets and voltage stability.
Storage areas: Temperature mapping of warehouse, cold storage, quarantine area etc.
Drains and piping: Verification of slope of all drains, accessibility to drains and the material used for construction for the drain piping etc.
Documents Needed for Facility Qualification
Facility qualification requires significant amount of document in order to establish traceability, verification and approval throughout each stage of the facility qualification process. Documents required include:- User Requirement Specifications (URS)
- Design Qualification Report (DQ)
- Installation Qualification Protocol (IQ), Operational Qualification Protocol (OQ), Performance Qualification Protocol (PQ) and their respective reports.
- Calibration and maintenance records.
- As built drawings/layouts
- Standard Operating Procedures (SOP) for utilities, cleaning.
- Deviations, Corrective Action(s) and Approvals.
- Summary Report of Final Qualification.
- Documentation establishes compliance with GMP and provides documentation for Regulatory Inspection.
Requalification
Facilities are periodically requalified to ensure that they continue to operate as intended and are requalified:1. After significant maintenance or modification
2. Following extended shutdowns
3. At predetermined intervals typically every two or three years.
How often to perform requalification will be determined by both risk assessment and previous performance history. For example, HVAC and water systems may require annual requalification while static sources such as clean room panels only require requalification when necessary.
Regulatory Requirements for Facility Qualification
USFDA (21 CFR Part 211): Facility and equipment should have documented evidence of their design, maintenance and operation to produce quality products (21 CFR Part 211.42 – Design Construction and 21 CFR Part 211.63 - Equipment Design).WHO-GMP: The following regulatory requirements regarding facility qualification.
- Critical utilities HVAC and cleanroom systems must be qualified prior to process validation.
- Change control and requalification after a change must be controlled by a document and must be documented.
EU-GMP Annex 15: It has the following regulatory requirements regarding facility qualification.
- EU-GMP Annex 15 provides, in detail, EU GMP Qualification Stages (DQ, IQ OQ PQ).
- EU-GMP Annex 15 allows Risk Based Qualification Scope Definitions.
- EU-GMP Annex 15 requires a written Validation Master Plan (VMP) that Summarizes the Qualification Strategy.
Regulatory authorities expect that facility qualification will be completed using a systematic, documented and risk based process for all critical facilities and systems.
Download Facility Qualification Checklist
Findings Related to Facility Qualification
Common audit findings on facility qualification audits include:- Lack of complete DQ, IQ, OQ or PQ documentation
- Lack of requalification after modifications
- Validation of HVAC performance is inadequate
- Unapproved design changes and poor change control
- Calibration and maintenance records are incomplete
- Improper documentation or closure of deviation
Best Practices for Effective Facility Qualification
- Developing a validation master plan that includes all facility and utility systems
- Utilizing best practices to determine facility qualification priority according to the organization’s risk based resource allocation.
- Maintaining traceability between URS, design, qualification and validation reports.
- Utilizing a multidisciplinary approach for the entire qualification process (QA, engineering, production and validation).
- Integrating the calibration and preventive maintenance program throughout the entire qualification process.
- Providing access to qualification data to facilitate regulatory inspections.
- Training of qualification personnel regarding the qualification process as well as the principles of GMP.
The execution of a well organized qualification program has control over the process, reduces risk and develops trust during the inspection process. Deploying a formal, structured approach to completing a facility qualification and maintaining complete, detailed documentation demonstrates both regulatory compliance and safe products.
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