While utilities are typically viewed as engineering systems, they can have a direct impact on product quality, contamination control, process performance and batch release in a GMP facility. Qualification of utilities offers the evidence that a utility is designed, installed, operated and shown to function successfully in a given pharmaceutical application.
Some examples of utility equipment common in the pharma industry include purified water, water for injection (WFI), HVAC, clean or pure steam, compressed air, nitrogen and other process gases. Depending on the facility, chilled water, cooling water, vacuum, electricity and other support systems may also need to be qualified or verified.
In short, a good utility qualification program must ask the following question first: What consequences could the failure of a utility have?
For instance, WFI employed in formulations has direct and important impact on product quality. Also, compressed air in contact with the product or the surface of the product must undergo thorough analyzing of chemical, particulate and microbiological risks. HVAC serving sterile processing area of products is exposed to another level of risk than the HVAC serving non-GMP warehouse.
Risk assessment includes assessment of the following issues:
1. Direct contact with a product and the product-contact surfaces;
2. Various contaminating or cross- contamination contributions;
3. Critical process parameters affected by the utility;
4. Microbiological and chemical quality requirements;
5. Possible failure modes and alarm situations;
6. Any seasonal or other operational changes;
7. Type of redundancy and options for recovering.
In general, risk-based approach helps to avoid two situations: inspection of an important utility is insufficient; on the other hand, the procedures performed on the system with minor impact on GMP are performed excessively.
The User Requirements Specification (URS) provides the requirements that need to be fulfilled by the utility, such as its capacity, quality characteristics, operating range, control requirements, monitoring, alerts and relevant GMP requirements.
The design needs to go through Design Qualification (DQ) to be confirmed that the design meets the needs outlined in the URS.
For example, the design review for the pharmaceutical water system may deal with the construction material, storage capacity, distribution loop design, sanitizing method, flow, temperature, dead legs and sampling points. As for HVAC, such terms as pressure differentials, air flow, filtration, temperature, humidity and air change are of essence.
According to the EU GMP Annex 15, qualification is a life cycle process in terms of equipment, buildings, utilities and systems.
Typical IQ evidences include the following:
The tests should not only include tests conducted under ordinary operational conditions, the risks should also be taken into account and results obtained in extreme conditions in addition to limits of operations, functionality of alarms and interlocks.
For instance, HVAC OQ may include verification of temperature, humidity, differential pressure, air flow, alarms and control subsystems. Compressed air systems require verification of pressure, air flow and alarm and quality characteristics.
The WHO qualification guidance describes similar meaning of the term Operational qualifications.
This is significant to note. It is possible for a system to pass the IQ test and the OQ test yet fail to perform during its use.
For a water system for pharmaceuticals PQ may mean the need for extensive monitoring of the chemical and microbiological quality in various places of use. Performance qualification in terms of HVAC may include checking sustainable environmental performance in representative conditions.
The WHO clearly state that pharmaceutical water systems need to be constructed, installed and maintained in a way that ensures high quality of the produced water.
In order for a utility to qualify, it must continuously stay qualified and controlled through calibrations, maintenance, monitoring, applicable change control and frequent reviews, including requalification if necessary.
To illustrate this, let us consider the case of a purified water distribution loop. The initial qualification process may show that the utility is qualified in terms of conductivity, TOC and microbiological parameters. However, any modifications in the sanitization frequency, pump design, storage temperature, flow characteristics, piping or any of the outlets of the system may affect its validated conditions.
WHO advises that the pharmaceutical water systems should be continuously monitored and specified by relevant online indicators and offline physical, chemical and microbiological tests and trend change investigations should be provided where needed.
Here are some specific aspects that need to be considered during the evaluation.
1. Was the risk assessment documented and critical parameters identified?
2. Were the specifications of acceptance criteria clear beforehand?
3. Were the calibration of the qualification instruments conducted and up-to-date?
4. Were the deviations documented properly or just "closed"?
5. Were the test failures studied for their influence on solution or system?
6. Do the sampling points correspond to their actual use points?
7. Were the extreme and seasonal conditions taken into consideration where relevant?
8. Were maintenance and calibration procedures exported to corresponding procedures?
9. Were the modifications of the system properly regulated according to the change-process requirements?
10. Will the qualification data prove the correctness of the monitoring plan?
An inspector may ask a simple but rather interesting question: "How can you confirm that the utility is qualified?"
Another existing problem is ineffective change management. Changing a pump or a distribution cycle, replacing a HEPA filter configuration or modifying control system may look insignificant from a technical point of view, however, the change of state must be taken into account.
Impact assessment is therefore necessary to clarify if only partial or full re-qualification is to be carried out.
In the case of pharmaceutical manufacturing industries, this is particularly important for utility systems like water systems, HVAC, clean steam and process gases as their failures may not always be apparent during the finished product.
From a practical point of view, the aim of utility qualification is not to generate another validation record, but to provide sufficient evidence that the manufacturing process support system can safely and reliably perform its GMP duties throughout its lifecycle.
In short, a good utility qualification program must ask the following question first: What consequences could the failure of a utility have?
Start with Utility Impact and Risk
Different utilities have different qualifications. To begin with, realizations of impact assessments or quality risk assessments must be conducted that help decide the utility's major role in maintaining product quality.For instance, WFI employed in formulations has direct and important impact on product quality. Also, compressed air in contact with the product or the surface of the product must undergo thorough analyzing of chemical, particulate and microbiological risks. HVAC serving sterile processing area of products is exposed to another level of risk than the HVAC serving non-GMP warehouse.
Risk assessment includes assessment of the following issues:
1. Direct contact with a product and the product-contact surfaces;
2. Various contaminating or cross- contamination contributions;
3. Critical process parameters affected by the utility;
4. Microbiological and chemical quality requirements;
5. Possible failure modes and alarm situations;
6. Any seasonal or other operational changes;
7. Type of redundancy and options for recovering.
In general, risk-based approach helps to avoid two situations: inspection of an important utility is insufficient; on the other hand, the procedures performed on the system with minor impact on GMP are performed excessively.
Qualification Begins Before Installation
One common misconception is considering qualification as just an IQ/OQ procedure that will take place after the equipment is delivered. The proper utility qualification starts way earlier.The User Requirements Specification (URS) provides the requirements that need to be fulfilled by the utility, such as its capacity, quality characteristics, operating range, control requirements, monitoring, alerts and relevant GMP requirements.
The design needs to go through Design Qualification (DQ) to be confirmed that the design meets the needs outlined in the URS.
For example, the design review for the pharmaceutical water system may deal with the construction material, storage capacity, distribution loop design, sanitizing method, flow, temperature, dead legs and sampling points. As for HVAC, such terms as pressure differentials, air flow, filtration, temperature, humidity and air change are of essence.
According to the EU GMP Annex 15, qualification is a life cycle process in terms of equipment, buildings, utilities and systems.
IQ, OQ and PQ: What Should Each Stage Signify
Each of the qualification stages should have well-defined purposes other than physical checks done by engineering.1. Installation Qualification
IQ entails confirmation that the utility has been installed according to approved drawings, engineering specifications and design requirements.Typical IQ evidences include the following:
- Piping and Instrumentation Diagrams
- Equipment and components’ identification
- Material certificates
- Weld and inspection reports if applicable
- Instrumentation calibration status
- Installation verification
- Specification of equipment
- Approved drawings and instructions
- Identification of important instruments and valves
2. Operational Qualification
OQ shows the operational integrity of the utility in a range of conditions.The tests should not only include tests conducted under ordinary operational conditions, the risks should also be taken into account and results obtained in extreme conditions in addition to limits of operations, functionality of alarms and interlocks.
For instance, HVAC OQ may include verification of temperature, humidity, differential pressure, air flow, alarms and control subsystems. Compressed air systems require verification of pressure, air flow and alarm and quality characteristics.
The WHO qualification guidance describes similar meaning of the term Operational qualifications.
3. Performance Qualification
When it comes to PQ, a utility needs to show that it is capable of performing the required operations adequately and consistently in normal operating conditions.This is significant to note. It is possible for a system to pass the IQ test and the OQ test yet fail to perform during its use.
For a water system for pharmaceuticals PQ may mean the need for extensive monitoring of the chemical and microbiological quality in various places of use. Performance qualification in terms of HVAC may include checking sustainable environmental performance in representative conditions.
The WHO clearly state that pharmaceutical water systems need to be constructed, installed and maintained in a way that ensures high quality of the produced water.
Critical Utilities Require More Than Just a Qualification Report
One of the main practical aspects of the qualification is that it does not stop when the PQ report is finalized.In order for a utility to qualify, it must continuously stay qualified and controlled through calibrations, maintenance, monitoring, applicable change control and frequent reviews, including requalification if necessary.
To illustrate this, let us consider the case of a purified water distribution loop. The initial qualification process may show that the utility is qualified in terms of conductivity, TOC and microbiological parameters. However, any modifications in the sanitization frequency, pump design, storage temperature, flow characteristics, piping or any of the outlets of the system may affect its validated conditions.
WHO advises that the pharmaceutical water systems should be continuously monitored and specified by relevant online indicators and offline physical, chemical and microbiological tests and trend change investigations should be provided where needed.
What QA Should Look for During Utility Qualification
When reviewing a utility qualification package, I will evaluate the protocols involved. An evaluator should focus on the relationship and equivalence of design intent, hazards, testing procedures and routine controls.Here are some specific aspects that need to be considered during the evaluation.
1. Was the risk assessment documented and critical parameters identified?
2. Were the specifications of acceptance criteria clear beforehand?
3. Were the calibration of the qualification instruments conducted and up-to-date?
4. Were the deviations documented properly or just "closed"?
5. Were the test failures studied for their influence on solution or system?
6. Do the sampling points correspond to their actual use points?
7. Were the extreme and seasonal conditions taken into consideration where relevant?
8. Were maintenance and calibration procedures exported to corresponding procedures?
9. Were the modifications of the system properly regulated according to the change-process requirements?
10. Will the qualification data prove the correctness of the monitoring plan?
An inspector may ask a simple but rather interesting question: "How can you confirm that the utility is qualified?"
Common Weaknesses in Utility Qualification
The same issues are often faced in practice, including qualifying the equipment without assessing the whole utility system, applying non-specific acceptance criteria, failing to rationalize sampling sites, neglecting seasonal variability, not conducting sufficient testing of alarm activation level and using engineering commissioning documentation instead of GMP qualification.Another existing problem is ineffective change management. Changing a pump or a distribution cycle, replacing a HEPA filter configuration or modifying control system may look insignificant from a technical point of view, however, the change of state must be taken into account.
Impact assessment is therefore necessary to clarify if only partial or full re-qualification is to be carried out.
Qualification Should Produce Evidence, Not Just Documentation
An effective utility qualification package relates a consistent story: the system has been built for its purpose, installed correctly, operates on the defined limits, has been functioning reliably and is still under control in normal manufacturing processes.In the case of pharmaceutical manufacturing industries, this is particularly important for utility systems like water systems, HVAC, clean steam and process gases as their failures may not always be apparent during the finished product.
From a practical point of view, the aim of utility qualification is not to generate another validation record, but to provide sufficient evidence that the manufacturing process support system can safely and reliably perform its GMP duties throughout its lifecycle.
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