HVAC qualification has become one of the fields of the pharmaceutical validation protocol that can generate a great number of deviations. Temperature can drift out of acceptance limits, room pressure fails to maintain necessary cascading, airflow can be lower than planned, there can be problems with the HEPA filter integrity, or the smoke study shows there are no desirable airflow patterns.
It should be noted that HVAC is not simply an engineering measurement. The performance in this field can affect the process of contamination control, cross-contamination prevention, environmental conditions, product quality and operator safety. The World Health Organization standards highlight the significance of HVAC as one of the important control areas in pharmaceutical manufacturing and give recommendations involving a science-and-risk-oriented approach to manufacture process lifecycle.
What is more important, HVAC validation deviation should not be closed on the basis that the parameters come back within limits. The analysis of the issue should be made considering what went wrong, why, whether the qualified state was impacted and if the failure can create problems for the product or environment.
There are many reasons due to which the room may not to have required pressure, including incorrect air balancing, insufficient air supply or exhaust, leakage, door opening, filter blockage or wrong setting of the damper.
In my check, I would start not with calibration of the pressure sensor. First of all it is necessary to find whether the room pressure was simply measured wrong or it was wrong in reality.
You should check the following places:
Sometimes, there could be errors in the fan speed modulation when the desired value of air flow is reached and thereafter the error is cancelled. However, although this solves the problem temporarily, it doesn’t uncover the reason why the system was underperforming.
To fully address failure of a test, one needs to do more than change the filter and perform the test again. One should investigate whether the reason behind the failure was:
Thus, all test results have to be correlated with the functional record right since the last successful check-up.
Another key issue is whether qualifications were conducted in realistic or worst case scenarios.
For instance, an HVAC system can maintain 22 degree Celsius during comfortable conditions, but becomes ineffective during periods of large temperature differences. The WHO says that the temperature, humidity, and ventilation conditions should be adequate for manufacturing and storage process and be non-injurious to the product and equipment functionality.
Furthermore, sensor location should be considered. It should be noted that although one favourable reading was obtained, it does not guarantee that uniform environmental control exists across the whole area of the room.
The appearance of features in airflow pattern such as unexpected turbulence, stagnant zones, improper backflow, overly strong flow towards exposed product or poor airflow at the equipment can be of particular importance for classified/aseptic areas.
As per FDA guidance, smoke study refers to a procedure, which not only allows to visualize airflow pattern, but also any turbulence and eddies allowing dissemination of contamination.
In case smoke study does not yield good results, simple shifting of the diffuser position may not be enough. Importance of making dynamic adjustments in terms of equipment placement, operator movement, door functionality, material transfer, etc. should be considered wherever appropriate.
Possible causes of failure include the following:
An investigation must differentiate between actual HVAC problems and unfavorable testing conditions like too many staff members moving around or an invalid challenge.
Calibration errors, wrong ranges for the measurements, wrong BMS settings, software errors, alarm timing, and communication issues can create misleading but false data.
Consequently, the QA department needs to check calibration certificates, ID numbers of measuring instruments, raw data from the BMS and other systems instead of relying solely on the validation summary.
With regard to systems that have influence on the quality of the product, the FDA guidelines Q7A specify that HVAC and other related systems are to be validated and adequately monitored, with actions taken in case of the violation of the limits.
The first step is to check data and instrumentation validity. The second step involves checking the HVAC components and operational environment. The next step is to assess if the problem is isolated or affects connected rooms/systems.
An investigation involves checking for:
In a case of improper balancing, the system must be rebalanced and checked after that. When the cause is found to be an ineffective control strategy, changing the working set point may require an engineering evaluation and change control. If the reason is inadequate maintenance, the frequency and methods of preventive maintenance must be improved.
Doing the qualification test again and again until the test passes is clearly not a proper CAPA.
At the end of the assessment, the need for requalification has to be established, as well as the potential influence on the other rooms /AHUs and effects on the qualified position.
An appropriate technical approach associates the deviation with the design intent of the HVAC system, establishes the actual failure mechanism, assesses how much the deviation affects GMP, prepares a suitable CAPA plan and proves that the system has returned to a state of control.
QA and validation teams need this evidence to turn HVAC qualification from simple testing into a reliable proof of environmental control.
What is more important, HVAC validation deviation should not be closed on the basis that the parameters come back within limits. The analysis of the issue should be made considering what went wrong, why, whether the qualified state was impacted and if the failure can create problems for the product or environment.
Where HVAC Validation Deviations Usually Appear
HVAC qualification refers to the evaluation of different coordinated elements. The World Health Organization qualification guidelines specify things like temperature, humidity level, amount of air supplied, amount of air returned, pressure inside the room, rate of air changes, direction of the air flow, amount of particles in the air, efficiency of cleaning, speed of unidirectional airflow, and stability testing for HEPA filters. Since these parameters are connected, the deviation of one parameter may indicate the existence of a problem with the whole system.1. Differential Pressure Failures
Differential pressures are very important by the fact that they influence the air movement between the rooms.There are many reasons due to which the room may not to have required pressure, including incorrect air balancing, insufficient air supply or exhaust, leakage, door opening, filter blockage or wrong setting of the damper.
In my check, I would start not with calibration of the pressure sensor. First of all it is necessary to find whether the room pressure was simply measured wrong or it was wrong in reality.
You should check the following places:
- Calibration of differential pressure transmitter
- Measurement of airflow supplied by fan and exhausted from the room
- Condition of the door and its opening sequence
- Position of the damper
- Condition of the filter
- Possible air leakage in the room
- BMS settings and alarms
2. Airflow and Air Change Rate Deviations
The supply of air can either be low or not increased enough due to several issues; either the failure of the blowers, wrong filter performance, improper balancing, damper operation, or the resistance of the system.Sometimes, there could be errors in the fan speed modulation when the desired value of air flow is reached and thereafter the error is cancelled. However, although this solves the problem temporarily, it doesn’t uncover the reason why the system was underperforming.
3. Instances of HEPA Filter Integrity Failures
Testing the integrity of a HEPA filter can uncover leaking from the construction material, frame, gasket or installation interface.To fully address failure of a test, one needs to do more than change the filter and perform the test again. One should investigate whether the reason behind the failure was:
- Construction damage
- Incorrect installation
- Faulty gasket or joint
- Manual errors in handling the construction item in general
- Problems with housing or installation position
- Problems with testing equipment elements
Thus, all test results have to be correlated with the functional record right since the last successful check-up.
4. Temperature and Humidity Variations
Temperature and humidity variation may occur during qualifications due to insufficient HVAC system capability, probe positioning, loop control issues, or seasonal variations in weather conditions causing excess temperature.Another key issue is whether qualifications were conducted in realistic or worst case scenarios.
For instance, an HVAC system can maintain 22 degree Celsius during comfortable conditions, but becomes ineffective during periods of large temperature differences. The WHO says that the temperature, humidity, and ventilation conditions should be adequate for manufacturing and storage process and be non-injurious to the product and equipment functionality.
Furthermore, sensor location should be considered. It should be noted that although one favourable reading was obtained, it does not guarantee that uniform environmental control exists across the whole area of the room.
5. Smoke Study and Airflow Pattern Deviations
Smoke studies are capable of detecting issues which typical airflow measurement techniques may never be able to detect.The appearance of features in airflow pattern such as unexpected turbulence, stagnant zones, improper backflow, overly strong flow towards exposed product or poor airflow at the equipment can be of particular importance for classified/aseptic areas.
As per FDA guidance, smoke study refers to a procedure, which not only allows to visualize airflow pattern, but also any turbulence and eddies allowing dissemination of contamination.
In case smoke study does not yield good results, simple shifting of the diffuser position may not be enough. Importance of making dynamic adjustments in terms of equipment placement, operator movement, door functionality, material transfer, etc. should be considered wherever appropriate.
6. Particle Count and Recovery Failures
While airflow requirements can be met, particle count and recovery tests may fail.Possible causes of failure include the following:
- Low air volume
- HEPA leakage
- Bad air distribution
- More particles generated than normal
- Mistakes in classification or maintaining pressures correctly
- Insufficient recovery
An investigation must differentiate between actual HVAC problems and unfavorable testing conditions like too many staff members moving around or an invalid challenge.
7. Instrument Related Deviations
An HVAC deviation does not necessarily take place within the HVAC system.Calibration errors, wrong ranges for the measurements, wrong BMS settings, software errors, alarm timing, and communication issues can create misleading but false data.
Consequently, the QA department needs to check calibration certificates, ID numbers of measuring instruments, raw data from the BMS and other systems instead of relying solely on the validation summary.
With regard to systems that have influence on the quality of the product, the FDA guidelines Q7A specify that HVAC and other related systems are to be validated and adequately monitored, with actions taken in case of the violation of the limits.
How to Investigate an HVAC Validation Deviation
An effective investigation involves the flow of information in the following sequence: measurement → apparatus → system → environment → impact.The first step is to check data and instrumentation validity. The second step involves checking the HVAC components and operational environment. The next step is to assess if the problem is isolated or affects connected rooms/systems.
An investigation involves checking for:
- Raw qualification data and instruments
- Calibration status
- Historical qualification data and trends
- AHU operational parameters
- Filter differential pressure
- Fan and motor performance
- Dampers’ position
- Trends and alarms of the building management system (BMS)
- Repair and maintenance records
- Any recent changes or modifications
- Environmental monitoring data in pertinent cases
- Specific negative impact on production or operations
CAPA Should Address the Actual Failure Mechanism
The corrective action must be based on the root cause of the problem.In a case of improper balancing, the system must be rebalanced and checked after that. When the cause is found to be an ineffective control strategy, changing the working set point may require an engineering evaluation and change control. If the reason is inadequate maintenance, the frequency and methods of preventive maintenance must be improved.
Doing the qualification test again and again until the test passes is clearly not a proper CAPA.
At the end of the assessment, the need for requalification has to be established, as well as the potential influence on the other rooms /AHUs and effects on the qualified position.
What an Inspector May Ask
An inspector's questions can cover multiple areas, for example:- How can you be sure that your HVAC is operating properly?
- Do you have the data available that evidences the previous pressure irregularities?
- How is it resolved when alarms are activated?
- When did you have the last integrity test of the HEPA filter?
- What were your actions when the airflow was insufficient?
- Was there any plan for arriving at acceptance values for the smoke study?
- And were the changes in the HVAC system subject to change control?
- Can you prove that there were no previous problems with the process that caused any trouble with product quality?
An appropriate technical approach associates the deviation with the design intent of the HVAC system, establishes the actual failure mechanism, assesses how much the deviation affects GMP, prepares a suitable CAPA plan and proves that the system has returned to a state of control.
QA and validation teams need this evidence to turn HVAC qualification from simple testing into a reliable proof of environmental control.
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