HVAC System Validation in Pharmaceuticals | A Complete Guide to Compliance and Best Practices

In pharmaceutical manufacturing, HVAC system plays an important role in maintaining controlled environmental conditions that are necessary for product safety and regulatory compliance. Validation of accuracy system ensures that it performs according to design specification and meets regulatory requirements.

This blog post explains the purpose, regulatory expectations, validation tests, documentation and best practices for HVAC system validation in pharmaceutical industry.

Importance of HVAC Systems in Pharmaceuticals

Pharmaceutical products are very sensitive to environmental conditions like temperature, humidity, particulate matter and microbial contamination. The HVAC system helps to:

• Maintain cleanroom class according to ISO 14644-1 guidelines
• Control temperature and relative humidity in the classified area
• Ensure air flow patterns and pressure differentials
• Reduce cross-contamination risks
• Provide filtered and conditioned air for sterile and non-sterile areas.

A validated HVAC system reduces different risks and ensures regulatory compliance. An unvalidated or poorly functioning HVAC system can lead to cross-contamination, product recalls and regulatory noncompliance.

Regulatory Guidelines for HVAC Validation

Different global regulatory bodies require proper design, qualification and maintenance of HVAC systems in pharmaceutical manufacturing facilities. Some of them are listed here.

1. US FDA 21 CFR Part 211 – It defines the control of environmental conditions.
2. WHO Technical Report Series (TRS) 961 – It guides on HVAC systems in pharmaceutical facilities.
3. ISO 14644 – It explains the cleanroom classification and testing methods.
4. EU GMP Annex 1 – It has contamination control strategy and cleanroom classifications.
5. ISPE Good Practice Guides – It has guidance on HVAC and cleanroom design.

Regulatory agencies expect documented evidence to prove that HVAC system consistently performs within specified parameters and limits.

Stages of HVAC System Validation

HVAC system validation includes for types of qualifications, design qualification (DQ), installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ).

1. Design Qualification (DQ)

Design qualification of HVAC system ensures that HVAC system design meets user requirements and regulatory expectations. Following activities are done during the design qualification.

• Review user requirement specification (URS) and function design specification (FDS) for the area.
• Confirm required air change rates, required filtration levels like HEPA or ULPA, temperature and humidity control requirements and pressure cascade design for monitoring.
• Verify required clean room classification for each area like ISO class 5, 6, 7, 8 etc., and document it.
• Check contamination control measures and strategies in clean room design.

2. Installation Qualification (IQ)

Installation qualification verifies that HVAC system is installed properly according to the design specifications. It includes the following activities.

• Check proper installation of HVAC components like AHUs, ducts, dumpers, sensors, filters etc.
• Verify calibration of temperature, humidity and pressure sensors installed in system.
• Confirm correct HEPA filter installation
• Document as build drawings and equipment lists

3. Operational Qualification (OQ)

Operational qualification ensures that HVAC system operates according to the specifications under controlled conditions. Following tests are done in operational qualification.

3.1 Air Flow Pattern

3.1.1 Take the titanium tetrachloride stick.
3.1.2 Burn the stick.
3.1.3 Place the burning stick in front of the running Air Handling Unit (AHU).
3.1.4 Observed the flow of air with the help of a smoke distribution in the room.
3.1.5 Make a chart diagram of the flow of air in the room for each room.

3.2 Air Flow Velocity And Change Per Hour

3.2.1 Scan the area of the HEPA Filter with the anemometer probe, 6 inches from the filter face.
3.2.2 For the case of the experiment, divide the area of the HEPA Filter into four equal, hypothetical grids.
3.2.3 Record the velocity readings taken at the center of the grids, and at the junction of dividing lines (center of HEPA Filter) in 5.5.
3.2.4 Calculate the Average Velocity (V in feet per minute) as :
V = (V1+V2+V3+V4) -------- (Eq.1)
                     4
Vi = Velocity observation at each point
3.2.5 Measure the dimensions of each air inlet i.e. HEPA Filter, in feet and record it.
3.2.6 Calculate the Area (A in square feet) of each Air inlet as a product of the length and the width as :
A = l x w -------- (Eq.2)
where l = length of inlet
w = width of inlet
3.2.7 Calculate the Total Air Volume (T in cubic feet per minute) supplied in each zone by using the formula :
T = A x V -------- (Eq.3)
where A = Area of particular Air inlet in square feet
V = Average air velocity at a particular air inlet in feet per minute
3.2.8 Calculate the total volume of the room by multiplying the length of the room, the breadth of the room and the height of the room.
Volume = L x B x H
3.2.9 The total air change is divided by the total volume of the room, giving the air change per hour. Fill in the record in the form.

3.3 Filter Leak Test

3.3.1 Place the velometer at the front of the AHU unit.
3.3.2 Check the velocity of air in all corners of the AHU. The air velocity should be within the higher limit of the HEPA filter.
3.3.3 If the air velocity is higher than the higher limit, change the gas cut to prevent the air leakage.

3.4 Particle Count

3.4.1 Switch on the air handling system one hour before the test operation. Take a suitable particle counter and operate it to check the particles in the room at non-working operation.
3.4.2 Collect the information from the particle counter and fill it into the format.
3.4.3 Operate the particle counter when work is in progress in the area. The particles should be counted when more than one hour of work has been completed in the area. Record the data in the format.
3.4.4 Operate the particle counter for the room, maintaining grade A, grade B, grade C & grade D.

3.5 Viable Monitoring

3.5.1 Expose the Plate Count Agar and Saboraud Dextrose Agar media plates in a sterile manufacturing area (Fabrication, Vial Filling, Vial Sealing & Sterile passage) as per the location plan given on the back of the paper sheet. Similarly, expose the plates in Change Room II and III and de-gowning I twice a week and once a week in Vial Washing, Bung Washing and Component Preparation.
3.5.2 Monitor the microbial load on the surface of the sterile manufacturing area by swab sampling and testing, following the SOP. Carry out swab sampling daily in Vial Filling, Vial Sealing, Sterile Buffer and Blending III; and twice in a week in Sterile Passage, Change Room II, Change Room III and De-gowning I. Similarly, carry out the swab sampling once in a week in Change Room I, Degowning II, Vial Washing, Bung Washing and component preparation. Record the results.
3.5.3 Place the media strips or Petri dishes in the air sampler on operating the air sampler as per the standard operating procedure of the equipment.
3.5.4 Record the data in the format.
3.5.5 Monitor the microbial load on the surface of hand gloves of the operators daily once in each working shift at random during activity, follow the SOP and record the result in HVAC Documents. Record the data in the format.
3.5.6 In case of repeated failure during two observations, the corrective action shall immediately be planned and implemented.
3.5.7 Monitor the critical functions of the HVAC system, Water System and personnel's behaviour in sterile and investigate the cause of adverse results immediately after observation.

3.6 Filter Integrity Test ( DOP / PAO Test for HVAC)

3.6.1 Generate DOP or PAO Aerosol using the Aerosol generator by subjecting DOP/PAO to 20 psi air pressure. Direct test aerosol at the supply duct in the Air Handling System.
3.6.2 Switch the photometer "ON" and allow to stabilize for five minutes.
3.6.3 Ensure that 100 % upstream concentration is achieved at all the terminal HEPA filters.
3.6.4 Scan the filter matrix and perimeter by passing the receptor probe 1 inch from the filter surface, in overlapping strokes traversing at approximately 10 FPM to check for leaks, if any.
3.6.5 Test all the HEPA filters as per the above steps and record the observations in the format.

3.7 Pressure Difference

3.7.1 Attach all the rooms (Under Test) to the manometer, which is attached to the wall of the adjacent area.
3.7.2 On the air system inside the tested area and wait for the pressure to stabilize in the area.
3.7.3 Observed the pressure difference from all rooms and from room to room.
3.7.4 Record the data in the format.

3.8 Recovery (Temperature & Humidity)

3.8.1 Turned off the HVAC system and checked the humidity of the area using a hygrometer.
3.8.2 If the humidity of the area is within specification. Increase the humidity by spraying hot water in the area up to 75%.
3.8.3 Wait to stabilize the humidity in the area about 75%.
3.8.4 Operate the HVAC system and note the time. Wait to stabilize the humidity in the area within the specification limit.
3.8.5 Note and record the time in the format.
3.8.6 For the recovery test, increase the temperature of the area by using a hot air blower in the area and increase the temperature 40C.
3.8.7 Operate the HVAC system and note the time. Wait to stabilize the temperature in the area within the specification limit.
3.8.8 Note and record the time in the format.

3.9 Temperature and Humidity Uniformity Test

3.9.1 Place the calibrated thermometer in a different location.
3.9.2 Operate the HVAC system and note the time. Wait to stabilize the temperature in the area within the specification limit.
3.9.3 Check and record the temperature of the area in the format.
3.9.4 Place the calibrated hygrometer in a different location.
3.9.5 Operate the HVAC system and note the time. Wait to stabilize the humidity in the area within the specification limit.
3.9.6 Check and record the temperature of the area in the format.

3.10 Fresh Air Determination

3.10.1 On the concerned AHU and wait to stabilize the air pressure in the room.
3.10.2 On the fresh air dumper for fresh air and observe and calculate the intake air by the dumper in the room. Observe and calculate the total air change in the room.
3.10.3 The intake fresh air is divided by the total air change in the room and multiplied by 100 to calculate the % fresh air intake on each cycle by the HVAC system in the tested room.
3.10.4 Record the data in the performance format record.

4. Performance Qualification (PQ)

Performance qualification confirms that HVAC system performs consistently as per requirements in actual production conditions. It includes following activities.

• Conduct environmental monitoring for viable counts and non-viable particles.
• Monitor parameters over a defined period.
• Verify performance during worst case production loads.
• Ensure cleanroom classification is maintained during manufacturing operations.

Documentation in HVAC Validation

It is essential to have proper documentation for regulatory compliance during HVAC validation. Documents include.

• URS (User Requirement Specification)
• FDS (Functional Design Specification)
• Design Qualification (DQ) Protocol and Report
• IQ, OQ, PQ Protocols and Reports
• Environmental Monitoring SOPs
• HEPA Filter Integrity Test Reports
• Calibration Certificates of Probes, Sensors and Gauges
• Maintenance Logs

Common Challenges in HVAC Validation

• Inadequate personal differences due to faulty damper or door seals
• HEPA filter leakage due to improper installation
• Temperature and humidity fluctuations due to faulty control systems
• Airflow turbulence affecting laminar air flow
• Extended recovery times after cleanroom disturbances
• Documentation gaps or missing documents

Best Practices for HVAC Validation

• Involve cross functional team from Quality Control, Quality Assurance, Engineering and Production departments from design stage.
• Use validated instruments for all measurements
• Follow ISO 14644-1 for testing methods
• Perform periodic requalification (annually or as per risk assessment)
• Conduct smoke test during initial qualification and after any modification
• Monitor critical parameters in real time
• Create and implement preventive maintenance schedule for AHUs, filters and sensors

Requalification and Change Control

For sterile manufacturing, HVAC system is required to qualify after major maintenance like filter replacement, duct modification or AHU replacement. Any changes made in HVAC system must be conducted through a change control process to assess the impact on product quality.

Validation of HVAC system in pharmaceuticals is not just a regulatory requirement, but it is also a critical quality system that ensures product safety and prevents contamination in pharmaceutical manufacturing. When companies complete all four stages of qualification, they prove that their HVAC systems are working properly and comply with GMP requirements.

Share

Tweet

Share

Pin it

Share