Validation of Utility Systems in Pharmaceutical Facilities : Pharmaceutical Guidelines

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Validation of Utility Systems in Pharmaceutical Facilities

Many types of utilities are used in pharmaceutical manufacturing facility. It is important and mandatory to validate the utilities before its use in pharmaceutical manufacturing.
This chapter provides a summary of the key validation test functions and acceptance criteria for each utility system. These are provided as a guideline for those involved in the validation of ABC Pharmaceutical. Approval of this Master Plan neither provides approval of these test functions and acceptance criteria nor does it limit the test functions and acceptance criteria included in any protocol. Final approval of test functions and acceptance criteria is made by approval of the Installation, Operational, and where applicable, Performance Qualification protocols.

A. Plant Steam

Utility Validation

Test Functions

1. Perform Installation Qualification of deionizer and distillation equipment, holding tanks, clean steam generator, and distribution system.
2. Complete and document all required pre-start‑up maintenance procedures (including cleaning).
3. Perform general operational controls verification testing.
4. Operate system throughout the range of operating design specifications or range of intended use.
5. Confirm that the pressure‑reducing regulators in the sub-branches are set at the predetermined operating pressure ±2 psi.
6. Verify that the system has adequate steam capacity during peak hours of operation. Confirm that the steam pressure is within 5 psi of the recom­mended operating pressure.
7. Record the range of all process/ equipment parameters (set points, pressure, timing sequences, etc.) verified during operational and perfor­mance qualification testing.
8. Test the water produced by the system to ensure adequate conductivity.
9. Check that the holding tank water quality does not change adversely during storage in holding tanks.

Acceptance Criteria

1. The system is installed in accordance with design specifications, manufac­turer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifica­tions.
3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. System regulators must operate within ±2 psi of design levels.
5. The system capacity must be sufficient to operate all systems at peak demand periods.

B. Pure Steam

Test Functions

1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use.
4. Verify that clean steam is fed by a purified water system or WFI system.
5. Confirm that the pressure‑reducing regulators in the sub-branches are set at the predetermined operating pressure ±2 psi.
6. Verify that the system has adequate steam capacity during peak hours of operation. Confirm that the steam pressure is within 5 psi of the recom­mended operating pressure.
7. Operate the system per applicable SOPs. Perform sampling as per the sampling procedure and schedule. Test steam condensate samples for con­formance to current USP Water for Injection monograph (also endotoxin, sterility).
8. Record the range of all process/ equipment parameters (set points, pressure, timing sequences, etc.) verified during Operational and Perfor­mance Qualification testing.
Related: Validation of Pure Steam

Acceptance Criteria

1. The system is installed in accordance with design specifications, manufac­turer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifica­tions.
3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. The system capacity must be sufficient to operate all systems at peak demand periods.
5. Operate the system per applicable SOPs. Perform sampling over a 1‑month period as per the sampling procedure and schedule. Test samples for conformance to current USP Water for Injection monograph.
6. All samples must meet the following criteria:
  • Chemical Testing: Test samples must meet the acceptance criteria of the chemical tests as described in USP 24 Monograph on Water for Injec­tion.
  • Bacteriological Purity: All samples must contain no more than 10 cfu/100 ml; no pseudomonas or coliform is detected.
  • Endotoxins: Less than 0.25 EU/ml.

C. Water For Injection (WFI)

Test Functions

1. Perform Installation Qualification. Verify piping, fittings, proper dimen­sions, drawings, wiring, PC software, calibration, and quality of materials.
2. Check flow rates, low volume of water supply, excessive pressure drop, resistivity drops below-set point, and temperature drop or increase beyond a set level.
3. Perform general operational controls verification testing.
4. Operate system throughout the range of operating design specifications or range of intended use.
5. System regulators must operate within ±2 psi of design level.
6. Operate the system per applicable SOPs. Perform sampling over a 1‑month period per the sampling procedure and schedule. Test samples for con­formance to current USP Water for Injection monograph, microbial con­tent, and endotoxin content. Identify all morphologically distinct colony forming units (CFUs) to at least the genus level.
7. Measure the flow rate and calculate the velocity of the water, or measure the velocity directly at a point between the last use point and the storage tank.
8. Record the range of all process/ equipment parameters (set points, flow rates, timing sequences, concentrations, etc.) verified during Operational and Performance Qualification testing.
Related: Water for Injection (WFI) System Validation Process

Acceptance Criteria

1. The system is installed in accordance with design specifications, manufac­turer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifica­tions.
3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. The system flow rate must be in compliance with design specifications.
5. All samples must meet the following criteria:
  • Chemical Testing: Test samples must meet the acceptance criteria of the chemical tests as described in USP 24 Monograph on Water for Injec­tion.
  • Bacteriological Purity: All samples must contain no more than 10 cfu/100 ml; no pseudomonas or coliform is detected.
  • Endotoxins: All samples must contain no more than 0.25 EU/ml.
  • Physical Properties: The temperature of the hot Water for Injection must be greater than 80°C.
  • Particulate Matter: Small Volume Injection: The Small Volume Injection meets the requirements of the test if the average number of particles it contains is not more than 10,000 per container that is equal to or greater than 10 µm in effective spherical diameter and not more than 1000 per container equal to or greater than 25 µm in effective spherical diameter.

D. Compressed Air

Test Functions

1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use.
4. Verify that the compressed air system is capable of supplying pressurized compressed air to all use points. Perform an operational test of the distri­bution system and pressure regulators by monitoring the pressure output at the respective use points.
5. Perform a capacity test to verify that the system is capable of supplying the required gas, pressure, and flow rate at each use point.
6. Verify that in-line filters are integrity tested. Confirm that all documentation clearly indicates acceptable test results.
7. Perform dew point measurement.
8. Perform hydrocarbon content measurement.
9. Perform viable particulate count, microbiological at critical use points after sterile filters (refer to Federal Standard 209E).
10. Identification of oxygen content.
11. Record the range of all process/ equipment parameters (set points, flow rates, timing sequences, concentrations, etc.) verified during Operational and Performance Qualifications testing.
Related: Validation of Compressed Air

Acceptance Criteria

1. The system is installed in accordance with design specifications, manufac­turer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls, alarms, and interlocks operate in accordance with design specifications.
3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. The compressed air distribution system must consistently deliver pressur­ized compressed air to the use points at the design pressure as specified.
5. All in-line filters are integrity tested and qualify per manufacturer’s oper­ating specifications.
6. Dew point must be <0° or lower.
7. Hydrocarbon content must be ð1 ppm.
8. Viable particulate must be <1.0 cfu/10 ft3.
9. Nonviable particulate counts must be <100/ft3 of 0.5 microns or larger at all critical use points.

E. Nitrogen (N2)

Test Functions

1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use.
4. Verify that the nitrogen gas system is capable of supplying pressurized nitrogen to all use points. Perform an operational test of the distribution system and pressure regulators by monitoring the pressure output at the respective use points.
5. Perform a capacity test to verify that the system is capable of supplying the required gas, pressure, and flow rate at each use point.
6. Verify that the filters are integrity tested. Confirm that all documentation clearly indicates acceptable test results.
7. Perform dew point measurement.
8. Perform hydrocarbon content measurement.
9. Perform nitrogen gas identification (USP 24 Monograph).
10. Check bioburden if necessary.
11. Record the range of all process/ equipment parameters (set points, pressure, timing sequences, etc.) verified during Operational and Perfor­mance Qualifications testing.

Acceptance Criteria

1. The system is installed in accordance with design specifications, manufac­turer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls, alarms, and interlocks operate in accordance with design specifications.
3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. The nitrogen distribution system must consistently deliver pressurized nitrogen to the use points at the design pressure specified.
5. All filters are integrity tested and qualified per manufacturer operating specifications.
6. Dew point must be –20°C or lower.
7. Hydrocarbon level must be <1 ppm.
8. Gas quality must conform to the USP 24 Monograph for nitrogen purity.
9. The microbiological test must meet the approved specification require­ments.

F. Carbon dioxide (CO2)

Test Functions

1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use.
4. Verify that the carbon dioxide gas system is capable of supplying pressur­ized carbon dioxide to all use points. Perform an operational test of the distribution system and pressure regulators by monitoring the pressure output at the respective use points.
5. Perform a capacity test to verify that the system is capable of supplying the required gas, pressure, and flow rate at each use point.
6. Verify that the filters are integrity tested. Confirm that all documentation clearly indicates acceptable test results.
7. Perform dew point measurement.
8. Perform hydrocarbon content measurement.
9. Perform viable particulate count (microbiological particulates).
10. Perform nonviable particulate count.
11. Perform CO2 gas identification (USP 24 Monograph)
12. Record the range of all process/ equipment parameters (set points, pressure, timing sequences, etc.) verified during operational and perfor­mance qualifications testing.

Acceptance Criteria

1. The system is installed in accordance with design specifications, manufac­turer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls, alarms, and interlocks operate in accordance with design specifications.
3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. The carbon dioxide distribution system must consistently deliver pressur­ized carbon dioxide to the use points at the design pressure specified.
5. All filters are integrity tested and qualified per manufacturer’s operating specifications.
6. Dew point must be –20°C or lower.
7. Hydrocarbon level must be <1 ppm.
8. Viable particulates must be <1.0 CFU per 10 ft3.
9. Nonviable particulate counts must be <100/ft3 at 0.5 microns or larger.
10. Gas quality must conform to USP 24 Monograph for carbon dioxide purity.

G. Heating, Ventilation, and Air Conditioning (HVAC)

Test Functions

1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use.
4. Integrity test all HEPA filters with dioctyl phthalate (DOP) smoke (0.3 microns).
5. Measure the average face velocity of each terminal HEPA filter. Measure the average velocity 1 ft above the workspace, exposed product areas, or exposed component areas in all Class 100 laminar flow rooms or areas.
6. Verify that system air flows have been balanced to within ±10% of design criteria.
7. Verify that directional air flows are consistent with design drawings by verifying relative differential air pressures.
8. Verify that each room maintains the design temperature range for three (3) consecutive days.
9. Verify that each room maintains the design relative humidity range for three (3) consecutive days.
10. Verify that air flow patterns within Class 100 laminar flow areas are non­turbulent and unidirectional by performing smoke‑stick air flow studies and recording the test on videotape.
11. Verify that rooms identified with particulate classifications are certified per Federal Standard 209E for their respective classification (Class 100, 10,000, and 100,000).
12. Verify that AHUs, fans, and heat exchangers operate per design ratings.
13. Record the range of all process/ equipment parameters (set points, flow rates, timing sequences, etc.) verified during operational and performance qualifications testing.
Related: HVAC System Validation Process

Acceptance Criteria

1. The system is installed in accordance with design specifications, manufac­turer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifica­tions.
3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. HEPA filters are 99.99% efficient when tested with DOP smoke (0.3 ).
5. All terminal HEPA filter face velocity measurements are within ±30% of the average filter velocity.
6. The average face velocity of terminal HEPA filters servicing Class 100 laminar flow rooms is 90 ft/min ±20%, with no points below 75 ft/min or above 105 ft/min.
7. All room supply, exhaust, and return flow rates must be within ±10% of design flow rates.
8. Directional air flows (as determined by room differential pressure) must be consistent with design drawings.
9. Each room must maintain the design temperature range for three (3) consecutive days.
10. Each room must maintain the design relative humidity range for three (3) consecutive days.
11. Airflow in Class 100 laminar flow areas must be nonturbulent and unidi­rectional, as demonstrated by smoke‑stick studies.
12. All classified rooms are certified to meet their particulate classification per Federal Standard 209E.
13. AHU, fan, and heat exchanger operations must meet or exceed their respec­tive design ratings.

H. Emergency Power (Standby Generator)

Test Functions

1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use.
4. Verify that the emergency power generation system has adequate power to provide all intended users upon normal power source interruption.
5. Record the range of all process/ equipment parameters (set points, etc.) verified during operational and performance qualifications testing.

Acceptance Criteria

1. The system is installed in accordance with design specifications, manufac­turer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifica­tions.
3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. All intended users must operate under normal power source interruption conditions.
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Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of Pharmaceutical Guidelines, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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