Design, Construction,
Commission, and Qualification
of Critical Utility Systems:
Part III
B Y D AV I D W. V I N C E N T A N D H E R B E RT M AT H E S O N
❖
HEATING, VENTILATION, AND AIR
CONDITIONING (HVAC) SYSTEMS
INTRODUCTION
Whether a parenteral facility is designed for manual or
automated operation, environmental control is a critical fac-
tor in determining the successful operation of the facility.
The design and construction that relates to the clean room
must include consideration for:
• Air Volume
• Air Velocity
• Particulate Loading (especially viable organisms)
• Temperature
• Relative Humidity
• Pressure Differentials
There are many documents that are helpful guides in de-
termining the requirements for the design and construction
of your controlled environmental system. The Federal Stan-
dard 209-E is a document intended to provide standardiza-
tion of definitions and air cleanliness classes for clean
rooms. The American Society of Heating, Refrigerating,
and Air-conditioning Engineers’ (ASHRAE) handbook is
another guide that also can be helpful.
During construction, documenting procurement and
verifying construction activities are critical components of
successful Installation Qualification (IQ). It is important to
witness certain tests, such as the Heating, Ventilation, and
Air Conditioning (HVAC) duct leak test, and cleaning pro-
8 Journal of Validation Technology
cedures. It is important to collect data on the silicone used
for sealing penetrations, on the flooring material, and on the
paints that are used on the walls and ceiling. The cleanliness
of the job site during construction should be strictly en-
forced and all ducts should be capped or sealed then cleaned
before being used.
DESIGN QUALIFICATION
A facility’s room classification or design specification
should be identified based on the product being manufac-
tured and the processes being used. It is important that the
HVAC system meets the required specifications based on
the needs or requirements of the products and processes. For
example, one would not design a system to meet aseptic
conditions if the product to be produced was not meant to
be sterile. Therefore, it is important to define your product
and process requirements before designing your HVAC sys-
tem. The clean room classification requirements found in
Figure 1 should be considered when designing an HVAC
system.
CONSTRUCTION QUALIFICATION (CQ)
The construction of a pharmaceutical manufacturing fa-
cility requires strict adherence to the requirements outlined
in the Code of Federal Regulations (CFR) 21, Part 211.42,
the current Good Manufacturing Practice regulations
(cGMPs) for processing human drugs. A great deal of em-
 David W. Vincent and Herbert Matheson

Figure 1
______________________________________________________________________________
Airborne Particulate Cleanliness Classes (by cubic meter)

Number of Particles per Cubic Meter by Micrometer Size

CLASS
0.1 µm 0.2 µm 0.3 µm 0.5 µm 1 µm 5 µm
ISO 1 10 2
ISO 2 100 24 10 4
ISO 3 1,000 237 102 35 8
ISO 4 10,000 2,370 1,020 352 83
ISO 5 100,000 23,700 10,200 3,520 832 29
ISO 6 1,000,000 237,000 102,000 35,200 8,320 293
ISO 7 352,000 83,200 2,930
ISO 8 3,520,000 832,000 29,300
ISO 9 35,200,000 8,320,000 293,000

The larger, bolded font in ISO rows five through eight and in columns headed, 0.5 µm and 5.0 µm,
denotes classification and particle size usually used in the certification of clean rooms for the
Health Care Industries.
Note: The new FDA Guideline for Industry "Sterile Drug Products Produced by Aseptic Processing —
Current Good Manufacturing Practice," requires testing for only the 0.5 µm particles/m3 sizes during rou-
tine monitoring for aseptic processes

phasis is usually placed on design compliance with cGMP HVAC System

requirements; this is because the effects of cGMP issues on During the execution of IQ for an HVAC system, the
construction are profound and must be understood by own- following installation attributes should be verified:
ers, facility operators, and contractors.
• Utility Connections
INSTALLATION QUALIFICATION • Air Handling units
• Ductwork
Although there are many items that require validation • Ventilation and Pressure Airflow Requirements
during the construction of a new facility, only the items as- • Systems Design codes
sociated with the validation of clean rooms will be dis- • Insulation Material
cussed here. The IQ is a documented plan for the perfor- • Damper and Air Volume Control Devices
mance of inspections and the collection of documentation to • High Efficiency Particulate Air (HEPA) and Pre-fil-
verify the static attributes of a system. ters
The IQ describes what the system is intended to do, or • Fire Detection System
what its function is, and it summarizes all major compo- • Direct Digital Control (DDC) System or Building
nents of the system. A complete analysis of the system is Management Systems (BMS)
performed prior to start-up. A field inspection is performed
to check and verify static attributes.

N o v e m b e r 2 0 0 5 • Vo l u m e 1 2 , N u m b e r 1 9
David W. Vincent and Herbert Matheson
Test, Balancing, and Adjustment
After the critical utilities IQ has been verified, it is im-
portant to conduct the next important step of the qualifica-
tion: Test, Balancing, and Adjustment (TBA). TBA is the
culmination of the long and costly process of designing and
constructing an HVAC environmental control system. TBA
ensures that the completed installation will produce the en-
vironment intended by the original system design and con-
tributes to the continued efficient performance of the system
after it is in operation. The TBA technician will verify hy-
drostatic and HVAC balancing, along with air change rates
and volumes. Clean room velocities will also be verified dur-
ing the testing.
Clean Room Testing and Certification
After the HVAC system has been balanced and accepted,
it is now time to certify the clean rooms. This involves the
testing and certification of certain physical attributes of the
clean room.
The clean room testing and certification contractor
should perform the following tests:
• DiOctyl Phthalate (DOP) Test of HEPA Filters
• Noise Levels
• Light Levels
• Air Patterns: Parallelism and Unidirectional tests in
the aseptic fill area
• Induction Testing
• Humidity and Temperature
• Room Non-Viable Particulate Counts using
209-E calculations (Clean Room Classification)
• Recovery Time Testing
• Room Air Change Rates
• Differential Pressure
• Air Flows Direction
The clean room must meet all the design criteria before
the next stage of the validation can be performed. The cer-
tifying contractor must formalize all results obtained during
the certification process in an official report.
10 Journal of Validation Technology
OPERATIONAL QUALIFICATION
Once the clean rooms have been certified, the next step
of the validation process is the Operational Qualification
(OQ).
During the execution of the OQ it is important to verify
the following steps:
1. Review the HVAC IQ final report, instrument cali-
bration, and operation and maintenance procedures.
2. Review the testing and balancing final report.
3. Review the clean room testing and certification
final report (HEPA filter certification).
4. Verify HVAC control functions and alarms.
5. Verify Building Management System controls and
communication.
6. Verify pressure differentials and airflows between
clean rooms.
7. Complete shutdown and start-up tests to verify that
the HVAC systems return to normal conditions.
8. Verify Environmental Control Functions
It may be necessary to repeat the particle counts and
temperature and humidity test after the shutdown and start-
up procedure.
After the environmental controls have been tested and
accepted, the clean rooms are ready for the Performance
Qualification (PQ) study.
PERFORMANCE QUALIFICATION
Microbiological validation of any facility should be ex-
ecuted in three phases, with varying degrees of severity. The
initial protocol should cover the baseline environmental
sampling plus installation and initial operational qualifica-
tion of critical systems, beginning just after construction
clean-up. The second stage involves the actual validation of
systems and equipment, including both static and dynamic
environmental testing, once all air-handling systems are bal-
anced and fully qualified. The third and final stage covers
the routine Environmental Monitoring Program; Standard
Operating Procedures (SOPs), such as, gowning, mainte-
nance, and cleaning procedures; operation limits of test
methods; plus any follow-up items generated from the first
two stages.
The overall intent of the first two phases is to determine
the limits and capabilities of the facility and to get a general
profile of the resident population of organisms. The infor-
 David W. Vincent and Herbert Matheson

Figure 2
______________________________________________________________________________
Air Classificationsa

Clean Area Microbiological Microbiological Settling

Classification ISO > 0.5 µm Active Plates Action Levelsc,d
(0.5 µm particles/ft3) Designationb particles/m3 Air Action Levelsc (diam. 90mm; cfu/4 hours)
(cfu/m3)
100 5 3,520 1e 1e
1000 6 35,200 7 3
10,000 7 352,000 10 5
100,000 8 3,520,000 100 50

a- All classifications based on data measured in the vicinity of exposed materials or articles dur-
ing periods of activity.
b- ISO 14644-1 designations provide uniform particle concentration values for cleanrooms in mul-
tiple industries. An ISO 5 particle concentration is equal to Class 100 and approximately
equals EU Grade A.
c- Values represent recommended levels of environmental quality. You may find it appropriate to
establish alternate microbiological action levels due to the nature of the operation or method
of analysis.
d- The additional use of settling plates is optional.
e- Samples from Class 100 (ISO 5) environments should normally yield no microbiological conta-
minants.

Figure 3
______________________________________________________________________________
USP 1116: Microbial Levels for Surface Monitoring

Classifications Zone Surface CFU/ 2 in2 Personnel CFU/ 2 in2

Critical Area 100 M 3.5 3 3 - gloves 5 - mask/gown

(ISO 5)

Non-critical 10,000 M 5.5 5 (walls, ceilings, benches, 5 - gloves 1 - mask/gown

(ISO 7) equipment, etc.)
10 (floors)

Support Areas 100,000 M 6.5 20 (walls, ceilings, benches, 15 - gloves 30 - mask/gown

(ISO 8) equipment, etc.)
30 (floors)

The microbial levels for surfaces samplings are detailed in the following table and are based on
USP <1116> requirements.

1
Adjacent to critical area, 2
Support Areas - Product

N o v e m b e r 2 0 0 5 • Vo l u m e 1 2 , N u m b e r 1 11
David W. Vincent and Herbert Matheson
mation for these studies can then be used to develop a rou-
tine environmental monitoring program that provides the
highest probability of detecting any failure or problems,
while still being manageable for operating and testing per-
sonnel. The data in Figure 2 is based on the new FDA
Guideline for Industry “Sterile Drug Products Produced by
Aseptic Processing — current Good Manufacturing Prac-
tice,” for routine monitoring of aseptic processes.
Baseline Sampling
The initial sampling for the baseline is intended to get a
general profile of the microbial population before cleaning.
This sampling usually involves taking random sampling
throughout the clean rooms. The sampling of the controlled
environments involves high levels of samples and sampling
frequencies, often using two selective growth media for both
surface and air monitoring, (Sabouraud Dextrose Agar
(SDA): for molds and yeast and Tryptic Soy Agar (TSA): for
bacteria). This is done to check the sub-population of organ-
isms and to determine which sample sites are the “hot-spots.”
Static and Dynamic Sampling
This stage of the validation involves performing three
static and dynamic state studies. The sample locations are
pre-determined based on the clean room particle count stud-
ies and results from the baseline study (hot-spots). Again,
duplicate samples with different media and incubation tem-
peratures and times should be used. This stage of the vali-
dation is also used to qualify the cleaning procedures based
on the data from both the baseline (before cleaning) and the
static and dynamic states studies. It is important to maintain
accurate facility maintenance and cleaning logs. The infor-
mation from these logs will be compared with the environ-
mental results to determine whether the cleaning and main-
tenance procedures are acceptable. The personal gowning
and operator aseptic technique should also be validated dur-
ing the PQ study.
The following conditions should be tested and moni-
tored during the Performance Qualification Study:
• Viable and Non-Viable Airborne Particulates
• Viable Surface Samples
• Temperature and Relative Humidity
• Magnehelic Gauge Readings
• Manufacturing Personnel Gowning
• Aseptic Media Fills
• Building Management System Trending Data
12 Journal of Validation Technology
After the PQ study is completed, the data is reviewed
and a final report is written summarizing the results. The in-
formation from the PQ final report is than used to establish
a routine environmental monitoring program.
PHARMACEUTICAL GAS SYSTEMS
INTRODUCTION
Since gases are used in the application and production of
pharmaceutical drugs and can have a direct impact on prod-
uct quality, they are considered critical systems. Gases are
used in various manufacturing processes. Gases are typi-
cally used to transfer fluid products from one location to an-
other and in the manufacturing processes.
The most commonly used gases in the pharmaceutical
industry are the following:
• Carbon Dioxide
• Nitrogen
• Clean, Dry Compressed Air
Other gases such as helium, oxygen, and argon may also
be used. This article will discuss only those gases most
commonly used in the Pharmaceutical Industry that may
come in contact with the product.
VALIDATION OF GASES SYSTEM
Gas System Design
Since gas systems can be used for various manufacturing
processes, the design of the system can be considered
straightforward. The application for which these gases will
be used should be the major consideration during the design
phase.
The following are some considerations for the design of
gas systems:
• Safety Issues (Oxygen)
• Materials of Design
• Fabrication
• Code Requirements
• Product or Process Demands
• Testing Requirements
• Installation Requirements
• Functional and Control Requirements
• Gas Purity
 David W. Vincent and Herbert Matheson

Pharmaceutical Compressed Figure 4

___________________________________________________
Air System
Basic Gas System
The following are some
components that usually are a
part of gas systems:
Storage Tank
Dessicant Filter
• Compressor Inlet Air Ambient
Filter Vaporizer

• Inlet Silencers Source Valve

• Compressor (oil free)
• Intercooler Cryogenic Gas
• After-cooler
• Mechanical Separator
• Air Receiver
• Coalescing Pre-filter
• Desiccant Air Dryer Gas Backup Cylinders
• Particulate After Filter
• Activated Carbon Oil
Vapor Adsorbed
• Compressor Motor Particulate Removing Filter
• Instruments
• Control Panel
• Distribution System

Note: The pharmaceutical Point of Use Point of Use Point of Use

compressed air system with filters with filters with filters
should be capable of
Particulate Removing Filter
delivering 100% oil free
air.

Pharmaceutical Gas Systems

• Cryogenic Storage
Tank
• Desiccant Air Dryer
• Particulate Filters
• Point of Use Filter
• Distribution Systems
• Control Panel
The diagram shown in Figure 4 illustrates a basic gas
system, including a cryogenic storage tank in which the gas
supply refills on a regular basis. The ambient vaporizer
brings the gas to usable temperature since it is stored at a
very low temperature. The desiccant filter is used to remove
any moisture from the system. The particulate removing fil-
ters eliminate any foreign particulate matter from the sys-
tem before it reaches the point of use. The 0.2 µm hy-
Point of Use Point of Use
with filters with filters
drophobic filter is used to remove any microbial contami-
nants at the points of use. The distribution system should
also have pressure regulators and measuring devices at all
points of use to adjust and monitor the pressure of process
gas. There is also a backup system that will supply gases on
an emergency basis when the main supply tank is depleted.
Depending on the sophistication of the system, there may be
an alarm generated when the major supply tank is empty
which alerts the supply company of the problem.

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David W. Vincent and Herbert Matheson
CONSTRUCTION QUALIFICATION
The construction of a pharmaceutical company’s process
gas system requires strict adherence to the requirements
outlined in 21 CFR, 211.42, the current Good Manufactur-
ing Practices (cGMPs) for processing human drugs. The
construction of gas systems should also include the require-
ments of local, state, and federal codes and regulations. The
Food and Drug Administration (FDA) guidelines, published
to assist in the construction and design of Compressed Med-
ical Gases, should be used.
INSTALLATION QUALIFICATION
The IQ describes what the system is intended to do, or
what its function is, and it summarizes all major compo-
nents of the system. A complete analysis of the system is
performed prior to start-up, and field inspection is per-
formed to check and verify static attributes.
Gas System
During the execution of the IQ for gas systems, the fol-
lowing installation attributes should be verified:
• Utility Connections
• Drawings (“as-built”)
• Materials of Construction
• Distribution Systems
• In-line Filters
• Storage Tank
• Systems Design and Safety Codes
• Valves
• Alarms and Control Devices
• Backup System
• Major Components
• Point of Use Filters
• Components, Tagged and Labeled
14 Journal of Validation Technology
OPERATIONAL QUALIFICATION
The next step is to verify that the gas systems are func-
tioning according to design specifications.
During the execution of the OQ it is important to com-
plete the following steps:
1. Verify that the gas distribution system has been
cleaned.
2. Review the hydrostatic test data.
3. Review the filter integrity test data.
4. Verify the gas system control functions and alarms.
5. Verify the points of use design pressures.
6. Verify the backup system and safety features.
7. Verify the critical instrumentation calibration.
After the Operational Qualification’s tests have been
completed and accepted, the gas systems are ready for the
Performance Qualification (PQ) study.
PERFORMANCE QUALIFICATION
The PQ is performed to verify that the gas systems de-
liver high quality gas that will meet the manufacturing qual-
ity specifications and to establish the baseline information
on the performance of the gas systems used in the manufac-
turing areas. This study will also include qualifying three
lots of gas supplied by the vendor and thirty consecutive
days of testing to qualify the compressed gas system.
Acceptance Criteria
The performance qualification testing shall be per-
formed on three lots of nitrogen supplied by the vendor.
Thirty consecutive days of testing will be completed to
qualify the compressed gas system.
Gas and Compressed Air samples collected during the
PQ test period shall meet the criteria detailed in Figure 5.
Processing Samples for Testing
Sample the process gases as outlined in this PQ proce-
dure. Collect the appropriate equipment, Draegar tubes, and
glass sampling cylinders, and clearly mark them for sam-
pling tracking purposes. Only the gas identity test requires
a sampling container. The other tests (oil mist, dew point,
bioburden, and particulate tests) are performed in situ using
specific portable pieces of equipment.

Figure 5
______________________________________________________________________________
Test Criteria for Gases Samples
Item
˚C
Figure 6
______________________________________________________________________________
Clean Room Classification of Particle Sizes
Environmental Particulate 0.5µ and greater
Sizes Classification
Test Equipment and Materials
• Equipment and materials necessary to perform pu-
rity analysis
• Equipment and materials necessary to perform dew
point determination
• Equipment and materials necessary to perform Het-
erotrophic Plate Count (HPC) using the
Matson/Garvin or SMA sampler
• Equipment and materials necessary to perform oil
mist testing
• Equipment and materials necessary to perform mea-
sured gas flow
• Equipment and materials necessary to perform par-
ticulate counts (particle count diffuser)
David W. Vincent and Herbert Matheson
Criteria
3
See
5.0 µ and greater
Sampling and Test Procedures
Assemble all necessary equipment and materials. Perform
dew point, oil mist, particle counts, and HPC tests at each
sample port according to the standard sampling schedule.
Obtain Certificate of Analysis (C of A) for the three lots
of gas used during validation. Verify the C of A by sampling
each lot at the source, and at critical points of use, such as
at sterile filling machine. Verify that they all meet specifi-
cations in accordance with the United States Pharma-
copoeia (USP) standards and that the lot has been released
from quarantine.
Sampling Method
1. Use aseptic technique when gathering all samples.
2. Flush each port for at least 10 - 15 seconds (with
the valve fully open) before sampling.
3. Flow meter should be set to correct flow rates when
testing.
4. Take microbial, dew point, particle counts, as well
as oil mist and nitrogen purity samples from speci-
fied sample valves.
N o v e m b e r 2 0 0 5 • Vo l u m e 1 2 , N u m b e r 1 15
David W. Vincent and Herbert Matheson
5. Perform viable and nonviable particulate testing at
worst-case sampling point, usually the point far-
thest away from the source.
Data Analysis
The testing of gas systems for microbial count may not
give any beneficial information if certain environmental con-
ditions for the systems are not recreated during incubation.
For example, if a sample from a nitrogen gas system is taken
and incubated aerobically, certain organisms may not grow
in those conditions (oxygen environment). It would be more
logical to incubate the growth media in the same environ-
mental conditions to which the organism is accustomed.
Therefore, under certain conditions, anaerobic monitoring
may be acceptable for monitoring certain types of gases.
Most companies test for microbial contaminants using
TSA, which is incubated aerobically and at 30˚ - 35˚C for
48 - 72 hours. This may not be effective in isolating organ-
isms that may not survive under these environmental condi-
tions. When performing this test, consider what you are try-
ing to accomplish. If it is to verify that the gas is free from
microbial contaminants, then proper growth conditions
should be simulated. Also, most organisms will not survive
in the harsh environments created by certain gas production
and storage. Whatever test method is used to detect micro-
bial contaminants, it should be properly validated.
ROUTINE MONITORING PROGRAM
FOR CRITICAL UTILITIES
Once the PQ is completed, the “real time” validation of
the critical utilities begins. Usually, the PQ study is per-
formed over a short period of time and with intensive sam-
pling. But the routine environmental monitoring is per-
formed during the life of the facility and usually involves
less intense sampling. The data collected from routine envi-
ronmental monitoring programs includes: seasonal varia-
tions and manufacturing activities along with maintenance
and cleaning activities. The most effective environmental
monitoring programs are the ones with clear and precise
procedures.
16 Journal of Validation Technology
Routine Environmental Monitoring Program
When establishing a routine environmental monitoring
program, the data for the PQ study should include the start-
ing point for determining the sampling sites and frequencies
of testing. It is also important to have an accurate drawing
indicating the sampling sites. The program should also in-
clude environmental worksheets to record the test results.
The worksheet data can be entered into a computer-aided
software program, which can be used to trend and perform
queries on environmental data.
Establishment of Alert and Action Limits
Alert Limits - The concentration of viable and non-vi-
able particulate in a controlled environ-
ment that, when exceeded, signals a poten-
tial drift from normal operating conditions.
Action Limits - The concentration of viable and non-vi-
able particulate in a controlled environ-
ment that, when exceeded, signals a poten-
tial drift from normal operating conditions,
and which requires an investigation and
corrective action.
Alert and action limits are usually derived statistically
from historical data. These limits are conservative measures
designed to signal potential drift from historical or design
performance characteristics.
The establishment of alert and action limits should be
written and utilized in a consistent, non-arbitrary manner. It
is important to remember that alert and action levels should
not be extensions of the product specifications. If an alert
level is exceeded, corrective action may not be required, but
records should show that the excursion was recognized. If
the alert levels consistently exceed their set limits, an inves-
tigative action should be taken.
If an excursion occurs above an action level, at mini-
mum, one should review the data. Additional action should
be taken in the form of an investigation, and corrective and
alert notices to responsible parties and departments should
be completed and delivered to those parties.
When an action limit is exceeded, an investigation and
corrective action should be performed. A list of the types of
actions to be taken follows; actions should be appropriate to
the situation and should not necessarily be limited to these
suggestions:

• Generate an Environmental Deviation Report
(EDR) form.
• Issue an Alert Notice.
• Investigate the Environmental Deviation.
• Perform Corrective Action.
• Resample Out of Limit Locations.
• Review maintenance and cleaning logs.
• Perform gram stain/identification of isolated organ-
ism(s).
• Determine sensitivity of isolate to disinfectant
being used.
• Review risk of product contact.
When acceptable levels are re-attained, no further action
is usually required. The results from the retest are recorded
on the Environmental Deviation Report form, disposition as
Pass, and filed for future reference.
If the retest indicates that acceptable levels have not
been met, the Quality Control (QC) Department will initiate
an Investigation Report to Directors of Quality Assurance
(QA) and Manufacturing with a description of the deviation.
It is the responsibility of the Manufacturing or Facility De-
partment to conduct an immediate investigation and to initi-
ate corrective actions to restore the area to normal operating
conditions. QA is responsible for evaluating the impact of
the conditions on product quality.
After corrective actions have been taken, the affected lo-
cation(s) should be retested at least three times. Acceptable
levels are re-attained if three consecutive re-tests meet ac-
ceptable levels. Once the system is again in compliance, QA
is responsible for releasing the system to Manufacturing.
Corrective Action Program for Critical Utility Systems
The purpose of a corrective action program is to investi-
gate critical system failures, to report and document these
failures, and to make the necessary corrective action to
bring the system into compliance.
The following program is applicable to critical utility
systems, which include: controlled environmental Heating,
Ventilation, Air Conditioning (HVAC), Purified Water,
Water-For-Injection (WFI), Process Gases, and Clean
Steam systems.
Program Procedures
An environmental investigation applies to any situations
not considered an immediate threat to a critical system, but
which, if allowed to continue, may become serious.
An Environmental Deviation Report (EDR) must be
David W. Vincent and Herbert Matheson
filled out under the following or similar circumstances:
Water Systems
1. When a QC sample consistently exceeds alert limits
for all QC test results
2. When a QC sample of water exceeds the action
level for bacterial count
3. When a QC sample of water exceeds the action
level for endotoxin limits
4. When a QC sample of water exceeds the limit for
USP chemistry
5. When a possible minor malfunction in the water
system is observed
Clean Steam Systems
1. When a QC sample consistently exceeds alert limits
for all QC test results
2. When a QC sample of clean steam condensate ex-
ceeds the action limits for bacterial count
3. When a QC sample of clean steam condensate ex-
ceeds the action limits for endotoxin levels
4. When a QC sample of clean steam condensate ex-
ceeds the action limits for USP chemistry
5. When a possible minor malfunction in the water
system is observed
HVAC Systems
1. When a QC sample consistently exceeds alert limits
for all QC test results
2. When a questionable condition (such as sanitation,
or potential contamination) in the core and associ-
ated areas is observed
3. When an environmental monitoring sample exceeds
the action level for microbial or particulate counts
4. When a temperature or humidity reading is outside
the specified range
5. When a pressure differential reading is outside the
specified range
6. When a possible minor malfunction in the HVAC
system is observed
Gases Systems
1. When a QC sample consistently exceeds alert limits
for all QC test results
2. When gas system test results are outside the speci-
fied range
3. When a QC sample of gas exceeds the action level
for bacterial count
4. When dew point exceeds the action level
N o v e m b e r 2 0 0 5 • Vo l u m e 1 2 , N u m b e r 1 17
David W. Vincent and Herbert Matheson
5. When a QC sample for gas purity fails
6. When a QC sample of gas exceeds the action level
for oil mist
Investigation and Corrective Action
The following steps should be taken:
1. QA and the responsible Facility (facility related) or
Production (process or equipment related) Depart-
ment will investigate the system and recommend
corrective action.
2. Document the proposed corrective action on the
Environmental Deviation Report (EDR) form.
3. The facilities or production manager will sign the
EDR form and return it to QA for review and ap-
proval of corrective action.
4. Perform the corrective action immediately, if possi-
ble. If the action requires planning, materials, or
time to implement, perform it as soon as possible.
5. QA will review the proposed corrective action and
any subsequent QC retesting data. If the investiga-
tion or the data shows that the system is in control,
QA will sign the form, distribute copies, and file
the QA copy of the form.
6. Distribute copies to QA, Facility Manager, Produc-
tion, and the system and product files.
Manufacturing Alert Notice for Action Limit Failures
A Manufacturing Alert Notice applies to any situation
that is considered an immediate threat to a critical system or
process equipment and that may have a direct impact on the
quality of the product. A manufacturing alert notice is is-
sued to the Manufacturing Department notifying them that
a system may or may not be used (depending on the cir-
cumstance and severity of the problem) until corrective ac-
tion has been taken to bring it back into compliance. A man-
ufacturing alert notice form must be filled out under the fol-
lowing or similar circumstances:
1. When two or more retest samples exceed the ac-
tion limits
2. When a questionable condition (such as sanita-
tion, or potential contamination) is observed
3. When a possible minor or major malfunction in
the utility system that could possibly compromise
the integrity of the production area is observed
4. When a QC test sample exceeds the action limits
5. When a system is still not in compliance after the
first environmental corrective action or investiga-
tion was taken
18 Journal of Validation Technology
Corrective Action Program
An Environmental Deviation Report form is initiated
immediately when action levels are exceeded. A number is
assigned to the deviation for traceability. The number con-
sists of three groups of digits: the first group represents the
system, the second group represents the year, and the third
group is an assigned sequential number (e.g., Environmen-
tal Monitoring: EM-05-01; Water-For-Injection: WF-05-01;
Clean Steam: CS-05-01; and Nitrogen Gas: NG-05-01).
The Manufacturing Manager, or appropriate individ-
ual(s), is immediately notified of the type of deviation; the
appropriate corrective action is taken and the manager’s sig-
nature and the date are obtained.
An Environmental Deviation Report form will usually
include the following sections:
Section 1
1. EDR number
2. System affected
3. Location where levels have been exceeded
4. Room number
Section 2
1. Sample Type (surfaces, viable or non-viable air-
borne particles)
2. System Sampled (Gas, WFI, Purified Water, Clean
Steam, HVAC)
3. Area Classification (if applicable)
Section 3
1. Initial Sample Data
2. QC Test Results (collection data, site, sample data
action levels)
3. Recommended Corrective Actions (if applicable)
Section 4
1. Corrective Actions Taken (requires a description of
the action taken)
Section 5
1. Retest Sample Data
2. QC Test Results (collection data, site, sample data
action levels)
3. EDR Disposition (re-sampling results: pass or fail)
Section 6
1. Other Action Taken (if applicable)
2. Results Acceptable (no further steps required)
3. Not Acceptable (investigation continues)

After the investigation is completed, any supporting doc-
umentation should be included as a part of the final investi-
gation report. Maintain a history file on each system to de-
termine whether there are any recurring failures that may re-
quire modification or redesign of the system.
Water Systems Corrective Action
Corrective actions for pretreatment water, Purified
Water, and Water-For-Injection systems may be included,
but are not limited to, the following:
• Additional sampling and testing
• Review and repeat sanitization procedures
• Review sampling and testing technique
• Review validation data
• Check on possible unusual events during sampling
and testing
• Review 0.2mm filter and tank vent filter integrity
test results
• Review maintenance and sanitization logs
• Perform gram stain identification of isolated organ-
ism(s)
• Steam-In-Place (SIP) entire system
• Inspect all major components on the pretreatment,
purified, and WFI systems
• Review risk of product contact
Corrective Action For Clean Steam System
Corrective actions for clean steam systems may include,
but are not limited to, the following:
• Additional sampling and testing
• Review sampling and testing techniques
• Review validation data
• Check on possible unusual events during sampling
or testing
• Review WFI test results
• Review maintenance logs
• Perform gram stain identification of isolated organ-
ism(s)
• Check sampling condenser
• Review risk of product contact
Corrective Action For HVAC System
Corrective actions for controlled environments may in-
clude, but are not limited to, the following:
• Additional sampling and testing
• Review and repeat sanitation procedures
• Review sampling and testing techniques
• Review validation data
David W. Vincent and Herbert Matheson
• Retrain clean room personnel on proper techniques
• Check on possible unusual events during sampling
or testing
• Review pressure differential information
• Review clean room and HEPA filter certification
data
• Review maintenance and cleaning logs
• Perform gram stain identification of isolated organ-
ism(s)
• Determine sensitivity of isolate to disinfectant
being used
• Review risk of product contact
Corrective Action For Gas Systems
Corrective actions for gas systems may include, but are
not limited to, the following:
• Additional sampling and testing
• Review sampling and testing technique
• Review validation data
• Check on possible unusual events during sampling
and testing
• Review point of use filter integrity test results
• Review maintenance logs
• Perform gram stain identification of isolated organ-
ism(s)
• Review Certificate of Analysis from vendor
• Review risk of product contact
No further action is required when acceptable levels are
re-attained. Record retest results on the Environmental De-
viation Report form, disposition as Pass, and file for future
reference.
If retest indicates that acceptable levels have not been
met, initiate another Investigation Report to Directors of QA
and Manufacturing with the description of the deviation. It
is the responsibility of Manufacturing to conduct an imme-
diate investigation, and to initiate corrective actions to re-
store the area to normal operating conditions. QA should be
responsible for evaluating the impact of the conditions on
product quality.
After corrective actions have been taken, the affected lo-
cation(s) will be retested at least three times. Acceptable
levels are re-attained if three consecutive re-tests meet ac-
ceptable levels.
N o v e m b e r 2 0 0 5 • Vo l u m e 1 2 , N u m b e r 1 19
David W. Vincent and Herbert Matheson
Revalidation of Critical Systems
Revalidation will occur when any significant changes or
alterations occur to any above systems, (e.g., construction,
changing and adding new HEPA filters, and modification of
WFI, gas, and clean steam system). The extent of the test-
ing will be determined on a case-by-case basis and will be
properly documented and filed. Revalidation for a critical
utility should be performed annually or semi-annually de-
pending on the criticality of the system. The revalidation
SOP should be written to include the extent of testing and
the system under the program.
CONCLUSION
As facility construction costs continue to escalate,
healthcare companies will struggle with the challenge of
meeting regulatory requirements and running a profitable
business. The “current” in cGMP requires continuous im-
provement, so Industry must persist in searching for meth-
ods that reduce costs and improve efficiency. As life science
professionals, we should never allow ourselves to become
complacent about investigating and employing new ap-
proaches and technologies in our industry. The integration
of qualification activities into the commission phase can be
a cost effective method for bringing critical utilities online.
The most effective method of ensuring the quality of any
product is through a strong, routine environmental monitor-
ing program. Alert and action limits are the heart of the
monitoring program. The FDA Guidelines state: “Maximum
microbial limits should be established along with a definite
course of action to be taken in the event that samples are
found to exceed the limits.”
There is no real continuity within the industry when it
comes to the validation of most critical utility systems. The
inspection of these systems varies from inspector to inspec-
tor. This is why it is important to use the regulatory guideline
documents when writing and executing critical utility system
validation protocols. This article is just one example of how
critical systems can be validated or qualified. There are many
methods of qualifying critical utility systems, but a sound,
logical approach is the basis of any good method. ❏
(This concludes “Design, Construction, Commission,
and Qualification of Critical Utility Systems.” The first part
of this article, An Overview of Critical Utility Systems, ap-
peared in the May 2005 issue of this Journal. The second
part, “Water Systems,” appeared in the August 2005 issue.)
20 Journal of Validation Technology
ABOUT THE AUTHORS
David W. Vincent has over 25 years experience in
the Biopharmaceutical Industry with 19 years dedi-
cated to the fields of validation and engineering. He
has a B.S. degree in Microbiology and Mechanical
Engineering Technology; Mr. Vincent has consulted
for many companies both nationally and interna-
tionally. He has presented many training seminars
and has written numerous articles and technical
guides regarding validation topics. Mr. Vincent
teaches “Validation Program for the Pharmaceuti-
cal, Biotechnology, and Medical Device Industries”
at San Diego State University (SDSU) for their Reg-
ulatory Affairs Master Degree program.
Currently, Dave is the Chief Executive Office (CEO)
for Validation Technologies Incorporated (VTI), a
worldwide validation and technical services com-
pany. VTI is also a certified commissioning com-
pany that offers commissioning and startup func-
tions for the Healthcare Industry. Dave can be
reached by phone at 800-930-9222, by fax at 858-
673-3677, or by e-mail at davidv@validation.org.
(Web site is located at www.validation.org)
REFERENCES
1. Center for Drugs and Biologics, Center for Devices and Ra-
diographic Health, “Guidelines on General Principles of
Process Validation,” FDA Rockville, Maryland, 1987.
2. “cGMP Compliance in Architecture and Construction of Bio-
pharmaceutical Manufacturing Facilities” BioPharm, Pre-
pared January-February, 1993.
3. “Code of Federal Regulations Section 21 Parts 200 to 299
and Parts 600 to 799,” Food and Drug Administration
(FDA).
4. “Guidelines for Bulk Drug Manufacturers,” Food and Drug
Administration (FDA).
5. Center for Drug Evaluation and Research, Center for Bio-
logics Evaluation and Research, Office of Regulatory Af-
fairs, “Guidelines on Sterile Drug Products Produced by
Aseptic Processing,” FDA Rockville, Maryland, June 1987.
6. PDA Environmental Task Force, “Fundamentals of a Micro-
biological Environmental Monitoring Program,” Vol. 44, Sup-
plement 1990.
7. The Institute for Applied Pharmaceutical Sciences, “Microbi-
ological Control and Validation,” March 7-9, 1994.
8. Powell-Evans, K., “Streamlining Validation: Value Added
Qualifications.” Institute of Validation. December 2000.
Newsletter.
 David W. Vincent and Herbert Matheson

IVT is Currently
9. Graham C. Wrigley and Jan L. du Preez, Ph.D., “Facility
Validation: A Case Study for Integrating and Streamlining
Accepting Nominations
the Validation Approach to Reduce Project Resources”
Journal of Validation Technology Volume 8, Number 3, May
For This Year’s
2002, pp: 214-235.
* References noted above apply to the entire three-part arti-
cle and represent both specific references and suggested
reading.

Article Acronym Listing

ASHRAE American Society of Heating, MICROBIOLOGIST
Refrigerating and Air- Conditioning
Engineers, Inc. OF THE YEAR 2005!
BMS Building Management System ★ ★ ★ ★ ★
CFR Code of Federal Regulations
CFU Colony Forming Units NOMINEES WILL BE JUDGED IN ONE
cGMP Current Good Manufacturing Practice OR MORE AREAS INCLUDING:
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CQ Construction Qualification • ACHIEVEMENTS IN MICROBIOLOGY
DDC Direct Digital Control • DEDICATION TO INDUSTRY
DOP DiOctyl Phthalate • INDUSTRY CONTRIBUTION
EDR Environmental Deviation Report
EM Environmental Monitoring This new award program is being created to
FDA Food and Drug Administration recognize and honor industry’s most talented
HEPA High Efficiency Particulate Air microbiology professionals. As recipient of this
HPC Heterotrophic Plate Count honor, the Microbiologist of the Year will receive:
HVAC Heating, Ventilation, and Air
✓ IVT’s Microbiologist of the Year 2005 Award
Conditioning
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ISO International Organization for guest of the 2005 banquet and award
Standardization ceremony
OQ Operational Qualification
✓ Complimentary registration to IVT’s
PDA Parenteral Drug Association
Microbiology of the Year Event in 2006
PQ Performance Qualification
QA Quality Assurance ✓ A feature article and biography in
QC Quality Control Pharmaceutical Technology published
SDA Sabouraud Dextrose Agar by Advanstar Communications, Inc.
SIP Steam-In-Place
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SOP Standard Operating Procedure and program guide on the MICROBIOLOGY
TBA Test, Balancing, and Adjustment EVENT OF THE YEAR 2006
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