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 factor 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 determining the requirements for the design and construction
of your controlled environmental system. The Federal Standard 209-E is a document intended to provide standardization 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 pro8
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 enforced 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 manufactured 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 system. 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 facility 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
ISO 4
1,000
10,000
237
2,370
102
1,020
35
352
8
83
ISO 5
100,000
23,700
10,200
3,520
832
29
ISO 6
ISO 7
ISO 8
ISO 9
1,000,000
237,000
102,000
35,200
352,000
3,520,000
35,200,000
8,320
83,200
832,000
8,320,000
293
2,930
29,300
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 routine monitoring for aseptic processes
phasis is usually placed on design compliance with cGMP
requirements; this is because the effects of cGMP issues on
construction are profound and must be understood by owners, facility operators, and contractors.
INSTALLATION QUALIFICATION
Although there are many items that require validation
during the construction of a new facility, only the items associated with the validation of clean rooms will be discussed here. The IQ is a documented plan for the performance of inspections and the collection of documentation to
verify the static attributes of a system.
The IQ describes what the system is intended to do, or
what its function is, and it summarizes all major components of the system. A complete analysis of the system is
performed prior to start-up. A field inspection is performed
to check and verify static attributes.
HVAC System
During the execution of IQ for an HVAC system, the
following installation attributes should be verified:
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Utility Connections
Air Handling units
Ductwork
Ventilation and Pressure Airflow Requirements
Systems Design codes
Insulation Material
Damper and Air Volume Control Devices
High Efficiency Particulate Air (HEPA) and Pre-filters
• Fire Detection System
• Direct Digital Control (DDC) System or Building
Management Systems (BMS)
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David W. Vincent and Herbert Matheson
Test, Balancing, and Adjustment
After the critical utilities IQ has been verified, it is important to conduct the next important step of the qualification: 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 environment intended by the original system design and contributes to the continued efficient performance of the system
after it is in operation. The TBA technician will verify hydrostatic and HVAC balancing, along with air change rates
and volumes. Clean room velocities will also be verified during 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:
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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 certifying contractor must formalize all results obtained during
the certification process in an official report.
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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 calibration, 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 startup 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 executed in three phases, with varying degrees of severity. The
initial protocol should cover the baseline environmental
sampling plus installation and initial operational qualification 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 balanced and fully qualified. The third and final stage covers
the routine Environmental Monitoring Program; Standard
Operating Procedures (SOPs), such as, gowning, maintenance, 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
Classification
(0.5 µm particles/ft3)
ISO
Designationb
Microbiological Settling
Microbiological
Plates Action Levelsc,d
Active
Air Action Levelsc (diam. 90mm; cfu/4 hours)
(cfu/m3)
> 0.5 µm
particles/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 during periods of activity.
b- ISO 14644-1 designations provide uniform particle concentration values for cleanrooms in multiple 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 contaminants.
Figure
3
______________________________________________________________________________
USP 1116: Microbial Levels for Surface Monitoring
Surface CFU/ 2 in2
Personnel CFU/ 2 in2
Classifications
Zone
Critical Area 100
(ISO 5)
M 3.5
3
3 - gloves
5 - mask/gown
Non-critical 10,000
(ISO 7)
M 5.5
5 (walls, ceilings, benches,
equipment, etc.)
10 (floors)
5 - gloves
1 - mask/gown
Support Areas 100,000
(ISO 8)
M 6.5
20 (walls, ceilings, benches,
equipment, etc.)
30 (floors)
15 - gloves 30 - mask/gown
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
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David W. Vincent and Herbert Matheson
mation for these studies can then be used to develop a routine environmental monitoring program that provides the
highest probability of detecting any failure or problems,
while still being manageable for operating and testing personnel. The data in Figure 2 is based on the new FDA
Guideline for Industry “Sterile Drug Products Produced by
Aseptic Processing — current Good Manufacturing Practice,” for routine monitoring of aseptic processes.
After the PQ study is completed, the data is reviewed
and a final report is written summarizing the results. The information from the PQ final report is than used to establish
a routine environmental monitoring program.
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 organisms and to determine which sample sites are the “hot-spots.”
Since gases are used in the application and production of
pharmaceutical drugs and can have a direct impact on product quality, they are considered critical systems. Gases are
used in various manufacturing processes. Gases are typically used to transfer fluid products from one location to another and in the manufacturing processes.
The most commonly used gases in the pharmaceutical
industry are the following:
• Carbon Dioxide
• Nitrogen
• Clean, Dry Compressed Air
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 studies and results from the baseline study (hot-spots). Again,
duplicate samples with different media and incubation temperatures and times should be used. This stage of the validation 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 information from these logs will be compared with the environmental results to determine whether the cleaning and maintenance procedures are acceptable. The personal gowning
and operator aseptic technique should also be validated during the PQ study.
The following conditions should be tested and monitored during the Performance Qualification Study:
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.
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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
Journal of Validation Technology
PHARMACEUTICAL GAS SYSTEMS
INTRODUCTION
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:
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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
Air System
Figure
4
___________________________________________________
Basic Gas System
The following are some
components that usually are a
part of gas systems:
Storage Tank
Dessicant Filter
• Compressor Inlet Air
Filter
• Inlet Silencers
• Compressor (oil free)
• Intercooler
• After-cooler
• Mechanical Separator
• Air Receiver
• Coalescing Pre-filter
• Desiccant Air Dryer
• Particulate After Filter
• Activated Carbon Oil
Vapor Adsorbed
• Compressor Motor
• Instruments
• Control Panel
• Distribution System
Note: The pharmaceutical
compressed air system
should be capable of
delivering 100% oil free
air.
Ambient
Vaporizer
Source Valve
Cryogenic Gas
Gas Backup Cylinders
Particulate Removing Filter
Point of Use
with filters
Point of Use
with filters
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 filters eliminate any foreign particulate matter from the system before it reaches the point of use. The 0.2 µm hy-
Point of Use
with filters
Particulate Removing Filter
Point of Use
with filters
Point of Use
with filters
drophobic filter is used to remove any microbial contaminants 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
OPERATIONAL 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 Manufacturing Practices (cGMPs) for processing human drugs. The
construction of gas systems should also include the requirements 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 Medical Gases, should be used.
The next step is to verify that the gas systems are functioning according to design specifications.
During the execution of the OQ it is important to complete the following steps:
INSTALLATION QUALIFICATION
The IQ describes what the system is intended to do, or
what its function is, and it summarizes all major components of the system. A complete analysis of the system is
performed prior to start-up, and field inspection is performed to check and verify static attributes.
Gas System
During the execution of the IQ for gas systems, the following installation attributes should be verified:
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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
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 deliver high quality gas that will meet the manufacturing quality specifications and to establish the baseline information
on the performance of the gas systems used in the manufacturing 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 performed 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 procedure. Collect the appropriate equipment, Draegar tubes, and
glass sampling cylinders, and clearly mark them for sampling 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.
14
Journal of Validation Technology
David W. Vincent and Herbert Matheson
Figure
5
______________________________________________________________________________
Test Criteria for Gases Samples
Item
Criteria
˚C
3
See
Figure
6
______________________________________________________________________________
Clean Room Classification of Particle Sizes
Environmental Particulate
Sizes Classification
0.5µ and greater
Test Equipment and Materials
• Equipment and materials necessary to perform purity analysis
• Equipment and materials necessary to perform dew
point determination
• Equipment and materials necessary to perform Heterotrophic 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 measured gas flow
• Equipment and materials necessary to perform particulate counts (particle count diffuser)
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 specifications in accordance with the United States Pharmacopoeia (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 specified sample valves.
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David W. Vincent and Herbert Matheson
5. Perform viable and nonviable particulate testing at
worst-case sampling point, usually the point farthest away from the source.
Data Analysis
The testing of gas systems for microbial count may not
give any beneficial information if certain environmental conditions 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 environmental 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 organisms that may not survive under these environmental conditions. When performing this test, consider what you are trying 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 microbial 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 performed over a short period of time and with intensive sampling. But the routine environmental monitoring is performed during the life of the facility and usually involves
less intense sampling. The data collected from routine environmental monitoring programs includes: seasonal variations and manufacturing activities along with maintenance
and cleaning activities. The most effective environmental
monitoring programs are the ones with clear and precise
procedures.
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Journal of Validation Technology
Routine Environmental Monitoring Program
When establishing a routine environmental monitoring
program, the data for the PQ study should include the starting 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 include 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-viable particulate in a controlled environment that, when exceeded, signals a potential drift from normal operating conditions.
Action Limits - The concentration of viable and non-viable particulate in a controlled environment that, when exceeded, signals a potential 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 investigative action should be taken.
If an excursion occurs above an action level, at minimum, 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:
David W. Vincent and Herbert Matheson
• 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 organism(s).
• Determine sensitivity of isolate to disinfectant
being used.
• Review risk of product contact.
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
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 Department to conduct an immediate investigation and to initiate 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 location(s) should be retested at least three times. Acceptable
levels are re-attained if three consecutive re-tests meet acceptable levels. Once the system is again in compliance, QA
is responsible for releasing the system to Manufacturing.
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 exceeds the action limits for bacterial count
3. When a QC sample of clean steam condensate exceeds the action limits for endotoxin levels
4. When a QC sample of clean steam condensate exceeds the action limits for USP chemistry
5. When a possible minor malfunction in the water
system is observed
Corrective Action Program for Critical Utility Systems
The purpose of a corrective action program is to investigate 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
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 associated 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 specified range
3. When a QC sample of gas exceeds the action level
for bacterial count
4. When dew point exceeds the action level
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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) Department 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 approval of corrective action.
4. Perform the corrective action immediately, if possible. 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 investigation 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, Production, 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 issued to the Manufacturing Department notifying them that
a system may or may not be used (depending on the circumstance and severity of the problem) until corrective action has been taken to bring it back into compliance. A manufacturing alert notice form must be filled out under the following or similar circumstances:
1. When two or more retest samples exceed the action limits
2. When a questionable condition (such as sanitation, 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 investigation was taken
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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 consists 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., Environmental 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 individual(s), is immediately notified of the type of deviation; the
appropriate corrective action is taken and the manager’s signature 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 airborne 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)
David W. Vincent and Herbert Matheson
After the investigation is completed, any supporting documentation should be included as a part of the final investigation report. Maintain a history file on each system to determine whether there are any recurring failures that may require 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 organism(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 organism(s)
• Check sampling condenser
• Review risk of product contact
Corrective Action For HVAC System
Corrective actions for controlled environments may include, but are not limited to, the following:
• Additional sampling and testing
• Review and repeat sanitation procedures
• Review sampling and testing techniques
• Review validation data
• 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 organism(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 organism(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 Deviation 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 immediate investigation, and to initiate corrective actions to restore 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 location(s) will be retested at least three times. Acceptable
levels are re-attained if three consecutive re-tests meet acceptable 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 testing 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 depending 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 improvement, so Industry must persist in searching for methods that reduce costs and improve efficiency. As life science
professionals, we should never allow ourselves to become
complacent about investigating and employing new approaches 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 monitoring 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 inspector. 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, appeared 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 dedicated 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 internationally. He has presented many training seminars
and has written numerous articles and technical
guides regarding validation topics. Mr. Vincent
teaches “Validation Program for the Pharmaceutical, Biotechnology, and Medical Device Industries”
at San Diego State University (SDSU) for their Regulatory Affairs Master Degree program.
Currently, Dave is the Chief Executive Office (CEO)
for Validation Technologies Incorporated (VTI), a
worldwide validation and technical services company. VTI is also a certified commissioning company that offers commissioning and startup functions for the Healthcare Industry. Dave can be
reached by phone at 800-930-9222, by fax at 858673-3677, or by e-mail at [email protected].
(Web site is located at www.validation.org)
REFERENCES
1. Center for Drugs and Biologics, Center for Devices and Radiographic Health, “Guidelines on General Principles of
Process Validation,” FDA Rockville, Maryland, 1987.
2. “cGMP Compliance in Architecture and Construction of Biopharmaceutical Manufacturing Facilities” BioPharm, Prepared 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 Biologics Evaluation and Research, Office of Regulatory Affairs, “Guidelines on Sterile Drug Products Produced by
Aseptic Processing,” FDA Rockville, Maryland, June 1987.
6. PDA Environmental Task Force, “Fundamentals of a Microbiological Environmental Monitoring Program,” Vol. 44, Supplement 1990.
7. The Institute for Applied Pharmaceutical Sciences, “Microbiological 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
Accepting Nominations
For This Year’s
9. Graham C. Wrigley and Jan L. du Preez, Ph.D., “Facility
Validation: A Case Study for Integrating and Streamlining
the Validation Approach to Reduce Project Resources”
Journal of Validation Technology Volume 8, Number 3, May
2002, pp: 214-235.
* References noted above apply to the entire three-part article and represent both specific references and suggested
reading.
Article Acronym Listing
ASHRAE American Society of Heating,
Refrigerating and Air- Conditioning
Engineers, Inc.
BMS
Building Management System
CFR
Code of Federal Regulations
CFU
Colony Forming Units
cGMP
Current Good Manufacturing Practice
CoA
Certificate of Analysis
CQ
Construction Qualification
DDC
Direct Digital Control
DOP
DiOctyl Phthalate
EDR
Environmental Deviation Report
EM
Environmental Monitoring
FDA
Food and Drug Administration
HEPA
High Efficiency Particulate Air
HPC
Heterotrophic Plate Count
HVAC
Heating, Ventilation, and Air
Conditioning
IQ
Installation Qualification
ISO
International Organization for
Standardization
OQ
Operational Qualification
PDA
Parenteral Drug Association
PQ
Performance Qualification
QA
Quality Assurance
QC
Quality Control
SDA
Sabouraud Dextrose Agar
SIP
Steam-In-Place
SMA
Sterilizable Microbial Atrium
SOP
Standard Operating Procedure
TBA
Test, Balancing, and Adjustment
TSA
Tryptic Soy Agar
USP
United States Pharmacopoeia
WFI
Water-For-Injection
MICROBIOLOGIST
OF THE YEAR 2005!
★ ★ ★ ★ ★
•
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•
•
NOMINEES WILL BE JUDGED IN ONE
OR MORE AREAS INCLUDING:
MICROBIOLOGICAL ADVANCES
ACHIEVEMENTS IN MICROBIOLOGY
DEDICATION TO INDUSTRY
INDUSTRY CONTRIBUTION
This new award program is being created to
recognize and honor industry’s most talented
microbiology professionals. As recipient of this
honor, the Microbiologist of the Year will receive:
✓ IVT’s Microbiologist of the Year 2005 Award
✓ The opportunity to be the honored
guest of the 2005 banquet and award
ceremony
✓ Complimentary registration to IVT’s
Microbiology of the Year Event in 2006
✓ A feature article and biography in
Pharmaceutical Technology published
by Advanstar Communications, Inc.
✓ A special announcement in IVT’s brochure
and program guide on the MICROBIOLOGY
EVENT OF THE YEAR 2006
✓ A free one-year subscription to IVT’s
Journal of Validation Technology or
Journal of GXP Compliance
TO LEARN MORE VISIT:
w w w. i v t h o m e . c o m / n o m i n a t e
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
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