Qualification and Routine
Environmental Monitoring of
Critical Utility Systems
21th Annual Validation Week
Day Three, Session 10:30am – 12:00 pm
Qualification and Routine
Environmental Monitoring of Critical
Utility Systems
1
CONTACT INFORMATION
for Course Leader
Ed Winnett/VP Operations
Validation Technologies, Inc.
San Diego, CA
Office: 800-930-9222
Fax:
858-676-3677
Email: edw@validation.org
Website: http://www.validation.org
2
PRESENTATION OVERVIEW
 SUPPORT DOCUMENTATION
 CONSTRUCTION QUALIFCATION
 QUALIFICATION OF CRITICAL SYSTEMS
 ESTABLISHING A ROUTINE
ENVIRONMENTAL PROGRAM
 TRENDING AND DATA SUMMARY
 “PROBLEM AREAS” - UTILITY SYSTEMS
 REVALIDATION
3
Part 1
Documents to Support
Equipment Qualification
DQ
IQ
PQ
OQ
PV
IQ OQ
IQ/OQ Documentation
PQ VC
CQ
4
Support Documents
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The User Requirements Specification (URS)
Design Specifications
Functional Specifications
Purchases Requisitions
Turn-Over- Packages
Vendor Manuals
P&IDs
Manuals
Commissioning
FAT/SAT
Change Management
5
Part 2
Critical Utility Project
Strategy
Plan the Work and Work the Plan
6
PROGRAMS REQUIRED FOR FACILITY & CRITICAL
UTILITIES QUALIFICATIONS
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PROJECT DESIGN SPECIFICATION
VALIDATION MASTER PLAN
PROJECT SCHEDULE
CONSTRUCTION QUALIFICATION PACKAGES
INSTALLATION QUALIFICATION PROTOCOLS
FACILITY STARTUP/COMMISSIONING
STANDARD OPERATING PROCEDURES
CALIBRATION PROGRAM
OPERATIONAL QUALIFICATION PROTOCOLS
ANALYTICAL METHODS VALIDATED
PERFORMANCE QUALIFICATION
7
PROJECT SCHEDULE
• DEFINED CRITICAL PATHS
• CONSTRUCTION ACTIVITIES
• COLLECTION OF CONSTURCTION QUALIFCATION CQ
DATA
• DEVELOPMENT OF PROTOCOL FORMAT
• WRITE IQ & OQ PROTOCOLS
• EQUIPMENT INSTALLATION ACTIVITIES
• EXECUTION OF IQ PROTOCOLS
• COMMISSION OF SYSTEM
• EXECUTION OF OQ PROTOCOLS
• ANALYTICAL METHODS VALIDATED
• WRITE & EXECUTE PERFORMANCE QUALIFICATIONS
8
PROJECT SPECIFICATION
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EQUIPMENT DATA SHEETS
SPARE PARTS LIST
VENDOR CERTIFICATION
FACTORY ACCEPTANCE TEST REPORT
MATERIALS OF CONSTRUCTION
ON SITE TESTS
CLEANING REQUIREMENTS
COMPONENTS SELECTION
9
VALIDATION MASTER PLAN
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VALIDATION PROJECT ROAD MAP
FACILITY & PROCESS DESCRIPTION
VALIDATION PROGRAM
EQUIPMENT & UTILITY LIST
PROJECT RESPONSIBILITIES
VALIDATION PROJECT DESCRIPTION
10
Part 3
Commissioning and
Construction
Program
11
Good Engineering Practice (GEP)
• “Established Engineering methods and
standards that are applied throughout the
project lifecycle to deliver appropriate
cost-effective solutions”
12
Good Engineering Practice (GEP)
• GEP project scope
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Documentation
Organization and Communication
Requirements Phase
Design Phase
Construction Phase
Project Controls
Commissioning and Qualification
Project Closeout and Turnover
13
Commissioning Plan
•
Commissioning Plan should contain the following
deliverables: (Direct Impact Systems)
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Commissioning Plan
Commissioning Schedule
Commissioning Budget
Overall Test Plan
Factory Acceptance Test/Report
Site Acceptance Test/Report
Inspection Plan/Report
Functional Test/Report
System Test Summary Reports
Commissioning Summary Reports
14
Scope of the Commissioning and
Qualification Guide
Engineering Change Management
Impact Assessment
QA Change Control
Design
Development
Enhanced Design
Review
commissioning
PQ
Process
Validation
IQ & OQ
Design for Impact
Scope of Guide
GEP Contribution
Of Interest to the Regulatory
15
System Impact and Component
Criticality
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•
•
•
Indirect Impact or No Impact system are
comprised of non-critical components only
Direct Impact system have both critical and
non-critical components. (Components
deemed non-critical may be managed within
Good Engineering Practices (GEP) alone)
Design for Impact reduces the scope of the
system and components to Qualification
Practices allowing appropriate focus on the
components presenting a risk to product quality
Should an Indirect Impact or No Impact system
incorporate one or more critical components,
either the system has been mis-classified or
the component was wrongly assessed.
16
Impact Assessment
•
“Direct Impact” Systems are expected to
have an impact on product quality
•
Indirect Impact systems are not expect to
have an impact on product.
–
–
Both types of systems will require
commissioning; however, the “Direct Impact”
system will be subject to qualification practices
to meet additional regulatory requirements of
the FDA and other regulatory authorities
System Impact Assessment Form Direct HVAC
System Template Part 1.doc
17
System Impact Assessment
Process Overview
Identify System
Develop System
Boundaries
Yes
Does the system have a direct
impact on product quality
No
Is the system linked to
Direct Impact System
Yes
“Indirect Impact”
system
“Direct Impact”
system
No
“No Impact System”
Develop Supporting
Rationale
18
Qualification Risk Based
Assessment
•
•
•
“Direct Impact” Systems are expected to
have an impact on product quality
therefore the level of validation or
qualification must be determine by using
Qualification Risk Based Asessment
Qualification Level Analysis Form Direct
HVAC Template Part 2.doc
Qualification Level Analysis Results Form
Direct HVAC Template Part 3.doc
19
Component Criticality
Assessment Process
•
•
The components within “Direct Impact”,
Indirect Impact” and in some cases “No
Impact” systems should be assessed for
criticality.
Must have updated Piping and Instrument
Drawings (P&IDs)
20
Component Criticality
Assessment Process
•
Applicability of any of the following
criteria to a given component will
provide an indication that component
is critical:
1.
2.
3.
The component is used to demonstrate compliance
with the registered process.
The normal operation or control of the component
has a direct effect on the product quality.
Failure or alarm of the component will have direct
effect on the product quality.
21
Component Criticality Assessment
Process (Continued)
•
Applicability of any of the following criteria to
a given component will provide an indication
that component is critical:
4.
5.
6.
7.
Information from the component is recorded as part of
the batch record, lot release data or other GXP related
documentation.
The component has direct contact with product or
product components
The component controls critical process elements that
may affect product quality, without independent
verification of the control system performance.
The component is used to create or preserve a critical
status of a system.
22
System Impact and Component
Criticality
•
•
•
•
•
Indirect Impact or No Impact system are comprised
of non-critical components only
Direct Impact system have both critical and noncritical components. (Components deemed noncritical may be managed within Good Engineering
Practices (GEP) alone)
Design for Impact reduces the scope of the system
and components to Qualification Practices allowing
appropriate focus on the components presenting a
risk to product quality
Should an Indirect Impact or No Impact system
incorporate one or more critical components, either
the system has been misclassified or the component
was wrongly assessed.
Critical Component Analysis Form Direct HVAC
Template 4.doc
23
Part 4
Qualification of
Critical Utilities
Systems
Design, Construct, Commission then
Qualify
24
Critical Utility Qualification
• Construction Qualification
– During construction, document procurement and
verification of construction activities, are critical
components of a successful Installation Qualification
(IQ). Must have Engineering Turnover Packages (ETOP)
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Design/Functional Specifications
Test Reports
Material Certifications
Purchase Specification & Orders
State and Local Code Compliance
ASME, ANSI and other Certifications
Pipe Specifications
Cleaning and Passivation Reports
Stainless Steel Weld Documentation
Vendor/Manufacturer's Submittals
Manufacturer's Mechanical Specifications
Instrumentation Specifications
25
Commissioning Phase: Leverage
Support Document
• FAT/SAT can be leverage to support IQs and
OQs
• Some of the test and information collected during
the commission phase can be used to support
I/OQ protocol execution
• Most of the information contain in the FAT such
as material of construction can used to support
the IQ document.
• Some of tests performed in the SAT are
duplicated during the execution of the OQ
therefore it only make sense to leverage of SAT
to support some of the tests in the OQ protocol
26
Utility Qualifications
• Basic checklist is used for IQ • Defined Direct/In-Direct/Non-Impact System
• Manufacturer information: contact info., specs,
P.O., manuals, etc.
• Equipment description (make, model, serial
number, etc.)
• Instrumentation
• Spare Parts
• Control Panels
• Safety
• PM
• Calibration
• Support Utilities
27
IQ : IS IT INSTALLED CORRECTLY?
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Full description of equipment capabilities, design features and
company's specific intended use in manufacture.
Vendor, equipment ID, serial number, etc.
Location of installation
Process Equipment Listing
Drawings or Flow Diagrams
Operator’s Manual
Maintenance Procedures and Schedule; Cleaning Schedule
Calibration Procedure and Schedule
Spare Parts List
Configuration of Components, Drawings
Materials of construction,
Interface with other equipment (peripherals); Interface with utilities,
facility
Safety
Appropriate Environmental Conditions
28
Critical Utility Qualification
• Installation Qualification - is a documented plan
for the performance of inspections and the
collection of documentation to verify static
attributes of a system.
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System Location
System Description
Major Components Identification Summary
Field Inspection Report- Comparison of Actual to
Specified
– Instrumentation List
– Spare Parts List
– Documentation/Drawings List
29
Utility Qualifications
• Operational Qualification - Does the
equipment function as intended?
• Challenge the process (equipment)
parameters under worst case testing. This
is where you determine the degree of
“robustness” with the equipment.
• Objective, Scope, Description, etc.
• Operational testing
• Acceptance criteria
• Deviations (Excursions, etc.)
• Approvals
30
Critical Utility Qualification
• Operational Qualification (OQ) - is a documented plan for the
performance of inspections and tests to verify specified
dynamic attributes of a system.
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SOP Review
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Calibration Review
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Test of Alarms
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Test of Controls
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Test of Interlocks
– Start Up/Shutdown Sequence Verifications
– Normal Run Mode Verification - Monitoring Applicable
Indications:
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Pressure
Temperature
Time
Resistivity/Conductivity
Flow
pH
31
PERFORMANCE QUALIFICATION
PROTOCOL FOR CRITICAL UTILITIES
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OBJECTIVE
IDENTIFICATION
SYSTEM PERFORMANCE DESCRIPTION
REFERENCES
RESPONSIBILITIES
PROCEDURE
ACCEPTANCE CRITERIA
PERFORMANCE QUALIFICATION TEST
COMMENTS
DEVIATION/EXCEPTIONAL CONDITION
ATTACHMENTS
32
Utility Qualifications
• Performance Qualification • Objective, scope, description, equipment
testing, approvals, etc.
• Documented verification that the equipment
operates the way it is purported to do. This
operation must be reliable and reproducible
within a specified, predetermined set of
parameters under nominal or normal
production conditions.
33
Critical Utility Qualification
• Performance Qualification (PQ) - is a documented
plan for the execution of tests to demonstrate the
effectiveness and reproducibility of a
system/process as a fully integrated functional
entity.
– All installed critical instruments shall be calibrated prior to
execution of the protocol.
– All test instruments used to execute the protocol shall be
calibrated and certified prior to use.
– Test methods, analytical procedures and sampling
techniques, when not defined in a protocol, shall be
written and approved as SOPs.
– The system can consistently meet its predetermined
acceptance criteria.
34
Critical Utility Qualification
• Performance Qualification (PQ) - Standard Testing
Intervals
– Water For Injection Systems - 30 to 45 Days (30
- 40 days Standard @ Shut Down Recover Test)
– Purified Water Systems - 30 Days
– Clean Steam Systems - 30 Days
– Gases/Clean Dry Air Systems - 7 to 14 Days or
three lots
– HVAC System (Controlled Environment)- 1
Baseline (Before cleaning), 3 Static States, 3
Dynamic (20 -30 days)
35
Part 5
Validation of Purified
Water Systems
Purified Water is used in Aspect of GMP
Manufacturing Operations
36
Water Usage in
Pharmaceutical Production
• Water Requirements
– Potable - EPA
– USP Purified
– USP Water For Injection
37
Validation of Critical Water Systems
• FDA Requirements: Phase 1
• All water systems should have
documentation containing a system
description and accurate drawing.
• The drawing needs to show all equipment in
the systems from water input to points of
use. It should also show all sampling points
and their designations.
38
Validation of Critical Water Systems
• FDA Requirements: Phase 1
• After all the equipment and piping has
been verified as installed correctly and
working as specified, the initial phase of
the water system validation can begin.
39
Validation of Critical Water Systems
• FDA Requirements: Phase 1
• During the initial phase the operational
parameters and cleaning/sanitation
procedures and frequencies will be
developed. Sampling should be daily after
each step in the purification process and at
each point of use for two to four weeks.
40
Validation of Critical Water Systems
• FDA Requirements: Phase 1
– The sampling procedures for point of use should
reflect how they are taken, e.g. use of hose, and
time for flushing. At the end of the two (2) or
four (4) weeks the firm should have developed
its SOPs for operation and maintenance of the
water system.
41
Validation of Critical Water Systems
• FDA Requirements: Phase 2
• The second phase of the water system
validation is to demonstrate that the system
will consistently produce the desired water
quality when operated in conformance with
SOPs.
42
Validation of Critical Water Systems
• FDA Requirements: Phase 2
• The sampling is performed as in the initial
phase and for the same period . At the end
of this phase the data should demonstrate
that the system will consistently produce the
desired quality of water.
43
Validation of Critical Water Systems
• FDA Requirements: Phase 3
• The third phase of validation is designed to
demonstrate that when the water system is
operated, in accordance with the SOPs,
over a long period of time it will consistently
produce water of desired quality.
44
Validation of Critical Water Systems
• FDA Requirements: Phase 3
• Any variations in quality of the feedwater,
that could affect the operation and ultimately
the water quality, will be noticed during this
phase of the validation.
45
Validation of Critical Water Systems
• FDA Requirements: Phase 3
• Sampling is performed according to routine
procedures and frequencies.
• For Water for Injection systems samples
should be taken daily from a minimum of
one point of use, with all points of use
tested weekly.
46
Validation of Critical Water Systems
• FDA Requirements: Phase 3
• The validation of the water system is
completed when the firm has collected data
for a full year.
• The FDA states that “while the above
validation scheme is not the only way a
system can be validated, it contains the
necessary elements for validation of a water
system.”
47
Validation of Critical Water Systems
• FDA Requirements: Phase 3
• First, there must be data to support the
SOPs.
• Second, there must be data demonstrating
that the SOPs are valid and that the system
is capable of consistently producing water
that meets the desired specifications.
48
Validation of Critical Water Systems
• FDA Requirements: Phase 3
• Finally, there must be data to demonstrate
that seasonal variations in the feedwater do
not adversely affect the operation of the
system or the water quality. This last part of
the validation is the compilation of the data,
with any conclusions into the final report.
49
Microbiological/Chemical Limits
Tests
pH
TOC
Conductivity
Bacteria
Endotoxins
Potable
Water
Purified
Water
Water for Injection
N/A
N/A
N/A
500 cfu/mL
N/A
5.0 - 7.0
500 ppb
4.7 to 5.8 S/cm
100 cfu/mL
Not Specified
5.0 - 7.0
500 ppb
USP Specifications
10 cfu/100mL
0.25 EU/mL
cfu = Colony Forming Units
50
Critical Utility Qualification
• Performance Qualification (PQ) Standard Testing Intervals
– Water For Injection Systems - 30 to 60 Days (20
- 40 days Standard @ Shut Down Recover Test)
– Purified Water Systems - 30 Days
WFI –PW Systems reduce sampling (3 Phases 1st
15 days, 2nd Phase 15 days, if results are acceptable
system be have interim release for GMP use)
 3rd Phase 350 days (52 weeks or 1 yrs) systems
can be considered fully validated, historical data can
be trended to set true alert and action levels
51
ESTABLISHING ENVIRONMENTAL
MONITORING PROGRAM
• When establishing a routine
environmental monitoring program, the
PQ study data should be the starting point
for determining the sampling sites and
testing frequencies.
52
HIGH PURITY WATER SYSTEMS
ENVIRONMENTAL MONITORING PROGRAM
• Sample Site and Frequencies Determination
– For Water for Injection systems samples
should be taken daily from all point of use.
– For Purified Water systems samples should
be taken daily from a minimum of one point
of use, with all points of use tested within a
week.
53
HIGH PURITY WATER SYSTEMS
ENVIRONMENTAL MONITORING PROGRAM
• Sample Site and Frequencies Determination
– For Water for Injection systems samples
should be taken daily from all point of use.
– For Purified Water systems samples should
be taken daily from a minimum of one point
of use, with all points of use tested within a
week.
54
HIGH PURITY WATER SYSTEMS
ENVIRONMENTAL MONITORING PROGRAM
Water Type
WFI
RO/DI
Potable Water
Sample
Description
USP/EU
Conductivity/
TOC Tests
USP/EU
USP/EU/CP
Microbial/
Endotoxin
Chemistry
(Heavy
Metals/Nitrates)
/ Appearance
pH / Ion
Testing
Coliform
Steam Quality
Testing
Beginning of ,
Post Circulation
Pump and WFI
still outlet
Daily read/
Weekly data
collection
Weekly
No Routine Sampling
Not Required
Monthly
(information
Only)
Quarterly
Point of Use Ports
Weekly or Use
Data from inline
device
Monthly
Weekly
Not Required
Not Required
Not Required
End of Loop
Sample
Daily/Compare to
inline device
Daily
Daily
Weekly
Not Required
Not Required
RO Before EDI
(DI System)
Supply Inlet to
WFI Still
Weekly
Weekly +
Coliform
No Routine Sampling
Weekly
Weekly
Not Required
DI Supply Inlet to
WFI Still
Sample Weekly
Weekly +
Coliform
No Routine Sampling
Weekly
Weekly
Not Required
Infeed water to
RO/DI System2
Grab Sample
Weekly
Weekly +
Coliform
No Routine Sampling
Weekly
Weekly
Not Required
55
Part 5
Validation of Clean
System Systems
Clean Steam is used in certain aspects of
GMP Manufacturing Operations
56
Clean Steam Usage in
Pharmaceutical Production
• Clean Steam Requirements
– Steam-In-Place (SIP)
– Sterilization Process
– SIP Water For Injection
57
Validation of Critical Water Systems
• FDA Requirements: Phase 1& 3
• Same requirements as WFI system
Qualification.
58
Validation of Critical Water Systems
• FDA Requirements: Phase 3
• The validation of the clean steam system is
completed when the firm has collected data
for a full year.
59
CLEAN STEAM SYSTEM ENVIRONMENTAL
MONITORING PROGRAM
• Sample Site and Frequencies Determination
– For Clean Steam systems samples should be
before manufacturing process i.e. SIP,
autoclave, etc. and from a minimum of one point
of use, with all points of use tested weekly.
60
CLEAN STEAM SPECIFICATIONS
Table: Microbiological/Chemical Limits
Tests
pH
TOC
Conductivity
Bacteria
Endotoxins
Clean Steam
5.0 - 7.0
500 ppb
Current USP Specifications/
method
10 cfu/100mL (Information Only –
None Routine)
0.25 EU/mL
cfu = Colony Forming Units
61
CLEAN STEAM SYSTEM MONITORING
PROGRAM
Type
Pure (Clean)
Steam
Sample
Description
USP/EU
USP/EU/CP
Microbial/
Endotoxin
Chemistry
(Heavy
Metals/Nitrates)
/ Appearance
Endotoxin
Weekly
Grab Sample
Monthly
Monthly
USP/EU
Conductivity/
TOC Tests
Steam Generator
pH / Ion
Testing
Coliform
Steam Quality
Testing
Weekly
Not Required
Not
Required
Quarterly
Endotoxin
Monthly
Monthly
Not Required
Not Required
Not Required
Monthly
Quarterly
No Routine
Sampling
No Routine
Sampling
Annually
Weekly
Point of Use
(SIP)
Autoclave
Point of
62
Part 5
Validation of
Compress Gas
Systems
There are many different types of gases
used in a GMP manufacturing operation
63
Compress Gases Usage in
Pharmaceutical Production
• Compress Gases Requirements
– Preserve the Status of Product
– Drying after Cleaning
– Assist Cell Growth
– Instrument Actuation
– Move Fluid
64
Compress Gases Usage in
Pharmaceutical Production
• Types Of Gases
– Clean Dry Air
– Nitrogen
– Carbon Dioxide
– Helium
– Oxygen
– Argon
65
COMPRESSED GAS MAJOR COMPONENTS
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•
•
•
•
•
•
•
•
Cylinders
Dryer
Manifold
Automatic/Manual Switchover System
Valves
Pressure Gauges
Filters
Control System (Low Gases, Low Oxygen)
Distribution System (SS or Type L copper)
66
COMPRESS GAS SYSTEMS ENVIRONMENTAL
MONITORING PROGRAM
• Sample Site and Frequencies Determination
– For compress gas systems samples should
be taken daily from all point of use for one
week.
67
COMPRESS GAS SPECIFICATIONS
Table: Microbiological/Chemical Limits
Tests
Compress Gas
Dew Point
Hydrocarbon as Oil Mist
Gas Content
< -10 oC
< 1 ppm
Current USP
Specifications/
method for Purity
< 0.1 CFU/ft3
Room Classification
Bacteria
Non-Viable Particulate:
cfu = Colony Forming Units
68
COMPRESS GAS MONITORING PROGRAM
Sample
Location
Dew Point
Hydrocarbon
as Oil Mist
Bacteria
Non-Viable
Particulate
Quarterly
Monthly
Monthly
Not Required
Weekly (day of
filling process)
Weekly (day of
filling process)
With each new
lot
Monthly
Monthly
Not Required
Not Required
Weekly
Weekly
Monthly
Monthly
Annually
With each new
lot or
Quarterly
Not Required
Not Required
Weekly
Weekly
Type
Gas
Content
Source
Clean
Compressed
Air
USP/EU
Monthly
Annually
Point of Use
Grab Sample
Monthly
Source
Monthly
Not Required
Annually
Carbon
Dioxide (CO2)
Point of Use
Grab Sample
Monthly
Source
Monthly
Nitrogen
Point of Use
Grab Sample
Monthly
69
Part 6
Validation of HVAC
Systems
HVAC is used in Aspect of GMP
Manufacturing Operations
70
Clean Room Standards
• This ISO committee will produce 10 new standards
documents that relate to cleanrooms or clean
zones (described below). The first two standards
have been published: ISO 14644-1 and -2.
– The first document, ISO 14644-1, Cleanrooms
and associated controlled environments Part 1:
Classification of airborne particulates has been
released as a final document.
– The second document, ISO 14644-2, Cleanrooms
and associated controlled environments Part 2:
Testing and monitoring to prove continued
compliance with ISO 14644-1; has been released
as a final document.
71
Clean Room Standards
• The cleanliness classification levels defined by FS209E
and ISO 14644-1 are approximately equal, except the new
ISO standard uses new class designations, a metric
measure of air volume and adds three additional classes
- two cleaner than Class 10 and one beyond than Class
100,000.
• The second new ISO standard, ISO 14644-2, gives
requirements for monitoring a cleanroom or clean zone
to provide evidence of its continued compliance with
ISO 14644-1.
72
Clean Room Certification
• Clean Room Certification Testing
–
–
–
–
–
–
–
–
–
–
–
Differential Air Flow
Humidity/Temperature
Supply Air Volume/Room Air Change Rate
Room Differential Pressures
DOP Test of HEPA Filters
Room Non-Viable Particulate Counts
Light Levels
Noise Levels
Recovery Time
Unidirectional and Parallelism
Enclosure Induction
73
Monitoring Program
• Controls/Alarms – reports verification
and review (procedure)
– Weekly reports
– Alert vs Action Limits
– Failure investigations
• Laboratory testing – viable and nonviable counts
– Analysis of Trends (Quarterly)
– Alert Limits
• Refer to ISO-14644-2 and 14644-3 for
frequency guidelines and test
equipment recommendations
74
HVAC SYSTEMS ENVIRONMENTAL
MONITORING PROGRAM
• Sample Site and Frequencies Determination
– Would the act of sampling at a given site disturb the
environment sufficiently to cause erroneous data or
possibly cause the product to be contaminated?
– At which site would the potential of microbial
contamination most likely affect product quality
adversely?
– During the PQ study which sites were highest in
microbial contaminates.
– What sites would be the most difficult to clean?
– Should site selection involve statistical design or
should it be based on a grid profile?
– How often is a particular area or process used?
75
Physical, Microbiological Testing Parameters
•TABLE 1- Air Classification
–
–
–
–
–
a- All classifications based on data measured in the vicinity of exposed materials/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.
76
SURFACE MONITORING
Table 2: USP’s  1116 microbial levels for Surface Monitoring
Surface
CFU/ 2 in2
3
(floor/except)
Personnel
CFU/ 2 in2
3 - gloves
(5-mask/gown)
Frequency of
P Montoring
M 5.5
5
(10 floor)
5-gloves
(10-mask/gown)
Each Shift1
2x/week2
M 6.5
20
(30-floor)
15-gloves
(30-masks/gown)
Weekly
Classifications
Zone
Critical Area
Class 100
M 3.5
Each Shift
(ISO 5)
Non-critical
Class 10,000
ISO 7
Support Areas
Class 100,000
ISP 8
1
2
Adjacent to Class 100
Support Areas - Product
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CLEAN ROOM MONITORING PROGRAM
Classification
Sample Method
Minimum Sampling Frequency1
Grade A ( ISO Class 5)
Surface Viable
Viable Particulates
Total Airborne Particulates
Weekly or when Filling process is
being performed including during
each shift
Grade B
(ISO class ISO-5.5 Or 6)
Surface Viable
Viable Particulates
Total Airborne Particulates
Weekly or when Filling process is
being performed including each shift
Grade C (ISO Class 7)
Surface Viable
Viable Particulates
Total Airborne Particulates
Weekly or when entering into Grade
B and A area during filling operations.
Grade D ( ISO Class 8)
Viable Particulates
Total Airborne Particulates
Monthly or when entering into Grade
C which leads into Grade B and A
area during filling operations.
Surface viable sampling should be
performed every quarter.
Restricted Areas With Monitoring
Viable Particulates
Total Airborne Particulates
Monthly
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Part 7
Maintenance
Program for Critical
Utility Systems
Maintenance of Critical Utility Systems
insure the life cycle approach to validation
79
CHANGE CONTROL PROGRAM
• Change Control Program (CCP) Maintains Utility
Systems Life Cycle Approach To Validations
• Supports Revalidation Activities.
• Should have established Change Control Program
which includes critical review process when
changes are made to any critical utility system.
• CCP should include changes made and extent of
validation required.
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REVALIDATION PROGRAM
• Annual review of change control forms for each
critical utility system.
• Annual review of the maintenance and cleaning
logs associated with each critical utility system.
• Annual review of routine environmental monitoring
data.
• Annual abbreviated PQ study may be required
under certain conditions.
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VALIDATION MAINTENANCE PROGRAM
(CONT.)
• Validation Maintenance Requirements:
1.
System Specific Operation, Maintenance, Cleaning Procedures
2.
System Specific Routine Monitoring Programs
3.
Trend Analysis
4.
Calibration Program
5.
Preventive Maintenance Program
6.
Change Control Program
7.
QA Auditing
8.
Deviation /Investigation Reporting
9.
Revalidation Program
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“PROBLEM AREAS” - UTILITY SYSTEMS
• No diagrams provided, no narratives
• Diagrams not detailed
• Validation data summaries insufficient
–
–
–
–
–
–
monitoring too infrequent
sampling plan inadequate
monitoring not performed during production
inappropriate parameter tested
validation period too short
inadequate alert and action limits and specs
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“PROBLEM AREAS” - UTILITY SYSTEMS
• Validation data summaries insufficient
– no SOP for corrective actions
– no “historical data base” development
• No discussion of system / equipment
maintenance or calibration
• inadequate proposal for routine monitoring
program
84
Thank You
Question and Answers
Validation Technologies Inc.
85