HVAC, Water, and Other Critical Utility Qualifications PDF

HVAC, Water, and Other
Critical Utility Qualifications
16th Annual Validation Week

Oct. 25-27th, 2010
Philadelphia, PA
Park Hyatt
CONTACT INFORMATION
for Course Leader
Stephen Nwodo PMP, ASQ-CSQE

Sr. Project Manager
Validation Technologies, Inc.
San Diego, CA
Office: 800-930-9222
Fax: 858-676-3677
Email: validation@validation.org
Website: http://www.validation.org
Validation Technologies Inc. 2
1
PRESENTATION OVERVIEW
9 SUPPORT DOCUMENTATION
9 CONSTRUCTION QUALIFICATION
9 QUALIFICATION OF CRITICAL SYSTEMS
9 ESTABLISHING A ROUTINE
ENVIRONMENTAL PROGRAM
9 TRENDING AND DATA SUMMARY
9 PROBLEM AREAS - UTILITY SYSTEMS
9 REVALIDATION
Part 1
Documents to Support
Equipment Qualification
DQ
PQ IQ
OQ
PV
IQ OQ
IQ/OQ Documentation
PQ VC
CQ
2
User Requirements Specifications
(URS)
The URS describes critical installation and

operating parameters and performance
standards that are required for the intended
use of the equipment, and provides the
basis for qualification and maintenance of
the equipment.
The URS documents the design
qualification and rationale for selection of
equipment.
Design Specifications
Validation in general is accomplished

first through proper design. Design
specifications for each system are
established based on the engineering
and manufacturer specifications.
A design review and design qualification

(DQ) are indicated as required by many
firms.
3
Purchase Requisitions
Document specifying the purchase of an

item and the documentation to support it.
Usually pre-empted by a bid request to

various vendors for cost comparisons.
Should be reviewed by QA or validation prior

to issuance.
Construction Documentation
During construction, documents are

generated indicating that items/systems
have been installed. These documents
would be things such as weld certifications,
material certifications, punch lists,
installation inspections, etc.
4
Vendor Documentation
These could be any of the following:

Specifications
Cut Sheets
Advertisement
Descriptions
Equipment Drawings
Maintenance Manuals
Vendor Test Protocols
Other manuals
Spare Parts Lists
Turnover Package
Documentation collected by the

vendor during the construction
activities to support installation
qualification. (submittals, purchase,
component cut sheets,
certifications, etc.
5
Acceptance Testing
FATs are standard tests that are

executed at the factory to verify
proper operations before the
system leaves the plant.
SATs are standard tests that are
executed at the end user site to
verify proper operations before the
system is ready for validation.
Piping & Instrumentation Drawings

(P&IDs)
Engineering drawings that indicates
piping and instrumentation size,
type, location, controls, alarms etc.
The base detail drawings for
systems
PFD (Process Flow Diagrams) are
predecessors to P&IDs.
6
Isometric Drawings
3-D renderings of piping diagrams. Usually

developed for the purpose of weld location.
Typically drawn for sanitary piping systems.
Equipment/Instrument Lists
Engineering documents, which lists all the

equipment and instruments associated with the
design of the facility. Typically these lists are
generated from the P&IDs. The instrument list
may not be an indicator of criticality. A separate
list should exist for this purpose.
7
Engineering Change Management
Documents
Engineering change management

system is used during the
construction and installation phase
of the project. Implemented before
systems qualification.
Calibration Reports
Calibration is a comparison of a
measurement system or device with
another, known good measurement
system or device (standard)
8
Standard Operating Procedures
(SOP)
A document required by cGMP

A document used to give
instruction typically by step, on how
to perform a specific task or
operation.
Master Plans
Validation Master Plan

A document which summarizes the firms overall
philosophy, intentions and approach for establishing the
reliability and consistency of the equipment, systems, and
processes in the facility, as well as the ongoing program for
maintaining a validated state of control.
Commissioning Plan
A document which summarizes the firms intentions,
philosophies, and policies regarding the commissioning or
facility equipment and systems.
9
Qualification Protocol
Establishing documented evidence which provides a high

degree of assurance that a specific process will consistently
produce a product, meeting its pre-determined specifications
and quality attributes1
Each of these systems, including many others, must be

evaluated in terms of installation and performance.
1. FDA definition (Guideline on Process

Validation)
Part 2
Critical Utility Project
Strategy
Plan the Work and Work the Plan
10
PROGRAMS REQUIRED FOR FACILITY & CRITICAL
UTILITIES QUALIFICATIONS
PROJECT DESIGN SPECIFICATION

VALIDATION MASTER PLAN
PROJECT SCHEDULE
CONSTRUCTION QUALIFICATION PACKAGES
INSTALLATION QUALIFICATION PROTOCOLS
FACILITY STARTUP/COMMISSIONING
STANDARD OPERATING PROCEDURES
CALIBRATION & MAINTENANCE PROGRAM
OPERATIONAL QUALIFICATION PROTOCOLS
ANALYTICAL METHODS VALIDATED
PERFORMANCE QUALIFICATION
VALIDATION MASTER PLAN
VALIDATION PROJECT ROAD MAP

VALIDATION PROJECT DESCRIPTION
FACILITY & PROCESS DESCRIPTION
EQUIPMENT & UTILITY LIST
VALIDATION PROGRAM
PROJECT RESPONSIBILITIES
REFERENCE DOCUMENTS
GENERAL ACCEPTANCE CRITERIA
11
PROJECT SCHEDULE
DEFINED CRITICAL PATHS
CONSTRUCTION ACTIVITIES
COLLECTION OF CONSTRUCTION QUALIFICATION 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
GENERAL PROJECT MANAGEMENT
Contractor Selection Process
Proper education, experience, and training to

perform their job function. A rsum is the
document that shows this for your V/Q & C
contractors. Supplement training with
pharmaceutical manufacturers specific procedures
and/or policies. Be sure the rsum is filed in the
permanent record.
12
Facilities VMP
This plan describes what (in general )

will be done to qualify the
facilities/utilities.
It references specific protocols that are
to be developed for the specific things
to be qualified or validated (such as the
HVAC and the Process water systems.)
The real specific information should be
in the protocols not the plan.
Validation of Facilities/Utilities
With the exception of the performance

qualification of water systems, which requires
a full year of test data, the Validation Master
Plan (VMP) for the facilities and utilities is
completed prior to beginning the work of
validating the manufacturing processes.
13
CONSTRUCTION QUALIFICATION PACKAGE
CQ DATA COLLECTION
DAILY SITE INSPECTION SHEETS
VIDEO & PHOTO OF CONSTRUCTION SITE
PURCHASE ORDERS & SPECIFICATIONS
MATERIAL SAFETY DATA SHEETS
DRAWING LIST
CODE COMPLIANCE
SITE TEST VERIFICATION
CLEANING REPORTS
VALIDATION DOCUMENT FLOW

S p e c if i c a ti o n :
S y st e m R e q u i r e m e n t
D o c u m e n t,
D e s ig n ,
D r aw i n g ,
E n gi n e e r , D e s ig n
P u r c h a se ,
C o n s tr u c ti o n , Q u a lif ic a t io n
U s er R eq .
V e n d o r S u b m i t ta l s
M an u al s
P u r c h as e O r d e r s ,
P r oj e c t S p e c .,
P u r c h as e S p e c .,
D r a w i n g s,
C o n s t r u c t io n
T e st R e p o r ts , Q u a lif ic a t io n
W e l d i n g P r ogr am ,
C l ea ni ng R epo rts ,
P r e s s u r e T e s t,
M S D S,
C o n st r u c t i o n
B u ll e t i n s ,
I n s t a lla t io n
Q u a lif ic a t io n
Q U A L I T Y R E V IE W
P ro g r a m S u m m a r y D o c u m e n t
A p p r o v a l/ N o n - A c c e p t a n c e o f
S y s te m
C h a n g e C o n t ro l R e v ie w
O p e r a t io n a l
P e r fo r m a n c e
M e th o d s
V a lid a t io n
F i n al R e p or t
B ac k g r ou n d
T e st R e s u l t s S u m m a r y
E x h i b it s, G r a p h , P h o t o s
D a t a T r e n d in g / A n a l y s is
S t a t i st i c a l P r o c e s s C o n t r o l
C a l ib r a ti o n
D e v ia t io n s , D i s c r e p a n c ie s
R e vi e w & S u m m ar y of
A c c e p ta n c e C r it e r io n
C o n c l u s io n / C e r t if ic a t i o n
(A c c e p ta n c e / N o n -
A c c e p ta n c e )
14
INSTALLATION QUALIFICATION
PROTOCOL FOR CRITICAL UTILITIES
OBJECTIVE
IDENTIFICATION
SYSTEM DESCRIPTION
REFERENCES
RESPONSIBILITIES
PROCEDURE
ACCEPTANCE CRITERIA
SYSTEM COMPONENT INSPECTION
DRAWING
COMMENTS
DEVIATION/EXCEPTIONAL CONDITION
STANDARD OPERATING PROCEDURE

FOR CRITICAL UTILITIES
OPERATION AND MAINTENANCE

IQ, OQ & PQ PROCEDURES
FINAL REPORT PROCEDURE
CHANGE CONTROL
CALIBRATION
TEST METHODS
REVALIDATION PROCEDURE
15
CALIBRATION FOR CRITICAL
UTILITIES
CALIBRATION PROGRAM
SCHEDULE CALIBRATION FOR CRITICAL
INSTRUMENTS
LIST OF CRITICAL INSTRUMENTS
OPERATIONAL QUALIFICATION
PROTOCOL FOR CRITICAL UTILITIES
OBJECTIVE
IDENTIFICATION
SYSTEM FUNCTIONAL DESCRIPTION
REFERENCES
RESPONSIBILITIES
PROCEDURE
ACCEPTANCE CRITERIA
OPERATIONAL QUALIFICATION TEST
COMMENTS
ATTACHMENTS
16
TEST METHODS QUALIFICATION
VALIDATED BEFORE THE START OF PQS

INTRODUCTION
METHODS
EQUIPMENT & MATERIALS
PROCEDURE
REPORT
Part 3
Commissioning and
Construction
Program
17
Good Engineering Practice (GEP)
Established Engineering methods and

standards that are applied throughout the
project lifecycle to deliver appropriate
cost-effective solutions

GEP is comprised of the following:
Professional and competent project management
(processes, procedures, and staff)
Professional and competent engineering design,
procurement, construction and commissioning
Full consideration of applicable safety, health, and
environmental statutory requirements
Full consideration of operation and maintenance
requirements
Full consideration of recognized standards and guidance
Appropriate documentation for ongoing operation and
maintenance, and to demonstrate compliance with
applicable regulations and codes.
18
GEP project scope
Documentation
Organization and Communication
Requirements Phase
Design Phase
Construction Phase
Project Controls
Commissioning and Qualification
Project Closeout and Turnover
Commissioning
A well planned, documented, and

managed engineering approach to the
start-up and turnover of Facilities,
systems, and equipment to the End User
that results in a safe and functional
environment that meets established
design requirements and stakeholders
expectations.
19
Commissioning
Term Commissioning typical

encompasses the following tasks:
Physical Completion and Inspection
Setting to Work
Regulation and Adjustment
Testing and Performance testing
Planning and preparation associated with
managing the above activities
Commissioning Strategy
Commissioning Strategy should contain the
following items: (Direct Impact Systems)
Scope
Plan Approval and Changes
System Overview
Deliverables
Roles and Responsibilities
Inspection (Construction and Installation Oversight)
System Walk Down
Regulations and Adjustment
Testing and Performance
Training
Turnover
Commissioning Plan Close Out
ISPE Commission and

Qualification Guidance Validation Technologies Inc. 40
20
Commissioning Testing
9 Organizing and Planning
9 Factory Acceptance Test (FAT)
9 Site Acceptance Testing (SAT)
9 Static Testing (pre-commissioning)
9 Operator Training
9 Walk Down & Tagging
9 Full Functional Testing
9 As-Built Documentation
9 System & Equipment Manuals
9 Spare Parts Management
Commissioning Plan
Commissioning Plan should contain the following
deliverables: (Direct Impact Systems)
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
21
Relationship between Systems
and Components
Critical Non-Critical
Direct
Impact
5 5
Systems
In-Direct/ X
No Impact
5
GEP only
Validation Technologies Inc. GEP + Qualification Practices 43
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
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 misclassified or the
component was wrongly assessed.
22
Part 4
Qualification of
Critical Utilities
Systems
Design, Construct, Commission then

Qualify
Critical Utility Qualification
Construction Qualification
During construction, document procurement and
verification of construction activities, are critical
components of a successful Installation Qualification
(IQ).
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
23
Installation Qualification - is a documented

plan for the performance of inspections and
the collection of documentation to verify
static attributes of a system.
System Location
System Description
Major Components Identification Summary
Field Inspection Report- Comparison of Actual to
Specified
Instrumentation List
Spare Parts List
Documentation/Drawings List
Operational Qualification (OQ) - is a documented plan for the

performance of inspections and tests to verify specified
dynamic attributes of a system.
SOP Review
Calibration Review
Test of Critical Alarms
Test of Controls
Test of Interlocks
Start Up/Shutdown Sequence Verifications
Normal Run Mode Verification - Monitoring Applicable
Indications:
Pressure
Temperature
Time
Resistivity/Conductivity
Flow
pH
24
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.
PERFORMANCE QUALIFICATION PROTOCOL

FOR CRITICAL UTILITIES
OBJECTIVE
IDENTIFICATION
SYSTEM DESCRIPTION
REFERENCES
RESPONSIBILITIES
PROCEDURE
ACCEPTANCE CRITERIA
PERFORMANCE TESTS
COMMENTS
25
Example Performance Qualification (PQ) -

Standard Testing Intervals
Water For Injection Systems - 30 to 60 Days (30
- 40 days Standard @ Shut Down Recover Test)
Purified Water Systems - 30 Days
Clean Steam Systems - 30 Days
Gases/Clean Dry Air Systems - 14 Days or three
lots
HVAC System (Controlled Environment)-
Baseline (Before cleaning), Static States,
Dynamic (20 -30 days)
Part 5
Validation of Water
Systems
Water is used in aspects of GMP

Manufacturing Operations
26
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.

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.
27
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.

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.
28

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.
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.
29

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.

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.
30

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.

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.
31

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.

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.
32
Microbiological/Chemical Limits
Test Portable USP PW USP WFI

TOC N/A 500ppbC USP <643>
Cond (S/cm) N/A 4.7 -5.8 USP <645>
Bacteria1 500cfu/ml 100cfu/ml 10cfu/100ml
Endo N/A N/S 0.25EU/ml
1- Total bacteria count free from objectionable organism
USP 32-NF27 2009 www.usp.org

FDA Guide to Inspections of High Purity Water Systems (7/93)
FDA Guide To Inspections of Microbiological Pharmaceutical Quality Control Laboratories (May, 1993)
CFU = Colony Forming Units
N/S = Not Specified
N/A = Not applicable
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
33
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.
PURIFIED 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.
34
Part 5
Validation of Clean
Steam Systems
Clean Steam is used in certain aspects of

GMP Manufacturing Operations
FDA Requirements: Phase 1, 2 & 3

Same requirements as WFI system
Qualification.
35

The validation of the clean steam system is
completed when the firm has collected data
for a full year.
CLEAN STEAM SYSTEM ENVIRONMENTAL

MONITORING PROGRAM

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 bi-weekly.
36
CLEAN STEAM SPECIFICATIONS
Table: Microbiological/Chemical Limits
Tests Clean Steam
TOC 500 ppb

Conductivity Current USP Specifications/
method
Bacteria 10 cfu/100mL
Endotoxins 0.25 EU/mL
EN 285 Below
Non-condensable gases 3.5%

Dryness 0.90
Superheat Not greater than 5oC
Part 5
Validation of
Compressed Gas
Systems
There are many different types of gases

used in a GMP manufacturing operation
37
Compressed Gases Usage in
Pharmaceutical Production
Compressed Gases Requirements
Preserve the Status of product
Drying after cleaning
Assist Cell Growth
Instrument Actuation
Move Fluid
Compressed Gases Usage in

Pharmaceutical Production
Types Of Gases
Clean Dry Air
Nitrogen
Carbon Dioxide
Helium
Oxygen
Argon
38
COMPRESSED GAS SYSTEMS
ENVIRONMENTAL MONITORING PROGRAM

For compressed gas systems samples should
be taken daily from a minimum of one point
of use, with all points of use tested weekly.
(Dew Point and Oil)
One sample per representative sample point
taken on any three non-consecutive days
distributed over the 14-day (initial PQ) period
for a total of three samples per representative
sample point (particulates only)
COMPRESSED GAS SPECIFICATIONS
Table: Microbiological/Chemical Limits

Tests Compress Gas
Dew Point < =-40 oC

Hydrocarbon as Oil < 1 ppm
Mist
Gas Content Current USP
Specifications/
method for Purity
Bacteria < 0.1 CFU/ft3
Non-Viable Particulate: Room Classification
cfu; = Colony Forming Units
39
Part 6
Validation of HVAC
Systems
HVAC is used in aspects of GMP

Manufacturing Operations
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.
40
By U.S. law, FS 209E can be superseded by new
international standards. It is expected that 209E will
be in use in some industries through the next five
years, but that eventually it will be replaced
globally by ISO 14644-1.
IES RP-CC-0006 This is a very popular test

standard that provides test procedures for most
environmental parameters that may be required,
some of these procedures include filter integrity
testing, room pressurization, temperature and
relative humidity, room recovery testing to name a
few. (See also NSF-49, ISO 14644-3)

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
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.
41
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
Clean Room Certification
Clean Room Certification Testing

Establishing of Sampling location (ISO 14644-1
Annex B)
Derive the minimum number of sampling point
locations from equation:
NL = A
NL is the minimum number of sampling point locations
(rounded up to whole number).
A is the area of the cleanroom or clean zone in square
meters
42
Typical Clean Room Performance
Tests:
Non-
Unidirectional
Test Procedure Unidirectional Comments
Airflow Room
Airflow Room
This test may be performed
Supply Volume A,B,C A,B,C with an air velocity meter or
flow hood
Using an aerosol challenge
Filter Leak Test A,B A,B depending on product
sensitivity
Performed with an airborne
Airborne Particle particle counter with size
A,B,C A,B,C
Count sensitivity suitable for room
classification
Room Pressurization A,B,C A,B,C Using digital micromanometer
Using Dry Ice Fogger and
Room Airflow
A,B A,B visual, still photo or video tape
Uniformity
recording.
Using particle generator and
Room Recovery Test A,B A,B
airborne particle counter
A - Indicates the test is best performed in an "As Built" condition.
B - Indicates the test is best performed in an "At Rest" condition.
C - Indicates the test is best performed in an "Operational" condition
Typical Clean Room Performance

Tests:
Non-
Unidirectional
Test Procedure Unidirectional Comments
Airflow Room
Airflow Room
Room Recovery Using particle generator and
A,B A,B
Test airborne particle counter
Particle Fallout Using fallout plate monitors at
A,B,C A,B,C
Test critical locations
Room Lighting Using digital photometer per
A,B,C A,B,C
Level IES handbook
Generally performed for
Room Noise
A,B,C A,B,C contractual compliance or
Level
safety requirements.
Taken at each particle count
Temperature &
A,B,C A,B,C location or long term trend
Humidity
studies as required
Generally performed for
Vibration Level A,B,C A,B,C contractual compliance or
safety requirements.
Using RCS samplers, contact
Bioburden Test A,B,C A,B,C
plates or fallout plates.
43
Monitoring Program
Controls/Alarms reports verification

and review (procedure)
Weekly reports
Alert vs Action Limits
Failure investigations
Laboratory testing viable and non-
viable counts
Analysis of Trends (Quarterly)
Alert Limits
Refer to ISO-14644-2 and 14644-3 for
frequency guidelines and test
equipment recommendations
Maintenance Requirements
Preventive Maintenance procedures are being

followed
Repairs equivalent replacement parts
Changes following Change Control procedure
44
Calibration of Instrumentation
NIST Traceability
Calibration procedures per type of
instrument
Control software/hardware maintained as
per procedures
HVAC SYSTEMS ENVIRONMENTAL

MONITORING PROGRAM

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?
45
CONTROLLED ENVIRONMENT
Nonviable (ft3) Viable

Classifications (ft3)
0.5 m 5.0 m (CFUsa)
Class 100 (ISO 5) 100 (3,520/m3) 0 (29/m3) 0.1
Class 10,000 (ISO 7) 10,000 (352,000 /m3) 70 (293 m3) 0.5
3
Class 100,000 (ISO 8) 100,000 700 (29,300/m ) 2.5
(3,520,000/m3)
Airborne nonviable and viable particulate class limits
a
Colony-Forming Units
SURFACE MONITORING
Table 2: USPs < 1116> microbial levels for Surface Monitoring

Classifications Zone Surface Personnel Frequency of
CFU/ 2 in2 CFU/ 2 in2 UP Montoring
Critical Area M 3.5 3 3 - gloves
Class 100 (floor/except) (5-mask/gown) Each Shift
Non-critical M 5.5 5 5-gloves Each Shift1
Class 10,000 (10 floor) (10-mask/gown) 2x/week2
Support Areas M 6.5 20 15-gloves Weekly
Class 100,000 (30-floor) (30-masks/gown)
1
Adjacent to Class 100
2
Support Areas - Product
46
Part 7
Maintenance
Program for Critical
Utility Systems
Maintenance of Critical Utility Systems

insure the life cycle approach to validation
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.
47
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.
VALIDATION MAINTENANCE PROGRAM
Once the critical utility systems are

validated and turned over
Engineering/Facilities, Manufacturing and
QA will be responsible for maintaining the
validated state of each systems.
48
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
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
49
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
SUMMARY
Project Strategy
Qualification of critical utility systems
Establishing routine environmental program
Problem areas
Revalidation
50
Thank you
51

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HVAC, Water, and Other

Critical Utility Qualifications

16th Annual Validation Week

Stephen Nwodo PMP, ASQ-CSQE

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The URS describes critical installation and

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Validation in general is accomplished

A design review and design qualification

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Document specifying the purchase of an

Usually pre-empted by a bid request to

Should be reviewed by QA or validation prior

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During construction, documents are

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These could be any of the following:

Documentation collected by the

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FATs are standard tests that are

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Piping & Instrumentation Drawings

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3-D renderings of piping diagrams. Usually

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Engineering documents, which lists all the

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Engineering change management

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A document required by cGMP

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Validation Master Plan

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Establishing documented evidence which provides a high

Each of these systems, including many others, must be

1. FDA definition (Guideline on Process

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Plan the Work and Work the Plan

PROJECT DESIGN SPECIFICATION

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VALIDATION MASTER PLAN

VALIDATION PROJECT ROAD MAP

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GENERAL PROJECT MANAGEMENT

Contractor Selection Process

Proper education, experience, and training to

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This plan describes what (in general )

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With the exception of the performance

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VALIDATION DOCUMENT FLOW

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STANDARD OPERATING PROCEDURE

OPERATION AND MAINTENANCE

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