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: [email protected] Website: http://www.validation.org
Validation Technologies Inc. 2
PRESENTATION OVERVIEW
SUPPORT DOCUMENTATION CONSTRUCTION QUALIFICATION QUALIFICATION OF CRITICAL SYSTEMS ESTABLISHING A ROUTINE ENVIRONMENTAL PROGRAM TRENDING AND DATA SUMMARY PROBLEM AREAS - UTILITY SYSTEMS REVALIDATION
Validation Technologies Inc.
Part 1 Documents to Support Equipment Qualification
DQ PQ OQ PV IQ OQ IQ
IQ/OQ Documentation
PQ VC CQ
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.
Validation Technologies Inc. 5
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.
Validation Technologies Inc. 6
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.
Validation Technologies Inc. 7
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.
Validation Technologies Inc.
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
Validation Technologies Inc. 9
Turnover Package
Documentation collected by the vendor during the construction activities to support installation qualification. (submittals, purchase, component cut sheets, certifications, etc.
Validation Technologies Inc.
10
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.
Validation Technologies Inc. 11
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.
Validation Technologies Inc.
12
Isometric Drawings
3-D renderings of piping diagrams. Usually developed for the purpose of weld location. Typically drawn for sanitary piping systems.
Validation Technologies Inc.
13
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.
Validation Technologies Inc.
14
Engineering Change Management Documents
Engineering change management system is used during the construction and installation phase of the project. Implemented before systems qualification.
Validation Technologies Inc.
15
Calibration Reports
Calibration is a comparison of a measurement system or device with another, known good measurement system or device (standard)
Validation Technologies Inc.
16
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.
Validation Technologies Inc.
17
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.
Validation Technologies Inc. 18
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)
Validation Technologies Inc.
19
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 Technologies Inc. 21
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
Validation Technologies Inc.
22
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
Validation Technologies Inc.
23
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.
Validation Technologies Inc.
24
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 Technologies Inc.
25
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.
Validation Technologies Inc.
26
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 Technologies Inc.
27
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 , P u r c h a se , C o n s tr u c ti o 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
D e s ig n Q u a lif ic a t io n
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, T e st R e p o r ts , 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 ,
C o n s t r u c t io n Q u a lif ic a t io n
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 Q u a lif ic a t io n
P e r fo r m a n c e Q u a lif ic a t io n 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 )
Validation Technologies Inc.
28
14
INSTALLATION QUALIFICATION PROTOCOL FOR CRITICAL UTILITIES
OBJECTIVE IDENTIFICATION SYSTEM DESCRIPTION REFERENCES RESPONSIBILITIES PROCEDURE ACCEPTANCE CRITERIA SYSTEM COMPONENT INSPECTION DRAWING COMMENTS DEVIATION/EXCEPTIONAL CONDITION
Validation Technologies Inc.
29
STANDARD OPERATING PROCEDURE FOR CRITICAL UTILITIES
OPERATION AND MAINTENANCE IQ, OQ & PQ PROCEDURES FINAL REPORT PROCEDURE CHANGE CONTROL CALIBRATION TEST METHODS REVALIDATION PROCEDURE
Validation Technologies Inc.
30
15
CALIBRATION FOR CRITICAL UTILITIES
CALIBRATION PROGRAM SCHEDULE CALIBRATION FOR CRITICAL INSTRUMENTS LIST OF CRITICAL INSTRUMENTS
Validation Technologies Inc.
31
OPERATIONAL QUALIFICATION PROTOCOL FOR CRITICAL UTILITIES
OBJECTIVE IDENTIFICATION SYSTEM FUNCTIONAL DESCRIPTION REFERENCES RESPONSIBILITIES PROCEDURE ACCEPTANCE CRITERIA OPERATIONAL QUALIFICATION TEST COMMENTS DEVIATION/EXCEPTIONAL CONDITION ATTACHMENTS
Validation Technologies Inc. 32
16
TEST METHODS QUALIFICATION
VALIDATED BEFORE THE START OF PQS INTRODUCTION METHODS EQUIPMENT & MATERIALS PROCEDURE REPORT
Validation Technologies Inc.
33
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
Validation Technologies Inc.
35
Good Engineering Practice (GEP)
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.
Validation Technologies Inc.
36
18
Good Engineering Practice (GEP)
GEP project scope
Documentation Organization and Communication Requirements Phase Design Phase Construction Phase Project Controls Commissioning and Qualification Project Closeout and Turnover
Validation Technologies Inc.
37
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.
Validation Technologies Inc.
38
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
Validation Technologies Inc.
39
Commissioning Strategy
Commissioning Strategy should contain the following items: (Direct Impact Systems)
ISPE Commission and Qualification Guidance
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
Validation Technologies Inc. 40
20
Commissioning Testing
Organizing and Planning Factory Acceptance Test (FAT) Site Acceptance Testing (SAT) Static Testing (pre-commissioning) Operator Training Walk Down & Tagging Full Functional Testing As-Built Documentation System & Equipment Manuals Spare Parts Management
Validation Technologies Inc. 41
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
Validation Technologies Inc.
42
21
Relationship between Systems and Components
Critical Direct Impact Systems Non-Critical
X
43
In-Direct/ No Impact
Validation Technologies Inc.
GEP only GEP + Qualification Practices
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.
Validation Technologies Inc. 44
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
Validation Technologies Inc. 46
23
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.
System Location System Description Major Components Identification Summary Field Inspection Report- Comparison of Actual to Specified Instrumentation List Spare Parts List Documentation/Drawings List
Validation Technologies Inc. 47
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.
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
Validation Technologies Inc. 48
24
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.
Validation Technologies Inc. 49
PERFORMANCE QUALIFICATION PROTOCOL FOR CRITICAL UTILITIES OBJECTIVE IDENTIFICATION SYSTEM DESCRIPTION REFERENCES RESPONSIBILITIES PROCEDURE ACCEPTANCE CRITERIA PERFORMANCE TESTS COMMENTS DEVIATION/EXCEPTIONAL CONDITION
Validation Technologies Inc.
50
25
Critical Utility Qualification
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)
Validation Technologies Inc. 51
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.
Validation Technologies Inc.
53
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.
Validation Technologies Inc.
54
27
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.
Validation Technologies Inc.
55
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.
Validation Technologies Inc.
56
28
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.
Validation Technologies Inc.
57
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.
Validation Technologies Inc.
58
29
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.
Validation Technologies Inc.
59
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.
Validation Technologies Inc.
60
30
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.
Validation Technologies Inc.
61
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.
Validation Technologies Inc.
62
31
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.
Validation Technologies Inc.
63
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.
Validation Technologies Inc.
64
32
Microbiological/Chemical Limits
Test TOC Cond Bacteria1 Endo
(S/cm)
Portable N/A N/A 500cfu/ml N/A
USP PW 500ppbC 4.7 -5.8 100cfu/ml N/S
USP WFI USP <643> USP <645> 10cfu/100ml 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
Validation Technologies Inc.
65
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
Validation Technologies Inc.
66
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.
Validation Technologies Inc.
67
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.
Validation Technologies Inc.
68
34
Part 5 Validation of Clean Steam Systems
Clean Steam is used in certain aspects of GMP Manufacturing Operations
Validation of Critical Water Systems
FDA Requirements: Phase 1, 2 & 3
Same requirements as WFI system Qualification.
Validation Technologies Inc.
70
35
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.
Validation Technologies Inc.
71
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 bi-weekly.
Validation Technologies Inc.
72
36
CLEAN STEAM SPECIFICATIONS
Table: Microbiological/Chemical Limits Tests TOC Conductivity Bacteria Endotoxins Clean Steam 500 ppb Current USP Specifications/ method 10 cfu/100mL 0.25 EU/mL
EN 285 Below
Non-condensable gases Dryness Superheat 3.5% 0.90 Not greater than 5oC
Validation Technologies Inc.
73
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
Validation Technologies Inc.
75
Compressed Gases Usage in Pharmaceutical Production
Types Of Gases
Clean Dry Air Nitrogen Carbon Dioxide Helium Oxygen Argon
Validation Technologies Inc.
76
38
COMPRESSED GAS SYSTEMS ENVIRONMENTAL MONITORING PROGRAM
Sample Site and Frequencies Determination 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)
Validation Technologies Inc.
77
COMPRESSED GAS SPECIFICATIONS
Table: Microbiological/Chemical Limits Tests Dew Point Hydrocarbon as Oil Mist Gas Content Compress Gas < =-40 oC < 1 ppm Current USP Specifications/ method for Purity < 0.1 CFU/ft3 Room Classification
Bacteria Non-Viable Particulate:
cfu; = Colony Forming Units
Validation Technologies Inc.
78
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.
Validation Technologies Inc.
80
40
Clean Room Standards
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)
Validation Technologies Inc.
81
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 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.
Validation Technologies Inc.
82
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
Validation Technologies Inc.
83
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
Validation Technologies Inc.
84
42
Typical Clean Room Performance Tests:
Test Procedure Unidirectional Airflow Room A,B,C NonUnidirectional Airflow Room A,B,C Comments This test may be performed with an air velocity meter or flow hood Using an aerosol challenge depending on product sensitivity Performed with an airborne particle counter with size sensitivity suitable for room classification Using digital micromanometer Using Dry Ice Fogger and visual, still photo or video tape recording. Using particle generator and airborne particle counter Supply Volume
Filter Leak Test
A,B
A,B
Airborne Particle Count
A,B,C
A,B,C A,B,C A,B A,B
Room Pressurization A,B,C Room Airflow Uniformity A,B
Room Recovery Test A,B
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
Validation Technologies Inc.
85
Typical Clean Room Performance Tests:
Test Procedure Unidirectional Airflow Room NonUnidirectional Airflow Room A,B A,B,C A,B,C A,B,C Comments Using particle generator and airborne particle counter Using fallout plate monitors at critical locations Using digital photometer per IES handbook Generally performed for contractual compliance or safety requirements. Taken at each particle count location or long term trend studies as required Generally performed for contractual compliance or safety requirements. Using RCS samplers, contact plates or fallout plates.
86
Room Recovery A,B Test Particle Fallout A,B,C Test Room Lighting A,B,C Level Room Noise Level Temperature & Humidity Vibration Level Bioburden Test A,B,C
A,B,C
A,B,C
A,B,C A,B,C
A,B,C A,B,C
Validation Technologies Inc.
43
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
Validation Technologies Inc. 87
Maintenance Requirements
Preventive Maintenance procedures are being followed Repairs equivalent replacement parts Changes following Change Control procedure
Validation Technologies Inc.
88
44
Calibration of Instrumentation
NIST Traceability Calibration procedures per type of instrument Control software/hardware maintained as per procedures
Validation Technologies Inc.
89
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?
Validation Technologies Inc.
90
45
CONTROLLED ENVIRONMENT
Nonviable (ft3) Classifications Class 100 (ISO 5) Class 10,000 (ISO 7) 0.5 m 100 (3,520/m3) 5.0 m 0 (29/m3)
Viable (ft3) (CFUsa) 0.1 0.5
3
10,000 (352,000 /m3) 70 (293 m3)
700 (29,300/m ) 2.5 Class 100,000 (ISO 8) 100,000 (3,520,000/m3) Airborne nonviable and viable particulate class limits a Colony-Forming Units
Validation Technologies Inc.
91
SURFACE MONITORING
Table 2: USPs < 1116> microbial levels for Surface Monitoring Classifications Critical Area Class 100 Non-critical Class 10,000 Support Areas Class 100,000 Zone M 3.5 M 5.5 M 6.5 Surface CFU/ 2 in2 3 (floor/except) 5 (10 floor) 20 (30-floor) Personnel CFU/ 2 in2 3 - gloves (5-mask/gown) 5-gloves (10-mask/gown) 15-gloves (30-masks/gown) Frequency of P Montoring Each Shift Each Shift1 2x/week2 Weekly
1 2
Adjacent to Class 100 Support Areas - Product
Validation Technologies Inc.
92
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.
Validation Technologies Inc.
94
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 Technologies Inc.
95
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.
Validation Technologies Inc.
96
48
VALIDATION MAINTENANCE PROGRAM (CONT.)
Validation Maintenance Requirements:
1.
2. 3. 4. 5. 6. 7. 8. 9. System Specific Operation, Maintenance, Cleaning Procedures System Specific Routine Monitoring Programs Trend Analysis Calibration Program Preventive Maintenance Program Change Control Program QA Auditing Deviation /Investigation Reporting Revalidation Program
Validation Technologies Inc.
97
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
Validation Technologies Inc.
98
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
Validation Technologies Inc.
99
SUMMARY
Project Strategy Qualification of critical utility systems Establishing routine environmental program Problem areas Revalidation
Validation Technologies Inc.
100
50
Thank you
Validation Technologies Inc.
101
51
