hvac, water, and other critical utility qualifications

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HVAC, Water, and Other Critical Utility Qualifications

16th Annual Validation WeekOct. 25-27th, 2010 Philadelphia, PA

Park Hyatt

CONTACT INFORMATION for Course Leader

Stephen Nwodo PMP, ASQ-CSQESr. Project ManagerValidation Technologies, Inc.San Diego, CAOffice: 800-930-9222Fax: 858-676-3677Email: [email protected]: http://www.validation.org

Validation Technologies Inc. 2

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PRESENTATION OVERVIEW

SUPPORT DOCUMENTATIONCONSTRUCTION QUALIFICATIONQUALIFICATION OF CRITICAL SYSTEMSESTABLISHING A ROUTINE ENVIRONMENTAL PROGRAMTRENDING AND DATA SUMMARY“PROBLEM AREAS” - UTILITY SYSTEMSREVALIDATION


Part 1Documents to Support Equipment Qualification

IQ/OQ Documentation

IQIQPQPQ

OQOQ

DQDQ

OQOQ

CQCQ

VCVC

PVPV

PQPQ

IQIQ

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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.


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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.


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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.


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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.


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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.


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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)


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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 firm’s 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 firm’s intentions,

philosophies, and policies regarding the commissioning or facility equipment and systems.


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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 attributes”1

• Each of these systems, including many others, must be “evaluated” in terms of installation and performance.

1. FDA definition (Guideline on Process Validation)


Part 2Critical Utility Project Strategy

Plan the Work and Work the Plan

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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


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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 résumé 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 résumé is filed in the permanent record.


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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.


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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 FLOWS p e c if i c a ti on :

S y st e m R e q u i r e m e n t D oc 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 on ,U s e r R e q .

V e n d or S u b m i t ta l sM an u al s

C o n s tr 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

D e s ig n Q u a lif ic a t io n

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

F i n al R e p or t

B ac k g r ou n dT e st R e s u l t s S u m m ar y

E x h i b it s, G r a p h , P h ot osD a t a T r e n d in g/ A n a l ys is

S t at i st i c a l P r oc e s s C on t r o lC al ib r a ti on

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 ofA c c e p ta n c e C r it e r io n

C on c l u s io n / C e r t if ic at i on(A c c e p ta n c e / N on -

A c c e p ta n c e )

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 aw i n g s,

T e st R e p or ts ,W e l d i n g P r ogr am ,C l e a n i n g R e p o r t s ,

P r e s s u r e T e s t,M S D S ,

C on st r u c t i onB u ll e t i n s ,

Q U A L I T Y R E V IE WP ro g r a m S u m m a r y D o c u m e n tA 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 mC h a n g e C o n t ro l R e v ie w

M e th o d sV a lid a t io n


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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


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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• DEVIATION/EXCEPTIONAL CONDITION• ATTACHMENTS


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TEST METHODS QUALIFICATION

• VALIDATED BEFORE THE START OF PQS• INTRODUCTION• METHODS• EQUIPMENT & MATERIALS• PROCEDURE• REPORT


Part 3Commissioning and ConstructionProgram

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Good Engineering Practice (GEP)

• “Established Engineering methods and standards that are applied throughout the project lifecycle to deliver appropriate cost-effective solutions”


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.


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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


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.


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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

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Commissioning Testing

Organizing and Planning Factory Acceptance Test (FAT)Site Acceptance Testing (SAT)Static Testing (pre-commissioning)Operator TrainingWalk Down & TaggingFull Functional TestingAs-Built DocumentationSystem & Equipment ManualsSpare 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


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Relationship between Systems and Components

Critical Non-CriticalDirect Impact

In-Direct/ No Impact

Systems

GEP onlyGEP + Qualification Practices

X


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.


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Part 4Qualification 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


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• 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


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• 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• DEVIATION/EXCEPTIONAL CONDITION


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• 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 5Validation of Water Systems

Water is used in aspects of GMP Manufacturing Operations

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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.



• 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.


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• 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.


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• 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.


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• 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.


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• 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.



• 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.”


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• 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.


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Microbiological/Chemical Limits

Test Portable USP PW USP WFITOC N/A 500ppbC USP <643>Cond (µS/cm) N/A 4.7 -5.8 USP <645>Bacteria1 500cfu/ml 100cfu/ml 10cfu/100mlEndo 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


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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 aweek.


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Part 5Validation 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.


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• FDA Requirements: Phase 3• 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

• 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.


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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 0.90Superheat Not greater than 5oC


Part 5Validation of Compressed Gas Systems

There are many different types of gases used in a GMP manufacturing operation

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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


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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)


COMPRESSED GAS SPECIFICATIONS

Table: Microbiological/Chemical Limits Tests Compress Gas

Dew Point < =-40 oC Hydrocarbon as Oil Mist

< 1 ppm

Gas Content Current USP Specifications/ method for Purity

Bacteria < 0.1 CFU/ft3 Non-Viable Particulate: Room Classification

cfu; = Colony Forming Units


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Part 6Validation 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.


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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)


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.


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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


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Typical Clean Room Performance Tests:

Test Procedure Unidirectional Airflow Room

Non-Unidirectional Airflow Room

Comments

Supply Volume A,B,C A,B,C This test may be performed with an air velocity meter or flow hood

Filter Leak Test A,B A,B Using an aerosol challenge depending on product sensitivity

Airborne Particle Count A,B,C A,B,C

Performed with an airborne particle counter with size sensitivity suitable for room classification

Room Pressurization A,B,C A,B,C Using digital micromanometer

Room Airflow Uniformity A,B A,B

Using Dry Ice Fogger and visual, still photo or video tape recording.

Room Recovery Test A,B A,B Using particle generator and 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:

Test Procedure UnidirectionalAirflow Room

Non-UnidirectionalAirflow Room

Comments

Room RecoveryTest A,B A,B Using particle generator and

airborne particle counterParticle FalloutTest A,B,C A,B,C Using fallout plate monitors at

critical locationsRoom LightingLevel A,B,C A,B,C Using digital photometer per

IES handbook

Room NoiseLevel A,B,C A,B,C

Generally performed forcontractual compliance orsafety requirements.

Temperature & Humidity A,B,C A,B,C

Taken at each particle countlocation or long term trendstudies as required

Vibration Level A,B,C A,B,CGenerally performed forcontractual compliance orsafety requirements.

Bioburden Test A,B,C A,B,C Using RCS samplers, contactplates or fallout plates.


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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


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Calibration of Instrumentation

• NIST Traceability• Calibration procedures per type of

instrument• Control software/hardware maintained as

per procedures


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?


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CONTROLLED ENVIRONMENT

Classifications

Nonviable (ft3) Viable (ft3)

0.5 μm 5.0 μm (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

Class 100,000 (ISO 8) 100,000 (3,520,000/m3)

700 (29,300/m3) 2.5

Airborne nonviable and viable particulate class limits

aColony-Forming Units


SURFACE MONITORING

Table 2: USP’s < 1116> microbial levels for Surface Monitoring

Classifications Zone Surface CFU/ 2 in2

Personnel CFU/ 2 in2

Frequency of P Montoring

Critical Area Class 100

M 3.5 3 (floor/except)

3 - gloves (5-mask/gown)

Each Shift

Non-critical Class 10,000

M 5.5 5 (10 floor)

5-gloves (10-mask/gown)

Each Shift1 2x/week2

Support Areas Class 100,000

M 6.5 20 (30-floor)

15-gloves (30-masks/gown)

Weekly

1 Adjacent to Class 100 2 Support Areas - Product


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Part 7Maintenance 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.


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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.


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.


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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


“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


SUMMARY

• Project Strategy• Qualification of critical utility systems• Establishing routine environmental program• Problem areas• Revalidation


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Thank you


hvac, water, and other critical utility qualifications

Documents

proper design

installation qualification

design qualification

construction documentation

design review

isometric drawings

critical installation

selection of equipment