Design, Construction, Commission, and Qualification of...

Journal of Validation Technology236

Design, Construction, Commission, and

Qualification of Critical Utility Systems

Part I: Overview

INTRODUCTION

Overview of Critical Utility SystemsThe use of critical utility systems in the pharmaceutical

industry is very important to final product quality. That iswhy the design, construction, commissioning, qualification,and routine monitoring of these systems is important in en-ssuring that the end product will maintain a reproduciblequality. Critical utility systems can be considered the back-bone of any production facility and should be the first sys-tems to be validated. Without properly functioning utilities,the quality of any product will be open to question.

Critical utilities found in pharmaceutical, medical device,and biotechnology production facilities usually support var-ious equipment and processes. These utilities must meet bothquantitative and qualitative specifications in order to be con-sidered satisfactory. The actual criteria may vary from oneutility system to another and may even be influenced by theparticular equipment being supported. The design, construc-tion, commissioning, qualification, and monitoring of eachutility will vary depending on the system. Therefore, it is im-portant to follow a logical, comprehensive scheme when at-tempting to validate or monitor these systems.

This article will discuss the various phases of design,construction, commissioning, qualification, and the routinemonitoring of various critical utility systems. While it takesa great deal of time and effort to qualify most critical utili-

ties, this article will only cover general procedures used tobring these systems to a validated state and, once they arevalidated, to establish a routine environmental program. TheRoutine Environmental Monitoring (REM) program is de-signed to ensure that the validation lifecycle is maintainedfor these systems. The REM program also ensures that thesystems are capable of maintaining the same quality outputthroughout the life of the system.

This article will not describe the detailed proceduresneeded to validate these systems. It is impractical to discussall the existing methods and procedures used to validateutility systems within the scope of this article. However, thisarticle will discuss an approach to integrate the commis-sioning and qualification phases of the project in order tostreamline the qualification phase while verifying that thecritical utilities meet their pre-determined design features.

The critical utilities that will be addressed in the articleare as follows:

1. Water systems2. Clean steam system3. Heating Ventilation and Air Conditioning (HVAC)

systems4. Process gasesThis article is the first of three-parts. Part I is an

overview of critical utility systems and the planning neededbefore specific utilities may be addressed.

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B Y D A V I D W . V I N C E N T A N D H E R B E R T M A T H E S O N

David W. Vincent and Herbert Matheson

May 2005 • Volume 11, Number 3 237

User Requirement Specifications

The development of User Requirement Specifications(URS) is one of the most critical elements in the compliancedocumentation process. A successful project is dependenton clear definition, communication, the understanding ofproject scope and objectives, as well as other stakeholderrequirements as defined by them and the end user. At theoutset of the project, after the front end conceptual study hasbeen completed, the user must specify the requirements forindividual aspects of the utility systems in terms of function,throughput, operation, and applicable regulatory require-ments to the engineering service provider. This enables thedevelopment and assessment of specific engineering op-tions. These requirements are normally formalized in a de-tailed URS document.

The URS describes critical installation and operating pa-rameters. It includes performance standards that are re-quired for the intended use of the equipment and providesthe basis for the qualification and maintenance of equip-ment. The URS should be prepared by the equipment ownerin collaboration with representatives from departments thatwill participate in qualifying and maintaining the equip-ment, and from departments that will be affected by the op-eration of that equipment.

Design Specifications and the Design Review Phase

Design specifications for each system are establishedbased on engineering and manufacturing provisions, as wellas input from various organizations and departments. Designspecifications are the foundation for the development of thequalification document acceptance criteria. It is necessary totrack compliance with specifications throughout the valida-tion project. In the end, validation activities will demonstratethat the design intent has been achieved through the propertracking and control of design specifications.

A formal design review process at the beginning of theproject will decrease the number of deviations associatedwith improper control of design specifications during theexecution of Installation and Operational Qualification(I/OQ) protocols. A design review process compares the de-sign of equipment and systems with the applicable user andprocess requirements as defined in the current URS, pro-cessing requirements, product specifications, license com-mitments, manufacturing records, and applicable StandardOperating Procedures (SOP). The design review is intended

to ensure and record that system design meets user require-ments.

One of the first steps that should be considered is defin-ing which areas are to be qualified and what their intendeduses will be. A facility room classification or design speci-fication should be based on the product being manufacturedand the processes being used. It is important that the Archi-tecture and Engineering (A/E) team who are creating thedesign and layout are aware of those areas.

The reasons for this are as follows:1

• To define exactly those areas for which qualifica-tion data must be developed.

• To prevent any misunderstanding, either by theowner or the Food and Drug Administration(FDA), as to what areas will be subject to qualifi-cation. During a pre-construction review of thedrawings with the FDA, the list of areas that werespecified should be discussed. Then, if there areany differences of opinion between the owner andthe FDA, they can be resolved before constructionstarts. It should also be added that drawings are re-quired of the entire facility noting production fea-tures and functions. If the A/E firm knows ahead oftime that as-built drawings are required, the fieldpeople who are responsible for monitoring the con-struction activities will make the changes to thedrawings as the actual changes are being made inthe field. This is the way to be assured that as-builtdrawings will truly be “as builts,” instead of “Ithink-builts.”

Good Manufacturing Practices (GMPs) call for the fol-lowing pertaining to layouts:

• Smooth flow of personnel and product• Adequate space to perform each operation• Spatial separation, where appropriate, to prevent

product mix-ups, component mix-ups, etc.• Adequate lighting• Environmental controls

The design and construction of any facility requires ateam effort. The Design Qualification (DQ) phase of theproject requires the assistance of various departments andprofessionals such as Quality Control (QC) and Quality As-surance (QA), Regulatory Affairs (RA), Facilities/Engineer-ing, Validation, Manufacturing, as well as the general con-tractor and sub-contractors.



A simplified approach can be summarized as follows:• Determine facility design task force (QA, QC, En-

gineering, Manufacturing, Validation, etc.)• Determine process environment requirements• Determine operation requirements, including per-

sonnel flow and material and waste flows• Quantify production, process, and equipment space

requirements• Develop conceptual layout • Approve final facility layout• Develop detail system engineering• Prepare designs and specifications• Obtain acceptance of the design review team• Prepare bidding documents• Determine bidding and acceptance process• Determine construction start date

It is important to remember that the products and manu-facturing processes usually determine the design and layoutof the facility. It is also important to arrange a pre-construc-tion meeting with the FDA. This meeting can decrease theeffort expended in justifying the design after the fact. By de-veloping a formalized and well-documented design reviewprocess, the critical component, design specification, and pa-rameters can be referenced in the validation protocols,thereby decreasing and streamlining the amount of informa-tion that requires verification in the qualification protocols.

Impact Assessments

Impact assessments are a formal process used to identifysystems and the components of those systems that have a di-rect impact on product quality. “Direct impact” systems areexpected to have an impact on the product quality, whereasan “indirect impact” system is not expected to have an im-pact on the product quality. Both systems require commis-sioning; however, the direct impact system will be subject toqualification practices to meet the additional regulatory re-quirements of the FDA and other regulatory authorities. Theimpact assessment process decreases the scope of IQ/OQprotocols by allowing the validation activities to focus onthose systems and components that have been identified ashaving a direct impact on product quality, rather than all sys-tems and components within those processes.

Impact assessments should be performed on two levels:the system level and the component level.

System Level Impact Assessment

System impact assessments are performed to differenti-ate those systems that have a direct impact on product qual-ity from those having indirect or no impact on product qual-ity. The system impact assessments are preliminary until thecompletion of subsequent component impact assessmentsfor each of the systems. The results of the component im-pact assessments could change the results of the system im-pact assessments, which is why the initial system impact as-sessment should be considered preliminary.

The advantage of performing system impact assess-ments is that only direct impact systems require qualifica-tion. Indirect impact and no impact systems are subject toless stringent test and inspection procedures based on busi-ness risk and typical Good Engineering Practices (GEPs). Anumber of utility systems that were commonly qualified inthe past, such as plant steam, chill water, industrial coldwater, and heating hot water, are typically no longer quali-fied based on the results of system impact assessments.

The following summarizes the system impact assess-ment process:

• Identification of the system and system number:This information is typically obtained from theproject Process and Instrumentation Diagrams(P&IDs). Complete the system description with ageneral narrative of the system and its major com-ponents, design, operation, functional capabilities,and critical functions.

• System Boundary Definition: Identifying theboundaries and scope of the system is typicallydone using the system P&IDs as well as otherdrawings and specifications, as appropriate. Theeasiest and clearest way to accomplish this is tomark the system P&IDs to identify the systemboundaries and all components of the system in-cluded within those bounds. Specify systemboundaries by inserting a horizontal or vertical lineat the boundary. These lines should be placed toclearly identify whether or not the adjacent compo-nent is part of the system.



To help in establishing a system boundary, utilize thefollowing general guidelines (there may be exceptions tothese guidelines):

➣ If the component number of a valve, etc., is la-beled as part of the main system being assessed,then it generally will be part of that system.

➣ The control system I/O for a given system willbecome part of that system.

➣ Disposable, flexible piping connectors, portabletanks, etc., should not be highlighted as part ofthe system and should be noted either on thedrawing or in the comments section of the formso it is clear that not highlighting them was in-tentional.

• System Impact Assessment: Once the system hasbeen identified and the system boundaries defined,the impact of the system may be determined. Theimpact of the system is determined by answering aseries of seven questions about the system. In Figure1, the Impact Assessment Questions show how theassessment could be completed for the example of ahypothetical nitrogen gas system.

System Classification

The system is classified as “direct impact,” “indirect im-pact,” or “no impact” as follows:

• If the response to any of challenges one through sixin Figure 1 is “Yes,” then the system shall be clas-sified as a “direct impact” system.

• If the response to challenges one through six is“No,” but the response to challenge seven is “Yes,”the system shall be classified as an “indirect im-pact” system.

• If the response to challenges one through seven is“No,” the system shall be classified as a “no im-pact” system.

Based on the above criteria, the hypothetical nitrogensystem would be classified as “direct impact” because it hasdirect product contact. Document the reasons for this clas-sification with a brief explanation to ensure the understand-ing of future reviewers and approvers.

Figure 1______________________________________________________________________________Impact Assessment Questions

Challenge Yes No

1. Does the system have direct contact with the product (e.g. air quality) or direct contact with a product contact surface [e.g.: Clean in Place (CIP) solution]?

2. Does the system provide an excipient, or produce an ingredient or solvent[e.g.: Water For Injection (WFI)]?

3. Is the system used in cleaning, sanitizing, or sterilizing (e.g.: clean steam)?4. Does the system preserve product status (e.g.: nitrogen purge for oxygen

sensitive products)?5. Does the system produce data that is used to accept or reject product (e.g.:

electronic batch record system, critical process parameter chart recorder, orrelease laboratory instrument)?

6. Is the system a process control system (e.g., PLC, DCS) or does it contain aprocess control system that may affect the product quality and there is nosystem for independent verification of control system performance in place?

7. Is the system expected to not have a direct impact on product quality, butsupports a direct impact system?



Component Criticality Assessments

After system impact assessments have been completed,component criticality assessments are performed to identifythose components within a system that have direct, indirector no impact on product quality. The results of the compo-nent criticality assessments have a direct bearing on the val-idation of the system, in that IQ and OQ testing of the sys-tem can be focused on those components identified as hav-ing a direct impact on product quality.

Volume 5, “Commissioning and Qualification,” of theInternational Society for Pharmaceutical Engineering(ISPE) Pharmaceutical Engineering Guides for New andRenovated Facilities recommends that components withindirect impact, indirect impact, and in some cases, no impactsystems, should be assessed for criticality. This is suggestedto ensure that systems previously judged to have indirect orno impact in the early, high level assessment, have not sub-sequently acquired a critical function as the detailed designhas progressed to conclusion.

The component criticality assessment process requiresthe detailed review of the system P&IDs and system instru-ment lists. Like the system impact assessment, the compo-nent criticality assessment is performed by answering a se-ries of questions about each of the system components. Thequestions proposed by the ISPE “Commissioning and Qual-ification Guideline” are as follows below in Figure 2.

System Classification

• A positive answer to any questions in Figure 2identifies the component as a critical componentthat should be verified during IQ and OQ testing.

• When answers to all the questions in Figure 2 arein the negative, the component is thereby identifiedas a non-critical component of the system that doesnot require verification during IQ and OQ testing.

Component Approval

The construction contractors translate the project speci-fications and design documents created by the A/E teaminto a completed facility. The project specifications createdby the A/E team are typically detailed and often specify acomponent to a specific manufacturer and model, allowingthe use of an “approved equal.” The construction contrac-tors are required to submit to the A/E team technical data onthe components that they intend to use during the construc-tion of the facility so that the A/E team can approve the pro-posed components.

Due to a number of legitimate reasons, including costand availability, the components that contractors submit foruse often do not match all the detailed specifications createdby the A/E team. The A/E team reviews the technical dataprovided by the contractor to determine whether the pro-posed components are acceptable for use. Oftentimes, the

Figure 2______________________________________________________________________________Component Criticality Assessment Questions

Challenge Yes No

1. Is the component used to demonstrate compliance with the registeredprocess?

2. Does the normal operation or control of the component have a direct effecton product quality?

3. Will the failure or alarm of the component have a direct effect on productquality or efficacy?

4. Is information from this component recorded as part of the batch record, lotrelease data, or other GMP-related documentation?

5. Does the component have direct contact with the product or product compo-nents?

6. Are the component controls critical process elements that may affect productquality without independent verification of the control system performance?

7. Is the component used to create or preserve a critical status of a system?



A/E team determines that a component is acceptable eventhough it does not exactly match all of the project specifica-tions; they indicate approval with a stamp on the submittal.

In the real world, gaps in the submittal process are com-mon, such as in the following situations:

• Contractors often submit generic product datasheets that do not adequately specify the compo-nent that will be installed. In example, a genericvalve data sheet may identify the options availablefor materials and finishes, but may not identifywhich of these options the contractor will select.

• The submittal process is often slow and may not becompleted for all components before the compo-nents are installed in the facility.

• Submittals are often stamped as approved by theA/E but not by a designated representative of theclient for whom the facility is being constructed.

Submittal Review

A review and approval of the submittals by the buildingowner is a useful process to resolve these discrepancies andto improve the efficiency of the IQ process. A submittal re-view should be completed for each of the critical compo-nents identified by the component criticality assessment.

The submittal review process proceeds as follows:• Identify the critical component by description and

tag number as appropriate.• Identify the system that contains the component.• Identify the specification number that applies to the

critical component.• Identify the submittal number that applies to the

critical component.• In a “Specified Attribute” column, list the critical

attributes of the component as indicated in the ap-plicable specification, such as manufacturer, modelnumber, materials of construction, capacity, etc.

• In an “Actual Attribute” column, enter the existentcomponent information for each of the critical at-tributes as determined by the component vendor.

Note: It is especially important to identifywhere the component varies from the speci-fied attribute in order for reviewers to makean informed decision as to the acceptabilityof the component.

• Attach supporting vendor technical literature to thesubmittal review form.

• Appropriate representatives of the building ownershould check the submittal review package. Theserepresentatives typically should include the systemowner along with Facilities, Engineering, and Qual-ity Assurance personnel. The acceptability of a com-ponent is determined based on its intended use andits compliance with project specifications. The dis-position of a component is identified typically asACCEPTED,ACCEPTED WITH COMMENTS, orREJECTED. The reviewers then approve the form.

This process ensures that there is an approved submittalpackage for each of the critical components identified dur-ing the component criticality review.

Note: The IQ protocols can be simplified, be-cause the IQ need only verify that the in-stalled critical components match the ap-proved submittals by manufacturer andmodel numbers. This is allowed because thecritical attributes of the components have al-ready been approved through the submittalreview process.

Systematic Risk Assessment for SystemQualifications

The Risk Assessment section discusses the potential im-pact on current Good Manufacturing Practice (cGMP) op-erations associated with the use of the equipment, and thesteps that will be taken to reduce those risks. Identify con-ditions that could lead to failure of the equipment and the ef-fects of failure on cGMP operations. Evaluate the degree ofrisk to product quality, company operations, and the safetyof personnel and equipment.

During the risk assessment, it is important to perform animpact assessment on the system. An impact assessment isthe process by which the effects of the system - and the crit-ical components within those systems - on product qualityare evaluated. System risk assessment is measured in a min-imum of three categories: direct product impact, indirectproduct impact, and no direct product impact. By perform-ing design impact assessments, companies can reduce thescope of the systems and the components subject to qualifi-cation, and allow appropriate focus to be placed on the com-ponents that may present a potential risk to the product.

B. Quality Risk Management Score



Figure 3______________________________________________________________________________Impact Analysis

• Summarize risks and associated controls in an impact and complexity analysis. Rate the impact of theequipment on product quality, safety, and purity, and on the safety of personnel and equipment. Evaluatethe systems in place to control those risks.

A. Quality Impact Score

No impact: Equipment will not be directly or indirectly associated with cGMP activity. Minimal impact: Equipment indirectly affects cGMP processes or procedures. (Non-directproduct impact)Potential Impact: Equipment performs or directly supports a cGMP process or procedure;failure could potentially affect product quality. Equipment failure could negatively impactoperational efficiency or costs. (Indirect product impact) Direct Impact: Equipment is an essential component of a cGMP process or procedure, oris in direct contact with the drug substance or product. Equipment failure could result inloss of product; safety hazard; damage to materials, equipment, or facility; or negative in-spection findings. (Direct product impact)

No risk control necessary.Failure of the equipment would be detected immediately and be corrected before affectinga cGMP process or procedure.Failure could not go undetected. Systems and procedures are in place to detect negativeimpact on product quality safety or purity before significant loss of productivity.Failure could potentially go undetected and cause failure of other processes or procedures.

0

1

2

3

0

1

2

3

Risk Assessment Example

The elements in Figures 3 and 4 indicate one example of how applying risk assessment to a validatablesystem can be beneficial in developing a scientific rationale and justification for the selection of the differ-ent types of qualification needed to support a system.

David Vincent

Highlight



D. Technology Risk Management Score

Figure 4______________________________________________________________________________Complexity Analysis

• Describe the technological risks and controls associated with the equipment. The complexity analysisevaluates the risk of failure due to technical sophistication of the equipment, and the relative difficulty ofmaintaining the equipment in a state of control.

C. Technology Risk Score

Very simple system; minimal chance of failure. Commonly understood technology, rugged equipment; low probability of failure.Somewhat complex equipment, generally reliable technology, components, and controls. Highly complex or sensitive equipment, sophisticated technology, unique components, or processes.

Control and repair possible without impacting cGMP activities. Equipment requires that minimal training, simple maintenance procedures; backup, repair,or like-for-like replacement is readily available.Requires trained operators and maintenance technicians. Backup systems, repair, maintenance, and replacement are readily available.Operators and maintenance technicians must be highly trained. Maintenance, repair, or replacement requires specialized or time-consuming effort; backup systems, repair, maintenance, or replacement are not readily available.

012

3

0

1

2

3

Risk Score

• The calculation used to evaluate the overall risk (as seen in Figure 4) of the equipment combines the individ-ual impact and complexity scores in the following formula:

(A + B) x (C + D)

Where: A = Quality ImpactB = Quality Risk ManagementC = Technology Risk D = Technology Risk Management



Figure 5______________________________________________________________________________Qualification and Validation Justification

Risk Score Qualification Requirements Validation Maintenance Requirements

0

1 to 3

4 to 6

≥7

Document installation and commissioning

IQ

IQ/OQ

IQ/OQ/PQ

• Documentation maintained byusers or Facilities Department.

• Installation, commissioning,maintenance, and change controldocumentation maintained byQA.

• Operate, maintain, and calibrateaccording to written SOPs.

• Document preventive and corrective maintenance and calibration according to SOPs.

• Apply change control proceduresaccording to SOPs and changecontrol programs.

• Perform operation, maintenance,calibration, and performance verification tasks according towritten procedures.

• Document preventive and corrective maintenance and calibration according to SOPs.

• Apply change control proceduresaccording to SOPs and changecontrol programs.

Validation Requirements

Identify the qualification requirement for the equipment based on the impact and complexity analysis asshown in Figure 5. For smaller, less complex system qualification, protocols can be combined into I/OQ orIQ/OQ and Procedure Qualification (PQ) protocols. Any additional information to support and justify the valida-tion requirements should be included.



Construction Qualification (CQ) Activities

The construction of a pharmaceutical manufacturing fa-cility requires strict adherence to the requirements outlinedin the Code of Federal Regulations (CFR), title 21, section211.42 of the cGMPs2 for processing human drugs andnewly proposed regulatory requirements. A great deal ofemphasis is placed on design compliance with cGMP re-quirements, but the effects of construction issues on cGMPcompliance are profound and must be understood by own-ers, facility operators, and contractors.

Integration of construction and qualification activities iscritical to a successful validation project. Document pro-curement and the verification and documentation of con-struction activities are critical to supporting InstallationQualification (IQ).

The proper integration of qualification and construction,commissioning, and startup activities will:

• Accelerate the start-up effort.• Produce superior documentation.• Reduce time to completion of subsequent IQ

and OQ activities.• Ensure that product is produced in a GMP-

compliant facility.

Critical SystemsThe following are common critical systems that should

be inspected during the CQ phase:• Cleanroom HVAC• Purified Water (WP) system• Water For Injection (WFI) system• Computerized systems• Product contact compressed gases• Clean-in-Place (CIP) systems• Product Piping systems• Architectural finishes

DocumentationIn order to utilize tests and inspections performed during

the construction phase of the project, it is necessary that thetests be performed and documented in compliance withcGMP requirements, including:

• The tests and inspections must be performed perwritten and approved procedures.

• The personnel performing and documenting thetests and inspections have been trained in the testprocedures, and that training has been documented.

• The test results have been documented using GoodDocumentation Practices (GDP).

The SOPs necessary to support these requirements mustbe reviewed and approved by the appropriate contractor andthe QA Department owner. The following is a partial list oftypical SOPs necessary to support the integration of con-struction activities into the qualification process:

• Contractor training• Good Documentation Practices• Equipment and component receipt verification• Red line drawing control• Air duct cleaning and inspection• Air duct leakage testing• HEPA filter installation• HEPA filter leak testing• Boroscope inspection procedures• Slope verification procedures• Weld inspection procedures• Weld log procedure• Welder qualification procedures• Piping system walk down procedures• Hydrostatic pressure testing• Pneumatic pressure testing• Cleaning and passivation• Clean build protocol

Coordinator and Team MembersDepending upon the project size, a CQ coordinator and

CQ team with engineering and construction background,should be assigned to monitor and document the construc-tion activities necessary to support the qualification process.A CQ coordinator is most successful in the role when he orshe reports directly to the client or is a representative of theclient. This direct reporting relationship will eliminate theconflict of interest that would derive from the coordinatorbeing part of the construction company.

The Construction Qualification Team is tasked to per-form the following duties:

• Work closely with the general contractor and me-chanical contractors, to procure, verify, and organ-ize documentation for the Turn Over Packages(TOPs) for direct and indirect impact systems aspart of Good Engineering Practices:

➣ Project specifications ➣ Vendor or manufacturer submittals➣ Manufacturer mechanical specifications➣ Purchase orders➣ Vendor test reports



➣ Material certifications➣ Calibration data➣ State and local code compliance ➣ ASME, ANSI, and other certifications➣ Pipe specifications➣ Cleaning and passivation reports➣ Stainless steel weld documentation➣ Instrumentation specifications➣ Drawings➣ Material and finish verification➣ MSDS➣ Any other useful documentation

• Monitor the construction schedule as it relates tovalidation activities to ensure that the required testsand inspections are documented.

• Verify during component receipt inspection that theactual components delivered to the jobsite matchthe components approved for use during the sub-mittal review process. This requirement applies tothe components identified as being critical duringthe component criticality assessments.

• Witness tests and inspections performed during theconstruction process necessary to support the qual-ification of the critical utility systems. The tests andinspections should be witnessed to assure that theprocedures are performed according to specifica-tions and should be fully documented.

• Audit the construction site for cleanliness and com-pliance with specified construction sequences, prac-tices, and craftsmanship standards. Enter observa-tions into a Construction Site Audit Log.

• Document and report any problems that may affectthe construction schedule or have a negative impacton the qualification phase of the project.

Specific Documentation Packages Format

Items listed in the previous sections are included in theCQ packages according to the following guidelines:

➣ CQ Summary SheetThe CQ Summary Sheet, placed before the CQpackages defined here, will briefly describe CQfindings. Specific items for discussion should in-clude identification of construction and installationcontractor(s), start and completion dates, historicaloverview of CQ effort, and a description of CQdocumentation. Both the CQ coordinator and proj-ect manager, serving as approval for the entire CQpackage, will approve the CQ Summary Sheet.

➣ CQ Section IndexThe CQ Section Index shall list all major CQ sec-tions.

Figure 6______________________________________________________________________________Tests Required for Two Common Critical Utility Systems

System Test or Inspection

Critical component receipt inspectionAir duct cleaning and inspectionAir duct leakage testingHEPA filter installationHEPA filter leak testingDrawing verificationCritical component receipt inspectionWeld documentation and inspectionHydrostatic pressure testingSlope verification proceduresDrawing verificationCleaning and passivation

HVAC

WFI



➣ Project SpecificationsProject specifications are provided by the archi-tect(s) of the project and serve as guidelines for con-struction. Only those project specification sectionsapplicable to the CQ system should be included.

➣ Purchase OrdersAll available purchase orders for equipment andmaterials within the system will be included. Eachindividual purchase order will be included in a sep-arate subsection. Dollar amounts may be removed.

➣ Purchase SpecificationThe Purchase Specifications section will immedi-ately follow "Purchase Orders." Purchase specifica-tions should include documentation provided fromthe vendors, contractors, and manufacturers.

Purchase specifications should serve as succeedingdocumentation for the Installation Qualification (IQ)protocol of the CQ system. In addition, those areasof the purchase specification giving direct evidenceto IQ requirements should be highlighted, using asingle color.

➣ Test ReportsThe Test Reports section will immediately followPurchase Specifications. Test reports include docu-ments such as pressure test reports, factory test re-ports, and certifications. Test reports included in CQpackages should depict the static attributes of thesystem, not operational testing. Wherever practical,the CQ coordinator or validation team membershould witness tests.

➣ DrawingsThe Drawings section will be the final section of theCQ package. Drawings will be classified as eitherreference or as built. Reference drawings should bereviewed and signed by at least one person, whileas-built drawings should be reviewed and signed(and red lined, if necessary) by at least one person.(It is desirable to have two reviewers for as-builtdrawings.)

➣ Additional SectionsAny additional sections will be included in the CQbetween the Test Reports and the Drawings sections.

Figure 7_____________________________________Table of Contents Example for a Typical CQPackage

Section 1 - General1. DESIGN SPECIFICATIONS2. PURCHASE ORDERS

Section 2 - Equipment3. EQUIPMENT DATA SHEETS4. EQUIPMENT CHECKLIST5. SPARE PARTS LIST6. VENDOR TEST REPORTS7. VENDOR CERTIFICATION

• ASME• ANSI• MATERIAL CERTIFICATIONS

8. OPERATION AND MAINTENANCE MANUALS

9. DRAWINGS

Section 3 - Piping and Duct10. SPECIFICATION LIST/INDEX11. MATERIAL CERTIFICATIONS12. WELD DOCUMENT

• WELDER QUALIFICATIONS• WELD LOG• WELD INSPECTIONS• WELD AUDIT

13. HYDROSTATIC TEST REPORTS14. CLEANING REPORTS15. PASSIVATION REPORTS16. LINE SLOPE VERIFICATION17. VALVE LABEL VERIFICATION18. LINE LABEL VERFICATION19. TAG INSPECTION20. LINE SUPPORT

Section 4 - Drawings21. PIPING AND INSTRUMENTATION

DIAGRAMS22. ISOMETRIC23. RED-LINED DRAWINGS



➣ ReviewOnce each document is received and verified, itshould be stamped "CONSTRUCTION QUALIFI-CATION Reviewed by" the CQ coordinator withsignature and date.

➣ CQ Section IndexThe CQ Section Index listing all major CQ sectionsshould be included immediately following the CQSummary Sheet.

Commissioning and Startup

The ISPE Baseline Guide, Volume 5, defines commis-sioning as:

"A well planned, documented, and managedengineering approach to the start-up andturnover of facilities, systems, and equipmentto the end-user that results in a safe andfunctional environment that meets estab-lished design requirements and stakeholderexpectations."

The commissioning phase of the project, which typi-cally occurs after mechanical completion of the system andprior to turnover of the system to the owner, is another op-portunity to integrate qualification activities into the facilityconstruction, commissioning, and start-up process. Whilethe qualification activities during the construction phase ofthe project primarily support IQ, qualification activities dur-ing the commissioning and start-up phase will primarilysupport Operational Qualification (OQ).

Pharmaceutical manufacturing facilities, laboratories,and even office buildings demand a complete program ofstart-up, functional challenge, training, documentation, andturnover. It is incumbent upon the individuals responsiblefor design and construction to finish the job by handing overa completely operable and documented facility so that vali-dation activities can follow with minimal problems. Toooften, an owner's project manager will move on to his or hernext big project before the whole job is finished, leavingmaintenance technicians, facility operators, and validationpersonnel with the tasks of: struggling to locate as-builtdocuments, making equipment work, calling vendors fortraining, working off the punch list, and attempting to en-force warranties.

Note: There is no clear demarcation betweenthe construction qualification and commis-sioning phases of the project. CQ and com-missioning activities will often take placeconcurrently. As in the CQ phase, tests andinspections performed during the commis-sioning phase of the project must be per-formed and documented in compliance withwritten and approved SOPs.

Aspects of Commissioning

Commissioning activities should encompass all aspectsof the completion phase of any facility built. Some of thekey aspects include:

• Organizing and planning• Factory testing• Static testing (pre-commissioning)• Operator training• Walk down and tagging• Startup reports• Full functional testing• Turnover and punch lists• As-built documentation• System and equipment manuals• Spare parts management• IQ documentation (as applicable)• OQ documentation (as applicable)

Commissioning Team

Every project team needs a leader who is empowered bythe company to manage the project from start to finish, frominception to completion. "Completion" should be defined asa time when the appropriate signatures on all punch lists,commissioning documents, as-built drawings, validationprotocols, and SOPs are attained. The project leader or proj-ect manager should not leave the project until the "ink is dry"on each of those documents. Organizing and planning forcommissioning are the keys to a successful project. Each ofthe project members should report to one individual, whocan ensure that all project objectives (cost, quality, schedule,safety, etc.) are continuously considered in decision making.

Commissioning suffers when the project team does notplan or organize itself early enough. The commissioningmanager must be selected early and should report to the proj-ect manager. By early selection, the commissioning manager



and team can plan for completion when project engineersand construction staff are actively involved in the daily rig-ors of construction. Selection of the commissioning manageris extremely important; the individual must have operationsexperience as well as good planning and interpersonal skills.The commissioning manager must then select an appropriatecomplement of field technicians, calibration and metrologystaff, document specialists, and technical writers. Some ofthese individuals may be sometimes "loaned" by mainte-nance and operation groups and then returned to thosegroups after project completion. In fact, the loaning of teammembers is often the best solution because it enables start-up knowledge to transfer from project team to operations.

Commission Plan

The commission plan is, properly, one of the most im-portant criteria documents that will be used on the project.The commissioning plan should indicate the various com-mission activities for both GMP and non-GMP systems.The plan should identify the overall commissioning strategyfor the project and complement the Validation Master Plan(VMP) to identify the integration of commissioning andvalidation activities. It also should define the roles and re-sponsibilities of each functional department and their ven-dors as they relate to the commissioning and integration ofthe qualification activates.

The following items describe the key elements of suc-cessful commissioning plan:• A description of the equipment and systems to be com-

missioned including their means of automation• A description of the methods and tools to be used in

commissioning execution• A detailed description of the commissioning strategy in-

cluding integration of commissioning and validation ac-tivities

• Overall sequence of commissioning activities• A detailed description of project deliverables including

identification of the parties responsible for providing thedeliverables

• Roles and responsibilities of personnel involved in thecommissioning effort throughout construction and com-missioningThe commissioning plan should include a strategy for

integrating the qualification phase into the commissioningactivities.

• Pre-Delivery Activities

Provide detail and instructions for each pre-delivery ac-tivity.

Examples of pre-delivery activities include:➣ Control of specifications➣ Review of vendor submittals➣ Vendor audits➣ Third party inspections of off-site fabrication➣ Module and equipment vendor quality control and

inspections➣ Factory Acceptance Testing (FAT)➣ Factory inspection plan

• Equipment and Material Receipt Control

Describe the procedures, documentation, and methods ofcontrol to be utilized for equipment and material receipt. The system should include the following:➣ Approving and rejecting components and equip-

ment➣ Defining storage locations and conditions for criti-

cal components (direct contact copper tubing versesnon-critical copper) to minimize mix-up

➣ Separation of non-GMP materials from GMP mate-rials

• Construction Quality Assurance Activities

It is critical to define the role and responsibility of thequality unit during the commissioning phase. While it isclearly understood that commissioning is usually an engi-neering function, sometimes it is not clear what the QualityUnit role is during the commissioning phase of the project.During the engineering phase of the project, QA may auditthe approved equipment and utility system vendors to ver-ify that they have the necessary quality systems in place toensure the quality of their product or service. Part of the in-tegration concept also involves auditing design and con-struction activities for compliance with cGMPs, verifyingdocumentation, and keeping a close eye on the installationprogress throughout the project’s construction phase.

The Quality Unit must be aware that GMP requires qual-ification activities. Whether some of the qualification is per-formed during the commission phase or not, the regulationsrequire these activities be reviewed and signed-off by theQuality Unit. Therefore, if any aspects of the qualification



activities are being captured during the commissioningphase, the Quality Unit must at least agree and sign-off onthe commissioning plan or strategy. (Because some qualifi-cation activities are integrated into the commissioning phasedoes not mean that they are no longer GMP activities.)

➣ Describe the roles and responsibilities for all proj-ect quality control and quality assurance activities.

➣ Define the scope of the quality control program,authorized documentation, and responsibilities forthe implementation and maintenance of the pro-gram.

➣ Detail the requirements for in-process inspectionsand the methods to be used to document the in-spections.

➣ Describe the requirements for the creation, mainte-nance, and verification of red-line, as-built drawings

➣ Specify the requirements, methods, and proceduresto be utilized for foreign material exclusion for di-rect impact components and materials.

• Commissioning Execution

➣ Pre-Commissioning

A pre-commissioning phase includes the comple-tion of tasks necessary to verify that the system ismechanically complete and ready for the initiationof subsequent commissioning activities.

These activities include:• Mechanical completion• Safety reviews• Code inspections• Site Acceptance Testing• Tagging and labeling verification• Valve or damper lineups• Installation of temporary strainers and filters• Walk down of the system

➣ Startup and Formal Commissioning

This section of the commission plan should de-scribe, in detail, the components of startup andcommissioning execution. Components may include:• Special pre-startup checks• Notification to stake holders that startup activi-

ties will commence that may affect certainprocess equipment or systems, i.e.: backup gen-erator, etc.

• Startup procedures• Setting to work and initial shakedown• Software structural testing• Inspections• Functional testing• Cycle development• Special testing

➣ Commissioning Documentation and Turnover Pack-ages

This section of the commission plan should de-scribe, in detail, the commissioning documents andrequirements for turnover packages.

Components may include:• Commissioning Documentation that specifies the

requirements for commissioning including: re-quired documentation, references, documenta-tion practices, and final reports.

• Turnover Packages, which provide an outline ofthe procedures and requirements for the assem-bly and turnover of system manuals and otherturnover packages.

➣ Commissioning Completion and Turnover to Owner

This section of the commission plan should de-scribe, in detail, the commissioning completionand turnover to owner. Project closeout procedures,deliverables, and responsibilities must be clearlydefined well before construction commences. Themethod of project turnover, whether phased or insingle project completion turnover package, shouldbe clearly defined in this section.



Components of turnover strategy may include:• Deliverables including final release of liens, cer-

tificate of occupancy, final as-built drawings andspecifications, turnover packages, finalizedpunch list, etc.

• Project supplied training• Spare parts• Owner acceptance of operational responsibilities

Commissioning Documentation List

Commissioning starts with the preparation of many lists,which ultimately form the foundation for planning and doc-ument management. An orderly set of equipment lists, in-strument lists, vendor lists, etc., will allow the commission-ing manager to organize his thoughts and begin paying at-tention to details early.

The key to preparing the needed lists is an exhaustivereview of all systems in the facility and selecting the rightnumber of turnover packages. This is best accomplished byreviewing Process Flow Diagrams (PFDs) or P&IDs, keydocuments for any manufacturing facility. These diagramsare best used to distinguish the boundaries of each system.The turnover packages will become a central theme forcommissioning and will be described later in more detail.The various lists may well be the most tedious and time-consuming part of the commissioning manager's job.

A few of the key lists and the related data are recom-mended below:

Drawings and Specifications List• Drawing or revision number(s)• Drawing title• Drawing status• Drawing developed by . . .• Final walk down completed on . . .• Applicable system number (cross reference)

Equipment List• Equipment tag number

(should match maintenance system tag)• Equipment name• Critical or non-critical?• P&ID reference• Vendor name• Installation date• Vendor submittal received (date and time)• SOP required? (yes or no)

• Start-up date• Applicable system number (cross reference)

Instrument List• Instrument tag number• Instrument name• Critical or non-critical?• P&ID reference• Vendor name• Manufacturer submittal received (date and time)• Local or panel mounted

The Role of Qualification Phase in Commissioning

Qualification is a process that focuses on systems affect-ing product quality - those defined as direct impact systemsduring the system impact assessment process. However, thisrepresents only a fraction of what must be done to properlycommission and document an entire facility. The qualifica-tion phase, therefore, must be considered a part of the com-missioning umbrella. IQ and OQ activities should beplanned to take advantage of key commissioning activities,which take place in parallel.

As the schedule indicates, commissioning and qualifica-tion should start together and should be executed together.Validation documents should be considered supplementaland complimentary to commissioning documents, and du-plication should be avoided. This approach, if adopted, willyield the earliest possible project delivery. Figure 8 is a typ-ical validation flow chart.

Use of an Integrated and Streamlined Validation Ap-proach

One cost effective method for managing the validationproject is the using of an integrated and streamlined ap-proach to optimize commissioning and validation activitieson a project.

Using an integrated approach, project success would in-clude the following benefits:

• Reduced project schedules and better overallschedule management

• Reduced start-up time needed in the field• Reduced project costs• Fewer defects or deviations during the qualification

phase• Reduced internal resource needs at the end of the

project



Figure 8______________________________________________________________________________Typical Validation Flowcart

Front End Concept Study

Decommissioning

Release and Use

Validation Master Plan (VMP)

Tender

Install

Commission

Formal Project Turnover

Procedure and Construct

Functional and Detail Design

Engineering Specifications/UserRequirement Specification (URS)

GMP Audit, Design Qualification(DQ) and Impact Assessment

Factory Acceptance Test (FAT)

Pre-delivery Inspection (PDI)

Protocol Development

Formal Installation Qualification (IQ)/Operational Qualification (OQ)

Formal Equipment PerformanceQualification (EPQ)

Periodic Review, Change Controland Revalidation

Generateand Address

Snag List

Generateand Address

Snag List

Generateand Address

Snag List

Generateand Address

Snag List

Engineering Validation



• Adherence to compliance requirements• Overall project quality improvement

During streamlining, the commissioning and validationactivities should adhere to the following basic principles:

• Start the project by evaluating the impact of a systemon product quality

• Focus resources on the qualification of systems with"direct impact" on product quality according toGMP

• Focus on critical components that will have a directimpact on the project quality

• Establish system boundaries in the early phase of theproject

• Evaluate system design from both a quality perspec-tive and a risk-based approach

• Provide contractors, vendors, and engineers with theproject validation requirements up-front to enablethem to plan installations to meet these requirements

• Design and commission those systems that have no"direct impact" on product quality according to GEP

• Enhance the commissioning, qualification, and vali-dation documentation generation, review, and ap-proval processes

• Integrate the commissioning and qualification activ-ities to avoid duplication of work

• Conduct training of employees, contractors, con-sultants, and other personnel early in the projectlifecycle

Strategies

The following section includes some detailed strategiesthat could be followed to reduce project resource require-ments and improve the efficiencies of the commissioningand validation programs.

Integrate Validation Schedules into the Overall ProjectSchedule

The project manager, with support of team members,should ensure the development of a commissioning and val-idation plan as an integral part of the project plan and sched-ule. Integrating validation into the overall project schedulecan save both time and money. Integrated schedules shouldbe developed with input from the construction and valida-tion project teams and be maintained and updated at regularintervals.

IQ/OQ may be conducted as part of the physical com-

pletion of the facility, thus tying IQ/OQ closely to the con-struction contractor’s scope of work that includes commis-sioning. To avoid the effort and inconvenience of discover-ing and rectifying basic problems, it is recommended thatall systems go through an informal shakedown phase beforeIQ/OQ commences. This will help ensure a smooth transi-tion between IQ and OQ, and will minimize the number ofdeviations that may occur during the IQ and OQ phases.

Scheduling of PQ is particularly critical because PQtesting is often the most time consuming part of the qualifi-cation. Scheduling should take into account any prerequi-sites that should be achieved prior to PQ execution (such ascommissioning of all support systems, availability of SOPs,system interdependencies). The PQ protocol often receivesthe greatest amount of scrutiny from the approval team.Again, it is important that IQs and OQs are completed andthat there are no major deviations that may have negativeimpact on the PQ phase.

Integrate Commissioning with Validation Activities

There are considerable advantages of time, cost, andquality in integrating the many functions carried out byskilled resources, such as engineering, contractor, and vali-dation teams. The responsibility for timely and appropriateexecution should be a combination of both the validation andengineering teams, this will reduce the time spent on vali-dating the facility and scaling up to production. The use of acompetent, expert, multi-disciplinary team will ensure thatbest practice is deployed and that duplication of activities isavoided.

Integrating activities such as Design Qualification, Con-struction Qualification, Factory Acceptance Testing, Site Ac-ceptance Testing and commissioning into qualification andvalidation activities can control validation costs and mini-mize project delays. Instruments, components, and equip-ment can be verified at the vendor site during the FAT andCQ phases of the project. This reduces delays caused byidentifying potential problems before equipment is deliveredto the job site. If these items are not altered or dismantled inany way for transport, these checks, if properly documented,could be used in support of SAT or qualification activities.

For OQ, the duration of the testing can be shortened byidentifying the critical operational criteria that require test-ing prior to the facility, utility, or equipment being used inproduction and planning the schedule accordingly. Thiscan be performed by determining which functional con-trols are critical and non critical in the early stages of theDQ phase of the project. Testing the non-critical functions



during the FAT or SAT will reduce the amount of testingrequired during OQ phase.

If FAT is executed for equipment, i.e., alarms and inter-locks testing, some or all of these tests can be performed atthe vendor site, or these tests can be performed as part ofcommissioning, and can be used in support of the OQ. Per-formance testing carried out as part of commissioning cancontribute to PQ when performed consistently with qualifi-cation practices. Thus, if the integrated approach is used andproper inspections, field verification, documentation, andcertain required field execution work is accomplished by theconstruction vendors and contractors, then the qualificationscope can be reduced to that of review, verification, crosslinkage to FAT and SAT documents, monitoring, and com-piling. The integration of commissioning and qualificationmerges activities, minimizes resource requirements, andstreamlines the validation effort by reducing the number ofprotocols and reports.

Approaches to streamline the amount of paperwork re-quired to give sufficient documented evidence of validationmay include:

• Using standardized protocol and report templateswherever possible, so that reviewers become accus-tomed to protocol formats and contents.

• Using procedures and forms that can minimize re-dundancy normally found in qualification proto-cols.

• Structuring executed protocols as reports to obviatethe need for writing a separate report.

• Combining IQ and OQ documents (to I/OQ) willresult in fewer documents to develop, track, review,and approve. However, the IQ section must becompleted before OQ commences.

• Including only critical tests in the protocol, and notrepeating non-critical ones already conducted inFAT or SAT phases, simply verifying that these testhave been performed in the qualification protocols.

• Understanding upfront the critical and test items tobe included in the qualification can reduce bothcost and unnecessary deviations.

• Establishing realistic protocol acceptance criteriabased upon the process demands for reproducibil-ity and product quality.

• Recording deviations in the qualification protocolattachments and then having them immediately re-viewed and approved by the Quality Unit ratherthen waiting until the entire protocol is executed.

• Ensuring that commissioning documentation for

direct impact systems are appropriately planned,created, organized, and authorized so that they maybecome an integral part of the qualification supportdocumentation.

• Combining engineering and validation informationto minimize duplication.

Once qualification protocols are written, they should beapproved, and this may be a time consuming process. Sev-eral ways to streamline this process include:

• Minimizing the number of approvals required bydeveloping approval matrixes.

• Clarifying the review process with all parties earlyin the project.

• Instituting a formalized protocol tracking process.• Minimizing the number of review cycles allowed

by the team.• Implementing a simple review and approval proce-

dure with time limit for the review cycle. • Instituting protocol review meetings for all parties

involved.• Ensuring the protocol review and approval process

is included in the overall project schedule.

Define which activities the vendors are responsible forexecuting when utilizing an integrated approach to com-missioning and validation activities. Figure 9 is an exampleof the integration of commissioning, qualification testing,and verification activities related to WFI skid and distribu-tion system (See Figure 9):

Note: Vendors performs 100% loop checkduring commissioning phase. Validationengineer performs 10% during Qualifica-tion Phase. If failure is detected duringthe 10% verification, then 100% inspec-tion is performed by validation engineeror validation engineer witnesses 100%performed by vendor. ❏



Figure 9______________________________________________________________________________Commissioning and Qualification Integration Approach

Tests and VerificationActivities

Functional Design, Verification,and Design SpecificationsFacility As-built and Piping and Instrumentation Drawings Electrical drawingsCritical Component Verification Materials of Construction Welding DocumentationAlarm and Interlock TestControl System Component Verification Hydrostatics Testing Material Incoming Receipt Cleaning and Passivation Steam in Place StartupSurface Finish Documentation ReportVent Filter Integrity Spare Part Inventory Operation Control Function Non-Critical Operation Control Function CriticalSoftware Installation Verification Operation and Maintenance Procedures VerificationPump and Motor Checkouts (Ro-tation, Lube, Alignment, Belt, etc.)Control System Function *Loop Check Verification Compliance (ASME Certifications)Control System Security Accessand Password ProtectionSequence of Operations Radio Frequency Interference TestVoltage testShut Down and Startup sequence Data Trending Ability Operation Parameter ControlBaseline Performance

Commissioning Phase Qualification Phase

CQ FAT SAT IQ OQ PQ

✓ ✓

✓ ✓ ✓

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CQ = Construction Qualification DQ = Design Qualification FAT = Factory Acceptance TestingIQ = Installation Qualification OQ = Operational Qualification PQ = Performance Qualification SAT = Site Acceptance Testing



This is the first part of a three-part article. Parts II and IIIwill be published in the Journal of Validation Technology inthe August and November 2005 issues, respectively.

About the Author

David W. Vincent has over 25 years experience in theBiopharmaceutical industry with 19 years dedicatedto the fields of validation and engineering. He has aBS degree in Microbiology and Mechanical Engineer-ing Technology; Mr. Vincent has consulted for manycompanies both nationally and internationally. He haspresented many training seminars and has writtennumerous articles and technical guides regarding val-idation topics. Mr. Vincent teaches "Validation Pro-gram for the Pharmaceutical, Biotechnology, andMedical Device Industries" at San Diego State Uni-versity (SDSU) for their Regulatory Affairs Master De-gree program.

Currently, Dave is the Chief Executive Office (CEO)for Validation Technologies Incorporated (VTI), aworldwide validation and technical services company.VTI is also a certified commissioning company thatoffers commissioning and startup functions for thehealthcare industry. Dave can be reached by phoneat 800-930-9222, by fax at 858-638-5532, or by e-mail at [email protected]. (Web Site is located atwww.validation.org)

The following references are those applicable to Part I.The full list of references used in the three-part articlewill appear with Part III in the November 2005, Journalof Validation Technology.

References

1. Center for Drugs and Biologics, Center for Devices andRadiographic Health, "Guidelines on General Principlesof Process Validation," FDA Rockville, Maryland, 1987.

2. "cGMP Compliance in Architecture and Construction ofBiopharmaceutical Manufacturing Facilities" BioPharm,Prepared January-February, 1993.

3. "Code of Federal Regulations Section 21 Parts 200 to299 and Parts 600 to 799," Food and Drugs Adminis-tration (FDA).

4. "Guidelines for Bulk Drug Manufacturers," Food andDrugs Administration (FDA).

5. Center for Drug Evaluation and Research, Center for

Biologics Evaluation and Research, Office of Regula-tory Affairs, "Guidelines on Sterile Drug Products Pro-duced by Aseptic Processing," FDA Rockville, Mary-land, June 1987.

6. Center for Drug Evaluation and Research, Center forBiologics Evaluation and Research, Office of Regula-tory Affairs, "Guidelines on Sterile Drug Products Pro-

Article Acronym Listing

A/E Architecture and EngineeringANSI American National Standards InstituteASME American Society of Mechanical

EngineersCFR Code of Federal RegulationscGMP Current Good Manufacturing PracticeCIP Clean in PlaceCQ Construction QualificationDCSDQ Design QualificationFAT Factory Acceptance TestFDA Food and Drug AdministrationGDP Good Documentation PracticeGEP Good Engineering PracticeGMP Good Manufacturing PracticeHEPA High Efficiency Particulate AirHVAC Heating, Ventilation,

and Air ConditioningI/O Input/OutputIQ Installation QualificationISPE International Society for

Pharmaceutical EngineeringMSDS Material Safety Data SheetOQ Operational QualificationP&ID Process and Instrumentation DiagramPFD Process Flow DiagramPLCPQ Performance QualificationPW Purified WaterQA Quality AssuranceQC Quality ControlRA Regulatory AffairsREM Routine Environmental MonitoringSAT Site Acceptance TestingSOP Standard Operating ProcedureTOP Turn Over PackageURS User Requirement SpecificationVMP Validation Master PlanWFI Water For Injection



duced by Aseptic Processing," FDA Rockville, Mary-land, June 1987.

7. PDA Environmental Task Force, "Fundamentals of a Mi-crobiological Environmental Monitoring Program," Vol.44, Supplement 1990.

8. "Microbiological Control and Validation," The Institutefor Applied Pharmaceutical Sciences, March 7-9, 1994.

9. Powell-Evans, K., "Streamlining Validation; ValueAdded Qualifications." Institute of Validation Technol-ogy. December 2000. Newsletter.

10. Graham C. Wrigley, Pfizer Global Manufacturing, andJan L. du Preez, Ph.D., "Research Institute for Indus-trial Pharmacy Facility Validation: A Case Study for In-tegrating and Streamlining the Validation Approach toReduce Project Resources," Volume 8, Number 2, Feb-ruary 2002.

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