Commissioning and qualification ASTM approach

JULY/AUGUST 2008 PHARMACEUTICAL ENGINEERING 1

Commissioning, Qualification, and Verification

©Copyright ISPE 2008

Solving the Terminology Conundrum

by Robert Adamson, Nuala Calnan, Robert E. Chew,and Steven J. Wisniewski

Introduction

In today’s biopharma and pharmaceuticalindustries, three related, but distinct termsare in common use: commissioning, qualification, and verification. Inconsistent in-

terpretation and application of these termsleads to misunderstandings and inefficiencieson the part of vendors, service providers, andmanufacturing personnel from company to com-pany. This article, through a review of theindustry definitions and associated practices,is intended to stimulate discussion on resolv-ing this terminology conundrum and providekey input to pending publications of ISPEBaseline® Guides.

In 2001, ISPE issued the Baseline® GuideVolume 5: Commissioning and Qualification,that provided definitions for two of these terms:Commissioning and Qualification. In 2007,ASTM E2500-07: A Standard Guide for theSpecification, Design, and Verification of Phar-maceutical and Biopharmaceutical Manufac-turing Systems and Equipment was issued.This standard introduced the term “verifica-tion” as a new term for demonstrating suitabil-ity and fitness for intended purpose, in place ofthe terms commissioning and qualification.

The terms “verification” and “commission-ing” are used in many industries and have afairly consistent meaning. The term “qualifica-tion” has been used by the regulated pharma-ceutical and biotech industries, and can befound in EU regulations, as well as US, EU,and ICH guidance documents. Do these termsmean the same thing (more or less) or do theyconvey three different necessary and uniquemeanings?

This article is divided into two parts:

1. definitions and use of the terms found inpublished regulatory and guidance docu-ments

2. analysis of the terms in light of currentpractices

The authors invite readers to respond to thisdiscussion, either through the ISPE Commis-sioning and Qualification Community of Prac-tice (C&Q COP) discussion board, or via directcommunication. Such input will be consideredwhen any related updates to the Baseline®

Guides are undertaken.

Part I – Definitions and CitationsQualificationThe term qualification, while not specificallyfound in US GMP regulations, is found in EUregulations, ICH Q7A, and ICH Q9, as well asWHO and other country regulations and guid-ance documents.

US – FDAThe US GMPs do not explicitly mention theterm qualification – in that there is no specificregulatory requirement to produce documentslabeled installation, operation, or performancequalification. However, there are clear expec-tations of a process that demonstrates fitnessfor intended use and assures proper perfor-mance.

US GMPs require that:

• Facilities be “suitable... to facilitate cleaning,maintenance, and proper operation.”

• Equipment is to “be of appropriate design...to facilitate operations for its intended use.”(21 CFR 211.42, 211.63, 606.40, 606.60,820.40, 820.60).

• Automated systems are required to be “checkedaccording to a written program designed toassure proper performance” (211.68).

The medical device regulations (21 CFR 820)require that: “computer software programs shallbe validated by adequate and documented test-ing” (820.61).

21 CFR Part 11 requires [for those systems to

This articlediscusses theterms“commissioning,”“qualification,”and“verification.”Do the termsrefer to thesame ordifferent ideas?How should thepharmaceuticalandbiotechnologyindustries usethese terms in aconsistent andmeaningfulway? Thisarticle providesa compilation ofhow theseterms are usedin regulationsand by variousindustries, andprovides aproposal forclear definitionsto be used asISPE updatesand createsBaseline®Guides.

Reprinted from

PHARMACEUTICAL ENGINEERING®

The Official Magazine of ISPE

July/August 2008, Vol. 28 No. 4

2 PHARMACEUTICAL ENGINEERING JULY/AUGUST 2008



which Part 11 applies]: “Validation ofsystems to ensure accuracy, reliability,consistent intended performance, andthe ability to discern invalid or alteredrecord.”

The 1987 FDA guidance on processvalidation first introduced the termqualification in these terms:

Installation qualification studies estab-lish confidence that the process equip-ment and ancillary systems are capableof consistently operating within estab-lished limits and tolerances. After pro-cess equipment is designed or selected, itshould be evaluated and tested to verifythat it is capable of operating satisfacto-rily within the operating limits requiredby the process. This phase of validationincludes examination of equipment de-sign; determination of calibration, main-tenance, and adjustment requirements;and identifying critical equipment fea-tures that could affect the process andproduct. Information obtained from thesestudies should be used to establish writ-ten procedures covering equipment cali-bration, maintenance, monitoring, andcontrol. In assessing the suitabilityof a given piece of equipment [em-phasis added], it is usually insufficientto rely solely upon the representations ofthe equipment supplier, or upon experi-ence in producing some other product.Sound theoretical and practical engi-neering principles and considerationsare a first step in the assessment.

The Food and Drug Administration’s(FDA’s) current thinking on the topic ofActive Substances Used as StartingMaterials is represented by the ICHQ7A guidance, which includes refer-ences to Qualification.

EU – EMEAEU Volume 4: EU Guidelines to GoodManufacturing Practice MedicinalProducts for Human and VeterinaryUse, Annex 15 (Qualification and Vali-dation), while specifically referencingboth qualification and validation, fur-ther outlines in its lead Principle State-ment that:

quirements for Active Substancesused as Starting Materials, whichalso includes specific references toqualification activities.

ICH Q9 has recently been adopted bythe EU as part of its Vol 4 GMPs asAnnex 20.

ICH Harmonized TripartiteGuidelinesThe ICH International guidance docu-ments contain additional references toqualification. ICH Q7A, GMPs for Ac-tive Pharmaceutical Ingredients statesthat:

“Before initiating process validationactivities, appropriate qualification ofcritical equipment and systems shouldbe completed. Qualification is usuallycarried out by conducting the followingactivities, individually or combined:

• Design Qualification (DQ): docu-mented verification that the proposeddesign of the facilities, equipment, orsystems is suitable for the intendeduse.

• Installation Qualification (IQ): docu-mented verification that the equip-ment or systems, as installed or modi-fied.

• Operational Qualification (OQ):documented verification that theequipment or systems, as installedor modified, perform as intendedthroughout the anticipated operat-ing ranges.

• Performance Qualification (PQ):documented verification that theequipment and ancillary systems, asconnected together, can perform ef-fectively and reproducibly based onthe approved process method andspecifications.

The recent ICH Q9, Quality Risk Man-agement, includes an appendix of ap-plications of quality risk management;Appendix II.4 describes how to usequality risk management for facilities,equipment, and utilities, including:

“...manufacturers identify what vali-dation work is needed to prove controlof the critical aspects of their particularoperations... A risk assessment approachshould be used to determine the scopeand extent of validation.”

The Annex goes on to describe the fol-lowing validation and qualificationactivities as:

• The first element of the validation...could be design qualification.

• Installation qualification should beperformed on new or modified facili-ties, systems, and equipment.

• Operational qualification shouldfollow installation qualification.

• Performance qualification shouldfollow successful completion of in-stallation qualification and opera-tional qualification.

The annex includes specifics regardingthe content and execution of qualifica-tion work. Content requirements in-clude the items typically found in anIQ, OQ, or PQ protocol, such as instal-lation verification, collection of equip-ment manuals, calibration, materialsof construction, testing across operat-ing ranges, etc. Execution requirementsinclude:

• Written protocol specifying criticalsteps and acceptance criteria.

• Protocol reviewed and approved(does not specify by whom).

• A report written summarizing re-sults, including recommendingchanges necessary to correct defi-ciencies, and documenting changeswith appropriate justification.

• Formal release to the next step inqualification or validation as a writ-ten authorization (does not specifyby whom).

ICH Q7A has been incorporated intothe EU GMPs as Part II: Basic Re-




“...to determine the scope and extentof qualification of facilities, buildings,and production equipment...”

ISPE Baseline® GuideThe 2001 Commissioning and Qualifi-cation Baseline® Guide defines IQ, OQ,and PQ in similar terms:

• Installation Qualification: the docu-mented verification that all aspectsof a facility, utility or equipmentthat can affect product quality ad-here to approved specifications (e.g.,construction, materials) and are cor-rectly installed.

• Operational Qualification: the docu-mented verification that all aspectsof a facility, utility, or equipmentthat can affect product quality oper-ate as intended throughout all an-ticipated ranges.

• Performance Qualification: the docu-mented verification that all aspectsof a facility, utility, or equipmentthat can affect product quality per-form as intended meeting predeter-mined acceptance criteria.

World Health Organization(WHO)World Health Organization (WHO)Guidance on Validation defines Quali-fication as “Action of proving and docu-menting that any premises, systems,and equipment are properly installedand/or work correctly and lead to theexpected results.”

CommissioningEU – EMEAEU GMPs Annex 11, ComputerisedSystems positions commissioning as acomponent of computer validation:

[The computer validation life] “cycleincludes the stages of planning, specify-ing, programming, testing, commission-

ing, documentation, operation, moni-toring and modifying.”

ISPE Baseline® GuideThe 2001 Commissioning and Qualifi-cation Baseline® Guide defines Com-missioning as “A well planned, docu-mented, and managed engineering ap-proach to the start-up and turnover offacilities, systems, and equipment tothe end-user that results in a safe andfunctional environment that meets es-tablished design requirements andstakeholder expectations.”

The material that follows this defi-nition positions commissioning as aprocess that includes inspections, op-erational testing, and performance test-ing.

Commissioning as defined by non-drug industries:

• Building commissioning providesdocumented confirmation that build-ing systems function according tocriteria set forth in the project docu-ments to satisfy the owner’s opera-tional needs (Building Commission-ing Association).

• Commissioning means to verify thatthe building’s energy related systemsare installed, calibrated and per-form according to the owner’s projectrequirements, basis of design, andconstruction documents (LEED re-quirements).

• Building commissioning is the pro-cess of ensuring that building sys-tems and equipment are designed,installed, tested, and capable of be-ing operated and maintained accord-ing to the owner’s operational needs(US Department of Energy).

• Process of ensuring that new build-ings and their systems perform asdesigned (Oak Ridge National Labo-ratory).

VerificationUS – FDA21 CFR Part 820 (U.S. medical devicequality system regulations) definesVerification to mean: “confirmation byexamination and provision of objectiveevidence that specified requirementshave been fulfilled.” This definition maybe contrasted with the Part 820 defini-tion of Validation, “confirmation by ex-amination and provision of objectiveevidence that the particular require-ments for a specific intended use can beconsistently fulfilled.”

EU – EMEAEU Volume 4: EU Guidelines to GoodManufacturing Practice MedicinalProducts for Human and VeterinaryUse, Annex 15 (Qualification and Vali-dation), Glossary, includes the samedefinitions for DQ, IQ, OQ, and PQ asoriginated in the ICH Q7A document,which defines these activities in termsof a “Documented Verification.”

ASTM E2500 defines Verification as:“A systematic approach to verify thatmanufacturing systems, acting singlyor in combination, are fit for intendeduse, have been properly installed, andare operating correctly. This is an um-brella term that encompasses all typesof approaches to assuring systems arefit for use such as qualification, com-missioning and qualification, verifica-tion, system validation, or other.”

According to ISO 9000:2000 Verifica-tion is defined as the: “Confirmation,through the provision of objective evi-dence, that specified requirements havebeen fulfilled.” Objective evidence isdefined as “data supporting the exist-ence or verity of something.”

IEEE Standard 1012-2004, Standardfor Independent Verification and Vali-dation, defines Verification as: “Pro-cess for determining whether the soft-

“We leave it to industry to debate these proposals; it is important that we achieve aconsistent understanding and application of these terms. Once the debate is complete, it is

for ISPE to incorporate the results into upcoming Baseline® Guides.”




ware products of an activity fulfill therequirements or conditions imposed onthem in the previous activities.”

Of note, the definition of Validation inIEEE standard 1012-2004 is: Valida-tion – process for determining whetherthe requirements and the final as-builtsystem or software product fulfills itsspecific intended use.

Part II – Analysis in Light ofCurrent Practices

The question is, do these three terms –verification, commissioning, qualifica-tion – describe the same or differentthings?

The simplest term to analyze is verifi-cation. For the most part, the defini-tions of verification are consistent (asfound in 21 CFR 820, ISO 9000, IEEE1012-2004, and other sources). Thesedefinitions focus on the idea of “con-firming, through objective evidence,that a specified requirement has beenmet (fulfilled).” ASTM E2500 definesVerification using the same base word:“to verify.” The standard assigns abroader mission for verification, “a sys-tematic approach to verify... systemsand equipment are fit for intended use,properly installed, operating correctly...an umbrella term.”

The term commissioning is more com-plex – different organizations in ourindustry assign different meanings tocommissioning. Some view it as thework that is necessary to make a pieceof equipment ready to start, i.e., thepre-functional inspections and checks(sometimes referred to as pre-commis-sioning). Other organizations are morealigned with the 2001 Commissioningand Qualification Baseline® Guide defi-nition, which positions commissioningas a project lifecycle activity that con-sists of a planned, managed, and docu-mented approach to bringing equip-ment or systems to a full operationalstate, and demonstrating conformancewith specifications and user require-ments. Depending on system complex-ity, the start-up, setting to work, regu-lation and adjustments, cycle develop-

ment, and related work can be signifi-cant, not to mention the actual inspec-tions and testing activities. Using thisidea of commissioning means it mayinclude a number of diverse activitiesrequiring significant planning and co-ordination. Other industries definecommissioning in terms that empha-size the performance testing of a sys-tem or group of systems against end-user requirements.

Finally, qualification, as shown above,is specifically mentioned in EU regula-tions as well as ICH Q7A and ICH Q9.Although the word Qualification is notexplicitly mentioned in US GMP regu-lations, the concept of equipment andfacilities being suitable for their in-tended use is clearly referenced. Fur-thermore, US GMPs do contain a re-quirement to validate certain automa-tion systems, and everyone recognizesthat the typical current industry prac-tice is to include installation, opera-tion, and performance qualification.

How do we reconcile this TerminologyConundrum? Are we to adopt the stancethat if one uses the term “verification,”that this implies a science- and risk-based approach as defined by ASTME2500, whereas use of the terms “com-missioning” and “qualification” impliesa more traditional approach not basedon science and risk? Or do these threeterms describe three different ideas orprocesses, each of which can have auseful place in our approach to deliver-ing equipment, systems, and automa-tion that are suitable for their in-tended use?

1. Irrespective of an organization’sregulatory compliance strategy ofusing either a program labeled “Veri-fication” or “Qualification,” facili-ties and equipment will still need tobe commissioned as defined above.Therefore, a well planned, managed,and documented effort to start-upand place into service a system,equipment, or combination thereof,including automation, will need tobe undertaken – commissioning.

This phase includes safe start-up,setting to work, regulation and ad-justment, cycle development, etc.,which contribute to achieving a fulloperational state.

2. A significant amount of valuableverification work may occur duringthis commissioning process, e.g.,physical inspections, documentationreviews, operational testing, andperformance testing. Retention ofthe term commissioning for this com-plex process of placing equipmentinto operation may therefore be ap-propriate, and for this term to ex-tend to and include, the verificationwork that may occur at this time.

3. Assignment of the term verificationto the act of confirming, throughobjective evidence, that a particularspecification has been met is appro-priate, given the common under-standing of the meaning of this termand its use by the medical deviceregulations, ICH guidance, etc. Thisconfirmation can take many forms:physical inspection, operationaltesting, performance testing, as wellas other methods such as review ofa material certification document,software code inspection for con-formance to programming stan-dards, etc.

a. This verification could occur atany point in the overall lifecycleof, design, fabrication, installa-tion, pre-start-up, start-up, orinitial operation of the overallsystem or process.

b. This verification should occur atthe most appropriate point in theoverall lifecycle – as defined andjustified though the Quality RiskManagement (QRM) process.

c. This verification work may occurduring factory acceptance, siteacceptance testing, installation,or formal commissioning phasesof the project.

d. This verification work is per-formed under Good Engineering




Practice (GEP), and executed byappropriate Subject Matter Ex-perts (SME).

4. A common requirement of all of theregulatory references above is thatfacilities, equipment systems, andassociated automation are docu-mented and authorized as suitablefor the intended use. The determina-tion that systems are suitable fortheir intended use present a diffi-culty in ensuring that there is aclear understanding of what suit-ability means. Suitability for usecan be defined in many ways, andthere may be different possible de-sign solutions, which will achieve adesired result. We strongly recom-mend that suitability for use is notequivalent to meeting a particularengineering design specification.Instead, we propose that suitabilityfor use be defined in terms of abilityto meet product and process require-ments necessary to manufacture aquality product, and ability to pro-vide sufficient control of risks to thepatient (this is what ASTM E2500has as its approach). Suitability foruse is therefore linked to:

a. A specific manufacturing processand product (or class of prod-ucts).

b. It is based on knowledge of theprocess and an analysis of risk tothe patient.

Qualification should mean that equip-ment has been found to be suitable forits intended use, based on the designcriteria (process requirements orequivalent) and the verification workthat was performed throughout thedelivery process, in particular includ-ing that which occurred during thecommissioning phase. Qualified nolonger means the completion of an IQ/OQ/PQ protocol as traditionally for-mulated – leveraged or otherwise, butis instead a state or condition of certi-fied suitability for use. Graphically,these three terms relate as illustratedin Figure 1.

The question is, can we adopt this

use of the word qualification withoutinvoking the non-value added prac-tices of the past? Can people get pastthe habit of creating separate IQ, OQ,and PQ protocols, and instead adoptthe idea that qualification is a “state”achieved as shown above? Or shouldwe adopt a different definition? Or dropthe use of the term altogether (as ASTMhas done), and leave it to the operatingcompany to explain how their programnonetheless meets the intent of EUand other global regulations?

For those who feel the need to havesome form of qualification documen-tation, the determination that equip-ment is suitable for its intended use

could be equivalent to either the Ac-ceptance and Release phase describedin ASTM E2500 or to the Qualifica-tion Summary Report phase currentlyundertaken in many traditional com-pliance programs, as illustrated inFigure 2.

Both these representations and therelationship of the terminology meetthe intent of all regulations for demon-strating Suitability for Use and do notpresent non-compliance concerns withinthe ICH or EU regulated regions. De-sign qualification also can fit into thisscheme should that be desired. There-fore, the idea that suitability for use canbe determined based on patient risk

Figure 2. Verification, commissioning, and qualification as distinct steps. Note that in thismodel, there is no extra qualification-related field work or documentation when compared tothe ASTM E2500 process. It is simply a repackaging of the acceptance and release phasefor those organizations that require a document labeled “qualification protocol/ report.”

Figure 1. Relationships between the concept of verification, commissioning, andqualification.




The authors invite readers torespond to this discussion,

either throughthe ISPE Commissioning

and Qualification Communityof Practice (C&Q COP)

discussion board throughwww.ISPE.org/cops

or via direct communication.

and process requirements is wellgrounded in EU regulations and ICHdocuments, and is supported by US regu-lations and guidance documents.

We leave it to industry to debatethese proposals; it is important that weachieve a consistent understanding andapplication of these terms. Once thedebate is complete, it is for ISPE toincorporate the results into upcomingBaseline® Guides.

About the AuthorsJohn Robert (Bob)Adamson is Managerof PharmaceuticalCompliance and Vali-dation with FosterWheeler based inReading, UK. He has38 years of experience

in the pharmaceutical industry includ-ing positions with Foster Wheeler,Beecham, and Glaxo (now GSK), andexperience in R&D, production man-agement for APIs, and sterile manu-facturing. He has been responsible forthe start-up of new facilities and anumber of major refurbishments. He isa chartered chemist and chartered en-gineer. His experience includes com-pliance, regulatory topics including lat-est risk-based approaches, qualifica-tion and commissioning of: oral andsterile dosage forms, biotechnology andAPI facilities to meet EU, FDA, andMHLW requirements. He worked witha wide variety of clients and on occa-sions has represented them at FDAmeetings. Bob is Co-chair of the ISPECOP for C&Q, is actively involved inhis local affiliate, has written and pre-sented a number of papers, and con-tributed to a number of books. He waselected U.K. Fellow of the Year in 2003.He can be contacted by telephone: 44-1189133041 or by e-mail: [email protected].

Foster Wheeler Energy Ltd.,Shinfield Park, Reading, Berks RG29FW, United Kingdom.

Nuala Calnan is aPrincipal Consultantwith Project Manage-ment Group, Irelandand has more than 17years experience in thepharmaceutical in-dustry, with experi-

ence across the secondary pharmaceu-tical sector and the biopharmaceuticalsector. She is the current a member ofthe ISPE International Board of Direc-tors, Chair of the International Execu-tive Education Committee, a memberof the Steering Committee for the Com-missioning and Qualification Commu-nity of Practice (C&Q COP) and a mem-ber of the UK and Ireland Process Ana-lytical Technology (PAT) COP. She isactively involved in responding to therecent initiatives within the regula-tory environment and was a member ofthe Author Task Team which producedthe recent ASTM International Stan-dard on Commissioning and Qualifica-tion and is also a member of the teamcurrently updating the ISPE BaselineGuide for C&Q. She graduated in 1991with a Bachelor of Science in engineer-ing (BSc Eng) degree and achieved herMBA in 2002. She can be contacted bytelephone: +353-1-4040700 or by e-mail: [email protected].

PM Group, Kilakee House, BelgardSquare, Tallagh, Dublin 24, Ireland.

Robert E. Chew, PE,is President of Com-missioning Agents,Inc. He initiated theeffort to develop thisstandard, and was in-volved in the ASTME2500 writing effort

throughout its three year process. Chewhas a BS in Chemical Engineering andis a registered Professional Engineer.He can be contacted by telephone: +1-317-710-1530 or by e-mail: [email protected].

Commissioning Agents, Inc., 1515N. Girls School Rd., Indianapolis, Indi-ana 46214, USA.

Steven J. Wisniew-ski is Senior Associ-ate and Director ofCompliance for Inte-grated Project Services(IPS), a full-service en-gineering firm special-izing in the delivery of

technical complex projects, and thatoffers complete design/build, commis-sioning, validation, and FDA compli-ance services for the pharmaceutical,biotech, health care, and specialtymanufacturing industries. Wisniewskihas more then 30 years experience inthe pharmaceutical, biotech, and de-vice industries. Prior to joining IPS, hewas senior consultant for drug anddevice associates and has served insenior management roles at SterlingWinthrop and Bausch & Lomb. He hascompleted a wide variety of pharma-ceutical manufacturing, filling, andcritical support operations to majorR&D laboratories, facilities, and up-grades. He holds a BSME fromRensselaer Polytechnic Institute, is aMember of PDA, and an active Mem-ber of ISPE. He has served on the ISPEboard of directors since 1982, and waschairman of the board in 1991. Cur-rently, Wisniewski is chairman of theISPE Community of Practice for Com-missioning and Qualification, is on theISPE task teams that developed theASTM E2500 Verification Standard,and is working on the revised C&QBaseline® Guide. He can be contactedby telephone: +1-610-828-4090 or by e-mail: [email protected].

IPS, 2001 Joshua Rd., Lafayette Hill,Pennsylvania 19444, USA.

Documents

Commissioning and qualification ASTM approach