ISPE.RISK.ASTM E2500 PE article NovDec07.pdf

38 PHARMACEUTICAL ENGINEERING NOVEMBER/DECEMBER 2007

Commissioning and Qualification

Continued on page 40.

This articleclarifies theprinciples andpractices in thenew ASTMStandard andpresents howthe newstandard willimpact the ISPEC&Q BaselineGuide Revision.

Commissioning and Qualification:A New ASTM Standard GMPRegulations

by Robert E. Chew and David Petko

In May, 2007, the ASTM Committee E55voted to approve a new standard, A Stan-dard Guide for Specification, Design, andVerification of Pharmaceutical andBiopharmaceutical Manufacturing Systemsand Equipment. This recently published stan-dard has the ASTM designation of E2500. Ithas been three years since the risk-based con-cept for this standard was first discussed at ameeting at ISPE headquarters in Tampa. Sev-eral draft versions have been issued in theintervening time, and people at a number ofconferences and speaking engagements haveaddressed the concepts in the standard to audi-ences around the world. It is ISPEs intent toupdate the Commissioning and QualificationBaseline Guide to reflect the principles andpractices outlined in this standard; otherBaseline Guides will be updated in due time.Due to the general guidance nature of thisstandard, there is significant room for inter-pretation. This article is intended as a precur-sor to the update of the C&Q Baseline Guidein order to clarify certain aspects of the stan-dard and to help ensure that industry doesntmisinterpret and then misapply the newstandard.

For most companies, qualification is a costlyand time consuming process that in some casescan delay the launch of critical medicines topatients. There are aspects of qualificationthat can add value in terms of ensuring theequipment and systems are ready to reliablymanufacture a quality product. There are otheraspects and documentation practices thatclearly do not add this value. And it can beargued that the rigid rules that surround quali-fication (as practiced today) can detract fromits overall effectiveness. If one examines GMP

regulations, one can easily find the basis forwhat we call qualification, but no specific re-quirements that relate to how qualification ispracticed today - Sidebar 1. Furthermore, if onereviews the 1987 Guideline to Process Valida-tion, which is where installation qualificationwas first mentioned, one finds qualificationconcepts discussed, but not specific how toimplementation nor the controls and practicestypically applied today.

It can be argued that many of the non-valued-added aspects of qualification as prac-ticed today stem from a lack of understandingas to the intent of the GMPs related to equip-ment suitability. Instead of acquiring and de-ploying this understanding, companies havechosen to avoid ill perceived risk, seeking tocreate procedures that are at least as onerous ifnot more so than those of their fellow manufac-turers (safety in numbers). Thus, they haveimplemented a plethora of structural, over-sight controls, and other rigid practices, whichwhen taken to the extremes many companiestake them, obscure the underlying value thatcan and has been added by the intent of currentGood Manufacturing Practices (cGMPs). Thisconcept is simple: were the equipment andsystems properly installed, do they operateproperly, do they perform to meet processrequirements, do they control risks to prod-uct quality, and will they support processvalidation?1 It is the spirit and practical ap-plication of this concept that is addressed bythe ASTM Standard.

The ASTM standard adheres to the currentGood Manufacturing Practice (cGMP) regula-tions and describes a high level process to ensuremanufacturing systems and equipment (includ-ing automation) are fit for intended use such



that risks to product quality and publichealth are effectively managed. To ac-complish this, the standard (1) specifiesa minimum set of activities that meetGMP regulations to form a framework

and risk-based concepts of ICH Q8 andQ9. The standard is based on a set of 10principles that were first presented tothe Societys International LeadershipForum in April 2005 - Sidebar 2. Thestandard was purposefully written at arelatively high level to allow firms theflexibility to adapt to their particularorganizational breakdown of responsi-bilities, and to allow firms to developinnovative approaches to implement-ing these principles. Figure 1 illustrateshow the standard fits within a regula-tory framework and incorporates prin-ciples of Quality Risk Management(QRM).

The preceding paragraphs give uscause to celebrate, but also pause toexercise caution. By studying both theletter and understanding the intent ofthe GMPs, and by understanding thisASTM standard, we can expunge manyof the non-value added qualificationpractices of today. We can even rede-fine what we mean by the term quali-fication or to qualify. Several projectshave taken the step of deleting IQ/OQper se, and have passed an FDA pre-approval inspection. However, we can-not use this standard as an excuse fornot meeting GMPs. But we can use thisstandard to separate GMP require-ments from folklore qualificationpractices and expectations we ourselveshave invented over the past 20 years,

for specifying, designing, and verifyingmanufacturing equipment, systems, andassociated automation; (2) describes anapproach to specifying, designing, andverifying that incorporates the science

Figure 1. Relationship of ASTM Standard to GMP regulations and guidance documents.

NOVEMBER/DECEMBER 2007 PHARMACEUTICAL ENGINEERING 41

A New ASTM Standard

not to meet the intent of GMPs, but inan ill-designed attempt to avoid regu-latory risk. Frequently, systems thatwere qualified via formal qualificationprotocols simply did not work correctly,even though they had been signed offas qualified. We can use this stan-dard to help us devise and implementbetter, more effective ways of ensuringour facilities, equipment, systems, andassociated automation are delivered inan efficient manner using good engi-neering practices. Regardless of whichmethodology we choose, at the end ofthe day our manufacturing systemsmust be fit for purpose able to sup-port the reliable manufacture of qual-ity products and able to control risks tothe patient to an acceptable level.

The standard was developed usinga consensus approach, with contentbased on science and sound qualityassurance principles. The ASTM orga-nization and the consensus processmean this standard can be traceable tothe World Trade Organization. Objec-tions to any portion of the standardmust be justified based on science; goodscience was the same criteria by whichcomments to the draft standard wereassessed. Use of the standard is volun-tary. However, if one chooses to use thestandard, it must be implemented inits entirety; a piecemeal or partial ap-proach is the same as not implement-ing the standard at all.

ASTM E2500 andthe GMPs

The first thing to note about ASTME2500 is absence of the term qualifi-cation. The term appears, but once, inthe definitions section: Verification...is an umbrella term that encompassesall types of approaches to assuring sys-tems are fit for use such as Qualifica-tion, Commissioning... It is interest-ing to note that the US GMPs do notmention the term qualification,nor do the US GMPs require docu-ments labeled IQ, OQ, or PQand hence, neither does the stan-dard. Instead, the standard describesa process, backed by key concepts, thatallows a project team to meet the in-tent of what the GMPs do require -Sidebar 1.

1. The GMPs (211.22c) require thequality unit to approve proceduresand specifications that impact theidentity, strength, purity of thedrug product. Here is how ASTME2500 supports this requirement:

a. 7.4.1.3 specifies that the qual-ity unit approve verification ac-ceptance criteria of critical as-pects (i.e., critical to product qual-ity and patient safety) These

critical aspects are defined ear-lier in 6.4.1 as functions, fea-tures, abilities, and performancecharacteristics necessary for themanufacturing process to ensureconsistent product quality andpatient safety.

b. 7.4.2.3 describes use of an over-all verification plan to define theverification strategy, what con-stitutes acceptable documenta-tion, etc. The verification plan




structured and documented qualityprogram based on good engineeringpractices as something to be done onlybecause regulators expect it. This isnot the case try taking such a positionwhile working for Intel or Motorola orFord or any other world-class manu-facturer! The quality unit is respon-sible to see that the project verificationplan, which spells out the overall ap-proach to verification and project qual-ity assurance, is robust and is imple-mented properly. How such responsi-bility is discharged will depend on theconfidence the quality unit has in theproject delivery team.

2. The GMPs (211.25a) require the useof persons of appropriate educa-tion, training, or experience, or com-bination thereof... ASTM E25006.7.1 defines Subject Matter Ex-perts in similar fashion. In somecircumstances, the quality unit is asubject matter expert, for example,on the application of appropriatelevels of quality control. Hence, thequality unit must approve the over-all project verification plan, whichwould describe the tasks necessaryto apply various quality control andquality assurance strategies andpractices. In other cases, engineer-ing should be the subject matterexpert, such as to determine howbest to inspect or test a piece ofequipment, review the results ofthese inspections or tests, and evalu-ate any departures from engineer-ing specifications. A person fromthe quality department may or maynot have the requisite education,training, or experience to be able toperform these often very technicalfunctions; hence quality unit in-volvement in these aspects of verifi-cation is not required. This is per-haps one of the more significantchanges from current qualificationpractices of today.

The role of quality is focused on threethings: (1) ensuring that critical as-pects and associated acceptance crite-ria have been identified, based on sci-entific knowledge of the process and ananalysis of risks to the patient that

can be thought of as similar towhat we find today in validationproject plans, or commissioningplans, or other plans that governhow the quality of the installa-tion, operation, and performanceare to be inspected, tested, orotherwise verified. If the scope ofthe project verification plan in-cludes systems with critical as-pects, the quality unit shouldapprove this plan. The verifica-tion plan, or related procedures,can be considered procedures thatmay fall within the requirementsof 211.22c.

c. 6.8.3 requires quality unit ap-proval when vendor documenta-tion will be used to support veri-fication of critical aspects.

d. 7.5.4 requires quality unit ap-proval of the final documenta-tion that confirms the manufac-turing system is fit for its in-tended use. This documentationincludes a review of the results ofthe verification activities, includ-ing any non-conformance withacceptance criteria for critical as-pects. It should be noted that thisdoes not infer use of deviationpractices as we know them to-day, wherein problems encoun-tered during start-up are treatedthe same way as batch recordnon-conformances, with formalinvestigations, corrective actions,etc. Instead, this requirement ismeant to ensure any non-con-formance of critical aspects thatremain after all start-up, settingto work, adjustment, and testinghave all been completed, aredocumented and that an assess-ment is made to determine theimpact of this open non-conform-ance on patient safety.

The above does not imply that the qual-ity unit should only become engaged atthese specific times. Firms must en-sure a responsible and effective qual-ity program exists. For some firms,engineering project teams are diligentabout ensuring the quality of systeminstallation and operation. For otherfirms, project teams have viewed a


A New ASTM Standard

may arise through the manufacturingprocess, equipment, or systems; (2) asa subject matter expert on the applica-tion of quality principles, the qualityunit approves the overall project veri-fication plan; (3) the quality unit ap-proves the final determination that amanufacturing system containing criti-cal elements is fit for its intended use.All other aspects of the specification,design, and verification process de-scribed by the standard are to be per-formed by other appropriate subjectmatter experts such as engineering,product/process development, opera-tions, etc. in many cases, using amulti-disciplined team that may or maynot involve the quality unit as deemedappropriate by the individual firm.

3. The GMPs, both US and EU, spellout requirements for certain itemssuch as materials of construction,calibration of critical instruments,etc., that have typically been a partof what is called IQ/OQ/PQ. WhileASTM E2500 does not list specificverification activities, it describesverification as A systematicapproachto verify that manufac-turing systems, acting singly or incombination, are fit for intendeduse, have been properly installed,and are operating correctly. It goeson to incorporate the idea of qualityrisk management as found in ICHQ9 and EU Annex 15, along withengineering and business risk: Theextent of verification and the levelof detail of documentation shouldbe based on risk, including that as-sociated with product quality andpatient safety, and the complexityand novelty of the manufacturingsystem. (7.4).

4. Documentation has traditionallybeen viewed as an onerous require-ment carried out because the regu-lators demand it. Even the currentversion of ISPEs Commissioningand Qualification Baseline Guideuses the term enhanced documen-tation... to satisfy the demands ofthe regulators. It is unfortunatethat our industry has adopted thisviewpoint, for it leads to the misap-

plication of peoples time (and hencecost) in how documents are createdand controlled. Instead, documentsshould be viewed as serving a use-ful, practical purpose. Documentshelp ensure the intended actionsare performed in the field in a delib-erate, controlled manner. Details indocuments are an invaluable toolwhen a person is standing at a ma-chine inspecting or testing it; hence,on-the-fly field research is notneeded because the document cre-ator did the research. Recording ofoperational or performance dataserves as a valuable record for fu-ture operations, maintenance, orchange. Where we have gone astrayis the rigid nature of our qualifica-tion protocols, including computersystem validation documentation.Current documentation practicesare based on the premise that thedetailed engineering specificationsare perfect; there is no allowance forlearning, adjustments, or changesto the physical or functional designduring start-up. This is not to saythat uncontrolled changes may bemade (see below).

Commissioning, as described in thecurrent ISPE Baseline Guide, is to bea more flexible exercise, and acknowl-edges the learning and adjustmentsand cycle development that occur dur-ing any project. Qualification does nothave that same flexibility, and thisdistinction has lead to a two-phaseactivity, commissioning followed byqualification, or a one-phase activitythat was just qualification with a newname, but the same old constrainingpractices. More recently, the use ofProcess Analytical Technology (PAT)has highlighted the issue of learningduring installation and operationalcheckout; such projects often requiresignificant changes to the original de-sign, and trying to accomplish thisunder a traditional qualification and/or computer validation regime canquickly kill such projects. As PAT ap-plications become more sophisticated,moving from simple feedback loops to aprocess controller that is programmedto adapt a process based on a complex




mathematical model of many raw ma-terials and in-process variables, thetraditional computer validation modeljust wont work. Hence, documenta-tion must be used in a way that servesboth purposes: inspection and testingcontrol and record-keeping, along withadaptability for start-up learning andadjustment.

ASTM E2500 requires that verifica-tion activities be documented. Manydifferent sections require documenta-tion, from critical aspects, to verifica-tion activities, to results. The standardis purposefully vague on what consti-tutes acceptable documentation, leav-ing that to the individual firm and to bespelled out in the overall verificationplan. An earlier draft version of thestandard defined acceptable documen-tation as that which clearly demon-strates to a subject matter expert thatthe acceptance criteria were met. Thecurrent standard requires that verifi-cation results be reviewed by appropri-

throughout the project. Changemanagement includes use of appro-priate subject matter experts to ap-prove changes with notification ofthe quality unit of changes to criti-cal aspects. This is acceptable, asthe manufacturing systems, duringthese stages of the project, are notyet producing product.

Additional ASTM E2500Requirements

While ASTM Standard E2500 doesmuch to eliminate the folklore waste-ful practices such as excessive focus ondocumentation practices that havecome to permeate qualification, it alsocontains provisions that are not typi-cally part of many projects, or if used,arent given as much attention as GMPrequirements. These provisions in-clude science-based process require-ments, specification and design re-views, risk management, and applica-tion of good engineering practices. With

ate subject matter experts, which im-plies that the documentation need beunderstandable by a subject matterexpert. The only specific requirementregarding documentation in the stan-dard is found under Acceptance andRelease 7.5.3, The documentationshould contain a clear statement as towhether or not the manufacturing sys-tem is fit for intended use

5. The GMPs require pre-approval bythe quality unit of changes oncemanufacturing operations have com-menced. Many project teams haveextended this pre-approval furtherand further into the early stages ofinspection and testing, even as farback as design. The ASTM standardmakes the distinction between pre-approval by the quality unit, andchange management as may be prac-ticed by subject matter experts. Thestandard requires that change man-agement processes be established

US GMPs210.3, Definitions (20) Acceptancecriteria means the product specifica-tions and acceptance/rejection criteria,such as acceptable quality level andunacceptable quality level, with anassociated sampling plan, that are nec-essary for making a decision to acceptor reject a lot or batch (or any otherconvenient subgroups of manufacturedunits).

211.22 Responsibilities of the QualityControl Unit. (c) The quality controlunit shall have the responsibility forapproving or rejecting all procedures orspecifications impacting on the iden-tity, strength, quality, and purity of thedrug product.

211.25 Personnel Qualifications. (a)Each person engaged in the manufac-ture, processing, packing, or holding ofa drug product shall have education,training, and experience, or any combi-nation thereof, to enable that person toperform the assigned functions

211.42 (Facility) Design and construc-tion features. (a) Any building or build-ings used in the manufacture, process-

ing, packing, or holding of a drugproduct shall be of suitable size, con-struction and location to facilitate clean-ing, maintenance, and proper opera-tions.(several specific items are listed insubsequent sections and subsections)

211.63 (Equipment) Design, size andlocation. Equipment used in the manu-facture, processing, packing, or hold-ing of a drug product shall be of appro-priate design, adequate size, and suit-ably located to facilitate operations forits intended use and for its cleaning andmaintenance.

211.65 Equipment construction.(a) Equipment shall be constructed so

that surfaces that contact compo-nents, in-process materials, or drugproducts shall not be reactive, addi-tive, or absorptive so as to alter thesafety, identity, strength, quality,or purity of the drug product beyondthe official or other established re-quirements.

(b)Any substances required for opera-tion, such as lubricants or coolants,shall not come into contact withcomponents, drug product contain-

Sidebar 1. GMP Regulations Relating to Qualification.


ers, closures, in-process materials,or drug products so as to alter thesafety, identity, strength, quality,or purity of the drug product beyondthe official or other established re-quirements.

211.68 Automatic, mechanical, andelectronic equipment.(a) Automatic, mechanical, or electronic

equipment or other types of equip-ment, including computers, or re-lated systems that will perform afunction satisfactorily, may be usedin the manufacture, processing,packing, and holding of a drug prod-uct. If such equipment is so used, itshall be routinely calibrated, in-spected, or checked according to awritten program designed to assureproper performance. Written recordsof those calibration checks and in-spections shall be maintained.

(b)Appropriate controls shall be exer-cised over computer or related sys-tems to assure those changes inmaster production and controlrecords or other records are insti-tuted only by authorized personnel.Input to and output from the com-puter or related system of formulas


A New ASTM Standard

ASTM E2500, they are not optional.Proper application of this standard re-quires all provisions to be carried outalthough there can be much latitude asto how these provisions are met.

Many projects develop user require-ments specifications slanted towardthe V-model: system by system so thatsystem PQs can easily line up one forone. While system-based user require-ments specifications can serve usefulprocurement functions, they are oftenvery detailed and cover a range of re-quirements well beyond those neces-sary to assure product quality and pa-tient safety. ASTM E2500 focuses onwhat one could call process require-ments, those that are relevant to prod-uct and process safety, and which arebased on scientific understanding ofthe product and process. If a firm hasemployed the principles of Quality byDesign (QbD) to develop a well-charac-terized process design space, then pro-cess requirements become defined bythis multi-dimensional space. WhetherQbD is used or not, these manufactur-

ing process requirements must includeanything impacting the ability to meetcritical product quality attributes, andinclude the critical process parameters.

The project team should develop aprocess by which the process require-ments are communicated to the designteam, to ensure that the design is de-veloped from this knowledge of prod-uct and process requirements. As partof the design effort, those aspects thatare critical to product quality and pa-tient safety must be identified. Designreviews (plural) are conducted through-out the project with a number of crite-ria to be checked (standard 8.2). Thedesign reviews are performed by ap-propriate subject matter experts andare documented.

Risk assessments should be per-formed by appropriate subject matterexperts. Several kinds of risks can beevaluated. Risks to the patient andproduct quality are a must. In addi-tion, business risks such as vendor orconstruction risk, and technologicalrisks, especially as they pertain to prod-

uct quality, also should be evaluated.Risk management is an iterative pro-cess, and will likely result in designchanges. The degree of verificationchecks and the nature of the verifica-tion documentation also is based onthe outcome of risk assessments. Theentire verification effort is thus risk-based.

Risk assessments can help identifythe critical aspects, and thus can re-place the generic criteria used in thecurrent ISPE Commissioning andQualification Baseline Guide impactassessments. A top-down risk assess-ment has been shown in real projectcase studies to be a more effective andefficient way (vs. system and compo-nent impact assessments) to identifythe critical aspects that control risks tothe patient and otherwise supportmeeting process requirements.

If a project team uses a solid designdevelopment and design review pro-cess, integrated with a risk-based un-derstanding of the product and processupon which the design is based, then




what can be achieved is a dimension ofQuality by Design. The term Qualityby Design is meant to refer to thedesign of the manufacturing processand an understanding of the processdesign space within which successfulmanufacture of a quality product canoccur. However, this term can be justas appropriately applied to the infu-sion of quality principles into the engi-neering design. The ASTM Standardrequirements for a design basis, de-sign development, design communica-tion, and design review process basedon process understanding and riskmanagement principles provides us aclear program for achieving this infu-sion of quality principles: Facility andEquipment Engineering Quality by De-sign.

While nearly all projects at leastpay lip service to the application ofgood engineering practice, this stan-dard requires the use of good engineer-ing practice throughout the specifica-

missioning or verification. Inspectionsand testing to demonstrate equipmentis fit for purpose, performed under areasonable level of control with docu-mentation sufficient to control andrecord the relevant information andreviewed by subject matter experts, iswhat is required. A rose, by any othername, is still a rose. Activities, and theassociated documents, should be struc-tured in a manner that constitutes themost effective approach to inspectingand testing each piece of equipment,each system, and associated automa-tion - based on sound engineering prac-tices. Dont try to force fit these activi-ties into traditional IQ/OQ/PQ struc-tures, as that approach may be subop-timal for any given piece of equipment.

Alternative Approach #2Follow the ASTM standard, and con-sider the final acceptance phase theact of qualifying. There is some logicto this approach. If the purpose of quali-

tion, design, and verification phases. Acomplete discussion of good engineer-ing practice is beyond the scope of thisarticle; additional information may befound in current and soon-to-be re-leased ISPE Baseline Guides and GoodPractice Guides.

Implementation Optionsand Case Studies

What follows are some suggestions anda case study for restructuring qualifi-cation, while meeting GMPs and ASTME2500. Other approaches are also pos-sible. Again, it is important to notethat to be in conformance with thestandard, one does not have the optionof picking and choosing which aspectsof E2500 to implement on a particularproject.

Alternative Approach #1One could simply follow the ASTMstandard and not worry about whetherdocuments are called IQ/OQ or com-

Sidebar 1. GMP Regulations Relating to Qualification. (continued)

Continued from page 44.or other records or data shall be checked

for accuracy...

EU GMPsAnnex 15.It is a requirement of GMP that manu-facturers identify what validation workis needed to prove control of the criticalaspects of their particular operations...A risk-based approach should be usedto determine the scope and extent ofvalidation.

The key elements of a validationprogram should be clearly defined anddocumented in a validation master planor equivalent documents.

After completion of a satisfactoryqualification, a formal release for thenext step in qualification should bemade as a written authorization.

The first element of the validation ofnew facilities, systems or equipmentcould be Design Qualification (DQ).The compliance of the design withGMP should be demonstrated and docu-mented.

Installation qualification, operationalqualification, and performance qualifi-cation are specified and defined as totypical content focus.

Qualification of existing facilities is

discussed in terms of verifying theoperating parameters and limits for thecritical variables of the operating equip-ment.

Annex 11 Computerized SystemsWhere a computerized system replacesa manual operation, there should be noresultant decrease in product quality orquality assurance.

Persons should be appropriatelytrained and have appropriate expertiseas applicable to a computerized sys-tem. The extent of validation neces-sary will depend on the intended use,whether validation is to be prospectiveor retrospective, and whether or notnovel elements are incorporated.

The computerized system is furtherdiscussed, including, but not limitedto, topics such as: Software should be produced in

accordance with a system of Qual-ity Assurance.

Access to data should be limited. When critical data is entered, there

should be a check on the accuracy. The identify of operators editing or

confirming critical data should berecorded.

Alterations should be via a defined

procedure. Data should be secure and pro-

tected by backup, etc. Procedures to be followed when the

system fails should be established. When outside agencies are used,

there should be a formal agreement,including responsibilities of the out-side agency.

Only authorized, Qualified Personsshould have the ability to release abatch.

ICH Guidance DocumentsICH Q7A Good Manufacturing PracticeGuidance for Active PharmaceuticalIngredientsBefore initiating process validation ac-tivities, appropriate qualification of criti-cal equipment and ancillary systemsshould be completed. Qualification isusually carried out by conducting thefollowing activities, individually or com-bined: DQ, IQ, OQ, PQ.

ICH Q9 Quality Risk Management[Quality Risk Management can be used]to determine the scope and extent ofqualification of facilities, buildings, andproduction equipment... To determinedesign of facilities/equipment.


A New ASTM Standard

fication was to demonstrate that equip-ment and systems were fit for theirintended use, then one would need toshow that the equipment and systemscan support manufacture of a particu-lar product using a particular process.The final acceptance phase includes areview of the verification work to con-firm that process requirements havebeen met and risks to the patient ad-equately controlled. In short, progres-sively qualified.

Imagine a multi-product facility forwhich no product has yet been identi-fied. How can one qualify it? In thepast, the approach has been to base IQ/OQ/PQ on engineering specifications,perhaps related to a generic futureproduct/process. But qualification isnot about meeting engineering specifi-cations, it is about being fit for pur-pose. Hence, qualification should betied directly to a particular productmanufactured via a particular process.

1. Focus on that which affectsproduct quality.

2. Requirements. User require-ments, based on the process (andnot on equipment or systems), arethe key to acceptability.

3. Risk assessments, process de-velopment, and experimental de-sign are used to identify criticalfeatures, functions, and criticalprocess parameters.

4. Only critical process param-eters will be used as the basis onwhich to define the formal quali-fication information.

5. All activities must contributevalue to the start-up and deliveryof manufacturing capacity. Wewont do anything just for the sakeof regulatory compliance.

6. Risk-based asset delivery. Dif-ferent types of equipment and sys-tems (custom, off-the-shelf, simple,and complex, etc.) require differ-ent levels of attention to ensurequality.

7. Value-added documents. Docu-ments serve a useful purpose ofcontrolling activities, they ensurecompleteness, and they serve as arecord of what occurred. Only datawhich serves a useful purposeshould be collected.

8. Use of supplier documentation.Suppliers standard inspection andtest documentation may be usedand no other documents be pro-duced that duplicate this informa-tion, provided that documentationclearly shows the items of interesthave been verified or tested in anappropriate manner.

9. Test planning. Defined testsshould only be carried out once,unless there is a clear justificationfor undertaking further tests at alater stage of commissioning.

10. Fostering innovation. Any pro-gram must remain flexible enoughto apply sound and qualified scien-tific and engineering judgmentbased on the situation at hand.

Sidebar 2. ISPE International LeadershipForum (ILF) White Paper Guiding Principles.




Each product/process combination hasa potentially unique set of process re-quirements, and a potentially uniqueset of risks to the patient inherent inthe manufacturing process. Hence, theact of verifying should be to definethose process requirements, identifythe risks and how they are to be con-trolled, and then review commission-ing/verification documentation to con-firm those items can meet the specifi-cations for that product/process. Ofcourse, for a multi-product facility, theproduct/process requirements and riskswill be similar across all productsmanufactured therein. Regardless, theact of qualifying now becomes a reviewof the verification work, which is howASTM E2500 describes the Final Ac-ceptance phase (7.5).

Alternative Approach #3Follow the ASTM standard, and labelthe verification documentation IQ/OQ/PQ as appropriate. However, if thisapproach is to achieve cost/schedule/quality improvements over todayspractices, then the current non-value-added qualification practices need tobe stripped away. This is easier saidthan done since current qualificationpractices that would need to be elimi-nated can be many, but the major onesthat impact cost/schedule/quality are:

A discrepancy handling process thatmimics batch record deviations instead, let the subject matter ex-pert deal with the situation. If acritical aspect cant be met AFTERefforts have been made to correct,then quality needs to be involved toreview the impact on patient safetywith implementation of other mea-sures to control a particular risk orotherwise meet a process require-ment.

Pre-mature implementation of QApre-approved change control thisis not required if product for humanuse is not yet being manufactured.However, project teams must imple-ment a workable system of changemanagement using good engineer-ing practice to ensure changes arenoted, appropriate documents up-

The following is a proposed approach to aligning ISPEs GAMP guidance with theprinciples embedded in ASTM E2500 and the associated update to the ISPECommissioning and Qualification Baseline Guide.

touch points with those specified inASTM E2500 or as otherwise man-dated by GMP regulations.

4. Documentation practices. GAMPguidance should revisit any recom-mended documentation practices andprovide guidance that is consistentwith minimum GMP regulations andthe intent of the ASTM E2500 stan-dard. The principle of ICH Q9 thatstates, The level of effort and asso-ciated documentation should be com-mensurate with the risk to the pa-tient should be applied to all docu-mentation practices.

5. Software delivery project controls.GAMP should provide practical guid-ance that aligns with practices fromother industries relative to the controlof software projects, such as configu-ration (change) management, soft-ware test reporting (discrepancy man-agement), preliminary and critical de-sign reviews (traceability of require-ments to design, and the robustnessof the logic design), etc.

6. Software verification. GAMPsmost important contribution is in thearea of verification strategies, basedon the wide range of types of soft-ware/automation systems, from simplespreadsheet or data base applications,to enterprise systems, to MES, toDCS, and PLC-based controls, etc.GAMP guidance has been, and shouldcontinue to be, invaluable in how toapproach verification of these varioussystems from both a structural andfunctional perspective. A critical analy-sis of the most efficient means toverify these systems may challengethe perhaps overly simplistic V-model;especially as complex PAT systemsare developed and deployed whichadapt a process based on a multitudeof input variables. It is the authorsopinion that breaking free from the V-model so as to employ verificationstrategies tailored to the specific ap-plication will result in improved soft-ware quality and savings of cost andtime.

Sidebar 3. Integrating ASTM E2500 and GAMP.

1. Common elements. GAMP guid-ance documents and ASTM E2500share many common elements andunderpinning principles. First, bothadvocate a life cycle that is based onrequirements definition, design anddesign reviews, inspection and test-ing, and acceptance. Second, bothadvocate use of risk managementprinciples to determine the scope andextent of inspection and testing(whether one calls it validation, veri-fication, or qualification.). In thecase of GAMP, there are categories ofautomation systems. Depending onthe category, one engages a set ofactivities designed to assure the ro-bust operation of the system. Thiscategorization and the quality assur-ance activities associated with eachcategory is, in and of itself, a form ofrisk management. Riskier customsoftware is subjected to a full set ofrequirements, design, design review,code development, coding standards,and verification activities. Less riskyoff-the-shelf software is subjected toa reduced set of these activities. Theseand other risk analysis methods havebeen a part of GAMP for some time.

2. Risk. GAMP categories are onedimension of risk. Other risks assess-ment dimensions can include:

a. The intended use (Is the sys-tem, feature, or function impactingto product quality? What is thenature and stage of the process?)

b. The genesis of the function,feature, or system

c. The ability to detect a defect orOut of Specification condition, e.g.,downstream quality checks in place

Thus, automation, software, and com-puters must be managed within theintended use environment using anappropriate set of practices and docu-mentation.

3. Role of Quality. GAMP guidanceshould revisit any specified qualityunit touch points and realign those


A New ASTM Standard

dated, and appropriate groups, in-cluding QA when warranted, arenotified of the change.

Use of a rigid IQ/OQ/PQ protocoltemplate and procedures that re-quire a laundry list of inspections ortests and a laundry list of docu-ments for the turnover package such prescription means every pieceof equipment is subject to the sameinspections or tests, leading to bothunnecessary testing and also gapsin testing. There is no requirementfor an enhanced turnover packagein order to qualify a system. Thereis an expectation that firms willhave accurate drawings and suffi-cient information to operate, main-tain, and change their equipmentand systems. A signature by theoperations and maintenance man-agers should be sufficient to signifyan acceptable documentation pack-age for these purposes. Other com-mon turnover package contents in-clude records of pre-start-up activi-ties and pre-commissioning inspec-tions and checks. Having these onhand to support start-up and com-missioning is a good engineeringpractice.

Having QA pre-approve IQ/OQ pro-tocols instead, have QA pre-ap-prove the acceptance criteria of criti-cal aspects, and the process require-ments. It is up to subject matterexperts to determine how to inspectand test these items; QA will get topost-approve the fact that those criti-cal aspects and process require-ments were met. The GMPs requirenothing more than this.

A process that does not recognizethe need to adjust the design duringstart-up and initial operations some necessary initial operationalchecks dont have clear acceptancecriteria, and in a rigid test environ-ment, these are sometimes not per-formed because they dont conformto IQ/OQ/PQ structure very well. Ifwe have a more flexible test pro-gram, a more robust test programwill result. This is especially impor-

Concludes on page 50.



tant when dealing with PAT or othercomplex, novel technologies.

If these practices are stripped away,then it doesnt matter what things arecalled; the process will be more effi-cient and will add more value. A rose,stripped of its thorns, is still just asbeautiful and fragrant.

Integration with GAMPThe Good Automation ManufacturingPractices (GAMP) Community of Prac-tice has over the years developed anumber of guidance documents de-signed to address the software life-cycle, including the subject of computervalidation. These documents have beenwidely accepted and used by industry.Efforts to integrate GAMP guidancewith this ASTM Standard and with theupdate to the ISPE Commissioning andQualification Baseline Guide are on-going. At a minimum, industry needsto eliminate the duplication of effortwhereby manufacturing systems andequipment are subject to an IQ/OQ/PQprogram, and the associated DCS/PLCor other automation that runs thisequipment is subject to a separate com-puter validation program. This is inef-ficient, costly, and time-consuming. SeeSidebar 3 for a discussion of how theseguidance documents might be harmo-nized.

Case StudyA biotech process development/clini-cal manufacturing facility was beingbrought out of mothball status. It wasdesired to both leverage commission-ing to streamline qualification, andalso to use a risk-based approach tofocus qualification. Risk assessmentswere used to identify the risks to thepatient that could result from themanufacturing process. Risk controlmechanisms were identified for eachrisk. These risk control mechanismstook the form of automation controls,detection mechanisms, design fea-tures, procedures, and other means.These risk control mechanisms be-came the substance of the IQ/OQ pro-tocols. The protocols were developed

as a checklist of these mechanisms the protocol for a bioreactor ran all of12 pages, with the first six being frontmatter. A thorough, documented com-missioning of the mechanical and au-tomation systems took place as part ofstart-up. Commissioning included in-spections, tests, start-up procedures,setting to work activities, and any-thing else deemed necessary to bringthe system to a fully operational state,verified to be installed and operationalper engineering specifications. Theexecution of the IQ/OQ consisted ofreviewing the commissioning work toverify each risk control element waschecked satisfactorily, and that pro-cess requirements were met. The ex-ecution and report writing for an IQ/OQ protocol took all of a half a day (onaverage) to complete. Following IQ/OQ, a more traditional PQ was con-ducted for the sterilize-in-place per-formance, and for PQ of other typicalaspects of clean utilities, etc.

Summary and ConclusionASTM Standard E2500, StandardGuide for Specification, Design, andVerification of Pharmaceutical andBiopharmaceutical ManufacturingSystems and Equipment is a high levelstandard describing what must bedone to deliver manufacturing solu-tions that meet process requirementsand control risks to the patient. Thedetails of how these activities arecarried out are left to individual firms.ISPEs update to the Commissioningand Qualification Baseline Guide willprovide much guidance regarding thesehows. The ASTM standard is designedto conform to US and EU GMPs, and toprovide an approach that is in accor-dance with GMPs for the 21st Centuryand ICH Q8 and Q9.

Teams that make use of this newstandard, and who do so in a mannerthat does not impose the inefficientpractices of qualification on what canbe called commissioning or verifica-tion, stand to gain significant com-petitive advantage in terms of time tomarket and facility cost, while improv-ing the design to better meet process

requirements and control risks to thepatient. Manufacturers and consum-ers should both win as a result of thisstandard. ASTM E55 committee is cur-rently working on a number of otherstandards relating to pharmaceuticalmanufacturing. The future looks prom-ising!

Reference1. In similar vein, process validation

is the confirmation that the overallmanufacturing process has beenproperly designed, monitored, andcontrolled so that the resulting drugproduct is of consistently high qual-ity and meets all of its specifica-tions.

About the AuthorsRobert E. Chew, PE,is Vice President ofC o m m i s s i o n i n gAgents, Inc. He initi-ated the effort to de-velop this standard,and was involved in theASTM E2500 writing

effort throughout its three year pro-cess. Chew has a BS in Chemical Engi-neering and is a registered ProfessionalEngineer. He can be contacted by tele-phone at: +1-317-710-1530 or by e-mail at: [email protected].

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

David E. Petko, PEwas chairman of thecommittee that cre-ated ASTM E2500.Petko is Senior Direc-tor of Auxilium Phar-maceuticals, Inc. He isa licensed professional

engineer and holds a BS in engineeringfrom Drexel University in Philadel-phia, Pennsylvania. He can be con-tacted by telephone at: +1-267-960-1865 or by e-mail at: [email protected].

Auxilium Pharmaceuticals, Inc., 102Witmer Rd., Horsham, Pennsylvania19044, USA.