Rational Revalidation

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84 J OURNAL OF V ALIDATION T ECHNOLOGY [SPRING 2010 ]

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P E E R - R E V I E W E D

9001 of 1987 is an example of a quality management

system implementation that did not take economicfactors into account. It became a bureaucratic burdenthat did not deliver its full potential, a situation that

was subsequently rectified in the 2000 version. This paper discusses various aspects of revalidation

specifically related to business costs. By revalida-tion we mean any validation exercise that takes placeafter the original validation when the product wasfirst being introduced. These include revalidationsdue to change, periodic time-based revalidation, andother causes. We star t by giving justification (i.e.,

why we may need to revalidate a system). Next weoutline a strategy to prioritise among the systems tobe revalidated and to decide on what, how, and whento revalidate. We then consider how to identify theneed for revalidation and to reduce this need. Next

we discuss the costs associated with revalidation, andfinally the different business models for approachingthe problem. Throughout we attempt to integratethe business decisions with the technical ones in apragmatic way. Considerations in these discussionsdo not compromise patient safety and product quality;these are a given in the pharmaceutical industr y forethical, regulatory, and business reasons (i.e., corpo-rate image and avoiding litigations).

In our context, we will use the term system in abroad sense to incorporate the process, the equip-ment on which it is implemented and the procedureto follow in executing it. This discussion is appli-cable to both secondary dr ug manufacturing (i.e.,manufacture of dosage forms) and primary manufac-turing (i.e., active pharmaceutical ingredients [API]manufacturing).

WHY REVALIDATE?It is not uncommon in the pharmaceutical industr y to

view validation as a one-time event to be performedonce, and not to be revisited unless a major change

to a system takes place. In fact, validation should beregarded as a state to maintain rather than an activ-ity to perform.

There are several reasons for revalidating a systemafter it has been in operation for some time. Some ofthese are desirable while others are mandatory (TableI). The most compelling is that it is often a regula-tory requirement. Regulatory authorities mandaterevalidation after a change to a process (includingequipment, instruments, procedures, and methods)that may impact product quality. The European Union(EU) good manufacturing practice (GMP) guideline

refers to periodic revalidation irrespective of such

change (2). Chapter five in the EU GMP documententitled “Production” states, “Processes and proce-dures should undergo per iodic critical re-validationto ensure that they remain capable of achieving theintended results.” Furthermore, Annex 15 of the sameGMP entitled “Qualif ication and Validation” states,“Facilities, systems, equipment, and processes shouldbe periodically evaluated to verify that they are stilloperating in a valid manner,” although this requiresonly an evaluation of the validated status of a system.If this leads to unacceptable results, revalidation maybe expected.

Periodic revalidation is also required by the WorldHealth Organization (WHO) guidelines on GMP (3).

Annex 4 of the WHO GMP document entitled Supple-mentary Guidelines on Good Manufacturing Practices:Validation states, “There should be periodic revali-dation, as well as revalidation after changes.” Thefact that WHO is an international body (as opposedto a multinational one such as the EU or the Phar-maceutical Inspection Convention/PharmaceuticalInspection Co-operation Scheme [PIC/S]) indicatesa degree of worldwide consensus especially outsidethe ICH countries.

Other regulations introduced in the past such asthe US Food and Drug Administration’s 21 CFR Part11 addressing electronic records and electronic sig-natures necessitated the revalidation or at least theassessment of legacy systems that were in place beforesuch regulations were introduced. Given the chang-ing nature of technology, it is not unreasonable toexpect further changes in regulations in the futurethat may cause revalidation of existing systems. PATis an example of such a technology; depending onhow PAT is utilized (monitoring and data collection

vs. integrat ing into a control loop), this may causeprocess change necessitating revalidation.

Another reason for revalidation is the change in

regulatory expectations even when the regulationsthemselves do not change, as manifested by changein focus of regulatory inspections. This is also evidentin the changes and updates to existing guidance docu-ments by regulatory authorities or the introductionof new ones. A prominent example of that is againthe change in regulatory expectations with regardto the implementation of Part 11 even though theregulation itself did not change (4). This has alsobeen the case with validation altogether over the pastthree decades. Changes in regulatory expectationscan also be inferred from warning letters or com-


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g x p a n d j v t . c o m J OURNAL OF V ALIDATION T ECHNOLOGY [SPRING 2010 ]

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H O S A M A L E E M , T I M M C C A RT H Y, A N D R O D GE R E D WA R D S

ments from pre-inspection assessments by regulatory

authorities. It should be noted that the 2008 FDAdraft guidance for process validation (5) has removedthe explicit reference to revalidation that was in theoriginal 1987 guidance document. Instead it sug-gests a system lifecycle approach that incorporates“continued process verification,” which in essence is

validation maintenance.Changes that occur in the practice of validation in

industry may cause a firm to revalidate its systems toalign itself with current best practices. This is exem-plified by the introduction of the International Societyfor Pharmaceutical Engineering (ISPE) Baseline Guide5: Commissioning & Qualification and its impact on the

way qualification is performed (6). Such concepts asimpact assessment and enhanced design review havebecome more formalized and common place with theintroduction of this guide. This does not necessarilymean repeating the whole validation but possiblyonly producing the aforementioned documents inretrospect as an aid for future change control.

The issues outlined above related to regulations andindustry best practices can be regarded as external toa firm in the sense of being beyond its control. Incontrast there are other causes for revalidation thatare considered internal to a firm. Also, mergers andacquisitions may prompt revalidation to align differ-ent standards and practices of validation between theorganizations, especially if they are global corpora-tions. There are the usual causes for revalidation suchas following a change that may impact product quality,and to maintain a validated status of a system.

A further motivat ion in assessing the validatedstatus of a system is the benefits accrued from suchan endeavour, especially from a business perspective.

These include maintaining a current view and controlof the process and ensuring that it is always in anaudit-ready state. This update may merely involveupdating the documentation and does not necessarily

require a full-fledged testing regime.

SETTING A REVALIDATION STRATEGY Once the need for revalidation has been identified,a strategy is determined. Specif ically, this includes

what, how, and when to revalidate.

What To RevalidateClearly all systems with potential impact on prod-uct quality must be kept in a validated state at alltimes. When revalidating such systems, constraintson resources including time, cost, and expert ise (i.e.,

business considerations) make prioritization of revali-dation inevitable. The first step is thus to prioritizeamong the different systems needing revalidation.

The common approach is to start with systems usedfor parenterals, followed by those for other less criticalproducts such as orals then topicals. However, webelieve that the prioritization should also include abusiness aspect (i.e., systems that produce productsthat are critical for the surv ival of the business suchas blockbuster drugs). Producing a parenteral thatis not financially viable while ignoring a less criti-cal yet profitable product will mean that eventuallyproduction of the former will not be sustainable ifthe business fails.

All products are required to be manufactured withrobustly validated processes. When resources arelimited, however, there are short-term alternativesto revalidation (Table II). One such alternative is totemporarily discontinue production of one productuntil revalidation of other more financially viableones is completed. A second alternative for a multi-site firm is to transfer production to another site thatdoes have the resources for validating the process. Athird alternative is to temporarily continue productionbut with additional procedural controls such as 100%inspection, additional in-process controls, and morefrequent product reviews. This is similar to the caseof manufacturing active pharmaceutical ingredients(APIs) for investigational products as outlined by theICH GMP guide for API, Q7 (7). In the unlikely eventthat none of the above options is attainable, produc-

tion can be contracted out, but in this case validationat the contract site must then be considered. Theseare temporary measures and are not meant to replaceperforming the required revalidation exercise, unlessof course moving a product to another site, contractingit out or possibly licensing it or even selling the intel-lectual property r ight (IPR) to another manufactureris part of the firm’s strategic objectives.

After priorit ization of the different systems to berevalidated, prioritization within a system (Figure 1)is assessed. This means deciding on which functionsand features within a system to validate. Such deci-

Table I: Possible drivers for revalidation.Changes in the process

Changes in regulations

Changes in regulatory expectations of current regulations

Changes in industry or company best practices

Maintaining an updated view of the process, audit readiness


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sions will likely be different from those of the origi-nal validation. The original validation may includehealth and safety issues addressed as an adjunct to the

validation exercise for convenience and cost reasons(commissioning). This, however, need not be thecase in revalidation.

The requirements to be verified for any systemcan be classified into two main categories: busi-ness requirements (e.g., line capacity) and regula-tory requirements (Figure 1). The latter in turn arefur ther classified into GXP requirements and othersincluding environmental, health, and safety (EHS),and statutory. We believe that in the case of revalida-tion, only GXP requirements are to be verified. Thisdoes not mean that other regulatory and businessrequirements are unimportant, but that they shouldbe verified outside the scope of the revalidation.

The GXP requirements to be verified will be deter-mined by the assessment of their impact on productquality. It is becoming commonplace in validation toemploy a risk management process, for example as out-lined in ICH Q9 (1), where the philosophy is that theeffort should be commensurate with the potential risk.

This is also in line with the FDA risk-based approach toGMP (8). One of the common methods used for riskidentification, assessment, and mitigation planning isthe failure mode effect analysis (FMEA) method.

How To RevalidateNow we turn our attention to the extent revalidation is

to be performed (i.e., setting the acceptance criteria by which to judge the process). In a new project, and whenordering new equipment, the full extent of its usage isnot always known. Specifications are thus set both forcurrent and expected future usage. Factory acceptancetesting (FAT), site acceptance testing (SAT), and valida-tion often test against specifications that correspond tothe performance limits of the equipment. One of thepurposes of that is to ensure that contractual obligationson the supplier are met. In revalidation, however, test-ing against a much more narrow operating range maybe appropriate.

Revalidation should be against the current processrequirements. If those do not formally exist, a “real-istic” user requirement specif ication (URS) should bedeveloped in retrospect to provide acceptance speci-fications. Examples of such a case include a mixerthat is operated at certain speeds that are less than itsmaximum possible. There is no point in qualifyingthe maximum, which is not employed in the processand may possibly be unachievable as with old equip-ment. Other examples are line speed for a packagingline or speed of a depyrogenation tunnel that is knownto operate at a speed much slower than its maximumto guarantee performance. Another example is forautoclaves that normally include several types of steril-ization cycles. There is no need to validate the perfor-

mance of all cycles if they are not used. The validationreport must clearly specify the parameters for whichthe system is validated in case the equipment is neededin the future for a different process.

The purpose of revalidat ion is to verify processrequirements rather than other engineering require-ments such as throughput or capacity. Meeting theseother requirements does not guarantee meeting prod-uct specifications. The problem of loss in throughput

will still need to be addressed albeit on a more strate-gic level than that of revalidation, such as site capacityexpansion or major equipment overhaul.

Table II: Temporary options for a processawaiting revalidation.Discontinue production until revalidation is ready

Transfer production to another site within the organization capableof validating the process

Impose additional procedural controls (such as 100% inspection)

Outsource manufacturing

Requirements

Business Regulatory

GXP

Prioritization within a system

EHS = Environmental, Health, and Safety

Other(e.g., EHS, Statutory)

Figure 1: Prioritization for revalidation.


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When To Revalidate According to all GMP regulations, any change withpotential impact on product quality must be assessedthrough change control; revalidation may be requiredas a possible outcome. Additionally, as outlined inthe EU GMP and the WHO guidelines, this assess-ment should be carried out periodically. We lookat those issues here and try to put them in a unifiedframework. We classify the need for revalidation intoevent-based and t ime-based (Figure 2).

Event-based Revalidation. Event-based revali-dation essentially refers to revalidation following achange. This change can be either inadvertent orpredetermined. The former means that the changehas to be performed in order to be able to keep pro-ducing product with the required specifications. Forexample, this can occur when a part with impact onproduct quality malfunctions and has to be replaced.

This kind of change is usually unplanned. Another e xample is when a change in regulation

causes a part to become unsuitable for productioneven if it is functioning correctly possibly due tochanges in material certif ication requirements. Insuch a case, the replacement will have to be revali-dated if the original part was deemed GMP critical.

A firm does not have the choice of not performing therevalidation; hence, we term it inadver tent.

Predetermined changes are planned ahead oftime. Those can be further classified according tothe purpose into reactive and proactive. The formerare changes in reaction to a recurring problem, which,

while not causing stoppage or non-conformity, maycause repeated product problems. Proactive changesare ones whose purpose is to improve the process with-out it currently suffer ing any problems. For example,this can narrow product variability in spite of beingalready in spec, or for technical improvement likereplacing a machine part with a more efficient one.It can also be for purely economic reasons such as

increasing throughput or reducing energy consump-tion. Such proactive changes can fall under processoptimization. Those would naturally take lower prior-ity than unplanned changes whose purpose is to keepproduction going and maintaining product quality.

In either case, whether the change is planned orunplanned, a rigorous change control procedureshould be in place. For the planned changes, thisshould stipulate the assessment of the change andits impact on product quality and process integrity inaddition to health and safety issues before the changeis implemented. This will ensure not only that the

resulting system after change is compliant, but alsothat other processes are not affected while the changeis taking place. An example of this is when modifica-tions are made to a hall or a building that houses othersystems, or to utility lines that feed other processes.

All planned and unplanned changes require updatingdocumentation and records post modification.

Time-based Reval idation. Time-based revalida-tion, as is evident from the term, is performed periodi-cally and is most common in aseptic processing andsterilization. It is required by the WHO guidelineson GMP. The timing can be based on operating timeor calendar time. The choice of which approach totake is based on the risk to product quality. Whenappropriate, economic factors are also considered. Acalendar-time based approach is often taken becauseit is easier to plan and implement; however, this is notnecessarily always the best choice from an economicpoint of view. Consider the case of a system that israrely used due to low demand on its product. It maynot be economically sound to validate it periodicallyin spite of the low utilization, as there is potential forit not being used between two consecutive valida-tions. On the other extreme, there is a system that isin continual usage possibly on shift basis—for such a

system, taking a purely calendar-time based approachcan be too risky to the product quality. If at revalida-tion the system is found to be in significant deviation,this would jeopardize the entire product that has beenproduced since the last successful validation. In sucha case, revalidation based on the number of batchesproduced may be safer both to product quality andeconomically. Thus in practical terms and to reducethe risk to product quality, the shorter of both timesshould be taken.

The idea of operating time-based actions is commonin preventive maintenance programs whereby dif fer-

Reva at on

Time based Event based

Calendar time Operating time Inadvertent(unplanned)

Predecided(planned)

Figure 2: When to revalidate.


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ent parts are replaced after certain hours in opera-

tion. In validation this corresponds to the numberof batches produced.

The essence of this section is that the choice of whento revalidate, whether it is event based (planned orunplanned change) or time based (operating or cal-endar time), should ultimately be based on potentialrisk to the product.

The concepts of time-based and event-based actionscome from the field of programmable control, wheretime-based refers to timers while event-based refers tocounters, activation of limit switches, or other condi-tions. Strict ly speaking, one can consider time-basedactions as event-based ones whereby the e lapsingof the time period is itself the event. However, theconvention has been to t reat them as dist inct.

HOW TO IDENTIFY AND REDUCE THENEED FOR REVALIDATIONUltimately one can argue that the need for revali-dation arises due to the occurrence of a change.

This change may be known and decided, whetherplanned or unplanned. Alternatively, it can occur

without being detected, which time-based revalida-tion attempts to mitigate (3), as waiting for the changeto manifest itself in an out-of-specification productis unacceptable. Hence to take a more structuredapproach, there should be mechanisms to detect andif possible predict this change as soon as possible (seeFigure 3). Such mechanisms already exist in practicealthough not always tied to validation.

Statistical Process ControlStatistical process control (SPC) allows the continu-ous monitoring of the process and can detect gradualshifts from its current (ideally controlled) state. Thebasis of SPC is to maintain the process in a state of“statistical control,” meaning that its only variabilityis due to “chance causes” and does not include any

“assignable causes” (9). Assuming that a process isin statistical control at inception, when an SPC chartdetects an out of control condition, this signals that achange has occurred and has manifested in an increasein process variability. Such a situation would promptinvestigations that may reveal problems with somepart of the equipment or line on which the processis running. If such a part needs replacement and isdeemed to be critical to product quality, then thismay lead to revalidating the process after replace-ment. If the replacement is of a “like-for-like” nature,

validation may not be necessar y. On the other hand,

if the investigation reveals the recurrence of the SPC

trends after replacement of the relevant equipmentparts, then a major process change may be neededas indicated in the discussion of change control withrevalidation as a highly likely outcome. It should benoted that in the statistical sense, an out-of-controlcondition does not necessarily mean an out-of-speci-fication product. However, such a condition if notaddressed may lead to a non-conformity. Thus SPCserves as an early warning against non-conformity.

Variations of SPC such as multivar iate SPC (MSPC)(10) are more discriminating in diagnosis and hencea more powerful tool.

SPC is a convenient tool and can be implementedat minimal cost. Many modern systems include therequired functionality as standard. This includes datagathering and processing such as calculating means,standard deviations, and control limits. Examplesof such systems include modern tablet presses andtablet auto testers. When applying SPC, one shouldbe aware of its underlying assumptions and, conse-quently, its limitations.

Product Quality Review Another mechanism t hat is c urrently used is theproduct quality review, which has to be conductedperiodically as mandated by the GMPs. As part of thisexercise, the EU GMP states, “A review of critical in-process controls and finished product results” shouldtake place, in addition to a host of other reviews (2).Such reviews would detect any major deviations in theprocess and would hence trigger an investigation thatmay lead to revalidation of one or more of the systemsassociated with the deviation. Such a product qualityreview already takes place on regular basis and willnot constitute any additional cost. The usefulnessof this exercise in detecting the need for revalidationdepends on the frequency with which it is conducted.

As with the case of periodic revalidation, risk to the

product is a major factor in the choice of the reviewperiod. Product quality reviews are commonly con-ducted annually.

Preventive Maintenance To reduce the need for revalidation (see Figure 3), afirm should ensure the timely execution of effectivepreventive maintenance plans. This will help keepequipment at a high level of performance, reduce vari-ability and performance problems, and minimize theneed for revalidation. Another important factor thatcontributes to reducing this need is strictly executing


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the calibration plan. It is the measuring instruments

and devices that detect any deviations from specifica-tions. Thus, the reliability of the decisions based ontheir results including the potentially costly decisionto revalidate a system will depend on the accuracy ofthose measurements.

COSTS ASSOCIATED WITHREVALIDATION

We now focus on the business aspects of revalidationincluding cost and the alternative associated businessdecisions. We attempt to rationalize the revalidationprocess in the wide sense including aspects of its man-agement process.

The most costly phase of revalidation is when per-forming it for the first time. This is especially so forsystems that have been in operation for a long time asthere is potential risk of drifting from the original vali-dated status. The high cost of the first revalidation forsuch systems is due to the following main reasons. Someaspects of the validation status may either be not knownor cannot be verified, and hence there is a potentiallylarge cost involved in the assessment of this status. Thecumulative effect of minor changes to the system soincreases the risk of it becoming sufficiently deviatedfrom its initial validated state that the cost of bringingit back into this state will be high. These high costs willbe due to capital investment in the system in the form ofmajor replacement or maintenance of some of its compo-nents. However, after such an overhaul, a major costly

validation exercise would be needed (see Figure 4).

Cost Of Assessment Of The ValidationStatus

The major contribution to the assessment cost is thedifficulty in locating the necessary information about asystem, especially about the equipment used in the pro-cess. This may be due to equipment being so old that itsdocuments are misplaced or lost. Such important docu-

ments include validation files with supporting certificatesand reports and machine operation and maintenancemanuals. Documents for equipment relocated fromanother site may have been lost in transit. Documents fortransferred equipment may be available but in a differentlanguage. These scenarios are not unrealistic in light ofthe mergers and acquisitions, and with the subsequentclose down or downsizing of facilities. The time takento locate documents and information indirectly trans-lates into financial cost. In addition, there are the directcosts associated with the validation personnel involvedin this assessment.

Cost Of Performing The Revalidation This is the cost of actually performing the tests,recording, and reporting conclusions in addition tothe cost incurred due to taking the equipment outof production. There are other costs associated withthis issue.

If validation documents are not available, revalida-tion may need to be conducted. This can be a lengthyexercise depending on the nature of the missing docu-ments. Major effort may be required, including gener-ating a URS. Even if all the documents are available,new testing may be required to comply with currentregulations or industry expectat ions. Computersystems and source code availability was not a pastrequirement. Equipment may have product contactparts or lubricants that were previously acceptable butare not currently approved. Obtaining such data canbe a challenge. Suppliers may not be in business. Anequipment model may be discontinued and associ-ated documentation is not available. Equipment may

still be available, but certain information may not beavailable or may not be normally generated by the vendor. This is not an uncommon case with suppli-ers for whom the pharmaceutical market representsa small share of their overall business. Again suchmissing information will have to be generated by thepharmaceutical firm and can be very costly, such asthe case with positive material identification.

In addition, there is the cost of actually performingthe revalidation tests even if all the necessary informa-tion and documents are available. This includes thetime, labor, instruments, and the product or placebo

Change

Detection Reduction

SPC PQR PM Calibration

Detection of gradually occuring changes

SPC = Statistical Process ControlPQR = Product Quality Review

Reduction of the need for a change

PM = Planned Maintenance

Figure 3: Some means for detecting and reducing the need

for revalidation.


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if required. Finally, as in the case of assessment costs,

there is the cost of lost opportunity (i.e., the time thatthe equipment is out of use and the personnel aretaken off their regular jobs).

Considerations of the costs and associated activi-ties will determine the future validation program andthe level of revalidation required. For example, if in-process data and the regular product quality reviewsindicate a recurring problem from a given piece ofequipment and in addition this is coupled with miss-ing or unobtainable data to verify its performance,then it might be more cost effect ive to replace theequipment. This will save the time and costs involvedin assessing the state of this equipment and bringingit up to the current validation standards. In a widercontext, this would apply to all the systems on siteneeding validation and can help to narrow downthe priorit ization process mentioned earlier. Moreimportantly, it will help reduce the risks by replac-ing problematic systems with new equipment that isexpected to provide superior performance and compli-ance—and be more economic in the longer term.

THE BUSINESS MODEL Once the scope of the revalidation exercise is decided,the business approach to execution is determined.

This plan will include the budget, targets , and mile-stones. We are still in the context of the first revalida-tion as it is likely to be the most resource demanding.It is also the most benef icial since subsequent revali-dations will be merely maintaining the new statusachieved through change control.

There are two main business options for performingthe first and major revalidation, either to use in-housestaff or contract staf f (see Figure 4).

In-House Staff Two approaches can be taken in using in-house staff on arevalidation project. The first is to use the regular valida-

tion staff to perform this task beside their daily valida-tion duties. Whilst the direct cost of such an approachis low compared to others, experience indicates that itis hard to establish focus and to maintain commitment.

The second approach is to form an ad-hoc committeeto handle the revalidation project until its completion.

This does provide better focus and more commitmentbut still takes a long time to achieve the target.

Contract Staff Again there are two possible approaches. The first is toemploy contract staff on an individual basis and man-

age them by a competent person from the in-house

staff. This person will have to have both adequatetechnical abilities and excellent managerial skills, asthey will have to manage an inhomogeneous teamof individuals of different professional, industrial,educational, and possibly cultural backgrounds (suchas the case in the free movement of labor within theEU). This will obviously be costlier than having thein-house staff perform the job, but will entail highercommitment and a defined time frame.

The second option is to contract out the revalidationjob; whereby, a validation consultant/contractor willhandle the job altogether with only a liaison personfrom the owner side. In terms of direct costs, thisoption is normally the costliest especially if assess-ment of the validation status is in the remit of the con-tractor. In addition there are indirect costs involvedin auditing and approving such contractors as part ofa firm’s supplier audit procedures. On the other hand,the owner will get higher commitment with respectto time, and can stipulate penalties in the contract ifmilestones or time obligations are not met. Further-more, the contractor by virtue of working on differentprojects for different customers brings in significantexperience to the firm. The down side of employing acontractor is the loss of knowledge of the process oncethey have left. Attempts should be made to capture asmuch of this knowledge as possible whether in writ-ing or in person by the in-house staff. Unfortunately,experience indicates wide variability in the cost andcommitment of validation contractors.

The pur pose of this section is not to give the bestapproach or to provide a one-size-f its-all solution, butrather to present different options. The final deci-sion will not only depend on the budget a firm iscommitting to this exercise, but also on the level ofexpertise in the firm. For example, some biotechnol-ogy star t-ups may lack the engineer ing or regulatoryexperience necessary to perform validation activities

for commercial production, in which case a consul-tant/contractor may be the only option.Once the first revalidation is completed and all

the product quality impacting systems have beenbrought into compliance, it is imperative to keepthem in the validated state. This will necessitateregular (in any of the senses mentioned earlier) revali-dation or re-evaluation of those systems. This canbe achieved by making the re-evaluation part of theregular staff tasks, or by employing staff dedicatedsolely to managing the re-validation and the changecontrol processes.


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In general there are several models for utilizing

personnel for performing the validation functionin an organization depending on where validationresponsibilities lie. For example, when validationis part of process development, staff may be aligned

with products or product classes. When part of engi-neering, they are aligned either with facilities, suchas certa in sections of a site, or with lines and equip-ment. Alternatively, validation can be part of thequality assurance (QA) function, in which case vali-dation personnel tend to work on different projectsinvolving different products, facilities, and equipment.Cleaning, microbiological, and analytical methods

validation are normally within the remit of the qualitycontrol laboratories.

CONCLUSION This discussion described a strategy for planning andexecuting revalidation of existing systems, with particu-lar emphasis on the first revalidation. This emphasisis based on the assumption that the system has eitherdrifted too much from its originally validated statusor that this status cannot be reliably verified. If all thenecessary documentation and information are availableand valid from the original validation, an evaluationof the current validation status should be sufficient.Consequently, for a well-maintained and controlledprocess, the cost of revalidation would be minimal.

Change management is a key component to therevalidation strategy. Change management deter-mines the need for revalidation and subsequentlyguarantees maintaining the acquired validated status.

Another key component is the structured approachto validation maintenance as time-based and event-based with sub-categories of each. We believe thisapproach to be a pragmatic and rational one. Its mainessence is to base the key decisions on the potentialrisk associated with the dif ferent activities, mainlyrisk to the patient but also incorporating risk to the

business when appropriate. It is not suggested thatthe features and functions to be validated in a systemare to be determined solely by business issues. Rath-er, the business factors only determine the order in

which the systems are to be revalidated; those await-ing revalidation have other alternatives. Under nocircumstances would the product of a manufacturingprocess that is not validated to regulatory expecta-tions be released.

REFERENCES1. ICH, Q9 Quality Risk Management , 2005 avai lable at

www.ich.org.2. European Commission, The Rules Governing Medicinal

Products in the European Union , Volume 4 Good Manu-facturing Practices, 1998 Edition updated in 2008,available at ec.europa.eu/enterprise/pharmaceuticals/eudralex.

3. WHO, Supplementary Guidelines on Good Manufacturing

Practices (GMP): Validation , October 2005, available at www.who.int.

4. FDA, Guidance for Industry Part 11, Electronic Records;Electronic Signatures–Scope and Application, August 2003,available at www.fda.gov.

5. FDA, Guidance for Industry Process Validation: GeneralPrinciples and Practices, Draft Guidance , 2008 availableat www.fda.gov.

6. ISPE, Baseline Pharmaceutical Engineering Guide: Volume5 Commissioning & Qualification , 2001.

7. ICH, Q7 Good Manufacturing Practice Guide for ActivePharmaceutical Ingredients , 2000, available at www.ich.

Revalidation costs

Revalidation stafng

In-house

Regular staff Ad-hoc committee Individuals Firm

Time

Denite

Long/Open

Contract

In-house

Cost

High

Low

Committment

High

low

Contract

Assessment costs Performance costs

Figure 4: Business issues related to revalidation.


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org. Also incorporated into Volume 4 of the EU GMP as

part II in 2005, and as a guidance for industry by FDAin 2001.

8. FDA, Pharmaceutical CGMPs for the 21st Century: A Risk-based Approach, “A science and risk-based approach toproduct quality regulation incorporating an integratedquality systems approach,” 2002 available at ww w.fda.gov.

9. E. Grant and R. Leavenworth, Statistical Quality Control ,7th ed., McGraw-Hill, 1996.

10. Elaine Mar tin, Julian Morr is and Steven Lane, “Moni-toring Process Manufactur ing Performance,” IEEE Con-trol Systems Magazine, October 2002 pp 26 – 39. JVT

ARTICLE ACRONYM LISTINGAPI Active Pharmaceutical IngredientEHS Environmental, Health, and SafetyEU European UnionFAT Factory Acceptance Testing

FDA US Food and Drug Administration

FMEA Failure Mode Effect AnalysisGMP Good Manufacturing PracticeICH International Conference on HarmonisationIPR Intellectual Property RightISO International Organization for

StandardizationISPE International Society for Pharmaceutical

EngineeringMSPC Multivariate Statistical Process ControlPAT Process Analytical TechnologyPIC/S Pharmaceutical Inspection Convention/

Pharmaceutical Inspection Co-OperationQA Quality AssuranceR&D Research and DevelopmentSAT Site Acceptance TestingSPC Statistical Process ControlURS User Requirement SpecificationWHO World Health Organization