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Organizing for ValidationRonald J. SimkoManalapan, New Jersey, U.S.A.

INTRODUCTION

Process validation and its role within a pharmaceuticalorganization have come a long way from its inception inthe 1970s. At that time, the effort was primarily focusedon sterilization validation and demonstrating that theconditions to achieve sterility were met. As a result, themission was often managed from within the sterilemanufacturing organization using a small team.

In the 1980s validation organizations were createdand began interacting with the other traditional groupssuch as Research, Engineering, Production, Manufac-turing, and Quality Assurance. At that time, severalpapers describing specific organizational strategies werepresented at a Pharmaceutical Manufacturers AssociationSeminar (1–4). Just as it was then, there still is no singleway that validation issues are addressed. Validation stilldepends on the overall organization and how it definesits mission. Where there were large multinational corpo-rations in the 1980s, there are now even biggermultinational organizations resulting from the merger ofsome of the largest corporate names of the 1980s. Whilethis has been occurring, there has also been the continualcreation of new pharmaceutical companies. Some of thesehave a research focus that applies new technologies, whileother firms have been created simultaneously with thepurchase of commercial products from the aforemen-tioned large multinational companies. Since annualproduct sales of $100 million are often no longer largeenough for large pharmaceutical companies to retaininterest, these products are often sold off to emergingfirms at six times or more of annual sales. The net effectof all this is that there are pharmaceutical firms of all sizes,and some of themhave commercial products,while othersdo not. The matter of organizing for validation becomes adifferent thought process in each of these circumstances.

Overlaying this wide spectrum of companies hasbeen the continual evolution of the validation mission asit now has become a key component in managing thesupply chain for those companies that are commerciallyactive. For those other firms with products still in variousclinical phases, the need to address process validation isalso a key issue. This chapter will discuss these issues andprovide an update on how the pharmaceutical industry isorganizing for validation.

ESTABLISHING THE MISSION

Formulating a mission is essential to ensure properdefinition of a department role in the organization. Thisis necessary so that not only process validation staffmembers understand the breadth of their jobs but alsothat other corporate groups with whom they interactunderstand it as well.

Although there is broad diversity of Validationdepartment missions within the pharmaceutical industry,themission that is germane to all Validation departments isthe satisfying of the regulatory requirement to haveprocesses validated. The industry discovered this in themid-1970s when the FDA demanded that the sterilizationprocess for injectable drugs be validated. This began anera in which the focus of validation expanded at theFDA’s request into other pharmaceutical processes: sterilefiltration, solid dosage manufacturing, topical ointmentsand creams, cleaning validation, and computer systemvalidations. During this period, the pace of new construc-tion also accelerated and such activities as IQ, OQ, and PQbecame fundamental elements of a comprehensive vali-dation program. The prevailing mindset in the industrywas, however, that validation was an obligation, a burdenimposed by the FDA, which only added to the cost ofmanufacturing. In the earlier editions of this chapter, it wasprojected that “validation need not be an expense of doingbusiness in the pharmaceutical industry,” but that “it hadthe potential for being a key contributor to a cost efficientbusiness strategy.” This thinking has continued to takehold and, in fact, has become the basis for the ultimatesuccessful management of the supply chain.

The successful conclusion of a validation effortsimply proves that the process step being evaluatedreliably does what was expected of it. A successfulprocess validation effort thus builds quality into theprocess so that reliance on end-product testing can beminimized. It, in effect, provides greater statistical confi-dence about the process thandoes final testing. This, too, isthe hallmark of TQM philosophies, which speak ofcontinual improvement. Once such confidence about thereliability of the process is achieved, the company canschedule the production of product with the commensu-rate confidence that a given delivery date will bemet. Thismeans that inventories can be managed more precisely,and costs can be controlled. In essence, validation becomesa tool in the successful management of the supply chain.

Since the mid-1980s, the movement to embrace thequality principles, espoused by Deming et al. (5) andwhich has formed the foundation upon which thesesupply chain advances have been achieved, has begun to

Abbreviations used in this chapter: FDA, Food and Drug Adminis-tration; GMP, good manufacturing practice; IQ, installationqualification; OQ, operational qualification; PQ, performance quali-fication; R&D, research and development; SOPs, standard operatingprocedures; TQM, total quality management.

find a receptive audience in the pharmaceutical industryand influence its mission. The notion of constantly tryingto improve one’s work processes is really an expansion ofthe concept begun in the 70s—that of validating a process.

What does this mean to the effort to organize forvalidation today? For companies in which TQM philos-ophies are well-ingrained, the validation effort becomesindistinguishable from the corporate-wide mission ofconstant improvement. The process validation effort isjust one of the tools. In the large multinational corpo-rations in which these initiatives play a major role, thevalidation organization is typically a part of either theManufacturing or the Quality organization. Where matrixmanagement and cross-functional teams are oftenemployed, there are inevitably close working relation-ships established with the other functions attempting tosupport the TQM approach to management. In theselarge pharma situations, validation efforts are oftenmanaged at the site level while oversight is provided bythose in corporate who ensure a common approach acrossall of the company’s locations.

Certainly the validationmission is influenced by thesize of the company as well as its product lines. Compa-nies, often the large multinationals, who haveincorporated validation concepts into the supply chainbusiness model, approach this issue differently than thelarge number of emerging companies. These smallerfirms, sometimes with only a few products, often needto rely on outside firms for validation support. Thissupport is provided to fulfill the fundamental reason forvalidation, that of regulatory compliance. Because of thecritical regulatory impact of validation, it is important thatthe small pharmaceutical firmunderstands clearlywhat isbeing done by the contractor. In some situations, thatcontractor may actually be a manufacturer or a packager,who is contract manufacturing or packaging the product.In these circumstances, both the small firm (productowner) and the manufacturer are vulnerable if the vali-dation effort is flawed. As a result, it is imperative thatthey collaborate to ensure that validation protocols andreports have been reviewed and approved by both parties.In examining the organizational structure for validation inthis example, the contract manufacturer probably has anorganizational structure not too unlike what has beenaddressed for larger firms. That is, there is a validationunit reporting either into Manufacturing or Quality thatdefines strategy, writes protocols, implements the plan,and writes up the final reports. These reports get circu-lated throughout both the contract manufacturingorganization and the client’s organization for approval.

For the typical small firm that may be contractingout the manufacturing and validation, these functionsmay be handled by only one individual or a small team.Because, in these situations, a person wears many hats,process validation being just one of them, there is a needto rely on consultants to provide back up support forprojects as needed.

STAFFING ISSUES

When staffing a Validation group, the mission and theorganization do exert a degree of influence, primarily inthe academic backgrounds of the members. Because of

the aforementioned diversity, a considerable variety ofacademic backgrounds are usually found among vali-dation professionals, with members having degrees inchemistry, microbiology, pharmacy, statistics, computerscience, biochemistry as well as engineering disciplines.When the mission is directed toward a sterile productsfocus, having a microbiology degree would be quitebeneficial, as an example.

In a general sense, probably more importantthan the actual area of academic background are thesethree skills: problem-solving capability, interpersonalskills, and oral and written communication abilities.The technical talent to recognize and solve problems isfundamental to validation. Because of its pivotal role inthe company, considerable interactions are required withothers. Strong interpersonal skills are required formaximum effectiveness. Finally, unless validation objec-tives and concerns are effectively expressed both orallyand in written form, the best of efforts in the field may bewasted. What emanates from the field work must beattractive written documentation. By presenting thedocumentation clearly in written form, a well thought-out and organized effort will be conveyed. If the vali-dation professional can successfully communicate orally,especially during an FDA visit, the strength of thevalidation package is even greater.

A position that can also be used effectively,especially in a large pharmaceutical company is that ofValidation Technician. These individuals are usuallyexperienced production operators who have beenpromoted to the next job classification. The positionprovides the technician with an opportunity to contributeto problem solving, which may have been inhibited in aproduction environment. To the Validation department,there is the benefit of providing awork force of competentpeople who provide stability while others in the depart-ment may be in more dynamic career paths. The existenceof technicians also provides validation professionals withthe opportunity to develop their supervisory skills.

While the above describes what one might find inthe Validation group of a large firm, the staffing at a smallfirm is distinctly different. As indicated before, onetypically wears many hats in a small firm, and whilethe academic backgrounds that may have prepared the“small company” validation professionals are similar tothose in the large firms, there is often a lot of learning “onthe job.” For these folks, it can be a rewarding andbroadening career opportunity. The individuals pressedinto validation duty may be from research, production,quality, or anyone possessing an interest in the subject.That is the way it often is in a small firm. For firms whooutsource the manufacturing and validation, there is aneed for one to not only have the technical competencybut also some business acumen. The individuals have tohave the willingness to learn and also the courage to telltheir management what they do not know, both from atechnical and from a business perspective. The conse-quences of failing to do this could lead the firm down atreacherous path. That is where the use of experiencedconsultants can play an important role in the staffingsupport for validation at these smaller firms.

With a large number of consulting firms to choosefrom, the selection criteria become ever so important.There are large entities that have assembled many

6 I: INTRODUCTION

associates to provide support for their clients. There arealso the one- and two-person organizations. Whichevertype of firm is chosen, be certain that the individualsassigned to the project fully understand the task at handand possess the expertise to accomplish it. There are adiversity of manufacturing processes, facility installa-tions, computer systems, and analytical methods thatrequire validation, and it is rare that one individual hasexpertise in all areas. Additionally, it is critical thatsomeone within the company has an indepth under-standing of all validation activities that are contractedout. This is essential to ensure that the company canassess the quality of the validation service beingprovided, and furthermore, be able to fully defend thevalidation when the FDA comes to inspect. After all, theconsultant will probably not be present at the inspectionto answer for what was done. The validation knowledgemust be in-house. This leads to what should be afundamental truth for the use of a consultant. Do notlook for the consultant to possess expertise that theorganization does not have. Instead, hire the consultantto meet periods of peak activity. The other basic demandson the consultant are to meet the time and budgetconstraints imposed on the project. To ensure this, theinternal expert should really serve as a project manager.Regular meetings should be held verifying that theproject is still on target from a budget, time, and technicalcompetence perspective. This is essential, even for thoseorganizations that are small in size.

DEPARTMENT INTERACTIONS

Once department missions have been formalized and thevalidation operation organized, the challenge is toimplement the plan. That implementation requires thevalidation organization to interact with many peergroups. Within the company, those other departmentsinclude the following:1. R&D: involved with new product development and

new process improvement.2. Engineering: involved with new or modified equip-

ment or facilities.3. Production: concerned with processes that require

validation.4. Maintenance: concerned change control, calibration,

and preventative maintenance.5. Quality Control: involved with the testing labo-

ratories.6. Quality Assurance: concerned with GMP compliance.

Additionally, for those companies that outsourcethe manufacturing or packaging of their products, theseinteractions occur with the contracting firm’s Validationdepartment. This poses an additional set of dynamics.

R&DThe research organization is involved with new productintroductions and often existing process improvements. Itshould be the Validation department’s key objective ininteracting with R&D to ensure the acceptability (and thusvalidatability) of new products or “improved” processesin the manufacturing area. Some firms have “older”processes that perform at a less than optimum level.A successful accomplishment of validation objectives

ensures that new products or processes do not fall victimto the same fate.

Communication is critical in accomplishing this.The R&D organization must be made aware of thevalidation plan and resulting acceptance criteria. Theawareness of these expectations should prompt an R&Dtesting regimen that will enhance the probability ofacceptance of the product (or process) to manufacturing.It also affords the analytical R&D laboratories the oppor-tunity to develop and validate analytical methods duringthe development phase. The results from this plan areproducts or processes that are expected to be validatablein the production plant. Of course there can always besurprises, especially when a product does not scale-up asexpected. In this situation, the Validation, Manufacturing,Quality Assurance, and R&D departments must work outa suitable solution, because the product should not beintroduced to production if it cannot be first validated inthe pilot plant.

EngineeringThe relationship that, along with R&D, possesses thegreatest potential for long-term validation benefits iswith the Engineering groups involved with new facilityor equipment start-ups. In the initial stages of capitalprojects, there exists the ideal opportunity to ensure theacceptability of the processes later on. The concern ofvalidation must be built in at the design phase andcontinued through construction. It is one thing for awater-for-injection system to be designed properly, andquite another for it to be constructed properly. Thus, inthis example, it is necessary for the validation effort toinclude such activities as the documentation of weldquality and distribution piping slope verification duringthe construction.

In applying this to biotech production, Hill andBeatrice discussed the qualification and validation chal-lenges in 1989. They said “the validation of the actualprocesses (operations) should not be an afterthought inthe design of plants producing biotech-derived products.Rather, plans for the qualification/validation programsshould be an integral part of the preliminary plantconcepts and specifications.” They continued by sayingthat validation “should not be looked upon solely as aburdensome requirement for complying with FDArequirements, but as a means of increasing productivitythrough consistently producing lots of products that meetall specifications” (6).

Once construction is complete, the qualificationphase can begin. Qualification protocols defining designand operating criteria need to be developed and signedoff by all parties involved. This ensures that there are nomisunderstandings as to what is expected of the facility.Production, Quality Assurance, Engineering, and Vali-dation all need to approve this plan in writing.

It should be noted that one of the ways theevolution of validation has manifested itself has beenthe increasing role that validation has played at equip-ment manufacturers. They often stand ready to providequalification and/or validation support services for theirproducts. This often takes the form of equipment testingbeing done at their production site. The purchaser of thisequipment should take advantage of the opportunity to

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be on site for this test phase of the equipment before it isshipped. The best time to uncover flaws is then, and notafter it arrives following a trans-Atlantic shipment.

ProductionInteractions with production personnel should stress thebenefits of a validation program. If the benefits are reallyunderstood, production personnel will be supportive ofthese efforts rather than skeptical. This is probably lessof an issue in the 21st century than it was in the early daysof validation. Production personnel today often see thecontributions a well thought-out validation program canbring to the supply chain, and the resulting cost savings.There are fewer rejects, retests, and reworks—meaningdollar savings. Production schedules can be created witha higher level of confidence that they will actually be met.These positive effects of a validation program justify theefforts for economic reasons, rather than justregulatory compliance.

After the completion of a validation study, theresults are presented in a written report which is thenapproved by all protocol signatories. Signed off reportsshould then be distributed to all affected operations sothat procedural changes or acceptable process parameterranges discerned from the validation report can beincorporated into SOPs. This procedure further ensuresthat production SOPs reflect validated conditions.

MaintenanceWithout the support and cooperation of the maintenanceorganization, the best designed and implemented vali-dation study will soon be rendered worthless. This willoccur the instant that an undocumented change is madeto a validated piece of equipment. As a result, aneducation program is essential to make maintenancepersonnel understand the effect of their preventative oremergency maintenance activities. Once this is under-stood, the documentation of any changes made to asystem must be communicated so that an assessmentcan be made. One must realize that changing a belt on adry-heat sterilizer fan motor could affect airflow withinthe sterilizer and thus change “cold spot” locations andperhaps sterilizing capabilities within the oven.

Quality ControlBecause there is a reliance on Quality Control laboratoriesfor testing support, effective communication is extremelyimportant. This communication may be with the QualityControl department within a large firm, or with acontracted Quality Control Lab. Certainly validationprotocols that require laboratory support should requirelaboratory management sign-off. This ensures thatlaboratory personnel know not only the number andtype of tests required for the study but also how thetesting fits into the overall validation program. Thisaffords them the opportunity to understand how thedata will be used and to avoid situations in whichthe laboratory personnel’s test invalidates the intent ofthe validation. Additionally, validation staff membersshould acquire an understanding of laboratory testingprocedures. What results is two-way communication thatensures good understanding of both organizations’ inten-tions. Ensuring this understanding and buy-in by Quality

Control makes good business sense. If Quality Control isnot prepared to meet the validation plan’s timetable, theotherwise best-laid plan will not be accomplished onschedule, and product launches could be delayed.

Quality AssuranceSignificant interactions also occur with Quality Assur-ance. These interactions are designed to ensure a firm’sregulatory compliance. Through the technical compe-tency of the validation staff and the GMP complianceexpertise existing within the Quality Assurance group,these efforts should be successful. The key point is tocommunicate so that the regulatory compliance objectiveof validation is met.

Professional AssociationsInteractions of validation professionals with counterpartsat other pharmaceutical firms prove extremely valuable.Most frequently, this is accomplished through meetingssponsored by societies, universities, or seminar organi-zations. These gatherings are extremely beneficial, notonly because of the knowledge imparted during thestructured presentations, but also because of the oppor-tunities available for informal discussion of problemsand concerns.

Food and Drug Administration/European MedicinesEvaluation AgencyNo discussion of interactions of validation personnel canbe complete without the inclusion of the regulator. Theseinteractions are part of any validation professionalswork experience. Although heightened anticipationexists when the inspector is in the plant, the potentialis certainly there for a valuable learning experience.The interactions during these investigations frequentlyprove challenging and can be constructive both for thefirm as well as the individual defending the validationpackage.

Contract ManufacturersWith many firms relying on the use of contract manufac-turers and packagers for the production of bothcommercial and clinical products, the challenges of com-munication are many and varied. These interactions aretypically guided by both a supply agreement and a qualityagreement. Once defined in these agreements, it will beimperative from a business sense that these roles bedutifully adhered to. Certainly the company that ownsthe products and has contracted its manufacturing musthave enough validation expertise to engage the contractorin important validation discussions. Protocols as well asfinal reports will need to be reviewed and signed off. It isalso recommended that the contracting firm be in attend-ance when the process validation study is beingimplemented. The contracting firm must have the vali-dation expertise to fulfill all of these roles. Employingconsulting support is highly recommended if resourcesare stretched to ensure validation issues are properlyaddressed. In reality, the interactions between thecontracting firm and the contractor are similar to thatbetween two “internal” departments. However, in thiscase both companies have vulnerability if things do not gowell, as batches not getting shipped will certainly affect

8 I: INTRODUCTION

both firms. The best approach is to establish a closeworking relationship when it comes to validation issues.Anounce ofmedicine isworth apoundof cure, as they say.

MAINTAINING THE ORGANIZATION

Continuing EducationFor the continued realization of validation objectives, thequality of the staff must be maintained. A program ofcontinuing education is critical to achieving this. It isnecessary for the organization to provide staff memberswith opportunities to take courses that can aid them inremaining current technologically. At the same time, it isthe employees’ responsibility to avail themselves of thoseopportunities made available. Job-related courses andseminars are frequently sponsored by various tradeassociations and are often offered in conjunction withmeetings designed to keep their membership technicallycurrent in their related fields. Universities and profes-sional seminar organizations also add to the complementof technical education courses available.

In general, courses should be chosen to bring staffmembers to a basic level of understanding of the skillsneeded to do the job. The most effective learning experi-ence, though, is found on the job. If, for example, avalidation professional is assigned to sterile productsvalidation, then a course on microbiology and engin-eering of sterilization processes would be appropriate. Itis probably best scheduled, however, after several monthsof on-the-job training. This would set the stage for thecourse to have maximum effectiveness.

Beyond those specific training courses are generalcourses of study that should be made available on abroader scale to validation staff members. All non-phar-macy majors should be exposed to a short course onpharmaceutics, for example. These are typically offeredby pharmacy schools and provide attendees with ageneral overview of the subject. Computer educationhas also become critically important, while a course thatteaches problem-solving and decision-making skillssurely will assist Validation Engineers in their work.With cost consciousness around us at all times, opportu-nities to teach larger number of employees by purchasingcourses that are on DVDs should be considered. In-houseor interactive training is still another option.

Because continuing education is a necessary aspectof everyone’s career, it must be treated as such and usedto supplement on-the-job learning. Because the nature ofthis education is both varied in content and in presen-tation format, its inclusion in the career development of avalidation professional cannot be ignored. With theproliferation of information available on the Internet, italso behooves those in Validation departments to take itupon themselves to search out information. Many tradejournals have websites accessible to subscribers, forexample. The key is to search out these opportunities,as it has become an essential way of staying current intoday’s world.

Organizational TransfersAnother way of building the strength of the entireorganization is through interdepartmental personnel

transfers. Validation professionals are conscientiouslyaware of quality manufacturing procedures and canapply these concepts in a Production or Quality Assur-ance organization. Technical areas within Engineering orR&D may also find validation talent helpful in fillingopenings. Because the validation operation interacts soclosely with all of these other areas, a smooth transition toother assignments can be achieved. Certainly situationssuch as this are a two-way street, as professionals fromother departments within the company can also transferinto the Validation department in an attempt to broadentheir own career. This can provide the staff greater depthand strengthens each person’s ability to qualify forpromotional opportunities.

BROADENED REGULATORY FOCUS

Just as the emergence of TQM philosophies in thepharmaceutical industry can be traced to the gradualbuilding-in of quality consciousness, which startedin the days of sterilization validation, one can also lookat the expansion of validation concepts in another way.

In the late 1970s, it used to be enough to validate thesterilization processes performed in an autoclave or dry-heat oven. Then it was all other manufacturing processes,including cleaning. The mid-1980s saw the coming ofcomputer system validations. Then there was bulkchemical production, and other bulk processes, such asfermentation and purification. Recognizing this, Sawyerand Stotz, when they outlined the “Validation Require-ments for Bulk Pharmaceutical Chemical Facilities” (7)alluded to validation organization strategies stating theimportance of “broad pharmaceutical/FDA/cGMP andstrong chemical process experience.” They recommendedan on-site team with a designated on-site projectmanager, a client/contractor steering committee for theproject, and the need for “good interpersonal skills” forall involved.

More recently, the need to validate training andinspection processes has been identified. As with theprocesses mentioned earlier, all of these are importantto the quality of the finished product. They need to be in astate of control and need to be conducted with consistentquality. This is still good advice in the 21st century.

The requirement for validation from a regulatoryviewpoint has expanded in still another way. Formerly, itwas sufficient to validate only those products marketedcommercially. However, for those whose responsibilitiesinclude clinical products, there must be recognition thatthese processes must be characterized in such a way as toassure reproducibility, and can be correlated to theprocess that is ultimately commercialized. The sterilityaspects of clinical supplies must be validated to the sameextent as commercial materials.

So how is this validation effort to be organized toachieve this expanding regulatory focus? The answer isonce again dependent upon the size of the firm. For thesmall firm that is producing product solely for clinicalstudies, the Manufacturing unit (or person) is probablycharged with the responsibility of validating both bulkpharmaceutical processes as well as those “finishing”processes. These firmsmay also be employing contractorsrequiring the need to manage this outsourced service as

2: ORGANIZING FOR VALIDATION 9

stated earlier. This is important when the product is in theclinical phases, and becomes vital as the first productsapproach commercialization. Staffing the organization tofulfill this role becomes critically important.

As these small firms grow, their facilities will alsovary from rather small, dedicated facilities to large multi-product plants with a diversity of processing capabilities.At these large installations, the validation efforts moreclosely resemble those conducted at the traditionalpharmaceutical firms. This makes sense because of thediversity of products and processes. What should be inplace, however, to guide this growth is some corporateoverseer of validation, who ensures a common approachto validation within the company. By serving as a liaisonbetween groups, information beneficial to one can betransmitted to the other saving the “reinventing thewheel” syndrome.

CONCLUSION

Despite the events that have influenced validation sincethe early days, the issues of organizing to meet thevalidation challenges have not changed appreciably.Whether the process is a bulk process or one of thefinishing steps; whether the process is a proprietarypurification process, a steam sterilization process, or aconventional nonsterile process; whether the focus is aclinical manufacturing lot or commercial production;or whether the effort is accomplished within the firm,contracted out in conjunction with an outsourced manu-facturing agreement, or with the assistance of aconsultant, the validation staff must possess four things:1. Technical expertise, allowing a thorough under-

standing of the process being reviewed.

2. Understanding of the fundamentals of validation andthe ability to apply them to the process.

3. Interpersonal skills necessary to deal with all of theorganizations within and outside of the firm. Somebusiness acumen would be a great attribute for thoseinvolved with contract manufacturers.

4. Support from management, which positions thevalidation effort as a critical element in the company’ssuccess.These are the basics and arewhatwill ensure that the

validation effort is successfully accomplished. This wastrue in the early days, and will remain true in the future.

REFERENCES

1. Primm TM. Organizing for validation—engineeringdivision. Presented at the PMA Seminar on Validation ofSolid Dosage Form Products. Atlanta, GA, May 1980.

2. Papariello GJ. Organizing for validation—process develop-ment. Presented at the PMA Seminar on Validation of SolidDosage Form Products. Atlanta, GA, May 1980.

3. Guillemoteau JY. Validation of solid dosage forms—anorganization within the manufacturing division. Presentedat the PMA Seminar on Validation of Solid Dosage FormProducts. Atlanta, GA, May 1980.

4. Green W. Organizing for validation—quality assuranceviewpoint. Presented at the PMA Seminar on Validation ofSolid Dosage Form Products. Atlanta, GA, May 1980.

5. Gitlow H, Gitlow S. The Deming Guide to Quality andCompetitive Position. Englewood Cliffs, NJ: Prentice Hall,1987.

6. Hill D, Beatrice M. Facility requirements for biotech plants.Pharm Eng 1989; 9(4):35–41.

7. Sawyer CJ, Stotz RW. Validation requirements for bulkpharmaceutical chemical facilities. Pharm Eng 1992;12:44–52.

10 I: INTRODUCTION