Biotech CIP Cycle Development: Case Study Examples ...

SEPTEMBER/OCTOBER 2006 PHARMACEUTICAL ENGINEERING 1

CIP Cycle Development

©Copyright ISPE 2006

This articlepresents casestudy examplesof CIP cycledevelopmentactivities andlessons learnedfrom severalmodernbiotechnologyfacilities. TheCIP CycleDevelopmentprogramincorporatesaspects ofQuality RiskManagement(QRM) to meetthe needs of thebiotechnologyindustry intoday’sregulatoryenvironment.

Biotech CIP Cycle Development:Case Study Examples Utilizing QRM

by Matt Wiencek

AClean-In-Place (CIP) Cycle Develop-ment (CD) program for a large scalebiotech manufacturing facility was de-scribed in the September/October 2004

issue of Pharmaceutical Engineering. A threestage program of water, chemical, and soiledCIP CD and a project execution strategy utiliz-ing the ISPE Baseline® Commissioning andQualification Guide were presented. The pur-pose of the CIP CD program was to identify andresolve cleaning challenges prior to beginningthe Cleaning Validation (CV) program. Thisfollow up article will present practical casestudy examples and describe the manufactur-ing efficiencies gained. Finally, some aspects ofQuality Risk Management (QRM) will be ad-dressed as they apply to CIP CD. This article isnot intended to be a complete overview of QRMconcepts.

QRM Applied to CIP CDQRM applied to the pharmaceutical industry isintended to protect the patient from adulter-ated drug products. The ICH Harmonized Tri-partite Guideline Q9, Annex II, explains thepotential applications for QRM. Annex II.3(QRM as Part of Development) and Annex II.4(QRM for Facilities, Equipment, and Utilities)can be interpreted in part to promote the use ofCIP CD as a risk management tool based on theexamples cited. Annex II.3 lists one purpose ofQRM to be:

“To establish appropriate specifications,identify critical process parameters, andestablish manufacturing controls.”1

Annex II.4 provides another example:

“To determine acceptable cleaning vali-dation limits.”2

The cleaning of equipment through the use ofvalidated procedures may mitigate the risk of

producing adulterated drug products. There-fore, QRM principles can be applied to CIP CDand CV to identify important risk factors to beeliminated or minimized to acceptable levels.

How then might QRM be used to develop aCIP CD program and validated cleaning cycles?Annex I (Risk Management Tools and Meth-ods) describes several structured approaches toQRM. Formal methodologies can be applied,including Failure Mode Effects Analysis(FMEA), Failure Mode Effects and CriticalityAnalysis (FMEAC), and Hazard Analysis andCritical Control Points Analysis (HACCP). Casestudy examples of these structured risk assess-ment approaches to CV and equipment clean-ing and hold strategies have been published.3

However, Q9 also states the following:

“The use of informal risk managementprocesses (using empirical tools and/orinternal procedures) can also be consid-ered acceptable.”4

A structured approach to CIP CD focusing onthe development of cleaning control param-eters, yields data which can be used to mitigaterisk of product contamination. Defined as such,CIP CD is an informal risk management tool.The data gathered during a CIP CD programcan be used to determine control and alarmsetpoints and ensure cleaning cycles are ro-bust, repeatable, and efficient. Practicallyspeaking, operational knowledge gained by theend users results in improved cleaning proce-dures and enhanced personnel training.

Finally, the FDA’s Guide to the Inspection ofCleaning Validation Processes states the fol-lowing:

“It is not unusual to see manufacturersuse extensive sampling and testing pro-grams following the cleaning process with-out ever really evaluating the effectivenessof the steps used to clean the equipment.”5

Reprinted from

PHARMACEUTICAL ENGINEERING®

The Official Magazine of ISPE

September/October 2006, Vol. 26 No. 5

2 PHARMACEUTICAL ENGINEERING SEPTEMBER/OCTOBER 2006



This guidance document does not explicitly recommend astructured approach to CIP CD. However, a CIP CD programdoes facilitate the methodical evaluation of steps used toclean the equipment when the program includes all themanufacturing and quality stakeholders.

Practical Examples of CIP CD IssuesHaving established that CIP CD is an informal risk manage-ment tool and can be used for cleaning process data analysis,two questions remain:

1. What are some practical lessons learned from a CIP CDprogram?

2. What efficiencies can be gained which demonstrate aReturn On Investment (ROI), in a CIP CD program?

The first question will be addressed in a general manner thatdescribes case study examples that could be applied to anybiotechnology manufacturing facility that utilizes automatedCIP cycles. The second question cannot be answered com-pletely. How can one quantify the cost savings to a project ofproblems resolved during CIP CD that otherwise would havebeen encountered during validation lots or at some point inthe life cycle of the facility? The best way might be to profiletwo similar projects, one which included a CIP CD programand another which did not, and to somehow quantify theproject and product life cycle costs incurred by both resultingfrom cleaning problems. This type of analysis is beyond thescope of this article so “order of magnitude” estimate methodswill be used. However, the benefit of manufacturing improve-ment projects has become so obvious to some big-pharmacompanies that they have stated a policy of:

“...treating projects to improve manufacturing as a re-search investment: anyone who proposes such a projectdoes not have to submit a return-on-investment analy-sis.”6

QRM is a “new” development in the pharmaceutical industry.CIP CD is not new and there is no single correct method toplan and execute a CIP CD program. Each project mustaccount for limitations imposed by cleanability studies, equip-ment availability, procedures, resources, objectives, time,and money. However, all well executed CIP CD programshave the following common characteristics:

1. a clear definition of system boundaries and mechanicalconfiguration

2. detailed knowledge of the automation specifications3. definition of an engineering/science rationale for the val-

ues of configurable parameters associated with the CIPcycle

4. understanding of equipment, CIP circuit, and residuegrouping strategies

5. understanding of the critical cleaning process controlparameters: time, temperature, flow, chemistry, and clean-ing action

6. definition of a scope of work via a protocol, study, or

checklist which defines the acceptance criteria that allstake holders pre-approve

7. good project management skills used to execute the workwith available resources based on a schedule and budget

8. assurance that the goals of the CIP CD program align withthe requirements of the Cleaning Validation program

9. definition of CIP CD and CV completion based on accept-able analytical results, repeatability, and cycle time. Whatconstitutes “done?”

The CIP CD approach utilized a three step process of optimiz-ing a CIP cycle: functional check-out with water, chemicalCIP cycle testing (no soil) to confirm circuits can be rinsed ofdetergent residue, and finally, some degree of a soiled chal-lenge. An assessment of risk tolerance determined the levelof soiled CIP circuit sampling required prior to proceeding tocleaning validation.

The following points outline practical lessons learnedapplicable to any biotech process which utilizes automatedCIP cycles and identifies potential risk mitigation areas.

Define Cleaning User RequirementsIn general, User Requirement Specifications (URS) should bedeveloped prior to beginning the design and construction ofany biotech facility. If this has not occurred, the first step ofthe CIP CD program should be to assemble all the stakehold-ers (manufacturing, engineering, quality, and validation)and agree on cleaning user requirements for each CIP circuittype. The user requirements should specify “what” the CIPcycle process should accomplish to meet chemistry, tempera-ture, time, flow, and cleaning action specifications. The CIPCD team will then utilize the equipment, automation, andconfigurable parameters to establish “how” the user require-ments are implemented. It is important to understand thedistinction between “what” and “how.”

The vendor should be included in the user requirementdevelopment process for specialty equipment such as centri-fuges, Tangential-Flow-Filtration (TFF) skids, and homog-enizers. Examples of user requirements to define for TFFskids are: required shear rate, rinse/wash volumes, andtemperature ranges, chemical concentrations, dirty and cleanwet hold strategies, post CIP membrane storage require-ments, and steam or chemical sanitization requirements.Centrifuge user requirement definition includes: productcontact surface area boundaries, volumetric flowrate/through-put and backpressure specifications, discharge frequencyand interval length, and valve composite cycle timing forparallel paths. ASME BPE 2001, Section SD-4.15 CIP Sys-tems and Design also should be referenced when defining aURS for vessel and piping circuits. The URS should be pre-approved by all stakeholders prior to starting the CIP CDprogram.

CIP CD Equipment IssuesIdentify the Appropriate CIP Chemistry andTemperatureAn assessment of the proper cleaning chemistry and tem-




perature is a critical aspect of the development of a CIP CDprogram. The FDA’s guide states that:

“As with product residues, it is important and is ex-pected that the manufacturer evaluate the efficiency ofthe cleaning process for the removal of residues. How-ever, unlike product residues, it is expected that no, or forultra sensitive analytical methods very low, detergentlevels remain after cleaning. Detergents are not part ofthe manufacturing process and are only added to facili-tate cleaning during the cleaning process. Thus theyshould be easily removable. Otherwise, a different deter-gent should be selected.”7

“Cleanability” studies utilizing soiled “coupon” testing mayidentify the proper cleaning chemistry and temperature at abench top scale. The CIP chemical vendor also can be con-tracted to conduct a cleanability study. Studies should assessdifferent materials of construction and unit operations. TFFmembranes usually require cleaning chemistries and tem-peratures that are different than all other unit operations.Establishing specifications for each unit operation may mini-mize the need to test multiple CIP chemistries at the produc-tion scale. The “worst-case” soil may be identified and used todevelop CIP circuit group testing strategies for CD and CV.There may be cases of residues that prove difficult to removethat cannot be predicted from coupon studies and must betested at full scale.

Batch Chemical Solutions EffectivelyAfter the wash concentration and temperature are defined,the CIP CD program will establish a repeatable method tobatch solutions. The strategy employed will be a function ofthe CIP skid design. Is the chemical dosing controlled basedon volume or time? Are chemicals delivered via a distributionheader or drum pump? Volume based dosing systems willmeasure the quantity of wash water delivered into the washtank and meter in the correct volume of chemical. Time basedsystems will open the chemical delivery valve based on aconfigurable parameter determined during CIP CD. Timebased systems running off of a distribution header maydeliver variable dose volumes due to fluctuations in pressure.In either case, testing at minimal, nominal, and maximumwash volumes is recommended. The required mixing time onthe CIP skid should be determined for multiple wash volumesto ensure the required solution homogeneity is achieved.

Rinse Time ConstraintsA typical CIP cycle utilizes single pass rinses and recirculatedwashes. The single pass rinse configuration can presentchallenges if the rinse water reservoir is limited in sizecompared to the CIP circuit hold-up volume. An engineeringbasis should be developed for establishing the minimumrinse time. Utilizing the volumetric flowrate, the circuit hold-up volume (which is often significant), and the rinse time, theCD team can estimate the rinse volume required. For largescale biotech facilities, it is not unusual to use single pass flowrequirements on the order of 200-300 gallons at 50 gpm.

Delivering this amount of water may require multiple rinsetank batching. Excessive rinsing can significantly increasewater use, generate excessive waste, and add hundreds ofhours of CIP cycle time during the course of a productioncampaign. Specifying a rinse time that is robust enough toremove chemical and process residues in a minimal amountof time can be accomplished in a number of ways, includingspecifying circuit turnover volumes, monitoring return con-ductivity, and obtaining grab samples. These can be analyzedfor Total Organic Carbon (TOC), conductivity, pH, bioburden,and endotoxin levels.

Vessel CleaningThe important points to consider in vessel cleaning include:ensuring adequate spray coverage as defined by ASME BPE2001, Section SD-5.1 (Sprayball Test), minimizing poolingin the vessel, and ensuring turbulent flow through all inletpathways. It is common practice to design vessel spraydevices and conduct riboflavin coverage tests on vessels at2.5-3gpm/linear foot of tank circumference. The CD teamshould ensure that the flowrate for vessel cleaning is thesame used for sprayball coverage tests within allowabletolerances. The ASME recommends +/- 20% of rated flow.Verifying that the CIP skid can deliver the specified flowthrough a complex piping network will ensure proper cover-age and drainage of rinse and wash solutions. The primarycleaning action in a vessel is fluid impingement and flow ofa turbulent sheet on the sidewall. Pooling in the vesselbottom dish impedes this mechanism and can be minimizedby using overlay pressure and/or a Clean In Place Return(CIPR) pump. Vortex breakers decrease air entrainmentand will reduce pooling. Vessels CIP circuits often includecomplex valve cycling composite functionality designed toclean diptubes, entry ports, and inoculation lines. Ensuringturbulent flow through these parallel paths and adequatevolume turnover should not be overlooked. Agitators andother internal parts should be installed in the vessel duringthe riboflavin coverage test and inspected to ensure propercoverage.

Figure 1. Sprayball coverage flow using ASME recommendations.Vertical cylindrical vessels with dished heads.




Identify Dead Legs with a Chemical CIP CycleA dead leg can be commonly described as a section of the CIPcircuit which does not experience flow in the turbulent regimeas defined by the Reynolds number. These areas can hold upresidue or detergents and could result in product contamina-tion and/or excessive rinse times. It is common in modernmanufacturing facilities to achieve Length/Diameter (L/D)ratios of two or less.8 Dead legs can be identified by runninga chemical CIP cycle without soil. CIP final rinse failures mayoccur during this portion of testing due to dead legs, valvecycling issues, or inadequate pipe velocities. Automationand/or mechanical changes are required to fix these deficien-cies. Chemical CIP cycle CD can be expedited by using CIPcircuit grouping strategies based on mechanical similarities.The most conservative approach is testing with caustic andacid washes enabled irregardless of CV strategy. The equip-ment should not be soiled for the first time without data (viaa CIP chemical test) demonstrating a high degree of assur-ance that residues can be removed. This is often overlookedduring fast paced start-up schedules where firms are underpressure to start test batches as quickly as possible.

Transfer Line CleaningTransfer line cleaning CIP CD is more challenging than itmay appear. A velocity of 5 ft/sec is frequently cited asnecessary to ensure complete wetting and sweeping away ofair pockets, particularly at high points in the system.9 If thetubing is not wet, it will not be cleaned. Difficulties can beencountered when implementing volumetric flow rates at 5ft/sec. Rarely is a transfer line one pipe diameter size along itscomplete length beginning at the Clean In Place Supply (CIPS)header through the process line and returning through theCIPR header. For these circuits, establishing 5ft/sec flow in thelargest diameter within the circuit is not always possible. In-line reducers, filter housings, and other fittings may imposepressure drop restrictions. A CIP CD specification that may beused to determine wash and/or rinse time length is the turn-over ratio. Once the hold-up volume is known, a turnover ratioof three to five times for example, may be employed as a wayto ensure lines receive an equivalent amount of cleaning. The

hold-up volume can be determined by measuring the change inthe wash tank level during recirculation. The simple formulabelow can be used to determine overall wash time: (Hold-upVolume X Turnover Ratio)/(Volumetric Flow) = Wash Time.The appropriate turnover ratio and hold-up volumes should bedocumented during CIP CD. This formula is a starting pointonly and its efficacy must be verified through sampling or in-line measurements.

Recirculated and Single Pass CIP CircuitsThe mechanical configuration of CIP circuit boundaries maybe designed as single pass circuits. For these circuits, washand rinse solutions are not returned to the CIP skid, but arepumped through the CIP circuit directly to drain. Achievingrequired rinse times for one pass circuits is generally not aconstraint since most rinses are directed to drain at the CIPskid anyway. Ensuring enough wash volume is available maybe difficult however. For instance, a circuit with a hold-upvolume of 250L might have the following restrictions utiliz-ing the formula outlined above: (250L X 5)/100LPM = 12.5minutes of wash time required. For this example, if the CIPskid wash tank volume is not at least 1250L, the functionalityof the CIP skid will need to permit multiple tank washes,which adds a significant amount of cycle time.

Tangential Flow Filtration (TFF)Skid CIP CD IssuesThe vendor should be consulted about the proper TFF CIPchemicals, temperature, shear (flow) requirements, and ex-posure times. The retentate side of the membrane is cleanedby “shear” while the permeate side cleaning is a function ofTrans Membrane Pressure (TMP). Generally, cleaning andrinsing the permeate side of the membrane and the permeatepiping is more difficult than cleaning the retentate side. Thisis because CIP solutions are forced through the membranesusing TMP, but may not be at a rate which permits flow in thepermeate piping of 5ft/sec. TFF systems may be mechanicallyconfigured to permit flow directly to waste from the permeateor retentate lines. During soiled testing and cleaning valida-tion, rinse sample sites should be designated for these loca-tions.

Centrifuge CIP CD IssuesThe centrifuge is arguably the most mechanically complex“non-vessel” utilized in the biotechnology manufacturingoperation and can be challenging to clean. The vendor shouldbe involved early in a project to specify the cleaning URS sothat proper CIP operation can be designed into the CIP cycle.For the disk stack type centrifuge, definition of productcontact surfaces in the bowl should be accomplished duringCIP CD with the aid of a detailed mechanical drawing of thebowl internals. Swabbing these areas requires disassembly.This activity should be carried out by trained individuals ina manner that does not compromise the sample site. Theproduct contact surface areas in the bowl internals aresubject to the same visual inspection requirements for visibleresidue and moisture that are applied to other equipment.

Figure 2. Wash/Rinse time for transfer line cleaning based onturnover volume. 3X, 4X, 5X for flowrates of 20gpm, 30gpm,and 40 gpm.




Bioreactor CIP CD IssuesThe bioreactor is typically the most mechanically complex“vessel” utilized in a biotechnology facility. Developing theswab sample plan for a bioreactor will require the assessmentof many swab sites based upon the mechanical design. Ensur-ing that coverage testing has been properly carried out is apre-requisite for a successful CIP CD program. Ideally, thecoverage test will document the minimum amount of timenecessary to rinse the surface clear of riboflavin. This infor-mation can be used to develop an optimized wash timeexposure for the tank internals where one might specify, forexample, that the wash time be equivalent to three to fivetimes the sprayball coverage time as a starting point. Thecycle development study can focus on increasing or decreas-ing the time based on the analytical and visual results. Thisis critical for efficient CIP cycle times because of the numberof “parallel paths” that are cleaned with the vessel. A detailedanalysis of the hydraulic balance of the CIPS flow with thespecified valve cycling composite will ensure fluid turbulencethrough piping and proper spray coverage. The sparge tube isoften utilized as a pathway for CIP solutions to clean thebottom of impellers.

Portable Vessels, Depth Filter, and HoseCleaning CIP CD IssuesPortable vessels, depth filters, and hoses present uniquecleaning challenges. Portable vessels are usually the leastmechanically complex biotech equipment; however, cleaningis not always straight-forward. Portable tanks in the range of50 to 300 liters typically have low sprayball flow rates on theorder of 10 to 20 gpm. If a single tank is cleaned at a utilitypanel and tied into a CIPR header and pump via a hose, thelow flow rate to the vessel sprayball may limit the ability torinse out the CIPS and CIPR lines efficiently because turbu-lent flow is not being supplied to the piping. Depth filters canpresent unique challenges due to the configuration of thehousing flange/o-ring mechanical design. Special care needsto be made when specifying this interface to ensure thatchemical or residue hold-up is not an issue in and around theo-ring. CIP skid cycles for hoses should be configured with thesame velocity and turnover volume requirements used forhard piped transfer lines. Consideration should be given tothe logistics of tracking dirty and clean hoses during CIP CDand incorporated in cleaning procedures.

CIP CD Instrumentation IssuesDiaphragm Failures and Valve FaultsAn automated CIP cycle may fail and enter a HOLD state fora variety of reasons. Two sources of failures encounteredduring CIP CD are valve fault alarms and diaphragm valvefailures. The valve faults encountered are typically related toa faulty limit switch or a valve that is not able to close becausea line is full of liquid. A more difficult problem to solve froma CIP CD perspective is detecting a failed diaphragm. In thisfailure mode, the valve actuator and limit switch combina-tion will stroke full open and closed without any fault.However, because the diaphragm has torn away from the

actuator, the CIP flow path is blocked resulting in a HOLDtypically due to no CIP return flow which is measured at theCIP skid. Diaphragm failures can be found through thepressurization and venting of individual flow paths. Path-ways that are blocked will not vent properly.

On-line Testing and Calibration IssuesOn-line sample testing is currently available for conductivityand TOC assays. The benefits of using on-line measurementsversus grab samples are the minimization of sample contami-nation, continuous on-line measurement availability, reduc-tion of laboratory costs, decreased glassware use, and de-creased variability.10

The final rinse conductivity is a typical acceptance crite-rion specified in the CV program and also should be the targetutilized for CIP CD. The FDA’s Guide To Inspections Valida-tion of Cleaning Processes states that,

“Check to see that a direct measurement of the residue orcontaminant has been made for the rinse water when itis used to validate the cleaning process. For example, itis not acceptable to simply test rinse water for waterquality (does it meet compendia tests) rather than test itfor potential contaminants.”11

The final rinse conductivity specification needs to be corre-lated to acceptable levels of detergents and/or process resi-dues to be a meaningful value. Most CIP skids utilize aconductivity sensor that is mounted on the CIPR header.Conductivity is a function of temperature and the sensor mayutilize configurable temperature compensation algorithms.The calibration method should be appropriate for the tem-perature compensation configuration and both the calibra-tion and compensation are in alignment with the CV accep-tance criteria. For example, one conductivity sensor vendoroffers several compensation settings for high purity waterapplications: 2%/oC linear, ASTM 5391, or non-temperaturecompensated.

On-line TOC analyzers are becoming available for Water-For-Injection (WFI) and Purified Water (PW) systems al-though applications for CIP use are not as common.12 Ad-dressing these issues during the CIP CD program mayminimize the need to obtain grab samples CV.

CIP CD Automation IssuesHolds, Stops, and AbortsOne purpose of CIP CD is to identify and eliminate the causeof HOLD, STOP, and ABORT states used in automated CIPcycles. CIP cycles have the ability to be placed into one ofthese states due to a critical process alarm or condition.During normal operations (post CV), a limited number ofRESTARTS is generally permitted because the CIP cycle stepwill be repeated, thus delivering more than the minimumcleaning regiment. A critical question might be: are datagathered from a CIP cycle that experiences a RESTARTacceptable for CIP CD or CV? If the efficacy of the restartedCIP cycle is not equivalent to a normal CIP, the answer isprobably “No,” because the extended cycle being tested does




not represent worst case. A determination of when RE-STARTS are permitted for CV requires input from the CIPCD team, validation, engineering, and quality.

CIP CD Data ManagementFor a large scale biotech facility, the amount of data accumu-lated during a CIP CD program can be prodigious when rinseand swab samples are taken. The CIP CD and CV programsmay require rinse sampling for TOC, conductivity, pH,bioburden, and endotoxin, and swab samples for TOC andbioburden. It is not unusual to have on the order of 50 to 100CIP circuits within the project scope. Sampling each of thesecircuits for the required assays can produce thousands of datapoints which need to be analyzed and correlated to otherfactors such as: batch ID, equipment ID, CIP circuit ID, CIPstart time, CIP end time, soil type, dirty hold time, clean holdtime, sampler, sample date and time, sample location, visualinspection status, RESTART status, and analytical resultacceptance limits. Utilizing a database to track these inputsallows the CD team to produce reports that can be used toassess the efficacy and robustness of the CIP cycles. Inaddition, the database can be used to track CIP cycle failureinvestigations and values of recipe configurable parameters.It is not unusual to have the need to specify and trackthousands of configurable parameters which is difficult usinga simple spreadsheet.

CIP CD Soiled Testing IssuesClean Hold TimeMost CV programs specify a Clean-Hold-Time (CHT) testingrequirement. CHT is a validated time the equipment canremain out of service in a clean state before the equipmentmust be re-cleaned prior to use. Equipment that is left in a drystate will have a decreased risk of failing CHT validationbecause of low bioburden loads The typical CIP cycle will endwith an air blow step to remove excess water and dry theequipment or piping surface. The length of the final air blowmay need to be longer than intermediate air blows to achievethe required level of dryness. Following the final air blow,small droplets adhering to the side-wall are usually accept-able. Leaving the vessel in a pressurized state at the end ofthe cycle should inhibit the ingress of microbial contami-nants, but poses a risk to personnel requiring equipmentaccess. The CD team should determine the proper state thatthe equipment should remain in at the end of a CIP cycle.Other means of microbial ingress should be evaluated foreach unit operation.13

Dirty Hold TimeCV programs should include definition of the Dirty-Hold-Time (DHT) validation strategy. During DHT testing, a pieceof equipment is soiled and quarantined for a specified holdperiod.

“The time duration for the stationing of soiled equip-ment must be optimal for the survival of bioburden in aphysiological state to survive subsequent cleaning. Assoiled equipment dries, the solute concentration in-

creases with attendant reduction in water activity. It iswell established that with low environmental wateractivity that microorganisms lose viability; during equip-ment drying the surface borne bioburden will similarlylose viability, such that upon complete loss of water thereis an overall reduction in bioburden. Furthermore, thesurviving population of microorganisms will not be inthe optimal physiological state to survive or advantagesubsequent cleaning process. Worst-case dirty hold timeis highly dependent upon the duration of equipmentdrying.”14

Conducting dirty hold testing during soiled CIP CD willmitigate the risk of failures encountered during CV by deter-mining the worst case hold time based on maximum viablebioburden load and/or dried residue. The worst case DHT interms of bioburden load may not be defined by a dry piece ofequipment.

Practical Rinse Sample ConcernsMost firms have SOPs which describe the rinse sampletechnique, containers to be used, and subsequent samplehandling and processing. However, biotechnology manufac-turing equipment and piping is often not designed with apermanent sample port needed for CIP CD and CV programs.The CIP CD team should identify all rinse sample locationsand ensure that samples are obtained and handled in amanner which ensures that it is representative of the streambeing sampled. The sample procedure should include flush-ing of the sample port prior to obtaining the sample.

Practical Swab Sample ConcernsDefinition of a swab site matrix and the swab strategy isessential to effectively planning a CIP CD program. Swabsampling is intended to capture surface data from a variety ofproduct contact materials that are representative of hard-to-clean and easy-to-clean sites. The definition of these locationsshould be based on the equipment configuration and the clean-ing method employed. The use of PIDs, mechanical drawings,and/or equipment walk-downs is recommended for identifyingthese locations. CIP CD data can be used to quantify wherehard-to-clean sites are located. The CV program then might benarrowed to a more limited regiment of locations. Gainingaccess to swab locations can be challenging and may requireconfined space entry, equipment disassembly, or the use of aswabbing pole. If a swabbing pole is used, the qualified swab-bing technique should account its use.

Visual Inspection IssuesWith respect to cleaning procedures, 21 CFR Part 211.67 (6)states the following:

“These procedures shall include, but are not necessarilylimited to, the following: Inspection of equipment forcleanliness immediately before use.”15

Firms should have a visual inspection requirement inte-grated into the overall CV program to comply with goodmanufacturing practices. It also has been documented that incertain applications, visual inspection may be the only neces-




sary acceptance criteria for equipment CV.16

In any case, it is advantageous to begin the visual inspec-tion process during the soiled testing step of CIP CD. A VisualInspection SOP should be used to define what is deemed an“acceptable” visual inspection. However, in general, equip-ment which fails a visual inspection can exhibit streaks orspots of residue, a general haziness of the surface finish, and/or undrained rinse water. The visual inspection is one methodto determine if an acid wash demineralization step is neces-sary as a typical part of a CIP cycle. Certain intermediates,products, and detergents themselves may have a tendency tocause the build-up of an inorganic residue layer on the vesseland piping. This can be mitigated through the use of ademineralization step. Including an acid wash step willincrease CIP cycle times, but may be the only way to preventmineral and/or rouge build up on stainless steel surfaces.

Derouge IssuesRouge has been defined as:

“...an iron oxide film that forms on the surface of stain-less steel with the industrial use of distilled and highpurity water... It is a form of superficial corrosion thatgoes unnoticed and unreported in most industries, but isa major problem wherever exceptional cleanliness isrequired.”17

The most efficient method to control rouge is the specificationof materials of construction that will be highly resistant torouge formation. Nonetheless, practical experience has shownthat rouge may start to become visible during the start-upprocess as equipment comes into contact with high puritywater and other oxidative processes such as Steam-In-Place(SIP) cycles. Rouge removal can be accomplished as a periodicmaintenance activity. The CIP chemical vendor typically canprovide recommendations for CIP chemistry that are specificfor derouge applications. Concentrations are typically muchhigher and exposure times significantly longer than a normalCIP. The derouge cycle can place an increased burden onmanufacturing production in terms of cycle times and pro-duce a significant amount of concentrated chemical waste.The CD team will need to assess if enabling a normal acidwash during a CIP cycle is more advantageous than a derougeCIP cycle run as part of a preventative maintenance program.

CIP CD Process ImprovementsSuccessfully completing a CIP CD program requires plan-ning and good project management practices. It involves timeand resources during the start-up schedule; and therefore,adding cost to the overall project. Is this cost and effortjustified? The following examples are a few of many qualita-tive approximations of efficiencies gained.

Water Use Minimization During Wash StepsOptimizing wash volumes will reduce the amount of waterusage. For a facility that has 100 CIP circuits with an averageCIP circuit hold-up volume of 200L, the following approxi-mates the water savings:

Assumptions1. 100 CIP circuits are used to clean all equipment and

transfer lines twice a month.2. The average hold-up volume of all circuits is 200L.3. The optimized wash volume is 250L developed during CIP

CD.4. The non-optimized average wash volume would have been

400L based on using maximum working volume of thewash tank.

5. The facility uses a caustic and acid wash for all CIP cycles.

100 CIP circuits × 2 cycles/month × 12months × (400L-250L) × 2 washes/cycle = 720,000 L/year of water savings.Assume a nominal chemical concentration of 1% by vol-ume for caustic and acid washes.720, 000L × 1% = 7,200L of chemical additives not used.Total volumetric waste savings = 720,000L + 7,200L =727,200 L/year.

Optimized CIP Cycle TimesIt is not uncommon for a caustic/acid CIP cycle to take on theorder of two to four hours when optimized. If the CIP CDprogram achieves a 20% improvement in cycle time efficiency(by addressing the issues outlined above) than would haveotherwise been implemented, the following might apply.

Assumptions1. 100 CIP circuits are used to clean all equipment and

transfer lines twice a month.2. The average optimized CIP cycle takes 2.0 hours.3. The average non-optimized CIP cycle would have taken

2.5 hours.

100 CIP circuits × 2 cycles/month × 12 months × 0.5 hours= 1,200 hours of production/year.

Selective Enabling of Acid WashAs stated above, the CIP CD program can be used to identifyequipment that is at risk for inorganic residue depositionduring production. Such equipment is a candidate for a PMderouge cycle or a CIP cycle configured with a dilute acidwash. If the equipment utilizing the acid wash does not needto be derouged, the following might apply.

Assumptions1. 50 of 100 CIP circuits exhibit a tendency to form inorganic

residue films after use.2. The 50 circuits without an acid wash need to be derouged

twice a year.3. The derouge cycle requires 20 times the normal acid wash

concentration (10% by volume as opposed to 0.5%) andtakes 6 hours.

4. The normal CIP cycle with the acid wash enabled takes anadditional hour.

50 CIP circuits × 2 cycles/year × 6 hours = 600 hours ofadditional PM cycles.




50 CIP circuits × 2 cycles/month × 12 months × 1 hour =1,200 hours of acid wash time.1,200 - 600 = 600 hours of saved production time by usingPM cycles.

However, this time savings must be balanced againstincreased chemical usage.

50 CIP circuits × 2 cycles/month × 12 months × 250L x 0.5%= 1,500 L used for wash.50 CIP circuits × 2 cycles/year × 250L × 10.0% = 2,500 Lused for PM cycles.

The benefit of 600 hours of saved production time needs tobe weighed against increased waste discharges of 1,000Lof acid chemicals.

Grouping of Parallel PathsBioreactors are designed with multiple inlet ports and otherpathways that are cleaned with the vessel. These includemedia inlet, inoculation, acid, base, vents, overlay, sparge,and sample lines. The valve cycling composite controls theopening and closing of these pathways while providing flow tothe sprayball and typically includes 10-15 individual flowpaths.

Assumptions1. Bioreactor has 15 parallel paths that are cleaned includ-

ing the sprayball.2. The sprayball exposure time = 10 minutes and each

parallel path = 2 minutes for each rinse and wash.3. The non-optimized valve cycling composite opens each

pathway sequentially.4. The optimized valve cycling composite groups the paths

into five “families,” while ensuring that each branch isturbulent.

5. The CIP cycle includes five steps: pre-rinse, caustic wash,intermediate rinse, acid wash, pre-final rinse, and finalrinse.

Non-Optimized: 10 min + (15 × 2 min) = 40 minOptimized: 10 min + (5 × 2 min) = 20 min

Optimized CIP Cycle Time Savings: 5 × (40 - 20) = 100minutes/cycle.2 cycles/month × 12 months/year × 100 min = 2,400 min =40 hr/year production time/reactor

Optimizing Gravity Drains and Air Blow TimesGravity drains and air blows are utilized to clear the circuitof wash and rinse solutions in an efficient manner. Theoptimal times need to be verified by visual inspection at thepoint where the circuit is piped to drain and/or by utilizing theCIPR flow switch.

Assumptions1. 100 CIP circuits that utilize the five step CIP defined

above2. Each rinse is divided into two parts which gives the CIP

cycle a total of eight steps utilizing gravity drains and airblows (GD/AB).

3. The average optimized combined GD/AB step is five min-utes and the non-optimized would have been seven min-utes.

100 circuits × 2 circuits/month × 12 months × (7 to 5min-utes) × 8 CIP steps = 38,400 minutes = 640 hr/year

ConclusionCIP CD is an activity that can be incorporated into the overallstart-up schedule of a biotechnology manufacturing facilityprovided it is well planned and managed. The activity pro-vides an opportunity to apply the concepts of QRM to a criticalmanufacturing process. CIP cycles can be configured to run ina robust and efficient manner. Costly CV failure investiga-tions can be minimized. All the manufacturing facility stake-holders benefit from implementing such a program, includ-ing most importantly, the patient.

References1. International Conference on Harmonization of Technical

Requirements for Registration of Pharmaceuticals forHuman Use, ICH Harmonized Tripartite Guideline, Qual-ity Risk Management Q9, p. 17. (ICH Q9).

2. ibid, p 18.3. Tidswell, Edward, “Risk Based Approaches Facilitate

Expedient Validations for Control of MicroorganismsDuring Equipment Cleaning and Holding,” AmericanPharmaceutical Review, November/December, 2005, pp.28-33.

4. ICH Q9, p. 1.5. FDA Guide to the Inspections Validation of Cleaning

Processes. 1997, p. 2.6. “Special Report: The End of Validation As We Know It?”

Pharmaceutical Technology, August 2005, pp. 36-42.7. FDA Guide to the Inspections Validation of Cleaning

Processes, 1997, p. 6.8. ASME BPE Guide, 2001, Part SD, Design for Sterility and

Cleanability, p. 9.9. ibid, p. 9.10. Martinez, Jose, “On-Line TOC Analyzers Are Underused

PAT Tools,” Bioprocess International, December, 2004, pp30-38.

11. FDA Guide to the Inspections Validation of CleaningProcesses, 1997, p. 5.

12. Martinez, Jose, p. 30-38.13. Tidswell, Edward, p. 32.14. ibid, p. 31.15. Code of Federal Regulations, 21 CFR Part 211.67, Equip-

ment Cleaning and Maintenance.




16. Forsyth, Richard, Nostrand, Vincent, and Martin, Gre-gory, “Visible-Residue Limit for Cleaning Validation andits Potential Application in a Pharmaceutical ResearchFacility,” Pharmaceutical Technology, October, 2004, pp.58-72.

17. Tuthill, Arthur, Brunkow, Roger, “Stainless Steel forBioprocessing,” Bioprocess International, December, 2004,pp. 46-52.

About the AuthorMatt Wiencek holds a BS in chemical engi-neering from Cleveland State University anda Bachelor of Environmental Design fromMiami University. He has been a ValidationEngineer and Project Manager with Com-missioning Agents, Inc. since 2000 and alsohas held positions as a process design engi-neer and architectural consultant. Wiencek

has accomplished project work in the areas of plant commis-sioning, CIP and SIP cycle development, cleaning validation,and process validation of biotechnology and bulk pharmaceu-tical chemical facilities. He is currently a member of the ISPEGreat Lakes Chapter. He can be contacted by telephone at 1-440-653-1577 or by e-mail: [email protected].

Commissioning Agents, Inc., P.O. Box 40060, Bay Village,Ohio, 44140.


Biologics Process Simulation


This articledescribes theapplication ofstandardprocesssimulationtechniques topredict theperformance ofan existingbiologics plantafter recentupgrades of thefacility. Thework confirmedthe viability ofthe proposeddesign, but withqualifications.

The Role of Process Simulation in aRenovated Biologics Facility –A Case Study

by Daniel Lavin, Himabindu Gopisetti, andPeter N. Notwick, Jr.

Figure 1. Schematic ofupstream process.

Introduction

Process simulation is a well-establishedpractice in the biopharmaceutical in-dustry that has been applied exten-sively to all types of biologics capital

projects. Simulation is used to guide the designof major grassroots facilities and incrementalexpansions as well as for production schedul-ing, planning and optimization of operations inexisting facilities.

The universal demand for process simula-tion has spawned a number of solution meth-ods as well as solution providers. Both home-grown and commercially available softwaretools have been developed and used with vary-

ing degrees of success. As might be expected,the simulation tools vary widely in capabilityand applicability. Some are globally adaptableto nearly any sort of problem, while others weredeveloped to model one particular type of facil-ity or system. Most privately developed simula-tors are spreadsheet based, while the commer-cial software packages frequently use a data-base platform.

The primary question that process simula-tion attempts to address is the number and sizeof production and support resources that arerequired to meet the manufacturing goals ofthe plant. This article describes a somewhatunusual case study that illustrates one more

Reprinted from







aspect of the applicability of modeling to biologics plantproblem-solving.

BackgroundIn this study, a clinical manufacturing facility operated by amajor pharmaceutical manufacturer was being pressed intoservice as the commercial launch facility for a new product.The original plant had been designed to be used as a non-GMPdevelopment facility. Over the years, it had been expanded andupgraded incrementally to produce clinical trial material. Toaccomplish its new mission, the facility had recently under-gone upgrades to bring it into full compliance with cGMPsprior to the FDA Pre-Approval Inspection (PAI) for licensing.

Due to the strategic criticality of manufacturing sufficientquantities of the new product, the management of the facilitywanted a high level of confidence that they could meet theirobjectives. Chief among their concerns was whether or notthe non-personnel resources (primarily process systems ca-pacity and utility supplies) were sufficient to support thetarget production rate. This requirement was reduced to twoquestions:

• Can the process systems produce the target annual amountof product?

• Do the clean utility systems have sufficient capacity tosupport production?

The ProblemDue to the incremental nature of past facility expansions, theproduction and support systems were neither integrated norsymmetrical. The configuration of the plant included:

• a cell culture operation that included four seed trains thatfeed six 5000L production bioreactors

• two identical cell separation trains

• three purification trains, each with four chromatographycolumns and two UF/DF steps, as well as its own dedicatedbuffer prep and hold

• four purified water generating trains whose distributionsystem feeds the WFI and clean steam generators

• three WFI stills of various capacities

• two non-overlapping WFI distribution systems

Figure 2. Schematic of downstream process (partial).




• one clean steam generator

One significant advantage was that the simulation woulduse as its “model” a process that had been operated exten-sively in the plant at scale. Therefore, reliable data existednot only for the process parameters, but also for the actualcycle times that had been achieved. As a result, the expec-tation was that this simulation would be “realistic” (i.e.,highly reliable).

The primary specifications or production basis that set theground rules for the analysis consisted of:

On-Stream: Each process system operates 351 days peryear. Note that the scheduled shutdown of individualoperating areas would be staggered in order to maximizeproductivity, resulting in an annual “rolling” shutdown.

Maintenance Shutdown: 14 days of shutdown per sys-tem per year. Due to the long start-up and shut-downsequences, all systems would not be in a “cold” shutdownstate at the same time.

Cell Culture Batch Size and Titer: Typical for this sortof manufacturing process.

Production Bioreactor Cycle Time: 15 days averagefrom inoculation of one batch to inoculation of the nextbatch (i.e., includes cleaning, steaming, and preparation).

Production Bioreactor Success Rate: 90%

Cell Separation Recovery: 85% based on assumed cellculture yield

Purification (Downstream) Yield: 43% based on as-sumed cell culture yield

As anyone familiar with the operation of biologics plantsknows, these specified parameters are only averages. Inpractice, even the best characterized and controlled processexperiences “normal variability” in its performance. Forinstance, the time required for the production bioreactor toachieve its target titer can vary by two days from the average.In addition, there is an acceptable band of variation in finaltiter that triggers the decision to harvest. Similar tolerancesexist for all of the process operations.

Recognizing this, the manufacturing management wasnot satisfied with a “snap-shot” of the facility performancethat considered only the average case. Rather they requiredTable A. Example of rules-based operating parameters.

• SIP initial heat up period is 5 minutes for small equipment, 10minutes for vessels < 1000L.

• SIP hold times are 50 minutes at sterilization temperature.

• Autoclaves and glass-washers are operated exclusively during theday shift; each unit is operated 3 times per day.

• Net water consumption of each glass washer is 100 gallons percycle and each cycle lasts 15 minutes.

• POU heat exchangers are steamed and flushed once per day. Coldflushes occur once per hour on idle units.

• WFI and RO water tanks call for make up at 75% and continue fillinguntil they reach 100% working volume

Figure 3. Rolling shut-down and start-up sequence.




the analysis of certain key parameters to determine the effectof their normal variability on operations and productivityover the long term.

ApproachThe two primary aspects of process simulation are the strat-egy and the tools.

StrategyMost simulation strategies require that a base “static” (i.e.,deterministic) model be developed. The model at this stagestrings together all of the unit operations of the productionand support systems into an integrated whole. The staticmodel is usually based on the average performance scenario.

This base model serves as a template for the availableoperating data. In the process of using the data to build anddebug the model, deficiencies in that data come to light,which must be addressed by supplying additional data or byapplying reasonable assumptions. Eventually, this processresults in a complete, coherent, functioning representation ofthe operating systems. Therefore, regardless of the ultimateobjective of the simulation exercise, the development of thestatic model is an essential first step in reaching the overallobjectives.

ToolsIn this case study, the manufacturing user group recom-mended the particular suite of simulation software that wasused. Unfortunately, one of the limitations of this softwareat the time we used it was the fact that it could accommodateonly a “single train” process, i.e., one bioreactor train and onepurification train. This was obviously not suitable for theplant configuration that was being simulated. However, oncethe single train model has been developed, its results can bedownloaded into a companion application. The latter processscheduling tool can accommodate multiple trains in theasymmetric configuration of the actual plant. It also cansimulate the sharing of common resources and provide anoverall schedule of events, identifying bottlenecks.

The net result was that the first step of the model develop-ment process actually consisted of two steps: the develop-ment of the single train model followed by the preparation ofthe multi-train resource scheduling model.

When the static resource scheduling model had beenexercised sufficiently to demonstrate that there were nolimitations in the average performance case, the remainingtask was to test the effects of the variability of the majorprocess parameters with a dynamic (stochastic) simulation.In this type of simulation, the target parameters are allowedto vary between limits based on a normal (symmetrical) orskewed (asymmetrical) distribution around each parameter’saverage. The Monte Carlo method is the most popular statis-tical analysis tool for this purpose. For this dynamic simula-tion study, Decisioneering’s Monte Carlo-based Crystal Ballsoftware was chosen.

Single Train Static ModelOne of the most challenging aspects of this component wasdata gathering and conditioning. This is due in large measureto the sheer volume of detailed information that is requiredby the software to simulate each unit operation.

Gathering some of the information was relatively straight-forward because certain items could be stated succinctly.Rules laid down for clean utility usage or CIP and SIPtreatment parameters fell into this category. Table A givesexamples of these operating rules.

Determining the values of actual process parameters wasmore problematic. While it was generally true that theprocess operating in the context of this particular plant waswell known, the detailed operational information was notreadily accessible to the modelers. The data was primarilycontained within completed batch records that had to beobtained and then “mined” for the desired information. Themanufacturing user group provided a summary of the typicalvalues for the measured process parameters. However, ob-taining the typical durations and utility consumptions of theindividual steps of the various CIP and SIP cycles requiredparticular effort because these are not tracked by manufac-turing operations.

Although the single train model was only the first step inthe development of a static model that simulated the clinicalmanufacturing facility, it did yield some results that pro-gressed the study and indicated a favorable ultimate out-come. Some of the salient results were:

• The calculated yield per batch of finished product wasreconciled with actual plant operating experience. Thiswas a check on the consistency of the performance datasupplied for the individual operations.

• The duration of virtually all high rate WFI demand epi-sodes was less than 15 minutes. Only one type of WFIdemand was found to have a long duration (60 minutes) athigh rate. This meant that the generators had frequentand sustained opportunities to replace used volume.

Figure 4. WFI inventory for multiple batches.




• No WFI demand rate exceeded the generation rate, anindication that the WFI surge vessel’s capacity would notbe taxed. In fact, the level of the vessel never fell below 75%– the point at which the generator is turned on.

Figures 1 and 2 present some of the graphical output thatfacilitated debugging by permitting a visual confirmation ofcorrect connectivity among the process systems.

Static Resource Scheduling ModelWith the data vetted and the single train model accuratelysimulating the process, the data for individual unit opera-tions were loaded into the process scheduling tool. Here,parallel operations could be propagated to represent theactual plant configuration. This included the ability to repre-sent multiple sources of WFI; the key study resource.

An important aspect of the WFI system was that the threegenerators overlapped their duties by being able to supplyeither of the two storage and distribution systems. The actualoperating scheme dedicated one still to each of the twostorage and distribution systems with the third (largest) stillas a common backup. However, recall that the user popula-tions of the two storage and distribution systems did notoverlap so the two systems could not back-up each other. Inpractice, the plant’s control system could direct the output ofthe common backup still to either of the storage and distribu-tion systems based on perceived need. However, the softwaredid not permit a rule-based allocation of WFI still output inthis way. The work-around was to permanently apportion thebackup still’s output between the two users. The results of thesingle train model provided the guidance for this selection.

The lack of modules that could be used to represent cleansteam and WFI stills (with their attendant blow down andstart-up requirements) was addressed by treating these aspoint sources with no attributes. This necessitated that theevaluation of the adequacy of the primary water treatmentsystem be carried out by manual calculation of primary waterdemand, adding the consumption of these generators.

Another manual intervention was the inclusion of thebioreactor success rate. There was no provision in the soft-ware to accommodate the rule that approximately 10% of thebatches are expected to fail over time for various reasons.However, it was a simple matter to determine the requiredsuccess rate from the number of batches that the modelpredicted could be produced in a year.

When the static resource scheduling model was debuggedand ready for use, it was used to simulate operation overincreasingly longer time periods. This permitted analysis ofthe model output to determine whether there was a gradualaccumulation of systemic errors in the model. Finally, theresource scheduling model was run for a period simulating atwo year operation, including the annual rolling shutdown.

The rolling shutdown is a feature peculiar to commercialscale cell culture plant operation schedules. A brief consider-ation of the nature of a cell culture-based biologics facilitymakes obvious why this type of shutdown is required.

Consider that the purification of a batch of crude, har-

vested product requires approximately 7.5 days. Thus, by thetime the last batch before a shutdown has been cleared frompurification (i.e., filled), the bioreactor that produced it hasbeen idle for 7.5 days. The bioreactor that produced theprevious batch has been idle for 2.5 days longer than that, etc.So by the time the last batch has been purified and filled, thefirst bioreactor to be idled has been empty for almost threeweeks. Moreover, the inoculum lab and the seed bioreactortrains have been down longer than that. Therefore, in orderto maximize productivity, the front end operations should beundergoing maintenance while the last batches of productare being purified.

This staggered shutdown has to be performed in reverseduring startup. The inoculum lab must be in operation 20days before the cell culture is grown up sufficiently to inocu-late the first seed reactor. An additional 23 days must elapsebefore the first batch of cell culture is ready for purification.This is ample time to conduct the annual maintenanceprogram on the downstream portion of the plant and returnit to readiness.

The primary complication is that the clean utility systems,which are an indispensable part of these operations, alsorequire annual maintenance. If only one generation anddistribution system of each type is available for the entirefacility, it would not be possible to perform a true rollingshutdown. At some point, the entire plant would have to beidled while the utility systems are serviced. The usual prac-tice in designing a new plant is to provide separate, dedicatedutility systems for the upstream and the downstream. In thatway, the utility systems can be maintained while the corre-sponding section of the plant is down. The caveat is that thededicated clean utility system for a given area of the facilityhas to be the last system shut down and first system returnedto service.

Returning to the timelines described above, it turned outthat the inoculum lab must be returned to service before theWFI system that supplies it can be shut down for mainte-nance. In a new plant, this is often handled by providing a

Figure 5. RO water inventory for multiple batches.




Figure 6. Plot showing the utility usage over a certain period of time.

cross-tie that allows the early restart systems such as theinoculum lab to be supplied with WFI from the downstreamWFI system which is still in operation at that point. In anoperating plant, adding that provision can prove challengingbecause of the downtime required to install, qualify, andvalidate the new cross-over piping.

The target of 14 days shut down for each system is by nomeans rigorous. Figure 3 presents the actual results from thesimulation of the rolling shutdown for this case. It will benoted that the shutdown of certain systems is actually shorterthan 14 days while for many systems the shutdown is muchlonger. This is the natural result of the interplay of the cycletimes, the sequence of operations, and the configuration ofthe plant.

Results of theScheduled Resource Static Model

The static resource scheduling model did confirm that thetarget production could be met with the plant as currentlyconfigured. However, there were a few qualifications.

• The 14 day shutdown target could not be met for somesystems. The cell culture WFI system could tolerate onlya 13 day shutdown. More importantly, the primary watertreatment system could be down for only nine days. Like-wise the allowable outage for the clean steam generatorwas only nine days. In grassroots designs, these sorts ofconflicts are addressed by adding redundancy to the gen-eration systems and cross-ties to the distribution systems.For existing plants, other remedies must be sought. In thiscase, the one day WFI system shortfall was deemed not tobe a problem. The primary water treatment system actu-ally consists of four trains. Maintenance work on thesecould be staggered so that the nine day outage, (which isrequired only for the storage and distribution portion ofthe system) could be adequate. Clean steam could besourced from a unit in an adjacent plant that has anindependent water supply and is cross-tied to the distribu-tion system serving this facility.

• The requirement for WFI in order to maintain operation ofthe inoculum prep lab during start-up while both WFIsystems are shut down can be met with bottled WFI, whichcan be obtained commercially.

• The bioreactor batch success rate would have to reach 94%instead of the target 90% rate.

Aside from those qualifications, the simulation predictedthat the facility’s resources were adequate to meet the pro-duction targets as follows:

• Overall, clean utility capacity is more than adequate.

• The instantaneous WFI demand never exceeds the totalgeneration capacity of the available stills.

• Neither the primary water surge nor the WFI water surgeever fall below the 75% “refill” level - Figures 4 and 5.

• The downstream processing capacity is not limiting pro-duction.

Since the combined clean utility capacity cannot be obtaineddirectly from the static model, the individual consumptiondata for Reverse Osmosis (RO) water, clean steam, and WFIfor a selected high demand period of time were loaded into aspreadsheet. The plot generated by this application showsthat at any point in time, the total demand of the cleanutilities does not exceed the overall generation capacity -Figure 6.

Finally, the multiple year run of the static resource sched-ule simulation confirmed that there were no subtle effectsthat would eventually prevent production of the requirednumber of batches in a given year.

The Monte Carlo Dynamic SimulationIn order to analyze the effect of the normal variability ofprocess and operating parameters on production, a MonteCarlo simulation was carried out. However, due to softwarecompatibility issues, the static process resource schedulingmodel could not be directly linked to the dynamic model.Therefore, a separate model was developed utilizing theresults from the static process model as inputs to a spread-sheet. In this way, a simplified system of six bioreactors andthree purification suites was simulated.

The variables and their selected ranges reflect the “nor-mal” variation in cycle times in the process. The variablesselected for this sensitivity analysis are production bioreactorcycle time and purification process batch cycle time.

The following specifications were selected for this study:

• A new batch is harvested from one of the six bioreactors atan average interval of 2.5 days.

• The cycle time of each bioreactor varies between 13 to 17days with the most likely cycle at 15 days.




Forecast Name 1 year’s batches 1000 batches

Forecast

Trials 1,000 1,000

Mean 0.02 0.64

Median 0.05 0.61

Standard Deviation 0.79 0.87

Skewness -0.03 -0.08

Minimum -1.87 -1.52

Maximum 1.93 2.84

Table B. Monte Carlo dynamic simulation results.

• The cycle time to complete purification of a batch wasspecified to be in the range of six to 7.5 days with the mostlikely duration at seven days. The reason for choosing 7.5days as the maximum limit for the purification cycle timewas to match the average bioreactor batch cycle time (thisalso was the basis for the static model). In fact, the detailedresults from the static model showed that much shorterpurification cycle times were possible.

Results of the Dynamic SimulationThe dynamic sensitivity analysis was carried out for twocases: production for a period simulating a one year opera-tion and production of 1000 batches. The latter, whichrepresents more than eight years of operation, was chosenarbitrarily as a time sufficiently long to expose any subtlelong term trends. The model output for the 1000 batch casehad a slightly higher negative skew than the output for theone year case - Table B. This higher negative skew is due tothe specification of the purification batch time ranging from-1 to + 0.5 day around the most likely cycle time of sevendays. This seven day period was derived from the study ofindividual downstream unit cycle times using the staticmodel. While the average cycle time and variability of theproduction cell culture was well known, at the time of thisstudy, the facility was not staffed to maintain round-the-clock operations. Consequently, the achievable purificationcycle time had not been demonstrated. Therefore, someprudent judgment had to be exercised concerning the aver-age cycle time as well as the variability for downstreamprocessing.

The result reported is the combined effect of varying thecycle times of both the production bioreactors and the batchpurification process. Due in part to the selection of an asym-metric variation in downstream cycle time, more early batches(hence, higher production rate) is indicated. This means thatover time, the production limitation tends to shift from cellculture to purification operations.

The results suggest that if labor is not a limiting factor,then the production capacity of the plant can be increasedslightly over time by the effective management of the purifi-cation suites’ cycle times.

ConclusionThis process simulation confirmed that the upgraded facilityhad the capability to achieve the customer’s production objec-tives with certain caveats. These qualifiers included suchitems as the need to provide WFI from a source outside of theplant for a short period of time after the inoculum lab isrestarted and the need to sustain a 94% cell culture successrate instead of the proposed 90%.

More generally, the need to manage the expectations of theend user with regard to the delivery of results should not beoverlooked when undertaking this type of project. It is alwaysincumbent on the modeler to educate his customer that thepreparation of a model requires significant time and effort onthe order of man-weeks at a minimum. Even if the processinput data is readily available, significant effort is required

to condition the input, construct the model, enter the data,and then debug the model.

All computer models and simulations only approximateactual operations that take place in the real world. As such,the simulation output should be regarded as guidance ratherthan quantitatively precise predictors of future results. De-pending on the sophistication of the end user, conveying thisunderstanding also may present a challenge.

All other considerations aside, process simulation can androutinely does produce very useful results. Perhaps moreimportantly it provides excellent insights into the nature ofthe manufacturing operation, including what factors limitproductivity and where the opportunities to streamline andoptimize the process lie.

References1. Lavin, D., Gopisetti, H., Doody, D., and Notwick, P., “The

Role of Process Simulation in Biologics Plant Revamps,”Interphex-PR, 17 February 2006.

2. Petrides D., Koulouris A., and Lagonikos P., “The Role ofProcess Simulation in Pharmaceutical Process Develop-ment and Product Commercialization,” PharmaceuticalEngineering, January/February 2002, Vol. 22, No. 1, pp.56-65.

3. Petrides D., Koulouris A., and Siletti C., “ThroughputAnalysis and Debottlenecking of Biomanufacturing Fa-cilities,” BioPharm 15(8), 28 (August 2002).

4. ISPE Baseline® Pharmaceutical Engineering Guide, Vol-ume 6 - Biopharmaceutical Manufacturing Facilities, In-ternational Society for Pharmaceutical Engineering (ISPE),First Edition, June 2004, www.ispe.org.

AcknowledgmentsThe authors would like to express their gratitude to thepharmaceutical manufacturing company who allowed us touse their operating information in reporting on this casestudy. The reader will note that certain data that the ownerconsidered too sensitive was omitted from this report, includ-ing the company’s name.




About the AuthorsDaniel Lavin has more than 17 years ofbiopharmaceutical process experience, whichis evenly divided between biotech operatingcompanies and engineering design firms. Inhis present position as Director, Biophar-maceutical Technology with Parsons, he de-signs cGMP processes and facilities and de-termines manufacturing strategies for many

leading pharmaceutical companies. He has used processsimulation to optimize the operations of existing facilities,and to design future facilities. In his previous positions atGenetics Institute (now Wyeth BioPharma) and Repligen, hedeveloped, scaled up, transferred, and operated clinical pro-duction processes based on cell culture and microbial processtechnology. He has been active in ISPE for 10 years, servingon the Board of Directors and as President of the ISPE BostonArea Chapter.

Himabindu Gopisetti has one year of phar-maceutical process plant design experience.In her present position as Process Engineerwith Parsons, she manages the process de-sign activities of capital projects for thedivision’s pharmaceutical clients. Her previ-ous position has been with a paper manufac-turing facility. She holds a Masters degree in

chemical engineering from Tennessee Technological Univer-sity and a Bachelors degree in chemical engineering fromAndhra University, India.

Peter Notwick has more than 20 years ofpharmaceutical process plant design experi-ence in a capital project career that spansmore than 35 years. In his present position asDirector, Process Engineering with Parsons,he manages the technology transfer and pro-cess design activities of capital projects forthe division’s pharmaceutical clients. His

previous positions have been with a variety of manufactur-ing, as well as engineering and construction companies. Heholds degrees in chemical engineering from Villanova Uni-versity and the New Jersey Institute of Technology. He is alicensed professional engineer in PA and NJ.

Parsons Corporation, 1880 JFK Blvd., Philadelphia, PA.,19103.


Robotic Processing


This case studypresents a LifeCycle Cost(LCC) analysisapplied to anexample of aroller bottle cellculture processthat suggestshow the processcan be furtheroptimizedthrough achange in theprocessprotocol.

Robotic Processing in Barrier–IsolatorEnvironments: A Life Cycle CostApproach

by R.L. Dutton and J.S. Fox

Figure 1. Acquisitioncost for capitalequipment commonlyrepresents only a smallfraction of its total lifecycle cost. (Source: U.K.Office of GovernmentCommerce)

Introduction

Since their introduction more than adecade ago, barrier-isolator systemshave improved environmental controlin aseptic and potent compound manu-

facturing. Barrier-isolator designs have im-proved over the years, and systems have beenintegrated into production lines in ways thatwould previously have been unimaginable.

The rapid adoption of barrier-isolators con-taining automation for continuous processessuch as fill-finish is well documented.1 Themarket for the technology in the potent com-pound environment is growing as well.

About 25% of all drugs currently under de-velopment are considered highly potent, i.e.,those classified within Occupational ExposureBands (OEBs) of three or more, compared to 5%to 10% of potent drugs currently on the market.This growth in hazardous liquids and solids

will inevitably lead to greater use of barrier-isolators, and probably of automation withinthese mini-environments. It has been estimatedthat potent compound production is alreadyresponsible for up to 20 times the number ofisolators used in fill finish operations.

Barrier-Isolators and cGMPThe advantage of mini-environments in phar-maceutical production is obvious. Not only dothey minimize operator exposure but, whenproperly used, they minimize cross-contamina-tion, aid in risk assessment, and lend them-selves to redundant systems to avoid cata-strophic events. In the case of potent com-pounds, it has been shown that a full isolatorrepresents Personal Protective Equipment(PPE) that can be up to 10,000 times moreeffective than a fume hood, or 1000 times moreeffective than an air line full face pressure

system.2

Recent FDA guidelines,and a 2002 FDA conceptpaper also support the ad-vantages of isolators rela-tive to conventional manualprocesses during asepticproduction. The FDA andother regulatory agenciesappear to be most comfort-able with hard wall con-struction, positive pressure,high transfer integrity,chemically disinfected de-signs; especially when com-bined with good ergonom-ics and a well planned andstrictly enforced operatortraining program.3

Reprinted from





Robotic Processing


According to the FDA:

“Aseptic processing using isolation systems separatesthe external cleanroom environment from the asepticprocessing line and minimizes its exposure to personnel.A well-designed positive pressure isolator, supported byadequate procedures for its maintenance, monitoring,and control, offers tangible advantages over traditionalaseptic processing, including fewer opportunities formicrobial contamination during processing.”4

All of this suggests that barrier-isolator use will continue toincrease, and may even accelerate in the long term. Further,discrete robotic applications which minimize interactionthrough gloveports, may well represent the next significantadvance in the technology. We note, in this regard, thecurrent availability of washdown-compatible robotics andeven robots compatible with automated vaporous hydrogenperoxide decontamination.

Although barrier-isolators make sense in terms of processcontamination and operator safety, it has always been as-sumed that it inevitably makes economic sense. But are theya panacea for all aseptic (or, for that matter potent compound)processes?

Given the anticipated “boom” in barrier-isolator use, andparticularly the probable appearance of many new discreteautomation applications within isolation, it seems appropri-ate to re-examine the economic assumptions relating to the

technology. In the following, one sample application is pre-sented, roller bottle cell culture, while introducing a rigorousnew financial tool – a life cycle cost model designed specifi-cally for aseptic pharmaceuticals.

Introduction to Life Cycle CostDefinition and ObjectivesLife Cycle Costing (LCC) is a financial model that is com-monly used to capture all of the elements of cost to produce aproduct over its total anticipated lifespan. In this article, weintroduce LCC as a predictor of total cost over the service lifeof the capital equipment and building assets used to producesingle or multiple products in the aseptic pharmaceuticalenvironment.

In manufacturing, LCC is widely used as a decision sup-port tool where management faces a choice of procurementand/or process layout options. The accuracy of LCC analysisdiminishes as it projects further into the future so it is mostvaluable as a comparative tool when long term assumptionsapply to all the options and consequently have the sameimpact.5

In summary, LCC is the discounted dollar cost of acquir-ing, operating, maintaining, and disposing of a piece ofcapital over a period of time. It can be defined as follows:

Life Cycle Cost = Acquisition costs + other capital costsassociated with acquisition + recurring and non-recurringoperating costs + direct and indirect support costs + disposalcosts; where

• Acquisition costs = Product price = Product costs + selling,general and administrative + warranty costs + profit;where- product is the capital item- Product costs = Recurring production costs + non-

recurring production costs allocated to the product

• Recurring operating cost = production labor + direct mate-rials + process costs + overhead + outside processing

• Non-recurring operating costs = development costs + tool-ing

Value of LCC AnalysisThe up-front or visible cost of most capital purchases in mostmanufacturing environments represent only a small fractionof overall life cycle costs. Its total cost is incurred throughoutthe life of an asset. Operating cost usually represents thelargest cost element, but end-of-life costs also can be signifi-cant.

Purchase price may represent 15% to 25% or less in thearea of production automation.6 Yet the purchasing decisionnormally commits the user to much greater costs with verylittle scope to change these once the capital has been ex-pended.

Given that in many pharmaceutical companies the capitalpurchase and operating funding come from different sources,there has been little incentive to use detailed LCC models for

Figure 2. Typical aseptic roller bottle process flow for vaccineproduction, as well as typical roller bottle throughput rates perbatch for pilot and production scales. Cell Expansion and ViralAmplification are incubation steps which represent significant waittimes between manipulations during the process.


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purchasing decisions. Nevertheless, the values of its use aremany, including:

• evaluation of competing options in purchasing- Options with the same purchase cost can have radically

different life cycle costs.- Options with high purchase cost can result in signifi-

cant savings on a total acquisition and operating costbasis, and vice versa.

• improved awareness of the total costs associated withcapital expenditures- Using LCC, management can deconstruct and evaluate

the elements of the factors contributing to a capitalpurchase, and hence, make better decisions.

- Principle cost drivers can be identified, and these canbecome the drivers relating to purchase and produc-tion.

• modeling performance trade-off against life cycle cost- LCC allows purchase costs to be weighed against all

production costs and efficiencies, i.e., it allows financial“what if” analysis, including sensitivity analysis over awide variety of production parameters.

Therefore, LCC is an important risk mitigation tool which isvery much in the spirit of the FDA’s thrust toward “Risk-based GMPs.” This is particularly the case when integratedwith other models, such as process simulation.

LCC in IndustryLCC modeling has a history of use in construction, particu-larly as a tool for selecting the best investment options – newconstruction or retrofit. It also has been used in planning forreliability and maintenance for other complex engineeringsystems in defense, railway, aerospace, and other applica-tions.

Whereas the focus in most cases has been on infrastruc-ture, mature manufacturing industries also have begun toapply LCC to capital equipment. One example is automotive,where lean manufacturing processes include the balanceduse of people, equipment, and material yielding the lowestlife cycle cost. Lean equipment design is very much a part ofthis, causing suppliers to the industry to focus on LCC issuesin upgrading their products to the extent of identifyingguidelines for equipment design and providing a lean equip-ment checklist.7

LCC also has been used in semiconductor manufacturingto compare the cost of competing equipment technologies,without bias. One industry association sanctions a particularLCC model and has concluded that LCC analysis provides avaluable way to identify cost reductions, and has identifiedmajor cost elements of one particular generic wafer produc-tion process.8

LCC in PharmaceuticalsLCC modeling is not new to the pharmaceutical industry.Traditionally, it has been used to determine economic riskrelated to infrastructure and facilities. Anecdotal evidencesuggests that its use is growing for process equipment, butnot necessarily for equipment in the aseptic environment.Models that we have seen are simple, capturing only acquisi-tion costs (sometimes including cost of validation) and asmall number of operating cost variables such as labor,utilities, and maintenance.

There is one pioneering effort to quantify the life cycle costissues relating to barrier isolator fill-finish suites in relationto costs of the cleanrooms they supplant.9 Porter clearlydemonstrates the viability of the isolator barrier option onthe basis of life cycle costing quantitatively with relation tofacility vs. equipment size, cost, and energy consumption,and qualitatively on the basis of labor, and utilization levels.There also is another model focusing on potent compoundapplications.2

The following shows how we have built on Porter’s effort byadding additional detail through acquisition, operating, andresidual value-related parameters such as:

• environmental monitoring costs

• labor costs

• maintenance costs

• throughput

• system Overall Equipment Efficiency (OEE)

• cleaning and consumables

• QA/validation costs

Case StudyDeveloping a life cycle cost analysis for an aseptic pharma-ceutical unit operation begins with understanding the pro-cess. Here, a detailed LCC model was developed for asepticprocessing using an example taken from the upstream por-tion of a biopharmaceutical process. In a bioprocess, theculture step(s) that result in the bioproduction of the productare known as the “at stream” steps of the process. Here, thespecific focus is on the “at stream” steps involved in theproduction of virus on animal cells in roller bottles.

A question immediately comes to mind – why roller bottles?Bioreactor technology is well developed with designs thataddress many diverse culture requirements. Nevertheless,roller bottles and T-flasks continue to find commercial appli-cation in animal cell and viral culture.

The decision to employ roller bottles at the commercialscale may be process or biology based. For example:


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• Roller bottles can be the culture vessel of choice for certainanchorage dependent, fastidious, or fragile animal cells,such as primary cells that are difficult to grow in therelatively harsh environment of a bioreactor.

• A product that can be manufactured from a small batchsize may not warrant use of a bioreactor or the develop-ment of bioreactor protocols, such as the production ofviruses on animal cells or many of the emerging cell andgene therapy products.

• In some cases, the use of micro-carriers for the growth ofanchorage dependent animal cells in a bioreactor mayprove problematic in either the culture portion of theprocess or in the downstream steps of the process.

There may be regulatory considerations involved in the use ofroller bottles at the production scale. Production in rollerbottles may have been established through their use inprocessing small volumes of pre-clinical and clinical mate-rial. Culture conditions may have been optimized in the rollerbottle environment. Moving production from a roller bottle toa bioreactor is a major change in technology, and hence, in theprocess with attendant regulatory hurdles. In contrast, scale-up by an increase in the number of roller bottles is notconsidered to be a (major) process change. The investmentrequired in implementing a major change to the process maynot be warranted.

The At Stream Roller Bottle ProcessA typical production of a virus on animal cells in roller bottlesis depicted in Figure 2. The culture steps include inoculatingthe animal cell population into the roller bottles; allowing the

cell population to grow (incubation); infecting the cell popu-lation with the virus; allowing the virus to amplify (grow) inthe cells (incubation); and harvesting the product from theroller bottles. Inoculating, infecting, and harvesting proce-dures are active manipulations of the roller bottles.

When the roller bottle is the culture vessel, scale-up of theprocess is achieved by increasing the number of roller bottles.For example, a pilot scale process may use 150 roller bottles,while the production (commercial) scale may require 1500roller bottles per lot. The number of days required for cellpopulation expansion or for viral amplification may vary withthe type of cell or virus or with the culture conditions. Thelengthy incubation periods represent processing wait timeduring which there are no active manipulations of the rollerbottles. Hence, this process negatively impacts overall equip-ment efficiency.

At Stream Roller Bottle Scale-Up AlternativesAssessing the pros and cons of the scale-up alternatives canbe a challenge. Typically, roller bottles are manipulatedmanually (i.e., inoculated, infected, harvested, etc.). A tech-nical team is composed of a supervisor, one or two roller bottlehandlers (technologists), an assistant, and an environmentalmonitor. In a typical process, a skilled technologist canhandle 150 to 250 roller bottles per shift. As the scaleincreases, costly skilled technical labor becomes significant.

Unlike the closed system of the bioreactor, the rollerbottles must be opened during each processing manipulation.When this is performed manually in a biohood, it is an openaseptic process, necessitating a Class A/B (Class 100 in Class10000) environment. A Class B cleanroom is costly to con-struct, maintain, and monitor. Class B gowning is both costlyand ergonomically unfavorable. As the scale increases, thecost of the facility increases.

Alternatives incorporate isolator technology, which inher-ently increases the quality by increasing the assurance ofmaintaining asepsis. A glovebox can be used in place of theopen biohoods, but the ergonomics of manipulating rollerbottles within a glovebox are even more unfavorable: thedexterity necessary to open and close roller bottle caps, addsmall volumes (e.g., 1 mL or less) to each roller bottle, swirlroller bottles, scrape cell layer of roller bottles, etc., is im-peded by the bulky gloves and limited freedom of movement.Manipulation of the roller bottles can be automated andperformed within an isolator. However, isolators and roboticscarry a high capital cost. Also, a switch from manual toautomated roller bottle handling may not be considered to bea minor change to the process.

The Economic Analysis –Equipment Capital Costs

In this case study, the manual process in biohood is comparedwith the use of a glovebox and with the automated processusing a roller bottle handling robotic arm in isolator over anassumed system life of 10 years. The assumed system life,which is relatively short, reflects the likelihood of process andequipment improvements over time. Cellmate™ is a typical

Figure 3. Typical automated roller bottle system for scaled-upproduction. The robotic arm is capable of handling approximately1500 roller bottles per batch, based on a single shift per day.


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automated roller bottle handling system that is manufac-tured by The Automation Partnership.10 This roller bottlehandling system incorporates a conveyor belt to move rollerbottles to and from a robotic arm. The robotic arm moves theroller bottles to various stations within the isolator wheremanipulations occur. Manipulations include capping anddecapping, inoculation, infection, medium addition, and re-moval, etc.

At the pilot scale (e.g., 150 roller bottles), the capital costsof equipment increase significantly from manual processingin an open biohood, through the glovebox option, to auto-mated processing in an isolator (Table A, Line 1). The purelyeconomic choice would seem to be obvious: compared withmanual processing in an open biohood, the equipment for theglovebox option is more than six times more costly, while therobotics in isolator choice is more than 20 times more costly.

In a typical virus production process, a single robotic armcan handle on the order of up to 1500 roller bottles per batch.So as the process is scaled 10-fold from pilot to commercialproduction, no increase in the number of automated systemsis required. In contrast, even with increasing the number ofshifts per day, the number of biohoods or gloveboxes must beincreased from one to three. Even so, on a basis purely ofequipment costs, at production scale the glovebox and auto-mation in barrier system options are seven to eight timesmore costly than the manual processing in open biohoodschoice - Table A, Line 10.

Expanding the Economic Analysis –Facility CostsThe capital cost of the processing equipment is far from thewhole LCC story. When the facility costs for the differentoptions are considered, a different story emerges. The ClassA/B aseptic processing environment requires a complicatedand costly facility. Regulatory requirements for single classi-fication step ups and step downs, and for separation ofpersonnel and material flows, translate into multiple roomsand airlocks. Gowning requirements add further complexityand cost.

As depicted in Figure 4, the two isolator options requireonly a Class D background environment, which can be accom-modated within a simple facility design that is much cheaperto maintain. At the production scale, the automation inisolator option requires only about half the square footage ofthe manual processing in open biohoods option.

Facility capital costs include both infrastructure and utili-ties capital costs. The utilities requirement to maintain thecleanroom environment is very costly, typically runninghigher than the infrastructure costs. For the manual process-ing in open biohoods option, the pilot scale facility for thisexample will run around $3.2 million (Table A, Lines 3 and 4);while the production scale facility will cost around $7 million(Table A, Lines 12 and 13). By comparison, the smaller,simpler, and lower cleanroom classification facility for theisolator options will cost only on the order of $1.5 million at

Figure 4: Comparative Infrastructures for a Class A/B aseptic processing environment for manual operations and a Class D environmentsuitable for an (automated) isolated roller bottle production system. MAL=material air lock; PAL=personnel air lock; CAL=combined airlock; U=unclassified.


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Pilot Scale (150 roller bottles per lot)

Line Item Manual Glovebox Automation in Barrier

1 Equipment Capital Cost $ 71,200 $ 446,200 $ 1,446,000

2 Total Acquisition Cost $ 117,880 $ 671,200 $ 1,804,707

3 Infrastructure Capital Cost $ 1,600,600 $ 698,450 $ 698,450

4 Utilities Capital Cost $ 1,811,103 $ 711,433 $ 718,417

5 Validation Cost $ 416,000 $ 224,000 $ 348,000

6 Environmental Control and Monitoring Annual Cost $ 1,800,000 $ 720,000 $ 720,000

7 Labor Annual Cost $ 181,440 $ 192,240 $ 168,734

8 System OEE1 10 % 15 % 3 %

9 LIFE CYCLE COST $ 26,188,107 $ 14,768,369 $ 14,993,859

Production Scale (1500 roller bottles per lot)

Line Item Manual Glovebox Automation in Barrier

10 Equipment Capital Cost $ 252,000 $ 1,777,800 $ 1,976,200

11 Total Acquisition Cost $ 353,640 $ 2,013,600 $ 2,378,100

12 Infrastructure Capital Cost $ 3,166,550 $ 1,450,300 $ 1,091,750

13 Utilities Capital Cost $ 3,730,654 $ 1,446,897 $ 1,130,228

14 Validation Cost $ 803,000 $ 525,000 $ 489,098

15 Environmental Control and Monitoring Annual Cost $ 2,140,000 $ 900,000 $ 800,000

16 Labor Annual Cost $ 547,200 $ 551,520 $ 231,830

17 System OEE1 48 % 51 % 19 %

18 LIFE CYCLE COST $ 58,468,644 $ 41,905,967 $ 26,149,4331 OEE = Overall Equipment Efficiency

Table A. Major LCC output data for a roller bottle at stream process. The economic impact of three different options for handling rollerbottles at the pilot and production scale over a system life of 10 years is presented.

the pilot scale and $2 to $3 million at the production scale,depending on whether or not the process is automated.

When facility costs are added to equipment costs, there ismuch less difference between the three choices. However, withthe additional consideration of ongoing environmental controland monitoring costs, the economic scales are tipped in favorof isolation at both the pilot and production scale for this rollerbottle animal cell and viral based example - Table A, Lines 6and 15. At the pilot scale, manual processing in gloveboxes isthe cheaper option compared with automation in isolators; butat production scale, the costs for equipment plus facilityinfrastructure and ongoing environmental maintenance aremore favorable for the automation in isolator option. Whencoupled with the ergonomic and quality benefits, the automa-tion in barrier option is clearly the best choice at the productionscale, and also may be at the pilot scale.

The choice at production scale can influence the choice atpilot scale. A change of equipment or a change to the processmay result in interruptions to material supply, costly valida-tions, and perhaps a requirement for bridging clinical trials.These are further cost considerations that have not beenevaluated here.

Expanding the Economic Analysis – ValidationCostsThe requirement for product quality is arguably more strin-

gent in pharmaceuticals than in any other industry. Theregulatory requirement for Quality Assurance (QA) in thepharmaceutical processing line takes the form of Validation(IQ OQ, PQ) of equipment and facility. Validation can run ashigh as 15 to 20% of the acquisition costs, and can take a yearor more to complete for a novel system. The relative validationcosts associated with the roller bottle processing alternativesare composite of both elements – equipment plus facility. Therelatively simple equipment needed for manual processingrequires minimal validation, while on the other hand, thecomplex automation in isolator option is a significant valida-tion challenge. In contrast, the facility associated with theisolator options carries a relatively low validation cost, whilethe facility needed for manual aseptic processing carries amajor validation cost. Combined, the validation costs forequipment plus facility is approximately the same for all threeoptions at the pilot scale - Table A, Line 5. However, at theproduction scale, validation associated with the manual asep-tic process is significantly more costly than that associatedwith the two isolator options, primarily resulting from thecomplex manual processing facility - Table A, Line 14.

Expanding the Economic Analysis – Labor CostsThere is no difference in labor costs between the options at thepilot scale as the minimum number of operators and techni-cians is required for all options - Table A, Line 7. At the


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production scale, the economic advantages of automationwith respect to labor costs are clearly seen. Even with consid-ering assumed economies of scale, the manual options (bothglovebox and open biohood) carry a labor cost that is morethan twice that of the automated option (Table A, line 16),which is approximately the same as the cost at the pilot scale.

Apart from these direct costs, what other labor-relatedimpacts do the options have? The impact of the options isimmediately obvious from the appearance of the associatedgowning requirements. However, apart from the costs of thegowns themselves, the costs associated with the differentgowning requirements for Class B versus Class D are noteasy to quantify. They include time and space for gowningand de-gowning; ease of movement within the gowns – and,hence, time requirements for carrying out manipulationsand potential for human errors; allowable work periods andbreak requirements; intangible costs associated with gen-eral comfort level. These qualitative and intangible consid-erations can be assessed in a LCC model through assigningquasi-quantitative values that can be optimized over timethrough trending and experience. For example, qualitativeor intangible considerations can be included in the LCCmodel by using a numerical ranking scale (e.g., 1-10), whichis linked to quantitative inputs such as Out-Of-Spec (OOS)percentages or to Overall Equipment Efficiency (OEE).Primarily resulting from the savings in expensive highlyskilled labor, in this example, automation in isolation isclearly the cheapest choice. When coupled with ergonomicand quality considerations, automation within isolators isthe clear choice.

Expanding the Economic Analysis – AdditionalConsiderationsOverall Equipment Efficiency (OEE) is the measure of theportion of time that the manufacturing equipment is actuallyprocessing material. OEE is equal to the equipment actualavailability times performance times yield. Planned down-time is excluded from the measure of theoretical availability(also known as planned production time). Actual availabilityis impacted by such things as machine failure, small stops,start-up/warm-up, speed losses, set up and adjustments, andshut-down procedures. Change over between batches andbetween products can have a major impact on availability.Performance is measured as the cycle time (procedure timeper unit) times the number of units processed, all divided bythe planned production time. Yield is the number of unitsprocessed minus the number of units rejected, all divided bythe number of units processed.

The pharmaceutical industry generally operates with lowOEE. A typical pharmaceutical plant will operate somewherearound 30% efficiency.11 Average overall equipment effec-tiveness is only 28% at the most inefficient companies, whilethe pharmaceutical industry-wide average OEE is less than50%.12 The industry’s lowest OEEs are often found inbiopharmaceutical processing facilities. There is room forsignificant improvement of OEE in the pharmaceutical in-dustry.

In this case study, the poor system overall equipmentefficiency for all three options at both pilot and productionscale (Table A, Lines 8 and 17) is reflective of the significantprocess wait time in this example. This suggests that a sub-batch protocol, which represents the opportunity to capitalizeon underutilized processing equipment, should be investi-gated. So, it can be seen that a robust LCC analysis can adddecision making value in yet another way – it can provideprocess optimization indicators. In this case, the LCC analy-sis suggests that the process can be further optimized througha change in the process protocol. While potentially improvingthe efficiency of all three of the processing choices, it isapparent that a sub-batch protocol could utilize the auto-mated system far more efficiently – increasing the potentialoutput and further decreasing the total life cycle cost.

Some other inputs that should be considered in a LCCinclude maintenance costs, cleaning and consumables, andchangeover and line clearance. These inputs are not signifi-cant in this example.

LCC: The Complete Economic Analysis –Putting it all Together

In spite of the high total acquisition cost (Table A, lines 2 and11) and low OEE, the automation in barrier choice returns aLCC that is around half of that for the manual choice - TableA, Lines 9 and 18. This robust analysis reveals that thecomplex facility and attendant utilities costs, coupled withthe ongoing high operating costs contribute to a surprisinglyhigh LCC for the manual choice. The low OEE associatedwith the robotic arm in isolator system is indicative of anopportunity to optimize the process and even further lowerthe LCC.

ConclusionLCC modeling can prove to be a valuable managerial decisionsupport tool in sterile operations, particularly given theimpending trend to increase automation. A rigorous anddetailed LCC analysis can lead to counter-intuitive results,particularly when equipment acquisition and life cycle costswere compared. Specifically, at the pilot scale, the gloveboxwas the best economic choice, but that automation couldbecome the desired economic choice if a higher value wasplaced on ergonomics.

Using a detailed LCC model, it was possible to demon-strate conclusively that an automated isolated solution wasclearly the best choice at the production scale. Roboticswithin an isolator provided the best balance of overall cost,ergonomics, and product quality. A different choice mighthave been made if purchase price or purchase price andfacilities costs alone had been considered.

In conclusion, life cycle cost modeling with LCC toolsdesigned specifically for the pharmaceutical environmentwill become essential managerial decision support tools,particularly as discrete automation and the isolator-barrierfield evolves. Indeed, by forcing the user to examine allaspects of the process from both financial and operatingefficiencies, modeling of this type can be an important aspect


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in the implementation of “risk based” GMPs. The value ofLCC can be enhanced when used in conjunction with othermodeling tools such as dynamic simulation when the latter isused to optimize process flows.

References1. Lysfjord, J. and Porter, M., “Barrier Isolation History and

Trends,” Pharmaceutical Engineering, Vol. 23, No. 2,2003, pp. 1-6.

2. Wilkins, J., “Containment,” Presentation given to theISPE Central Canada Chapter, 18 April 2005.

3. FDA, Guidance for Industry: “Sterile Drug Products Pro-duced by Aseptic Processing - Current Good Manufactur-ing Practice.” (Appendix 1), Sept 2004.

4. FDA, Guidance for Industry: “Sterile Drug Products Pro-duced by Aseptic Processing - Current Good Manufactur-ing Practice,” Draft Guidance 2003.

5. U.K. Office of Government Commerce: “2003 Life CycleCosting,” Internet publication. 2003.

6. Hayes, T., Fox, J., and Woloshyn, “Dynamic Simulation ofMaterial Flows in Pharmaceutical Planning and Opera-tions,” ISPE Presentation, Tampa, 11 February 2005.

7. Brown, A., “Delphi Lean Engineering Initiatives,” Auto-motive Manufacturing and Production, May 2000.

8. Muzio, E., “Optical Lithography Cost of Ownership (COO)– Final Report for LITG501,” International SEMATECHreport, 2000.

9. Porter, M., “Cost Issues for Barrier Isolators,” ISPEBarrier Isolator Conference, Zurich, 1995.

10. TAP, The Automation Partnership. Cellmate system over-view http://www.automationpartnership.com/tap/cell_culture/cellmate_sysover.htm.

11. Reitter, B., “A View to Performance Management forBetter Visibility Can Yield Improved Operations,” Phar-maceutical Processing, Internet publication March 2006.

12. Hirche, C., “Driving Down the Cost of PharmaceuticalProduction,” Trend Report No. 7: Pharmaceutical Tech-nology, ACHEMA, Frankfurt, 2006.

AcknowledgementsThe authors would like to acknowledge the valuable insightprovided by Rudy Dietrich and Xuefeng Yu of Sanofi-PasteurLtd., by Thomas Hayes of ATS Automation Tooling SystemsInc., and by James Spolyar of SKAN AG.

About the AuthorsDr. Roshni Dutton obtained a Bachelorsdegree in biology from the University ofManitoba, followed by BASc, MASc, and PhDin chemical engineering from the Universityof Waterloo with a focus on cell culture tech-nology. Over the past 15 years, Dr. Duttonhas applied her formal education in thebiopharmaceutical process development field,

most recently functioning as the Director of Cell and ViralProcess Development with Aventis Pasteur (now Sanofi-Pasteur). Dr. Dutton has collaborated on numerous investi-gations, presentations, and publications in thebiopharmaceutical field. Currently, she is consulting in theindustry, focusing on processing technologies. She is anactive member of ISPE’s Central Canada Chapter.

8 Maple Leaf Ln., Aberfoyle, Ontario N1H 6H9 Canada.

Dr. Joseph Fox obtained his first degreesfrom McGill University, and his PhD fromCambridge University, England. He has beeninvolved in industrial automation for the last15 years, focusing on pharmaceutical pro-cesses over the past six. He has presentedwith collaborators on dynamic simulationand process improvement in pharmaceuti-

cals and on the future of automation in the industry. Dr. Foxcurrently operates an industrial marketing company, focus-ing on the medical sector. He is an active member of ISPE’sCentral Canada Chapter.

82 Forest Lane Dr., Thornhill, Ontario L4J 3N8 Canada.


Industry Interview


Dr. Gomezdiscusses thegoal of theVaccineResearch Center(VRC),significantchanges in thedevelopment ofvaccines toimprove globalhuman health,and possiblenewtechnologiesthat couldchallenge thedrugmanufacturingindustry.

PHARMACEUTICAL ENGINEERING InterviewsPhillip L. Gomez, PhD, MBA,Director of Vaccine Production,Dale and Betty Bumpers VaccineResearch Center, National Institute ofAllergy and Infectious Diseases

Phillip L. GomezIII is the Directorof Vaccine Pro-duct i on a t theDale and BettyBumpers VaccineResearch Center(VRC), part of theNat iona l Ins t i -tu te o f A l l e rgyand In fec t i ousDiseases (NIAID).

The NIAID is a component of the NationalInstitutes of Health (NIH). At the VRC, Gomezis head of the Center’s Vaccine ProductionProgram. Gomez came to the Center fromBaxter Healthcare Corporation, where he wassenior director of process development in thevaccine business unit and project leader dur-ing the launch of the NeisVac-C™ vaccine inthe United Kingdom. He was a project man-ager and director of product development atAventis Pasteur. At Abbott Laboratories,Gomez held several positions in bioprocessdevelopment, including senior research scien-tist and team leader. He earned his Master’sand Doctorate degrees, both in chemical engi-neering, from Lehigh University. He receivedan MBA from the Smith School of Business atthe University of Maryland and a Bachelor’sdegree in engineering science from DartmouthCollege.

Q How long have you been in your currentposition?

A I joined the Vaccine Research Center in2001 as the first employee in the Vaccine

Production Program.

Q What past experience best prepared youfor your career with the VRC, and in

particular, your current position as Director ofVaccine Production?

A I spent my previous time as Director ofProcess Development at Baxter

Healthcare working on NeisVac-CTM scale-upand commercial launch (I was also corporateTeam Leader for the commercial launch), Di-rector of PD at Aventis (now Sanofi) Pasteur,and I started my career at Abbott Laboratoriesin BioProcess Development.

Q What do you like to do in your spare time,away from the office?

A My three year old daughter Zoë providesample activities for all of my spare time

as well as some of my non-spare time.

Q Could you give us some background onthe VRC? How, why, and when was the

VRC founded?

A Established in 1997 by former PresidentBill Clinton, the VRC is dedicated to

improving global human health through therigorous pursuit of effective vaccines for humandiseases. The primary focus of VRC research isthe development of a vaccine for HIV/AIDS.

The VRC building was completed in 2000 inBethesda, Maryland, and Dr. Gary Nabel was

Reprinted from





Industry Interview


How long would it take before an effec-tive vaccine is produced?

A The VRC is doing research on thedevelopment of influenza vac-

cines and is currently manufacturing acandidate vaccine against a strain ofavian flu. This vaccine will enter USPhase I clinical testing later this year.The VRC is examining ways to make amore broadly protective “universal in-fluenza” vaccine, but this will takemany years to develop.

Q Tell us about the Vaccine PilotPlant. What cutting edge tech-

nologies, processes are designed intothe manufacturing process?

A Central to the mission of the VRCis the ability to rapidly transi-

tion from basic research to clinical tri-als. Our new cGMP pilot plant is de-signed to help carry out this mission.Given the broad scope and mission ofthe VRC, the pilot plant was designedto manufacture a wide variety of vac-cines. Currently, VRC candidate vac-cines are based on genetic immuniza-tion strategies that utilize naked DNA(prokaryotic fermentation) and vari-ous viral vectors (eukaryotic cell cul-ture). However, it was critical that thepilot plant was designed with suffi-cient flexibility to allow for the produc-tion of the widest technology base pos-sible. The challenge of the design wasto incorporate the maximum flexibilityfor a multi-product facility operatingunder the most stringent complianceenvironment. For diseases such asAIDS, for which the economic incen-tives may not be sufficient for industryto invest the resources necessary foradvanced product development, thepilot plant was designed to allow forclinical production up to Phase III effi-cacy trials. Then, the technology istransferred to an organization thatwould seek licensure and distributionof the vaccine.

As a matter of fact, ISPE Baseline®

Guides were used as a reference duringthe design of the pilot plant. In particu-lar, the validation department usedthe ISPE Water and Steam SystemsBaseline® Guide, Volume 4, and theISPE Commissioning and Qualifica-

appointed as Director of the VRC in1999. After September 11, 2001, theVRC expanded its role to include thedevelopment of vaccines againstbioterrorism and emerging infectiousdiseases, while maintaining its pri-mary focus on HIV/AIDS. Initiallyspearheaded by the NIAID, the Na-tional Cancer Institute, and the NIHOffice of AIDS Research, the VRC isnow an intramural division of NIAID.The VRC is named after Dale andBetty Bumpers, two long-time leadersin the causes of childhood vaccinationand vaccine research. A former Gover-nor of Arkansas and a US Senator,Dale Bumpers was the acknowledgedleader on immunization issuesthroughout his 24-year career in Con-gress and was an advocate of funds tofight HIV/AIDS. Betty Bumpers isknown for her joint efforts withRosalynn Carter to improve the USimmunization program. Their effortsled to the first US comprehensive child-hood immunization initiative, whichled to laws, now in every state, requir-ing certain vaccinations before entryinto school.

Q What are your key priorities andresponsibilities?

A My key priority is the Center’sVaccine Production Program,

which is responsible for the manufac-ture, pre-clinical safety testing, and

regulatory submission of VRC vaccinesfor clinical trials. The VPP developsprocesses and releases tests that pro-vide material for up to Phase III clini-cal trials, with particular emphasis ontechniques suitable for eventual large-scale manufacture of vaccines. Themanufacture of candidate vaccines isoutsourced to the biopharmaceuticalindustry, or takes place in-house in theVRC’s new cGMP pilot plant.

Q How does your Agency interactwith pharmaceutical and biotech-

nology firms?

A The goal of the VRC is to facili-tate vaccine development by

working with industry during productdevelopment. We have collaborationswith large organizations such as Merckand Novartis as well as biotechnologycompanies such as Crucell, GenVec,and Vical.

The VRC’s mission is to facilitatecandidate vaccines that have tremen-dous technical challenges, and/or arenot being developed by pharmaceuti-cal companies (like an HIV vaccine),and “push” them down the productdevelopment pipeline until they can bepicked up by industry collaborators forultimate licensure and distribution.

Q Are you working with otherregulatory agencies outside the

US? Is there a collaborative processbetween EMEA and the FDA for ex-ample?

A NIAID/NIH has a tremendousnumber of programs (visit http:/

/www.vrc.nih.gov/VRC/ for more infor-mation.) In the regulatory group at theVRC, we routinely interact with theFDA and international regulatoryagencies, especially in the developingworld, regarding vaccine developmentissues. The VRC has been involved inrecent meetings on vaccine cell sub-strate regulatory issues as well as thepotency evaluation of candidate HIVvaccines.

Q In addition to candidate vaccinesfor HIV, Ebola, SARS, and the

West Nile Virus, is the VPP planningfor a potential Avian Flu pandemic?

Inside the VaccineResearch Center

The Center’s organization is simi-lar to a conventional pharmaceu-tical industry drug developmentoperation with laboratories en-gaged in basic discovery research,pre-clinical and clinical materialsproduction, pre-clinical safety andefficacy testing, clinical research,and immunologic assessment ofvaccine responses. VRC prod-ucts have included candidate vac-cines for AIDS, Ebola, SevereAcute Respiratory Syndrome(SARS), West Nile virus, andsmallpox.


Industry Interview


Vaccine Pilot Plant Facts and Figures• Location: Frederick, Maryland• Size: 126,900 square-feet• Operated by Scientific Applications International Corporation – Frederick,

Inc. (SAIC-F) as part of the National Cancer Institute Federally FundedResearch and Development Center in Frederick, Maryland

• Contains four independent production trains, with two trains operating at100 Liter scale, one train operating at 400 Liter scale, and one trainoperating at 2,000 Liter scale

• Contains a central inoculum preparation suite• Contains a media/buffer preparation suite which provides for internal

manufacture of all solutions for the operation• Fill suite is easily accessible from the production trains and have the

capability of performing smaller scale lots up to 5,000 units and larger scalework up to 30,000 units

• Warehouse is sized to handle raw materials and supplies sufficient tomaintain all four production trains operating simultaneously with coordina-tion and control through the adjacent dispensary

• Quality control laboratories are designed to provide all necessary testingactivities including raw materials, environmental monitoring, bioburden,water for injection and pure steam analysis, bulk and final product sterility,and in-process and final product release

• A quality assurance department is responsible for oversight of cGMPmanufacture including validation, compliance, lot release, and documentcontrol

tion Baseline® Guide, Volume 5, as areference for developing and commis-sioning the I/OQ documents.

QWhat significant changes do youanticipate in the next few years?

AThere are many new technologiesthat are attempting to impact the

manufacture, aseptic filling, and dis-tribution of influenza vaccine. Mul-tiple cell-based methodologies for pro-ducing influenza vaccines are underdevelopment which will try to displacethe current egg-based methods. Evenwith the success of these technologies,the ability to manufacture hundreds ofmillions of doses of influenza vaccinewill greatly challenge the engineeringsystems used for aseptic filling, cold-chain, and product distribution chan-nels.

Q What technological and opera-tional breakthroughs do you an-

ticipate within the next five years?

A In the next five years a new groupof technologies for vaccines will

be evaluated to see if they will become

the next generation of vaccines. His-torically, vaccines have been slow toadopt new technologies (recombinantDNA techniques, delivery methodolo-gies, adjuvants), but a tremendousnumber of new vaccines, if successful,may change this. Technologies such asDNA plasmids, adenoviral vectors, andnovel adjuvants are all under exten-sive evaluation for diseases like HIV,malaria, and tuberculosis.

Q Is there anything else that youmight want to say to our readers?

Any last thoughts?

A Vaccines have traditionally beenproduced in relatively small-

scale, dedicated facilities located at afew companies, but the challenges ofemerging infectious disease, re-emerg-ing infectious diseases, biodefense, andHIV may result in novel technologiesfor production as well as a group of newentrants into the vaccine fields, whichshould provide new and exciting chal-lenges for the engineers who providethe infrastructure to manufacturethem.

Gomez photo courtesy of NIAID.


Production Facility Comparison


This articlecompares acampaign with aconcurrentlarge-scale cellculturemanufacturingfacility;includingadvantages,disadvantages,investment cost,and productioncapacity.

Comparison of Campaign vs.Concurrent Large-Scale Cell CultureFacilities

by Dr. David Estapé and Frank Wilde

Figure 1. Main buildingorganizationcharacteristics ofcampaign andconcurrent large-scalecell culture facilities.

Introduction

The biopharmaceutical market has a sig-nificant growth rate strongly driven bythe production of monoclonal antibod-ies. Consequently, in recent years, the

number of large-scale cell culture facilities hasexperienced a significant growth that is ex-pected to continue.1

Biopharmaceutical companies are lookingto build efficient production plants to best fittheir demands. At first, low investment andshort realization time are the main interest.However, in the long term, a well establishedproduction plant model will be equally or even

more important.Multi-product production facilities have be-

come almost a “must have” when approachingthe realization of a new plant. In some cases,the plant is envisaged as a mono-product facil-ity. Even in these cases, certain multi-productdesign features are included.

There are two basic organization types of amulti-product facility: the Campaign Produc-tion Facility (CampPF) and the ConcurrentProduction Facility (ConcPF). In the CampPF,different products are produced in differenttime periods, or campaigns, separated by achangeover phase. In the ConcPF, two or more

products are producedat the same time at dif-ferent production areasor suites. In each indi-vidual suite, it is alsopossible to manufacturedifferent products on acampaign basis.

From the GMP pointof view, both types oforganization representdifferent approaches tominimize or avoid po-tential cross-contami-nation between prod-ucts, a main complianceconcern.

In the design of anew production facility,the first approach mayfavor the ConcPF dueto higher flexibility.This is based on the ca-pability to produce twoor more products simul-

Reprinted from







taneously. However, one also can expect higher investmentcosts based on a large number of equipment needed if two ormore products are manufactured in parallel.

The final decision to plan a CampPF or a ConcPF mayrequire determining how much flexibility is needed and therelated costs. High flexibility and low investment costs wouldbe ideal, but seem to be contradictory.

In reality, both facilities are organized totally different andalso will have different requirements. The result is two designsthat are not easy to compare and more difficult to qualitativelyidentify advantages and disadvantages for an objective evalu-ation. Finally, only an extensive analysis can help to identifythe appropriate design for a specific business case.

This article compares a CampPF with a ConcPF for large-scale cell culture manufacturing. It looks into the facilityorganization, process design, as well as investment costs andproduction capacity. The goal is to quantify and define howmuch more costly and how much more flexible a ConcPF iscompared to an equivalent CampPF.

Case StudyA biopharmaceutical company is planning to build a newlarge cell culture production facility. The facility should beequipped with six main production bioreactors with 10,000liters working volume each. If we assume 12 days cultivationcycle, an average titer of 1.2 g/l, and an overall yield of 75%,the anticipated theoretical total maximum annual produc-tion capacity is up to 1,600 kg of protein.

Figure 2. Production schedule of campaign and concurrent large-scale cell culture facilities.

Facility OrganizationThe facility will be located on an existing production site. Thesite will provide basic infrastructure like general utilities(i.e., black steam, etc). Apart from the production core, theplant will include three additional modules: a productionadministration building, including QA/QC, a Just-In-Time(JIT) warehouse, and a central utility area for generation anddistribution of process utilities (i.e., process water, etc).

Both facilities will be organized following state of the artdesign principles2 that will secure a good GMP level. Theproduction core will be divided between upstream and down-stream areas. Furthermore, the upstream area will be orga-nized in different production disciplines like media prepara-tion, inoculum preparation, and harvest apart from thebioreactor suite(s). The downstream area will be divided inbuffer preparation, buffer holding, and pre-viral and post-viral removal downstream suites. Other support areas likeproduct storage, washing areas, etc., also will be integrated.

The main difference between the CampPF and the ConcPFwill be the number of bioreactor and downstream (pre andpost-viral) suites. The CampPF will have only one singlebioreactor suite, one pre-viral, and one post-viral removaldownstream suite. On the other hand, the ConcPF will havethree suites of each type to be able to produce three differentproducts simultaneously and independently from each other.

Apart from the number of suites, the design of each facilitywill follow opposite design strategies. Whereas the CampPFwill be a high and compact building, the ConcPF will be low




and broad. The design strategy could be different, but theintrinsic characteristics of each facility support the preferreddesigns. In the CampPF all equipment will be dedicated toone single product. This allows a higher integration or opti-mization that will lead to the compact design. In the ConcPF,there will be a core facility that is repeated as many times asthe number of products that can be manufactured simulta-neously. This repetition will lead to the wide horizontaldesign.

Figure 1 summarizes the main characteristic of each plantand shows the main building structure as it is describedbelow.

Campaign Production FacilityThe facility will be organized around a compact productionbuilding. The administration-QA/QC module, the JIT ware-house, and the utility module will be attached to facilitate agood personal and material flows, in addition to a well

organized utility distribution. The production building willbe internally divided between upstream and downstreamand will have a vertical organization to facilitate processgravity flow. So, media preparation as well as the seed trainis envisaged to be located in an upper level above the bioreactorsuite. Similarly, buffer preparation will be located abovebuffer holding that will in turn be above the downstreamsuites. The different production areas in the fermentation orin the downstream will be arranged around a single corridor.

Concurrent Production FacilityThe facility will be organized in different modules around acentral corridor or spine. In that case, upstream will be atotally independent module from downstream. Both moduleswill be organized horizontally, limiting the gravity flow. Thethree different bioreactor suites or the three downstreamsuites will be located one next to the other and linked to asupply and a return corridor to facilitate unidirectional flows.

Figure 3. Upstream design of a campaign large-scale cell culture facility (A) and upstream design of a concurrent large-scale cell culturefacility (B).




Process DesignCultivation times are longer than downstream processingtimes and are the limiting step. This allows two or morebioreactors to share a common downstream suite. The num-ber of bioreactors per downstream suite is defined by therelation of the cultivation and the downstream processingtimes. The production cycle time is then defined by thecultivation time divided by the number of bioreactors.

In the CampPF, all six bioreactors will share a singledownstream suite. Assuming a cultivation time of 12 days,one batch will be transferred to downstream every two days.A two day cycle time is closed to a typical net downstreamprocessing time. The net downstream processing time is onlythe intrinsic time required to carry out the process and doesnot include time for cleaning and sanitization. Consequently,the equipment that has been already in use is cleaned andsanitized at the same time processing continues uninter-rupted. In addition, the downstream suite or each productionstep must be “fully equipped.” In a “fully equipped” suite,there is enough equipment that processing does not need to

be interrupted by waiting for a piece of equipment to beavailable.

The maximum theoretical number of pieces of equipmentin the CamPF can be reduced by maximizing the equipmentutilization time or in other words, minimizing the equipmentnot in use. However, this equipment optimization can notcompromise processing and equipment is always available atthe time it is needed to continue production without interrup-tion.

This equipment optimization is possible if the same equip-ment is used simultaneously or at a different time for differ-ent production steps. In that case, the shared equipment hasmultiple connections to the different users (i.e., productionsteps). The high number of possible transfers or connectionsrepresents a higher plant complexity (i.e., multiple piping,large number of valves, higher automation effort, etc).

In the ConcPF, two main 10,000 liter productionbioreactors will be installed in each of the three bioreactorsuites. Two bioreactors will share one downstream suite. Ifwe assume again a 12 day cultivation time, one batch will be

Figure 4. Downstream design of a campaign large-scale cell culture facility (A) and downstream design of concurrent large-scale cell culturefacility (B).




transferred to downstream every six days. If the net down-stream processing time is again limited to two days, therewill be sufficient production time left, four days, that clean-ing, sanitization, and processing do not need to be per-formed at the same time.

In that case, it is possible to further simplify the numberof pieces of equipment by an extended reuse of the equipmentduring production. So, the equipment used in an earlier stepcan be cleaned and sanitized and then used again in a laterstep. In that case, processing may need to wait until theequipment is available again.

Figure 2 shows an example of a time line for the productionof two products for both facilities. In the CampPF, an up-stream batch is transferred to the downstream every twodays. In the ConcPF, the transfer occurs every six days ineach suite. In this case, three upstream batches from thethree bioreactor suites are transferred simultaneously, eachbatch to one of the three different downstream suites. In otherwords, the maximum downstream processing cycle is limitedto two days for the CampPF and six days for the ConcPF. Thelonger downstream cycle of the ConcPF is required due to thereuse of equipment and includes the time for cleaning andsanitization between consecutive process steps. The shortdownstream cycle of the CampPF requires a higher process-ing efficiency. Cleaning and sanitization occur simultaneouslyto processing, thus, resulting in a shorter cycle.

Bioreactor Suite Process DesignFigure 3A shows the design of the bioreactor suite for theCampPF and can be directly compared to the envisageddesign for the ConcPF shown in Figure 3B. The differencesare discussed below.

For the ConcPF, two main 10,000 liter bioreactors will beinstalled in a single suite. Each production bioreactor willhave a dedicated seed train. As a result, there will be eightbioreactors of different volumes per suite. The three suitestogether will then hold a total of 24 bioreactors. Each bioreactorcan only transfer to one single bioreactor (except the produc-tion bioreactors that will transfer to downstream). There areonly 18 possible transfers between bioreactors.

For the CampPF, the six main 10,000 liter bioreactors willbe installed in the single cultivation suite. All will share anoptimized seed train with only three seed bioreactors for eachseed culture group. The total number of bioreactors in theCampPF will be 15 units, 38% less than in the ConcPF. Thereduction of the number of the bioreactors is possible byoptimizing the utilization time of each group of seed bioreactorssince the seed cultivation process is usually shorter than themain production cultivation.

However, there will be multiple transfers possible be-tween a seed bioreactor and the next consecutive bioreactorgroup. As a result, the total number of transfers in theCampPF will increase to 36, 100% higher than in the ConcPFdesign. This results in a higher plant complexity (i.e., mul-tiple piping, large number of valves, higher automationeffort, etc).

Downstream Suite Process DesignFigure 4A shows the design of the downstream suite for theCampPF. It can be directly compared to the envisaged designfor the ConcPF shown in Figure 4B. The differences arediscussed below.

In the CampPF, the downstream suite will consist of sevenprocessing stations. Each station will include a product tankand a docking location where different types of unit opera-tions can be connected. The station will be piped to allowrecirculation (i.e., from an ultra-filtration unit) or transfer tothe next station (i.e., after a chromatography step). So, theproduct will move from station one to seven as long as thesuccessive purification steps take place. The first five sta-tions will be dedicated to pre-viral purification steps. The lasttwo stations will accommodate the final purification stepsafter post-viral removal. All stations will share a commonbuffer holding group consisting of 16 tanks of different vol-umes. The number of buffer tanks can be optimized to thenumber of buffers used (each buffer tank should be dedicatedto a single buffer). The buffer distribution system will allowa transfer from each buffer tank to each station.

During a product campaign, all necessary unit operationsshould be connected in the sequential order to the down-stream stations. In this arrangement, the different purifica-tion steps are carried out in sequence without interruption.Cleaning and if necessary sanitization steps occur parallel tothe purification steps. The unit operations will only be inter-changed between product campaigns.

Summarizing, there are seven different product tanks/stations and 16 buffer tanks, a total of 23 tanks. The bufferdistribution will allow 112 different buffer transfers.

In the ConcPF, each of the three downstream suites willconsist of four stations, two for pre-viral and two for post-viralprocessing. The design of the station will be similar to theCampPF, but it will be possible to transfer the product backto a previous station. An exception will be between pre- andpost-viral steps. So, the product may be moved forth and backbetween stations in order to reuse stations. By reusingstations, it is not possible to clean or sanitize the equipmentparallel to the purification step. The design also shouldfacilitate interchanging the unit operation connected to thestation during processing of one batch.

Each downstream suite will have a buffer holding group ofeight tanks of different volumes. Each tank will be used forholding different buffers during the purification process. Inaddition, to ensure a higher flexibility, the buffer distributionsystem will allow a transfer from the eight buffer tanks to thefour stations.

Summarizing, there are 12 different product tanks and 24buffer tanks, a total of 36 tanks overall or 12 tanks perdownstream suite. The buffer distribution will allow 32different transfers per suite or a total of 96 transfers for thethree suites. This represents a 57% increase on the numberof tanks and a 14% decrease on the number of buffer transfersin respect to the CampPF.

Similarly, a defined number of media preparation, bufferpreparation, harvest tanks, and the required transfers orconnections are analyzed.




Table B. Production capacity for a large-scale campaign and aconcurrent cell culture facility depending on the number of differentproducts to be manufactured per year. Production capacity is givenas a % of the maximum capacity that corresponds to the mono-product facility (one product). Production downtimes werecalculated based on a two-week changeover period.

Product/Year Campaign Concurrent

1 100 100

2 96 99 - 100

3 91 97 - 100

4 87 96 - 99

5 83 94 - 97

6 79 93 - 96

7 74 92 - 94

8 70 90 - 93

9 66 89 - 92

10 61 87 - 90

Major Key Figures and CostThe major typical key figures that define the facilities asdescribed above are summarized - Table A.

The Table shows that the ConcPF will require a largenumber of pieces of equipment, but will not be as complex asthe CampPF as a result of the number of transfers. There willbe approximately seven transfers in average per main equip-ment in the CampPF, whereas there will only be four in theConcPF.

The large number of pieces of equipment together with theorganization of the building around a central spine/corridorand the production modules structured between supply andreturn corridors will make the ConcPF significantly larger insize than the CampPF.

From key figures and based on facility benchmarks we areable to estimate the corresponding total investment cost foreach facility. The projection for the CampPF is €225 million($282 million), whereas the projection for the ConcPF isestimated to €320 million ($400 million), which is 42%higher.

Concluding, the ConcPF will require a large investmentbased on a large number of pieces of equipment and buildingsize. However, the cost of the ConcPF will not be as high as ifit is assumed to be directly proportional to the cost of theCampPF because of its lower complexity.

The higher cost of the ConcPF seems to be a majordisadvantage. However, the study would not be complete if itis limited only to the investment cost. As already mentioned,we would expect a higher flexibility for the ConcPF. In thatcase, it is important to analyze the production capacities foreach facility.

Production CapacitiesIf the facilities are dedicated to one single product per year,they can be regarded as mono-product facilities. In that case,all six production bioreactors of each facility are manufactur-ing the same product the entire year without interruptionother than maintenance. If the cultivation step is the processbottleneck, both the CampPF and the ConcPF will be able toproduce the same amount of product at the end of the year.This amount of product defines the maximum capacity (or100%). It corresponds to 1,600 kg/year based on the assump-tions already described.

The production capacity will differ when two or moreproducts are manufactured. The production of multiple prod-ucts requires a changeover period between product cam-paigns. The changeover is regarded as a downtime or a loss ofproduction capacity. The changeover phase in the CampPFwill affect the entire facility since it will affect both, the singlebioreactor suite and the single downstream suite. On theother hand, the changeover in the ConcPF may not necessar-ily affect the entire facility and may be limited to one or twosuite groups (one bioreactor suite and one downstream suite).It can even be that the changeover phase is not required at all.As a result, the decrease of production capacity due tochangeover downtime will be higher for the CampPF than forthe ConcPF.

Figure 2 also shows the changeover phase between twoproduct campaigns, product campaign A and product cam-paign B. If the product demands require dedicating two thirdsof the annual production capacity to product A and one thirdto product B, only one changeover is required in the CampPF,but no changeover will be necessary in the ConcPF. In thatcase, two suite groups will be dedicated to product A and oneto product B. The total production capacity of the ConcPF willbe higher based on longer production time of two weeks.

The total downtime or capacity drop will depend on thenumber and the length of the changeovers. For the ConcPF,it also will depend on the number of suite groups affected bythe changeover.

First, the number of changeovers depends, at the end, onthe number of products to be produced. For more products,more changeovers are required and the loss of productioncapacity is more significant.

Second, the length of the changeover time depends on alarge number of factors, including the complexity as well asthe organization. That makes it difficult to define and shouldbe based on actual data. In any case, a special effort should bemade to minimize the required time.3

For example purposes, a two week period has been defined

Table A. Key design figures of a large-scale campaign and aconcurrent cell culture facility.

Campaign Concurrent

Main Equipment Tanks 54 75

Main Transfers Transfers 360 320

Automation I/O 14,500 16,300

Piping km 40 70

Manufacturing BuildingVolume m3 75,000 120,000Area m2 17,800 29,600

Total Investment Cost M€ 225 320M$ 282 400




Figure 5. COG of campaign and concurrent large-scale cell culturefacilities depending on the number of products to bemanufactured per year. COG is given as a % of the minimum COGthat corresponds to the campaign facility when only one productis manufactured. The calculation assumes a decrease ofproduction capacity with the increase of the number of productsas depicted in Table B. Depreciation was proportional to the totalinvestment costs as described in Table A. All other costs wereconsidered constant.

and seems to be a reasonable and feasible changeover time fora large cell culture facility. The same changeover time has beenused for the CampPF as well for the ConcPF. It could be arguedthat the smaller suites in the CampPF may require a shorterchangeover time. Note also that a changeover shorter than 12days (i.e., one week) will mean that two different products willbe produced simultaneously in the bioreactor suite of theCampPF. Simultaneous production of different products in thesame production suite may be regarded as a risk for cross-contamination or potential errors since two completely differ-ent production campaigns have to be followed simultaneously.

Finally, the number of suite groups involved in thechangeover in the ConcPF will depend on the demand or inthe distribution of the production capacity assigned to eachproduct. This may be different each year and depends on realscenarios. Nevertheless, the drop of production capacity canbe defined within a range determined by the minimum andmaximum number of suite groups involved in productchangeovers.

Table B summarizes the expected loss of production capac-ity as a function of the number of products for a two weekchangeover period for the different types of facilities. It isimportant to note the higher production capacities of theConcPF compared to the CampPF. For example, with sixproducts per year the production capacity of the ConcPF is19% higher than the CampPF.

The loss of production capacity is the major drawback ofthe CampPF and shows the flexibility of the ConcPF. It isclear that the number of products per year should be limitedin a CampPF.

Cost of GoodsThe combination of the total investment cost and the produc-tion capacity should be the key to define the advantages ordisadvantages of the CampPF and the ConcPF. An approachcould be through the calculation of the Cost Of Goods (COG)where both variables are combined.

The calculation of COG is defined by a large number ofvariables that, depending on how they are identified, mayintroduce a large uncertainty on the final conclusions. Aqualitative discussion on the COG for the CampPF and theConcPF is presented below.

The COG is determined by the sum of all cost incurred inthe manufacturing of a product, divided by the total amountof product manufactured. Included in the overall manufac-turing cost is the depreciation or capital cost that depends onthe total investment. The total output of the facility isdetermined by the capacity.

The depreciation is the investment cost divided by the totalamortization time. Different companies use different amorti-zation times of 10, 15, or even 20 years. It also can be thatdifferent amortization times are applied to different concepts(i.e., building, equipment, automation, etc). What is importantto note is that the investment cost is diluted by the amortiza-tion time and will have a lower impact on the COG than it couldinitially be expected. In addition, the depreciation is added toall other manufacturing costs that can be as high as or evenhigher than the depreciation. This dilutes even more the

influence of the investment cost in the COG. At the end,depreciation cost may account for 30% to 40% of the COG. 4, 5

On the other hand, the production capacity has a directinfluence on the COG through the total amount of productmanufactured. It is shown that a decrease in the capacityutilization from 100% to 80% may represent an increase ofthe COG sold from $300/g (240 €€ /g) to $375/g (300 €€ /g), a 25%increase.1

Therefore, the higher investment cost of the ConcPF isdiluted and may no longer be the main economical factor. Incontrast, the expected lower capacity of the CampPF affectsdirectly the COG that will significantly increase.

The key factor that defines the cost efficiency of theCampPF or the ConcPF is the number of products manufac-tured in the facility each year - Figure 5. As more products aremanufactured, more production downtime for changeoveroccurs. The production capacity is then lower and conse-quently the COG increases. The increase of the COG is muchmore severe for the CampPF since the capacity is much moresensitive to the number of products manufactured.

When a limited number of products is manufactured, theloss of production capacity of the CampPF is limited. Conse-quently, the COG of the ConcPF will be higher due to thehigher investment. The extreme example will be when onlyone product is manufactured. Both facilities can produce thesame amount of product, but the ConcPF will require a higherinvestment. The COG of the ConcPF will be clearly higherthan for the ConcPF.

When the number of products is high (eight to 10) there isa significant decrease of the production capacity of the CampPFcompared to the ConcPF. It can happen that the COG of theConcPF is more attractive than for CampPF due to its higherproduction capacity.

In other words, the higher investment cost of the ConcPF




is easily compensated by the higher capacity for multipleproducts per year. At the end, the COG for both facilities maynot differ in a great extent.

Even if the COG of the ConcPF is higher than thatcorresponding to the CampPF, the ConcPF may be still thechoice. In that case, the higher production capacity canprovide more product to the market and combined with theearnings margin of high value products may easily pay for thehigher investment.

ConclusionThe capital investment of a biopharmaceutical company on anew multi-product production facility is an important busi-ness step that needs to be well evaluated. The selection of thecorrect type of facility is an important piece of this study. TheCampPF or the ConcPF are the two facility models of choice.Each has different advantages and disadvantages in theshort as well as in the long run.

The CampPF allows an important optimization of thenumber of pieces of equipment, but requires a complextransfer strategy between equipment. The result is a com-pact, but complex facility with a lower initial capital invest-ment. In the CampPF, the changeover between two productcampaigns represents an important loss of production capac-ity since the complete facility is affected.

The ConcPF requires a large number of pieces of equipmentto be able to manufacture different products simultaneously,but with a simple transfer strategy. The result is a large facilitythat will require a larger initial investment. The productioncapacity in the ConcPF will be much less affected by thechangeover between product campaigns. On one hand, differentmanufacturing campaigns can be easily distributed in differentproduction areas of the facility; on the other hand, only part ofthe facility is affected during the changeover period.

When only few products are envisaged to be produced in amulti-product production facility, the CampPF model is thebest choice. It will provide the required multi-product capa-bilities at the lowest investment cost and guarantee the mosteconomical COG. However, when a high number of productsneed to be manufactured each year, a CampPF can becomeunproductive. In that case, a ConcPF would allow a betterallocation of the multiple campaigns and still guarantee ahigh production capacity. The initial higher COG due to ahigher investment volume becomes more cost-effective.

Nonetheless, the critical number of products at which aCampPF facility is no longer attractive depends on a largenumber of variables (investment cost, changeover time, manu-facturing cost, etc) that need to be determined case by case.The final selection between both types of facilities also shouldnot be an isolated analysis depending only on the intrinsiccharacteristics of each facility. The different advantages anddisadvantages have to be looked at taking into account allexternal and strategic factors case by case.

For example, if a biopharmaceutical company needs toinvest for their first large-scale multi-product productionfacility, it may be an advantage to invest in a ConcPF with itshigher flexibility (if a high flexibility is needed and the

investment cost is not a limitation). However, if thebiopharmaceutical company is already well established andhas one or more existing facilities, it may prefer a CampPFwith a lower investment since the flexibility may be securedby combining all production plants.

References1. Werner, R. G., “The Development and Production of

Biopharmaceuticals: Technological and Economic SuccessFactors,” A special supplement to BioProcess International,Vol. 3, No. 9, 2005, pp. 6-15.

2. ISPE Baseline® Pharmaceutical Engineering Guide, Vol-ume 6 - Biopharmaceutical Manufacturing Facilities, In-ternational Society for Pharmaceutical Engineering (ISPE),First Edition, June 2004, www.ispe.org.

3. Henry, J., “How to Develop and Implement a QuickChangeover Program,” Pharmaceutical Engineering,March/April 2002, Vol. 22, No. 2, pp. 36-44.

4. Boyd, J. H., “What it Costs to Operate a Biotech Facility,”Genetic Engineering News, Vol. 25, No. 4, 2005, pp. 6, 21.

5. Sinclair, A., and Monge, M., “Quantitative Economic Evalu-ation of Single Use Disposables in Bioprocessing,” Phar-maceutical Engineering, May/June 2002, Vol. 22, No. 3,pp. 20-34.

About the AuthorsDr. David Estapé works as a Facility De-sign Engineer and GMP Consultant at LSMWGmbH in Stuttgart, Germany. He joinedLSMW in 1996 and from that time, he hasbeen continuously involved in the design andthe realization of biopharmaceutical facili-ties. Previously, he graduated with a chemi-cal (engineering) degree at the University

Autonoma of Barcelona (Spain) and developed his PhD workat GBF (Germany). He can be contacted by telephone: +49-(0)711-8804-2843 or by e-mail: [email protected].

Frank Wilde is head of the business unitProcess Facilities 1 at LSMW GmbH inStuttgart, Germany. He has participated asprocess engineering manager and projectmanager in several large scale biotechprojects. Prior to his work at LSMW, heworked at a worldwide leading equipmentsupplier for the biopharmaceutical industry

in Switzerland. Wilde graduated at the University of AppliedSciences at Mannheim, Germany with a chemical engineer-ing/biotechnology degree. He can be contacted by telephone:+49-(0)711-8804-1874 or by e-mail: [email protected]

LSMW GmbH, Lotterbergstr. 30, 70499 Stuttgart, Ger-many.


Wireless Technology


This articledescribesmanagementstrategies toovercomeuncertainty,cost, andregulatoryvulnerability inwirelessimplementations.

Wireless Framework for EnterpriseExcellence: Managing, Securing, andValidating

by Janice Abel, Hesh Kagan, and Ian McPherson

The radio spectrum is an asset that phar-maceutical and biotechnology indus-tries are now beginning to exploit, andthe emergence of secure, affordable

wireless technology is making it easier forthem to do that every day.

Wireless technologies include wireless ac-cess points (gateways), transmitters, receivers,antenna, protocols, powering options and serv-ers, and security technology ranging from intru-sion detection devices to data encryption. Per-formance and reliability of wireless technologyhas been improving steadily, to the point atwhich it has become a very feasible cost savingoption for many industrial applications. Unlikecell phone networks which span many miles,most industrial settings are contained, repeat-able, and thus very manageable, provided that

the system is implemented at the enterpriselevel.

The most significant challenges to pharma-ceutical companies wishing to take advantageof wireless technology are in managing thelimited available bandwidth, integrating mul-tiple communication protocols and standards,and maintaining and supporting the ongoingsecurity requirements of wireless networks.Solving these problems requires resource plan-ning, performance management, and a com-mon wireless systems management platform.

This finite, relatively available resourcemeans that today - and for many years to come- reaping the many control benefits of wirelesscommunications will challenge technologymanagement much more so than technologyperformance.

Figure 1.Typicalinterrelated applicationswith different RF “needs.”

Reprinted from





Wireless Technology


Figure 1 illustrates the broad rangeof manufacturing areas that are nowimplementing some type of a wirelesssolution. For years, the medical deviceindustry has been using wireless tech-nology in such applications as intrave-nous pumps, pacemakers, wheelchairs,and more recently for metering insulininjections via a patch that calculatessugar intake and sends a wireless sig-nal to the patch for dosing, with verygood results. In September 2000, theCenter for Device and RegulatoryHealth (CDRH) issued a guidance forindustry, entitled Wireless TelemetryRisks and Recommendations.

As a result, the FDA has been exam-ining the use of telemetry andElectroMagnetic Interference (EMI) inmedical devices – especially since theFCC opened up radio frequency usagein December 2005 for a previously re-stricted medical device radio spectrumand has advised switching frequencieson some devices to avoid interference.More applications are just beginningto emerge in this industry.

“Pharmaceutical industry, businesssystems, such as Enterprise ResourcePlanning (ERP) software, which seeksto integrate financial and operationsdata company-wide, have been suc-cessfully using wireless technologiesin the pharmaceutical industry formany years. The functional scope andrange of these applications for the mostpart has been isolated to providingcontrol flexibility and validation for

discrete processes,” said Mike Howdenan Invensys Validation Technologiesconsultant, adding that Invensys hasdeveloped new programs to train tech-nical staff in expanding validated wire-less applications in pharmaceuticals.Other common wireless applicationsmanage personnel access for securitypurposes.

If wireless proliferates in the phar-maceutical industry as it has in otherindustries, those who purchase andimplement point solutions will likelyenjoy some initial success. But as usespreads to different departments anddifferent locations, the joys of wirelessfreedom will likely begin to fade. Usersmay begin experiencing increased in-terference on the links. Transmissionmay be interrupted. There may be avail-ability problems, data loss, and perfor-mance degradation. Furthermore, thisad hoc approach fails to consider thevarying criticality and time sensitiveaspects of disparate application datathat are contending for use of the spec-trum. If this growth continuesunmanaged, the technology that wouldpotentially offer a method to improveproductivity, efficiency, and cut costs,also could add uncertainty, cost, andregulatory vulnerability.

The Need for SystemsManagement

Fundamentally, wireless networks de-liver the same basic business benefitsas wired networks: they connect data

Figure 2. Potential wireless application areas for pharmaceutical facilities.

point A to data point B, enabling timelyinformation sharing for a wide range ofapplication and reporting functions.But because of the low cost of wirelesssensors, and the no-cost of runningwires, more points can be connected farmore cost-effectively than wired net-works. Wireless networks enable de-tailed measure of process variables,including measures of quality whichcould not be measured at all before, forexample, increasing process perfor-mance in applications which previouslyrequired mandatory laboratory analy-sis. Freed from the restrictions of wires,it is possible to set up measures forvirtually any point of the enterpriseand receive this information in realtime.

Because of the finite amount of ra-dio spectra at its disposal, care must betaken upfront to determine where thetechnology will be most beneficial. Fig-ure 2 shows some of the areas in whichwireless technology could benefit phar-maceutical and other bioscience manu-facturers. Following are more examplesof benefits that wireless implementa-tions could deliver the pharmaceuticalenterprise:

Enterprise Management• real-time monitoring of parts and

finished goods, across the entirevalue chain

• tighter process monitoring by in-creasing the number of checkpointsacross the enterprise or in remotelocations (e.g., cold chain applica-tion)

Logistics• Radio Frequency Identification

(RFID) for supply chain to preventcounterfeiting of drugs or improveproduct tracking and security

• improved management of shippingreceipts and returns processing

• improved inventory management,forecasting, and planning

Safety and Security• managing plant and system person-

nel access

Production• improved process execution by en-


Wireless Technology


Figure 3. Wireless standards and technologies now in use.

abling remote electronic capture ofprocess data (e.g., remote valida-tion protocol execution via wirelesstablet PCs)

• electronic product authenticationand electronic pedigree documenta-tion

• improved equipment availabilityand reduced maintenance coststhrough proactive condition moni-toring, for example, implementingwireless vibration sensors to indi-cate system malfunctions

• improved flexibility for quick pro-cess unit changeover

• reduced downtime and costs for wire-less sensors on skids by eliminatingthe need to connect instruments andcomputers to field networks

• faster process changes throughreconfigured operations

• better tracking of clean-in-placecomponents

• improved utilization of processequipment through more precisemeasurements of process variablessuch as temperature and pressure

• greater efficiency in enabling PATsolutions

Maintenance andInfrastructure Management• eliminating wiring related costs in

upgrading or installing control sys-tems

• improved plant safety and securitythrough proactive perimeter moni-toring, Weapons of Mass Destruc-tion (WMD) detection, and person-nel tracking

Although it is quite feasible for eachdepartment to present a strong busi-ness case for using wireless networksin its own operation, these consider-ations must be made at the enterpriselevel. Data integration, process inte-gration, and knowledge sharing aresome key performance enhancers inpharmaceutical production. Process,security, or logistics needs must beevaluated in the context of the overallenterprise strategy.

A company whose strategy is drivenby reducing costs might want to deploywireless vibration sensors to determinewhen assets are not operating opti-mally. They would then look for sav-ings on maintenance in the bottom-

line. Other applications for wirelesssensors might include temperaturemonitoring of product in storage andtransportation.

In contrast, a company whose strat-egy is to get to market faster, reliably,and securely, might find that the addedcost of an RFID product tracking sys-tem would improve their competitiveposition. According to a Gartner re-port, “industries with the greatest op-portunities to use RFID include retailand aerospace and defense, while thehealthcare, logistics, and pharmaceu-tical industries will adopt RFID thefastest.”1

The US Food and Drug Administra-tion (FDA) has stepped up its efforts toimprove the safety and security of thenation’s drug supply by promoting theuse of RFID technology. The FDAlaunched this effort by publishing aCompliance Policy Guide (CPG) forimplementing RFID programs that aredesigned to enhance the safety andsecurity of the drug supply. This actioncontinues the FDA’s commitment topromote the use of RFID by the USdrug supply chain by 2007.


Wireless Technology


The FDA believes that anti-coun-terfeiting is a major benefit of RFID.However, the benefits of RFID go wellbeyond the fight against counterfeitdrugs. The pharmaceutical industryrelies upon the integrity of many formsof data throughout the process of drugtrials, manufacturing, distribution, andretail sale. RFID’s ability to uniquelyidentify each item and securely cap-ture data without line-of-sight through-out the supply chain has many benefitsin the pharmaceutical industry.

RFID in the pharmaceutical supplychain is seen as a technique to enhancepatient safety and security and ad-dresses emerging regulatory require-ments like Florida’s anti-counterfeit-ing law. Preventing drug counterfeit-ing, for example, calls for drug prod-ucts to carry a genealogy of their his-tory. With drug counterfeiting on therise, pharmaceutical RFID security iscritical.

Implementation of wireless tech-nologies also aligns with the FDA’sefforts to increase efficiencies withinthe development and manufacturingsectors under their 21st Century Initia-tive as well as Process Analytical Tech-nology (PAT). Not to be mislead by thename, PAT allows pharmaceuticalmanufacturers to optimize the mannerthey use to manage their plant assetsto produce specific drugs with the ob-jective of reducing the price that theconsumer pays. PAT also allows phar-maceutical manufacturers to apply newtechnologies such as advanced processcontrol and wireless networks.

Managing SecureIntegration in a Regulated

EnvironmentThe greatest threats to wireless secu-rity are not from malicious interfer-ence, but from otherwise well-inten-tioned people engaged in sloppy net-working practices, such as not chang-ing passwords according to policy, us-ing obvious passwords such as initials,adding or deleting devices improperly,and any number of other lapses. Wire-less networks are also subject to inter-ference from other non-malicious fac-tors, environmental or accidental Ra-dio Frequency (RF) noise, broken RF

equipment, dynamic changes in thecharacterization of the RF site, and therange on non-compatible RF devicesgenerally available.

And as wireless usage expands, com-petition for the wireless spectrumwithin and around the plant will be-come the major issue. One networkuser might be taking wireless processmeasurements from a temperaturetransmitter. Another person in thesame plant might be running a wire-less video camera for perimeter secu-rity. A third might be running an RFIDinventory tracking application. Be-cause they are in different departmentsand locations and doing different thingson different protocols, they might thinkthey are isolated, but in reality, thoseradio waves are co-mingling creatingtremendous potential for performanceproblems and mismanagement.

Coordination of diverse wirelessneeds is critical, but not likely to emergeby consensus. If each department want-ing to deploy a wireless solution had tocheck with every other department tosee how their wireless activity wouldimpact them, there would be gridlock.There must be a higher level frame-work that respects what people need todo to perform their roles and responsi-bilities in the context of the businessstrategy and the related job responsi-bilities. At the same time, customersmust have assurance that if they imple-ment select technologies and practicesthat conform to company policy theywill enjoy reliable, secure, validatednetwork operations.

When considering the use of wire-less technologies in the pharmaceuti-cal industry, security and validationare at the forefront of most people’smind. Security is mandated by theFDA’s 21 CFR Part 11 regulation onelectronic signatures/electronicrecords. Because the wireless technol-ogy typically does not interface withthe product directly, validation issueswould be comparable to wired networktechnology. However, there is a need toassure that interference and securityare managed.

Financial reporting and disclosureregulations required by the FederalSarbanes-Oxley act, and the use of

Web-based interfaces also have in-creased the need for secure access con-trol to address compliance and liabilityconcerns.

Managing System Policiesand Standard Operating

ProceduresThe policies and Standard OperatingProcedures (SOPs) in place for wire-less networks must define all methodsusing, sharing, and securing the avail-able bandwidth. This has implicationsfor planning, implementation, opera-tion, maintenance, and expansion.Policy management and validation alsotie into the end user's existing IT re-quirements – one company might haveIT policies in place that are very differ-ent from another in the pharmaceuti-cal industry. The system must be de-signed to comply with corporate re-quirements for activities like reportingerrors, observing network behaviors,and performance based on that infor-mation. It must cover every aspect ofthe operations, from initial configura-tion to ongoing optimization.

Commissioning and qualification ofthe wireless network would be compa-rable to commissioning and qualifica-tion of any network, but with addedemphasis on security and interference.Interference would be addressed firstduring the RF site survey, which usesscientific tests to measure RF in theplant and in the local area surroundingthe plant.

Additional security and RF inter-ference testing also must be built intoroutine maintenance procedures toaccount for changing internal and ex-ternal conditions. Events ranging froma microwave oven at a new conveniencestore to full-blown competition for theRF spectrum from a new plant beingbuilt next door all represent potentialRF and security threats that must bedetected and may require re-valida-tion and re-qualification.

Policies and SOPs that meet regula-tory requirements also must be in placefor handling problems. Once the sys-tem detects interference, for example,what does it do? Will it reroute traffic,change frequencies, or reconfigure an-tennas to be active or inactive? Some of


Wireless Technology


education, guidance documentation,and interoperability of sensor networkswithin the industrial environment.4

Managing and ValidatingSystem Traffic

Unlike wired networks, which can befairly well isolated, closed by functionor protocol and kept independent ofother networks, wireless signals can-not be managed physically. Wirelesstraffic is controlled by agreements andrules, requiring buy-in from everyonewith access to the bandwidth spectrum.

The data may transmit across thesame virtual wire or air link, but wouldnot necessarily have to be interspersedwith like data. A process packet and anInternet Protocol (IP) packet would notnecessarily have to be on the samelink. Instead, rules could limit accessto process data to users on the processside of the house; or transmit data toreceivers on the same side. The com-pany has the power to dictate whatgoes where and to configure the rules.

One key to flexible, secure opera-tion is the ability to validate any packetof information moving across the net-work with a recognized and authorized

sender or receiver. This type of identitymanagement can be done by a numberof methods including certificates andtokens. Both can authenticate deviceswith a unique identifier. Managementmust determine how those certificatesare assigned, distributed, and evalu-ated, and what privileges that identi-fier would have. They must define ex-actly how to treat each user or device asan object with its own unique proper-ties or attributes. This is a much bettermethod for assigning a unique identi-fier than IP or other alternatives. Thisis a well understood technology, but itseffectiveness decreases significantlywithout enterprise-wide coordinationand validation of wireless applications.

From a technical and practicalstandpoint, there must be a single pointof access to the whole network of net-works, using a common network and acommon lexicon.

Managing System GrowthFrom a network management perspec-tive, it shouldn’t matter if signals trans-mit across wires or not. The networkmanagement center should see thewireless path as just another network

Figure 4. Measuring wireless benefits.5

the options depend on the capabilitiesof the technology, but within thatframework, policy and network man-agement is necessary to guide imple-mentation and network operation.

Performance, availability, and uti-lization are also among the reportingcriteria covered by systems manage-ment and also must be considered whenvalidating. Policies, such as alarm alerthandling which dictates alarm relatedoperator actions, are part of the sys-tems management function.

Managing the SystemArchitecture

Optimum execution of any enterprise-wide policy requires a network archi-tecture that can accommodate technol-ogy of every possible network vendor,emerging standards, regulatory guide-lines, and best wireless integrationpractices. The architecture must bebased on a secure model covering au-thentication and role-based access con-trol. This should provide for commonaddressing, routing, messaging, anddevice management. The architecturealso should provide consistent datastructures, storage, and reporting, anda common point of configuration for allbusiness rules and workflow.

Figure 3 illustrates the array of stan-dards now impacting wireless commu-nications. Some have been developedby industry standards groups compris-ing vendors and users. Bluetooth andWiFi are two of the better known, yetthese are seen as better for voice andgraphics applications. ZigBee is a low-power, slow-data standard that hasmany supporters for remote monitor-ing. Predictable, long-lasting power iskey for wireless monitoring, and ZigBeesupports battery life of 1,000 days ormore.

Members of IEEE, ISA, and WINAare currently working together on stan-dards that they hope will gain accep-tance by the InternationalElectrotechnical Commission (IEC).Just over a year ago, a new ISA stan-dards committee, ISA-SP100, wasformed to further standards and tech-nical documentation in the automa-tion and control arena. Project teamshave formed to focus on issues such as


Wireless Technology


Figure 5. Secure wireless architecture for the plant network.

that must be managed for performanceand security. But today, and probablyfor many years to come, wired andwireless networks will likely be man-aged by different technology. Eventhough IT and telephone networks maybe managed by a company’s IT organi-zation, for example, they typically usedifferent management systems. Voiceover IP is only now driving the need forintegrated management and valida-tion of IT and telephone systems, eventhough these technologies have beenevolving for years.

Even though wireless technology isclearly in a transitional phase, it ishighly unlikely that there will ever bea standard wireless protocol and fre-quency. Protocols and frequencies areoptimized based on very different ap-plication requirements and vendortechnologies. The requirements forpower management, distance, site char-acteristics, bandwidth, cost, and secu-rity will always result in the need for awide range of technologies, standards,procedures, and excellent validationmethodologies.

What is needed is an integrated, yetflexible network management strat-egy that can deliver benefits today whileadapting to businesses and technolo-gies as they evolve and change.

Solution for WirelessSystem Infrastructure and

ManagementThanks to standards and innovation,wireless technologies offer a compel-ling mix of cost and performance thatwill spur adoption throughout the en-terprise. “When asked how their orga-nization would measure the return onwireless investments, respondentslisted increased productivity, improved(internal) customer satisfaction, andreduced expenses/costs of doing busi-ness most frequently - Figure 4.”5

Moving beyond prototyping to con-trol-a future at which some companiesin other industries have already ar-rived-requires an overarching frame-work to accommodate and apply mul-tiple wireless technologies. Since thereis great heterogeneity to the applica-tions and no “one size fits all” wirelesstechnology solution, monitoring, man-agement, and security must span theentire enterprise. This will ensure themost efficient use of resources, whileallowing the disparate applications toshare the spectrum within the contextof their importance, time sensitivity,and mission criticality.

Like the networks themselves, sucha regulated wireless infrastructuremust be evolving, dynamic, and flex-ible. This environment demands an

integrated operating approach that willensure that wireless installations willbe scalable, secure, and extensible.Solutions must include architectureand management software, perfor-mance monitoring and reporting, andsecurity management as a single solu-tion - Figure 5.

Managing ImplementationWhile implementing a managementinfrastructure of this sort requires sev-eral months of preliminary cross-com-pany planning, implementation of thetechnology itself can usually be done inone or two weeks. Few companies havethe resources to maintain staff neces-sary for initial implementation, espe-cially because the demand for special-ists with relevant skills is very high.Companies that do not have the re-sources typically required to imple-ment a managed wireless network mayfind outsourcing to one of the emergingspecialist firms to be a cost-effectivesolution.

The following is a check list thatprocess manufacturers should considerwhen assessing wireless needs and de-signing a wireless network system thatis consistent with their wireless strat-egy, policies, and quality system:

• Survey the entire company to deter-mine where wireless technologiescan best support your business strat-egy.

• Create an enterprise-wide policythat will control wireless deploy-ment.

• Design an architecture that willachieve these goals effectively.

• Conduct an RF site survey to iden-tify potential sources of RF interfer-ence and locate wireless communi-cations devices, both internally andexternally to the plant.

• Work with a validation specialistwith experience in wireless tech-nologies and networks.

• Select and purchase hardware andsoftware that is most cost-effective,proven, and scalable.


Wireless Technology


• Develop a prototype in an area withhigh ROI potential for immediatepayback such as cycle time reduc-tions or counterfeiting exposure forhigh profile drugs.

• Build requirements and design docu-ments for a pilot wireless prototypeapplication running separately fromthe process for system validation.

• Pilot a project for integration to anexisting application.

• Integrate to the existing businessand operations systems.

• Measure and evaluate ROI effec-tiveness of application.

• Collect lessons learned, measurecost-effectiveness of improvements,reassess the strategy, and plan nextsteps, including additional sites,plants, and global solutions for arollout.

• Conduct ongoing monitoring, main-tenance, support, and optimizationservices, and incorporate relevantsecurity, regulations, standards, andtechnologies as they emerge.

SummaryTechnology is enabling a vast numberof wireless capabilities across the phar-maceutical enterprise. The nature ofwireless applications requires a highlevel of technical understanding forimplementing and validating wirelessnetwork applications.

As a result, it is important to estab-lish a strategy and plan before goingforward with wireless just for the sakeof going wireless. The plan should in-clude benefits that will be gained fromusing these new technologies whethertangible or intangible. Some of the stepsand guidelines for implementing wire-less include working with an experi-enced and knowledgeable company andworking with a wireless infrastructureand plan that will incorporate presentand future wireless needs. The infra-structure needs to be flexible enoughthat new wireless technologies, meth-odologies, and new regulations can be

easily incorporated. The bottom line isthat there is a potential wireless explo-sion on the horizon due to the enor-mous benefits that can be gained fromusing this technology and companiesneed to be ready to validate and imple-ment.

References1. “RFID is the Limit,” Gartner Re-

port, December 14, 2006.

2. Basta, Nick, “A Track-and-Trace-Future,” Pharmaceutical Manufac-turing, August 2003.

3. Paul, Thomas, “Inside GSK’s NewRFID Pilot”, Pharmaceutical Manu-facturing, May 2006

4. “A World without Wires?” Pharma-ceutical Manufacturing, April 2006.

5. “Applied Wireless: Making WirelessWork in business,” CIO Focus,www.TheCIOStore.com.

AcknowledgementsSpecial thanks to Mike Howden, Con-sultant, Invensys Validation Technolo-gies and Mark Cupryk, General Man-ager, Invensys Validation Technolo-gies, for their guidance and excellentcomments.

About the AuthorsJanice T. Abel is Di-rector of Pharmaceu-tical and Biotechnol-ogy Industries forInvensys Process Sys-tems. She has beeninvolved with thepharmaceutical and

biopharmaceutical industries through-out most of her 20-year professionalcareer. This includes consulting withclients on regulatory requirements, en-terprise control, risk management, andPAT. Her experience includes the au-tomation and application of bioreactorsand other processes in the pharmaceu-tical and biopharmaceutical industries.Abel has a Bachelor’s degree in chem-istry from Clark University, a Master’sdegree in chemical engineering fromWorcester Polytechnic Institute, and a

Master’s degree in Business Adminis-tration (MBA) from Worcester Poly-technic Institute. She is available [email protected].

Invensys, 33 Commercial St., B51-1A, Foxboro, MA 02035.

Harris (Hesh)Kagan is TechnologyDirector, New Ven-tures, Invensys Pro-cess Systems andPresident of the Wire-less Industrial Net-work Association

(WINA). He leads the Invensys wire-less technologies program, which as-sists companies in integrating wire-less networks for enterprise asset per-formance management, and for the last15 years, Kagan has been leading theeffort to coordinate development andtechnology across Invensys. He hasworked in the automation and controlsindustry for more than 25 years. He isavailable at [email protected].

Invensys, 33 Commercial St., N05-3A, Foxboro, MA 02035.

Ian McPherson, VicePresident of Market-ing for Apprion, hasmore than 15 years ofexperience in research,development, and de-ployment of networkinfrastructure and en-

terprise wireless technologies. Most re-cently, he was the Founder and Presi-dent of the Wireless Data ResearchGroup, providing syndicated primaryresearch and advisory services foremerging wireless technologies and ma-chine to machine communications. Heis available at [email protected].

Apprion, NASA Research Park,Moffett Field, CA 94035.


Process Solids Handling


This articlepresents a casestudy describingthe approachtaken forhandling processsolids for amulti-productbulk APIManufacturingFacility.

Process Solids Handling Approach forMulti-Product Bulk API Facility

by Prashant Desai and Pramod Biyani

Introduction

Multi-product bulk Active Pharma-ceutical Ingredient (API) manufac-turing facilities are becoming thenorm in the industry. This is largely

driven by the fact that only a small percentageof APIs in development make it to the market.Therefore, a pre-investment required for a dedi-cated facility is very risky. A multi-productfacility spreads the risk over multiple productsunder development and still allows manufac-turing of commercial quantities of API, oncethe product is close to being approved in arelatively short amount of time.

From the design perspective, multi-productfacilities introduce a set of complex challenges– among them the selection of a process solidshandling scheme. By its very nature, a multi-product facility must be designed to handlepoorly-flowing materials. The containment levelrequired to handle the potential solids mate-rial in the facility is another important consid-eration. Good judgment is required to set thecontainment level for the facility, based on theenvisioned characteristics of the potential prod-ucts and intermediates to be handled in thefacility. Containment level is determined bythe Operator Exposure Limit (OEL) and/orother toxicological properties of the solids ma-terial. Table A describes various containmentlevels and their implications for the design ofsolids handling equipment.

This article presents a case study describingthe approach taken for handling process solidsfor a multi-product bulk API ManufacturingFacility. This facility is designed as a flexible,multi-product facility with the capability ofhandling materials requiring up to Contain-ment Level 3 (Operator Exposure Limit of 10 to100 micrograms of airborne dust per cubicmeter of air over an eight hour time weightedaverage). The other basic design objective is tocomply with the latest GMP practices for themanufacturing of bulk active pharmaceuticalingredients. Ease of cleaning and validationare important considerations in any multi-prod-uct facility. All aspects of solids handling willbe covered, starting from the dispensing opera-tion in the warehouse, in-process solids han-dling, and final bulk product packaging. Equip-ment design and operational considerationswill be discussed, not only to meet the designcontainment level, but also to comply with thelatest GMP practices.

Facility OverviewAn overview of the process solid materials han-dling system in the Process Building and Ware-house/Dispensary Building is presented below.

Process BuildingThe process building is configured into seven“wet” processing (chemical synthesis) trains,seven “dry” processing (isolation) trains, and

Table A. Containmentlevels and associateddesign options.

Level OEL Range Design

1 > 1000 µg/m3 General room ventilation. Conventional open equipment with local exhaust ventilation (LEV).

2 100 to 1000 µg/m3 Semi-closed to closed material transfers; laminar flow/directionalized laminar flow,engineered LEV.

3 10 to 100 µg/m3 Transfers using direct coupling and closed systems, selected use of unidirectionalized airflow booths.

4 1 to 10 µg/m3 Totally enclosed processes; transfers using direct coupling; barrier/isolator technology.

5 < 1 µg/m3 Isolator technology; remote operations, fully automated.

Reprinted from







the infrastructure to support both areas.Each wet side train consists of a set of reactors and

receivers, provision for solids and liquid charging, a vacuumsource, and all attending support facilities (jacket systems,solvent/process transfer piping, and utilities). Reactor sizesrange from 8,000 to 20,000 liters.

Each dry side train consists of a crystallizer followed by acentrifuge and a dryer, or a combined filter-dryer. Threemilling rooms are provided on the dry side for size reductionpurposes, typically used only for the final bulk API.

The major features of solids handling equipment in theProcess Building are:

• contained charging stations by which the solids are intro-duced into the process main reactor without operatorexposure

• packout stations at the dryers and mills where the prod-ucts and intermediates are containerized

• intermediate packout and charging provisions betweenthe centrifuges and the dryers which allow interruption ofthe process flow to remove material and reintroduce it intonon-consecutive systems

Warehouse/DispensaryIncoming raw materials are subdivided and packaged forintroduction into the process in the dispensary, located incentralized warehouse. Incoming raw materials, which mayarrive in any of the several types of packages (bags, bulksacks, drums, and totes), are weighed into stainless steelIntermediate Bulk Containers (IBC) of various sizes rangingfrom 500 to 1500 liters. These containers are the primaryvessels used to convey pre-weighed charges of solid processmaterial to the manufacturing operation.

The Dispensary is a two-level facility designed to dispensecertain raw materials in Level 3 containment conditions.However, most of the raw-materials do not require this levelof containment. Operational measures also are taken tohandle certain Level 3 raw materials in the dispensary. Raw

materials are weighed and dispensed on the floor above andcollected into an IBC, located inside a downflow booth on thefloor below. Three of these setups of varying capabilities areprovided to handle expected throughput and wide spectrumof materials packaging including bags, drums, totes,supersacks, etc. Figure 1 shows a schematic representation ofone of these setups.

In addition to the weighing (e.g., bench and floor scales),transporting (e.g., pallet trucks), and conditioning (e.g.,delumper) equipment used in the dispensary itself, the ware-house also contains an IBC washer, full and empty IBCstaging areas, and shipping and receiving areas for supplyingand returning containers to/from the Process Building.

Process Building Operationsand Material Flow

To meet the containment requirements, it was imperative tomaximize the use of closed systems and use multiple orthogo-nal containment strategies (strategies that work indepen-dently of each other) where process connection/disconnectionis made, thereby potentially exposing the product into theexternal environment. This section discusses the operationand features of the solids handling equipment in the processbuilding.

Process Building Materials ReceiptThe materials from the central site dispensary are receivedinto the process building in an in-process staging area. Thematerials are in IBCs that are pre-weighed in the dispensaryand bar coded in order to avoid mix-ups. The materials arestaged as batch “kits” (sets of containers filled with all of thesolid material required to produce a single batch of interme-diate or product) and held until needed on the charging floor.

Figure 1. Dispensary stack up.

Figure 2. IBC docking station.




Material TransportThe materials are transported throughout the building byelectric forklift or by hand pallet truck. The movement fromthe staging area to the production area requires the materialsto be placed in an air lock to enter any clean areas (centrifug-ing, drying, and milling) and to be delivered directly to anyother use areas.

Material Charging FloorWhen batches of materials are delivered to the charging areaon the top operating level, they are staged in the staging areain front of the appropriate charging station (e.g., for reactors,mills etc.).

Reactor Charge Booth OperationThe main reactor in the process area is served by its ownsolids charging station, which is located on the floor above thereactor. A fixed chute provides the route for conveying thesolids from the IBC docked to the station to the reactor. Eachstation can charge the contents of an IBC to its reactor or canbe converted to charge from individual drums. Either opera-tion is designed to be effected in a contained manner. Thepreferred container is the IBC. However, the design is flexibleto allow the use of drums in special cases. Each charge stationis enclosed in a down flow booth. Figure 2 shows an IBCdocking station used for reactor charging.

The booth is set up with a docking device to receive theproper container for the charge (IBC or drum). Then thematerials are brought into the booth. The IBC is docked or thedrum is placed into the inverter.

In the case of an IBC, the dock station is actuated and theIBC is discharged. Following discharge, the IBC is discon-nected and undocked, weighed for a check tare, and sent tothe soiled IBC holding area.

In the case of drums, the pre-weighed drums are chargedand the empty drums are sent to the waste disposal area forremoval.

Dryer DischargeThe packout stations below the dryers are designed for thecontained discharge of dried material into IBCs. A containedIBC filling head is used to maintain Level 3 containmentduring filling. The dryer discharges via this IBC filling headinto an IBC.

Clean and empty IBCs are shipped from the warehouse.The IBC is stored in the in-process staging area when itarrives. When needed, it is placed in the dryer floor air lockto be picked up with a clean hand truck. The IBC is then taredand placed below the filling head. The filling head is thenlowered to mate with the IBC and dryer discharge is started.Once filled, it is weighed and staged for feeding to the mill.MillingAn IBC is placed on the docking station above the mill, and adrum is placed in a drum packout booth below the mill. Thedrum packout head incorporates a continuous liner system -Figure 3. The milling is started and the drums are changedout as required. The drums are tared before loading and

weighed after loading. The filled drums are transferred to theshipping area to be sent to the warehouse. The empty, soiledIBCs are sent to be washed in the warehouse.

Charging of Wet Cake The charging of wet cake into stainless steel drums is onlyrequired in an upset condition, such as a batch problem or adryer malfunction. This is done using a portable drum pack-ing head with fume and dust extraction. This also means thatany charging to a dryer from drums only be done for similarreasons. Charging the stainless drums to the dryer is accom-plished by removing a spool of the centrifuge charge chute,placing a lip seal on the open end of the chute, and chargingdrums via a portable drum inverter. The drums will be fittedwith cones, which mates with the lip seals. A portable extracthood will be provided at the point where the drum cone meetsthe lip seal.

Small Scale AdditionsSmall additions of dry ingredients to the process vessels (e.g.,reactor, crystallizer) are performed by using containersequipped with split-butterfly valves. The active butterflysection is attached to the process vessel and the passivebutterfly section is attached to the container. The pre-weighed

Figure 3. Drum packout head with a continuous liner.




Figure 4. Warehouse dispensary layout and material flow.

container, received from the dispensary, is manually lockedonto the active half of the split-butterfly valve on the processvessel. The split butterfly valve is then opened to dischargethe material and the empty container is returned to thewarehouse for cleaning.

CleaningThe portable docking stations are taken to a wash area in theprocess building and cleaned along with the used drum cones.The IBCs are transported to the warehouse for washing andclean storage. Clean IBCs are then filled in the dispensary ordelivered empty to the process building as needed.

Warehouse and Dispensary Operationsand Material Flow

The key to implementation of the process solids handlingscheme described above is the process material warehouseoperation. The basic premise of the solids handling design isthat all solid process raw materials will be prepared in acentral dispensary located in the warehouse. An additionalstipulation is the use of IBCs as a primary means to transportprocess solids from point to point. This requires that facilitiesbe included in the warehouse to clean and store these contain-ers. This section discusses the operation and features of thewarehouse and associated dispensary.

Material Flow and Layout ConsiderationsThe warehouse is designed to service the process building. Itsfunction is to receive, sample, inventory, and dispense rawmaterials destined for use in the process building, and toinventory and ship out the products manufactured in theprocess building. Raw materials are received in drums, totes,and bulk bags of assorted sizes. Provisions are made tohandle certain materials under Level 3 containment condi-tion in the warehouse dispensary.

Personnel and material flow within the warehouse anddispensary is to be conducive to GMP. Traffic flow is arrangedsuch that pass-through handling is used wherever appropri-ate (e.g., IBC washing, dispensary materials flow, etc.).Where not feasible, traffic flow is patterned such that rawmaterials and finished goods do not follow common pathsduring handling. Similarly, non-qualified materials boundfor quarantine and qualified materials being removed for usefollow different routes.

Within the warehouse, materials enter through the re-ceiving dock and exit through either the dispensary or theshipping dock. Innocuous waste products (outer packaging,wrapping etc.) are disposed through the trash compactor.Non returnable primary packaging, which may contain chemi-cal residue, are decontaminated according to the local re-quirements before being disposed of (resale, incineration,compaction etc.). Returnable primary containers are washedand decontaminated before being stored prior to being re-turned to the supplier. Incoming materials, outgoing materi-als, and waste products remain segregated at all times.

Material flow requirements within the dispensary also aresimilar. Components for manufacturing kits and clean IBCsenter the dispensary via a materials airlock. Waste packag-ing materials generated within the dispensary are baggedand tagged for disposal. Materials assembled into manufac-turing kits are transferred from the dispensary through thematerials airlock and staged at the dispensary shipping dockfor transfer to the process building. Incoming materials,outgoing manufacturing kits, and waste materials remainsegregated at all times. Primary containers are treated inmuch the same way as in the warehouse.

Secondary containers (IBCs) leave the warehouse filled aspart of manufacturing kits from the dispensary shippingdock. The empty, soiled containers are returned to the ware-house at a separate dock where they are staged for cleaning.




Figure 5. Weighing funnel located at the upper level.

The IBCs pass through the washer before entering the ware-house for clean container staging.

Dispensary OperationDispensary personnel enter the dispensary gowning room intheir plant whites. They complete their gowning procedure,including a one piece Tyvek suit with boots and gloves, andproceed into the dispensary. For emergency situations, suchas a break in containment, battery operated HEPA filteredbreathing air packs or other appropriate personnel protec-tion devices are available.

Raw material containers are transferred from the dispen-sary staging area into the dispensary airlock. Dispensarypersonnel retrieve the containers from the airlock and trans-fer them into the appropriate weigh booth via the cleancorridor. The containers are positioned on the upper level todischarge their contents through the floor into IBCs below.The IBCs are located on weigh stations, which indicate and/or control the flow of material into them.

Weigh Booth OperationSupersacks are handled in a weighing station equipped withsupersack handling and discharging equipment. Thesupersacks are brought into the weighing station by forklifttruck and positioned above the discharge hopper.

Drums, bags, and cardboard boxes are handled in one ofthe three weighing stations equipped with a weigh funnel -Figure 5. Drums are mated with a drum cone and attached toa fixed drum lift/inverter before being tipped into the weighfunnel. Sacks and boxes are tipped directly into the funnel.When the correct weight is registered in the funnel, thecontents are released into the IBC below.

Small Scale DispensingA separate small weigh room is located in the dispensary areafor dispensing small quantities of dry ingredients into a

container fitted with a split-butterfly valve. This operation isperformed under a laminar flow booth equipped with a benchweigh scale.

Container, Pallet, and Appurtenance Washingand StorageUsed IBCs are returned to the Warehouse Building from theProcess Building and are unloaded onto the washer receivingarea and transferred into the IBC wash area. IBC washersare utilized to clean the IBCs inside and outside. Containersare loaded onto the in-feed conveyor of the washer and are fedautomatically into the washer. The washing cycle is vali-dated and may vary according to the material to be removed.At the completion of the washing cycle, the containers areejected from the washer cabinet and are transferred byelectric forklift truck or pallet jack to the clean pallet stagingarea.

Soiled plastic pallets are staged, ready for washing close tothe in-feed of the pallet washer. They are manually loadedonto the washer in-feed. Pallets are transferred through thewasher and drying section. Upon exiting the drying section,pallets are removed from the washer by hand and stacked fortransfer to the pallet staging area.

ConclusionSolids handling is an important aspect of the overall multi-product bulk API facility. IBCs are a perfect choice totransport process solids material in these facilities, as theycan easily handle the range of solids material typicallyinvolved. IBCs also can be fitted with suitable loading anddischarging systems to not only handle poorly-flowing ma-terials, but also to meet varying level of containment re-quirements. Integrating suitable personnel and materialflow features, conducive to operation and GMP require-ments, into the overall facility layout is another key tosuccessful design.

About the AuthorsPrashant Desai is a Lead Process Engineerat Fluor Corp. He has more than 15 years ofexperience in process design for bulk phar-maceuticals, fine chemicals, specialty chemi-cals, and related industries. He is knowl-edgeable in process development, optimiza-tion, plant capacity and scale-up analysis,material and energy balance, utilities, eco-

nomic studies and evaluations, process flow diagrams, P&IDs,and instrument and equipment specifications. He has exten-sive field experience including validation of equipment, sys-tems, and facilities. He holds a BS in chemical engineeringfrom Nagpur University, and an MS in chemical engineeringfrom Bombay University. Fluor Corp. provides services on aglobal basis in the fields of engineering, procurement, con-struction, operations, maintenance, and project manage-ment.




Pramod K. Biyani is a Process Engineer atFluor Corp. He has more than 15 years ofexperience in the biotech, pharmaceutical,and chemical process industry. His experi-ence encompasses process development, con-ceptual and detailed process design, start-up, commissioning, and validation activities.He supervised engineering design for several

manufacturing facilities including facility integration as-pects. His biotech work focuses on process development anddesign of mammalian cell culture based processes to producebiopharmaceuticals, vaccines, blood substitutes, and DNAdiagnostic kits. His pharmaceutical work has been in theprocess design of manufacturing facilities to produce organicsynthesis based Active Pharmaceutical Ingredients (APIs),including highly potent APIs. He holds a BS in chemicalengineering from Indian Institute of Technology, Bombay,India, and an MS in biochemical engineering from the Uni-versity of Houston.

Fluor Daniel, 100 Fluor Daniel Dr., Greenville, SC 29607.


Cycle Time Analysis


This articleanalyzes thenecessity of apharmaceuticalexpansionproject or newplant byattempting tounderstand thebusiness andthe productioncapability of thefirm.

Using Cycle Time Analysis to EnhanceOperations and Improve Yield

by Robert F. Dream

Introduction

As pharmaceutical manufacturing sitesgrow and production demands in-crease, the question will arise: Howshould we best use existing operations

to meet increasing demand? Is it time to pro-cure a new line or build a new facility? Chal-lenges will increase as manufacturing spans tomultiple sites, numerous countries, and manyregulators with different regulatory back-grounds.

Project selection takes on different faces indifferent corporations. While the overall goal ofany project is to improve customer satisfactionand profitability, some projects will focus onindustrial processes and others will focus oncommercial processes. From the author’s pointof view, projects must be linked to the highestlevels of strategy in the organization and mustbe in direct support of specific business objec-tives.

The project(s) selected to improve businessproductivity must be agreed upon by both busi-

ness and operational leadership, and someonemust be assigned to “own” (be accountable for)the project and to execute the project. In thisarticle, we will introduce a means to analyzethe necessity of a pharmaceutical expansionproject or new plant by attempting to under-stand the business and the production capabil-ity of the firm before diving into building a newfacility. The following will be considered: YieldRate, Cost of Poor Quality, Capacity, CustomerSatisfaction, Internal Performance, Design, andSupplier Quality.

In order to understand the product(s), con-sider what and why a project is proposed. Whatis going to be manufactured and what capacityincrease is needed? Establish if the product(s)is being manufactured and if an increase incapacity is needed and/or additional manufac-turing capability of new product(s) is the issue.This will provide a road map for what we needto study and what data we have to collect, andhow to analyze the data.

If the product(s) exits, then we have to col-

Figure 1. A flow chartdepicting interview, datacollection, and analysissupporting Phase 0,Phase I, and Phase II ofthe S4.

Reprinted from





Cycle Time Analysis


Figure 2. Material Flow Diagram of process line investigated usingthe GAP(I) and GAP(II) matrices. Pinch Points are highlighted.

lect marketing data, manufacturing data of existing and newequipment, and a marketing forecast for now and where thefirm wants to be in future years (say three, five or 10 years).If the product is new, existing production data will be re-placed with pilot plant data and pilot plant equipment datawill be renewed instead of existing equipment data. Byselecting a format using Excel and/or another data baseplatform, the analysis will begin by looking at the biggerpicture, and produce options for the path forward. The pro-cess here is a mini-Six Sigma process localized to the project(s).

The following discussion will refer to “the Capacity En-hancement Tool,” which is based on utilizing “Six SigmaSmarter Solutions (S4),” i.e., Phase 0: Deployment Strategy;Phase I: Measurement; Phase II: Analysis; Phase III: Im-provement; Phase IV: Control.

When a project is funded, it is based on the firm’s managementdecision that the company has data supporting a capacity in-crease or change. The Capacity Enhancement Tool is an inte-grated collective of chosen project(s), collected data from market-ing, operations, and engineering functions. The data is used tosupport the definition of cycle time and required for the analysisto determine the optimum solution to implement the project as ananswer to the need of the marketability of the product in its bestpossible way. The results of the process must be implemented bychoosing one or more of the solutions produced. Then, furtherdeveloping/refining the choice to a final design for the project.

The following definitions will help lead-in to the process:

Cycle TimeCycle time is the total time from the beginning to the end ofthe process, as defined by you and your customer. Cycle timeincludes process time, during which a unit is acted upon tobring it closer to an output, and delay time, during which aunit of work is spent waiting to take the next action.

In a nutshell, cycle time is the total elapsed time to move

a unit of work from the beginning to the end of a physicalprocess. (Note: Cycle time is not the same as lead time).

Some of the most important data in any line balancingproject is the cycle time. In a paced line, the cycle time is oftenmeant to be the time it takes before the product leaves aworkstation and moves to the next one in the line. By thisdefinition, the cycle time is the same for all workstations inthe line. However, this definition is often too restrictive: inmany real lines, it is desirable to have a certain “reserve” oftime at the workstations at the end of the line so that possibleperturbations (e.g., equipment downtime) can be absorbedeasily by those workstations.

Optimum Line (OptiLine) defines the cycle time as thework time that should be spent on a workstation. As such, thecycle time is defined for each of the workstations separatelyand can differ from one workstation to another; in particular,it can decrease toward the end of the line. OptiLine’s optimiz-ing algorithm is capable of taking the varying cycle time intoaccount.

Because the cycle time is allowed to vary among worksta-tions, all the workstations and their respective cycle timesmust be fixed before the optimization can take place. Duringoptimization, the cycle time is taken into account in thefollowing manner. Because the objective of the optimizationis to balance the workload among workstations, the optimiz-ing algorithm aims to assign operations to workstations insuch a way that the ratio of the work time and the cycle timebe as equal as possible across all workstations.

For example, suppose that there are two workstations in theline, and the first workstation’s cycle time is double the cycletime of the second workstation. The optimizing algorithm willattempt to assign the operations such that the first workstationwill have double the work time of the second workstation. Incases where there are workstations with several operators, thework time on a workstation is taken to be the longest work timeamong all the operators assigned to the workstation.

Note that in real-world applications, it is usually impossibleto find an assignment of operations to workstations that wouldperfectly match the cycle times. As a consequence, if the cycletimes specified for the workstations are too tight compared tothe amount of time necessary to carry out the operations, thecycle time can be exceeded on some or all workstations. In thatcase, it may be necessary to add workstations (or operators) andrerun the optimization in order to find a feasible solution.Conversely, if the work times obtained in a solution are waybelow the available time, it may be possible to eliminateworkstations (or operators) and increase the efficiency of theline.

GAP AnalysisThe GAP analysis is a process of determining and evaluatingthe variance or distance between two items’ properties beingcompared.

• GAP(I): Comparing the state of a station (Equipment/System) at present condition vs. the needed state.

• GAP(II): Comparing the state of an integrated line/facility


Cycle Time Analysis


at present condition vs. the needed state. This is anintegrated situation of multiple equipment/systems ana-lyzed individually in GAP(I).

The GAP analysis is the fastest, most efficient way to assesshow your quality system measures up to the requirements ofa particular standard and to define the logical next steps inthe implementation/registration process.

• Assess compliance to the standard.• Identify missing elements required by a standard.• Determine if resources are adequate to complete the

implementation/registration project.• Identify training needs.• Define how best to proceed with registration or implemen-

tation.• Determine how to address the requirements of a standard.• Assess the efficacy and completeness of records and docu-

mented procedures.

ProcessProject Definition• Understand project background and your objectives.• Prepare an agenda of evaluation activities.• Determine the method for reporting for gaps.

Project Implementation• Tour the facility.• Conduct interviews with key process owners.• Review existing documentation.• Conduct internal audit of all major areas and processes.• Review compliance with applicable federal, state, and

local regulations and requirements.

Project Conclusion• Deliver Gap Analysis report to management (optionally,

deliver findings in an executive presentation).• Provide technical support on corrective action for report

findings.

Duration

The duration of the Gap Analysis depends upon such vari-ables as the size of the organization, geographical factors,organizational complexity, and the required level of detail.Generally speaking, the process will vary depending on thedepth of analysis required. The final schedule will be deter-mined after the project definition phase.

At the completion of the interview and inspection process,deliver a professionally written report detailing the findingsand suggestions. Also, conduct an executive presentation ifyou prefer a more interactive review of the findings.

The only way to know if your existing processes are givingyou the highest return on investment is to have a GapAnalysis performed.

The Capacity Enhancement ToolThe Capacity Enhancement Tool is based on Cycle TimeAnalysis and is used to examine process unit operationsacross a wide variety of different biopharmaceutical/pharma-ceutical plants and identify the equipment items in the linethat are acting as a constraint to current or forecasted output.Having identified the pinch points, the tool can be used in apredictive manner to quantify how modifications to the pro-cess line can result in improved capacity and can be used tominimize the capital expenditure required to reach requiredcapacity. The tool also can be used to indicate how existingintegrated equipment trains can be used more effectively toincrease output (product optimization).

The analysis is applicable to any process: Active Pharma-ceutical Ingredients (API), Oral Solid Dosage Form (OSD),Biological, Sterile Dosage Form, Ointments/Creams/Topical,Suspensions, Liquids, etc. Case studies (projects) have beenperformed to represent all of the above manufacturing forms.This analysis also has been applied to complex multi-productfacilities. This tool recently has been applied to increase thecapacity (by 50%) on an OSD, multiple Stock Keeping Unit(SKU), multiple country product for a confidential client. Italso has been successfully utilized to carry out worldwideproduct optimization for a second client of fill/finish pharma-ceuticals product manufacturer. The third example is anoptimization of multiple products across multiple dosage

Figure 3. Forecast Production Capacity Matrix which breaks down capacity in terms of tablets, kg, batches, and cartons based onpredicted demand for 2010. This is based on a similar matrix (Actual Production capacity) derived from existing capacity data.


Cycle Time Analysis


forms for another US-based multi-nation client in LatinAmerica. The fourth is a tripling of the capacity for a US-based firm among some of the examples.

An illustration of the process and data collection andanalysis is laid-out in the flow diagram depicted in Figure 1.This data collection and analysis will be described further indetail with the article.

For the purpose of cycle time analysis, operating andtheoretical data information is compiled in a matrix to repre-sent production capacity. This is applied to the process linefor a group of products. This matrix is then duplicated andmodified to indicate forecast production requirements. Thedata in the GAP(I) analysis matrix (Figure 4) shows eachoperation in the process line individually and the GAP(II)analysis matrix (Figure 5) combines this information toillustrate how the process line operates as a unit.

The process will be presented further in details on how thisprocess is applied and a case study involving a typical tabletproduction facility is herein included.

Capacity Enhancement Tool: The DetailsA breakdown of the steps required to implement the capacityenhancement tool and of the data that needs to be accumu-lated is included.

Establish a BaselineThe initial part of this process is to follow the flow of materialalong the process line. This includes preparing “as-built”drawings of the area and material flow diagrams. The “as-built” and the line “as-it operates” will form the base line forthe study and use marketing future forecast and equipmenttheoretical parameters to establish the needed change.

Gather InformationIt is essential that detailed and accurate data is obtained sothat a comprehensive analysis can be carried out. Communi-cation with all members of the production team is vital in orderto establish what is actually happening during production.Information can be gathered in a number of different manners,including questionnaires, meetings, and existing data.

Once the initial data has been compiled from separatesources, it will be collated and presented to the operatingteam for verification before analysis proceeds.

The required data can be split into a number of categories.The main categories are detailed below, but these may varydepending on the individual process line. This information isrequired for all of the products, product strength, and pack-aging permutations that are manufactured on the line.

Actual and Forecast OutputThe current output of the process line and the forecastedrequirements are essential for each product, product strength,and packaging permutation. Historical, continuously-recordeddata from the operation stripped of any modifications orinterpretation is the ideal.

Batch SizeThe batch size of each product and product strength isrequired, as well as how the batch is compiled and controlled.Number of Sub-BatchesSome of the equipment may be sized for loads that are smallerthan the batch size; in this case, the batch is divided into subbatches. The number of sub-batches (or lots) per batch isrequired.

Tablet Size, Weight, and ShapeTablet size, weight, and shape determine the number oftablets produced per batch and the how much waste isgenerated.

Packaging ConfigurationsThe number of blisters (or strips or bottles) per carton and thenumber of tablets per blister/strip/bottle affects the speed ofthe packaging line. The packaging section will operate atdifferent speeds for different packaging configurations. There-fore, it is necessary to know how each product is packaged.

The Working ScheduleDetermining the normal working hours of the plant and theshifts worked allows the theoretical process hours available

Figure 4. Typical GAP(I) analysis matrix, detailing the Granulation step.


Cycle Time Analysis


Figure 5. The GAP(II) analysis matrix for the entire process line summarizing the GAP(I) analysis results for each unit operation.

for each unit operation to be calculated.

Set-Up Time for Each Unit OperationThe time required to set up equipment decreases the avail-able process hours and needs to be incorporated into theanalysis.

Wait Time for Each Unit OperationProcess lines are not always designed to allow for the continu-ous movement of batches along the line. Occasionally, it isnecessary for a batch to wait until the equipment for the nextstep in the line is available. This time reduces the availableprocess time of the equipment and the output of the machine.

Cycle Time for Each Unit OperationThis is the actual time required for the batch to complete itscycle in the machine.

Cleaning Time for Each Unit OperationEquipment cleaning time is product and equipment specific.The cleaning time per batch must be calculated. Cleaning ispart of production and increases the downtime of the equip-ment, thereby reducing the available process hours.

Process Equipment Utilization for Each UnitOperationEquipment items are not available for production 100% ofthe time due to downtime and maintenance. The processequipment utilization is shown as a percentage of the totalavailable time for production. This percentage also may ormay not include the set-up time and cleaning/comprehen-sive cleaning time in situations where the data available forthe process does not specifically break out the set-up andcleaning hours.

WasteAll production lines produce a certain amount of wasteproduct, either product lost during the production (formula-tion compounding, etc.) during product transfer or productthat does not meet the required standards. The capacityfigures are adjusted to incorporate this waste product.

Data AnalysisOnce all the production data described above has been col-lected for each product, product strength, and packagingpermutation, it is combined together into an Actual Produc-tion Capacity Matrix. This matrix is then duplicated andmodified to reflect the forecast capacity requirements in theForecast Production Capacity Matrix. These matrices offerthe actual and forecast annual capacities in terms of numberof tablets, weight, number of batches, and number of cartons.

A GAP(I) matrix is then compiled for each unit operation,for each product, product strength, and packaging permuta-tion. The results in a single figure, represent the actual (andforecasted) production for the totality of different productpermutations in a given equipment unit as a fraction ofmaximum theoretical capacity. For forecast calculations, thisfigure should not exceed 1.0 (or 100%) if forecast require-ments are to be met with the existing process line.

Finally, the information from each individual GAP(I)matrix is used to create a GAP(II) matrix which summarizesthe GAP(I) information for the process line as a whole andallows pinch points to be identified for both actual andforecast product figures.

Capacity Improvement OptionsIf the GAP(II) matrix for the forecast figures indicates thatthe theoretical maximum capacity requirements will be ex-ceeded for one or more equipment items, then differentoptions for modifying the existing process line will need to beconsidered. As-built drawings are used to gauge the feasibil-ity of these options and the family of matrices already createdis used to quantify the benefits of each option. The optionsmight include the following:

• scheduling and procedural changes to optimize capacity ofan existing unit

• modifications to an existing equipment item to increasecapacity

• replacement of an existing equipment item with a newunit of higher capacity


Cycle Time Analysis


• introduction of a new process line(s) in parallel to theexisting process line(s)

Capacity Enhancement:A Typical Case Study

A complete oral solid dosage process line, from dispensing ofraw materials to packaging, has recently been analyzed for aconfidential client by using this method.

Once the analysis was complete, it became apparent fromthe GAP(II) matrix that under normal operation, the linewould not meet the forecast demand. After scheduling changeswere introduced, the line was capable of meeting demand onall but two units. The GAP(II) matrix highlighted that theTablet Press and the Cartoner would not meet the futuredemand of the plant - Figure 5.

The analysis was completed as follows: the Actual Produc-tion Capacity matrix was assembled first and this formed thebase line for the study. The matrix was then revised inaccordance with the figures based on predicted demand for2010 to generate the Forecast Production Capacity matrix -Figure 3. This information, in combination with equipmentspecific data, allowed the compilation of the GAP(I) matrices.A typical example is shown for Granulation - Figure 4. Usingthe GAP(I) matrix results for each of the unit operations, aGAP(II) summary matrix could be created which identifiedpinch points for the process line as a whole. Once this wascompleted, it became clear that the tablet press and cartonerwere the bottleneck unit operations - Figure 5.

A number of options were presented to the client and a wayforward was agreed upon as outlined below to ensure that theforecast requirements were met with minimum disruption tothe existing process.

Tablet PressIt was concluded from the analysis that the existing TabletPress would not meet the forecast output of the plant. It wasdecided that the most efficient solution to this problem was toreplace the press with a new one. Some of the issues that wereencountered during the design were the following:

• large diameter tablet• setting up of trials to produce this large tablet• replicating the conditions that exist on site during the

trials – humidity, angle of off-loading arm, and feeding ofproduct to the tablet press

• time scale of the project

CartonerThe Cartoner also was found to restrict the capacity of the lineas a whole. Various options, including modification of theexisting cartoner and introducing a second cartoner into theline, were offered as options.

For alternative options under review, it is possible torecalculate the matrices to allow an easy cost and spacecomparison for those options that eliminate the pinch points.This work was completed for the options under review, whichresulted in a saving of approximately 90% in both capitalcosts and space required between the final option chosen andthe original option of installing a second production line.

ConclusionThe process of the S4 rendered that we could have six optionsthat each in its own way will increase the manufacturingcapability of the products in question under this project tomeet the future demand; meet the marketing forecast withfew additional percentages as buffer. The summary of theoptions are as follows: go forward with the proposal as statedand go with the project as originally proposed for ($90 mil-lion* £50 million); improve the existing operations through-put at the pinch point with different type of medications toenhance the operation which the cost ranged between ($5.4million*/£3 million to $18 million*/£10 million). Additionalcosts on upper end options may be attributed to improve-ments made on the manual packing operation of the line.

*Used $1.80 exchange rate. Project year: 2004.

References1. Breyfogle, F. W., III, J. M. Cupello, and B. Meadows,

“Managing Six Sigma,” 2001, John Wiley and Sons, Inc.

About the AuthorRobert F. Dream is Director Pharmaceuti-cal/Biotechnology for CH2M HILL LockwoodGreene. He has 24 years of industrial experi-ence, which include cell culture, microbialfermentation, DSP, master planning, design,regulatory compliance (FDA and EMEA),cycle-time analysis, process scale-up, pro-cess yield and optimization, and manage-

ment of company assets. His work has been published innumerous industry textbooks and technical journals, and hehas participated in seminars and technical conferences forISPE, Pennsylvania Biotech Association (PBA), Interphex,InterphexCalifornia, AIChE, ASME, and has lectured atuniversities. He is a registered professional engineer and isan active member of ISPE. He is a graduate from IllinoisInstitute of Technology (BS and MS) and Drexel University(PhD).

CH2M HILL Lockwood Greene, 10123 Alliance Rd., Suite300, Cincinnati, OH 45242.


Drug Targeting Delivery


This articlepresents thefindings of areport thatdemonstratesthe potential forimmuno-liposomes astumor-targetedvehicles.

Tumor-Targeted Immuno-Liposomesfor Delivery of Therapeutics andDiagnostics

by Tamer A. Elbayoumi and Vladimir P. Torchilin

Figure 1. Tumortargeting vianucleosome-specificmonoclonal antibody2C5-modified long-circulating liposomes.

Introduction

The main goal in treating a patient witha drug is to maximize the potential ofproducing a therapeutic response whileminimizing the unacceptable toxicity.

The main problems currently associated withsystemic drug administration are: evenbiodistribution of pharmaceuticals throughoutthe body, the lack of drug specific affinity to-ward a pathological site, the necessity of alarge total dose of drug to achieve high localconcentration, and most importantly, non-spe-cific toxicity and other adverse side-effects dueto high drug doses. Drug targeting, i.e., pre-dominant drug accumulation in the target zoneindependent of the method and route of drugadministration, may resolve many of these

problems. Currently, the principal schemes ofdrug targeting rely on the application ofnanocarriers to deliver the drug into the af-fected zone. The most successful targeting strat-egies involve physical targeting (based on ab-normal pH value and/or temperature in thepathological zone), passive drug targeting (spon-taneous drug accumulation in the areas withleaky vasculature via the Enhanced Perme-ability and Retention-EPR-effect), and/or tar-geting using specific “vector” molecules (ligandshaving an increased affinity toward the area ofinterest).1

Liposomes are nano-vesicles formed by con-centric spherical phospholipid bilayers thatencapsulate an aqueous space. These particlesare completely biocompatible, biologically in-

Reprinted from







ert, and cause very little toxic or anti-genic reactions. For drug delivery pur-poses, various water-soluble drugs canbe entrapped in the liposomal inneraqueous space and hydrophobic drugscan be incorporated into liposomalmembrane.1 Liposomes of first genera-tions suffered from rapid eliminationfrom the systemic circulation mostlydue to uptake by the cells of theReticulo-Endothelial System (RES).1

Coating of the liposomal surface withwater-soluble, flexible polymer, com-monly Poly Ethylene Glycol (PEG),prevented liposomes from the interac-tion with opsonins in the blood, whichretarded their uptake by the RES.2

These PEGylated liposomes offered notonly increased circulation time,3 butalso were small enough (100 to 200 nm)so they can extravasate during theirpassage through the highly permeablevasculature of tumors, thus enablingtheir substantial accumulation in theinterstitial fluid at the tumor site, aphenomenon known as EPR effect.Additionally, this PEGylated liposometechnology decreased the accumula-tion of their cargos in non-targetedtissues.4

Development of Long-CirculatingLiposomes (LCL) allowed for creationof Doxil® - commercial formulation ofdoxorubicin, incorporated into long-cir-

culating PEG-coated liposomes, whichdemonstrates superior efficiency intumor therapy and diminished adverseeffects. Doxil® is currently approved forthe treatment of AIDS-related Kaposi’ssarcoma and ovarian cancer.5

Moreover, the use of liposomes ingeneral and the PEGylated type in par-ticular have been successfully employedas carriers for diagnostic moieties usedwith all the imaging modalities:gamma(g)-scintigraphy, Magnetic Reso-nance Imaging (MRI), and ComputedTomography (CT).6 Owing to their uniqueability to entrap different label metals,via the water-soluble chelator, DTPA,7

or the membranotropic amphiphilic che-late, DTPA-PE.8 LCLs were shown toaccumulate sufficient amount of reporteragents into the area of interest, generat-ing the appropriate intensity of signal todifferentiate this area from surroundingtissue. The use of these passively tar-geted LCL as carriers for contrast agentsis currently a major area of cancer re-search and clinical trial data on 111In-labeled LCL are impressive for the de-tection of lung cancer,9 skin cancer, andother malignancies.10

Several attempts were made to fur-ther improve the delivery efficiency ofLCL by actively targeting it with vectormolecules specific to receptors typicalfor cancer cells. Most of these vectormolecules being investigated now arespecific to certain types of tumors. Un-like these molecules, certain monoclonalAntinuclear Autoantibodies (ANAs)with nucleosome-restricted specificitypossess an ability to recognize a broadvariety of tumors. The monoclonal non-pathogenic ANAs, 2C5, and 1G3 de-rived from healthy aged BALB/C mice,for example, can recognize the surfaceof numerous tumors, but not normalcells. Apparently, tumor cell surface-bound nucleosomes (intact fragmentsof nuclear material, NSs) originatingfrom apoptotically dying neighboringtumor are the targets of these antibod-ies on the surface of the variety of tumorcells - Figure 1.11 The NS’s release bydying tumor cells was hypothesized as aself-defense mechanism to protect thesurviving tumor from host immune at-tack.12 Hence, the subsequent increasedbodily production of anti-NS cytotoxic

Figure 2. Schematics of antibody conjugation reaction with pNP-PEG-PE (A) showing theHPLC profile for mAb 2C5 conjugation with 40-molar excess of pNP-PEG-PE, after 24hours (A), and the immuno-modification of Doxil® using the post-insertion method showingsize measurement for both plain LCL and for LCL modified with antibody.




antibodies, like mAb 2C5, is considereda response to repress this tumor self-defense.13

Our report describes utilizing themAb 2C5 as a targeting ligand to ac-tively target long-circulating liposomes,either encapsulating chemotherapeu-tic agents, like doxorubicin, or incorpo-rating 111In-radioimaging moeity in theirmembrane, toward diverse cancer mod-els, in vitro and in vivo. We have devel-oped a simple and efficient way to at-tach mAb 2C5 to the liposomal mem-brane without compromising its spe-cific activity or significantly affectingthe amount or the stability of the encap-sulated drug.14 Earlier, a convenientprocedure15 for the attachment of aminogroup-containing ligands to the lipo-some surface using the lipid-conjugatedPEG with its distal terminus activatedwith p-nitrophenylcarbonyl group (pNP)was reported - Figure 2, Panel A. In theoriginal design, the activated PEG-PE(pNP-PEG-PE) was first incorporatedinto liposomes, which then were re-acted with ligands of interest.15,16 In ourcurrent work, an alternative design wasused, where a protein was first modifiedwith an activated lipid derivative andthen incorporated into liposomes by co-incubating the micelles of PEG3400-PE-modified proteins with drug-loadedor radio-labeled liposomes - Figure 2,Panel B. An advantage of this approachis that the preparation of liposomes andthe modification of proteins are per-formed separately, allowing the choiceof optimal conditions for each step.14

This “post-insertion” technique was ear-lier shown to provide a quantitative andstable association of antibodies andother proteins, peptides, and polymerswith liposomes.14,17 Furthermore, thesimplicity of this method offers the greatopportunity for easy, reproducible, andcontrollable industrial production scale-up, as well as unlimited tailoring possi-bilities using various targeting ligandsand liposomal formulations.17

In this report, we also examined theanti-cancer efficiency of the developedtargeted liposomal doxorubicin and rec-ognition of various cancer cell linesalong with the preferential localiza-tion ability of the 111In-radiolabeledmAb 2C5-targeted formulation in can-

cer-bearing mice for adequate visual-ization of tumors.

Experimental MethodsPreparation of Immuno-liposomesTo prepare antibody (mAb 2C5 or non-specific IgG) conjugates with PEG3400-PE, 40 molar excess of pNP-PEG-PEdispersed in 10 mg/ml micellar solutionof octyl glucoside in 5 mM Na-citrate,150 mM NaCl, pH 5.5, was added to anequal volume of 6.7mM of protein (mAb2C5 or IgG) in Tris-buffered saline(TBS), pH 8.5. The mixtures were incu-bated for 24 hr at pH 8.3 at 4°C.14

To obtain doxorubicin-loaded lipo-somes modified with mAb 2C5 or non-specific IgG, proteins conjugated withPEG3400-PE [IgG(PEG-PE)30 or2C5(PEG-PE)32] were mixed in equalvolumes with Doxil® or LCL (composedof HSPC:CHOL:MPEG2000-DSPE in3:2:0.3 molar ratio). Then, the remain-ing octyl glucoside and free, non-incor-porated mAb 2C5 were removed bydialysis (250,000 Da. cutoff size).14

Physical Characterization ofLiposomes Evaluation ofLiposomal DoxorubicinContent and ReleaseThe retention of doxorubicin by lipo-somes during and after the incorpora-tion of PEG-PE-modified mAb 2C5 wasestimated by doxorubicin fluorescencein dialyzed Ab(PEG-PE)30/liposomemixtures, where samples were lysedwith 0.3 N HCl in 50% ethanol and thefluorescence of obtained solutions wasdetermined with Hitachi F-2000 fluo-rescence spectrophotometer at excita-tion wavelength of 475 nm and emis-sion wavelength of 580 nm.14

The in vitro release of doxorubicinfrom the different Doxil® formulationswas conducted in DMEM cell culturemedium containing 10% Fetal BovineSerum (FBS). Liposomes at a concen-tration of 0.5 mg/ml of doxorubicin,diluted in the media, were sealed intodialysis tubes with cutoff size of 12,000to 14,000 Da. Then, the liposomes-loaded dialysis tubes were incubatedinto 50 ml of the media for 48 hours at37°C with continuous stirring at me-dium speed. At various time points,

aliquots were withdrawn, and replacedwith equal volume of the media. Thedoxorubicine concentrations were thenmeasured at 485 nm using a Hitachi U-1500 spectrophotometer.18

Characterization of the InVitro Behavior of LiposomalFormulations FACS AnalysisCells of each type – murine colon carci-noma (C26), Lewis Lung Carcinoma(LLC), and human breast carcinoma(MCF-7) – were grown in 25 ml cellculture flasks until they reached aconfluence of 70%. The cells were de-tached by the repetitive pipetting, andthen washed twice with 1% bovine se-rum albumin in PBS, pH 7.4. Lipo-somes labeled with 0.5 wt % of fluores-cein conjugated with phosphatidyletha-nolamine (FITC-PE, Avanti Polar Lip-ids; total lipid concentration was in therange between 0-8 mg/ml) were addedto the washed cells, and the sampleswere incubated for 30 min at 4°C, in 5%CO2. After the incubation, the cells werewashed twice with PBS, live-gated us-ing forward vs. side scatter to excludedebris and dead cells and analyzed(10,000 cells in average count).14

Confocal FluorescenceMicroscopyAfter an initial passage in tissue cul-ture flasks, murine colon carcinoma(C26), and human breast cancer (BT20)cells were grown in 6-well tissue cultureplates. After reaching 70-80%confluence, the plates were washed withHank’s balanced buffer, pH 7.4, thentreated with 1% BSA in 2 ml/well DMEMand incubated for 1h at 37°C, 5% CO2.To these cells, mAb 2C5-modified Doxil®

(total lipid concentration of 1 mg/ml)was added and cells were incubated forboth 1h at 37°C, in 5% CO2. After theincubation, cells were washed withHank’s balanced buffer and stained withDAPI nuclear stain (20 µl, 100 µM) for10 min, after fixation in neutral buff-ered formaline (NBF) for 30 min. Fol-lowing this, individual cover slips weremounted cell-side down on glass slidesusing fluorescence-free glycerol basedmounting medium and cells were viewedwith a an inverted Zeiss confocal laserscanning microscope.




Cytotoxicity AssayThe cytotoxicity of various preparationsof the liposomal doxorubicin againstLLC, C26, BT20 and MCF-7 cells wasstudied using a MTS test after 24 hourincubation of liposomes with doxorubi-cin concentration of up to 200 µg/ml orequivalent concentrations of lipid and/or protein components, dispersed inHank’s buffer with cells grown in 96-well plates. A ready-for-use CellTiter96® Aqueous One solution was usedaccording to the manufacturer protocol.The cell survival rate was estimated bymeasuring the color intensity of thedegradation product at 492 nm using aplate reader. Assay was performed twicefor each cell line.14

In Vivo Tumor Accumulationof 111In-labeled Liposomes andGamma Imaging in MiceTumor ModelsApproximately 105 cells of 4T1 andLLC tumors were S.C. implanted in 8-week old BALB/C and C57/BL micerespectively, when the tumor diameterreached five to eight mm, mice wereinjected with 0.1 ml of 4 mg/ml 111In-radiolabeled LCL formulations via thelateral tail vein. At two to 48 hourspost-injections, blood was collectedusing a Pasteur pipette from the retro-orbital plexus of the eye, and then, the

mice were euthanized by cervical dislo-cation followed by excision of the tu-mor and surrounding muscle. Theamount of radioactivity was quantifiedas CPM using a gamma-counter. Theamount of the accumulated radioactiv-ity per gram of tissue and tumor-to-normal ratios were calculated.15 For g-radioimaging, mice were injected with55µci of the respective 111In-radiola-beled LCL formulations via the lateraltail vein and at different time intervalspost injection, imaging was performedusing a radio-isotope camera equippedwith high energy collimator andNnMAC computer.

Results and DiscussionPreparation andCharacterization ofLiposomal FormulationsIn order to combine the unique proper-ties of long circulating and mAb 2c5-targeted liposomes in one preparation,we have adopted the “post-insertion”technique that was shown earlier14 toprovide a quantitative and stable asso-ciation of antibodies and other pro-teins, peptides, and polymers with li-posomes - Figure 2. The MW of PEGderivative used in our experiments tomodify antibodies (PEG3400) was cho-sen to be higher than the MW of PEG inthe composition of original Doxil®

(PEG2000) to prevent possible “protec-tive” effect of the liposomal PEG coat-ing onto the liposome-incorporated an-tibody. The reaction yield (in terms ofthe number of PEG3400-PE groupscoupled to a single protein molecule)was estimated by the loss of primaryamino groups by antibody moleculesdue to formation of the urethane (car-bamate) bonds between PEG-PE andmAb 2C5. At all polymer/protein ratiosstudied, the reaction yield varied be-tween 75% and 90%, possibly depend-ing on the accessibility to the availablefree amino groups on the protein mol-ecule - Figure 2, Panel A.

The preservation of the specific ac-tivity of PEG-PE-modified mAb 2C5samples was studied by ELISA usingnucleosomes as a binding substrateand showed that the introduction of upto 32 PEG-PE residues per single mAb2C5 molecule did not impair the anti-body-target specific binding. Any lossin the specific activity of an individualantibody was demonstrated to be eas-ily compensated after the attachmentof multiple antibody molecules to theliposome because of a multi-point in-teraction between immuno-liposomesand their targets.14 After successfulconjugation of mAb 2C5 with the acti-vated polymeric linker PEG3400-PE, the2C5 (PEG-PE)32 conjugate incorporatedsuccessfully into the liposomal mem-brane through the PE anchor withoutinducing a significant loss of encapsu-lated doxorubicin or changing the re-lease profile of the original Doxil® for-mulation - Figure 3. Moreover, the in-tegrity of the PEG-coat of the lipo-somes and the surface sharge of theliposomes did not virtually change af-ter the immuno-coupling of the anti-bodies (IgG/mAb 2C5). On the otherhand, the size of the immuno-liposomes(Figure 2, Panel B) was 10-15 nm largerthan original Doxil®, due to the pres-ence of antibody-molecules, attachedvia longer PEG-linker to the liposomalmembrane. The net amount of the lipo-some-attached antibody was deter-mined by using the fluorescently-la-beled mAb 2C5 as well as using SDS-PAGE - Figure 3. It was found that 55-to-60 µg of the antibody was bound perµM of HSPC, which corresponds to

Figure 3. Characterization of mAb 2C5-modifed Doxil®. Release profile of doxorubicin fromdifferent formulations in serum-containing culture medium (A); Doxorubicin retention afterimmuno-modification of Doxil®(B); and SDS-PAGE analysis of mAb 2C5-modifed Doxil® forthe estimation of amount of liposomes-bound antibody (C).




approximately 80 antibody moleculesper single 100 nm liposome.

In addition, unlike control nonspe-cific IgG-liposomes, liposomes modi-fied with 2C5-PEG-PE demonstratedsignificant binding to nucleosomemonolayer in ELISA test, which con-firmed the preservation of specific ac-tivity by the liposome-bound mAb 2C5(data not shown).

In Vitro Activity of Immuno-LiposomesThe ability of mAb 2C5-modified lipo-somes to selectively recognize targetcancer cells was confirmed using bothfluorescence microscopy and flowcytometry analysis (FACS) - Figure 4,Panel A. In all studied cell lines, bothfluorescently-labeled 2C5-liposomesand 2C5-Doxil®, displayed significantlyhigher cancer cell binding at 4°C andcellular uptake at 37°C respectivelythan analogous non-targeted IgG-for-mulations. The confocal microscopyimages Figure 4, Panel B taken after 1hour incubation at 37°C with mAb2C5-Doxil® demonstrated a lucid and out-standing internalization of liposomaldoxorubicin compared to the IgG-modi-fied or original Doxil® controls. Thesefindings indeed support the cell-inter-nalization scheme conceived for thesespecifically targeted liposomes

Moreover, the in vitro cytotoxicityprofile of 2C5-modified Doxil® was sig-nificantly, five to eight times, strongerthan that of even the most toxic controlformulation, non-specific IgG-Doxil®.At doxorubicin concentration of 50 g/ml, the mAb 2C5-targeted Doxil® for-

mulations killed approximately 75% to85% of cells compared to 30% to 35% ofcells in case of IgG-analogue. At thesame doxorubicin concentration, theoriginal Doxil® did not kill more than25% of cancer cells.

In Vivo Tumor Accumulationand Visualization UsingImmuno-LiposomesUsing different murine in vivo models,the biodistribution data demonstratedthat tumor accumulation ratios of 111Inradiolabeled 2C5-modified LCL (by ad-dition of 0.5 M% of amphiphilic chelate,DTPA-PE to lipid composition), com-pared to the neighboring muscle werealmost double that of the non-targetedformulations starting almost six hourspost-injection (Figure 5, Panel A) despitethe somewhat shorter plasma half livesof the immuno-liposomes (approximately12 hours) compared to the native/plain

LCL preparation (approximately 17hours). The presence of the whole anti-body (IgG/mAb 2C5) on the liposomalsurface made more prone for RES up-take, i.e., higher clearance by liver andspleen, leading to accelerated clearanceof the immuno-liposomes. Moreover, thewhole-body direct gamma-imaging oftumor-bearing mice shown at six hourspost administration (Figure 5, Panel B)confirms the preferential distribution ofthe 2C5-modified 111In-labeled LCL com-pared to control radio-formulations to-wards both 4T1 and LLC tumors anddemonstrate the enhanced tumor visu-alization in all studied models.

ConclusionsThe successful modification of doxoru-bicin-loaded long-circulating liposomeswith the anticancer monoclonal 2C5antibody, which specifically recognizesvarious tumors via the tumor cell sur-face-bound nucleosomes, proves fur-ther enhancement in the cytotoxicityand the in vivo targetability of theformulation. The application of thisnovel targeted liposomal platform ofdoxorubicin provides a promising po-tential for an effective treatment aswell as visualization of diverse tumors.

References1. Torchilin, V.P. (2005). Recent Ad-

vances with Liposomes as Pharma-ceutical Carriers. Nat Rev DrugDiscov 4 (2), 145-160.

2. Allen, T.M. et al. (1991). LiposomesContaining Synthetic Lipid Deriva-

Figure 4. Flow cytometry analysis of the surface binding of mAb 2C5-targeted and controlliposomes, labeled with FITC-PE, in human breast carcinoma cells, MCF-7(A); and three-DConfocal fluorescence microscopy of murine colon carcinoma C26 cells (B) incubated withmAb2C5-modified Doxil® formulation for one hour. Red color represents doxorubicindistribution and blue color represents nuclei of cells stained with DAPI stain.

Figure 5. In vivo tumor accumulation of various 111In-labeled liposomal formulations usingmurine Lewis lung carcimona (LLC) model (A) (n = 5, results indicated± SD); Whole bodygamma-imaging of murine breast 4T1 tumor-bearing mice, six hours after injection with2C5-modified 111In-labeled liposomes, Circles indicate tumor locations (B).




tives of Poly(ethylene glycol) ShowProlonged Circulation Half-Livesin Vivo. Biochim Biophys Acta 1066(1), 29-36.

3. Klibanov, A.L. et al. (1990).Amphipathic PolyethyleneglycolsEffectively Prolong the CirculationTime of Liposomes. FEBS Lett 268(1), 235-237.

4. Maeda, H. et al. (2000). TumorVascular Permeability and the EPREffect in Macromolecular Thera-peutics: A Review. J Control Re-lease 65 (1-2), 271-284.

5. Gabizon, A. et al. (1994). Clinical Stud-ies of Liposome-Encapsulated Doxo-rubicin. Acta Oncol 33 (7), 779-786.

6. Torchilin, V.P. (1996). Liposomes asDelivery Agents for Medical Imag-ing. Mol Med Today 2 (6), 242-249.

7. Tilcock, C. et al. (1989). LiposomalGd-DTPA: Preparation and Char-acterization of Relaxivity. Radiol-ogy 171 (1), 77-80.

8. Ahkong, Q.F. and Tilcock, C. (1992).Attachment of 99mTc to LipidVesicles Containing the LipophilicChelate Dipalmitoylphosphati-dylethanolamine-DTTA. Int J RadAppl Instrum B 19 (8), 831-840.

9. Koukourakis, M.I. et al. (1999). Li-posomal Doxorubicin and Conven-tionally Fractionated Radiotherapyin the Treatment of Locally Ad-vanced Non-Small-Cell Lung Can-cer and Head and Neck Cancer. JClin Oncol 17 (11), 3512-3521.

10. Harrington, K.J. et al. (2001). PhaseII Study of Pegylated LiposomalDoxorubicin (Caelyx) as InductionChemotherapy for Patients withSquamous Cell Cancer of the Headand Neck. Eur J Cancer 37 (16),2015-2022.

11. Iakoubov, L.Z. and Torchilin, V.P.(1997). A Novel Class of AntitumorAntibodies: Nucleosome-RestrictedAntinuclear Autoantibodies (ANA)from Healthy Aged NonautoimmuneMice. Oncol Res 9 (8), 439-446.

12. Iakoubov, L.Z. and Torchilin, V.P.(1998). Nucleosome-ReleasingTreatment makes Surviving Tu-mor Cells Better Targets for Nu-cleosome-Specific Anticancer Anti-bodies. Cancer Detect Prev 22 (5),470-475.

13. Chakilam, A.R., Pabba, S., Mongayt,D., Iakobouv, L.Z., Torchilin, V.P.(2004). A Single Monoclonal Anti-nuclear Autoantibody with Nucleo-some-Restricted Specificity Inhib-its the Growth of Diverse HumanTumors in Nude Mice. CancerTherapy 2 (4), 353-364.

14. Lukyanov, A.N. et al. (2004). Tu-mor-Targeted Liposomes: Doxoru-bicin-Loaded Long-Circulating Li-posomes Modified with Anti-Can-cer Antibody. J Control Release 100(1), 135-144.

15. Torchilin, V.P. et al. (2001). p-Nitrophenylcarbonyl-PEG-PE-Li-posomes: Fast and Simple Attach-ment of Specific Ligands, includingMonoclonal Antibodies, to DistalEnds of PEG Chains via p-nitrophenylcarbonyl Groups.Biochim Biophys Acta 1511 (2), 397-411.

16. Torchilin, V.P. et al. (2001). TATPeptide on the Surface of LiposomesAffords their Efficient Intracellu-lar Delivery even at Low Tempera-ture and in the Presence of Meta-bolic Inhibitors. Proc Natl Acad SciU S A 98 (15), 8786-8791.

17. Allen, T.M. et al. (2002). Use of thePost-Insertion Method for the For-mation of Ligand-Coupled Liposomes.Cell Mol Biol Lett 7 (3), 889-894

18. Xiong, X.B. et al. (2005). EnhancedIntracellular Uptake of StericallyStabilized Liposomal DoxorubicinIn Vitro Resulting in ImprovedAntitumor Activity In Vivo. PharmRes 22 (6), 933-939.

AcknowledgementsThis research was supported by theNIH grant R01-EB02995 to VladimirP. Torchilin. We thank Dr. B.A. Khawof Northeastern University for his valu-able help with the scintigraphic imag-ing studies.

About the AuthorsTamer Elbayoumi,PhD has a Bachelorsdegree in pharmacyfrom Alexandria Uni-versity (Alexandria,Egypt) and a Mastersin biomedical sciencesfrom Northeastern

University (Boston, Massachusetts).He is currently working as a Post-Doctoral fellow at the Center of Phar-maceutical Biotechnology andNanomedicine after receiving his PhDin pharmaceutical sciences from North-eastern University (Boston, Massachu-setts). In addition to his numerous pub-lications in the area of polymeric/lipidbased drug delivery systems, he wasthe ISPE Poster contest first place win-ner at the 2005 ISPE Boston AreaChapter student poster contest.Email: [email protected].

Vladimir Torchilin,PhD, DSc is the Dis-tinguished Professor ofPharmaceutical Sci-ences and Chairman ofthe Department ofPharmaceutical Sci-ences, Northeastern

University, Boston since 1998. Heearned his MS, PhD, and DSc from theMoscow State University and in 1991,he joined Harvard Medical School asthe Head of the Chemistry Program,Center for Imaging and Pharmaceuti-cal Research, and Associate Professorof Radiology. He is a Review Editor forthe Journal of Controlled Release andon Editorial Boards of 10 journals. Dr.Torchilin is the author of more than300 scientific papers and 90 reviewsand book chapters. He authored andedited eight books and holds more than40 patents. In 2005, he received theAAPS Research Achievement Awardin Pharmaceutics and Drug Delivery,and he is currently the President of theControlled Release Society.

Department of Pharmaceutical Sci-ences, Bouve College of Health Sci-ences, Northeastern University, MugarLife Sciences Building, Room 312, 360Huntington Avenue, Boston, MA02115, tel: 617-373-3206; fax: 617-373-8886; e-mail: [email protected].


New Products and Literature


Validation Services forClinical Markets

Millipore has announced the availabil-ity of validation and qualification ser-vices for the Elix® Clinical water puri-fication systems. Recently, the Clini-cal and Laboratory Standards Insti-tute™ issued a new guideline for“Preparation and Testing of ReagentWater in the Clinical Laboratory” thataddressed the merits and importanceof validation for water purification sys-tems. Specifically designed to meet thisneed, Millipore’s validation servicegives the user peace of mind in know-ing that their system has been installedand is operating according to pre-de-termined specifications.

Millipore Corp., 290 Concord Rd.,Billerica MA 01821, www.millipore.com.

Digital Vacuum Ovens

SP Industries has announced the avail-ability of their Hotpack brand Pro-grammable Digital Vacuum Ovenswhich feature microprocessor con-

trolled ramp and hold programmingcapability with up to eight steps fortemperature as well as vacuum setpoints. Engineered for more demand-ing test applications, Hotpack VacuumOvens provide high temperature oper-ating capability to 280ºC with bottom-out deep vacuum to 10 mTorr. Conve-nient digital setting and LCD readoutenable performance parameters to beaccurately set and monitored and analarm function provides audio alert ofany deviation from set points.

SP Industries, 935 Mearns Rd.,Warminster, PA 18974, www.spindustries.com.

Transducer withLocal Indication

The new Ashcroft® XmitrTM combinesthe advantages of the proven Ashcroft®

PowerFlexTM pressure gauge with thepatented transducer technology to cre-ate a single, convenient, dual-functioninstrument. Serving as “2 instrumentsin 1,” the XmitrTM provides traditionaltransducer features including 4-20mAand voltage outputs, CE ratings, and1% BFSL accuracy with electronic tem-perature compensation from -20°C to85°C. Pressure ranges from 30 psi to5000 psi are available in three configu-rations: Type X1005 with a 2" dial andType X2001 with a 2.5" or 3.5" dial.

Ashcroft Inc., 250 E. Main St.,Stratford, CT 06614, www.ashcroft.com.

Orbital Tube Welder

Arc Machines has announced the addi-tion of new features and system up-grades to the Model 307 Tube WeldingPower Supply. New features and sys-tem upgrades include: operating sys-tem upgrade to Windows XP; RAMincrease from 64 to 256 MB; slopingbetween levels that smoothes out“steps” seen in critical welds; slopedistance programmed in actual time ordegrees; and operation in 33 pre-pro-grammed languages. Upgrades are freefor existing Model 307 customers.

Arc Machines, Inc., 10500 OrbitalWay, Pacoima, CA 91331, www.arcmachines.com.

Validation Support Packagefor TOC Monitoring

The new 5000TOC Sensor ValidationSupport Package from Mettler-ToledoThornton helps achieve a fully quali-fied (IQ/OQ) system for total organiccarbon (TOC) measurements in phar-maceutical water production systems.It guides the operator through specificprocedures and facilitates compliancewith regulatory audits by providingstandardized protocols. The ValidationSupport Package supplies the toolsneeded to monitor operational condi-

Reprinted from





New Products and Literature


tions for regulatory requirements andfurnishes documented evidence thatthe instruments will produce accurateresults.

Mettler-Toledo Thornton, 36Middlesex Turnpike, Bedford, MA01730, www.thorntoninc.com.

Process System ResourceProcess System Solutions (PSS) is anew business group of Continental DiscCorporation. PSS provides single-source solutions for process systemprojects from concept through commis-sioning, qualification, and validation.The company offers engineered prod-ucts along with pre- and post-sale ser-vices to the pharmaceutical, biotech-nology, chemical, oil and gas, food andbeverage, wastewater, and OEM in-dustries.

Process System Solutions, 3160 W.Heartland Dr., Liberty, MO 64068,www. prosyssol.com.

Signal Conditioners

Action Instruments, a division ofEurotherm, has announced that theirsignal conditioners are now approvedfor use in hazardous area locations.The WV408 - DC voltage/current inputisolating signal conditioner and theWV428 - Thermocouple input isolatingsignal conditioner can both be installeddirectly in the Class I, Div 2 [Groups A,B, C and D] hazardous locations. Sig-nificant labor savings over traditionalprotection methods can be enjoyed be-cause there is no need for explosionproof enclosures and conduits.

Action Instruments, 741-F MillerDr., Leesburg, VA 20175, www.eurotherm.com.


ISPE Update


Annual Meeting to Feature FDA, Industry Leaders

ISPE officially invites you to the 2006ISPE Annual Meeting, where pharma-ceutical industry professionals will

gather from around the world to addressthe multi-layered challenges of innovation,5-8 November in Orlando, Florida, USA.

Moheb Nasr, Director, ONDQA, CDER,of the US FDA, will present the US FDAperspective on the need for strategic inno-vation in the industry. Nat Ricciardi, Presi-dent of Pfizer Global Manufacturing, willoffer insights and the necessities of innova-tions in our changing industry.

In addition, a major company will presentits experience of the FDA’s CMC pilot pro-gram and how they are applying science-based and risk-based approaches to thedevelopment of a new product.

The Annual Meeting is a premier oppor-tunity to bring pharmaceutical manufac-turing professionals from around the worldtogether for interactive workshops, discus-sion forums, keynote sessions to explore

major trends, and classroom seminars taught by leadingindustry experts from around the world.

Other highlights of the meeting include:• Workshops on the new Certified Pharmaceutical Industry

ProfessionalTM (CPIPTM) credential• A forum on the 2006 Facility of the Year Finalists• A chance for Members to join a Community of Practice to

learn and socialize with like-minded professionals andnetwork with an international roster of industry profes-sionals

• The National Institute for Pharmaceutical Technologyand Education (NIPTE) Colloquium

• Tech vendor sessions

___________________________________________

___________________________________________

Educational sessions include:• A Vision for the Future: Practical Applications of the

proposed ASTM Standard for a Science- and Risk-basedApproach to Qualification

• Drug Shortages and Industry Preparedness• Process Development in the New Quality By Design Frame-

work• Biotechnology: The Industry Impact on a Global Economy• RFID Trends, Challenges, and Solutions for Life Sciences• Commissioning Qualification (C&Q), and Validation of

Process Control Systems (VPCS): The Next Generation ofGAMP

• ASTM Standards for PAT and General PharmaceuticalManufacturing: A Status Report

Welcome to the New World

In an effort to focus on innovation, ISPE will promotethe Annual Event through its latest communication

vehicle, the ISPE blog, which will allow Members –both present and those not able to attend – to postcomments, insights, and information that would behelpful to other Members.

This Web log – or blog, for short — is similar to anonline diary or journal on a Web site and is displayedin reverse chronological order. The Society will postinformation about the Annual Meeting, and Memberscan send in questions or comments about the AnnualMeeting.

The blog will include summaries of important ses-sions, keynote speakers, photos of Members, and otherinformation about the Meeting. The blog will be linkedto the ISPE Web site for additional information. Mem-bers will be able to post comments on the blog at anonsite kiosk with laptop computers, or post from theirown computers.

In addition to the blog, the Society will featureInnovation I-Way, a historical look at the successes ofISPE in the past 25 years, leading up to its Communi-ties of Practice, relationships with the FDA and its newStrategic Plan which will help guide the pharmaceuti-cal manufacturing industry in the future.

Continued on page 4.

INNOVATINGCHANGE: GertMoelgaard, ISPEChairman, acceptsthe Commissioner’sSpecial Citation fromthe US Food andDrug Administration(FDA)from Dr. JanetWoodcock, theFDA’s DeputyCommissioner ofOperations, at theSociety’s 2005Annual Meeting. Thepresentation wasmade in recognition of ISPE’s “outstanding commitment and manyyears of continued support of crucial initiatives including the drugshortage program, the Process Analytical Technology Initiative,the reform of 21 CFR Part 11, and the Risk Based InspectionModel, as well as significant contributions to preparing for trainingthe pharmaceutical professionals of the future.”

Moheb NasrDirector,ONDQA,

CDER, FDA

Nat RicciardiPresident ofPfizer Global

Manufacturing

Reprinted from





ISPE Update


Join Your Community of Practice

In an industry that changes constantly,ISPE is at the forefront. ISPE under-

stands the critical need of profession-als to know the industry, particularlywhen it comes to tracking emergingtrends.

By joining an ISPE Community ofPractice (COP), Members have instantaccess to a network of like-minded prac-titioners who want to learn and worktogether to address regional, domestic,and global issues in their particularareas of expertise.

ISPE’s Communities of Practice al-low Members to target their needs byjoining like-minded professionals to ex-change ideas about their fields.

ISPE encourages Members with ex-perience, knowledge, or interest in anyof the disciplines represented by thevarious Communities to get involved.Becoming a COP Member is easy andconvenient and can be done by visitingwww.ispe.org/cops and clicking on the“subscribe” tab.

The purpose of ISPE COPs is to:

• Provide a forum for communityMembers to help each other solveeveryday work problems and en-gage in active networking.

• Develop and disseminate best prac-tices, guidelines, and procedures foruse by community Members

• Organize, manage, and research abody of knowledge from which Com-munity Members can draw

• Innovate and create breakthroughideas, knowledge, and practices

The Communities of Practice include:

Active PharmaceuticalIngredients (API)The API COP proactively advocatesthe importance of API in the drug prod-uct delivery process with the objectivesof providing a forum for Members todiscuss issues of common interestthrough: education and training; E-Discussions; regulatory cooperation; in-formation dissemination; and estab-lishment of links to internal and exter-nal groups with common interests.

Biotechnology (BIO)The Biotech COP aims to create a glo-bal focal point of support for pharma-ceutical professionals operating in theBiotech sector. Support means the cre-ating and delivery of training, techni-cal materials and information, and pro-viding opportunities for collaborationand networking.

Clinical Materials (CM)The Clinical Materials COP provides aforum for Members to discuss issues ofcommon interest, and when appropri-ate, to propose solutions to commonindustry problems; proactively advocatethe importance of Clinical Trials Mate-rials in the drug approval process; andsupport ISPE in achieving its goals.

Commissioning andQualification (C&Q)The C&Q COP aims to align theprocesses of commissioning andqualification with a science and risk-based approach, provide input andguidance into other documents, andto facilitate understanding and or-ganizational change necessary toimplement this approach. This willbe accomplished through: discus-sion and communications forums;education and training; guidelinesand standards review; and facilitat-ing links to other groups with com-

mon interests.

ContainmentThe Containment COP provides a fo-rum for all those involved in the safetyof patients and people from exposure,contamination, and cross contamina-tion of hazardous compounds and in-teract with all appropriate stakehold-ers to share, influence and changeknowledge, guidance, and regulationfor the good of all.

Critical Utilities (CU)The Critical Utilities COP provides adiscussion forum and network for Criti-cal Utilities professionals by encourag-ing the sharing of ideas relevant totopics such as system design, commis-sioning & qualification, process vali-dation, requalification, regulations, op-erations, and maintenance.

Good Automated ManufacturingPractice (GAMP)The GAMP Community exists to pro-mote the understanding of the regula-tion and use of automated systemswithin healthcare industries.

Heating, Ventilation, and AirConditioning (HVAC)The HVAC COP is the premier globalorganization that serves as a one-stop


ISPE Update


shopping outlet and provides relevant,timely information and solutions toreal-world problems related to HVACfor pharmaceutical facilities.

Investigational MedicinalProducts (IMP)The IMP COP provides a forum forMembers to discuss issues of commoninterest, proposes solutions to indus-try problems, and facilitates interac-tion with regulatory bodies.

Process AnalyticalTechnology (PAT) The PAT COP creates a global focalpoint of support and a discussion fo-rum for pharmaceutical professionalsinterested in Process Analytical Tech-nology. This means the creation anddelivery of training, technical materi-als and information, as well as provid-ing opportunities for collaboration andnetworking.

Process/ProductDevelopment (PPD)The PPD COP is a dynamic forum forprofessionals in product/process devel-opment to discuss and address issuesof common interest.

Project Management (PM)The Project Management COP is a dy-namic forum for professionals workingwithin the pharma industry who havean active interest in promoting “con-tinuous improvement” project manage-ment by creating a body of knowledgespecific to the professional needs of itsMembers.

Sterile Products Processing (SPP)The SPP COP aims to establish andmanage a forum that supports all facetsof sterile products processing; enablescommon interest discussions; providesaccess to relevant information; and sup-ports member networking.

Join Your COPContinued.

E-Letters Gives You Information You Need

New Electronic ISPEAK Sent to Membership

ISPE has changed its long-running Society newsletter, ISPEAK, to electronicformat, launching the premier issue 28 July. In addition to this newsletter sent by

e-mail, news is regionalized by Europe, Asia-Pacific, and North America and SouthAmerica. Please be sure to click on the ISPEAK link to get the full global newsletter.

Members can access the bi-monthly newsletter on our Web site under “publica-tions.” The next electronic edition of ISPEAK will be sent 29 September.

To submit information, please e-mail Marsha Strickhouser, Public RelationsManager, at [email protected] or contact her at +1-813-960-2105, ext. 277. Topurchase an advertisement, please contact Dave Hall, Director of Advertising, [email protected] or call +1-813-970-2105, ext. 208.

ticular, we heard great comments andsuggestions at our Washington Con-ferences in early June and at our Lead-ership Retreat in July. Many Mem-bers were eager to get on board andcontribute to another opportunity tostay connected to their area of inter-est.

If you are a member of a Commu-nity of Practice you will automaticallyreceive your COP’s E-Letter.

Starting in 2007, E-Letters will beon an opt-in basis, so you will need tolet us know which categories you areinterested in to be sure you get your E-Letter.

You can update your interests byfilling out a subscription form on ourWeb site. You can contribute to E-Letters by sending ideas or articles [email protected], or [email protected]. You can advertise in E-Let-ters by contacting Dave Hall [email protected].

ISPE is proud of its new E-Letters,our customized electronic newslet-ters geared toward Communities of

Practice. E-Letters address your needsas a professional in the pharmaceuti-cal industry based on your specific ar-eas of interest and feature industrynews about best practices, regulatorynews, technical articles, and innova-tive solutions.

In May, we released our first four E-Letters, which included newsletters oninformation about GAMP, Contain-ment, Clinical Materials, and PAT. InAugust, continuations of those letterswere sent out, with additional E-Let-ters on Biotechnology, C&Q, API, andPPD.

The next installment of E-Letterswill be mailed electronically in Novem-ber and will include PM, HVAC and CU.

We have received positive feedbackabout E-letters, including that it is avaluable addition for members. In par-

You can view all E-Letters at www.ispe.org/e-letters.


ISPE Update


Journal of Pharmaceutical Innovation Makes Debut This Month

ISPE has launched its new Journal of PharmaceuticalInnovation (JPI), a scientific, peer-reviewed journal forthe publication of research and review articles. As a

Member benefit, your copy was sent to you with this issue ofPharmaceutical Engineering.

The pilot journal was produced in partnership with ReedElsevier, which also publishes Cell and The Lancet. Two yearsago, the US FDA asked ISPE to play a prominent role in theFDA’s plan to be a catalyst for change “to enable fully flexiblemanufacturing concepts, within regulation, using the bestengineering and scientific principles available, improvingbusiness and taking risk into consideration.”

In response to this challenge and with Board of Directors’support, ISPE has embarked on several initiatives in consul-tation with the FDA, including launching this scientific peer-reviewed journal.

ISPE is pleased to have the support of James K. DrennenIII, Associate Professor, Duquesne University, Pittsburgh,PA, USA, who will serve as the Editor of JPI. Dr. Drennen isHead of the Pharmaceutical Sciences Division at DuquesneUniversity in Pittsburgh, Pennsylvania. He is co-founder andDirector of the Duquesne University Center for Pharmaceuti-cal Technology, and Associate Professor of Pharmaceuticals.

In addition, he is the North American Editor for theJournal of Near-Infrared Spectroscopy and PharmaceuticalEditor of the newsletter, NIRnews. Currently, Dr. Drennenserves as the Membership Secretary of ASTM InternationalCommittee E55 on Pharmaceutical Application of ProcessAnalytical Technology.

JPI is intended for the publication of research and reviewmanuscripts emphasizing new and innovative methods andtechniques used by pharmaceutical professionals serving allaspects of the industry including Manufacturing, AppliedPharmaceutical Science and Technology in Process, andProduct Understanding and Control.

JPI will be mailed to Members along with PharmaceuticalEngineering. The Journal of Pharmaceutical Innovation willreach 23,000 ISPE Members in 81 countries. In addition toISPE Members, JPI will have an additional distribution of15,000 international industry and academic professionals.The journal will be available in print and online versions freeto ISPE members.

The new journal will include the following categories ofarticles:

• Perspectives are opinion articles on controversial topicsor recent developments in the industry, or can coverstrategic industry issues, new areas of research, profiles ofnew research organizations or industry trends.

• Case Studies provide a critical analysis of the implemen-tation of a new method or technology.

• Research Letters are shortpapers reporting results that areof genuinely broad interest, butthat do not make a sufficientlycomplete story to justify publi-cation as a full Research Article.

• Research Articles describe, indetail, new and innovative meth-ods and techniques, with conclu-sions that are supported by ad-equate evidence. Scientific rigor and reproducible resultsare required.

• Reviews may address both the recent scientific advancesin drug development, pharmaceutical engineering, andmanufacturing, as well as the management, commercialand regulatory issues that increasingly play a part in howR&D is planned and performed.

For information or inquiries regarding editorial content,please contact Gloria Hall at [email protected]. To inquire aboutadvertising, please contact Dave Hall at [email protected].

Annual Meeting...Continued from page 1.

Register on-line now and watch www.ispe.orgfor updates, or call ISPE at +1-813-960-2105.

Sponsorship and exhibit opportunities are stillavailable for the 2006 Annual Meeting.

Please contact Dave Hall, ISPE Director ofSales, by tel: +1-813-960-2105, or e-mail:

[email protected]

• Energy Sustainable Design - Build Green Procurementand Contract Strategies for the Changing PharmaceuticalIndustry

• GAMP Data Migration Good Practice Guidance

And special series designed for your needs will feature:• Executive Series: The Real World of Project Management

- Critical Utilities Projects and Programs• Facilities Series: Vaccine Facilities of the Future• Regulatory Series: Quality By Design - What the ICH

Guideline Q8 Says About QBD6• Manufacturing Technology Series: Continuous Process-

ing in the Real World


ISPE Update


Taking the Initiative:

ISPE Joins Forces with University to Develop Training Program forHigh School, College Students

ISPE has joined forces with the Uni-versity of Florida, in Gainesville,Florida, USA, along with the Na-

tional Science Foundation, and 40 part-ners in education, government, andindustry, in order to train workers forFlorida’s growing biotechnology indus-try.

Recently, the NSF awarded$599,997 to the University of Florida’sCenter of Excellence for RegenerativeHealth Biotechnology (CERHB) to fundthe Florida Partnership for IndustrialBiotechnology Career Developmentand Training.

ISPE’s role in this partnership willbe to help develop the training pro-gram and teach community college andhigh school instructors the essentialsof “Good Manufacturing Practices” -inspection and certification standardsenforced by the US Food and DrugAdministration that are observed whenmanufacturing and testing drugs, medi-cal devices or other agents that come incontact with people.

“This will help students and work-ers get higher-paying jobs and findbetter careers,” said Richard Snyder,director of UF’s Center of Excellencefor Regenerative Health Biotechnol-ogy. “Likewise, having state-of-the-arttraining for our workforce will stimu-late the creation of high-wage, high-skill jobs in what is regarded as a cleanindustry. It’s definitely a win-win sce-nario.”

Snyder and Win Phillips, UF’s vicepresident for research, said the part-nership will create training programsat the CERHB’s education center, atSanta Fe Community College inGainsville, and within the Alachua andMarion County public school systems,with the expectation that these pro-grams will eventually be reproducedthroughout the state.

The partnership will begin by train-ing instructors and developingcoursework that is useful and appeal-ing to high school and college students,

as well as to workers interested inswitching to entry and mid-level ca-reers in the biotechnology industry,according to Bob Best, President andCEO of ISPE, a key collaborator in theeffort. The goal is to create model cur-ricula and programs that can be repro-duced throughout the state and thenation.

Most current training programs areconcentrated in existing biotechnologyclusters in states such as Californiaand Massachusetts, according to HarryOrf, vice president for scientific opera-tions and professor of chemistry atScripps Florida and chairman of theeducation and community outreach

committee for BioFlorida, a statewidebioscience organization.

“Addressing the need for a better-prepared workforce improves the can-didate pool for us,” Orf said. “Histori-cally, the biotechnology industry hasn’tbeen in place here, so there hasn’t beenthe need for the workers. If we’re goingto build the industry, we have to buildthe workforce.”

Work in the biotech field requiresunderstanding scientific principles in-volved in diverse areas such as DNAresearch, genetic analysis, protein pu-rification, drug manufacturing, andproduct testing. Furthermore, workers

ISPE Forms Partnership with North CarolinaColleges for Biotechnology Validation

ISPE has renewed its LicenseAgreement with the North Caro-

lina Community College System forthe development of the BioNetworkValidation Service Academy.

The North Carolina CommunityCollege BioNetwork Validation Acad-emy is a partnership betweenBioNetwork, ISPE, and the NorthCarolina Department of Commerce.The academy is a major attractionfor new companies wishing to openpharmaceutical or biomanufacturingfacilities in North Carolina, and forgrowing companies that are plan-ning facility expansions.

“Launching the BioNetwork Vali-dation Services Academy is an his-toric milestone in training pharma-ceutical and biotechnology manufac-turing professionals,” said Bob BestPresident and CEO of ISPE. “ISPEis proud to partner with NCCCS byoffering our training courses basedon a practical applications approachto learning utilizing their pioneeringtraining facility. This partnership isa monumental step forward by pro-

viding a bridge between academiaand industry.”

ISPE’s role includes that of vali-dation, the regulatory requirementfor biopharmaceutical facilities, andthe written proof a pharmaceuticalor biomanufacturer must be able toprovide to demonstrate with a highdegree of assurance that a processor system will consistently producetheir medicine to safe standards.

Jeff Odum, validation academymanager, is an ISPE member andchairperson of its North AmericanEducation Committee – the bodythat develops and executes interna-tional training programs for thebiopharmaceutical industry.

Odum, who is in charge of cur-riculum including case studies, re-search, and group activities, is anationally-recognized validationexpert and author who provides in-dustry insight in the areas of regu-latory compliance, facilities and pro-cess design, and project manage-ment for biopharmaceutical compa-nies.

Continued on page 6.


ISPE Update


need to know regulatory and qualitycontrol procedures.

It’s a unique set of skills, but onceacquired, students who have them willfind themselves in demand, accordingto Jackson Sasser, president of SantaFe Community College.

“Students have for a few years beenfilling every opening in Santa Fe’s Bio-technology Laboratory Technology de-gree program, and employers have beenhiring them once they graduate,” Sassersaid. “This is not surprising. SFCC andthe UF Biotechnology program are part-ners in this program, and its coursecontent is developed with advice anddirection from our partners in the bio-technology industry.”

Beyond the Gainesville area, whichincludes UF’s $500 million researchenterprise, area health-care facilitiesand sprouting biotechnology compa-nies, the market for skilled employeesin Florida is expected to become evenlivelier because of Scripps Florida, amajor research center planned in SouthFlorida. Scripps is expected to employmore than 500 workers and eventuallycreate 200 new businesses and 16,000new jobs.

ISPE Joins Forces...Continued from page 5.

Call for Submissions for 2007 Facilityof the Year Awards

ISPE, along with co-sponsorsINTERPHEX and Pharmaceutical

Processing, invites you to enter yoursubmissions of plans of new facilitiesfor pharmaceutical manufacturing or-ganizations, for its global 2007 Facilityof the Year Awards (FOYA) competi-tion.

FOYA, in its third year, is an an-nual competition to recognize state-of-the-art pharmaceutical manufacturingprojects that utilize new and innova-tive technologies to enhance the deliv-ery of a quality project, as well as toreduce the cost of producing high-qual-ity medicines. Award-winning facili-ties are those that demonstrate globalleadership and showcase cutting-edgeengineering, innovative new technol-ogy, or advanced applications of exist-ing technology.

FOYA was instituted to recognizeaccomplishments, shared commitment,and dedication of individuals in com-panies worldwide to innovate and ad-vance pharmaceutical manufacturingtechnology for the benefit of all globalconsumers.

“We want to give recognition to thosewho design, build, and operate world-class pharmaceutical manufacturingfacilities,” said Scott Ludlum, ISPE’sDirector of Business Initiatives. “Andthis year the Awards have expanded inorder to raise awareness for these vitalsegments of the global pharmaceuticalindustry.”

This year, several significant en-hancements have been added to theAwards program, including six awardscategories in:

• Process Innovation• Project Execution• Equipment/Innovation

• Facility/Integration• Energy Management• Operational Excellence

In addition to the new categories, win-ners will be recognized and introducedduring INTERPHEX 2007 in New YorkCity, where thousands of attendees con-vene for one of the largest industryevents worldwide.

The announcement of the overallwinner of the coveted Facility of theYear Awards competition will take placeat ISPE’s Annual Meeting in November2007 at Caesar’s Palace in Las Vegas. AFacility of the Year Awards display willfeature the Category Winners and Fa-cility of the Year Awards winner. Thewinner will receive the prestigious crys-tal and marble trophy, as well as vari-ous publicity initiatives through ISPE,Pharmaceutical Engineering, INTER-PHEX and Pharmaceutical Processing.Key contributing organizations also willbe included in overall publicity.

The deadline to submit applicationsfor the 2007 competition is 8 December2006. For complete information aboutthe Awards program and submissionprocedures, as well as to download theonline application form, please visitwww.facilityoftheyear.org. Specificquestions can be addressed to ScottLudlum, ISPE Director of Business Ini-tiatives, by tel: +1-813-739-2284 or bye-mail: [email protected]

The 2006 overall FOYA winner wasBaxter BioPharma Solutions. Final-ists last year included AstraZeneca,Daiichi Asubio, Janssen Pharmaceuti-cal, and Wyeth Pharmaceuticals. Spe-cial recognition went to Biolex Thera-peutics. For more information on win-ners from 2005 and 2006, visit www.facilityoftheyear.org.


ISPE Update


New CPIPTM Certification Program – Seal Your Career in Gold

Recognizing the need for change within the pharmaceu-tical industry to im-prove drug product manufacturingprocesses, quality, and consumer cost effectiveness, the

ISPE Professional Certification CommissionTM (PCC) hasannounced its Certified Pharmaceutical IndustryProfessionalTM credential — the first competency-based pro-fessional certification for pharmaceutical professionals. Andit could help you seal your career in gold.

“Our industry benefits from employees certified in diverseknowledge, and from the ability to apply this knowledgeacross all segments of our industry,” said Ali Afnan, PhD, USFDA. “In addition, it allows employers to be able to recognizetop performers, attain better product quality, industry-widerecognition, and commitment to innovation. Certified em-ployees will become more valuable as team leaders, developkeener awareness, and perform their job more efficiently.”

The CPIPTM credential will recognize professionals as“change agents” to help drive industry innovation. This callfor change encourages new science and risk-based approachesfor drug product development, manufacturing and distribu-tion, and is supported by government regulators. ISPE-PCCrecognizes the need for change and is leading the efforts bydeveloping and implementing this innovative certification asa means of advancement within and for the industry.

Eligibility applications will be available in November2006, along with several workshops offered onsite at theISPE 2006 Annual Meeting to be held 5-8 November inOrlando, Florida, USA. The first CPIPTM examination will bescheduled for July 2007.

“The certification program will help enact change in thepharmaceutical industry by recognizing professionals whofacilitate innovation in development and manufacturing,thereby enhancing opportunities for drug product excellence,”said Jerry Roth, PE, ISPE’s Director of Professional Certifi-cation.

The CPIPTM certification has appeal and value for profes-sionals from:

• Drug Product Development• Drug Product Manufacturing Operations• Facilities/Process Engineering• Facility and Process Equipment Manufacturing/Supply• Project Management• Regulatory Compliance/QA/Validation• Technical Support

The CPIPTM will have broad industry knowledge and experi-ence and apply key competencies to achieve cost-effective,risk-based approaches, innovation, quality by design, andcontinuous improvement.

The professional conferred the competency-based CPIPTM

credential will have demonstrated the application of compe-tencies including technical knowledge, leadership skills, andinnovative problem solving.

Employers benefit from employees’ certification because itassures that employees have diverse knowledge and theability to apply that knowledge across many segments of theindustry. The CPIPTM designation also allows employers theopportunity to recognize top performers, improve productquality, operate with global competency standards for profes-sionals, and realize industry innovation.

At the same time, pharmaceutical industry professionalsbenefit through increased professional advancement, en-hanced credibility, peer respect and recognition, a competi-tive edge for job seeking, new job opportunities, and personalsatisfaction.

The pricing structure for the CPIPTM credential is:

Application Fee ISPE Member: $100 USD, EUROS €80Nonmember: $200 USD, EUROS €160

Examination Fee ISPE Member: $300 USD, EUROS €240Nonmember: $400 USD, EUROS €320

Re-certification ISPE Member and Nonmember:Application Fee $225 USD, EUROS €180

All fees are non-refundable. Recertification will be requiredevery three years from the date the credential is conferred.

To learn more about the CPIPTM credential, and the eligi-bility criteria, visit www.ispe-pcc.org.


ISPE Update


Regulatory

ISPE/PDA Conferences to Examine Guidances for Industry with ICHThink Tankby Rochelle Runas, ISPE Technical Writer

Members of the InternationalConference on Harmonisation(ICH) Expert Working Groups

who wrote “Q8 Pharmaceutical Devel-opment” and “Q9 Quality Risk Man-agement” have been enlisted to de-velop content and give presentationsfor the upcoming joint ISPE/PDA Con-ferences.

“Challenges of Implementing Q8and Q9 – Practical Applications,” willbe held 6-7 December 2006 in Wash-ington, D.C., USA, and 12-13 February2007 in Brussels, Belgium, and on adate to be determined in 2007 in Ja-pan.

The conferences will be hosted byISPE and the Parenteral Drug Asso-ciation (PDA), two leading associationsin the pharmaceutical manufacturingindustry that have joined forces to fur-ther explore the recently publishedGuidances for Industry, ICH Q8 andQ9.

The FDA issued Q8 on 22 May, andjust two weeks later, issued Q9. TheGuidances for Industry are expected tohave a major impact on how the indus-try and those who regulate it will dobusiness.

Conference developers say theworthwhile event will take attendeeson a backstage tour of the ICH negoti-ating table, looking at not only what isin the Guidances for Industry, but alsoat what wasn’t included and why.Nearly 15 representatives of the ICHExpert Working Groups are involvedin the conference planning and presen-tations.

Regulators and industry represen-tatives from the US, Europe, and Ja-pan will describe the challenges in-volved with the implementation andapplication of the Guidances for Indus-try in their respective regions.

Regulators from the US FDA, EUEMEA, and the Japanese Ministry of

Health, Labor, and Welfare, will con-sider how to:

• conduct science and risk-based as-sessment of submissions

• balance expectations for a qualityby design-based submission andapproval of a product without rais-ing the bar

• provide regulatory flexibility whilestill assuring product quality

• handle legacy products

Industry representatives from all threeregions will provide their perspectiveof the challenges associated with theimplementation of the Guidances forIndustry, including a review of the po-tential benefits, such as enhanced pro-cess capability and robustness, betterintegration of review and inspectionsystems, achieving greater flexibilityin specification setting, and the man-agement of post approval changes.

In addition, through case studies,attendees will learn from regulatorsand industry representatives aboutexperiences with the FDA’s CMC PilotProgram, EFPIA’s PharmaceuticalDevelopment model, and the imple-mentations of strategies for qualityrisk management.

Representatives from both ISPE andPDA will provide updates on their as-sociations’ work relative to Q8 and Q9.Panel discussions will provide oppor-tunities for interaction between speak-ers and attendees. The conferences willbe structured so that all attendees havethe benefit of attending all sessionsand hearing all presentations.

Registration details will be forth-coming and will soon be available forviewing at www.ispe.org and www.pda.org.


ISPE Update


October 20065 Argentina Affiliate, Educational Activities, “Modulo 4: Sistemas para Distribucion y Acumulacion de Aguas PW/WFI,”

Hotel IBIS, Buenos Aires, Argentina5 Greater Los Angeles Area Chapter, Evening with Industry Executives, Facilities Presentation with Panel Discussion,

Facility Tour of Gilead, Los Angeles Area, California, USA5 Nordic Affiliate, GAMP Conference, “Outsourcing IT,” Park Inn Copenhagen Airport Hotel, Copenhagen, Denmark5 San Francisco/Bay Area Chapter, Commuter Conference, “Water Treatment Systems,” Pipe Trades Training Center,

San Jose, California, USA9 Midwest Chapter, Educational Session and Golf Outing, Millwood Golf Course, Springfield, Missouri, USA9 - 12 ISPE Prague Training, Crowne Plaza, Prague, Czech Republic10 Delaware Valley Chapter, Program Meeting, USA12 Ireland Affiliate, Seminar, “Pharmaceutical Documentation,” Dublin, Ireland12 Italy Affiliate, Seminar, “Cost Efficiency - New Technologies, Effectiveness, and Quality in Pharmaceutical Supply

Chain,” Grand Hotel Baglioni, Firenze, Italy12 UK Affiliate-North West Region, Seminar, “Management of Pharmaceutical Waste,” United Kingdom18 Boston Area Chapter, 2006 Vendor Night, Gillette Stadium Clubhouse, Foxboro, Massachusetts, USA19 Argentina Affiliate, Educational Activities, “Modulo 5: Definicion de un sistema integrado Generacion/Distribucion”

and “Microfiltracion aplicada a un sistema de aguas, filtracion esterilizante,” Hotel IBIS, Buenos Aires, Argentina19 DACH Affiliate, Workshop, Biberach, Germany19 France Affiliate, MES/EBR Conference, France19 New Jersey Chapter, Hot Topic Session, “Productivity Improvement within Pharmaceutical Industry,” Holiday Inn,

Somerset, New Jersey, USA19 San Diego Chapter, CIP Workshop and Dinner Meeting, TBD, California, USA24 Greater Los Angeles Area Chapter, Commuter Conference, California, USA26 Argentina Affiliate, Conferencia Magistral, Congreso ETIF 2006, Hotel IBIS, Buenos Aires, Argentina26 Nordic Affiliate, Seminar, “Freeze Drying,” Sodertalje, Sweden26 Puerto Rico Chapter, GAMP Forum, Puerto Rico, USA

November 20065 - 8 2006 ISPE Annual Meeting, Walt Disney World Dolphin, Orlando, Florida, USA9 UK Affiliate, Annual Awards Dinner, “Opportunities in UK Pharmaceuticals from Discovery to Manufacture,” The Royal

Bath Hotel, Bournemouth, United Kingdom13 Chesapeake Bay Area Chapter, Bio-Showcase, Hilton, Gaithersburg, Maryland, USA14 Delaware Valley Chapter, Program Meeting, USA15 Greater Los Angeles Area Chapter, CEO Night, California, USA16 Ireland Affiliate, Takeda Plant Visit, Bray, Ireland16 New Jersey Chapter, Hot Topic Session, “Product-to-Market,” Holiday Inn, Somerset, New Jersey, USA16 - 17 Poland Affiliate, Conference, “Pharmaceutical Development,” Poland21 - 22 Nordic Affiliate, PAT Conference in collaboration with Eupheps/IDPAC, Gothenburg, Sweden23 Nordic Affiliate, Annual Meeting, “Improving Operating Efficiency by New Quality Management,” Gothenburg,

Sweden

December 20064 Greater Los Angeles Chapter, Commuter Conference, Technical Training Series: Compendial Water at Amgen, LA

Area, California, USA4 - 7 ISPE Brussels Conference, Sheraton Brussels, Brussels, Belgium6 New Jersey Chapter, Holiday Event, Dinner and Dancing on the Bateux, New York, USA6 - 7 ISPE/PDA Conference, “Challenges of Implementing Q8 and Q9 – Practical Applications,” Omni Shoreham Hotel,

Washington, DC, USA7 Rocky Mountain Chapter Annual Holiday Party, USA12 Delaware Valley Chapter Holiday Party, USA14 Italy Affiliate, Christmas Night, Italy

Dates and Topics are subject to change

Mark Your Calendar with these ISPE Events


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Siemens Water Technologies, 125Rattlesnake Hill Rd., Andover, MA01810. (978) 470-1179. See our ad in thisissue.

Hoses/Tubing

AdvantaPure, 145 James Way,Southampton, PA 18966. (215) 526-2151.See our ad in this issue.

Label Removal Equipment

Hurst Corp., Box 737, Devon, PA 19333.(610) 687-2404. See our ad in this issue.

Passivation andContract Cleaning Services

Active Chemical Corp., 4520 Old LincolnHwy., Oakford, PA 19053. (215) 676-1111. See our ad in this issue.

Cal-Chem Corp., 2102 Merced Ave., SouthEl Monte, CA 91733. (800) 444-6786.See our ad in this issue.

Passivation andContract Cleaning Services (cont.)

Oakley Specialized Services, Inc., 50Hampton St., Metuchen, NJ 08840. (732)549-8757. See our ad in this issue.

Pumps

Watson-Marlow/Bredel, 220 BallardvaleSt., Wilmington, MA 01887. (978) 658-6168. See our ad in this issue.

Sterile Products Manufacturing

Tanks/Vessels

Lee Industries, PO Box 688, Philipsburg,PA 16866. (814) 342-0470. See our ad inthis issue.

Used Machinery

Validation Services

ProPharma Group, 10975 Benson Dr.,Suite 330, Overland Park, KS 66210;5235 Westview Dr., Suite 100, Frederick,MD 21703. (888) 242-0559. See our ad inthis issue.

Water Treatment

Christ Pharma & Life Science AG,Haupstrasse 192, 4147 Aesch,Switzerland. +41 617558111. See our adin this issue.

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Source: 2005 Publications Survey

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