White Paperwww.vaisala.comGMP Warehouse MappingStep-by-Step Guidelines for ValidatingLife Science Storage FacilitiesGood manufacturing practice (GMP) regulators in the United States,Canada, European Union, Japan, Australia, and China have sharpenedtheir focus on warehouse storage and distribution practices. Driving thistrend is a shift in regulatory thinking from quality-by-test to quality-bydesign systems with emphasis on level of risk to product quality andpatient safety. Other drivers include greater demand for storage facilitiesdue to globalization of manufacturing, increase in temperature-sensitivebiopharmaceuticals, and changes in technology.Regulators in these countriesrequire “mapping” the temperatureand relative humidity profiles ofwarehouses for environmentallysensitive life science products. Thisstep-by-step guide describes howto map a warehouse to complywith internationally recognizedGMPs, including many that havebeen published or revised recently.(See the end of this paper forlinks to relevant regulationsand guidance documents.)This guide, intended for use byany organization involved inthe storage and distribution ofproducts sensitive to temperatureand humidity in a GMP-compliantenvironment, draws on Vaisala’sextensive customer experiencethroughout North America andEurope. Vaisala solutions are usedin over 150 countries worldwide.
Step by Step –Good practices for warehouse mapping studiesVaisala recommends a nine-point process for successfulmapping of a warehouse or other regulated storage space:1.Create aValidation Plan 2. Identify areas at risk 3. Develop ProtocolInformation 4. Determine sensordistribution 5. Select suitabletechnology 6. Set up mappingequipment 7. Conduct test andreview data 8. Make modifications 9. Document andschedule mappingstudyThese nine steps will help youdesign and execute a successfulmapping plan. They will ensurethat you take into considerationthe most important elementsof validation, especiallyunderstanding where temperatureand humidity pose risks to productquality. Following these steps willgo a long way in demonstrating toa regulatory inspector that yourcompany is GMP compliant.Step 1: Create a validationplanThe validation plan, or validationmaster plan, is the documentused to specify the company’sdecisions about qualifying everyaspect of the facility, equipment,and processes to maintain a GMPcompliant environment. The planshould take a risk-based approach,with a rationale based on verifiabledata. The plan should focus onwhere environmentally sensitiveproducts and materials will bestored and whether environmentalcontrols can meet specifiedstorage requirements.The plan is also a starting point forregulators to evaluate the rationalefor the company’s goals andmethods.The validation master plan should: State the validation objectives. Identify roles and responsibilitiesof quality, metrology, and otherworking groups in the process. Identify validation activities,including processes, equipment,and space. Develop documentationand procedures, includingthe company’s response ifa temperature or humidityexcursion occurs. Determine a validation schedule. Specify the management approvalprocess, especially for adverseevents such as temperaturedeviations. Create change control protocolsso it’s clear when changes such asmaintenance, new construction,and reconfiguration of racks willrequire revalidation.Regulatory Note: GMPs requiremaintaining temperatureand humidity within storagerecommendations printed onproduct labels or providedby raw-material suppliers.These recommendations arederived from known chemicalproperties and stability testing.
Step 2: Identify areasat risk Independent energy sources, suchas space heaters, air conditioners,and fans, which create warm orcold spots.To map a warehouse or storagespace, you first must identify areaswhere product quality may beat risk because of unacceptablevariations in temperature andhumidity. Many factors affectthe control or variability of yourspace. (Because relative humidityis dependent on temperature,variations in temperaturewill affect humidity as well.)Considering each of these factorswill help you identify risks: Layout of racks, shelves, andpallets, which obstruct airflow. Location of HVAC control sensors.For example, a thermostat locatednear a source of heat or cold maycause the temperature of thespace to fluctuate excessively. Locations near sources of heat orcold, such as the roof and exteriorwalls, windows, and loading docks. High-traffic areas where productor equipment is moved often. Volume of space. A largewarehouse has different controlburdens than a small storagearea, with greater demandson the HVAC system and thepotential for greater variationsin temperature and humidity atvarious locations. Seasonal temperature changes orunusual weather events.Regulatory Note: You canachieve GMP compliancethrough sound justification ofyour approach to identifyingrisk. The more considerations theprotocol addresses, the betteryour rationale is likely to be. The capacity of diffusers or fansto adequately circulate air. Temperature gradients betweenthe floor and warmer air near theceiling.325784113129LoadingDoor1115Once you’ve identified areas ofrisk, develop a protocol for themapping study that describes thefollowing, with justifications foreach decision: Types of data to be generated –for example, temperature, relativehumidity, and measurementintervals. Five-minute intervalsoffer more data to evaluatetrends and modify the warehousesetting (see Step 8). Once youare satisfied that temperatureand humidity are relativelystable, 15-minute intervals may beadequate for the final mapping. Number of sensors to be used(see Step 4: Determine SensorDistribution). Schematic or diagram of sensorlocations. Duration of study. Your rationaleand protocol may support aseries of tests, each lasting twodays during normal operationsand into a weekend. A differentand equally defensible protocolmight specify a single run overa two-week period to accountfor a variety of activities, such asopening loading dock doors, inthe warehouse. Calibration requirements of thedata loggers. Acceptable range of variationover time and across the space,which will depend on the productstored. Acceptable limits for temperatureor relative humidity excursions.106Step 3: Develop protocolinformationDoor14Figure 1: . The even distribution of 15 sensors is a typical pattern for athree-dimensional mapping of a small space. Reporting requirements.Regulatory Note: Once youdevelop a protocol, follow itconsistently. If the protocolchanges, document thereasons.
TopViewFigure 2: Sensors placed in the middle of racks more closely reflect product temperatures. In this example, ninesensors are located on each double rack in this warehouse measuring 30 meters by 30 meters by 15 meters.Step 4: Determine sensordistributionHow many sensors will you need tomap a particular space? Where willyou put them? There are no simpleanswers. Sensor distribution mustbe adequate to assess temperatureuniformity. Good practice meansthat you use a sufficient numberof sensors to understand yourenvironment, especially areaswhere risk is greatest.You’ll need to place sensors ina uniform pattern in all threedimensions of the space – top tobottom, left to right, and frontto back. Add additional sensorswhere you suspect cool or warmareas exist, as well as near thecontrol sensors and monitoringsensors. Placement of temperatureand relative humidity sensors is afunction of the risks identified inStep 2.A walk-in chamber or smallwarehouse is often mapped inthree dimensions with 15 sensors(See Figure 1.) The protocol shouldinclude guidelines for the distancebetween sensors, for example, nogreater than six meters.In mapping a large warehouse,set sensors as far as 30 metersapart, with additional sensors invulnerable areas affected by: Heat or cold from external walls,solar heating, windows, lighting Air circulation or drafts fromentries, traffic, or the HVACsystem Temperature extremes in poorlyinsulated areas Localized effects of space heatersand air conditionersAnticipate that airflow andtemperature gradients may varydepending on whether shelves areempty or stocked with product.Taller racks will be subject to widertemperature gradients, requiringmore sensors top to bottom.You can mount sensors in openareas (for example outsideof racks or aisles) where theyare convenient to set up. Butconvenience must not takeprecedence over effectiveness.Sensors must measure theconditions that products areexposed to.If you don’t have an adequatenumber of sensors to map anentire warehouse in one study, youmay map one section at a time.Mapping in sections takes longer,and you may want to extend themapping time for each section tocompensate for the uncertainty ofmapping the space in sections. Todecide, calculate the equipmentsavings from a sectional mappingapproach against the additionaltime needed to complete theproject.If high or low relative humidity canadversely affect product quality,then you should map for relativehumidity as well as temperature.There are two approaches todetermining the number andlocation of relative humiditysensors.
Considerations forhumidityDetermining humiditysensor densityThe first approach is to usecomparatively few humiditysensors distributed throughout thewarehouse (as few as one for everysix temperature sensors). In thiscase you will rely on temperatureuniformity to make the case thathumidity is also within bounds. Thisapproach should be based on ahistory of temperature mapping indifferent seasons with consistentresults. With this history, a specialistwith an understanding of humiditymeasurement can effectively makethe case to an auditor or inspectorthat humidity measurements arenot needed at all data points. If youdecide to follow this strategy andcut back on the number of humiditysensors, it’s crucial to place thefew humidity sensors you do usein areas with poor air circulation,between HVAC fans or diffusers,and where temperature is mostvariable.Compared with temperaturesensors, relative humidity sensorsare far more prone to to loseaccuracy, or “drift,” over time. Driftmay be caused by poor design,poor calibration, or contaminationfrom water-vapor saturation orchemical vapors. A single errantreading at recalibration time willcall attention to your decisionto use fewer humidity sensors.Starting with fewer humiditysensors creates the risk ofnonconformance, because if onefails, or is out of specification, thatsingle sensor will represent a highpercentage of your total humiditymeasurements. Interpolatingrelative humidity from temperaturedata will require that a companyemployee with this specializedknowledge meet with the auditoror inspector. Ideally, your companyshould minimize the numberof contacts needed during aninspection as a way to streamlinethe process and reduce thepossibility of a misstatement.If you’re concerned about relativehumidity, a more defensiblemapping strategy is to tracktemperature and humidity at alllocations with data loggers thatrecord both measurements. It’simportant to use high-qualitydata loggers that are stable andregularly calibrated.Mapping with integratedtemperature and relative humiditysensors offers several advantagesover deducing humidity fromtemperature. Mapping bothtemperature and humidity at allsensor locations provides a morequantitative map of the entirestorage space for inspectors andauditors to easily comprehendwithout detailed explanation. Andrelative humidity excursions willbe easier to identify with morehumidity data points.Regulatory Note:Understanding the relationshipsbetween measured parametersis essential to successfulmapping studies and managingrisk in a GMP storage space.Step 5: Select suitabletechnologyUse equipment designedfor mapping. Software thataccompanies the sensors is usedto set up the equipment anddownload data. Software shouldproduce tabular and graphicalreports that meet all requirementsof 21 CFR Part 11 and comparableinternational standards, such asEuropean Commission Annex 11,and those contained in EuropeanUnion GMP Volume 4.When choosing data loggers, lookfor the following features: Minimum sources of error – that is,low measurement uncertainty. High accuracy in themeasurement range. VaisalaDL2000 data loggers, forexample, are accurate to 0.1 C over 20 C to 30 C,with humidity accuracy of 1 %RHin 10 to 80 %RH. Sensitivity to small temperaturechanges (high resolution). Themore rapid the response, themore closely the data point canbe associated with the time of themeasurement. Long-term stability, particularlyfor relative humidity sensors.Low-quality equipment needs tobe calibrated before and afterevery study. Traceable calibration performedwithin the measurement rangeand with equipment using anunbroken chain of comparisonsto an internationally recognizedstandard such as that of theNational Institute of Standardsand Technology (NIST). Clear, comprehensive, andaccessible calibration records.
Regulatory Note: GMPsrequire written proceduresfor calibrating, inspecting,and checking automated,mechanical, and electronicequipment (21 CFR 211.68).International standardssuch as ISO/IEC 17025:2017“General Requirements forthe Competence of Testingand Calibration Laboratories”are recognized best-practicereferences for calibration.Step 6: Set up mappingequipmentAfter you’ve identified riskareas and determined sensordistribution, it’s time to set upmapping equipment and conducta test of the storage space.The purpose of this initial testis to determine where variableconditions exist, and wheretemperature and humidity areuniform and suitable for productstorage. Work through thefollowing checklist and documenteach step: Equipment has been calibrated.Document by whom, when, andthe next calibration date. Thisconfirms that the data loggerperforms within the calibratedmeasurement range. Equipment has been validated.Installation qualification andoperation qualification (IQ/OQ) istypically provided by the mappingsystem supplier. Ensure mapping softwareaccess has been secured andauthenticated. Access privilegesrestrict who is allowed to use theapplication. Ensure the software reads andrecords hardware and firmwaremodel, version, and serial number. Ensure the warehouse areaand data logger locations areaccurately described. A schematicor diagram helps ensureconsistent sensor placement insubsequent mapping studies. Regular sample intervals havebeen determined. Intervalstypically run between five and 15minutes. Study duration has beendetermined. All data loggers areset to begin and end at the sametime. Data loggers link to an audittrail file for traceability. This is anessential requirement to showthat the data is trustworthy. Data loggers are functional andpositioned in defined locations.Regulatory Note: GMPs requirethe use of calibrated equipmentand calibration records. If yougathered data in electronicform, these records mustmeet regulations for electronicrecords as defined in 21 CFRPart 11, in EC Annex 11, and inEuropean Union GMP Volume 4.
Step 7: Conduct a testand review dataYou’ll need to establish thereporting information you’ll useto evaluate the test. When thetest is complete, the softwarewill read the secure files from thedata loggers, show recorded data,perform calculations, and graphthe results selected for a mappingstudy report. The test documentwill typically show the informationin Figure 3: Raw data with times and dates. Calculated values such astemperature minimum, maximum,and average. A graph of all sensors over thetest period.A graphical overview can helpidentify high-risk locations,especially where problems mayoccur sporadically. For example, atemperature spike may be linkedto a time when loading doorswere open. Instrument settings. Calibration information. Date and time of the test. Space for review and approvalsignatures on printed reports.Trend data from each sensor canbe compiled in a single graph toprovide an overview. Preset lines,such as acceptable minimumand maximum limits, can aid theanalysis.Such a variation might indicatea risk from routine workplaceactivity or suggest the need for abuffer zone.Regulatory Note: It’s betterto present a summary graphwith a clear conclusion than avery detailed report that maygenerate additional questions.Figure 3. The mapping report can show high and low limits to quickly visualize thresholds.
Step 8: MakemodificationsUse the results from the initialtest to identify locations wherethe product may be exposed tounacceptable conditions. Thenmake adjustments—for example,to the storage racks or HVACsystem—to correct this variation.Or simply decide where productswill not be stored. For example,many warehouses have a mezzaninelevel designated off-limits for rawmaterials or finished goods becauseHVAC controls are ineffective there.Name and describe these locationsand modify the validation plan. Also,modify your validation protocol inlight of the results from your initialmapping test.Regulatory Note: Modificationsto a newly commissionedwarehouse don’t need toappear in the inspectionrecord. But once your companyapproves a validation masterplan, then the plan mustdocument all subsequentchanges.Step 9: Document andschedule the mappingstudyAfter you adjust for environmentalvariability in the warehouse, it’stime to conduct and document amapping study for approval.How long should mapping last?As with your initial mapping test,there’s no fast rule. Your rationaleand protocol may support a singlelong study, or a series of shorterstudies. Either way, it’s importantto measure the environmentduring a range of different workactivities in the warehouse, suchas loading, moving product, andperiods such as weekends whenlittle activity might occur.How often should you mapa space?Some protocols call for mappingevery three months while otherscan justify mapping yearly or evenless frequently. The validationmaster plan should anticipatevariables that can change storageconditions after completionof a warehouse qualification.Warehouse construction, majorHVAC changes, and similarmodifications to the environmentrequire additional mapping.Seasonal changes and extremeweather may justify mapping thewarehouse with greater frequencyor rescheduling a test for a more“seasonable” temperature. Forexample, the validation plan maycall for a mapping study in July,when temperatures are typicallyhottest. But if July is unseasonablycool, it may make sense to delaymapping until a warm spell inAugust. The validation plan shouldprovide enough flexibility tocapture weather extremes. Forexample, depending on the climatein your area, your plan mightcall for mapping when summertemperatures exceed 30 C andwinter temperatures fall below 0 C.Regulatory Note: Maintaininguseful records is integral tomeeting GMPs. Records mustbe stored securely and easilyretrieved for review. Theymust be gap-free. They mustprovide an audit trail. Recordsmay be paper, electronic, ora combination. If they areelectronic records, they mustmeet the requirements of 21CFR Part 11 or EC Annex 11.
SummaryThe keys to a successfulwarehouse mapping studyinclude creating a validationplan and protocol, withjustification for each step.Document changes to the planand protocol.even these guidance documentscan lag behind technologicaladvances. In a race to keepup, regulatory agencies andindustry stakeholders worldwiderevise their interpretations ofGMPs, developing new guidancedocuments. So it’s imperativeto keep abreast of the changingstandards.Links to resourcesIdentify areas of risk in yourwarehouse to determine thedistribution of sensors andduration of the mapping.International Conference onHarmonisation:Select reliable technologysuitable to the task. ICH Q9 – Quality RiskManagementModify your storage spaceto ensure you are mapping acontrolled environment.Document and schedulemapping studies to accountfor changes in the warehouseenvironment.Keep records in a manner thatthey are secure and accessible.Document that your protocolwas followed consistently, andre-evaluate your proceduresperiodically.Regulations and guidanceWarehouse mapping regulationsrequire documented evidencethat an environment is in a stateof control and suitable for theproducts stored there. Regulatoryagencies and independentorganizations also issue nonbinding guidance documentsthat can provide greater detailthan regulations in applyingcurrent regulations. However, ICH Q7 - GMP Guidance for ActivePharmaceutical Ingredients ICH Q10 Pharmaceutical QualitySystemUnited States Pharmacopeia: USP Chapter 1079 Good Storageand Distribution Practices forDrug Products USP Chapter 1118 MonitoringDevices – Time, Temperature, andHumidityInternational Society ofPharmaceutical Engineering: ISPE Good Practice Guide –Controlled Temperature ChamberMapping and MonitoringParenteral Drug Association: PDA Technical Report No. 52 –Guidance for Good DistributionPractices for the PharmaceuticalSupply ChainEuropean Commission: EC Guidelines on GoodDistribution Practice of MedicinalProducts for Human Use PIC/S GMP Guide Part I: Guideto GMP for Medicinal ProductsSection 3.19 PIC/S GMP Guide Part II: Guideto GMP for Medicinal ProductsSections 7.42 and 10.1Health Canada GUI 0069: Guidelines forTemperature Control of DrugProducts During Storage andTransportationU.S. FDA: 21 CFR Part 210 cGMP inManufacturing, Processing,Packing, or Holding of Drugs 21 CFR Part 211 cGMPs forFinished Pharmaceuticals 21 CFR Part 820 Quality SystemRegulation 21 CFR Part 600 BiologicalProducts 21 CFR Part 111 cGMPs inManufacturing, Packaging,Labeling, or Holding Operationsfor Dietary Supplements 21 CFR Part 11 Electronic Records;Electronic Signatures Pharmaceutical CGMPs for the21st Century – A Risk-BasedApproachASTM (formerly American Societyfor Testing and Materials): ASTM E2500 Standard Guidefor Specification, Design, andVerification of Pharmaceutical andBiopharmaceutical ManufacturingSystems and Equipment Eudralex Volume 4 GoodManufacturing Practices –Medicinal Products for Humanand Veterinary Use, Annex 11:Computerized SystemsRef. B211170EN-B Vaisala 2020Please contact us utical InspectionConvention and PharmaceuticalInspection Cooperation Scheme:Scan the code formore informationThis material is subject to copyright protection, with all copyrightsretained by Vaisala and its individual partners. All rights reserved.Any logos and/or product names are trademarks of Vaisala or itsindividual partners. The reproduction, transfer, distribution orstorage of information contained in this brochure in any formwithout the prior written consent of Vaisala is strictly prohibited.All specifications — technical included — are subject to changewithout notice.
their focus on warehouse storage and distribution practices. Driving this trend is a shift in regulatory thinking from quality-by-test to quality-by-design systems with emphasis on level of risk to product quality and patient safety. Ot