cen lsc amer gmp warehouse mapping white paper b211170en a

8/10/2019 CEN LSC AMER GMP Warehouse Mapping White Paper B211170EN A

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Good manufacturing practice (GMP) regulators in the United States,Canada, European Union, Japan, Australia, and China have sharpenedtheir focus on warehouse storage and distribution practices. Drivingthis trend is a shift in regulatory thinking from quality-by-test toquality-by-design systems with emphasis on level of risk to productquality and patient safety. Other drivers include greater demand forstorage facilities due to globalization of manufacturing, increase intemperature-sensitive biopharmaceuticals, and changes in technology.

Regulators in these countriesrequire mapping the temperatureand relative humidity prole ofwarehouses for environmentallysensitive life science products. This

step-by-step guide describes how tomap a warehouse to comply withinternationally recognized GMPs,including many that have been

published or revised recently. (See Regulations and Guidance at theend of this paper for more detailed

citations of GMPs.) This guide,intended for use by any organizationinvolved in the storage and distributionof products sensitive to temperatureand humidity in a GMP-compliant

environment, draws on Vaisalasextensive customer experiencethroughout North America and Europe.

Indeed, Vaisalas environmental andindustrial measuring and monitoring

products are used in more than140 countries.


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Step by Step Good Practice WarehouseMappingVaisala recommends a nine-pointprocess for successful mappingof a warehouse or other regulatedstorage space:

1. Create a validation plan

2. Identify areas at risk

3. Develop protocol information

4. Determine sensor distribution

5. Select suitable technology

6. Set up mapping equipment

7. Conduct test and review data

8. Make modifications

9. Document and schedulemapping tests

These nine steps will help youdesign and execute a successfulmapping plan. They will ensurethat you take into considerationthe most important elements ofvalidation, especiallyunderstandingwheretemperatureand humiditypose risksto productquality.Following

these stepswill go a longway indemonstratingto a regulatoryinspector that yourcompany isGMP compliant.

Step 1: Create aValidation PlanThe validation plan, or validationmaster plan, is the documentused to specify the companyscommitments and decisions aboutqualifying every aspect of thefacility, equipment, and peopleto maintain a GMP-compliantenvironment. The plan shouldtake a risk-based approach, witha rationale based on scienceand verifiable measurements.The plan should focus on whereenvironmentally sensitive productsand materials will be stored andwhether environmental controlscan meet specified storagerequirements.

The plan is also a starting point forregulators to evaluate the rationalefor the companys goals and

methods.

The master validation 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 documentation and

procedures, including thecompanys response shoulda temperature or humidityexcursion occur.

Define a validation schedule.

Specify the management approvalprocess, especially for adverseevents such as out-of-temperaturedeviations.

Identify change-control protocolsso its clear when changes such as

maintenance, new construction,and reconfiguration of racksrequire revalidation.

Regulatory Note: GMPs requiremaintaining temperature

and humiditywithin storagerecommendationsprinted on

product labelsor provided by

raw-materialsuppliers.

Theserecommendations

are derived fromknown chemical

properties andstability testing.


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Step 2: Identify Areasat RiskTo map a warehouse or otherstorage space, you first mustidentify areas where productquality may be at risk becauseof unacceptable variations intemperature and humidity. Manyfactors affect the control orvariability of your space. (Becauserelative humidity is dependenton temperature, variations intemperature will affect humidityas well.) Considering each of thesefactors will help you pinpoint risk:

Volume of space. A largewarehouse has different controlburdens than a small storagearea, with greater demands on theHVAC system and the potential forgreater variations in temperatureand humidity at various locations.

The capacity of diffusers or fansto adequately circulate air.

Temperature gradients betweenthe cooler floor and warmer airnear the ceiling.

Independent energy sources, suchas space heaters, air conditioners,and fans, which create warm orcold pockets.

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 dock.

High-traffic areas where productor equipment is moved.

Seasonal temperature changes orunusual weather events.

Regulatory Note: You can achieveGMP compliance through goodscience and sound justificationof your approach to identifyingrisk. The more considerations thevalidation master plan addresses,the better your compliance rationaleis likely to be.

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Step 3: Develop ProtocolInformationOnce youve identified areas of risk,develop a protocol for the mappingtest that describes the following,with justifications for each decision:

Types of data to be generated forexample, temperature, relativehumidity, and measurementintervals. Five-minute intervalsoffer more data to evaluate trendsand modify the warehouse setting(see Step 8). Once you are satisfiedthat temperature and humidityare relatively stable, 15-minuteintervals may be adequate for thefinal mapping.

Number of sensors to be used(see Step 4: Determine SensorDistribution).

Map of sensor locations.

Duration of study. Your rationaleand protocol may support a seriesof tests, each lasting two daysduring normal operations and intoa weekend. A different and equallydefensible protocol might specifya single run over a two-weekperiod to account for a variety ofactivities, such as opening loadingdock doors, in the warehouse.

Calibration requirements of thedata loggers (specified by themanufacturer).

Acceptable range of variation overtime and across the space, whichwill depend on the product stored.

Acceptable limits for temperatureor relative humidity excursions.

Reporting requirements.

Regulatory Note: Once you developa protocol, follow it consistently.If the protocol changes, documentthe reasons.

Figure 1. The even distribution of 15 sensors is a typical pattern for three- dimensional mapping of a small space.


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Step 4: Determine SensorDistributionHow many sensors will you needto map a particular space? Where

will you put them? There are noformulas or pat answers. Sensordistribution must be adequate toassess temperature uniformity.Good practice demands you use asufficient number to understandyour environment, especiallyproblem areas where risk isgreatest.

Youll need to place sensors ina uniform pattern in all threedimensions of your space top to

bottom, left to right, front to back.Add additional sensors where yoususpect cool or warm areas mayexist, as well as near the controlsensors and monitoring sensors.Placement of temperature andrelative humidity sensors is afunction of the considerations andrisks you evaluated earlier in Step 2.

A walk-in chamber or smallwarehouse is often mapped in three

to set up. But convenience mustnttake precedence over effectiveness.Sensors must measure theconditions to which your productsor material are exposed.

If you dont have the sensors youneed to map an entire warehousein one test, you may choose to mapone section at a time. Mapping insections takes longer, and you maywant to extend the mapping time foreach section to compensate for theuncertainty of mapping the spacepiecemeal. To decide, weigh theequipment savings from a sectionalmapping approach against theadditional time needed to completethe project.

If high or low relative humiditycan adversely affect product ormaterial quality, then you shouldmap for relative humidity as wellas temperature. There are twoapproaches to determining thenumber and location of relative-humidity sensors.

dimensions with 15 sensors. Theprotocol should set bounds on thedistance between sensors, such asno greater than 6 meters.

In mapping a large warehouse,set sensors as far as 60 metersapart, with additional sensors invulnerable areas affected by draftsfrom loading docks, heat or coldfrom external walls, solar heatingfrom windows, heat generatedfrom artificial lights, air circulationfrom traffic or the HVAC system,temperature extremes in poorlyinsulated areas, localized effects ofspace heaters and air conditioners,and drafts from typical warehouseactivity. Anticipate 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 (outside of racks or aisles, forexample) where they are convenient

Figure 2. Sensors placed in the middle of racks reflect actual product temperatures. In this example, nine sensors are locatedon each double rack in this warehouse measuring 30 meters by 30 meters by 15 meters.

TopView


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The first approach is to usecomparatively few humiditysensors distributed throughoutthe warehouse (as few as one for

every six temperature sensors) andto rely on temperature uniformityto make the case that humidity isalso within bounds. This approachrelies on a history of temperaturemapping in different seasons withconsistent results. With this history,a specialist with an understandingof humidity measurement sciencecan effectively make the case to anauditor or inspector that humiditymeasurements are not needed at alldata points. If you decide to followthis strategy and cut back on thenumber of humidity sensors, itscrucial to place the few sensorsyou do use in areas with poor aircirculation, between HVAC fans ordiffusers, and where temperature ismost variable.

Such a strategy is notwithout risks.Compared with temperaturesensors, relative humidity sensorsare far more prone to to loseaccuracy, or drift, over time. Driftmay be caused by poor design, poorcalibration, or contamination fromwater-vapor saturation or chemicalvapors. A single errant readingat recalibration time will callattention to your decision to skimpon humidity sensors. Starting withfewer humidity sensors creates therisk of nonconformance, because ifone fails or is out of specification,

that single sensor will representa high percentage of your totalhumidity measurements. Deducinghumidity compliance throughtemperature uniformity will requirethat a company employee with thisspecialized knowledge meet withthe compliance inspector. Ideally,your company should minimizethe number of contacts neededduring an inspection as a way tostreamline the process and reducethe possibility of a misstatement.

If youre concerned about relativehumidity, a more defensible mappingstrategy is to track temperatureand humidity at all locations withdata loggers that record bothmeasurements. Its important to usehigh-quality loggers that remaindemonstrably accurate.

Mapping with integratedtemperature and relative humiditysensors offers several advantages

over deducing humidity fromtemperature. Mapping bothtemperature and humidity atall sensor locations provides aquantitative map of the entirestorage space for inspectors and

auditors to easily comprehendwithout detailed explanation.And relative-humidity excursions(caused, for example, by fire

sprinkler activation or otherunexpected moisture) will beeasier to identify and explain if youmeasure relative humidity directly.

Regulatory Note: Understandingenvironmental variability isessential to successful mappingoutcomes and managing risk in aGMP storage space.

Step 5: Select SuitableTechnologyUse equipment designed formapping. Sensors should beintegral with modern electronicdata loggers. Data loggersmeasure, store, and record datathroughout the validation test.Software that accompanies thedata loggers is used to set up theequipment and download data.Software should produce tabularand graphical reports that meetall requirements of 21 U.S. Code

of Federal Regulations Part 11 andcomparable international standards,such as European CommissionAnnex 11, and those contained inEuropean Union GMP Chapter 4.(See Regulations and Guidance fordetails.)

When choosing data loggers, lookfor the following features:

Minimum sources of error thatis, low measurement uncertainty.

Sensitivity to small temperaturechanges. The more rapid theresponse, the more closely thedata point can be associated withthe time of the measurement.


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Long-term stability, particularlyfor relative-humidity sensors,which are more prone thantemperature sensors to drift.

Low-quality equipment may needto be calibrated before and afterevery use. Stable, high-qualitydata loggers demonstrated to beaccurate for 12 months or morebetween calibrations will savetime and produce better results byeliminating the need to calibratebefore and after every use.

High accuracy in the range of use.Vaisala loggers, for example, areaccurate to 0.10C (0.18F) in an

operating range of -90 to 85C(-130 to 185F), and to 1 percentrelative humidity.

Traceable calibration performedwithin the measurement range that is, calibrated with equipmentusing an unbroken chain ofcomparisons to an internationallyrecognized standard such asthat of the National Institute ofStandards and Technology. Theloggers calibration certificate

should document all of the dataabove.

Clear, comprehensive, andaccessible calibration records.

Regulatory Note: GMPs requirewritten procedures for calibrating,inspecting, and checkingautomated, mechanical, and

electronic equipment (21 CFR111.25). International standardssuch as ISO/IEC 17025:2005 GeneralRequirements for the Competence ofTesting and Calibration Laboratoriesare recognized best-practicereferences for calibration.

Step 6: Set Up MappingEquipmentAfter youve identified likely riskareas and determined sensor

distribution, its time to set upmapping equipment and conduct amapping test of the storage space.The purpose of this initial test isto determine where risky (thatis, variable) conditions exist, andwhere temperature and humidityare uniform and suitable for productstorage.

Work through the followingchecklist, making sure each step iscompleted and documented:

Equipment has been calibrated by whom, when, next calibrationdate, and calibration confirms thatthe logger performs within thelimits of stated uncertainty.

Equipment has been validated.Installation qualification andoperation qualification(IQ/OQ) is typically provided by

the equipment supplier. Program access has been

secured and authenticated.Access privileges or permissionsrestrict who is allowed to setup the equipment and use theapplication.

Software reads and recordshardware and firmware model,version, and serial number.Software can identify each uniquepiece of equipment.

The warehouse area under testhas been precisely described.

Data logger locations are preciselydescribed. A pictorial maphelps ensure consistent sensorplacement in subsequent tests.

Regular sample intervals havebeen determined. Intervalstypically run between five and15 minutes.

Test duration has beendetermined. All data loggers areset to begin and end at the sametime.

Data loggers link to an audittrail file for traceability. Thisis an essential requirement toshow that documentation istrustworthy.

Data loggers have been positionedin defined locations.

Regulatory Note: GMPs requirethe use of calibrated equipmentand records to show maintenanceto acceptable standards. If yougathered data in electronic form,these records must meet regulationsfor electronic records as defined in21 CFR Part 11, in EC Annex 11, andin European Union GMP Chapter 4.(See Regulations and Guidance fordetails.)


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Step 7: Conduct Test and Review Data

Figure 3. The mapping report can show high and low limits to quickly visualize acceptance criteria.

Raw data with times and dates.

Calculated values such astemperature minimum, maximum,and average.

Graph of all sensors over the testperiod.

Instrument settings.

Calibration information.

Date and time of the test.

Space for review and approvalsignatures.

Overlay traces from each sensorcan be compiled onto a singlegraph to provide a quick look at anytemperature and relative-humidityextremes. Preset lines, such asacceptable minimum and maximumlimits, can aid the analysis.

The measured data becomepart of the secure record. Thisrecord can help identify high-risk locations, especially whereproblems occur sporadically. Forexample, a temperature spike maybe linked to a time when loading

Youll need to establish thereporting information youll use toevaluate the test. When the test iscomplete, software will read thesecure files from the data loggers,show recorded data, performcalculations, and graph the resultsselected for the mapping report. Thetest document will typically showthe following information:


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doors were open. Such a variationmight indicate a risk from routineworkplace activity or suggest theneed for a buffer zone.

Regulatory Note: 21 CFR Part11 and EC Annex 11 require thatcomputerized records be available,readable, reliable and secure. Itsbetter to present a summary graphwith an easy-to-draw conclusionthan a difficult-to-read report thatmay generate additional questions.

Step 8: MakeModificationsUse the results from the initialtest to identify locations wherethe product would be exposedto unacceptable extremes oftemperature or humidity. Thenmake adjustmentsfor example,to the storage racks or HVACsystemto correct this variation.Or simply decide where productswill not be stored. For example,many warehouses have amezzanine level designated off-limits to raw materials or finished

goods because HVAC controls areineffective there. Name and describethese nonstorage locations andmodifications in the validation plan.Modify your validation protocol inlight of the results from your initialmapping test.

Regulatory Note: Modifications toa newly commissioned warehousedont need to appear in theinspection record. But once yourcompany approves a validation

master plan, then the plan mustdocument all subsequent changes.

Step 9: Document andSchedule Mapping TestsAfter you adjust for environmentalvariability in the warehouse, itstime to conduct and document amapping test for approval.

How long should mapping last? Justas with your initial mapping test,theres no fast rule. Your rationaleand protocol may support a singlelong test, or a series of shortertests. Either way, its important tomeasure the environment duringa range of different work activitiesin the warehouse, such as loading,moving product, and periods suchas weekends when little activitymight occur.

How often should you map a space?Some protocols call for mappingevery three months while otherscan justify mapping yearly or evenless frequently. The validationplan should anticipate the manyvariables that can change storagetemperatures after completionof a mapping project. Warehouseconstruction, major HVAC changes,and similar modifications to thewarehouse environment requireadditional mapping. Seasonalchanges and extreme weather mayjustify mapping the warehouse withgreater frequency or reschedulinga test for a more seasonabletemperature. For example, thevalidation plan may call for a testin July, when temperatures aretypically hottest. But if July isunseasonably cool, it may make

sense to delay mapping until a warmspell in August. The validation plan

should provide enough flexibilityto capture weather extremes. Forexample, depending on the climatein your area, your plan mightcall for mapping when summertemperatures exceed 30C andwinter temperatures fall below 0C.

Regulatory Note: Maintaining usefulrecords is integral to meeting GMPs.

Records must be stored securelybut retrieved easily for review. Theymust be gap-free. They must providean audit trail. Records may be paper,electronic, or a combination. If theyare electronic records, they mustmeet the requirements of 21 CFRPart 11 or EC Annex 11.


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SummaryThe keys to successfulwarehouse mapping includecreating and following avalidation plan and protocol,with logical, scientific

justification for each step. Document changes to the plan and protocol.

Identify areas of risk in yourwarehouse to determine thedistribution of sensors and

duration of the mapping.

Select reliable technologysuitable to the task.

Modify your storage space tomake sure you can validate acontrolled environment.

Document and schedulemapping tests to account forchanges in the warehouse

environment. Keep recordsin a manner that they areboth secure and available forreview.

Document that your protocolwas followed consistently,and re-evaluate your

procedures periodically.

Regulations andGuidanceWarehouse mapping regulations,such as CFR Title 21 and comparableEuropean standards, requiredocumented evidence that anenvironment is in a state of control,suitable for the products storedthere. Regulatory agencies andindependent organizations also issuenonbinding guidance documents,which provide greater detail thanregulations do in defining GMPsand current regulatory thinking.However, even these guidancedocuments lag behind advances

in technology. In a race to keep up,regulatory agencies and industrygroups worldwide constantlyrevise their interpretations ofGMPs, developing new regulationsand guidance documents. So itsimperative to keep abreast of thechanging standards.

A selected list of regulations andguidance for mapping appearsbelow. Its intended to be useful butnot comprehensive.

International Conference onHarmonisation:

ICH Q10 Pharmaceutical QualitySystem (2009)

United States PharmacopeialConvention:

USP Chapter 1079 MonitoringDevices Good Storage andShipping Practices (under revision2011)

USP Chapter 1118 MonitoringDevices Time, Temperature, andHumidity

International Society ofPharmaceutical Engineering:

ISPE Good Practice Guide ColdChain Management (2011)

Parenteral Drug Association:

PDA Technical Report No. 52 Guidance for Good DistributionPractices for the PharmaceuticalSupply Chain (2011)

European Commission:

EC Guidelines on GoodDistribution Practice of MedicinalProducts for Human Use (underrevision 2011)

Pharmaceutical ConventionInspection and PharmaceuticalInspection Cooperation Scheme:

PIC/S GMP Guide Part I: Basic

Requirements for MedicinalProgram Sections 3.19 and 4.9

PIC/S GMP Guide Part II: BasicRequirements for ActivePharmaceutical IngredientsSections 7.42 and 10.1

U.S. FDA Code of FederalRegulations Title 21:

21 CFR 820.150 Storage

Health Canada:

GUI 0069: Guidelines forTemperature Control of DrugProducts During Storage andTransportation (2011)

The following are other relevantsources for regulations, guidanceand standards.

U.S. FDA Code of FederalRegulations Title 21:

21 CFR Part 210 cGMPs forManufacturing, Processing or

Holding of Drugs

21 CFR Part 211 cGMPs forFinished Pharmaceuticals

21 CFR Part 820 cGMPs forMedical Devices

21 CFR Part 600 cGMPs for BloodProducts


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21 CFR Part 111 cGMPs for DietarySupplements

21 CFR Part 11 cGMPS ElectronicRecords & Signatures

21 CFR 211.46, .68, .142, .194Ventilation, Air Filtration;Electronic Equipment,Warehousing; Laboratory Records

European Commission:

Eudralex Volume 4 GoodManufacturing Practices Medicinal Products for Humanand Veterinary Use, Annex 11:Computerized Systems (2011)

U.S. FDA: Guidance for Industry:

Quality Systems Approach toPharmaceutical cGMP Regulations(2006)

Pharmaceutical CGMPs for the21st Century A Risk-BasedApproach (2004)

International Conference onHarmonisation:

ICH Q8 PharmaceuticalDevelopment (2006)

ICH Q9 Quality Risk Management(2006)

ICH Appendix 2.4 Human andOrganizational Errors andCriticality of Records

International Society ofPharmaceutical Engineering:

ISPE GAMP 5: A Risk-BasedApproach to Compliant GxP

Computerized Systems

World Health Organization:

WHO Report 908 Appendix 2ASTM (formerly American Societyfor Testing and Materials):

ASTM E2500 Standard Guidefor Specification, Design, andVerification of Pharmaceutical andBiopharmaceutical ManufacturingSystems and Equipment (2007)

International Organization forStandardization:

ISO/IEC 17025:2005 GeneralRequirements for the Competenceof Testing and CalibrationLaboratories

ISO 10012:2003 MeasurementManagement Systems

ISO 14971:2007 Medical Devices Application of Risk Management


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Ref. B211170EN-A Vaisala 2012This material is subject to copyright protection, with allcopyrights retained by Vaisala and its individual partners. Allrights reserved. Any logos and/or product names are trademarksof Vaisala or its individual partners. The reproduction, transfer,distribution or storage of information contained in this brochurein any form without the prior wr itten consent of Vaisala is strictly

prohibited. All specications technical included are subjectto change without notice.

For more information, visitwww.vaisala.com or contactus at [email protected]

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