Warehouse Mapping. Best Practices for Warehouse Temperature Management and Control

Transcription

1 Wareouse Mapping Best Practices for Wareouse Temperature Management and Control

2 Tis guide does not purport to be an interpretation of law and/or regulations and is for guidance purposes only. PUBLISHED BY: Tis material is subject to copyrigt protection, wit all copyrigts retained by Cryopak and its individual partners. All rigts reserved. Te reproduction, transfer, distribution or storage of information contained in tis document in any form witout te prior written consent of Cryopak is strictly proibited. All specifications tecnical included are subject to cange witout notice Parkway Blvd Anjou, QC H1J 1R CANADA UNITED STATES OF AMERICA FRANCE 1053 Derwent Way 551 Raritan Center Parkway Community Road, suite 220 Delta, BC V3M 5R4 Edison, NJ Poway, CA rue Bertelot, ZI la Maine 760 Maromme, France +33 (0) sales@cryopak.com Tis guide does not purport to be an interpretation of law and/or regulations and is for guidance purposes only. Cryopak 20 2

3 Contents 1. AUTHOR & CONTRIBUTORS ABBREVIATION & DEFINITION SCOPE PROJECT REQUIREMENTS PROCESS Step 1 Protocol Writing Coosing te Perfect Moment Data Logger Distribution Study Duration Measuring Range Testing Step 2 Protocol Execution Programming Data Loggers Installing Data Loggers Documentation Removing Data Loggers Step 3 Report Data Compilation Mean Kinetic Temperature (MKT) Calibration and Post-Calibration Requirements Data Analysis CONCLUSION REFERENCES Tis guide does not purport to be an interpretation of law and/or regulations and is for guidance purposes only. Cryopak 20 3

4 1. AUTHOR & CONTRIBUTORS Jalal Belbal, B.Sc. (eng.) Main Autor Jalal Belbal, Validation & Regulatory Compliance Manager at Cryopak, as 10 years of experience in te parmaceutical, biotecnology, and life science industries. He as worked on a wide range of qualification projects including mapping process, laboratory equipment, packaging and software validation to elp te Life Science industry fulfill US and Canadian regulatory requirements and best practices, suc as te Guide 0069, PIC/s-Annex11, PDA Tecnical Report No.64, USP 36 Capter <1079>, GAMP and FDA s 21 CFR Parts 11, 210, 211, and 820. Jalal Belbal earned a bacelor s degree in Biocemistry & Environmental Engineering from University Laval, Quebec. Benoît Cedomme - Contributor Benoît Cedomme, Sales Manager Canada at Cryopak, as over 10 years of experience in te parmaceutical, biotecnology and life science industries. After immigrating to Canada in 2004, e joined Alternatives Tecnologie Parma, a start-up company tat grew to become a recognized national cold cain solution provider. Over te years, Benoît as elped many CRO/CMO, 3PL and parmaceutical wolesalers to comply wit regulatory requirements and optimize teir cold cain process. Benoît Cedomme earned a master s degree in Sales & Distribution Network from University of Montpellier, France. Geneviève Josep Contributor Geneviève Josep, Marketing Coordinator at Cryopak, as over 10 years of experience in retail sales & customer service. Se joined Alternatives Tecnologie Parma in 2012 as a documentation specialist, were se gained experience in mapping process and termal equipment qualification. Se joined te Sales & marketing team at Cryopak, its sister company, a year later. Geneviève Josep earned a degree in Political Science and a certificate in Professional Writing from University of Montreal, Quebec. Se is currently a McGill University student in Marketing. Tis guide does not purport to be an interpretation of law and/or regulations and is for guidance purposes only. Cryopak 20 4

5 2. ABBREVIATION & DEFINITION In order to aid te understanding of terms and acronyms used in tis document, a brief tecnical definition is sown below. Please note: Tis document only refers to temperature mapping. Tis service is also available for relative umidity. Terms / Acronyms Definitions HC HVAC HPRA EMA USP GMP PDA PIC/S WHO FDA ISPE ICH GDP MKT EMS 21 CFR NIST NCRC SOP Software Healt Canada Heating, Ventilation, and Air Conditioning Healt Product Regulatory Autority European Medicines Agency U.S Parmacopeia Good Manufacturing Practice Parenteral Drug Association Parmaceutical Inspection Co-operation Sceme World Healt Organization Food and Drugs Administration International Society For Parmaceutical Engineering Internal Conference on Harmonisation Good Distribution Practice Mean Kinetic Temperature Environmental Monitoring System Code of Federal Regulation, number 21 from Food and Drug Administration (FDA) National Institute of Standards and Tecnology National Calibration Reference Centre Standard Operating Procedure Software is a generic term for organized collections of computer data and instructions, often broken into two major categories: system software tat provides te basic non-task-specific functions of te computer, and application software wic is used by users to accomplis specific tasks. Tis guide does not purport to be an interpretation of law and/or regulations and is for guidance purposes only. Cryopak 20 5

6 Terms / Acronyms Data logger Parmaceutical products Protocol Protocol deviation Set point CAPA Seasonal Mapping Temperature Stratification Definitions An electronic device tat records data over time or in relation to location eiter wit a built-in instrument or sensor, or via external instruments and sensors. Increasingly, but not entirely, tey are based on a digital processor (or computer). Tey generally are small, battery powered, portable, and equipped wit a microprocessor, internal memory for data storage, and sensors. Some data loggers interface wit a personal computer and utilize software to activate te data logger and view and analyze te collected data, wile oters ave a local interface device (keypad, LCD) and can be used as a stand-alone device. Any product intended for uman use or veterinary product intended for administration to food production animals, presented in its finised dosage form tat is subject to control by parmaceutical legislation in eiter te exporting or te importing state and includes products for wic a prescription is required, products wic may be sold to patients witout a prescription, biologicals and vaccines. Medical devices are not included. A predefined, written procedural metod for te design and implementation of experiments to define and document te metodology and criteria required to assess te capability of a temperature and/or relative umidity controlled system to acieve te desired results. A deviation tat occurs wen a result is unexpected (i.e. fails to meet te predetermined acceptance criteria) or a procedure in te protocol cannot be executed as written (e.g., wen a callenge is met using a metodology oter tan tat described in te protocol or a process). Te specific temperature programmed by te user into te temperature controller unit tat establises te target temperature in te controlled environmental space. Corrective Action and Preventive Action Corrective Action: Action to eliminate te cause of a detected nonconformity or oter undesirable situation. Preventive Action: Action to eliminate te cause of a potential nonconformity or oter undesirable potential situation. Validation procedure performed during a particular time of year; mapping study done twice, once in winter, once in summer. Termal stratification; feature of gasses and liquids in wic ig energy molecules move to te top of a contained space, and cooler molecules move to te bottom; layering of differing temperatures from te floor of te facility to te ceiling. Tis guide does not purport to be an interpretation of law and/or regulations and is for guidance purposes only. Cryopak 20 6

7 3. SCOPE A mapping study is performed to generate a temperature profile of te facility, in order to ensure it maintains te temperature range required by te specific products. Temperature mapping studies elp manufacturers, distributors and transporters of parmaceutical, biotecnology and oter temperature sensitive products protect teir value by identifying potential environmental control problems before products are affected, as inadequately controlled environments can lead to ineffective and spoiled products. It s also an essential exercise to determine te location of te real-time monitoring system sensors.. Fundamental to any controlled process is te expectation tat parmaceutical and oter products tat are stored and sipped witin a controlled environment are maintained witin teir defined range, as all drugs sould be stored according to te conditions described on te label. Te temperature witin an environmentally controlled wareouse is expected to be maintained 1 : Reliably and consistently troug te entire period te product is stored witin te controlled environment; In compliance wit te product requirements for temperature at all locations in wic te product migt be stored (i.e. temperature and location/storage boundary). REGULATORY REQUIREMENTS Temperatures sould be controlled and monitored using calibrated monitoring devices and records of temperature and alarms, were applicable, sould be maintained. Monitoring of storage facilities is conducted at points representing te worst case scenarios of te temperature range based on temperature mapping. - Guidelines for Temperature Control of Drug Products during Storage and Transportation GUI-0069 Healt Canada Te recent canges in te FDA and Canadian regulations (GUI and various federal CFR codes), along wit te objective to eliminate te waste of time and money to fix environmental conditions failures as made temperature mapping an integral aspect of any storage area operation. 1 PARENTERAL DRUG ASSOCIATION. Tecnical Report No.64 Active Temperature Controlled Systems: Qualification Guidance, PDA, 2013, 58p. Tis guide does not purport to be an interpretation of law and/or regulations and is for guidance purposes only. Cryopak 20 7

8 4. PROJECT REQUIREMENTS Regulatory autorities underline te importance of storage and transportation temperature in maintaining drugs and temperature sensitive products quality witin distribution network. Temperature mapping is required to assess te ability of te facility to maintain its required temperature range. Canada United Sates Worldwide Oters Healt Canada Guidelines for Temperature Control of Drug Products during Storage and Transportation (GUI-0069) Food and Drug Regulation, Section C PIC/S Guide to Good Manufacturing Practice for Medicinal Products Annex. USP 36 USP General Capter <1079 Good Storage And Sipping Practices USP General Capter <1083 Good Distribution Practices- Supply Cain Integrity. FDA CFR Part Storage CFR 21 Guidance for Industry Part 11, Electronic Records, Electronic Signatures Scope and Application. WHO Good Distribution Practices for Parmaceutical Products TRS No.957.Annex 5 (2010) Model requirements for te storage and transport of time and temperature sensitive parmaceutical products TRS No.961, Annex 9 (2011). PDA PDA Tecnical Report No. 64- Active Temperature Controlled Systems: Qualification Guidance. Tecnical Report 58- Risk Management for Temperature Controlled Distribution. ICH Guidance for Industry Q1A (R2) Stability Testing of New Drug Substances and Products. ISPE Good Practice Guide Cold Cain Management (2011). Iris Medicines Board Guide to Control and Monitoring of Storage and Transportation Temperature Conditions for Medical Products and Active Substances. EMA (Europe) (2013/C 68/01) Good Distribution Practice of Medicinal Products for Human Use. HPRA Guide to Control and Monitoring of Storage and Transportation Temperature Conditions for Medicinal Products and Active Substances. Figure 1: Regulations and Guidelines around te World Te standards set fort in te Good Distribution Practice (GDP) guidelines provide te framework for conducting mapping studies. Temperature mapping studies are expected to collect te following information 2 : Ensure te facility meets parmaceutical industry specific regulatory requirements; Identify potential ot spots and cold spots witin te facility to ensure products remain witin temperature range at all time; Te impact of pysical interventions (door openings, HVAC, power failures, etc.); Temperature variations across te area; Temperature variations at specific locations; Duration of any potential temperature excursions; 2 (2013/C 68/01) Good Distribution Practice of Medicinal Products for Human Use Tis guide does not purport to be an interpretation of law and/or regulations and is for guidance purposes only. Cryopak 20 8

9 Identify and eliminate potential weaknesses or failures in te cold cain process; Identify any macinery tat migt generate eat in te wareouse; Protect and ensure te products quality tat are manufactured and distributed; Optimise te use of space and energy witin individual storage facilities. As regulators increase teir empasis on GMP requirements, te definitive metod to demonstrate tat all controlled storage equipment, or storage areas, stay witin te specified limits is troug a toroug temperature mapping study. 5. PROCESS Proper organization and documentation are critical to maintaining compliance and consistency. Cryopak s regulatory compliance experts strongly recommend te following 3 step approac: 5.1. Step 1 Protocol Writing Te protocol is a compreensive document used to guide te executants troug te verification of te temperature distribution witin te wareouse during worst case scenarios, wic are usually at te coldest and warmest extremes of te winter and summer seasons. Tis detailed protocol sould include a few elements tat are detailed below Coosing te Perfect Moment Coosing te perfect timing is an art our regulatory compliance experts ave mastered over te years. Temperature mapping sould be performed during te coldest week of te winter season and te warmest week of te summer season for all storage areas to ensure tat tey are likely to remain witin te specified temperature limits at all time troug te year. Tese seasons are cosen as extreme temperatures are more likely to adversely affect te temperature distribution witin te storage area. Altoug it is strongly recommended to map te storage area wen empty and loaded to get a better understanding of te temperature distribution, it is almost impossible to do so for practical reasons. However, customers opening a new facility or moving in a new building will likely perform an empty mapping in order to get teir license from te autorities Data Logger Distribution Tere are no standards or set formulas for te number or placement of data loggers tat sould be used for a mapping study. However, your study must demonstrate 3-dimensional uniformity and compliance wit your product requirements. Tese multiple data points account for gradients or Tis guide does not purport to be an interpretation of law and/or regulations and is for guidance purposes only. Cryopak 20 9

10 temperature extremes in critical areas were product will be stored. Good practice is to use a sufficient number to understand te environment, but not more tan needed. Not enoug sensors cannot justify te results; too many means andling more data tan necessary. You sould set te number of data loggers to use according to te wareouse volume. Wen determining sensor location, you need to identify areas were unacceptable temperature variations may affect te products quality. Large and open spaces are more difficult to maintain at a consistent temperature. Make sure to install data loggers at all potentially problematic and critical locations 3 : Temperature gradients between te cooler floor and warmer air at te ceiling: as eated air rises, make sure to measure any temperature stratification in larger spaces; HVAC system s capacity to move air, as well as te sizing of blowers or fans to adequately circulate air: poor airflow or a bad fan location can cause extreme temperature near sources of eat or cold, suc as HVAC ducts or windows; Layout of racks, selves, pallets and oter surfaces were products will potentially be stored: racking and selving configurations may create ot spots by obstructing te airflow. Close to te controllers; Doors, windows and oter risky areas, including outside walls tat may respond to external temperatures: doors or exits left open to regulate te overall temperature will affect te environmental conditions around nearby racks; Effect of incidences like power failures and vulnerable areas were tere may be wide variations in temperature, suc as sipping doors; Areas tat are non-selved, but deemed to be used as interim storage areas before placing on racking; Measure te external temperature during te study by installing one data logger outside. 3 ROBEY, Sara. Our blog Wicwareouse, [ttp:// (page consulted on April 14 t, 20) Tis guide does not purport to be an interpretation of law and/or regulations and is for guidance purposes only. Cryopak 20 10

11 Using a 3-dimensional temperature profile means installing data loggers on at least tree planes top to bottom, left to rigt and front to back (see figure 2), or on tree (3) rows in eigt (approximately at 6 feet, 12 feet and 18 feet ig) were ig racking exists. Additional data loggers sould be added were known cool or warm areas exist. No matter wic option you coose, make sure to use a consistent rationale for data loggers distribution. Figure 2: Example of Data Loggers Location For a larger wareouse, a justification of a 30 to 60-meter distance between data loggers could be used wit additional data loggers in vulnerable areas. Tese areas include loading docks, solar eating from windows, eat generated from artificial ligts, air circulation and uneven building insulation. To ensure even data logger distribution, it is recommended to divide te wareouse into smaller sections (see figure 3). Figure 3: Wareouse overview: different sections Tis guide does not purport to be an interpretation of law and/or regulations and is for guidance purposes only. Cryopak 20 11

12 Be sure to document te location of every data logger and label it to ensure tat it is installed at te rigt location during execution (see figure 4). Figure 4: Documenting and labeling data loggers Study Duration Te duration of te mapping study is also a key factor to create a meaningful set of data. Te total duration must capture enoug of te system s operation to justify consistent and repeatable operation. Te study must also attempt to capture events tat could be considered worst-case conditions of te temperature range based on temperature mapping. Initial mapping of an empty wareouse can be performed over a 3-day (72 our) period, during summer and winter seasons. If you are already operating, you may want to extend te mapping period from 7 days to two weeks (14 days) during summer and winter seasons, in order to capture te normal differences in scedule troug te workweek 4 and to ave a sufficient time frame to capture workflow variation tat may impact air flow and te resulting temperature fluctuation 5. 4 USP General Capter <1079> Good Storage and Sipping Practices, USP 28, Suppl. 2, August 1 st, WILLIAMSON, Mike. Mike Williamson Validation Blog, [ 2013/01/02/qualifying-controlled-wareouse-space/] (page consulted on April 14 t, 20) Tis guide does not purport to be an interpretation of law and/or regulations and is for guidance purposes only. Cryopak 20 12

13 Measuring Range Storage conditions for parmaceutical products and materials sould be in compliance wit te product labelling, wic is based on te results of stability testing storage conditions. All drugs sould be stored according to te conditions described on te label. Temperature, relative umidity, and ventilation sould be appropriate and sould not adversely affect te quality of parmaceutical products during teir manufacture and storage, or te accurate functioning of equipment. Te temperature acceptance limits tat will be tested and verified during te temperature distribution verification must be based on te label specification to prove tat te storage conditions reflects te labelling specifications. In case you ave various storage conditions, you need to test te smallest temperature range. Te establised acceptance limits will inform us if tere are excursions observed during te mapping period. All excursions outside te labelled storage conditions must be appropriately investigated and te disposition of te stock in question must be evidencebased (tecnical justification). Corrective actions (CAPA) sould be identified and implemented following te investigation to prevent reoccurrence Testing Te temperature distribution test is performed according to te procedure described in te protocol, wic identifies te steps required to perform and document te study. Tis test is designed to allow analysis of temperature distribution inside te wareouse. It will be analyzed as follows: Wareouse temperature distribution verification - winter season Wareouse temperature distribution verification - summer season Te temperature distribution during winter and summer seasons will be verified by conducting a 7-day to 14-day temperature mapping of te loaded wareouse by using a predetermined number 6 HPRA. Guide to Control and Monitoring of Storage and Transportation Temperature Conditions for Medicinal Products and Active Substances, IA-G Date 05/10/2011 Tis guide does not purport to be an interpretation of law and/or regulations and is for guidance purposes only. Cryopak 20 13

14 of data loggers, wic will be positioned as described in te protocol. Refer yourself to te section Data Loggers Distribution for more details on were to install te data loggers. Te reading interval will be set at minutes for te test. Te temperature set point of all termostats will be documented. Te external wareouse environmental conditions sould be taken into consideration. If tese conditions are stable, a sorter lengt of time migt be appropriate. However, if te conditions are variable, more time migt be required. Te temperature mapping sould be repeated every 3-4 years. Mapping sould also be redone after any significant modification to te premises, stock layout, or eating system. Heat gain of goods stored next to sun-facing windows, at ig level in poorly insulated stores, or next to eaters, sould be considered. Te temperature distribution verification must be conducted by trained and experienced tecnical personnel and must be documented in a scientific manner using an establised format. Tis study is meant to be representative and to be close to te real use of te wareouse. Te temperature distribution study is to be executed during normal working conditions Step 2 Protocol Execution Programming Data Loggers Cryopak can provide customers wit its iminiusb pdf data loggers to perform te study. Using our CFR 21 part 11 compliant software, ConsolePlus, program eac data logger according to te parameters specified in te protocol. To reduce te risk of uman error to a minimum, make sure to enter te data logger s identification number in te Description field (1). Once tis is done, pysically label te data logger wit te same ID. Select te temperature limits. Tese will only make it easier to identify te temperature excursion wen doing te data compilation (2) Once tis is done, select te reading interval. Tis parameter will determine ow often te data logger will take a measurement (3). Finally, it te program button (4). Before disconnecting te Tis guide does not purport to be an interpretation of law and/or regulations and is for guidance purposes only. Cryopak

15 data logger, make sure all te ligts blink on te data logger, meaning it was successfully programmed Installing Data Loggers Once you are ready to execute te temperature mapping, install te data loggers as per te protocol s plan. It is important to mention tat te locations and eigts indicated in te protocol are approximate and migt need to be adjusted. Make sure to document te exact location during installation. Secure te loggers in place to ensure tey do not fall during te full study duration. Tey sould be attaced to a stationary object suc as selving, racking, etc. Refer to te pictures below for more details. In te case of a large empty space, you can install data loggers on ropes anging from te ceiling Documentation It is crucial to properly document every section in te Test Data Seet section of te protocol. You must record any pertinent information and discussion of any unusual observations, exact data loggers location, as well as any oter information requested. Every cange to te protocol must be signed and dated Removing Data Loggers Once te study is over, remove all te data loggers by using te wareouse plan provided in te protocol. Tis will ensure no data logger is forgotten. By simply connecting your data logger to a USB port, download all te data under.cvt,.csv and.pdf formats. Send te files (or send te data loggers temselves) to te project engineer. Tis guide does not purport to be an interpretation of law and/or regulations and is for guidance purposes only. Cryopak 20

16 5.3. Step 3 Report Data Compilation Once te study is over and te data loggers ave 30,0 29,0 been removed, download te data and save all te 27,0 26,0 electronic files on your computer or network. All altered. Even if te original files usually require proprietary software in order to open tem, it is Hig Limit of 25 C 25,0 24,0 23,0 TEMPERATURE ( C) logged data is secured in a file tat cannot be SECTION 1: DISPENSARY STORAGE AREA (ROOM# 119) 28,0 22,0 21,0 20,0 19,0 18,0 17,0 16,0 Low Limit of C,0 13,0 12,0 11,0 DL-002 DL-003 DL-004 DL-005 DL-006 DL-007 DL-008 DL-009 DL-010 DL-011 DL-012 DL-013 DL-014 DL-0 DL-016 DL-017 DL-018 DL-019 DL-020 DL-021 DL-022 DL-023 DL-024 DL-025 DL-026 DL-027 DL-028 DL-029 DL-030 DL-031 DL-032 DL-033 DL-034 DL-035 DL-036 DL-037 DL-038 DL-039 DL-040 DL-041 DL-042 DL-043 DL-044 DL-045 DL-046 DL-047 DL-048 Part 11 requirements7. Data can also be exported into an Excel spreadseet for additional analysis. See Figures 5 and 6 for te Excel cumulative data and grap of a 7-day temperature mapping. However, exporting te data to Excel does not maintain te integrity of te data and is considered transcription. For tis reason, te original files must To ensure tat te data as not been Figure 6: Wareouse 7-day Temperature Cumulative transcription and calculations performed in Excel Mean Kinetic Temperature (MKT) Various regulatory autorities recommend using te MKT for establising profiles of storage facilities. Tey do not, owever, reference te use of MKT for determining te environmental effects (including ligt, umidity and temperature) during distribution. Te USP clearly states tat determining te ability of parmaceutical articles to maintain teir Parmacopeia requirements of identity, strengt, quality, and purity troug distribution may include, but is not limited to, te use of ICH stability studies, temperature cycling studies, stability 7 PATTERSON, Brandon J. & Justin PAWLIK. Journal of GxP Compliance, Monitoring By Data Logging. Tis guide does not purport to be an interpretation of law and/or regulations and is for guidance purposes only. Cryopak 20 to retrieve te data and generate reports must be compliant to PIC/S GMP Annex 11 and 21 CFR altered, a second person must verify all data Marc 02, 20 Figure 5: Wareouse 7-day Temperature Grap kept wit te executed protocol for future audits. It is important to mention tat te software used be stored HOUR (GMT ) February 23, save te original and PDF files on a CD tat will be DL ,0 universal access and viewing. It is mandatory to 14,0 02 often possible to save tem in Adobe PDF format for 16

17 sipping studies, ongoing regulatory stability commitment studies, market experience portfolios and product labelling commitments. Neverteless, a small number of manufacturers, distributers and sippers of temperature sensitive parmaceuticals rely solely on MKT calculations to justify teir sipping metods and packaging requirements, tereby sending teir products out in unqualified - and possibly inadequate - packaging, incapable of maintaining recommended storage requirements, and potentially putting teir product at risk. If needed, te MKT is a calculated fixed temperature tat simulates te effects of temperature variations over a period of time. It expresses te cumulative termal stress experienced by a product at varying temperatures during storage and distribution Calibration and Post-Calibration Requirements Calibration is a common topic in any parmaceutical activity tat involves instruments and data logging is no exception. Wen data are being collected for a mapping study, te instruments must be calibrated using an appropriate tolerance and range for te measurements taken. Te calibration sould be National Institute of Standards and Tecnology (NIST) traceable and be documented in a manner consistent wit Good Documentation Practices (GDPs). Tey sould also be post-calibrated after te study to ensure te instrument is still operating (in a calibrated state during te study period) witin its original specifications by comparing te compensation curves of te previous calibration and te new calibration results obtained to prove te accuracy is witin te specification. Te Healt Product Regulatory Autority (HPRA) ave recently acknowledged tat a 10% minimum of te data loggers sould be post calibrated following tis type of termal mapping exercise. Only single-use devices tat are supplied wit a manufacturer s calibration certificate do not need to be re-calibrated Data Analysis Te Excel exported data and graps become part of a complete report tat identifies any undesirable temperature patterns and recommends potential solutions. Te report contains copies of all data logger calibration certificates, questionnaires, and oter information used to complete te study. If te mapping study indicates undesirable conditions, Tis guide does not purport to be an interpretation of law and/or regulations and is for guidance purposes only. Cryopak 20 17

18 facility owners can take a wide range of measures, depending on te problems severity. Tey include: Removing products from problem areas (suc as ot spots near ceilings); Canging work practices (suc as keeping doors open or closed); Canging racking or selving configurations; Repositioning racks or selving to improve air circulation; Canging te location of eating devices; Installing an air conditioning system; Improving ventilation; Installing more or larger-capacity fans; Adding umidification or deumidification; Installing an HVAC control system. Te analysis can also identify te storage area s ot and cold spots. Te purpose of determining ot and cold spots is to identify te locations were te environmental monitoring system (EMS) sensors sould be installed to record te most vulnerable spots in te storage area and avoid any temperature excursions tat could affect te products. Hot and cold spots need to be determined seasonally. Determining ot spots: Any zone of te wareouse were te igest average temperature was recorded closest to te upper limit. Determining cold spots: Any zone of te wareouse were te lowest average temperature was recorded closest to te lower limit. An attractive option is to install monitoring sensors tat communicate continuously wit a Part 11 compliant environmental monitoring system (EMS). Te EMS can be programmed wit alarm set points to alert service tecnicians by , pager or telepone to notify canges in space conditions before it as any effect on te products. Real-time monitoring provides an added assurance tat space conditions matc product storage specifications. A continuous record can also be valuable in case of regulatory autorities inquiry or audits - all records must be retained for a duration as in accordance wit te legal requirements and be readily retrievable especially if te monitoring information is combined wit te detailed inventory data parmaceutical companies already keep. Wit bot kinds of data in and, a Tis guide does not purport to be an interpretation of law and/or regulations and is for guidance purposes only. Cryopak 20 18

19 company could document te location in wic a given parmaceutical product was stored and te temperature conditions tat existed wile it was tere. 6. CONCLUSION Temperature mapping is a valuable exercise. If regulatory requirements clearly explain wen a mapping study as to be done, internal procedures sould detail ow often tis exercise as to be repeated over te years. Initially, wen a Drug Establisment License as to be submitted, all protocols must be ready for your auditors. Extreme season mappings are in most cases executed winter and summer. However, in some parts of te world, umidity and oter factors sould be taken into consideration. Even if a company Quality Department is well equipped to perform a mapping project, partnering wit an external company can bring an independent approac. A clear assessment of te client s needs, as well as a good knowledge of national and international regulatory are crucial. Tis first step will elp wit te protocol writing. Te protocol must be complete and detailed, and clear about te approac to be taken and ow te study will be performed. Determining te position of loggers witin your area to be mapped is essential: it is always better to ave more loggers tan less and a scientific rational is always appreciated by all auditors and quality departments. Different 3D models exist, and te protocol as to explain te rational of logger placement. Clients will ave to make sure tat loggers used wit teir appropriate software are compliant for teir industry for calibration and also to make sure tat it complies wit oter regulatory requirements suc as CFR Part 11, NIST traceability and validation (Installation, Operational, and Performance). Final report conclusions must be clear and identify te pass and fail outcomes of te study. If no acceptance criteria ave been written in te protocol, it will be te customer s responsibility to take appropriate actions according to te results obtained. We strongly recommend tat mapping studies be repeated on a regular basis -every 3 or 4 years to demonstrate to your auditors tat you are in control of your cold cain, and tat products you are responsible for are maintained witin a proper temperature range. Tis guide does not purport to be an interpretation of law and/or regulations and is for guidance purposes only. Cryopak 20 19

20 7. REFERENCES PARENTERAL DRUG ASSOCIATION. Tecnical Report No.64 Active Temperature Controlled Systems: Qualification Guidance, PDA, 2013, 58p. (2013/C 68/01) Good Distribution Practice of Medicinal Products for Human Use ROBEY, Sara. Our blog Wicwareouse, [ttp:// (page consulted on April 14 t, 20) USP General Capter <1079> Good Storage and Sipping Practices, USP 28, Suppl. 2, August 1 st, 20. WILLIAMSON, Mike. Mike Williamson Validation Blog, [ (page consulted on April 14 t, 20) HPRA. Guide to Control and Monitoring of Storage and Transportation Temperature Conditions for Medicinal Products and Active Substances, IA-G Date 05/10/2011 PATTERSON, Brandon J. & Justin PAWLIK. Journal of GxP Compliance, Monitoring By Data Logging. Tis guide does not purport to be an interpretation of law and/or regulations and is for guidance purposes only. Cryopak 20 20