TEMPERATURE MAPPING IN PHARMACEUTICALS

Temperature Mapping is the process of recording and mapping the temperature in a 3 dimensional space. Temperature won't be the same everywhere,even it is in a small fridge, large cool room, freezer or warehouse and can vary by as much as 10°C from one location to another.Temperatures in the corners will most likely be different to the centre of the space being measured.

There are also "specific areas" within the cool room where the temperature also will differ such as: next to the cooling fans where the temperature will be at its coldest or close to the doors where it likely to be at its warmest.

Temperature Mapping and Temperature Monitoring are integral to the storage of pharmaceuticals because drug efficacy relies on good storage conditions.

In Pharmaceutical industry temperature mapping is done for Autoclaves
Dry Heat Sterilizers
ETO Chambers
Stabilty chamber
Incubators
Holding areas- warehouse


The purpose of temperature mapping is to ensure that all areas of the process equipment or storage area achieve the required temperature. The outcome of the test is a temperature map defining the cold spot of the process equipment or storage area.

Warehouse Temperature Mapping
Drug manufacturers are deeply concerned about consumer safety, product quality, and FDA compliance.Inadequately controlled environments can lead to ineffective and spoiled medicines.Most product warehouses have limited environmental control. Packaging obviously protects products against contamination and degradation from light, but the contents remain vulnerable to temperature and, in some cases,humidity. Warehouses for pharmaceutical raw materials and finished product must be maintained at controlled temperature and humidity.

There's increased emphasis by regulators on compliance with GMP requirements for controlled temperature storage requirements.


Clause 3.19 of the PIC/S GMP guide states:
"Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean and dry and maintained within acceptable temperature limits. Where special storage conditions are required (e.g. temperature, humidity) these should be provided, checked and monitored."

PIC/S doesn't offer much advice on what this means in practice. UK Guidance on Wholesale Distribution Practice, states:

"Large commercial refrigerators and walk-in cold rooms should be monitored with an electronic temperature-recording device that measures load temperature in one or more locations, depending on the size of the unit. Portable data-loggers that can be downloaded onto a computer may be used instead of a fixed device. Records should be checked daily. Internal air temperature distribution should be mapped on installation in the empty and full state and annually thereafter under conditions of normal use. Products should not be stored in areas shown by temperature mapping to present a risk (e.g. in the airflow from the refrigeration unit). Condensate from chillers should not be collected inside the unit.

All warehouses should be temperature mapped to determine the temperature distribution under extremes of external temperature. Mapping should be repeated every two to three years and after any significant modification to the premises, stock layout, or heating system.
Even in an open warehouse design temperature and humidity is not usually constant from one spot to another because:
1) Areas near the ceiling or exterior walls may stay warmer or cooler in response to outside temperatures.
 2) As warm air rises, temperatures stratify;
3) Temperatures are higher near heaters, and especially so if fans are undersized or placed in such a way that they cannot completely mix the air;
4) Hot spots are created by racking, shelving and pallet storage areas that obstruct air circulation; and
5) Frequently opened doors affect temperatures.

These and other factors may create substantial temperature differences from floor to ceiling and within building zones. In fact, variations of several degrees are common in large storage areas.Mapping of a warehouse is required to assure proper conditions are maintained during all hours of operation and seasons. Two or more mappings may be required to account for seasonal conditions (i.e. winter & summer).

　
Temperature Mapping vs Temperature Monitoring And Calibration


Temperature controlled storage areas in GMP facilities are usually continuously monitored by temperature probes . These are routinely calibrated, which might suggest that this all that is needed to meet regulatory requirements.

But temperature mapping is very different from calibration/routine monitoring. One of the key differences is the number of points the temperature is measured at in the temperature controlled area.

A temperature mapping exercise is expected to collect the following information:
* The impact of interventions (door openings / power failures, etc.),
* Identification of hot and cold spots,
* Variation of temperature at a single point,
* Temperature variation across the area,
* Length of time of any temperature excursions.


To record all this information effectively, each temperature mapping exercise should be governed by a protocol detailing:
* Selection of testing dates, with consideration to seasonal effects on the temperature controlled area,
* Number of probes to be used and justifications,
* Map of probe locations and justifications, including potential hot and cold spots,
* Duration of the exercise,
* What constitutes "normal use" and therefore levels of stock in the area that are to be used,
* Calibration requirements (pre and post),
* Acceptable number of probe failures,
* Acceptable limits for temperature excursions (which may be product dependent),
* Types of data to be generated,
* Reporting requirements.

Mapping is not a one-time job, but an ongoing process that takes into account changes in seasons, HVAC/R modifications, warehouse layout modifications and any other significant changes to the warehouse environment.

Proper organization and documentation are critical in maintaining compliance and consistency.

Important points should be considerd during Thermal Mapping

Thermocouples/data loggers should be checked before and after a validation study.
Temperature recording probes should have an accuracy of at least +/- 0.5 °C.

Warehouses should be temperature mapped in the empty and full states to determine the temperature distribution under extremes of external temperature. The mapping exercise should be performed both during summer and winter in order to assess worst case scenarios, as extremes of temperature may adversely affect the temperature distribution within the warehouse storage area.

Temperature monitoring should be conducted within a normal working day rather than on a weekend as the internal temperature of the space will vary depending on how many times the coolroom or warehouse doors are opened and closed.
Temperature mapping should be repeated after significant modification to the premises, changes in stock layout or changes to the heating system. Due considerations should also be given where the practice of turning off heating systems overnight or over weekends is employed. In general, medicinal products should not be stored next to sun facing windows, at high levels in poorly insulated stores, at high levels under or near fluorescent lights, or next to heaters. Medicinal products should not be stored in areas shown by the temperature mapping to be unsuitable.

Step 1 – Determine Critical Mapping Points

Problem Locations:Large open spaces present a considerable challenge when working to maintain a consistent temperature or temperature/humidity level. Problem spots include:

*Areas near the ceiling or exterior walls may stay warmer or cooler in response to temperatures outside.
* Temperature levels stratify due to the fact that warmer air rises.
* Temperatures will tend to be higher near heaters, if fans are undersized or improperly placed they  will be incapable of mixing the heated air effectively.
* Racking, shelving and pallet storage areas may create "hot spots" by obstructing air circulation.
* Doors that are left open will affect temperature conditions.

Additional Locations:In addition to problem spots logger placement is also critical for the following locations:
*HVAC outputs,
*Exits to unconditioned spaces (loading docs and staging areas),
*Outside (to compare outside temperatures to internal temperatures),
*High, medium and low locations in the general storage area.

Spacing:
Data loggers need to be strategically placed within the 3 dimensional space to map temperatures along a horizontal, vertical and depth plain as well as in locations that are likely to have temperature variations.Studies have shown that a spacing of every 100 to 300 feet in an open warehouse plan, without walls to block airflow, is adequate enough to accurately represent readings that are meaningful. A distance of greater than every 300 feet may yield data that does not accurately reflect conditions in the warehouse space, while spacing data loggers closer than every 100 feet will result in extra data that adds no value while creating extra work.

Step 2 – Determining Sample Frequency:The key to determining sample frequency is to not take too many or too few samples. Too many samples will create too much data making analysis cumbersome and difficult. Too few samples will not adequately represent changes in the warehouse environment. In most warehouses, one temperature or temperature and humidity sample every 15 minutes (for aperiod of one to two weeks) should adequately evaluate temperature trends.

Step 3 – Establish Data Logger Criteria and Select:Temperature and Temperature/Humidity Data Loggers come with many features. The goal is to select the data logger that will most effectively monitor your warehouse. Key features you should consider are:

Data Capacity: Data Capacity determines how many readings or sample points can be taken by a logger before memory is full. The more sample points a logger has, the more readings it can store.
Sample Rate: The frequency in which samples are taken. The logger should feature user selectable sample rates.
Monitoring Range and Accuracy: Be sure to select a data logger with a temperature range that can monitor temperatures even in the most extreme of cases. +/-2oF and +/-2% RH should be adequate for most warehouse mapping situations. For refrigerated storage areas or locations requiring tighter tolerances, data loggers with an accuracy of +/-.5 oF should be selected.
Size: Make sure the logger will fit in your selected locations.
Battery Life: Make sure the battery life is long enough to last between mapping sessions.
Calibrations: The data loggers should be calibrated at least every 12 months.
Software: Make sure the data logger software is easy to use.

Step 4 – Place Data Loggers at Pre Determined Points:Be sure to document the location of each data logger and label each data logger to ensure that it is repeatedly placed in the same location.

To ensure consistency practice the following rules:
Using the data logger software, name each logger by its location,
Label the outside of each logger by its location,
Label the exact spot where the data logger should be placed by the data logger’s location name,
Create a physical map with all data loggers marked by name.

Step 5 – Retrieve and download Logged Data: Once the loggers have been placed and data has been collected, collect the data loggers and transfer the logged data computer.

The logged data can be exported to Excel where Mean Kinetic Temperature can be calculated.

Mean Kinetic Temperature is a calculated fixed temperature that simulates the effects of temperature variations over a period of time. It expresses the cumulative thermal stress experienced by a product at varying temperatures during storage and distribution.In addition to calculating MKT it is also recommended that Min and Max temperatures should be monitored carefully and that the location and the time of day at which they occur should be recorded. Any trends should be investigated.

Step 6 - Document Processes and Repeat: After completion of first mapping, be sure to place the data loggers back in their original locations throughout the warehouse and make sure to document each and every step used.

Step 7 – Data Logger Maintenance and Calibrations:Over time the most robust data loggers can drift causing inconsistencies in recorded data thus requiring regular calibration in order to ensure accurate readings.

It is recommended that each data logger be calibrated at least every 12 months. In addition, it is prudent to request before and after readings when calibrating each data logger so corrections can be made to previously logged and mapped data.

Best practice recommends sending the data logger to a NIST certified calibration facility, and to the original manufacturer for calibration whenever possible.

Step 8 – Remediation:Results has to be evaluated to fix any trouble spots that show up in the calculations.

The graphs and charts and on-site observations become part of a complete report that notes any undesirable temperature or humidity patterns and recommends potential remedies.The report contains copies of all sensor calibration certificates, questionnaires, and other information used to complete the study. If the mapping study indicates undesirable conditions, facility owners can take a wide range of measures, depending on the problems’ severity. They include:

• Removing product from problem areas (such as hot spots near ceilings).

• Changing work practices (such as keeping doors open or closed).

• Changing racking or shelving configurations. Repositioning racks or shelving to improve air circulation.

• Changing the location of heating devices.

• Adding air conditioning.

• Improving ventilation.

• Installing more or larger-capacity fans.

• Adding humidification or dehumidification.

• Installing an HVAC control system.

Temperature mapping can be an extremely powerful tool to aid in regulatory compliance and create possible cost savings via implemented improvements and efficiencies. The key is to carefully analyze the warehouse space to ensure proper placement of data loggers, document logger locations and mapping processes.