Good manufacturing practice (GMP) regulatory bodies in the United States, Canada, the European Union, Japan, Australia, and China have focused their attention on warehouse storage and distribution practices. This trend is due to a change in the concept of regulation, which has gone from quality-by-test systems to quality-by-design systems, emphasizing the level of risk, product quality and patient safety. Other factors are the increased demand for storage facilities due to the globalization of manufacturing, the rise of temperature-sensitive biopharmaceuticals, and changes in technology.

Regulatory authorities in these countries require 'mapping' of the temperature and relative humidity profiles of environmentally sensitive life science product depots. This step-by-step guide describes how to map a warehouse to meet internationally recognized GMPs, including many recently published or revised. (See the end of this document for links to relevant regulations and guidance documents). This guide is intended for use by any organization carrying out the storage and distribution of temperature and humidity sensitive products in a GMP compliant environment and is based on Vaisala's extensive experience with customers in Europe and throughout the Americas. from North. Vaisala solutions are used in more than 150 countries around the world.

Step By Step – Good Practices For Warehouse Mapping Studies

Step 1: Create a validation plan

The validation plan, or validation master plan, is the document used to specify the company's decisions on the qualification of each aspect of the facility, equipment and processes to maintain a GMP-compliant environment. The plan should adopt an approach that is risk-based, with a foundation based on verifiable data. The plan should focus on where environmentally sensitive products and materials will be stored and should consider whether environmental controls can meet specified storage requirements.

In addition, the plan is a starting point for regulators to assess the rationale for the company's goals and methods.
The validation master plan should:

State the objectives of the validation.
Identify the roles and responsibilities in the process of the quality, metrology and other working groups.
Identify validation activities, including processes, equipment, and space.
Develop documentation and procedures, including the company's response if a deviation in temperature or humidity occurs.
Determine a validation schedule.
Specify the discharge process, especially for adverse events such as temperature deviations.
Create change control protocols to make it clear when changes such as maintenance, new construction, and rack reconfiguration will need to be revalidated.

Regulatory note: GMPs require maintaining temperature and humidity within the storage recommendations printed on product labels or provided by raw material suppliers. These recommendations are derived from known chemical properties and stability tests.

Step 2: Identify risk areas
To map a warehouse or storage space, you must first identify areas where product quality may be at risk due to unacceptable fluctuations in temperature and humidity. Many factors affect the control or variability of your space. (Since relative humidity is dependent on temperature, variations in temperature will affect humidity.) By considering each of these factors, you can more easily identify risks:

volume of space. A large warehouse poses different control tasks than a small one, as it has higher demands on the HVAC system and the potential for greater variations in temperature and humidity at different locations.
The capacity of the diffusers or fans so that the air circulates correctly.
The temperature gradients between the ground and the warmer air near the ceiling.
Independent energy sources, such as space heaters, air conditioners, and fans, which create hotter or cooler places.
Arrangement of supports, shelves and pallets, which obstruct the flow of air.
Location of HVAC control sensors. For example, a thermostat placed near a heat or cold source can cause the room temperature to change too much.
Locations near sources of heat or cold, such as the roof and exterior walls, windows, and cargo areas.
High-traffic areas where products or equipment are frequently moved.
Seasonal temperature changes or unusual weather events.
Regulatory Note: You can be GMP compliant by providing a strong justification for your approach to identifying risk. The more considerations the protocol addresses, the better its rationale.

Step 3: Develop information on protocols
Once the risk zones have been identified, develop a protocol for the mapping study that describes the following, with justifications for each decision:
• Types of data to be generated, for example, temperature, relative humidity, and measurement intervals. Five-minute intervals provide more data to assess trends and modify reservoir settings (see step 8). When you are satisfied that the temperature and humidity remain relatively stable, it may be convenient to move to 15 minute intervals for the final mapping.
• Number of sensors to use (see step 4: Determine the distribution of the sensors).
• Schematic or diagram of sensor locations.
• Duration of the study. Its rationale and protocol can support a series of tests, each lasting two days during normal operations and over a weekend. A different and equally justifiable protocol might specify a single run over a two-week period to account for various activities, such as the opening of loading dock doors, in the warehouse.

Calibration requirements for data loggers.
Acceptable range of variation in time and space, which will depend on the product stored.
Admissible limits for variations in temperature or relative humidity.
Reporting requirements.
Regulatory Note: Once you develop a protocol, you must follow it consistently. If the protocol changes, document the reasons.

Step 4: Determine Sensor Layout
How many sensors will you need to map a given space? Where will you put them? There are no simple answers. To assess temperature uniformity, the sensor layout must be correct. A good practice is to use a sufficient number of sensors to understand the environment, especially the areas where the risk is greatest.
You'll need to place the sensors in a uniform pattern in all three dimensions of space: top to bottom, left to right, and front to back. Add additional sensors where you suspect hot or cold spots, as well as near monitoring and control sensors. The placement of the temperature and relative humidity sensors is a consequence of the risks identified in step 2.

A large walk-in camera or a small warehouse is usually mapped in three dimensions with 15 sensors (See Figure 1). The protocol should include guidelines for the distance between the sensors, for example no more than six meters.
When mapping a large warehouse, place sensors up to 30 meters away, with additional sensors in vulnerable areas affected by:

Heat or cold of external walls, solar heating, windows, lighting
Air circulation or drafts from entrances, traffic, or the HVAC system
Extreme temperatures in poorly insulated areas
Localized Effects of Space Heaters and Air Conditioners
Anticipate that airflow and temperature gradients may vary depending on whether the shelves are empty or full of products. Higher supports will be subject to greater temperature gradients, and this will require more sensors from top to bottom.

You can mount sensors in open areas (for example, outside supports or corridors), wherever it is convenient to install them. However, convenience should not take precedence over effectiveness. The sensors must measure the conditions to which the products are exposed.

If you don't have an adequate number of sensors to map the entire warehouse in one study, you can do this in sections. Mapping by sections takes more time, and it may be desirable to extend the mapping time for each section to compensate for the uncertainty of mapping the space by sections. To decide, weigh the equipment savings from a sectional mapping approach against the additional time needed to complete the project.

If high or low relative humidity can negatively influence product quality, then you should map relative humidity and temperature. There are two approaches to determining the number and location of relative humidity sensors.

Density determination of humidity sensor
The first approach is to use comparatively few humidity sensors distributed around the tank (only one for every six temperature sensors). In this case, you will depend on the uniformity of the temperature so that the humidity is also within limits. This approach should be based on a history of temperature mapping in different seasons with consistent results. With this track record, a specialist who understands moisture measurement can effectively argue to an auditor or inspector that moisture measurements are not necessary at all data points. If you decide to adopt this strategy and reduce the number of humidity sensors, it is critical to place the few humidity sensors you use in areas with poor air circulation, between HVAC fans or diffusers, and where the temperature is most variable.

Moisture Considerations
Compared to temperature sensors, relative humidity sensors are much more likely to lose accuracy or "drift" over time. The drift may be due to poor design, poor calibration, or contamination from water vapor saturation or chemical vapors. A single wrong reading at recalibration time will call attention to your decision to use fewer moisture sensors. Starting with fewer moisture sensors creates the risk of non-compliance, because if one fails or is out of spec, that single sensor will account for a high percentage of your total moisture measurements. If relative humidity is interpolated from temperature data, it will be necessary for a company employee with this specialized knowledge to meet with the auditor or inspector. Ideally, your company should minimize the number of contacts required during an inspection as a way to streamline the process and minimize the chance of errors.

If you are concerned about relative humidity, a more justifiable mapping strategy is to track temperature and humidity at all locations with data loggers that record both measurements. It is important to use high quality data loggers that are stable and regularly calibrated.

Performing mapping with integrated relative humidity and temperature sensors offers several advantages over deducing humidity from temperature. A mapping of temperature and humidity at all sensor locations provides a more specific map of the entire storage space for inspectors and auditors to easily understand, without the need for detailed explanation. And deviations from relative humidity will be easier to identify with more humidity data points.

Regulatory Note: Understanding the relationships between measured parameters is essential to the success of mapping studies and to managing risks in a GMP storage space.

Step 5: Select the right technology
Use equipment designed for mapping. The software that accompanies the sensors is used to configure the equipment and download data. The software must produce reports in the form of tables and graphs that meet all the requirements of the FDA Title 21 CFR Part 11 and comparable international standards, such as Annex 11 of the European Commission, and those contained in volume 4 of the Guidelines for the EU on good manufacturing practices (GMP).

When choosing data loggers, look for the following features:

Minimal sources of error, i.e. low measurement uncertainty.
High precision in the measurement range. Vaisala DL2000 data loggers, for example, have an accuracy of ± 0.1 °C over a range of +20 °C to +30 °C, with a humidity accuracy of ± 1 %RH over a range of 10 at 80%RH.
Sensitivity to small temperature changes (high resolution). The faster the response, the more closely the data point can be linked to the measurement time.
Long-term stability, particularly for relative humidity sensors. Low-quality equipment must be calibrated before and after each study.
Traceable calibration performed within the measurement range and with equipment using an unbroken chain of comparisons to an internationally recognized standard, such as that of the National Institute of Standards and Technology (NIST).
Clear, complete and accessible calibration records.
Regulatory Note: GMPs require written procedures to calibrate, inspect, and verify automated, mechanical, and electronic equipment (21 CFR 211.68). International standards such as ISO/IEC 17025:2017 “General requirements for the competence of testing and calibration laboratories” are recognized as best practices for calibration.

Step 6: Set Up Mapping Equipment
Once the risk areas have been identified and the sensor layout established, it is time to install the mapping equipment and test the storage space. The purpose of this initial test is to determine where conditions vary and where the temperature and humidity are uniform and adequate to store the product. Work through the following checklist and document each step:

The equipment has been calibrated. Document who has done it, when and the date of the next calibration. This confirms that the data logger is operating within the calibrated measurement range.
The equipment has been validated. Typically, the installation and operation qualification (IQ/OQ) are provided by the mapping system vendor.
Ensure that access to the mapping software has been secured and authenticated. Access privileges restrict who is authorized to use the application.
Verify that the software reads and records the hardware and firmware model, version, and serial number.
Make sure the warehouse area and data logger locations are accurately described. A schematic or diagram is helpful to ensure sensors are placed correctly in upcoming mapping studies,
Regular sampling intervals have been determined. Intervals are usually between 5 and 15 minutes.
The duration of the study has been determined. All data loggers are set to start and end at the same time.
Data loggers are linked to an audit trail file for traceability. This is an essential requirement to demonstrate that the data is reliable.
The data loggers work and are placed in specific positions.
Regulatory Note: GMPs require that calibrated equipment and calibration records be used. If you have collected data electronically, these records must comply with the regulations for electronic records defined in Title 21 CFR Part 11, EC Annex 11, and Volume 4 of the EU Good Practice Guidelines manufacturing (GMP).

Step 7: Run a test and analyze the data
You will need to set the report information that you will use to evaluate the test. Once the test is complete, the software will read the data loggers secure files, display the recorded data, perform calculations and graph the selected results for a mapping study report. Typically, the test document will display the information in Figure 3:

Raw data with times and dates.
Calculated values ​​such as minimum, maximum and average temperature.
A graph of all sensors during the test period.
Instrument settings.
Calibration information.
Date and time of the test.
Space for review and approval signatures on printed reports.
Trend data from each sensor can be compiled into a single graph to provide an overview. Default lines, such as minimum and maximum acceptable limits, can be useful for analysis.

A graphical representation can help identify high-risk locations, especially those places where problems may occur sporadically. For example, a temperature spike may be related to when the cargo doors were open.

That variation could indicate a hazard caused by normal workplace activities or suggest the need for a containment zone.

Regulatory Note: It is better to present a summary graph with a clear conclusion than an overly detailed report that could lead to additional questions.

Step 8: Make Modifications
Use the results of the initial test to identify those places where the product may be exposed to unacceptable conditions. Then make adjustments, for example to storage media or the HVAC system, to correct for this variance. Or just decide in which places the products will not be stored. For example, many warehouses have a mezzanine level designated as off limits for raw materials or finished goods because HVAC controls are not effective there. Name and describe these places and modify the validation plan.

Also, modify your validation protocol in light of the results of your initial mapping test.

Regulatory Note: Modifications to a newly commissioned warehouse need not appear on the inspection log. But once your company approves a validation master plan, it must document all subsequent changes.

Step 9: Document and schedule the mapping study
Once the environmental variability in the warehouse has been adjusted for, it is time to conduct and document a mapping study for approval.

How long should the mapping take?
As with your initial mapping test, there is no hard and fast rule. Your rationale and protocol may support a single large study, or a series of shorter studies. Either way, it is important to measure the environment during a variety of different work activities in the warehouse, such as loading and moving products, and also during periods such as weekends when there may be little activity.

How often should a space be mapped?
Some protocols call for mapping every three months, while others may warrant annual or even less frequent mapping. The validation master plan must anticipate the variables that can alter the storage conditions once the qualification of a deposit is completed. The construction of a warehouse, major changes in the HVAC and other similar changes in the environment, require a new mapping. Seasonal changes and extreme weather conditions may warrant mapping the warehouse more frequently or rescheduling a test for a more "seasonal" temperature. For example, in the northern hemisphere, the validation plan may require a mapping study in July, when temperatures are typically hottest. But if July is unusually cold, it may make sense to delay mapping until a warm spell in August. The validation plan should allow enough flexibility to record weather extremes. For example, depending on the climate in your region, your plan might require mapping when summer temperatures exceed 30°C and winter temperatures drop below 0°C.

Regulatory Note: Keeping useful records is critical to complying with GMP. Records must be stored securely and must be easily accessible for review. They should not have gaps. They must provide an audit trail. Records can be paper, electronic, or a combination of both. If the records are electronic, they must meet the requirements of FDA Title 21 CFR Part 11 and CE Annex 11.