The biopharmaceutical industry is experiencing an unprecedented increase in demand, which is expected to continue for the foreseeable future. In response, companies are scaling up their operations as quickly as possible. However, since it is heavily regulated, rapid scale-up in biopharma is more complicated than other industries. Being able to scale up quickly and safely requires a detailed knowledge and adherence to GxP (good practices), and a healthy amount of planning.
In this article, we’re going to focus on temperature mapping, which is a GxP process that’s used when qualifying new storage areas or process units designed for thermal control. It is commonly done on:
- Refrigerators or freezers
- Refrigerated shipping containers
- Insulated packaging
- Process areas like holding rooms, loading docks, or labeling lines
- Environmental test chambers
- Sterilizing equipment
While temperature is the most commonly mapped environmental parameter, humidity is often mapped simultaneously.
In this article, we’ll cover some of the reasons that mapping is important, and provide a step-by-step guide for how to run a successful mapping project. Like most GxP processes, it is highly detail oriented and heavy on documentation, but with a well-designed plan, it can be straightforward and highly informative.
What Are Temperature Mapping and Validation?
One of the cornerstones of GxP is validation. In the context of pharmaceutical manufacturing, validation is the process of confirming and documenting that a piece of equipment or a process satisfies its intended purpose, through the use of objective data. For a temperature-controlled storage area, the intended purpose is to safely store materials, and the objective data is what you’ll generate in a mapping exercise.
Going one level deeper, validation of equipment is broken down into IQ, OQ, and PQ steps (installation, operational, and performance qualification). Mapping with the storage area empty and as-installed can be considered part of OQ, and mapping it with the storage area full, while simulating normal operations, can be considered part of PQ.
As the name suggests, mapping is the measurement of environmental conditions in three dimensions. This is done by systematically placing many temperature and/or humidity sensors throughout the area you are mapping, then monitoring them over a representative period of time. The results of a mapping project will help you understand environmental variations in critical spaces, as well as how the space is affected by stress conditions like loading, door opening, power outages, or anything else that might be expected during normal operations.
The sensors used for mapping are usually part of an integrated data logger that can store the recorded data internally, or continuously transmit it to a central location. A wide variety of logger configurations are available- we’ll talk more about where data logger and sensor selection should fit into your plan in the strategy section below.
It’s important to note that mapping is different from routine monitoring, when a smaller number of sensors are used during normal operations. (However, they are related, since mapping can guide your placement of sensors for monitoring.)
Why It Matters to Biopharma Companies
The primary goal of temperature mapping is quality control. Thoroughly mapping a storage space or process unit will confirm that the space is appropriate for its purpose, which is the central element of the qualification process.
Mapping can also indicate whether you need to rearrange your storage spaces- for example, by telling you how far from a warehouse door you should store materials, or whether boxes in a fully loaded freezer should be kept away from coils or fans. It’s also an indication of how well your environmental control equipment is working, and whether it is sized and tuned correctly.
Mapping is also a requirement for regulatory compliance. In the US, the FDA enforces safe handling of pharmaceuticals under various parts of 21 CFR, and you’ll see problems with temperature control come up frequently in observations and citations from audits. Compliance requires a justified, documented process for mapping, including how to follow up on mapping results.
Finally, the results of a mapping process are used to optimize the placement of monitoring sensors. For example, locations of temperature extremes can be used as monitoring points, to make sure that the sensors are capturing the full range of conditions in the space.
How To Create a Strategy That Works for Your Biopharma Company
The most important part of a mapping project is to have a detailed plan that is justified through a risk-based thought process. This is a general requirement for many GxP processes, but beyond that, a detailed plan will make the later execution steps much easier.
One part of the plan should be focused on higher level strategy, and include:
- Objectives and scope of the mapping study, and why it is being conducted. The ‘why’ can include your internal quality policy, as well as the regulations you’re required to follow.
- The data that will be collected, specifically temperature, humidity, or both
- The types of sensors and data loggers that will be used, and the rationale for their selection. Some examples:
- The choice of a particular sensor because of the expected temperature range
- Use of data loggers with external probes for extreme environments, or buffered probes, where the sensor is placed in glycol or teflon to better represent the temperature of a stored material
- Acceptance criteria to use when analyzing the results, based on knowledge of product stability or required process conditions
- A site survey or equipment diagram that will be used as the basis for sensor placement, which shows dimensions, positions of shelves, mezzanines, and the areas where materials will be stored (the storage envelope)
- Areas of particular risk, like doors, windows, lights, or vents
- Plans for re-mapping, and a process for making changes to the procedure
- Signature page listing the members of the mapping team
- Report templates
A second part of the plan should provide logistical details such as:
- A 3-dimensional map of the locations of the sensors during mapping. Note that the positioning of the sensors should be justified using the items listed above (like the dimensions of the space and particular risk factors)
- How long mapping data will be collected
- The loading conditions of the space during mapping
- Specific activities to be conducted during mapping, like door opening or loading/unloading
- ID numbers for each sensor
- Data recording frequency
The length of the mapping exercise and the placement of sensors should be determined in order to get a complete record of normal operations across the entire space. More specific guidelines are available from the WHO, ISPE, USP, and PDA. From a regulatory point of view, it’s important that any logistical choice you make is documented and justified.
Depending on the size of your organization, you may consider engaging with a third-party consultant for help with mapping. There are two main reasons for this: first, a large number of data loggers are needed for mapping, many more that you’re likely to use for routine monitoring. Second, the experience of a consultant can save time and effort on the part of your in-house staff.
Step by Step Temperature Mapping Implementation
Once you have a plan in place, here are the typical steps for executing a mapping project:
- Prepare the data loggers.
- Mapping should be conducted using calibrated sensors, since any measurement error will show up in your mapping data. The WHO recommends NIST-traceable 3-point calibration to ± 0.5 °C. When using multi-point calibration, try to bracket the expected temperatures with calibration points.
- A data collection interval of 1-15 min is typical, but the exact frequency depends on product sensitivity and the types of fluctuations you expect.
- Place the measurement equipment, recording the sensor ID’s, and any changes you have to make from their planned locations.
- Execute the data collection in your test plan, being careful to synchronize the start of data recording across all of the data loggers.
- Retrieve the measurement equipment
- Re-confirm that sensors were correctly placed based on their ID numbers
- Note anything unusual, like sensors having been moved or damaged
- Download and analyze the data
In the data analysis, you’ll want to include a few key points:
- Averages and extremes for each sensor
- Locations of cold and hot spots
- Graphs that show trends over space (like temperature as a function of height in a warehouse) and time (like fluctuations or over daily/weekly cycles)
- Thermal behavior near the high risk areas identified in the plan
- Sources of uncertainty
- Complete a mapping report, including:
- A brief re-statement of the high level mapping strategy
- Summary of the results, with high level conclusions
- A clear statement of whether the results meet the acceptance criteria you set out in the plan
- Any other documents generated by the project, like site surveys, raw data, and sensor IDs/locations, included as attachment
- Make recommendations based on the data
Here are some examples:
- Prepare the data loggers.
- Placement of sensors for routine monitoring. For example, in an oven, you might place sensors at hot and cold spots, and at a location that represents the average across the whole chamber.
- Alarm setpoints
- Additions or changes to storage SOPs
- Required improvements to the environmental control system
A final consideration for your report should be any events that would trigger re-mapping, like installing a new HVAC system or storing a different product mix, and whether re-mapping should be conducted on a regular basis.
Temperature mapping is a time consuming, meticulous process, but it is a necessary part of bringing new storage areas on line and expanding your operations. Having a detailed, well-documented plan is the most important element to making sure you’ll have a successful mapping project that generates actionable data and ensures regulatory compliance.
Questions about temperature mapping, validation, or environmental monitoring? Contact the experts at Dickson.