Understanding USP <1079.4>
USP General Chapter <1079.4> provides guidance on temperature mapping for the qualification of drug product storage areas. Temperature mapping evaluates whether a storage area can maintain the labeled temperature ranges required to ensure product efficacy and expiry. The results also determine where continuous monitoring devices should be placed.
Purpose
Many factors impact a storage area’s ability to maintain temperature: airflow, HVAC systems, wall and ceiling insulation, doors, traffic patterns, geography, and physical orientation. Temperature mapping identifies risk areas and validates mitigation strategies.
Scope
This chapter applies to storage and holding areas across the entire supply chain, from manufacturer to the point before the patient. It does not cover shipping systems or transportation. Entities that must comply include:
- Manufacturers of drug products, radiopharmaceuticals, biological products, and biotechnological products
- Repackaging operations
- Healthcare providers and institutions (hospitals, outpatient centers, vaccine clinics, emergency departments, medical/dental/veterinary offices)
- Pharmacies (retail, infusion, compounding, specialty, mail order, hospital, nursing home, hospice)
- Importers and exporters
- Wholesale distributors
- Third-party logistics providers, brokers, freight forwarders, and consolidators
Step 1: Evaluate the Storage Area
Before placing probes, the physical layout of each storage area must be documented:
- Dimensions: height, ceiling height variations, walls, wall openings (loading docks, passageways, personnel doors) and door types (automatic sliding, revolving, push/pull)
- HVAC equipment: location of heating, ventilation, air conditioning, space heaters, and air conditioners
- Environmental factors: sun-facing walls, geographic location, temperature variability outside the storage area
- Airflow: internal airflow patterns within the storage location
- Operational factors: workflow variation (weekday vs. weekend), loading volume, storage patterns, equipment capabilities (defrost mode, cycle mode)
- SOPs: working hours, door open times, assembly, reworking, packing, equipment placement
Step 2: Determine Probe Placement
USP 1079.4 provides volume-based guidance for the number of probes. Areas separated by a demising wall, doors, different ceiling heights, or floor layout should be treated as separate areas.
Probe Count by Volume
| Storage Area Volume | Probe Count |
|---|---|
| Less than 2 m3 (approximately 70 ft3) | 10 probes |
| 2 m3 to 20 m3 (70 to 706 ft3) | 16 probes |
| Greater than 20 m3 (706 ft3) | 28 probes |
Organizations may increase probe counts for extremely large areas. WHO Supplement 8 suggests probe placement every 5 to 10 meters covering length and width.
Probe Position Labels
- H = High probe (highest level product is stocked)
- M = Mid probe (middle level product is stocked)
- L = Low probe (lowest level product is stocked)
- T = Probe placed directly next to the thermostat controlling the area
Storage Area Examples
- Small reach-in freezer/refrigerator (less than 2 m3): 10 probes at H and L levels in corners, H at center, T next to thermostat
- Small walk-in unit (2-20 m3): 16 probes at H, M, and L levels across racking positions, T next to thermostat
- Large warehouse (greater than 20 m3): 28 probes at H, M, and L levels across racking bays, with additional probes for pallet staging areas
- Split-level units: Each level mapped separately, doubling the probe count (e.g., 20 probes for a split-level reach-in)
Probes should be placed at the outer limits of where product should be stored or staged, not at the inner limits.
Step 3: Obtain Monitoring Devices
- Obtain calibrated monitors for the storage range(s) being evaluated
- Include 5-10% extra monitors in case of mechanical failure
- For refrigerators, freezers, or ultra-low freezers: ensure the thermostat probe has a wire long enough (or wireless connectivity) to be read from outside the storage area without opening the door
- All devices and probes must be calibrated with documentation before mapping begins
- Program devices with the correct date, time zone, and temperature ranges
Step 4: Develop Probe Placement Map
- Place probes at locations where product may be stored or staged
- Areas divided by walls, doors, or different ceiling heights are separate mapping areas
- Probes must be securely fastened to remain in place during the study
- The thermostat probe provides verification of the set point used during mapping and can be observed during open-closed door and power on-off tests without opening the door
Step 5: Schedule and Execute Mapping
Duration and Conditions
- Duration should capture workflow variation impacting airflow — typically 1 day to 1 week depending on the workflow cycle
- Seasonal variations should be part of the mapping rationale
- For redundant refrigeration systems that cycle on/off, the mapping period must capture all systems and changeover periods
No-Load and Load Tests
- If mapping is done before product is stored or during a weekend/holiday without normal traffic, open-door tests should determine impact and recovery time
- Load tests may use actual product or simulated product matching expected thermal mass — the thermal load should never exceed actual product
- If mapping is completed before product is stored, mapping should be conducted again after product has been added
Open-Closed Door Tests
The goal is to determine how long a door can be opened before impacting product and how long re-equilibration takes:
- Open door for 15 seconds, 30 seconds, 1 minute, and 10 minutes
- After each opening, wait until the temperature recovers before opening again
- Door opening time and interval should match operational workflow described in SOPs
Power On-Off Tests
The goal is to test power failure and develop contingency plans:
- Turn off power — record until unit goes out of range (limit)
- Turn back on — record until temperature returns to set point
- Do not execute this test with product
If the area is on a backup generator, this test verifies the backup process is functional.
Risk Areas
Areas of risk such as dock doors, skylights, and windows should be included in the mapping as reference points to understand potential issues at product storage spaces.
Step 6: Determine Mitigation Strategies
When probes indicate temperatures close to or beyond storage limits, risks can be mitigated by:
- Ensuring the storage area is thermostatically controlled to prevent excursions (per USP <659>)
- Adjusting and securing thermostats
- Evaluating airflow turns and installing or adjusting fans to increase airflow
- Adding insulation to walls nearest the excursions
- Upgrading the temperature management system
Excursion Handling
- Short excursions (e.g., single data points) explained by a known event (door opening) should be documented in the test results
- Excursions from normal operations (door access) must be evaluated per USP <659> to determine if they are acceptable or require mitigation
- Areas that cannot maintain acceptable temperatures after mitigation must be labeled as not suitable for drug storage
Step 7: Complete Final Protocol
The final protocol report must include or reference:
- Acceptance criteria — minimum per USP <659> product storage temperatures, plus company risk management
- Detailed maps with dimensions, ceiling heights, doors, product racking, HVAC units, fans, thermostat locations, and probe placements
- Device list — temperature monitoring devices, serial numbers, and placements
- Calibration certificates for all devices
- Temperature readouts highlighting readings within storage ranges
- Deviation list with resolutions, if applicable
- Results as data/statistics and graphs, including time above and below temperature specifications
- Executive summary including the need for remediation, if applicable
Report Approval
Sign-off should follow organizational procedures and include (as appropriate):
- Study leader completing the report
- Quality and/or regulatory personnel sign-off
- Operations or business leader responsible for storage operations
Protocol and final mapping documentation should be maintained per the organization’s documentation retention procedures and applicable laws.
Step 8: Frequency of Remapping
After initial mapping, a rationale should be developed for when remapping should occur. This should follow local laws and at minimum be evaluated as part of change control. Triggers include:
- HVAC changes: set point, heating, air conditioning, cooling, or ventilation modifications
- Structural modifications: expansion or modification of storage areas, doors, passageways, or demising walls
- Operational equipment changes: racking configuration, machinery affecting airflow or heat, processes changing thermal mass, increased personnel
- Workflow changes: more frequent or longer door openings affecting warehouse temperature
How ATEK Supports USP 1079.4
Wireless Multi-Probe Deployment
ATEK’s wireless sensors enable flexible deployment per USP volume guidelines:
- Deploy 10 to 28+ probes without running wires through sealed storage areas
- Place probes at H, M, and L product levels with thermostat reference
- Reposition easily between mapping phases
- No need for wire leads outside refrigerators or freezers
Continuous Mapping Data Collection
Run mapping studies with automated data collection:
- Configurable logging intervals
- Continuous 24/7 recording for studies lasting 1 day to several weeks
- Automatic cloud synchronization with no data loss
- Captures workflow variation, door openings, and HVAC cycling
Automated Analysis and Reporting
Generate USP-compliant mapping reports:
- Statistical summaries (min, max, mean, standard deviation)
- Time above and below temperature specifications
- Excursion detection with root cause documentation
- Professional charts, graphs, and maps
- Exportable as PDF for regulatory submission
Calibration Management
ATEK tracks calibration lifecycle:
- NIST-traceable calibration certificates included with sensors
- Cloud platform tracks calibration expiration dates
- Automated alerts before recalibration is due
- Calibration records stored alongside mapping data
Ongoing Qualification Support
After initial mapping, ATEK continues to support compliance:
- Continuous monitoring detects drift that may trigger remapping
- Automated alerts if conditions approach temperature limits
- Historical trending identifies degradation patterns
- Simplified requalification when changes occur