Stability testing of pharmaceutical products is addressed by the ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) and the final guidance on stability testing has been adopted across Europe, Japan and the United States. Furthermore, the FDA states in 21 CFR part 203 section that manufacturers, authorized distributors of drugs and their representatives shall store and handle all drug samples under “conditions that will maintain their stability, integrity and effectiveness,” ensuring that the drug samples are free of contamination, deterioration and adulteration.
Within stability test chambers, parameters such as temperature, humidity, differential pressure, lighting, gas levels and other environmental conditions must be controlled, monitored and documented. To reduce the risk of failed studies, a monitoring system designed for both functionality and compliance is required. Functions should include data logging, automated date file backup, monitoring and reporting via Internet access, connectivity options including wireless, email, phone or text alarm notifications, multiple levels of data security, which can include digital signatures, complete event and interaction history and audit trail.
Ideally, sensors used for monitoring stability test environments are flexible enough for validation as well. The purpose of performing regular validation of stability rooms and chambers is to ensure that acceptance criteria are met throughout the chamber, i.e.: temperature and humidity are evenly distributed within. While the exact number of sensors will vary with the size of the chambers, most validation technicians use at least ten sensors, for example, one sensor at each of the chamber’s corners and at the center, or 3 sensors on each shelf. Traditionally, thermal mappings were conducted with thermocouples. Newer technology is now available. Wireless dataloggers containing temperature and humidity sensors are easy to use and can be installed quickly, reducing the total amount of time necessary for mapping a stability room or chamber.
Regulatory Guidance on Stability Chamber Temperature & Humidity Monitoring
Additionally, stability testing requires an alarm function that can detect and announce when an excursion from conditions defined in the study occurs. Pharmaceutical companies have adopted various methods for capturing and announcing abnormal conditions. These include:
- Alarms if monitored values go outside a predefined value
- Alarms on excursion conditions being breached (usually a set temperature or humidity for a particular time).
- Alarms based on rolling yearly MKT
- SMS or e-mail alerts triggered by alarms or events
The FDA, CDER, CBER and the ICH have published “Guidance for Industry: Q1A(R2) Stability Testing of New Drug Substances and Products,” which seeks to define what stability data package for a new drug substance or drug product is sufficient for a registration application within the three regions of the European Union (EU), Japan, and the United States. Under the General Principles of this guidance, the purpose of stability testing is stated as the need to produce evidence on how the quality of a drug substance or product is affected for a given amount of time and under the influence of a number of environmental factors, including temperature, humidity and light.
Stability testing should also help define a retest period, as well as recommended storage conditions for the determined life cycle of the drug. Another source of guidance on stability testing is the World Health Organization, which has published “Stability testing of active pharmaceutical ingredients and finished pharmaceutical products Annex 2” as part of their Technical Report Series. Both guidances contain key principles of designing and executing stability testing protocols.
Reducing the Risk of Inaccurate Stability Studies with Redundant Sensors
Because the drift usually won't show up on system displays or be detected by system alarms, you may not know there's a problem until stability testing, product quality, or patient health has been jeopardized. Although the consequences of sensor drift in a stability study can be serious, the solution is simple: installing independent monitoring sensors that function separately from the feedback control system can verify proper operation and detect potential drift early on. Feedback control systems rely on sensors to emit a signal proportionate to the parameter to be controlled (e.g., RH). The system compares this signal with a desired set-point (e.g., 50% RH) and automatically increases or decreases its output to eliminate the gap between the signal and the set-point. Many systems use a display or recorder and some feature alarms that indicate when the measured parameter falls outside an established range, but some of these methods are connected to the same control sensor.
In time, as the feedback control sensor is exposed to contamination or degradation, its output signal may become drift out of specification. However, because signal drift usually occurs gradually and incrementally, it will not be evident on the system display, nor will it trigger system alarms. Although sensor drift may occur too slowly to be detected, it can occur faster than most calibration cycles. Because sensors drift without any obvious system changes or indications, you likely won’t be aware that a problem exists until your operations or products have been compromised.
While this type of drift occurs in many types of feedback control sensors, it’s particularly prevalent in RH measurement. This is because the internal structure of an RH sensor must be in direct contact with the environment, leaving it vulnerable to dust, airborne chemicals, and other contaminants that cause sensor drift over time. Even small levels of contamination can cause significant and permanent drift. For this reason, many stability experts routinely build in sensor redundancy into their stability testing, for both monitoring and mapping.
Environmental Monitoring for Stability Chambers
The Vaisala viewLinc stability chamber monitoring system comprises viewLinc monitoring, alarming and reporting software and Vaisala’s NIST-traceable data loggers and instrumentation. Ideal for use in demanding stability testing applications, viewLinc is the proven solution for accurate and cost-effective monitoring and validation. Vaisala’s monitoring solution features an easy-to-use, browser based interface that connects to your existing network via standard Ethernet, PoE (Power over Ethernet), or WiFi.
The Vaisala continuous monitoring system reduces the risk of non-compliance with the requirements of the ICH and FDA for monitoring temperature, relative humidity, and other critical parameters. The flexible alarming capabilities reduce the risk of imprecise measurements due out-of-tolerance conditions and reporting is designed to be easily customizable and exportable to spreadsheet for manipulation and analysis.
The newest version of the viewLinc monitoring software is available in English, German, French, Chinese, Swedish and Japanese and can be used with a wide range of Vaisala sensors. viewLinc integrates easily with your facility’s existing network, eliminating the cost of installing and maintaining a dedicated network. Sensing devices connect via Ethernet, PoE, WiFi or a combination of all connectivity options.