Stability Testing of Pharmaceutical Products

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 and Humidity Monitoring

Regulatory bodies require that stability testing chamber applications meet the following criteria:

  • Proper documentation, including SOPs and periodical reports
  • Chambers and rooms are equipped with multiple sensors spread evenly throughout the controlled area
  • Generous multilevel shelving providing orderly storage and proper exposure to the controlled environment
  • Acceptable monitoring equipment (probes, data recorders, etc.)
  • Continuous recording of data and full traceability
  • Corrective action taken when stability factors go outside the specifications

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. These guidelines contain key principles of designing and executing stability testing protocols.

Reducing the Risk of Inaccurate Stability Studies with Redundant Sensors

The most common types of long term, short term and accelerated stability studies can include temperature, humidity, and light, but can also include pH, and oxidative stress testing. For some parameters, a redundant monitoring system for the chamber or room is desirable.

For instance, in the case of humidity sensors, which are prone to drift (especially in a long term stability study) secondary sensors can help offset the risk of distortion in the feedback control systems from the effects of sensor drift. Many pharmaceutical professionals and stability testing technicians may not account for the fact that a feedback control system can mask sensor drift.
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.