Table of Content
Under the term “pharmaceuticals”, all kind of materials and products are summarized such as drugs, medicinal products, bio-pharmaceuticals, API, research materials, human body samples or even medical devices. What they all have in common is that their properties and therefore their quality change with temperature – for example:
Compared to food products, pharmaceuticals typically don’t change their smell and optical appearance when exposed to wrong temperatures. But they change their potency and their effectiveness. Therefore loosing stability budget might be harmful to patient safety.
Common regulations don't list all temperature sensitive products in the pharmaceutical and healthcare environment. When the “cold chain industry” started in the 1980, temperature sensitive pharmaceutical products typically referred to refrigerated products like vaccines or bio-pharmaceuticals. In addition to that, blood and blood products as well as research materials and human body samples require temperature monitoring, too. Since the 2015 revision of the EU GDP guidelines, API and room temperature products, such as small molecules and over-the-counter drugs, were included into the scope of temperature controlled logistics, too. Since the new regulation on medical devices came into force, medical devices which include some sort of an active pharmaceutical ingredient (e.g. coating) must as well be considered inside the scope of temperature controlled logistics.
Like most supply chains of industrialized products, the pharma supply chain is complex and consists of multiple steps. Furthermore, the supply chain of every pharmaceutical product looks different and depends on the product complexity as well as the production region. While expensive products like genetically engineered drugs typically have a very short supply chain, low-price over-the-counter drugs like Aspirin have a much more complex supply chain with multiple steps between production and patient. What all pharma supply chains have in common is the distinction between the transportation of Active Product Ingredients (API) and finished packaged products. Lately, the scope of temperature data monitoring is increasingly including the last transportation mile to the pharmacy or even to the patient. Direct-to-Patient-Shipments (DtP) are becoming increasingly popular and important, especially with regards to clinical trials but also for personalized drugs.
Humidity is relative to temperature and represents the amount of water present in the air. Humidity is highly relevant in the pharmaceutical production as long as the product is in its open form before primary packaging (i.e. liquid or powder). After primary packaging, the relative humidity typically loses its direct relevance to patient safety. It is nevertheless common to monitor relative humidity in warehouses to avoid negative impact on the labeling and packaging (i.e. paper, cardboard). In most shipments however, the only quality relevant parameter is temperature. Data loggers therefore usually don't monitor Humidity inside the transportation container.
Although every pharmaceutical product has an individual stability budget, they are clustered into standard temperature data range groups for storage and for transportation. As storage conditions we typically see the temperature ranges -196°C, -80°C, -20°C, 2-8°C and 15-25°C. As transportation conditions the labels are "liquid nitrogen" (-196°C), "dry-ice" (-78°C), 2-8°C and 15-25°C. The storage condition “frozen” (-20°C) is not very often seen in transportation for mainly two reasons. Frozen products are in most cases not sensitive to ultra-low temperature. It is therefore cheaper to use dry-ice than to use expensive and complex compression cooling.
If a company wants to research, produce, store, transport or sell pharmaceutical products, they are subject to regulatory requirements. The laws and regulations are specific to each country and typically include a national or international authority like the FDA (in the United States), EU (in Europe) or Swissmedic (in Switzerland), all coordinated by the ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use).
In addition to official regulations, there are a number of important associations issuing guidance documents supporting and detailing the regulations and their application in specific situations. Some of the most influential organisations relevant to the pharmaceutical supply chain industry are the ISPE (International Society for Pharmaceutical Engineering), the USP (United States Pharmacopeia), the PDA (Parental Drug Association) and the WHO (World Health Organisation). The regulatory framework is therefore a living organism which changes almost daily with new laws becoming effective and new guidance documents being published.
From a drug supply chain perspective, the cornerstones of the regulatory framework are the Good Manufacturing Practice system (GMP) and the Good Distribution Practice system (GDP) – or often jointly referred to as GxP. While GMP lays its focus on activities around manufacturing (including testing, release & storage), GDP focuses on the distribution including transportation, storage & wholesale of pharmaceuticals products. Both, GMP and GDP aim to increase public health by ensuring the product quality.
In a nutshell: if you store or transport pharmaceutical products and want to comply to GMP and GDP guidelines you must:
The same applies to the transportation but with more focus on the requirements of fleets, containers, boxes and single-use equipment.
The history of monitoring solutions started more than 30 years ago with Autonomous Temperature Data loggers – like for example ELPRO’s legendary HAMSTER. Driven by a battery, the data logger recorded temperature and humidity measurements and was able to transmit its internal memory to the analysis software through an interface. Since the autonomous temperature data loggers were compliant to the Hazard Analysis and Critical Control Point (HACCP) standards, the food and beverage industry as well as heating, ventilation, and air conditioning companies (HVAC) used early applications of autonomous data loggers. Soon after that the pharmaceutical industry started to monitor refrigerators and cold rooms, too. Temperature data loggers were firstly used for laboratories and production facilities. Later on storage and transportation facilities were added to the scope.
A monitoring system typically consists of a sensor conducting measurements of temperature or other environmental data in a defined interval. The sensor transmits the values wired or wireless to a data logger, which acts as a communication bridge. The Software collects the values in real-time in order to perform the following functions:
In any production environment and in many warehouses, state of the art Building Management Solutions (BMS) are installed to conducting measurements of temperature and environmental data like humidity, as well as giving commands to the air conditioning system. What is the difference to an independent Monitoring Solution? Other than Building Management Solutions, Monitoring Solutions never have control loops but instead are fully independent from any control mechanism. The validated independence of a Monitoring Solution is an important requirement of any GxP-guideline.
Research, production, testing and filling of pharmaceutical products are often performed in a clean room environment in which various environmental parameters such as temperature, humidity, pressure, pressure differentials, C02 and particles play an important role regarding the quality of the product. Therefore, monitoring solutions must be open to process, evaluate and display all kind of environmental parameters. As soon as a product is filled into a bottle, blister, vial or syringe, temperature is the only relevant environmental data which is important to the quality of the product.
GMP and GDP guidelines require a qualification of the storage facility, refrigerator or transportation box. The most important part of the qualification is the thermal mapping process identifying the hottest and the coldest spot. Depending on the specific situation and the requirements, the right sensor can be chosen and placed. Depending on the scenario a mix between wired sensors (e.g. for 4to20mA transmitters) or wireless sensors (e.g. temperature and humidity) can be chosen.
Would you like to know more about the differences between wired and wireless sensors? Download our infosheet on everything you need to know about using wireless sensors for temperature monitoring.
In a storage facility (i.e. a refrigerator) air temperature will change very fast through the opening and closing of the door. The thermal reaction time (Tau90) measures the time it takes to adjust to 90% of the temperature change. In other words: if a door of the refrigerator (5°C) is open, it takes a lot of time until the temperature is adjusted to the ambient temperature (20°C). Since temperature sensors have a very small thermal mass, they immediately change temperature. But pharmaceutical products are normally either well packaged or have significant thermal mass, meaning that the core temperature of the products will adjust significantly slower. This effect is called the thermal reaction time. Depending on the thermal mass of the pharmaceutical product and the packaging this might be anytime between 15 minutes to more than one hour. To simulate this effect, thermal dampers (such as glycol bottles) or electronic damping mechanisms are used.
Humidity is relative to temperature. Relative humidity is a function of the ambient temperature and the water vapor pressure in the air. Humidity sensors use the dependency of the relative humidity ant the amount of moisture pressure inside the sensing element as a physical measurement principle. For electronic measurement, there are two different technologies available – each of them having their advantages and disadvantages:
*Clean Rooms have by definition very clean air with few particles only. However they are regularly disinfected with different types of gases. Those gases may cause clogging of the humidity sensor (resulting in drift = loosing measurement accuracy over time).
Find all elements and features of a GxP-compliant temperature monitoring solution on this page.
Find out more about the process of a calibration and why it is even necessary to calibrate a sensor.
If you work with pharmaceutical products and want to comply with GMP and GDP guidelines, you must know more about Qualification.