The temperature study is required to understand the behavior of the product and packaging withstand. The packaging depends on product compatibility and stability guidelines.
So, FDA has made guidance intended to define the stability data package for a new drug substance or drug product sufficient for a registration application within the European Union (EU), Japan (JP), and the United States(USA).
Temperature stability study of packaging material
The guidance represents the core stability data package for new drug materials and products. Still, it leaves sufficient flexibility to encompass various practical situations that may be encountered due to the evaluated materials’ specific scientific considerations and characteristics. Alternative proposals can be used when there are scientifically justifiable reasons.
Let it directly be said that temperatures cannot strictly be divided into such simple categories as were once conceived, i.e., market and home.
How can we decide the temperature?
We all know that the many pharmaceuticals or medicines will finish up in the kitchen or bedroom invariably. It means that the maximum temperature and humidity may be worse in the home and export conditions. So, the businesses should also perceive that goods transported in the boot or trunk of a representative’s car may infrequently reach temperatures over 60°.
If outdoor arctic or antarctic circumstances are included, then outcomes of packaging stability may be exposed from −60°C to +60°C, depending on the circumstances.
The pharmaceutical industry, therefore, until recently, tended to operate to no particular standard and selected from the following requirements for testing purposes:
• −18°C to −22°C deep freeze conditions (arctic, antarctic conditions)
• freeze-thaw advised for drug substance
• 4°C, i.e., refrigeration 0–8°C
• 15°C (lower temperate)
• 25°C (upper temperate/lower tropical)
• 37°C or 38°C (tropical, body temperature)
• 40°C a preferred condition for specific Japanese tests
• 45°C or 50°C upper maximums for medium-term storage, i.e., 3–6 months
• 55°C, 60°C, and 80°C usually short-term upper challenge conditions
Other than body temperature, the phrases in parentheses have evolved by tradition rather than on any scientific basis and should be interpreted accordingly.
The zone-wise temperature stability condition
Recent investigations based on kinetic mean (km) temperatures have divided the world into four zones:
Zone I km temperature 21 °C mean RH 45% (lower temperate Europe)
Zone II km temperature 26°C mean RH 60% (upper peaceful Europe) location.
Zone III km temperature 31°C represent RH 40% (tropical dry)
Zone IV km temperature 31°C mean RH 70% (tropical humid)
These temperatures are usually ’rounded’ to 25°C (zones I and II) and 30°C (zones III and IV) for stability-type programs.
Based on geographical condition
40°C 75% RH is now being widely adopted as an accelerated condition where practical. It has been used in Japan for many years. The above forms the basis of harmonization (ICH) investigation carried out by Europe, Japan, and the USA.
Generally, companies choose three temperature stability studies:
1. Accelerated testing: Studies intended to boost the rate of chemical degradation or physical change of a drug substance or drug product using extreme storage conditions as part of the formal stability studies. Data from these studies, in extension to long-term stability studies, can be used to assess longer-term chemical effects at nonaccelerated conditions and evaluate the impact of short-term excursions outside the label storage conditions that occur during shipping. Results from accelerated testing studies are not constantly predictive of physical changes. Accelerated tests may not continue to the standard rules, mainly where certain plastics are under strain. In these situations, the stress may be enhanced by lowering the temperature and reduced (by cold flow) by raising the temperature.
Regarding the packaging aspect, quite a few packaging materials will weaken, break down, or not function properly if consistently stored at 45°C and above. Thus individual higher temperature testing may accelerate product degradation through pack breakdown. Hence even short-term storage at higher temperatures cannot always provide a scientific means of predicting shelf life. It should also be noted that testing at an accurately controlled temperature condition does not compare with any actual climate where temperature fluctuations can lead to dimensional and pressure changes, which may encourage exchange between the product and the outside atmosphere.
2. Intermediate testing: Studies led at 30°C/65% RH and designed to reasonably raise the rate of chemical degradation or physical changes for a drug substance or drug product meant to be stored long-term at 25°C.
3.Long-term testing: Stability studies under the prescribed storage condition for the retest period or shelf-life purposed (or approved) for labeling.
Long-term formal stability, which uses controlled conditions, can be fully justified only if the actual effects of temperature, RH, and pressure differentials are evaluated in the investigational or feasibility stage of a pack-product assessment. Most formal stability work also involves static conditions, i.e., it does not include handling, warehousing, and distribution.
Variable condition for temperature stability study of packaging material
Rare cases where changeable conditions may cause differences other than arising from storage at a controlled temperature are:
1 the pack ‘breathes’—exchange may be in or out, or both
2 the closure loosens or tightens
3 laminates separate or delaminate, usually starting at the edges.
4 packaging materials, ‘age’ faster.
Declare storage conditions
So, we need to declare storage conditions (temperature). Serious attempts have recently been made to clarify the storage statements used for pharmaceutical products, to eliminate such imprecise phrases as ‘store in a cool, dry place.’
A single label statement (no storage temperature statement) is acceptable if the product
can withstand temperatures
to 30°C (based on support data). Below 30°C, storage statements are necessary, e.g.:
• up to 25°C
• 2–8°C—refrigerate, do not freeze
• below 8°C—refrigerate
• below −18°C—deep freeze
• protect from light
• store in a dry place.
These statements formed part of ICH harmonization discussions. Hence there are currently variants on these, i.e.:
• 8–15°C (USA)—a cool place
• 30–40°C (USA)—warm
• above 40°C (USA)—excessive heat.
Controlled room temperature (USA) refers to an expected control between 20 and 25°C with excursions that allow a total range of 15–30°C.