Establishing and Managing the Drug Product Stability Budget

First published by: Pharmaceutical Outsourcing

How long can a pharmaceutical product be exposed to temperatures outside the recommended storage conditions? How can product discard be prevented in cases of temperature excursions? How to establish and to manage the allowed time out of storage of a pharmaceutical product? The short answer is: It all depends on the chemical and physical properties of the product, the knowledge about product stability and the presence of temperature exposure data. In this article, the science behind the establishment of a stability budget for products that need to be maintained under controlled temperature conditions will be explored and guidance will be provided to manage the product stability budget in the (bio) pharmaceutical supply chain.

The chemical and physical properties of a drug substance and the drug product formulation determine the product stability and shelf life. During this shelf life pharmaceutical products like vaccines, tablets, crèmes and injectables are exposed to hazards that may impact their quality, efficacy, safety and aesthetics. These hazards may affect the rates of chemical and physical degradation of drug substances and it includes intrinsic factors such as the molecular structure of the drug itself and environmental factors, such as temperature, pH, buffer species, ionic strength, light, oxygen, moisture, additives, and excipients (Yoshioka & Stella, 2002). Temperature is one of the primary hazards that effects drug stability and shelf life. This temperature should be within the allowed and filed conditions established during stability testing programs, which are typically run at the beginning of the product life cycle. In these studies the impact of temperature, moisture (relative humidity), light, shock, vibration, drop, pressure etc. towards the product in its primary marketed package are determined. Here the formation of degradation products and decrease in label claim or potency are measured using stability indicating methods to the end of the product shelf life, which may go to 36 months or longer. During these stability studies, the product is stored under strict controlled conditions in climate chambers at for example +5 ± 3 °C and +25 ±2 °C (ICH 1QA(R2), 2003). At regular intervals samples are drawn from the controlled temperature chambers for testing. From these stability studies, the product shelf life and temperature conditions during manufacturing, packaging, distribution and storage are established (ICH 1QE, 2003)(WHO, 2009). This is not only determined for finished goods, but for drug substances, intermediates and formulated bulk products as well.

The temperature conditions at manufacturing and packaging sites are normally under strict control (GMP regulation) and any temperature deviation with potential impact to a product is investigated. However, as soon as a pharmaceutical product leaves the manufacturing and packaging plant, the level of control is likely to decrease. Especially during transport of these products, many hazards may arise: failure of refrigeration equipment, air flow disruptions, mistakes by employees, extreme weather, exposure to temperature extremes at (air)ports, shipment past the thermal package delivery date, and equipment power interruption are a few examples. If for example strict 2-8 °C storage conditions were to be applied for cold chain products during transportation, then it would be likely that a large portion of the goods would never reach the end customer (the patient) without a temperature excursion. This can happen during loading, in transit and unloading of refrigerated vehicles for example. Establishment of a stability budget that allocates time out of storage (TOS) to distribution activities could help to support temperature excursions within any step in the supply chain and it could eliminate unnecessary discards. Most importantly it can prevent unnecessary drug shortages and maintain the supply of critical medicines to patients.

Most pharmaceutical plants execute the manufacturing and packaging of cold chain products at room temperature (15-25 °C) using the allocated time out of storage (TOS) established by stability studies. The advantages are significant for the company: at room temperature, equipment performs better (less disturbances), label adhesion towards glass vials and syringes is better during secondary packaging, employees can better concentrate (e.g. make less errors while reading procedures), processes and environment are easier to control, and there are fewer temperature excursions compared to the strict 2-8 °C range. A reduction in temperate excursions has a huge advantage as it saves expensive time-consuming investigations, release delay, complexity and discards. However, one disadvantage of allocated TOS is that it may negatively impact the length of the product’s shelf life, which might be important for commercial success of a product. It is therefore a business decision to balance the allocated TOS and shelf life.

Before a pharmaceutical product reaches the patient, it is transported from the pharmaceutical plant via distribution center(s), (pre)wholesaler( s) and point of dispense (e.g. hospital, pharmacy, nursing care facility) using road, air and sometimes ocean as mode of transport. Compared to manufacturing, packaging and storage, the hazards during transportation have the potential for bigger impact due to physical product handling, changing ambient conditions, handovers to other (sub)contracted parties and uncontrolled delays. Thus the allocation of TOS is valuable in order to reduce temperature excursions and discards. Therefore many pharmaceutical companies have set up extended stability studies to determine the minimum and maximum allowed temperatures and time out of storage during transport. For example freeze-thaw cycling and thermal sequential stress studies followed by product shelf life testing (e.g. long term stability testing) might have proven that a product can be exposed for a limited time between -20 and +25 °C, while this product should normally be stored at 2-8°C. The result is a stability budget that allocates TOS to minimum and maximum temperatures during manufacturing, packaging, distribution, storage, atypical events (e.g. failure of refrigerator) and for end users (PDA TR 53, 2011).