Handling Temperature Excursions and the Role of Stability Data

• Claude Ammann Consulting

Summary

Pharmaceutical manufacturers are accountable for delivering medicinal products with the right quality attributes to patients. Control of storage and transport conditions is one key element in achieving this goal. It is not unusual for the storage to experience uncontrolled situations where temperature deviates from the specified values and for the transport to not follow the forecasted routes and scheduled plans. For temperature sensitive products, one possible consequence may be temperature excursions outside the specified range. What are the right tools to help make the right decision?

Introduction

Some medicinal products are sensitive to temperature and despite development team efforts they have to be stored within a limited temperature range until their expiry date. As a consequence, when the temperature range is exceeded, they experience temperature excursions from their specified storage or transport conditions. How should such temperature excursions be handled?

There are two potential areas of temperature sensitivity. The temperatures above and the temperatures below the range where the product has been shown to keep its unique properties until the expiry date. The product’s behavior is often different under these two conditions.

Products sensitive to high temperature can deteriorate by receiving thermal energy that will:

• Decrease active ingredient content through transformation of degraded components (oxidative, hydrolyzed, and others), some of them with possible toxic properties. The longer the time and the higher the temperature of exposure to the out-of-range conditions, the higher the amount of degradation products.
• Depreciate formulation properties, for example coloration of some components, dissolution rate modification, or separation of emulsions.

Products sensitive to low temperature are usually damaged by losing their therapeutic properties after the product has been frozen and the active ingredients structures have irreversibly changed.

Some products are sensitive not only to the absolute temperature but also to the temperature change itself, such as some creams or biologicals that lose their properties after freeze-thaw or temperature cycles.

Regulatory Requirements

The pharmaceutical manufacturers should clearly understand that they are accountable for a product’s quality until its final use. As such, they must guarantee that safety, efficacy and quality remain as stated within the registration files until final use. When temperature excursions occur, it is the manufacturer’s responsibility to take adequate steps.

Manufacturer’s Obligations

Manufacturers must prepare documentation to support the different parts of the files:

• Stability studies to support storage conditions
  • ICH has edited guidelines to harmonize testing conditions and methods to determine storage conditions and shelf-lives. The standard program starts with stress tests to determine the degradation pathways and the stability indicating methods, and describes long-term and accelerated conditions testing. Most manufacturers use these conditions. [1]
• Stability studies to support product handling during preparation and transport
  • The manufacturer must document temperature influence during handling of intermediates, bulk products, packed products until they are stored in the defined final storage conditions. For each product, the manufacturer should establish stability testing programs corresponding to the actual preparation and handling conditions. If deterioration is observed during these operations, conditions must be adapted to maintain product quality as stated.
  • The new EU GDP states under § 9.2, “The required storage conditions for medicinal products should be maintained during transportation within the defined limits as described by the manufacturers or on the outer packaging” [2]. This will require additional and sometimes useless efforts by manufacturers to change transport conditions. The possibility to define limits for transport conditions or on the external label is certainly a positive request and the application should be studied by manufacturers. This statement contributes to confusion with USP General Chapter <1079> [3] and WHO Time and Temperature Sensitive Pharmaceutical Products guidelines which allow manufacturers with satisfactory stability data and relevant scientific justification to transport drug products at temperatures outside of their labeled storage conditions [4].
• Studies to decide on product acceptance after temperature excursions
  • PDA has proposed methodologies to test product stability during transport. The proposed tests include temperature excursions and temperature cycling [5-9].

Temperature Excursions

Temperature excursion is a deviation from given instructions. It is defined in the WHO Model Guidance as “an excursion event in which a Time Temperature Sensitive Pharmaceutical Product (TTSPP) is exposed to temperatures outside the range(s) prescribed for storage and/or transport. Temperature ranges for storage and transport may be the same or different; they are determined by the product manufacturer, based on stability data” [4].

Temperature excursions during transport are not rare events. According to information obtained from many sources and during international conferences, excursions happen at a frequency of 1 – 5 % of transport events. This places transport as one of the least reliable pharmaceutical processes.

What makes temperature excursions difficult to handle is that there is often no way to predict the next condition that the product will be exposed to. Natural disasters or human-related events could interrupt the transport route.

Below are some regulatory texts dealing with temperature excursions. The new EU GDP states: “If a deviation such as temperature excursion or product damage has occurred during transportation, this should be reported to the distributor and recipient of the affected medicinal products. A procedure should also be in place for investigating and handling temperature excursions”.

ICH Q1A(R2) [1] states:

• Stability Testing of New Drug Substances and Products (2.1.7)
  • “…Data from accelerated stability studies can be used to evaluate the effect of short term excursions higher or lower than the label storage conditions that may occur during the shipping of drug products.”
• Storage Conditions (2.2.7)
  • Data from the accelerated storage condition and, if appropriate, from the intermediate storage condition can be used to evaluate the effect of short term excursions outside the label storage conditions (such as might occur during shipping)
• Drug Products Intended for Storage in a Freezer (2.2.7.5)
  • “In the absence of an accelerated storage condition for drug substances intended to be stored in a freezer, testing on a single batch at an elevated temperature (e.g., 5°C ± 3°C or 25°C ± 2°C) for an appropriate time period should be conducted to address the effect of short term excursions outside the proposed label storage condition, e.g., during shipping or handling.”
• Accelerated and Stress Conditions (ICH Q5C: § 6.3)
  • “… Studies under stress conditions may be useful in determining whether accidental exposures to conditions other than those proposed (e.g. during transportation) are deleterious to the product.”

WHO: Stability testing of active pharmaceutical ingredients and finished pharmaceutical products products states, “The effect of excursions due to equipment failure should be assessed, addressed and reported if judged to affect stability results. Excursions that exceed the defined tolerances for more than 24 hours should be described in the study report and their effects assessed” [10].

USP General Chapter <1079> gives directions on how to handle temperature excursions. The text allows using stability data to evaluate the effect of short-term excursions outside of the label storage conditions that might occur during storage and/or distribution [3].

What Does a Temperature Excursion Study Program Look Like?

It should start with the determination of global product characteristics, assess the risks of the distribution channels in relation with product characteristics, establish the study program and check the results to modify the product transport conditions if necessary (Figure 1).

Figure 1. Steps to build stability knowledge helping manufacturers to assess temperature excursions.

• Global Product Characteristics: The manufacturer can use preliminary or existing stability studies to determine the environmental conditions that are potentially causing product degradation.
  • What are the external parameters that can damage the product?

This question is best addressed by collecting the existing sources of information on the product under evaluation such as stress studies during which influence of temperature, as well as air, humidity, light and maybe vibration and X-Ray radiation have been determined. During transport, most of these parameters are usually under control with the exception of temperature, vibration or radiation if relevant.

• • Does an excursion have a critical consequence on the product’s quality?

Some products cannot tolerate any out-of-range situation. The best examples are some biologics that lose their therapeutic properties completely if they are exposed to freezing. In these situations, there is little margin to accept any temperature excursions.

For other products, the data allows excursions outside the storage conditions and it is important that manufacturers understand how to safely handle the products that have been submitted to temperature excursions.

• • Does the data support any short time temperature excursions?

Stability data are usually performed during a “long” time period, with the first testing time point after one month of storage. These periods are not adapted to transport times, which typically last a few days.

• • Who are the customers and how will patients receive/use the products?

The situation for over-the-counter products is not the same as it is for some oncology products that are dispensed by hospitals. Transport conditions can be controlled for hospital deliveries, but not when products are distributed to individuals for their personal use. Security factors used to determine storage and transport conditions should take into account these differences.

• • What are suitable transport channels?

Transport channels depend on the destinations, on the amount and type of products and on the pharmaceutical company’s distribution strategies.

• • Determine other environmental deleterious conditions
• Prepare a Risk Analysis: The customer/patient needs, product type, packaging specifications, and transport conditions should be taken into account.
  • This very useful step will help manufacturers to prioritize the actions that are most relevant to decrease the consequences of temperature excursions.
  • The outcome of this study should be setting up time/ temperature/ frequencies limits that products might be exposed to.
  • Based on product characteristics, security margins will be defined to address “unknowns” and consider the worst cases.
• Establish a Study Program: This should include temperature excursion studies, thermal cycling studies [5], transport studies, mathematical model (Figure 2) [11, 12], and freeze-thaw cycles as needed.
  Figure 2. Relationship between time and temperature as described by the mathematical model. It shows how much time a product can be placed at a defined temperature before it builds unacceptable amount of degradation products.
  • Studies parameters have been proposed in the appended references.
  • Actual parameters should reflect product specificities and transport risks. Time and temperature should be balanced reminding that studies’ conclusions should demonstrate when and how long products keep their properties.
  • The repetition of “excursions” during the life of a product should also be taken into account. What is the consequence of repeated excursions? Is the situation the same if temperature excursion occurs at the beginning of the shelflife or at the end of the shelf-life? How many cycles are relevant for the studies?
• Evaluate the Results: Once the results are checked, decide on the next necessary steps.
  • Do the results support the temperature excursions that were accepted during the risk analysis?
  • If so, are the protective measures adequate or are they much too efficient? Is an optimization of the transport conditions necessary?
  • If the results do not support temperature excursions, what are the next steps to be envisaged? What is the solution that could decrease the temperature excursion risk? A better container? Another transport channel?

What Should the Temperature Excursion Procedure Cover?

Temperature excursion procedure should clearly define the situations that are covered by studies and in which a batch can be released and those where it cannot (see Figure 3). It should include a decision chart conducting the reader from the incoming temperature excursion information through the different questions that are relevant to the decision.

Figure 3. Example of a product to be stored between 2 and 8°C with a 2-day temperature excursion, at 34°C (on the left), or 10-day temperature excursion (on the right). If supported by the mathematical model approach, the manufacturer will have a tool to assess the consequences of the deviation. (Green is product preparation temperature; yellow is different transport steps either between 2-8°C and 23-27°C; blue is product storage temperature; red is temperature excursions situations.)

Conclusion

Manufacturers should clearly understand what the consequences of temperature excursions are during products storage and transport from their manufacturing site to patients. They should evaluate if the available stability data are sufficient to address the potential temperature excursions. If this is not the case, they should consider starting additional studies to support the release decision in case of temperature excursions, and avoid batches that have adequate therapeutic properties destroyed by insufficient stability knowledge.

References

1. Stability Testing of New Drug Substances and Products International Conference on Harmonization (ICH) Q1A (R2) (originally published 1994, revised 2003).
2. Guidelines of 7 March 2013 on Good Distribution Practice of Medicinal Products for Human Use Official Journal of the European Union (2013/C 68/01)
3. <1079> Good Storage and Distribution Practices for Drug Products, USP
4. Model guidance for the storage and transport of time- and temperature–sensitive pharmaceutical products WHO Technical Report Series, No.961, 2011, Annex 9
5. Guidance for Temperature-Controlled Medicinal Products: Maintaining the Quality of Temperature-Sensitive Medicinal Products Through the Transportation Environment PDA Technical Report 39
6. Last Mile: Guidance for Good Distribution Practices for Pharmaceutical Products to the End User PDA Technical Report 46
7. Guidance for Good Distribution Practices (GDPs) For the Pharmaceutical Supply Chain PDA Technical Report 52
8. Guidance for Industry: Stability Testing to Support Distribution of New Drug Products PDA Technical Report 53
9. Risk Management for Temperature- Controlled Distribution PDA Technical Report 58
10. Stability testing of active pharmaceutical ingredients and finished pharmaceutical products WHO Technical Report Series, No. 953, 2009 Annex 2
11. A mathematical approach to assessing temperature excursions in temperaturecontrolled chains, Claude Ammann, European Journal of Parenteral & Pharmaceutical Sciences 2008; 13(2): 57-59
12. Stability Studies Needed to Define the Handling and Transport Conditions of Sensitive Pharmaceutical or Biotechnological Products, Claude Ammann, AAPS PharmSciTech, Vol 12 number 4, Dec 2011

Claude Ammann is the Director of Claude Ammann Consulting, advising pharmaceutical and biotech companies to enhance their quality capabilities since 2009. Claude has more than 30 years of industrial experience at Zyma and Ciba-Geigy, both now part of the Novartis group. He later became Site Manager and QA Director in various small companies. He is a Responsible Person as qualified by Swissmedic.