Stability Program Management

With regulatory authorities having an increased focus on safety and efficacy, a new drug product often requires at least 10 years of development time before reaching its intended market. An important element of this lifecycle is the determination of shelf-life (i.e., stability) of the drug product under various anticipated storage conditions. The stability studies examine the safety and efficacy of the drug product as a function of its exposure to certain defined environmental factors over time. For a contract research organization (CRO) that operates under GMP and whose sponsors have products that are globally marketed, it is important to understand the guidelines and regulations that govern the global pharmaceutical industry.

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When global distribution is the intent, it is crucial to assess product stability for the climate zones that the product will be subjected to during its manufacture, distribution, and usage. Although the pharmaceutical industry has recommended climate zones for long-term stability testing, a country can require condition(s) outside of this scope for its long-term storage (see Table I)(1).

Table I: Environmental storage conditions according to climate zone. RH is relative humidity.

For example, Europe, Japan, and the US adhere to their own practices, and have also adopted the International Conference on Harmonization (ICH) guidelines. Specifically, they follow Q1A (R2) Stability Testing of New Drug Substances and Products, which defines the stability data package for a new drug substance or drug product that is sufficient for a registration application (2). Other countries or regions do not necessarily follow these guidelines. For example, Brazil, India, and China, to name a few, have their own regulatory guidelines for stability. In addition to countries, agencies such as the World Health Organization (WHO) have their own stability guidelines. For Climate Zones III and IV, the ICH withdrew its Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV guideline in 2006. ICH left the definitions of storage conditions in Climatic Zones III and IV to the appropriate countries, regions, and the WHO. Also, if the medication is to be used for veterinary purposes, it may or may not be subject to any of the above regulatory agencies on top of the Center for Veterinary Medicine (CVM), the US Department of Agriculture (USDA), or the International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products (VICH).

Given the current regulatory environment, sponsors may require CROs to provide substantially more resources in support of a stability program than in years past. Consider the following: to support a general case drug product several years ago, evaluating product stability at 25 °C ± 2 °C/60% RH ± 5% RH (where RH is relative humidity) for 12 months (or longer) was considered sufficient. Now, however, a stability study may also need to be performed at 30 °C ± 2 °C/65% RH ± 5% RH or a combination of both the 25 °C ± 2 °C/60% RH ± 5% RH and 30 °C ± 2 °C/65% RH ± 5% RH. There are also cases where the long-term storage of a general case drug product will need to be at 30 °C ± 2 °C/75% RH ± 5% RH. Besides long-term storage conditions for general case drug products, testing using intermediate (30 °C ± 2 °C/65% RH ± 5% RH) and accelerated (40 °C ± 2 °C/75% RH ± 5% RH) storage conditions is also required for a minimum of six months. Note: if the long-term stability storage of 30 °C ± 2 °C/65% RH ± 5% RH or 30 °C ± 2 °C/75% RH ± 5% RH has been performed, no intermediate condition is necessary (1, 2).

General case drug products are not the only medications that are adding environmental conditions to their studies. More conditions have also been added to the stability study profiles of refrigerated drug products. Per ICH guidelines, long-term storage of refrigerated products should be 5 °C ± 3 °C for a minimum of 12 months. The accelerated condition is 25 °C ± 2 °C/60% RH ± 5% RH for a minimum of six months (2). Outside the ICH guidelines, this study setup may or may not be sufficient. While the long-term 5 °C ± 3 °C condition still applies, 30 °C ± 2 °C/65% RH ± 5% RH or 30 °C ± 2 °C/75% RH ± 5% RH is now often used for accelerated stability studies (1). Overall, adding these conditions provides a risk-based assessment for the product, especially if it is a biologic. With the required additional conditions and samples, where does this leave a CRO?

To support global stability practices, fundamental basics must be put in place. The first is to have validated and qualified stability chambers. A qualified and validated chamber must have the proper installation, with operational and performance qualifications completed before sample placement occurs. As well as validated hardware, a compliant CRO needs the correct standard operating procedures (SOPs) and quality control systems. This allows the flexibility to adapt chamber conditions as required for handling a variety of product lines.

It is imperative to fully understand the scope of any study; that is, how many primary and retained samples will be received, their storage conditions, and sample storage orientation. These conditions determine how much space a study will occupy and, from a risk mitigation standpoint, provide insight into the conditions that must be replicated.

Risk assessment is also crucial to a stability program. For example, having multiple stability chambers under the same conditions, or chambers with redundant temperature and humidity controls are approaches to mitigate effects of any mechanical failures. This redundancy prevents study restarts or additional testing to ensure the product was not compromised during an excursion or failure. A robust monitoring program is key and should assess temperature or humidity excursions. In collaboration with a good general preventive maintenance schedule, this monitoring can prevent mechanical failures from being catastrophic.

Finally, a CRO should have a suitable laboratory information management system (LIMS) to monitor the stability program. The LIMS should be able to track the progress of an entire study. The data collected include but are not limited to: recording sample receipt, placement of samples into the chambers, interval pulls, and test results. For laboratory personnel, the stability pull schedule should be readily available with information about the required conditions and tests. Tracking of turn around metrics should also be possible. The LIMS system needs to generate reports on instrument conditions and/or sample results as necessary. Although there are other aspects required for a stability program to ensure its integrity, without these basics, the program is not likely to function optimally in a global regulatory environment.

Deni Jo Williams is a GMP project manager at MPI Research, State College, PA.

References

1. WHO, Stability Testing of Active Pharmaceutical Ingredients and Finished Pharmaceutical Products, Technical Report Series 953, Annex 2 (2009).

2. ICH, Q1A (R2) Stability Testing of New Drug Substances and Products (2003).