The primary objective of stability testing is to determine the shelf life of a drug during storage. In essence, it assesses the drug’s stability under specific packaging and closed system conditions, encompassing its physical, chemical, microbiological, therapeutic, and toxicological specifications.

To adhere to best practices, stability studies are conducted in accordance with guidelines established by organizations like the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) and the World Health Organization (WHO).

The primary motivation behind conducting stability studies is to ensure the well-being of patients by establishing the appropriate shelf life and storage conditions for medicinal products. Through these tests, the impact of environmental factors on the drug substance or formulated product is evaluated, enabling the prediction of shelf life and determination of proper storage conditions and labeling instructions for patients.

Conclusion: Stability Testing Plays a Pivotal Role in Pharma

Stability testing is not merely a regulatory requirement but a critical aspect of ensuring the quality and efficacy of medicinal products. It plays a pivotal role in protecting patient health by establishing the appropriate shelf life, storage conditions, and labeling instructions.

As the pharmaceutical industry continues to advance, stability testing will remain an essential practice, upholding the highest standards of product integrity and patient care.

Stability Studies

The term ‘Stability’ can be defined as the period of time in which a product remains stable under the recommended conditions (as different products require different conditions), without compromising its integrity. This means that no physical or chemical changes occur, and the product retains the same quality as when it left the manufacturer. When a company is manufacturing a new product, it needs to perform a stability study.

These studies are performed with the goal of determining the shelf life (without compromising its composition), and appropriate storage conditions for the product. During the first year of manufacture, three initial batches are selected for the Stability Study. The following years, one batch, per strength, per year is selected to be put on stability. This is done to monitor ongoing quality and ensure that while the product is still on the market, it remains within specification. Such studies can be performed on pharmaceutical products, food and beverage products, cosmetics and also packaging.

This article will focus on Stability Studies performed for pharmaceutical products.

External Factors

External factors are also taken into consideration when performing a Stability Study, as these might have an effect on the product. Such external factors are light, heat, humidity, temperature, etc. The Stability Study performed will show what effect these factors might have on the product and determine the most ideal storage conditions, shelf life and packaging. In order to perform a Stability Study, it is required that the company follow the ICH Quality Guidelines on Stability Studies Q1A (R2).

These guidelines provide a very detailed overview of what is required when carrying out a Stability Study, including time points, analytical requirements, evaluation of analytical data obtained, specifications, etc. Over an extended period of time, or if the product is exposed to extreme storage conditions, its physical, chemical and microbiological properties might be compromised. This is the main reason for performing stability studies, in order to ensure that the product’s quality is maintained throughout its shelf life. Prior to starting a stability study, an adequate testing program must be written.

Stability Testing Program 

This program is created to ensure that all the stability characteristics of the product remain stable throughout their labelled expiry dates. Within this program, the sample size (at least three primary batches) must be written, along with the testing intervals which will be applied. The batches chosen for the study must maintain the same formulation and must utilize the same container closure system (packaging).

It is very important that during the stability studies, time points are also adhered to, i.e., if the product is to be sampled and tested during the nine-month interval this deadline is met. The storage conditions and references to the validated methods should be included in the protocol/program. All records of testing activities are to be adequately archived in case they need to be reviewed by an authority.

How is a Stability Monitoring Plan created? 

Stability monitoring and testing can be carried out in three ways; it is done by checking the product’s physical, chemical and microbial characteristics. Physical checks include changes in the product’s appearance, water retention, dissolution properties, disintegration properties, changes in its pH and changes in the viscosity of the product (more testing can be included as necessary). Chemical checks include the determination of any degradation impurities through the related substances analysis and also the assay content.

Microbial checks primarily identify the presence of any pathogenic microorganisms. In cases where the product comes with an applicator, such as an inhaler, the functionality is also assessed. The data used in the Stability Study needs to be quantitative. Two of the main types of Stability Studies performed are Real-Time Stability Testing and Accelerated Stability Testing.

What are Real-time Stability Studies? 

Real-Time Stability Studies are done on products which are stored according to their recommended conditions on the outer packaging. Continuous checks are performed on the product in order to confirm if the product is still within specification or not. Such checks are performed until the product fails; once it is not compliant with the specification then the shelf life can be determined.

According to the ICH guidelines the product is to be tested four times in the first year, at three-month intervals (at three, six, nine and twelve months). After the first year is concluded it is to be tested twice the following year at six-month intervals and then it is to be tested once every year until a failure result is obtained. Once a failure result is obtained, no more testing is carried out and the data obtained is evaluated to determine what the shelf-life of the product will be.

What is the Importance of an Accelerated Stability Study? 

An Accelerated Stability Study occurs when the targeted product is stored in exaggerated conditions, such as where factors such as temperature and humidity are accelerated. This is done to establish the worst-case scenario for the product. Stability chambers are used as they can be temperature and humidity controlled; if there are a larger number of products on stability the company can also invest in a walk-in stability room, which can also be precisely controlled and maintained at the desired set points.

It is essential that the stability chamber is qualified and well maintained. Its temperature and humidity levels are also to be regularly monitored with data loggers and alarm notifications must be sent to designated people when there are excursions in order to ensure that the required conditions are being applied to the product.

The testing timeframe should be a minimum of six months at the accelerated conditions. If for example, a product which is being kept within the conditions of 40°C/75% RH remains stable up to six months, it can be given a shelf life of up to 24 months.  The aim of an accelerated stability study is to determine the time of degradation of the product.

Therefore, based on the information obtained from the study, the storage conditions can be determined. Accelerated stability studies are also very useful in cases of temperature excursions, i.e., if there is a temperature excursion during transport, when the product was exposed to a temperature of 40°C, the stability data can be checked to see if the product quality was compromised by this temperature for the time it was exposed.

Prior to closing a stability study, it is essential that the results are trended. When the results are trended, a clear picture is given to the reviewer on the overall results obtained throughout the study. In this way, during the analytical data review, one can easily identify any abnormal trends within the extracted data.

Performing stability studies will confirm that a shelf life is adequately determined, appropriate storage conditions are ensured based on the properties of the product, and the study will aid in further product development. It is also important to have stability studies on products which are currently on the market (retained samples studies) to ensure continuous monitoring for efficacy and integrity of the product. Above all, the most important aspect is that product quality is maintained.

A stability study is a large body of work that is resource, time, and space intensive. For businesses that lack the space to house stability chambers, require additional storage capacity, or need assistance with study design for a complex drug product or substance, it is commonplace to outsource stability studies to a trusted partner. This article explores the considerations for commissioning stability storage and analysis projects.

Stability studies are used to determine the shelf life, active ingredient efficacy, and long-term safety and stability of a pharmaceutical product. They involve placing samples (within their container closure system and any other primary packaging) into environmentally controlled chambers to determine how the product or substance will change over time when subjected to specific environmental conditions. According to the study protocol, samples are periodically assessed for changes in physical, chemical, biological or microbial makeup. For example, changes to pH, degradation, dissolution, assay, microbial activity, and moisture content can be identified.

In the pharmaceutical sector, stability studies are essential for regulatory submissions as evidence of a product’s efficacy and safety over time. Stability studies typically start at the pre-clinical stage and continue during clinical trial phases. However, to streamline route-to-market, many pharmaceutical businesses are adopting stability studies into their development process, rather than conducting them later.

Standards for stability testing

While drug manufacturers must submit their applications to the regulatory body (e.g. FDA or MHRA), stability studies are guided by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). A typical stability study comprises of two key stages, stability storage and analysis. The ICH has guidance on the proposed length of the study and frequency of sampling based on the product and its intended shelf life, although some products may require custom conditions (anything from -80°C up to 70°C or 10-80% RH).

The ICH guidance explains three types of studies, long-term, intermediate and accelerated, and lays out specific storage conditions. These are intended to measure the product’s condition in different circumstances, such as near the end of its shelf life or during transport. In addition, depending on the product’s intended markets, the ICH guidance has created corresponding test conditions for the five climactic zones of the world.

Accelerated storage studies are an efficient way to highlight and troubleshoot any problem areas early on, supporting the early identification of potential degradation processes. In addition, accelerated storage conditions are used to support the extrapolation of real-time stability storage data. Forced degradation studies can help identify areas for future testing, and analytical chemists can use the results to devise a future testing program. This can help avoid costly reformulations and redesigns and accelerate time to market (TTM).

Study design

Before beginning a formal study, it is important to understand the product and its likely degradation pathways so that the study can be designed to follow those. Study design will depend on the drug product or substance, the drug delivery method, the stage of the drug development process, and more. For example, due to their sensitivity, biologics may need to be tested at a narrower temperature range. Or, it may be required to go beyond standard ICH environmental test conditions to check the product’s stability during simulated shifts from hot to cold that may occur during transportation. Ultimately, the study should be designed to answer product-specific questions.

Study design involves creating a plan that specifies sample sizes, testing times, specific storage conditions, validated test methods, and more. While guided by ICH, different regulatory bodies have different requirements, so the plan must be devised with a specific location in mind; some data is mandatory in some areas but not others and certain microbiological limits differ by region.

Industry changes ahead

Last updated in 2003, ICH Q1A-Q1F is in the process of refinement to become a combined Q1 guideline. The amended version will streamline the series, align it with other current ICH guidelines, promote harmonized interpretation, and cover new topics such as advanced therapies. The ICH’s business plan highlights that the first draft of the revised guidelines should be available for comment in late 2024.

It’s not just guidelines that are changing; the types of drug products and substances being tested are also changing. As other large molecule drug products, like biologics, come to market, stability storage and analysis must adapt — these molecules are more prone to degradation, and typically, this means more complex analysis, with additional parameters to measure or the need for custom test conditions. Biopharmaceuticals, for example, tend to exhibit more unpredictable degradation pathways than small-molecule APIs and may precipitate during the test due to their concentration and/or low solubility. Study design may be more challenging as a result.

Outsourcing stability studies

Pharmaceutical businesses outsource stability studies for several reasons: lack of space, facilities, or resources being common ones. In addition, stability testing and analysis is a specialist field. Outsourcing may offer a good solution if a company does not have in-house experts for method development and validation, particularly when working with a complex drug product.

Stability experts typically work with a manufacturer’s in-house scientists to consult on study design and create forward-looking testing strategies. With experience in similar studies, the partner should have a broad understanding of product types and their possible stress points and can suggest the best ways to monitor them proactively.

Some businesses will have broader scientific subject matter experts available, such as analytical chemists and toxicologists, who can help provide a complete analysis of test data, understand deviations, and troubleshoot problems. If the partner is also an expert in extractables and leachable (E&L), studies can be run in parallel, streamlining the route-to-market.

Finally, a partner with an in-house regulatory team can help prepare everything needed for submission to the regulatory body.

Data management

For stability studies, it is of the utmost importance to document that test conditions were maintained appropriately for the duration of the study, so that the study can be validated.

Therefore, the stability study provider must offer end-to-end quality-controlled processes for the receipt, management, and disposal of samples. This is typically managed by a Quality Management System (QMS) in line with GMP, GLP, or ISO/IEC 17025 requirements for sample management. Important factors include managing traceability, temperature controls and data logging, procedures for limiting cross-contamination, data integrity, and more.

Some study providers will go further by offering real-time access to stability data and trend reports through a secure Laboratory Information Management System (LIMS), validated to meet the requirements of FDA 21 CFR part 11 and MHRA Annex 11 for electronic record keeping and signatures. This can give manufacturers peace of mind that there are no changes to the chamber’s conditions.

Ahead of upcoming changes to ICH Q1A-Q1F and as more large molecules are put forward as drug candidates, pharmaceutical companies are looking for help with stability studies. A good stability study partner can consult throughout the process, give you confidence in the study design, and keep you up to date with the results.

Broughton has been offering stability services since 2006. Its chambers are controlled via a fully validated data management system in accordance with GMP requirements and ICH harmonized guidelines for stability testing new drug products and substances. The company currently has more than 250 live stability studies.

WHAT IS STABILITY TESTING?

Stability testing is the process of observing products over predetermined lengths of time in specific environmental conditions to determine if there is any change in the quality. When manufacturing FDA-regulated products, there are numerous factors that must be tested before the product is approved and released to the public for consumption. Manufacturers must take great care to observe the influence of various environmental factors such as light, temperature, and humidity on their product. Looking for professional stability testing solutions? Reach out to our team and get a free quote.

What is Pharmaceutical Stability Testing?

Pharmaceutical stability testing is the process by which drug manufacturers collect data on their product over predetermined lengths of time in specific environmental conditions to determine if there is any change in the quality of the Active Pharmaceutical Ingredient (API) or Final Product (FP). The data pharmaceutical manufacturers collect from stability studies is reported to the FDA so the product may be assigned a shelf-life and approved for release to the public. There are varying testing periods a drug manufacturer may be required to report on depending on how far along they are in production, and the FDA looks to the ICH guidelines for stability conditions.

WHY IS PHARMACEUTICAL STABILITY TESTING IMPORTANT?

Pharmaceutical stability testing is important for determining factors such as a product’s shelf life, optimal storage conditions, retest period, and assuring its overall quality for consumers. During a pharmaceutical stability test, manufacturers observe their product for any changes in the physical, chemical, biological, and microbiological makeup of the substance. All of these elements may impact the safety and efficacy of the product for the consumer, so it is vital to conduct extensive testing before putting a drug or cosmetic on the market.

WHO DETERMINES THE GUIDELINES FOR STABILITY TESTING OF PHARMACEUTICAL PRODUCTS?

The stability testing guidelines are set by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). Formed in 1990, the ICH is comprised of regulatory authorities and pharmaceutical professionals for the purpose of discussing scientific and technical aspects of drug registration. As stated on their website, the mission of the ICH is to “achieve greater harmonization worldwide to ensure that safe, effective, and high-quality medicines are developed and registered in the most resource-efficient manner.”

WHAT ARE THE ICH GUIDELINES FOR STABILITY STUDIES?

The ICH sets criteria for stability testing based on three different types of studies: long term stability studies (also referred to as real time), intermediate studies, and accelerated studies. These studies are conducted for different durations of time and are intended to measure a product’s condition at several different stages, such as the length of its proposed shelf life or how it reacts during short-term conditions (e.g. in transport).

The ICH guidelines for the three types of stability testing are as follows:

* It is important to note that it is up to conductors of the stability study to decide the storage condition for the long term stability testing and if 30°C 2°C/35% RH 5% RH is the long term condition, no intermediate testing is required.

In addition to varying the duration of the stability study, the ICH also sets guidelines for stability studies based on the five climatic zones of the world. The ICH stability guidelines are intended to simulate different climatic conditions to ensure a pharmaceutical product’s efficacy and integrity across all regions of the planet.

The following table describes the climatic zones and the recommended long term stability testing conditions:

WHAT IS LONG TERM STABILITY TESTING?

Long term, or real time, stability testing programs subject products to recommended storage conditions and normally utilize a longer monitoring period for degradation to establish product shelf-life. This long term stability testing procedure differs in comparison to accelerated shelf-life testing, which instead exposes products to elevated storage environments. The drug product is monitored under specified storage conditions until it no longer exhibits the expected quality standards. Long term stability testing typically lasts a minimum of 12 months, but may extend beyond that.

Why Would You Need Long Term Stability Testing for Drug Substances?

Long term stability testing is essential for determining the shelf life and storage periods of products under their expected environmental conditions. It provides manufactures and consumers insight as to when products will stop performing as intended. Even if the stability properties of an API are thought to be fully understood, long term stability testing may be utilized if there is a change in packaging or the formulation of the product has been altered.

What Are Accelerated Stability Studies?

In accelerated stability studies, pharmaceutical products are held at exaggerated stress conditions for a period of six months. The elevated conditions are meant to accelerate the rate of decomposition in the product. Conducting accelerated stability studies allows pharmaceutical professionals to then draw conclusions about the shelf life of the product. For instance, if a product holds stable at 40℃/75% RH for the duration of the six-month accelerated study, it can be assigned a shelf life of 24 months. Successful accelerated stability studies can expedite the process of getting a drug on the market, but full approval must be backed by “real-time” data.

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What Are Intermediate Stability Studies?

Intermediate stability studies are not always required, but they may be used if a significant change has occurred to the product at any point during accelerated testing. Intermediate studies are designed to moderately increase the rate of chemical degradation or physical changes for a drug substance or drug product.

How is a Stability Study Conducted?

A stability study is composed of many different tests and involves the careful handling and pulling of samples to precisely record their condition at various points in the study. The ICH recommends collecting stability data for at least three batches of product representative of the final quality of product that will be made to production scale.

Criteria for evaluation during a stability study may include tests for:

• Degradation
• Changes in PH
• Dissolution
• Assay
• Moisture content
• Microbial activity

To store these samples at the designated condition for the duration of the study, temperature-controlled humidity chambers and walk-in stability rooms are utilized to precisely control and maintain the desired set point. Failure to maintain the required condition for a stability study may mean a loss of several months or years of work, so it is of high importance to ensure that the equipment is built to exact specifications and will consistently hold the needed temperature and humidity levels. Read more about best practices for a successful accelerated shelf life test here.

How is Stability Data Evaluated?

Stability data must be thoroughly and accurately documented to be evaluated by regulatory bodies like the FDA. It is critical that pharmaceutical manufacturers have data to back up the findings of their study in the event of an FDA inspection. One of the primary pieces of data to be evaluated is documentation confirming that the required conditions were held consistently for the entire length of the study. If a failure occurred during the study, there must also be documentation of this occurrence to report to the FDA. The process of compiling mapping data for the chamber and documentation proving that stability protocols have been followed every step of the way is known as validation.  Read more about stability protocols and validation requirements here.

The data for stability studies is recorded through the stability chamber’s monitoring system software. The monitoring system provides real-time data on the chamber’s performance for temperature and humidity, C02 levels, uniformity, and any deviations from the designated set points. This data is typically accessible through either a cloud-based or physical company server and will notify the conductors of the study of any changes to the chamber’s conditions.

What Types of Chambers Do You Need For Long Term Stability Studies?

When acquiring a chamber for a long term stability study, pharmaceutical professionals will want to look for equipment that is stable and will reliably hold the specified conditions first and foremost. The equipment should be durable, proven for accuracy through methodic testing, and adhere to ICH standards. When purchasing a chamber for a long-term stability study it is also important to look for safety features such as high and low temperature deviation recognition, remote monitoring system services, and alarm notifications

Some of the most important considerations for purchasing a stability chamber are known as “The Three C’s”

1. Control – A programmable logical microprocessor puts you in control of the chamber. A single multifunction keypad is used for all setpoints. Simplistic – 21CFR Part 11 compliant.
2. Conditioning – Chamber must have uniform distribution of temperature and humidity throughout the interior and be capable of recovery from Open Door and Power Downs.
3. Construction – Foamed in place insulation for low heat transfer, Enamel exterior finish, stainless interior for easy cleaning, self-closing key lock doors, thermostatically controlled anti-condensate heater wire for door gasket.