Food supplements are intended to provide micronutrients and/or other substances with a nutritional or physiological effect in predetermined quantities and in pre-dosed forms. The qualitative-quantitative specifications of all nutrients and substances with nutritional and physiological effects must be guaranteed and the physical and organoleptic characteristics must remain unchanged throughout the shelf life of the product, i.e. until the expiration date indicated on the label. It is important to underline that the stability of products is fundamental not only to guarantee their quality but also to meet the needs and expectations of consumers. Factors capable of influencing product stability are many and include:

• environmental conditions (temperature, humidity, light, etc.);
• possible interactions between components;
• physical characteristics of the product (liquid, solid, size, etc.);
• characteristics of the packaging material (permeability to oxygen and water vapor, etc.).

These variables must be appropriately evaluated during the product design phase in order to adopt all the measures that can contribute to the realization of a plausibly stable formula compatible with the shelf life required by the market. In addition, after starting the distribution of the product, the stability of the product should be monitored with ongoing stability that will permit the detection of any stability issue associated with the formulation in the marketed package, during its period of validity.

The purpose of stability study

Stability studies are aimed at assigning a shelf life to products, verifying the suitability of the packaging materials, evaluating possible interactions between components not anticipated during formulation, and identifying suitable storage conditions for the product.

Long-term studies

The ideal approach to assigning a correct shelf-life involves conducting real-time studies for a period equal to or exceeding the proposed shelf-life. Tests under controlled temperature and humidity conditions are performed with the product in the primary packaging intended for marketing, at temperatures and relative humidity percentages representative of the climatic area of the country where the product will be marketed. Samples are stored for the period specified in the stability protocol in ovens where both temperature and relative humidity are controlled. In order to standardize as much as possible the storage conditions of samples for the execution of long-term studies in different countries, it has been proposed to divide the world into different climatic zones on the basis of the average annual thermo-hygrometric conditions of the different countries. This approach has been commonly accepted and included in the regulatory guidelines and in the Pharmacopoeia of the different countries and has become the standard for the development and market introduction of new drugs.

The ICH (The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) has issued special guidelines to provide guidance on the execution of studies in different climate zones.

According to the ICH Guidelines for stability studies, the climate of the world is divided into 5 different zones, as below:

*For these areas, the specific conditions required for conducting long-term studies for each state are defined by the WHO (World Health Organization).In the nutraceutical sector, ICHs are often used as a starting point for stability studies: the same climatic zones and conditions are used as a reference also in the case of food supplements. However, even if these guidelines are a valid reference point, they should not be considered mandatory.

Accelerated studies

Alongside these studies under standard conditions, there are studies under stressful ones (accelerated stability). These short-term studies are conducted at elevated temperature and humidity in order to increase the speed of chemical and physical degradation processes and analyze the effect of any temperature and/or humidity excursions that may occur during the distribution chain. The data obtained under these conditions can be also used to evaluate the impact of non-accelerated conditions over longer timescales. For accelerated stability testing, samples are generally stored at 40°C ± 2°C / 75% RH ± 5% RH. In case of failure of the accelerated study, intermediate conditions can be adopted. An intermediate study is conducted under less stressful conditions than the accelerated study, but more stressful than those of the long term study (at 30°C ± 2°C / 65% RH ± 5% RH). Sometimes it may be useful to carry out, during the formulation phase, preliminary studies of interactions between components under stressful conditions, to identify possible incompatibilities. As per ICH Guidelines, the minimum time period for an intermediate or accelerated stability study is of 6 months:

**If 30°C ± 2°C/65% RH ± 5% RH is the long-term condition, there is no intermediate condition.

Stability protocol

For correct planning of tests, choice of parameters to be monitored, and subsequent interpretation of data, it is necessary to evaluate the nature of the product and ingredients, the claims intended to be reported on the label, the expected storage conditions. The specifications, intended as a list of tests, analytical methods, and acceptance criteria, are defined in the Stability Protocol shared with the manufacturer and the laboratory of analysis that will conduct the study. A Stability Protocol is a detailed plan used to generate and analyze stability data in support of the shelf life of a Product. It should include time points and conditions employed (climatic zone).

In addition, the parameters that are generally monitored are:

• organoleptic characteristics (aspect, color, smell, taste, …)
• physical characteristics (e.g. humidity; solubility of powders and granulates; hardness, friability and disintegration time of tablets; viscosity and pH of semi-solid or liquid products)
• microbiological parameters (e.g.: total aerobic count, molds and yeasts, absence of pathogens, …)
• quantity of “active” ingredients declared on the label or of the less stable constituents.

Data analysis

At the end of the study, the results must be evaluated, in order to confirm or not the originally expected shelf-life. It is important to underline that the results obtained in accelerated studies are not always predictive; it may happen that reactions that occur in particular thermo-hygrometric conditions, do not occur in standard storage conditions, so it is useful to establish long-term stabilities too. In the case of active constituents that degrade over time, it is a well-established practice to increase the quantity compared to what is declared on the nutritional label; this overdosing ensures that the product specifications are respected until the end of the shelf life. OOS (Out Of Specification, i.e., values that do not meet product specifications) and atypical trends should be investigated in coordination with the Laboratories of analysis.

Stability study in Lo.Li. Pharma International

Lo. Li Pharma International for its Food Supplements entrusts to accountable companies and laboratories with high scientific standards, expertise, and reliable analytical methods to perform long-term and accelerated stability studies.

Lo. Li Pharma International’s products are now available in more than 60 countries worldwide, belonging to different climate zones. Therefore, Lo. Li Pharma International is committed to performing and following up stability studies under different conditions to be able to provide a product to the customer in compliance with the climatic conditions and needs in place.

References:

1. “ICH Guideline for stability” available at <ema.europa.eu/en/documents/scientific-guideline/ich-q-1-r2-stability-testing-new-drug-substances-products-step-5_en.pdf>
2. “EU GMP Chapter 6: Quality Control” available at <gmp-compliance.org/files/guidemgr/2014-03_gmp_chapter_6.pdf>
3. “Guidelines for Pharmaceutical Stability Study” available at <pharmaguideline.com/2012/02/guidelines-for-stability-study.html>
4. “Guidelines on the Quality of Food Supplements” available at <integratoriitalia.it/wp-content/uploads/2019/02/Linee-Guida-Qualità-Integratori-febbraio-2019.pdf>
5. “Stability studies: what are the requirements?” available at <it>