A clinical study, if conducted with care and for statistical significance, can encounter a substantial investment and often is what consumers ultimately desire. Therefore, it is critical that aspects related to its potential validity are fulfilled prior to planning and conducting it. Sometimes, due to project timeline commitments, manufacturers seek options to accelerate formulation development. Such practice should not compromise stability of the active compounds or the formulation. Cosmetic products are developed with the intention to maintain at least a two-year shelf life. If the formulation tested in a clinical study is a few days or weeks old and the active compound will degrade over time, the results acquired in the study may not be valid for a product that is purchased after two years of being in a warehouse or on a store shelf. Therefore, it is imperative that stability of both the active and the base formulation are ensured.
The term “stability” is used as a comprehensive description of the ability of a product to resist changes in composition and consistency and remain fit and acceptable for use over time. Such changes can adversely affect the performance of the product in providing its intended benefit or efficacy and its aesthetic properties.
A degraded active can create the following issues:
- Become less active or non-active;
- Impart adverse reactions; and
- Cause formulation to develop unpleasant odor, color and/or aesthetics.
The active compound may have exhibited biological activity in an in vitro setting when used fresh and for a short duration under specific conditions. However, when incorporated into a semi-solid cosmetic product, it may undergo degradation or oxidation that will compromise its stability and diminish its activity.
Many cosmetic formulations contain antioxidants that are inherently unstable and lose their original structure when exposed to light or elevated temperatures. It is essential that the formulation is composed with care and if the compound is known to be sensitive, that its stability is studied analytically over time in stability studies. For example, kojic acid, a tyrosinase inhibitor with a skin brightening effect, can oxidize over time, turn brownish and become less effective. Some essential fatty acids such as linoleic and linolenic used to improve skin barrier properties may oxidize as well and become rancid. Before conducting a clinical study, the active should be proven stable in the formulation over time and under its production, filling, packaging and storage conditions.
The stability of raw materials used for cosmetic applications is a key milestone that must be established after the raw material and its composition is characterized. Aged components can vary significantly from fresh ones. Instability and degradation can be accelerated under storage and handling and exposure to variety of conditions such as:
- Temperature variations,
- Exposure to air, and
- Exposure to light.
If the composition of the raw material changes significantly with time it can affect its performance in the formulation and on the skin. Instability may negatively impart performance in the finished formulation and consumer acceptance. Further potential consequence of changes in product composition and consistency is an adverse effect related to product safety such as skin irritation. The design of appropriate stability studies for cosmetic ingredients and finished formulations should be based on knowledge of the behavior and properties and experience gained from other relevant studies. The anticipated changes during storage and the rationale for the selection of attributes to be tested in the stability studies should be stated. Because of the wide variety of products and their inherent complexity, “standard” stability tests cannot be prescribed.
Manufacturers, who have an intimate knowledge of their products and packages, require the flexibility to modify testing protocols and to build a sound scientific basis for assessing product stability. Thus, specific tests may be developed in order to predict possible evolutions of the product, to address new/unusual technologies, or to be adapted to products having extended shelf lives.
The length of time a product remains fit and acceptable for use is termed its “shelf life.” The shelf life of a product carries important logistical and financial implication. It should be sufficient to provide adequate time for manufacturing and distribution, the expected time duration in retail, and the probable length of time the product will be used by the consumer, all under the environmental conditions anticipated in each segment. A product with a relatively short shelf life will require special efforts to accelerate distribution, more frequent re-stocking in retail, and risks of consumer dissatisfaction if it isn’t stable for a reasonable period of time when in the consumer’s possession. While the general parameters established for stability can pinpoint most issues, it typically takes three months to fully test a product and observe instabilities. There are tools for accelerated stability testing, that are correlated with traditional long-term stability. Generally accepted approaches to predict the stability of cosmetics ingredients and formulations include measuring the product’s resistance to common stressors such as temperature extremes and exposure to light. Accelerated temperature testing is often a long-term stability predictor.
The product can be exposed to various conditions for the durations stated and the physical/chemical parameters noted hereafter should be monitored and documented at pre-determined time intervals. At all times a “reference sample” that is either made fresh or maintained under ideal conditions (such as 4°C in the dark under nitrogen blanket) should serve as “control” for parameters tested. For markers analysis, a sample of the designated marker molecule (for example, in a natural product a specific polyphenol) should serve as an additional reference to determine if the composition of the compound serves as a protective environment for the individual components. Samples should be withdrawn at pre-determined time intervals and should be tested for various parameters such as appearance, odor, pH and viscosity. Quantitative data and subjective visual or olfactory observations should be carefully documented on a spreadsheet.
Rushing into a clinical study before full-term stability is established can be costly if the formulation is proven to be unstable during or after the study. Packaging can directly affect finished product stability because of interactions which can occur between the product, the package and the external environment.
Ideally, the finished formulation should be tested in the container of choice for a product launch. Formulation-container interactions may include:
- Interactions between the product and the container (e.g. adsorption of product constituents into the container, corrosion, chemical reactions, migration);
- Barrier properties of the container (its effectiveness in protecting the contents from the adverse effects of atmospheric oxygen and/or water vapor, and in ensuring the retention of water and other volatile product constituents). Stability testing should include packaging which is made of exactly the same material(s) and is as similar as possible in all other respects to the package in which the product will be marketed. If the product will be marketed in several different package types, it is advisable to study each package type. Where there is a range of package sizes, it is advisable to test the product in the smallest container. Appropriate controls (for example, product in glass containers) should be used. It is also customary to test the packaged product in various orientations (upright, inverted or on its side).
Typically, long term stability is conducted at 25 ± 2°C and short term at 40 ± 2°C. If at the accelerated storage condition the product fails to meet the established shelf-life criteria, alternative accelerated conditions may be used to ensure that at minimum, some acceptable accelerated data is available to demonstrate that the product can withstand the typical excursions experienced in the distribution chain once the product is marketed.
When packaged in impermeable containers sensitivity to moisture or potential for solvent loss is not a concern for the compound. Thus, stability studies for products stored in impermeable containers can be conducted under any controlled or ambient humidity condition. If packaged in semi-permeable containers, the product should be evaluated for potential water loss in addition to physical, chemical, biological and microbiological stability. This evaluation can be carried out under conditions of low relative humidity.
If a package allows exposure to light or if sensitivity to light can be imparted during handling and forecasted use, the product should undergo light stability testing. The lighting used in testing should simulate the intensity to which the product will likely be exposed. Photostability testing consists of products in their actual packaging and in glass as a control being placed under controlled light sources with broad spectrum output to account for variations in lighting that may be encountered. The samples are compared with a sample of the product that was not exposed to light to determine if significant changes occurred that were caused by the lighting. This testing may be omitted if a scientific justification can be provided demonstrating that the product in the container closure proposed for market will not be susceptible to photostability effects. The irradiation of the packaged product is to be conducted according to the relevant protocol for photostability testing of products. Generally, not all test parameters are required in order to assess photostability effects. Scientific judgment should be used in order to determine the appropriate subset of parameters required for the photostability assessment.
In summary, this column outlined a few basic concepts to stability testing and its importance in the overall R&D project. Each product, based on its composition, method of preparation, packaging, anticipated market launch and other relevant parameter should undergo a customized evaluation. Instability is linked to inefficacy and potential adverse reactions. It may actually narrow therapeutics window index, meaning reduce efficacy and elevate toxicity. Rushing into a clinical study before stability is fully assessed or not running a full stability scope of work can be costly if the formulation and/or the active is unstable because the study results may not be valid and the product may need to be re-tested.
Dr. Nava Dayan LLC
Nava Dayan Ph.D. is the owner of Dr. Nava Dayan L.L.C, a skin science and research consultancy and serving the pharmaceutical, cosmetic, and personal care industries. She has 25 years of experience in the skin care segment, and more than 150 publication credits.