Shelf Life Recommendations for Supplements 27.11.13

FINAL DRAFT 27.11.13

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Shelf-life Recommendations for Supplements Guidelines for Manufacturers

1. Background Supplements are designed to supplement the diet with nutrients and other substances that exert a physiological effect on the human body. In most parts of the world supplements are, along with dietetic foods and fortified foods, considered to be food products and are subject to food rather than pharmaceutical law. It is a part of good manufacturing practice that a product should meet qualitative and quantitative specifications for all ingredients throughout the product’s shelf-life, and products are generally labelled with a date through which the product’s potency is assured by the supplement manufacturer. A product’s stability is used to determine its shelf-life. For supplements, assurance of product stability is primarily related to the quality of the product and consumer confidence. The essential requirements of product stability for supplements are:

i) To ensure that no untoward organoleptic or other quality changes take place during the proposed life of the product. Such changes could relate to the colour, odour, flavour, texture or other factors related to the deterioration of a product.

ii) To ensure that the product meets the quantitative requirements for all the claimed active ingredients and physicochemical properties of the product throughout the proposed shelf-life.

Supplements are generally composed of active ingredients that have a well-established history of safe use. The activity (potency) of certain ingredients, such as vitamins, can decline over time in supplements. Unlike drugs, for which loss of activity can be a critical medical concern, the loss of activity of supplement ingredients is essentially a quality issue. The stability of such ingredients needs to be taken into consideration during the formulation, processing and packaging of supplements containing one or more active ingredients. Knowledge of the product’s stability is necessary for the accurate assessment of its shelf-life, as it must be ensured that the activity of the ingredients will meet the specifications to the end of shelf life and, hence, the consumer’s expectations. As the stability of active ingredients in supplements can vary, the levels of some may decline over the life of a product. Some ingredients do not deteriorate at the same rate. In, for example, a multivitamin product containing all 13 recognised vitamins, some of the vitamins will be more stable than others and the rate of loss under specified conditions can vary from vitamin to vitamin. An example of the actual percentage loss over six months of four vitamins in a multivitamin tablet packaged in a plastic container is shown in Table 1. A well-established technique employed to overcome variations in ingredient stability is to include an ‘overage’ for the more stability-sensitive vitamins, to ensure that all claimed levels are still met at the end of the declared shelf-life.


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The ‘overage’ is defined as the difference between the formulated and declared levels and is normally expressed as a percentage of the declared value. Thus, an input level of 45mg of vitamin C and a declared level of 30mg would provide an overage of 50%. The amount of ‘overage’ needed varies according to the known stability of the vitamins in the particular product composition, such as carriers, additives etc. (see section 2.3). Table 1 Example of actual percentage losses in a multivitamin tablet after six months in low-density polyethylene (LDPE) plastic containers at 298K (24.85°C) and 75% relative humidity

Vitamin Actual loss (%)

Vitamin A 44.0 Vitamin C 23.0 Vitamin B12 7.7 Folic acid 10.5

Source: Berry Ottaway & Associates Ltd., UK, private communication, 1991


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2. Factors Affecting Shelf-Life There are a number of environmental, chemical and physical factors which can affect the stability, and thus the shelf-life, of supplements and their ingredients. The most important factors are:

• Temperature

• Moisture

• Oxygen

• Light

• pH of the product, particularly liquid products

• Oxidising and reducing agents

• Presence of metallic ions (e.g. iron and copper)

• Presence of other ingredients

• Other components of food, such as sulphur dioxide

• Combinations of the above

The first four of the above list apply to almost every product containing organic (in the chemical sense) active ingredients. Products containing only inorganic mineral salts (such as calcium chloride) tend to be stable. When formulating a supplement product it is recommended that a critical evaluation of the proposed formulation is carried out in order to minimise the degradative effects of the factors listed above, both singly and in combination. It is also important that the form and composition of the packaging is selected to provide a good barrier to moisture, oxygen and light. The importance of the various factors affecting shelf-life is discussed below:

2.1. Chemical Stability:

Different ingredients and supplements have differing degrees of inherent chemical stability, depending on their chemical composition. Some kinds of molecules are very stable; they do not easily react with other molecules and will remain unchanged over long periods of time. For example, minerals such as silica or magnesium phosphate are quite stable, especially if kept away from moisture, and can remain unchanged over decades or longer. These types of molecules are often described as “inert.”

On the other hand, some kinds of molecules are less stable and react relatively quickly with other molecules to form degradation products. For example, unsaturated fatty acids such as eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) may oxidise over the course of a few months (or even less) when exposed to oxygen, especially if heat and/or light is present. These types of molecules may be described as “labile” or “reactive.”


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The inherent stability or reactivity of the chemicals present in a particular ingredient or supplement can often be determined, at least to some extent, through evaluation of the molecular structure of the compounds present. Additional information can be obtained through review of published literature, handbooks, or compendia; from vendors; or through stress testing or other testing (see Appendix II).

2.2. Microbiological Stability:

Different ingredients and supplements have differing susceptibilities to microbiological growth; for example, certain supplements in liquid form may be more susceptible to microbial growth than supplements in solid form. Excessive microbial growth may not only cause microbiological test results to exceed the specifications established for the product, but may also cause undesirable organoleptic and chemical changes.

Ingredients which contain no protein or carbohydrate are often incapable of supporting microbial growth; for example, minerals such as calcium carbonate or iron oxide are unlikely, by themselves, to grow bacteria or fungi. In addition, ingredients with low water activity (i.e. those which are very dry, or which contain high levels of salt or sugar), those which are highly acidic or alkaline (i.e. having a low pH or high pH), or which contain high levels of alcohol are also generally resistant to microbial growth. On the other hand, ingredients which are derived from plant or animal sources, especially if they are hygroscopic (tending to absorb moisture from the air), are more susceptible to microbial growth. In such cases, adequate shelf-life may be obtained by suitably processing the ingredient or supplement to reduce the level of microbes present, and/or by appropriate formulation, packaging, and/or storage to prevent microbes from multiplying to unacceptable levels.

2.3. Formulation: The formulation of an ingredient or supplement often has important effects on the

shelf-life. The most stable formulations are usually those which contain only inert ingredients, such as a trace mineral powder mix or calcium tablets.

Reactive ingredients (e.g. acids, bases, oxidants, or reducing agents) included in a formulation may accelerate the degradation of other ingredients in the product. For example, multivitamin-mineral formulations often include a wide variety of components, many of which can react with each other. Interactions can also occur between hygroscopic ingredients, for example excipients such as sorbitol and glycerol or fill matter containing traces of aldehydes, and the surrounding gelatine capsule, causing the capsules to become brittle and sometimes crack or split. Special steps may need to be taken to ensure adequate stability of these formulas, such as the use of ingredients that are microencapsulated to isolate them from other ingredients. Formulation overages are another means to ensure adequate shelf-life. In this case, the product formulator will intentionally include more of a particular ingredient than is initially needed to meet label claim. For example, if a supplement tablet packaged with a 3-year shelf-life has a label claim for 1.0 mg per tablet of a substance, and the substance typically degrades at a rate of 3% per year, then the formula may be


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designed to contain 1.1 mg of the substance at the time of manufacture. In this case the initial release specification for the product may require 1.1 mg of the substance per tablet, while the stability specification will require only 1.0 mg of the substance remaining throughout the product’s shelf-life (see section 4). Certain ingredients may be added to the formula for specific technical effects that serve to extend the shelf-life. For example, antioxidant ingredients such as butylhydroxytoluene (BHT), rosemary oil or vitamins C or E may be added to protect against oxidation; chelating agents such as ethylenediaminetetraacetic acid (EDTA) may be added to bind reactive metal ions, thereby minimising their degrading (oxidative) effects; and sorbate, benzoate or other preservatives may be added to inhibit microbial growth. The additives that can be used will depend on the national legislation in the country of the intended sale of the product. The legality of these ingredients in the proposed country of market should be checked before use, including whether / how they need to be declared on the label. Finally, tablet coatings and the use of hardshell or softgel capsules may also provide protective barriers to certain factors that affect stability, e.g. moisture, light or oxygen.

2.4. Physical Form:

The physical form of an ingredient or supplement can significantly affect the shelf-life.

Ingredients or supplements in solid form tend to be more stable than in liquid form, as molecules in a liquid are able to move freely and may thereby react with each other. In contrast, the molecules in a solid are less able to move and interact, and are therefore less likely to chemically react with each other. The particle size of a solid also often affects its stability, especially for molecules which are sensitive to light, moisture, or oxygen. The smaller the particle size, the more surface area is exposed to the environment; this leads to more rapid degradation. In contrast, larger particles have less surface area and are therefore usually more stable.

2.5. Packaging and Storage: Certain characteristics of a product’s packaging can affect shelf-life. The container

wall thickness, closure geometry, surface area to volume ratio, headspace to volume ratio, water vapour permeation rate, oxygen permeation rate, and light transmittance or opacity, all have important effects. Data on parameters such as permeation rates, light transmittance etc. may be obtained from the manufacturer of the packaging material. In addition, any packaging components included inside the container, such as desiccants, rayon or oxygen absorbers, may also affect the shelf-life.

The packaging for each product should be chosen based on the anticipated stability of the supplement. For example, supplements that are light sensitive should be packaged in opaque or dark containers, supplements which are moisture sensitive should be packaged in moisture-proof containers and/or with desiccant packs, etc. Information to guide the choice of packaging may be found in the literature,


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recommended by the vendor, or derived from experience with stress tests or other testing of the product (see Appendix II). Product labels should include storage recommendations based on how light, temperature, and humidity affect the shelf-life of the product. Most ingredients and supplements are stable for commercially appropriate lengths of time so long as they are protected from heat. Depending on the product and packaging, it may also be necessary to store the product away from strong light or excessive humidity. Other products require special handling such as refrigeration or freezing; if so, this should be indicated on the product label.

Based on the information above, it is possible to make some generalisations about factors which tend to affect a supplement’s shelf-life. These include:

• Presence of labile constituents in the supplement, especially if a quantitative label claim for those constituents is made.

• Presence in the formula of chemically reactive ingredients, which may accelerate degradation, such as acids, bases, oxidants, or reducing agents.

• Presence of water or moisture in the supplement, which may accelerate both chemical and microbiological changes.

• Supplement being in liquid form, as opposed to solid.

• Smaller particle size of the ingredients.

• Smaller proportion of fill to headspace in the container.

• Packaging which permits light, oxygen, or moisture to penetrate.

• Higher storage temperatures.

It is also possible to make some generalisations about ways to maintain a supplement’s required shelf-life. These include:

• Addition of chemical preservatives to the formula, such as antioxidants or chelating agents.

• Addition of microbiological preservatives to the formula.

• Use of ingredient overages at the time of manufacture.

• Use of ingredients specially designed to minimize reactivity, such as beadlets or microencapsulations.

• Use of desiccants or oxygen absorbing packets inside containers.

• Flushing storage containers with inert gas, such as nitrogen.

• Use of lower storage temperatures such as refrigeration (for example, at 0-3°C), particularly for liquid products.

• Use of processing to destroy microorganisms (e.g. processing with heat, steam, ethanol or ozone under conditions chosen appropriately to avoid excessive chemical degradation of the product).


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• Reducing the number of doses per container, so as to reduce the in-use period. It should be noted that it will often be necessary to reduce not only the number of doses per container but also the overall container size, in order to achieve the intended effect of improving the supplement’s stability.


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3. Stability / Shelf-life Testing The primary purpose of stability testing for supplements is to determine the product’s shelf-life; in other words, it should confirm that the product specification can be met throughout the shelf-life and that there are no obvious or unacceptable organoleptic changes during the declared shelf-life of the product. It is a requirement of good manufacturing practice that a supplement product should be sufficiently stable (chemically and physically) to meet label claims throughout the product’s shelf life when stored and utilised according to the label directions, bearing in mind that some common ingredients in supplements may have varying stability characteristics. The supplement manufacturer is responsible for the determination of the shelf-life based on an assessment of relevant data obtained under conditions similar to those under which the product is likely to be distributed, stored and used. The ideal approach for accurate shelf-life estimation involves conducting a ‘real-time’ study exceeding the time of the required shelf-life at a temperature and humidity simulating the most stressful conditions likely to be encountered. In certain cases, however, real-time studies before a product launch are not commercially viable, and shorter studies are utilised. These are commonly designated ‘accelerated studies’. Accelerated studies are based on the general presumption that the rate of a chemical reaction doubles with approximately every 10˚C rise in temperature. Therefore, accelerated studies involve storing the product at temperatures considerably above the expected ambient storage in the market place. Thus, if the ambient average temperature is 25˚C, the accelerated storage should be at temperatures of 35˚C and above. Accelerated studies can be used to estimate the shelf-life and, under certain circumstances, accelerated studies may be carried out at two or more elevated temperature points. This is particularly important where an extended shelf-life is required and for products containing multiple active ingredients. A study where there is only one temperature point at 10ºC above the ambient may in some cases only provide for an estimate of 2 x accelerated storage time. That is, if the accelerated storage time for certain products is 6 months, the estimated shelf-life is 12 months. While accelerated shelf-life studies can be useful for detecting instability in a product or packaging, there is limited precision in predicting the likely shelf-life unless a number of temperature points are used. It is recommended that real-time stability studies also be conducted in order to confirm the findings of the accelerated stability programme. Stability studies can be carried out for two purposes:

i) To estimate the chemical and physical stability of the product and to ensure that the claimed levels of active ingredients are retained during the intended shelf-life of the product.

ii) To confirm packaging protection and integrity. This is to ensure that the packaging is suitable for the product for the intended shelf-life and that it is not permeable to oxygen, moisture and ultra-violet light.

These objectives are inter-related as packaging integrity affects product stability. A product can be more stable in one package than in another.


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It is recommended that consideration is given to the suitability of the packaging before a product stability study is undertaken. The accuracy of both real-time and accelerated shelf-life studies depends on the selection of representative product ingredients or constituents, or specific product attributes, that can be examined qualitatively or tested quantitatively in relation to the product matrix. Well-characterised quantitative test methods are available from the literature and various compendia for all the vitamins and many other supplement ingredients (see Appendix II). For botanical products that do not declare specific levels of naturally-occurring constituents, a qualitative review of organoleptic attributes of taste, odour and colour may be appropriate to review product stability. In the case when a botanical constituent is declared on the label, a significant amount of analytical work may be needed on the product before a stability study can commence, unless a scientifically valid method is available for quantifying the level of the constituent. For products containing two or more ingredients, different ingredients may degrade at different rates, so reliance cannot necessarily be placed on one single ingredient or constituent; instead multiple assays may be needed. As already indicated, it is recommended that accelerated stability studies alone do not serve as the sole basis for estimating a product’s shelf-life. For products containing multiple ingredients, a single accelerated study provides an approximation of the shelf-life and it should be supported by real-time studies. Other data can consist of real-time experience on similar products or other information on the stability of the ingredients and constituents.


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4. Selection of Parameters for Shelf-life Testing For stability testing, the types of tests appropriate to establish each product’s shelf-life, and what criteria each such test should meet, should be determined. Shelf-life specifications should be established for those attributes which are susceptible to change during storage and which are likely to affect product quality and strength, or potency. The tests and examinations appropriate for any given ingredient or supplement depends on factors such as:

• The nature and specifications of the product;

• The nature and specifications of its ingredients;

• The product’s label claims;

• The product’s packaging and storage conditions. The shelf-life specifications should be documented for each ingredient or supplement. This should include a list of the tests to be performed, test methods to be used and acceptance criteria required for that ingredient or supplement. The group of tests and the criteria for each test result that are used for the shelf-life specification may be different to the tests and criteria for each test result used for initial release of the product at the time of manufacture. This is particularly the case if known changes are expected to occur during storage. There are a variety of types of tests and examinations which may be relevant to establish shelf-life of the finished product:

4.1 Organoleptic Testing: Organoleptic stability tests compare the general appearance, colour, odour, taste

and/or texture of aged product to those of freshly-made product. These tests are useful to evaluate whether the stored product will continue to be acceptable for use in production and/or to the consumer. With well trained and experienced evaluators, organoleptic stability testing is often able to discern more subtle changes than many quantitative chemical tests. Organoleptic stability testing has the advantage of examining the product in its entirety, which – especially for chemically complex materials such as botanicals – may provide a more reliable evaluation of product quality and stability than quantification of merely one or a few marker compounds can reveal.

4.2 Physical Attributes: Many physical characteristics play an important role in product

quality and may be appropriate to monitor for changes during product storage.

a. Significant changes during storage, in moisture content, loss on drying, water activity, and/or average dosage weight may affect the stability of the product. Where such changes are observed, further testing of chemical or microbiological attributes may be appropriate.

b. Disintegration and/or dissolution of tablets and capsules may change over time and may be appropriate to monitor during a shelf-life study.

c. Tablets and capsules may be monitored for changes in friability, hardness and/or seal integrity, as applicable to the product.


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d. Liquids and semi-solids may be monitored for changes in viscosity, pH, clarity, precipitation and/or phase separation, as applicable to the product.

e. Powders may be monitored for changes in re-suspendability, dissolvability and/or caking, as applicable to the product.

f. It may be appropriate to monitor the package integrity of the container-closure system, especially where unusual seals or closures are used or where the packaging serves a special technical purpose.

4.3 Microbiology:

The spectrum of microorganisms relevant to establishing a product’s shelf-life will depend on the type of product and the packaging.

Shelf-life specifications for many products typically include tests for total aerobic

count and yeast and mould. However, other tests may be more suitable for certain types of products; for example, stability tests for probiotic supplements may include testing the viable count of the species claimed on the label; tests for products with a low pH may include testing for Lactobacillus acidophilus and/or other acidophiles; and tests for products packed in a low-oxygen environment may include testing for anaerobes.

Products whose moisture content is too low to support microbial growth (e.g. those with a water activity aw below 0.50) may not require microbiological testing at each time point; it may be sufficient to test at the beginning and end of the shelf-life, if at all. For products susceptible to microbial growth, more frequent microbiological testing may be recommended.

Generally speaking, testing for pathogens in supplements which have been appropriately processed and are homogeneous need not be repeated throughout a product’s shelf-life, provided the batch was tested and found to be free of relevant pathogens at the time of manufacture.

4.4 Quantitative Chemical Tests: Where the content of a particular nutrient, phytochemical, or other chemically-

defined component is claimed on the product label, shelf-life testing should verify that the product maintains an appropriate level of that component throughout the labelled shelf-life.

The law in many countries requires supplements to provide 100% of their claimed

component levels throughout the shelf-life. The content of the claimed component may be determined at multiple time points throughout the product shelf-life, using an appropriate chemical test method.

However, in some cases such component testing may not be possible (e.g. in complex matrices where analytical methods of sufficient specificity and sensitivity are not readily available). Also, it may be unnecessary to test for every claimed component in a complex mixture; rather, it may be acceptable to test for those components known to be less stable and to extrapolate those results to the components known to be more stable.


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Quantitative chemical tests may also be important for other ingredients such as

microbial preservatives, antioxidants or known degradation products. In addition, the content of known components in the formula may be monitored as a guide to the product’s stability, even when no quantitative label claims for those components are made on the product label.

4.5 Chemical Fingerprints: So called “fingerprints” such as those produced from thin layer or high performance

thin layer chromatography (TLC or HPTLC), high pressure liquid chromatography (HPLC), Fourier-Transform infrared spectroscopy (FTIR), or other spectroscopic analysis of complex materials, can give a useful representation of a product’s chemical composition, particularly for products containing botanical ingredients, and may be indicative of product stability.

Criteria may be established to determine how much change in a fingerprint is

acceptable, such as the number of bands which may appear or disappear in a chromatographic fingerprint, or the amount of change allowed in the size or intensity of a peak. Fingerprints provide a broad view of a chemically complex material and may thereby yield more reliable and sensitive stability data than quantitative testing of one or a few marker compounds. To facilitate comparison of chromatograms, software such as Computer Aided Similarity Evaluation (CASE) has been developed.

4.6 Bioassays:

Occasionally, where appropriate, the biological activity of an ingredient or supplement may be evaluated. This type of test is typically conducted in vitro, i.e. in a culture of tissue, cells, or microorganisms, although it may also be conducted in vivo, i.e. in a living organism. Bioassays can be used to examine the effect of ingredients or supplements on macrophage activation, cytokine production, receptor binding, etc. Bioassays can be especially useful where it is known that a chemically complex ingredient or supplement produces a certain biological effect, but it is not known precisely which component(s) of the material are responsible for the effect.

4.7 Impurity Tests: In general, it is not necessary for a shelf-life specification to include tests for

impurities such as heavy metals or pesticides, since these should not change so long as the product is stored properly.

However, there are some impurities whose content may change during storage and

which may therefore be appropriate to be include in the shelf-life study. For example, mycotoxin levels may increase during storage if elevated fungal counts are observed.


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5. Sources of Shelf-life Data Where shelf-life dating is required, the supplement manufacturer should generate or compile data to support the shelf-life assigned to each product under labelled storage conditions. Data to support shelf-life may include the results of organoleptic, chemical, physical, microbiological and other tests and examinations as appropriate to the product. In this context “data” means at least two pieces of relevant information, such as replicated tests or different time points. This data may be extrapolated from existing sources or derived from actual testing. Some examples of existing sources are:-

1) Publicly-available Literature and Knowledge: In some cases the public domain may provide information relevant to the shelf-life of

a particular ingredient or supplement. For example, calcium phosphate is a commonly-used source of calcium in dietary supplements. This ingredient is a mineral and is known to be relatively stable chemically if kept dry. Furthermore, it is known that calcium phosphate does not support microbiological growth. If a calcium phosphate product is packaged in a manner that prevents moisture from reaching the product, and is formulated with other ingredients known to be compatible and chemically and microbiologically stable, then the manufacturer may reasonably assume the product to be chemically and microbiologically stable for at least several years. There is a considerable amount of information in the literature covering the stability of vitamins in supplements. This information also covers formulation issues, such as the interactions between vitamins and other substances in supplements. Similarly, the published literature may include studies examining the stability of a botanical ingredient under a defined set of packaging and storage conditions. Provided the product is the same as that studied and is packaged and stored under similar conditions, and the product formula does not include any substances likely to accelerate the degradation process, the product’s shelf-life may reasonably be assigned on the basis of the published study. A thorough literature search on stability information relevant to the product composition and its packaging should be carried out before engaging in the formulation of the product or initiating stability studies (see Appendix II).

2) Ingredient Manufacturers:

Ingredient manufacturers may be able to provide information and/or data regarding the stability of the ingredients they provide, and this information may provide supplement manufacturers with data relevant to the shelf-life of finished products that contain these ingredients. Such data will generally apply only to the ingredient on its own, and not in combination with other ingredients, and it will generally apply to the ingredient stored in bulk containers, not in unit dose form or retail packaging. However, information provided by the ingredient manufacturer may be applicable to the finished product in certain cases, especially when the retail product contains only one ingredient and/or when the retail packaging is more protective of the material than the bulk ingredient packaging. In contrast, the bulk material is sometimes


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packaged in optimal conditions, for example, using hermetic nitrogen-flushed containers.

When data such as described above are not available or not adequate to support shelf-life dating, the manufacturer of an ingredient or supplement may need to conduct tests or studies to obtain the necessary data. Means to accomplish this may include any of the following:

3) Retesting of Ingredient and/or Product Retained Samples:

Supplement manufacturers should retain samples of each product lot/batch and store the retained samples under conditions similar to those of the commercial product. In addition, supplement manufacturers should retain sufficient samples of each ingredient lot/batch, and ingredient manufacturers may retain samples of their raw materials and products. These retained samples may be retested periodically as appropriate to observe whether any degradation has occurred and if so, how much and in what time frame.

4) Retesting of Ingredients and/or Supplements Remaining in Stock:

Where commercial packages of ingredient or supplements remain in stock over an extended period of time, samples may be tested to observe whether any degradation has occurred and if so, how much and in what time frame. In the case of supplements, this can be a valuable and reliable source of shelf-life data, because it examines the stability of the material under actual commercial storage conditions.

5) Stress Testing:

Stress testing is used to determine a material’s susceptibility to degradation caused by elevated temperature, humidity, light, acidic or basic conditions, and/or oxidising or reducing substances. One common procedure is to store the material in open containers under a variety of temperature and humidity regimes, for example with temperature increasing in 10 °C increments above 35°C and humidity increasing above 75% relative humidity (RH). This type of test is called an “open dish” study and serves as a worst-case scenario because the open container provides little or no protection from the environment. Another common procedure is to store portions of the material in solution or suspension across a wide range of pH values, or combined with a variety of known oxidising or reducing substances to evaluate the effects of acids, bases, oxidants, and reductants on the material. Stress testing is normally conducted over short periods of time ranging from days to a few weeks. The stress test is normally conducted on ingredients, rather than supplements, and is helpful in deciding how best to formulate, package, and label supplements containing the tested ingredient. Stress testing normally does not yield results which can be extrapolated to establish an appropriate shelf-life for the commercial product, except in cases where the product formulation, packaging, and storage instructions are chosen to ensure any sources of degradation identified during the stress test are strictly avoided.

6) Food-type Shelf-life Studies: In the food industry, the shelf-life for many products is established by storing a

packaged product under each of several storage conditions (for example, refrigerated (2 - 4°C), room temperature (25°C), and warm (35°C)) for a defined period of time


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ranging from a few days to several weeks, and evaluating the product over the course of the study. One week of storage at 35°C is commonly assumed to represent one month of storage at room temperature. For foods stored below room temperature, the storage temperatures are adjusted appropriately, and additional stresses such as freeze-thaw cycles may be added. In another type of test, samples are stored in a hermetically sealed chamber saturated with 100% oxygen; since this concentration of oxidation is five times higher than exists naturally in the earth’s atmosphere it has to be assumed that the rate of oxidation under these conditions proceeds five times as fast as under commercial storage conditions. The characteristics examined in these food tests typically include organoleptic characteristics such as flavour and appearance, oxidation if applicable, and microbiology. For foods with carefully defined nutritional characteristics such as fortified cereals, an accelerated study examining nutrient content may be performed as discussed below, but these are not routine for most foods.

7) Long Term Testing: Also known as “real time” testing, long term testing is performed on ingredients or

supplements stored under the same environmental conditions as commercial batches and for lengths of time similar to those recommended for the shelf-life of commercial batches. Examples of long term testing include retesting of retained samples and retesting of ingredient or supplement batches remaining in stock. Real time testing provides more reliable shelf-life information than accelerated testing.

8) Accelerated Testing: Accelerated testing utilises the fact that, in general, the rate of a chemical reaction

doubles with approximately every 10°C rise in temperature. Therefore, accelerated studies involve storage of the product at temperatures considerably above the expected ambient storage in the market place. Thus, if the ambient average temperature is 25°C, the accelerated storage must be at temperatures of 35°C and above. The accelerated studies should be carried out at two or more elevated temperature points, particularly where extended shelf-life is required. A study where there is only one temperature point at 10°C above the ambient may in some cases only give confidence of 2 x accelerated storage time. That is, if the accelerated storage time for certain products is 6 months, the confidence for the shelf-life is only 12 months. Accelerated testing can also be used to evaluate the effect of brief excursions outside the desired storage conditions, for example during transportation. Accelerated testing has the advantage of providing preliminary shelf-life data in a relatively short time frame; however data from accelerated testing should be confirmed through real-time shelf-life testing since the assumptions involved are not always truly predictive. Accelerated testing is typically less predictive where the harsh accelerated conditions cause physical changes in the product, such as melting, softening, cracking, or phase separation or for temperature sensitive active ingredients.

9) In-use study:

In-use studies are used to evaluate the stability of a material in a multi-dose container once the container has been initially opened. The repeated opening and closing of the container increases the material’s exposure to oxygen, moisture, and microorganisms


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that may cause important changes during the period of time the container is used. This is due to the air changes that can take place each time the container is opened to remove a dose. It is recommended that at least 2 batches are studied, with one chosen towards the end of its shelf-life. If the material is sold in different strengths or container sizes, the in-use study examines the configuration in which significant changes are most likely to occur. The study is designed to simulate the actual conditions of use of the product, including the normal environmental conditions of storage and use, the ongoing reduction in fill level during the course of use, and any dilution or reconstitution which occurs prior to use. The appropriate physical, chemical, microbiological, or other specifications are examined at the beginning and end of use as well as at appropriate intermediate time points.


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6. Developing Shelf-life Data As described in section 5, there are numerous sources of data and information that can be used to support the shelf-life date assigned to an ingredient or product. In some cases it is possible to justify the shelf-life based on information in the public domain or available from suppliers. In other cases, the supplement manufacturer may need to develop their own data through various tests or shelf-life studies. Such testing must be customised for each company and each product. Below are some of the key parameters to be considered.

1) Shelf-life Specification: A shelf-life specification document should be created for each ingredient or supplement to

which a shelf-life will be assigned. In some cases it may be possible to develop shelf-life specifications which apply to groups of dietary ingredients or supplements, rather than each individual product. Products in each group should be appropriately similar to each other. The shelf-life specification should include the following:

a. The group of tests and examinations which need to be monitored. b. The method by which each test or examination will be performed.

c. The specifications or requirements which the product must meet at each time point tested.

The group of tests used for the shelf-life specification will usually be somewhat

different than the panel of tests used for initial release of the product at the time of manufacture. In addition, the criteria for each test result may differ between the shelf-life specification and initial release.

For example, where a particular component is known to degrade over time, the

content of that component at the time of manufacture will need to be higher than during the rest of the shelf-life; the shelf-life specification will list the minimum allowed content, while the initial release specification will be proportionately higher (see section 2.3 on overages). Similarly, if the microbial content of an ingredient or supplement is known to increase at a particular rate over time, the total aerobic count and/or yeast and mould count may need to be lower at the time of initial manufacture than during the rest of the shelf-life; the shelf-life specification will list the maximum allowed microbial counts, while the initial release specification will be proportionately lower.

2) Other Documentation:

All sampling, testing of samples, and equipment calibration related to the shelf-life tests or shelf-life study should be documented in accordance with applicable good manufacturing/laboratory practice. Where samples are stored under defined conditions, records of the storage conditions (such as logs or chart recordings) should be similarly maintained.

Where a formal shelf-life study is conducted, supplement manufacturers should

consider writing a formal protocol or plan for the study. Such a stability protocol should describe, at a minimum:


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a. The product(s) to which the protocol applies, including the packaging configuration(s).

b. The objectives of the shelf-life study.

c. The equipment to be used. d. The number of batches of each product to be included in the study.

e. Sampling procedures to be used to obtain samples for the study. f. Storage conditions for the study samples.

g. At what time points the study samples will be tested. h. The test methods to be used (unless already documented in the Shelf-life

Specification). i. Instructions for data handling and calculations.

j. Acceptance criteria for the data. k. Specifications with which the product must comply (unless already

documented in the Shelf-life Specification). l. Instructions for the documentation and evaluation of any deviations from

the established protocol that may occur during the study. m. Names, signatures, and dates of personnel approving the protocol for use.

An alternative to product-specific written protocols is to establish written standard operating procedures (SOPs) which apply to groups or types of products, with each SOP covering one or more of the topics listed above.

Supplement manufacturers should implement either a stability protocol or SOP, in

order to effectively manage the proper collection and evaluation of shelf-life data for various products over extended periods of time.

3) Batch Selection:

The number and type of product batches to be included should be carefully considered. Ideally, three product batches utilising different raw material lots of the active components would be subjected to accelerated testing; this allows for the evaluation of active ingredient variability and, thus, improves confidence in the results.

The batch(es) selected for testing should be at least pilot scale (manufactured using

the same manufacturing procedure as full-scale production batches), made from the same ingredients that will be used in the product, and of comparable overall quality as is usual for the product. As stated above, where multiple batches are tested, they should preferably be manufactured from different lots/batches of ingredient.

With regard to ingredients that are obtained from more than one supplier or source, it

may be appropriate to test one or more batches from each of these. It may also be appropriate to select additional batches for testing or study on an ongoing basis, either once per year or whenever a significant change occurs, such as a change in ingredient vendor or a change in the manufacturing procedure.


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4) Packaging: The material used for shelf-life testing or studies should be packaged in the same

manner as is intended for the commercial storage and distribution of the ingredient or product (including the primary container closure system, the amount of fill and headspace inside the container, the label, and any secondary packaging). If this is not possible, the samples should be packaged using at least the same materials of construction as the commercial material is packaged in (for example, brown glass, high-density polyethylene etc.), and should be proportionately similar in terms of fill level and headspace or appropriately bracketed as described in section 8 below.

5) Sampling: The size and nature of samples to be taken from each batch should be carefully

considered. Where study samples are all taken at the beginning of the study, the quantity must be sufficient to allow completion of all required testing over the course of as many time points as will be tested. On the other hand, where study samples are taken from existing inventory at various time points, the quantity collected need be sufficient only for testing at the given time.

In general, stability samples should be taken using proper sampling procedures to

ensure the material collected is properly representative of the whole batch at the time of manufacture or receipt. However, in cases where samples from existing commercial stock are taken for shelf-life testing, it may be appropriate to select samples from “worst case” conditions such as the warmest location in the warehouse.

The provenance of each sample used in the shelf-life study should be carefully documented in case questions arise. This may include data such as the date of the sampling, the person who took the sample, the sampling SOP(s) used, the total size and number of containers in the batch at the time of sampling, the warehouse or other storage location(s) sampled (where applicable), the number and identity of batch containers from which sample portions were taken, the total size and number of containers in the sample, and whether the final sample represents a composite or single sample. Supplement manufacturers may find it useful to assign a unique identification number to each unique sample taken.

6) Sample Storage Conditions:

Where shelf-life samples are taken at one point in time and then stored for an extended period prior to analysis, careful consideration should be given to the conditions under which the samples will be stored. The chosen storage conditions should, at a minimum, be monitored and documented throughout the storage period; many companies go further and actively control the storage conditions, for example by use of environmental chambers which keep the storage environment within strict ranges of temperature and humidity.

For real-time testing, the samples should be stored under conditions as similar as

possible to those experienced by the product in commercial storage. Most commonly, this means storage at room temperature, i.e. around 25°C, and humidity between 30-70% RH. However, it may be appropriate to conduct long-term testing at 30°C ± 2°C / 65% RH ± 5% RH. This may be warranted where there are large climatic variations


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in the country or where the product is exported to areas with high ambient temperatures. For materials and product intended to be stored and distributed under refrigerated or frozen conditions, the shelf-life conditions should be adjusted accordingly; for example in the drug industry, real time refrigerated studies are typically conducted at 5°C ± 3°C while real time frozen studies are typically conducted at -20°C ± 5°C.

For accelerated testing, samples are typically stored at either 30°C ± 2°C / 65% RH ±

5% RH and/or at 40°C ± 2°C / 75% RH ± 5% RH. Accelerated testing of refrigerated materials is typically conducted at 25°C ± 2°C / 60% RH ± 5% RH. Accelerated testing of frozen materials may be conducted at 5°C ± 3°C or at 25°C ± 2 °C.

If the container closure system has been shown to be impervious to moisture, it may

be unnecessary to monitor or control the relative humidity under which the shelf-life samples are stored.

In the context of sample storage, it is also important to consider the storage of control

samples and samples taken at the various time points in both real time and accelerated testing

As some of the changes in stability can be relatively small between some time points,

sources of analytical variation should be minimised. Differences in analysts, reagents etc. may have a significant effect on the accuracy of the results, particularly when external laboratories are used. One method for minimising these differences is to remove each sample at the appropriate time point, seal in a moisture and oxygen impervious container (for example, a foil pouch) and store at 0 - 2°C. Control samples should also be stored under the same conditions. At the end of the study all samples, both test and control, should be analysed at the same time under the same conditions. However, this method will not be suitable for all cases, as some vitamin losses, for example, may be observed at 0°C (for example, certain forms of vitamin E in particular product matrices).

7) Test Frequency:

The time points at which shelf-life testing will be performed depend on the type of study, the composition of the product and the intended shelf-life of the product or material.

For real time studies of product with long shelf lives (longer than 1 year), testing is

generally performed at least at the beginning (T = 0) and end of the shelf-life. It may be appropriate to test every 3 months throughout the first year (T = 3, 6, 9, and 12 months), every 6 months during the second year (T = 18 and 24 months), and annually thereafter until the end of the shelf-life. For accelerated studies, testing is generally performed at the beginning, middle, and end of a 6-month study (T = 0, 3, and 6 months). In certain cases, it may be considered appropriate to continue the testing beyond the assigned shelf-life, in order to see how long the product may remain stable.

As the degradation of some substances during storage may not always follow a linear

pattern, it is recommended, if all the supplement ingredients are known to be stable


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at very low temperatures, that samples be taken at each time point and stored at 0 - 2°C in impervious containers so that they can be analysed at a later date if required. This may reduce the need to have to repeat substantial parts of the stability study.

If the product has a much shorter expected shelf-life, the time points may need to be

adjusted accordingly and the test frequency measured in days or weeks, rather than months or years.

If experience or other data indicates that a significant change may potentially occur

in the product during the shelf-life testing, it may be appropriate to add additional time points for testing. Conversely, if experience or other data indicates that no significant change is likely to occur in the product during the shelf-life testing, it could be justified to use fewer time points for testing.

If a significant change occurs in the product during the shelf-life testing, such that the

product fails to meet the established specifications, it is generally not necessary to continue the testing or study.

In situations where shelf-life testing is conducted concurrently with commercial

distribution of the product and a shelf-life test failure occurs, the supplement manufacturer should evaluate the situation of any product currently on the market or previously distributed. The reason for the test failure and its potential consequences may help determine the proper course of action. Such actions could include cessation of distribution, relabelling with a shorter shelf-life, notification of customers, withdrawal of previously distributed material or a complete recall of product.

In determining the appropriate action, factors to be considered include the nature of

the test failure, whether it contravenes any applicable laws or regulations (for example, failure to meet label claim or failure to meet specifications for antimicrobial preservatives), whether it is organoleptic (for example, development of off-flavours or an unappetising appearance) and whether it would pose a health risk to the consumer.

Where no significant change is observed during the shelf-life testing, it may be

possible to extend the shelf-life of the material beyond what was originally expected. 8) Bracketing:

Where a company has several products which are identical except for (a) strength or potency or (b) container size or fill, it is generally not necessary to test the shelf-life of every configuration. Rather, a bracketed shelf-life study may be used, in which only the extremes of each factor are tested.

(a) Strength or Potency: Strength or potency may be varied by changing the portion of a formula (e.g. by tableting varying amounts of the same granulation, or by using different metering devices on a bottled liquid) or by changing the proportions within the formula (e.g. by varying the relative amounts of ingredients vs. excipients in the formula). In such cases, the highest and lowest formulated strength or potency of the product may be chosen for shelf-life evaluation.


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Bracketing is not generally advisable where different ingredients or different excipients are used among different versions of the formula.

(b) Container Size or Fill: Where either the container size or fill varies, bracketing can generally be applied so long as the container closure system remains the same. In such cases, the largest and smallest container or the highest and lowest fill level are chosen for shelf-life evaluation.

In cases where both the container size and the fill vary at the same time, it may be

possible to choose appropriate extreme conditions for testing, but it cannot be assumed that the largest and smallest containers represent those extremes; rather, the extremes must be identified through due consideration of all relevant factors, such as surface area to volume ratio, headspace to volume ratio, water or oxygen permeation rate per unit of fill, etc.

Bracketing is generally not appropriate where the materials of construction vary

between different package sizes. If the stability of the extreme cases prove to be different from each other, the shelf-

life of the intermediate cases should be considered to be no more stable than the least stable extreme case.

9) Matrixing: Matrixing can be useful for shelf-life testing where a company has numerous

variations of a formula. In a matrixed shelf-life study, a selected subset of the variants is tested for one attribute at one time point; at the next subsequent time point, a different subset is tested for the same attribute, and so on throughout the study. This study design assumes that the stability of each subset of samples tested is representative of all the samples at that time point.

Matrixing can be applied to design factors such as:

• Different strengths or potencies with identical or closely related formulations.

• Different container sizes and/or fills in the same container closure system.

• Different container closure systems if it can be shown that relative moisture and oxygen transmission rates remain similar.

• Different batches made using the same process and equipment. Matrixing should generally not be performed across different test attributes or across

different storage conditions. The matrixing design should be as balanced as possible so that each combination of

factors is tested equally over the duration of the study. All selected factor combinations are usually tested at the initial and final time points, while only a subset of the combinations is tested at each intermediate time point.

Due to the reduced amount of data collected, a matrixing shelf-life study has less precision and yields a shorter shelf-life than the corresponding full study. Furthermore, use of a matrixing design should be limited to where experience or other information indicates that the shelf-life of the product is predictable. If there is uncertainty or variability, a full study is generally preferable.


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Annex I

Glossary of Terms

Batch See Lot.

Finished product A supplement which has undergone all the stages of manufacture.

Labile constituent A substance that is constantly undergoing or likely to undergo change; unstable.

Light transmittance The ratio of the intensity of the light that has passed through a substance to the intensity of the light when it entered the substance.

Lot A quantity of any supplement produced during a given cycle of manufacture and from a specific formulation order, that is uniform in character and quality (the essence of a manufacturing lot is its homogeneity).

Manufacture The complete cycle of production and quality control of a supplement from the acquisition of all materials through all stages of subsequent processing, packaging and storage to the distribution or release of the finished product.

Manufacturer The person or business that is involved in the manufacture of a finished product.

Overage The quantity of a substance above the amount claimed on the label that is added to the supplement during manufacture to cover losses that may occur from degradation during processing and storage of the product.

Packaging All operations, including filling, sealing and labelling, that a bulk product has to undergo in order to become a finished product.

Packaging material Any material, including printed material, employed in the packaging of a supplement, such as containers, closures, bags, packing, label materials (labels, inserts, etc.), seals, binding materials, adhesives and tapes.

Permeation rate The speed at which a liquid or gas moves into or through a porous or permeable solid over a specified period of time.


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Shelf-life The period during which a finished product retains its specific properties when properly stored.

Stability Ability of a substance to remain unchanged over time under stated or reasonably expected conditions of storage and use.

Water activity (aw) In the context of supplements, water activity is a measure of the propensity for microbiological growth and chemical reactions. The higher the aw, the more unstable the product may be.


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Appendix II

Resources ‘Chemical deterioration and physical instability of food and beverages’. Ed. Leif Skibsted, Jens Risbo and Mogens Andersen. Woodhead Publishing, UK. 2010. ISBN 1 84569 495 3, ISBN-13: 978 1 84569 495 1 ‘Food and beverage stability and shelf life’ Ed. David Kilcast. Woodhead Publishing, UK. 2011. ISBN 1 84569 701 4, ISBN-13: 978 1 84569 701 3 ‘Fundamentals in food chemistry’. Ed. Bimlesh Mann. Woodhead Publishing India. 2012. ISBN-10: 0857091069, ISBN-13: 978 085709 106 2 ‘Global Guide to Good Manufacturing Practice for Supplements’. International Alliance of Dietary / Food Supplement Associations, Belgium. 2011. www.iadsa.org ‘Oxidation in foods and beverages and antioxidant applications Volume 1: Understanding mechanisms of oxidation and antioxidant activity’. Ed. E Decker. 2010. ISBN: 978 1 84569 648 1 ‘Oxidation in foods and beverages and antioxidant applications Volume2: Management in different industry sectors’. Ed. E Decker. 2010. ISBN: 978 1 84569 983 3 ‘Shelf Life Dating of Botanical Supplement Ingredients and Products’. Staci, Managing Editor. The American Herbal Products Association, USA. 2011. www.ahpa.org ‘Stability testing guideline for dietary supplements’. NSF International, USA. 2011. www.nsf.org ‘The stability of vitamins in fortified foods and supplements’. Berry Ottaway P. In ‘Food Fortification and Supplementation’ Ed. Peter Berry Ottaway. CRC Press Ltd., USA. 2008. ISBN 978 1 42007 201 3

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