Shelf Life Dating of

Botanical Supplement
Ingredients and Products

Staci Eisner, Managing Editor

July 2011

Prepared by
The American Herbal Products Association

This document is the property of the American Herbal Products Association (AHPA) and is for
AHPA purposes only. Unless given prior approval from AHPA, it shall not be reproduced,
circulated, or quoted, in whole or in part, outside of AHPA, its committees, and its members.
Cite as: American Herbal Products Association. July 2011.
Shelf Life Dating of Botanical Supplement Ingredients and Products. AHPA: Silver Spring, MD.
 Shelf Life Dating of Botanical Supplement Ingredients and Products

Table of Contents

Introduction........................................................................................................... 1

Acknowledgements ................................................................................................ 1

SECTION 1: U.S. Regulations................................................................................ 2

SECTION 2: Shelf Life Tests and Examinations ...................................................... 5

SECTION 3: Factors Affecting Shelf Life ................................................................11

SECTION 4: Sources of Shelf Life Data................................................................. 16

SECTION 5: Developing Shelf Life Data.............................................................. 22

SECTION 6: Handling Shelf Life Issues During an FDA Inspection........................ 29

Conclusion.......................................................................................................... 29

Appendix 1: Glossary .......................................................................................... 31

Appendix 2: Federal Register Excerpt: Remarks of the Food and Drug

Administration Regarding Shelf Life Dating of Dietary Supplements ..................... 33

Appendix 3: References...................................................................................... 36

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 Shelf Life Dating of Botanical Supplement Ingredients and Products

Introduction
This document provides an overview of federal regulations regarding the use of shelf
life dates for dietary ingredients and dietary supplements sold in the United States,
with a particular emphasis on botanical ingredients and products. In addition it
presents various strategies for meeting those requirements.
It is important to note at the outset that neither dietary ingredients nor dietary
supplements are required to be identified with shelf life dates; such that any such
dating is voluntary on the part of companies that market these products. At the same
time, when shelf life dating is used it should be supported by data, though individual
companies may decide what kind and how much data to use to support a stated shelf
life date.
This document is not intended as a detailed step-by-step guide to implementing a
shelf life or stability study. For that purpose the reader should contact an appropriate
expert such as a consultant or laboratory that conducts shelf life studies. While AHPA
believes that all of the information here is accurate, any company that chooses to use
this information is advised to discuss all aspects related to this subject matter with a
qualified consultant, an attorney or with relevant FDA staff.

Acknowledgements
This document was developed under the auspices of the AHPA Standards
Committee with significant involvement from AHPA staff members Steven Dentali
and Michael McGuffin. Thanks are due to the AHPA shelf life working group of the
Standards Committee, consisting of Katie Huggins of Traditional Medicinals,
Alexandra Kameda of Vitamin Research Products, Michael Lelah of Now Foods,
Brad Marr of New Chapter, Helen Oketch of Herb Pharm, Sidney Sudberg of
Alkemist Laboratories, and Jeff Stassi of Covance, that met on numerous occasions
to develop the document. Special thanks are due to Dr. Stassi for creating the first
draft.

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 Shelf Life Dating of Botanical Supplement Ingredients and Products

SECTION 1: U.S. Regulations

Dietary supplement current good manufacturing practice (cGMP) regulations1 do
not require dietary supplement products to bear shelf life, expiration or “best-if-
used-by” (“best-by”) dates (referred to hereinafter as shelf life dating2). In fact, shelf
life dating is mentioned in the cGMP regulations only in the form of the comment
“if shelf life dating is used” in sections related to recordkeeping and sample
retention.3
Furthermore, in the preamble to the 2007 Federal Register notice in which the final
cGMP rule was published, the Food and Drug Administration (FDA) explicitly
states “…the final rule does not require that you establish an expiration date…”4
FDA mentions in this preamble several reasons why any requirement for product
shelf life dating was omitted from the regulations, including uncertainty regarding
the availability and/or validation of analytical methods, and insufficient scientific
information regarding the biological activity of certain dietary ingredients.5
Thus it is clear that use of shelf life dating is entirely voluntary for manufacturers
and packagers of dietary supplements. In addition, should a manufacturer or
packager choose to implement shelf life dating the cGMP regulations themselves
provide no guidance as to how the shelf life should be determined. However, in this
2007 preamble FDA makes a number of remarks on this subject, the first of which
refers to the 2003 proposed cGMP rule.6
“The preamble to the 2003 CGMP Proposal emphasized that, if you use an
expiration date on a product, you should have data to support that date (68 FR

1 21 CFR Part 111.

2 Shelf life dating is the term used in this document and by FDA with respect to the requirements for the keeping
of records, (21 CFR 605(a)) (“You must keep written records required by this part for 1 year past the shelf life
date, if shelf life dating is used, or 2 years beyond the date of distribution of the last batch of dietary
supplements associated with those records”) and the keeping of reserve samples (21 CFR 465(b)) (“You must
retain reserve samples for 1 year past the shelf life date (if shelf life dating is used)”). The terms “Expiration
date,” “best-if-used-by date,” and “best-by date” are functionally equivalent. Although the term “best-by date”
may sound less firm or softer than “expiration date,” FDA makes no distinction between them and requires all
applicable specifications to be met throughout the shelf life designated for the product, irrespective of the
terminology used.
3 21 CFR §111.83(b)(3), 21 CFR §111.465(b), and 21 CFR §111.605(a).

4 72 FR 34856.

5 72 FR 34855.

6 The 2003 CGMP Proposal is FDA’s proposed rule for dietary supplement GMPs, published in 2003. FDA, like

all U.S. regulatory agencies, publishes proposed rules for public comment before issuing significant new
regulations (final rules).

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 Shelf Life Dating of Botanical Supplement Ingredients and Products

12157 at 12204). We recommended that you have a written testing program

designed to assess the stability characteristics of the dietary supplement, and that
you use the results of the stability testing to determine appropriate storage
conditions and expiration dates.”7
FDA’s second statement regarding data to support a product’s shelf life is:
“Because the final rule does not require that you establish an expiration date, we
decline to offer guidance on the type of data that are acceptable to support an
expiration date, other than to repeat that any expiration date that you place on a
product label (including a “best if used by” date) should be supported by data.”8
In the 2007 preamble FDA also summarizes several comments received from the
public regarding the 2003 proposed rule, which include the question of whether
“the required level of supporting data [should be] similar to the requirements for
drug labeling, rather than the requirement for food shelf life labeling.”9 FDA does
not express any opinion regarding this point but does state that “data [to support
shelf life] could come from a manufacturer’s experience with the product or
accelerated stability testing on similar products with the same storage container.”10
Thus, it can be seen that where shelf life dating is used for a dietary supplement:

• FDA expects the manufacturer or packager to have data to support the shelf
life date.

• It is unclear whether FDA expects the manufacturer or packager to have a

formal, written testing program designed to assess product shelf life, since
FDA recommended such a written testing program only in the preamble to
the 2003 proposed rule and did not repeat that recommendation in the
preamble to the 2007 final rule.

• The type(s) and amount(s) of data necessary to support a product’s shelf life
are entirely up to the manufacturer or packager to decide.
Dietary ingredients (as opposed to dietary supplement products) are regulated
under food cGMP11 rather than dietary supplement cGMP. There is no requirement

7 72 FR 34855.
8 72 FR 34856.
9 Ibid.

10 Ibid.

11 21 CFR Part 110.

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 Shelf Life Dating of Botanical Supplement Ingredients and Products

under the food cGMP for dietary ingredients (or for that matter for conventional
food ingredients or finished food products) to be marked with shelf life dates.
Nevertheless, if an ingredient manufacturer uses shelf life dating, customers and/or
regulators may expect the date to be supported by an adequate justification.
Ingredient manufacturers can use much of the information in this document to
develop such a justification and/or data.
Manufacturers of dietary supplements who warehouse ingredients for any
extended period of time would be well advised to ensure each ingredient lot meets
the appropriate specifications at the time it is used in any manufactured batches lest
the finished product fail to meet its required specifications as established under
dietary supplement cGMP.
Although use of shelf life dates is voluntary for dietary ingredients and dietary
supplements sold in the United States, manufacturers of these may nevertheless
find it beneficial and/or necessary to implement a shelf life program of some kind.
This may be due, for example, to requirements imposed by customers or by
regulatory authorities in countries to which ingredients or products are exported. In
addition, the use of shelf life dates serves to minimize the company’s liability since
the use of a date indicates that the manufacturer is only responsible for
requirements such as the quality, strength or potency, freedom from contamination,
suitability for consumption, compliance with current regulations, etc. up until the
stated shelf life date.
An additional benefit to the voluntary use of shelf life dating on dietary
supplements is that the time required under dietary supplement cGMP to retain
written records and reserve samples may be significantly reduced. For example,
reserve samples are required to be retained “for 1 year past the shelf life date (if
shelf life dating is used), or for 2 years from the date of distribution of the last batch
of dietary supplements associated with the reserve sample[s].”12 Similarly, the
many written records that must be made to comply with all of the various sections
of the dietary supplement cGMP must be kept “for 1 year past the shelf life date, if
shelf life dating is used, or 2 years beyond the date of distribution of the last batch
of dietary supplements associated with those records.”13

12 21 CFR 111.83 (b)(3) and 111.465 (b).

13 21 CFR 111.605 (a).

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SECTION 2: Shelf Life Tests and Examinations

Companies should consider what types of tests are appropriate to establish each
product’s shelf life, and what criteria each such test should meet. Shelf life
specifications should be established for those attributes which are susceptible to
change during storage and which are likely to affect product quality, safety, and
strength or potency. The tests and examinations appropriate for any given dietary
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 compiled into a “shelf life specification”
document for each dietary ingredient or supplement, which should include a list of
the tests to be performed, test methods to be used, and acceptance criteria required
for that ingredient or supplement. Acceptance criteria for a shelf life test may be
different than those used for the same test during initial release of manufactured
batches, especially where known changes are expected to occur during storage.14
However, cGMP does not require companies to establish new or additional
specifications (e.g. for quantitative marker content) simply for the sake of
conducting a shelf life study.
There are a wide variety of types of tests and examinations which may be relevant
to establish shelf life.
1) Organoleptic testing. Organoleptic tests compare the general appearance,
color, odor, 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 testing is often
able to discern more subtle changes than many quantitative chemical tests.
Organoleptic testing has the advantage of examining the product in its
entirety, which – especially for chemically complex materials such as
botanicals – often provides a more reliable evaluation of product quality and

14 For example, see section 3-3 below.

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 Shelf Life Dating of Botanical Supplement Ingredients and Products

stability than quantitation of merely one or a few marker compounds can

reveal.
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 indicate a
problem. 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 also be monitored for changes in friability,
hardness, and/or seal integrity, as applicable to the product.
d. Liquids and semi-solids may also be monitored for changes in
viscosity, pH, clarity, precipitation, and/or phase separation, as
applicable to the product.
e. Powders may also be monitored for changes in for resuspendability,
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.
3) Microbiology. The panel 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 mold. However, other tests may be more suitable for certain
types of products; for example, probiotic supplements may require testing the
viable count of the species claimed on the label; products with a low pH may
require testing for Lactobacillus acidophilus and/or other acidophiles ; and products
packed in a low-oxygen environment may require testing for anaerobes.
Products whose moisture content is too low to support microbial growth 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.

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Generally speaking, testing for pathogens in materials 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) 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 labeled shelf life.
FDA requires most foods and dietary supplements to provide at least 100% of their
claimed component levels throughout the shelf life; this is known as the “100%
rule.” However, where the claimed component is naturally occurring and its
content has not been manipulated (e.g. the naturally occurring vitamin C in
powdered acerola berries), FDA allows the content to dip as low as 80% of the label
claim, so long as the product is formulated with the intent to provide at least 100%
of label claim at the time of manufacture.15
In either case, 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 preferable to test for those
components known to be less stable and to extrapolate those results to the
components known to be more stable.
Quantitative chemical tests may also be important for other ingredients such as
microbial preservatives, antioxidants, or known degradation products. In addition,
some companies may choose to monitor the content of known components in the
formula as a guide to the product’s stability, even when no quantitative label claims
for those components are made on the product label.
5) Chemical fingerprints. So called “fingerprints” such as those produced from
thin layer chromatography (TLC), high pressure liquid chromatography
(HPLC), Fourier-Transform infrared spectroscopy (FTIR), or other
spectroscopic analysis of complex materials can give a useful representation

15 21 CFR 101.36 (f)(1) citing 21 CFR 101.9 (g)(4).

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of a product’s chemical composition. Changes in the fingerprint may be

indicative of product aging.
Companies may establish criteria 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.16
6) Bioassays. Where applicable, the biological activity of a dietary 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. One common test is the
antimicrobial preservative effectiveness test, in which the antimicrobial effect
of preservative(s) in a formula is tested against cultures of various
organisms. Other bioassays examine the effect of dietary ingredients or
supplements on macrophage activation, cytokine production, receptor
binding, etc.
Bioassays can be especially useful where it is known that a chemically complex
dietary 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.
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.17
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.
Here are a few examples of test panels for shelf life testing:

16 [Link]
accessed on June 21, 2011.
17 However, if improper storage or handling is suspected or possible, it may be wise to retest existing inventory

for the presence of such contaminants.

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 Shelf Life Dating of Botanical Supplement Ingredients and Products

Example 1: Steamed ginseng root slices packaged in LDPE bags, with no

quantitative label claims made regarding marker content.
In this case, shelf life might be adequately established by testing an appropriate
combination of the following panel of tests at 2 or more points in time: Appearance,
color, odor, flavor, texture (and/or friability), total aerobic count, yeast and mold
count.18 Some companies might choose also to include tests for loss on drying
and/or chemical fingerprint.
Example 2: Ginseng root hard-shell capsules packed in HDPE bottles, with no
quantitative label claims made regarding marker content.
In this case, shelf life might be adequately established by testing an appropriate
combination of the following panel of tests at 2 or more points in time: Appearance,
color, odor, disintegration, total aerobic count, yeast and mold count. Some
companies might choose also to include tests for loss on drying and/or chemical
fingerprint. Depending on the degree and type of processing of the ginseng root
powder, pathogens might also be appropriate to include in the test panel.
Example 3: Ginseng root water/ethanol liquid extract packed in amber glass
bottles, with no quantitative label claims made regarding marker content.
In this case, shelf life might be adequately established by testing an appropriate
combination of the following panel of tests at 2 or more points in time: Appearance,
color, odor, flavor, clarity, total aerobic count, and yeast and mold count. Some
companies might choose also to include tests for viscosity and/or chemical
fingerprint.
Example 4: Ginseng root extract tablets packed in HDPE bottles, with a label claim
for 2 mg ginsenosides per tablet.
In this case, shelf life might be adequately established by testing an appropriate
combination of the following panel of tests at 2 or more points in time: Appearance,
color, odor, friability, disintegration, ginsenoside content (quantitative), total
aerobic count, and yeast and mold count. Some companies might choose also to
include tests for loss on drying and/or chemical fingerprint.

18Arguably, the microbiology tests may not be necessary in any of these examples as long as the loss on
drying (or water activity) is too low or the ethanol content is too high to support microbial growth. However,
AHPA recommends consultation with an appropriate food safety expert before omitting microbiological
monitoring, especially if the company does not have historical microbiological test results on similar products
to demonstrate that microbial growth is not a problem.

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 Shelf Life Dating of Botanical Supplement Ingredients and Products

Example 5: Asian Ginseng Root USP.

In this case, the material must conform to all specifications listed in the USP
monograph for Asian Ginseng throughout its shelf life. In addition, the product
must meet the requirements in the USP Dietary Supplement Chapters, which
mandate use of accelerated and/or real-time shelf life studies. The following panel
of tests may be required as part of the shelf life study: TLC fingerprint, loss on
drying, ginsenoside Rb1, ginsenoside Rg1, total aerobic count, and yeast and mold
count.19

19USP allows some flexibility in designing the shelf life study, where data from similar products are available to
support shelf life estimation.

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SECTION 3: Factors Affecting Shelf Life

There are a variety of factors which affect the potential shelf life of a dietary
ingredient or supplement.
1) Chemical stability. Different dietary ingredients and supplements have
differing degrees of inherent chemical stability, depending on their chemical
makeup. 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 EPA or DHA may oxidize over the
course of a few months (or even less) when exposed to oxygen, especially if
heat is present. These types of molecules may be described as “labile” or
“reactive.”
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 consultation with a knowledgeable chemist who can evaluate 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. These
topics are described in more detail in section 4 below.
2) Microbiological stability. Different dietary ingredients and supplements
have differing susceptibilities to microbiological growth. 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.
Materials 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, materials with low water activity (i.e. those which are
very dry, or which contain high levels of salt or sugar), those which are

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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, materials which are derived from plant or animal
sources, especially if they are hygroscopic (tending to absorb moisture from
the air), are relatively likely to support microbial growth. In such cases,
adequate shelf life may be obtained by suitably processing the material to
reduce the level of microbes present, and/or by appropriate formulation,
packaging, and/or storage to prevent microbes from multiplying to
unacceptable levels.
3) Formulation. The formulation of a dietary ingredient or supplement often
has important effects on the shelf life. The most stable formulations are
usually those which contain (and make label claims for) only inert materials,
such as a trace mineral powder mix or calcium tablets.
If any reactive materials (e.g. acids, bases, oxidants, or reductants) are
included in a formulation, they will usually accelerate the degradation of
other materials in the product. For example, multivitamin-mineral
formulations often include a wide variety of chemicals, many of which can
react with each other. Special steps may need to be taken to ensure adequate
stability of these formulas, such as use of ingredients which 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
dietary supplement tablet packaged with a 3-year shelf life has a label claim
for 1.0 mg per tablet of hypericin, and the formulator knows that hypericin
typically degrades at a rate of 3% per year, then the formulator may design
the formula to contain 1.1 mg of hypericin at the time of manufacture. In this
case the initial release specification for the product may require 1.1 mg
hypericin per tablet, while the stability specification may require only 1.0 mg
of hypericin remaining at the end of the shelf life.
Finally, certain ingredients may be added to the formula for specific
technical effects which serve to lengthen the shelf life. For example,
ingredients such as BHT, rosemary oil, or vitamins C or E may be added for
their antioxidant effects; chelating agents such as EDTA may be added to
bind reactive metal ions, thereby minimizing their degrading effects; and

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sorbate, benzoate, or other preservatives may be added to inhibit microbial

growth.
4) Physical form. The physical form of a dietary ingredient or supplement can
significantly affect the shelf life.
Generally speaking, materials in solid form are more stable than in liquid
form (all else being equal) because molecules in a liquid are able to move
freely around and may thereby react with each other. In contrast, the
molecules in a solid are less able to move around 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.
5) Packaging and storage. Certain characteristics of a product’s packaging can
greatly affect shelf life. The container wall thickness, closure geometry,
surface area to volume ratio, headspace to volume ratio, water vapor
permeation rate, oxygen permeation rate, and light transmittance or opacity
all have important effects.20,21 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 what is known
about the stability of the material. For example, materials which are light
sensitive should be packaged in opaque or dark containers, materials 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, recommended by the vendor, or
derived from experience with stress tests or other testing of the product.
Product labels should include storage recommendations based on how light,
temperature, and humidity affect the shelf life of the product. Most dietary

20 Data on parameters such as permeation rates, light transmittance, etc. is generally available from the
manufacturer of the packaging material.
21 Tablet coatings and the use of hardshell or softgel capsules may also provide protective barriers which affect

the shelf life.

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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 labels.
Based on the information above, it is possible to make some generalizations about
factors which tend to decrease a material’s shelf life. These include:

• Presence of labile constituents in the material, especially if a quantitative

label claim for those constituents is made.

• Presence in the formula of chemically harsh ingredients which accelerate

degradation, such as acids, bases, oxidants, or reductants.

• Presence of water or moisture in the material, which may accelerate both

chemical and microbiological changes.

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

• Smaller particle size of the material.

• 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 generalizations about ways to increase a material’s
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 or freezing.

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 Shelf Life Dating of Botanical Supplement Ingredients and 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 material).

• Reducing the number of doses per container, so as to reduce the in-use

period.22
Most dietary ingredients and supplements are shelf stable at room temperature for
at least several years, so long as they are properly packaged and stored. It should be
noted that many foods, supplements, and dietary ingredients have been shown to
be stable for not just years but even decades.23 In fact, samples of 85-year-old black
cohosh root,24 43-year-old cannabis fluid extract,25 and 100-year-old hoodia26 have
been tested and found to have changed little, both qualitatively and quantitatively,
during their storage period.
On the other hand, certain types of materials may have much shorter shelf lives. For
example, many materials stored and distributed under refrigeration have a shelf life
of only weeks or months. In addition, probiotic materials may be susceptible to
relatively quick loss of potency as the beneficial bacteria die off during storage.

22 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 materials’ stability.
23 See for example [Link]

[Link] and the studies summarized at

[Link] accessed at
June 16, 2011.
24 Jian B, Yang H, Nuntanakorn P, Balick MJ, Kronenberg F, Kennelly EJ. “The value of plant collections in

ethnopharmacology: A case study of an 85-year-old black cohosh (Actaea racemosa L.) sample” J.
Ethnopharmacol. 96: 521-528, 2005.
25 Kurfna, R.K. et al, “Biological and chemical evaluation of a 43-year-old sample of Cannabis fluidextract” J.

Pharm. Sci. 61(1): 114-115, 1972.

26 Sudberg, S. Alkemists Pharmaceuticals, Costa Mesa, CA 92626 Personal communication, May 11, 2010.

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 Shelf Life Dating of Botanical Supplement Ingredients and Products

SECTION 4: Sources of Shelf Life Data

Where shelf life dating is used, the company should generate or compile data to
support the shelf life assigned to each product. Data to support shelf life may
include the results of organoleptic, chemical, physical, microbiological, and other
tests and examinations as appropriate to the product.27
This data may be obtained from existing sources or derived from actual testing,
such as:
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 chemically quite stable 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.28
Similarly, the published literature may contain a study examining the
stability of a botanical ingredient under a defined set of packaging and
storage conditions. So long as the company’s product is the same as that
studied and is packaged and stored under similar conditions, and so long as
the product formula does not include any substances likely to accelerate the
degradation process,29 the product’s shelf life may reasonably be assigned
based on the published study.30

27 By definition, “data” means at least two pieces of information. Merriam-Webster defines “data” as the “plural
of datum…factual information (as measurements or statistics) used as a basis for reasoning, discussion, or
calculation.” [Link] accessed on June 16, 2011.
28 Although chemical and microbiological testing may not be necessary to establish a product’s shelf life, it may

be appropriate to develop data regarding the physical and/or organoleptic stability of the product.
29 Substances likely to accelerate the degradation process are discussed further below under “Stress testing.”

30 See for example Jiang B, Lyles JT, Reynertson KA, Kronenberg F, Kennelly EJ. Stability evaluation of

selected polyphenols and triterpene glycosides in black cohosh. J. Agric. Food Chem. 2008 Oct 22;56(20):
9510-9519.

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 Shelf Life Dating of Botanical Supplement Ingredients and Products

2) Ingredient manufacturers: Ingredient manufacturers may be able to provide

information and/or data regarding the stability of the ingredients they sell,
and this information may provide supplement manufacturers with data
relevant to the shelf of finished products that contain these ingredients. It
must be kept in mind that such data will generally apply only to the
ingredient by itself, not in combination with other ingredients; and will
generally apply to the ingredient stored in bulk containers, not in unit dose
form or retail packaging. However, information provided by the
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.
When data such as described above is not available or not adequate to support shelf
life dating, the manufacturer of a dietary ingredient or supplement may need to
conduct tests or studies to obtain the needed data. Means to accomplish this may
include any of the following:
3) Retesting of ingredient and/or product reserve samples: Dietary
supplement manufacturers are required to retain reserve samples of each
product lot and to store the reserve samples under conditions similar to
those of the commercial product.31 In addition, many supplement
manufacturers maintain reserve samples of each ingredient lot, and
ingredient manufacturers may maintain reserve samples of their raw
materials and products. These reserve samples may be retested periodically
as appropriate to observe whether any degradation has occurred and if so,
how much in what time frame.
4) Retesting of ingredients and/or supplements remaining in inventory: Where
commercial packages of ingredient or supplements remain in inventory over
an extended period of time, samples may be pulled and tested to observe
whether any degradation has occurred and if so, how much in what time
frame. This can be an extremely valuable and reliable source of shelf life data
because it examines the stability of the material under actual commercial
storage conditions.

31 21 CFR §111.83 and 21 CFR §111.465.

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 Shelf Life Dating of Botanical Supplement Ingredients and Products

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 oxidizing or reducing substances.32 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 40 °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 adverse 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 oxidizing 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
dietary 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 package of product under each of several
storage conditions (for example, refrigerated (35 - 40 °F), room temperature
(75 °F), and warm (100 °F)) for a defined period of time ranging from a few
days to several weeks, and evaluating the product over the course of the
study; one week of storage at 100 °F 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 stressors 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 is assumed that the rate of
oxidation under these conditions proceeds five times as fast as under

32 This includes the oxygen present in air, which can cause oxidation in susceptible materials.

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 Shelf Life Dating of Botanical Supplement Ingredients and Products

commercial storage conditions. The characteristics examined in these food

tests typically include organoleptic characteristics such as flavor and
appearance, rancidity (if applicable), and microbiology. For foods with
carefully defined nutritional characteristics such as fortified cereal, an
accelerated study examining nutrient content may be performed as discussed
below, but these are not routine for most foods.
7) Pharmaceutical-type stability studies: In the pharmaceutical industry,
companies are required to perform extensive, formal, fully documented
stability studies on each drug substance and product before FDA will
approve the product to be marketed. The purpose of these studies is to
determine how the quality and strength of a drug substance or product
varies with time under the influence of various well-defined environmental
factors, and to establish shelf life and appropriate storage conditions.33
During these studies samples from multiple batches are exposed to carefully
controlled conditions with respect to temperature, humidity, and light using
validated environmental chambers and are tested at several time points for a
comprehensive set of physical, chemical, biological, and microbiological
specifications at each time point. The chemical specifications applicable to
the drug substance are tested using analytical methods specially validated to
distinguish the target substance from its degradation products, so that only
the target substance is quantified.34 Pharmaceutical-type stability studies can
be costly to perform, but are considered by many to be the “gold standard”
for shelf life testing due to the careful controls used and the extensive data
collected.35
8) Long term testing: Also known as “real time” testing, long term testing is
performed on dietary ingredients or supplements stored under the same
environmental conditions as commercial batches and for lengths of time

33 ICH Topic Q 1A (R2) Stability Testing of New Drug Substances and Products, CPMP/ICH/2736/99, EMEA
2006 available at
[Link]
(accessed on June 16, 2011).
34 An analytical methods is called a “stability indicating method” when it properly distinguishes the target

substance from its degradation products and is able to accurately and precisely quantify the target substance
alone.
35 The International Conference on Harmonization (ICH) guidelines for conducting pharmaceutical stability

studies are also available on the FDA website at

[Link] (accessed on June 16,
2011).

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 Shelf Life Dating of Botanical Supplement Ingredients and Products

similar to those recommended for the shelf life of commercial batches.

Examples of long term testing include retesting of reserve samples, retesting
of ingredient or supplement batches remaining in inventory, and
pharmaceutical-type stability testing performed under the same
environmental conditions as are recommended on the product’s labels. Real
time testing provides more reliable shelf life information than accelerated
testing.
9) Accelerated testing: Accelerated studies are designed to increase the rate of
chemical and physical degradation of an ingredient or product by using
harsh storage conditions such as elevated temperature and/or humidity. In
the food industry accelerated testing of products intended for room
temperature storage is commonly performed on a sample stored at 100 °F for
several weeks, with each week assumed to represent 1 month of real-time
storage. In the pharmaceutical industry, accelerated testing of products
intended for room temperature storage is commonly performed at 40 °C ± 2
°C / 75% RH ± 5% RH, with a 2-year shelf life tentatively assigned to
products which continue to meet all specifications after 6 months of
storage.36, 37 Accelerated testing can also be used to evaluate the effect of brief
excursions outside the desired storage conditions, for example during
shipping. Accelerated testing has the advantage of providing preliminary
shelf life data in a relatively short time frame; however data from accelerated
testing must be confirmed through real-time shelf life testing since the
assumptions involved are not always reliable. Accelerated testing may also
be unreliable where the harsh accelerated conditions cause physical changes
in the product, such as melting, softening, cracking, or phase separation.
10) 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 that may cause
important changes during the period of time the container is used. In-use
testing for pharmaceuticals generally requires at least 2 batches to be studied,

36 This assumption is based on the Arrhenius equation, which predicts a doubling of the rate of chemical
reaction for every 10 °C increase in temperature. However, this rule of thumb only works for reactions with
activation energies of about 50 kJ/mol near room temperature.
37 Accelerated testing at 30 °C ± 2 °C / 65% RH ± 5% RH is also common and is sometimes called

“intermediate” testing.

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 Shelf Life Dating of Botanical Supplement Ingredients and Products

one of which is 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.38 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.

38 See additional information below under “Bracketing.”

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 Shelf Life Dating of Botanical Supplement Ingredients and Products

SECTION 5: Developing Shelf Life Data

As described above, there are numerous sources of the data and information a
company can use 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 vendors. In other cases, companies will need to develop
their own data through various tests or shelf life studies. Such testing must be
customized 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 dietary ingredient or supplement to which a shelf life will be
assigned.39 The shelf life specification should include the following:
a. The panel 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 panel of tests required for the shelf life specification will usually be somewhat
different than the panel of tests required 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. 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
mold 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 proportionately lower.
2) Other documentation. At a minimum, all sampling, testing of samples, and
equipment calibration related to the shelf life tests or shelf life study should

39In 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.

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 Shelf Life Dating of Botanical Supplement Ingredients and Products

be documented in accordance with the normal good documentation practices

used for cGMP compliance. 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, companies should consider writing a
formal protocol or plan for the study. Such a stability protocol should describe, at a
minimum:
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.
While it is unclear at this time whether FDA will require written stability protocols
or SOPs as part of cGMP compliance, from a practical standpoint it is advisable for
companies to implement one or both; otherwise it will be difficult to manage the

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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. In the pharmaceutical industry, it is
commonly required for a minimum of 3 product batches to be subjected to
accelerated testing; this allows evaluation of batch-to-batch variability and
improves confidence in the results. On the other hand, for food shelf life
studies, stress tests, photostability studies, and in-use testing, it is common to
test just one batch. In any case, 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 as is usual
for the product, and of comparable overall quality as is usual for the product.
Where multiple batches are tested, they should preferably be manufactured
from different lots of ingredient. With regard to ingredients that are obtained
from multiple vendors or sources, 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 manufacturing procedure.
4) Packaging. The material used for shelf life testing or studies should be
packaged in the same manner as is used for commercial storage and
distribution of the ingredient or product (including the primary container
closure system, the amount of fill inside the container, the label, and any
secondary packaging). If this is not possible, the samples should be packaged
with the same materials of construction as the commercial material is
packaged in, and should be proportionately similar in terms of fill level and
headspace.
5) Sampling. The size and nature of samples to be pulled from each batch
should be carefully considered. Where study samples are all pulled 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 pulled from existing
inventory at various time points, the quantity collected need be sufficient
only for testing at the given time.

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 Shelf Life Dating of Botanical Supplement Ingredients and Products

In general, stability samples should be pulled 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 inventory are pulled 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 pulled 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
grab sample.40 Companies may find it useful to assign a unique identification
number to each unique sample pulled.
6) Sample storage conditions. Where shelf life samples are pulled at one point
in time and then stored for an extended period prior to analysis, careful
consideration must 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 (75 °F), and
humidity between 30-70% RH. However, some companies conduct long-term
testing at 30 °C ± 2 °C / 65% RH ± 5% RH. For materials 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.

40Composite samples, in which multiple portions of material are removed from various locations in the batch
and mixed together to form a homogenous blend, are useful for examining the average characteristics of a
batch. Grab samples, which each contain only material removed from the batch at a single location or time,
are useful for examining variability within the batch.

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 Shelf Life Dating of Botanical Supplement Ingredients and Products

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. Companies may use other conditions where justified.
If the container-closure system is impervious to moisture, it may be unnecessary to
monitor or control the relative humidity under which the shelf life samples are
stored.
7) Test frequency. The time points at which shelf life testing will be performed
depend on the type of study and the intended shelf life of the material.
For real time studies of materials 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. In
addition, it is common in the drug industry 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.41 For
accelerated studies, testing is generally performed at the beginning, middle, and
end of a 6-month study (T = 0, 3, and 6 months).
If the material has a much shorter expected shelf life, the time points are adjusted
accordingly and the test frequency is measured in days or weeks, rather than
months or years.
If experience or other information indicates a significant change may occur in the
material during the shelf life testing, it is often wise to add additional time points
for testing. Conversely, if experience or other information indicates that no
significant change is likely to occur in the material during the shelf life testing, it is
justified to use fewer time points for testing.
Where a significant change occurs in the material during the shelf life testing, such
that the material fails to meet the established specifications, it is generally not
necessary to continue the testing or study.42 Where no significant change is

41 Some companies continue the testing even beyond the assigned shelf life, in order to see how long the
material may remain stable.
42 Where shelf life testing is conducted concurrently with commercial distribution of the material, in the event of

shelf life test failure it becomes necessary to carefully evaluate the appropriate disposition of any material
currently in the marketplace or previously distributed. A company in this circumstance should carefully
investigate the failure and its potential consequences to determine the proper course of action. Cessation of
distribution, relabeling with a shorter shelf life, notification of customers, and withdrawal of previously
distributed material are all possible courses of action which may be appropriate, depending on the

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 Shelf Life Dating of Botanical Supplement Ingredients and Products

observed during the testing or study, 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 dietary 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.
Bracketing is not generally advisable where different dietary 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 recommended where the materials of construction vary
between different package sizes.

circumstances. Factors to be considered include the nature of the deficiency, whether the deficiency is
substantive (e.g. failure to meet label claim or failure to meet specifications for antimicrobial preservatives) vs.
preferential (e.g. development of off-flavors or an unappetizing appearance), whether the deficiency would
pose a health risk to the consumer, and whether the deficiency would cause the company to be in violation of
any applicable laws or regulations.

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 Shelf Life Dating of Botanical Supplement Ingredients and Products

If the stability of the extreme cases prove to be different from each other, the shelf
life of the intermediate cases should be considered 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, a matrixing design should be used only 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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 Shelf Life Dating of Botanical Supplement Ingredients and Products

SECTION 6: Handling Shelf Life Issues During an

FDA Inspection
AHPA recommends that companies who choose to label their dietary supplements
with a shelf life date compile a written dossier of information to support the shelf
life.
The dossier should begin with the most relevant quote from the Federal Register
preamble (72 FR 34856), “Because the final rule does not require that you establish
an expiration date, we decline to offer guidance on the type of data that are
acceptable to support an expiration date, other than to repeat that any expiration
date that you place on a product label (including a “best if used by” date) should be
supported by data.” This will establish the regulatory context in which the dossier
was created.
The dossier should include the procedures, specifications, data and rationale the
company used to establish the shelf life. The dossier should be marked
“Confidential” on each page and be otherwise in a form and format the company
would feel comfortable producing to FDA as proprietary information, not to be
disclosed under the Freedom of Information Act because it is trade secret
confidential commercial information.
Companies should decide in advance whether they plan to produce the dossier to
FDA during a cGMP inspection or not. The rationale for not producing the data
would be that these are not required records under 21 CFR 111. However, even if a
company decides not to routinely produce the dossier to FDA, there may be
occasions where the company determines it should voluntarily do so. As a result,
the dossier should be kept appropriately complete and formatted at all times.

Conclusion
Dietary ingredient and supplement manufacturers are not required by U.S. cGMP
to assign a shelf life date to their products, but doing so can help ensure product
quality and minimize legal liabilities. Where shelf life dating is used on a finished
dietary supplement, FDA has not established a formal regulation but has stated that
the manufacturer should support the dating with appropriate data. On the other
hand, FDA has provided neither commentary nor regulations in regard to justifying
shelf life dating for dietary ingredients. Nevertheless, ingredient manufacturers
may find it commercially prudent to develop such justification.

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 Shelf Life Dating of Botanical Supplement Ingredients and Products

Data to support product shelf life can be compiled or developed in numerous ways
which range from searching the published literature to conducting formal shelf life
studies. Whichever approach is chosen, it should be consistent with scientific
principles and produce data which is appropriate for the product in question. It is
not possible or appropriate to use a one-size-fits-all approach; the types and
amounts of data necessary must be customized for each product, depending on the
nature of the product and its ingredients, formula, label claims, packaging, storage,
and intended use.
FDA has issued no guidance to clarify its thinking with respect to shelf life dating.
Clearer standards for various types of products may evolve as industry and
regulators gain experience with the new cGMP.

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 Shelf Life Dating of Botanical Supplement Ingredients and Products

Appendix 1: Glossary
Acidic – An adjective used to describe compounds which are chemical acids or
environments containing chemical acids, i.e. having a pH below 7.0.
Acidophile – A microorganism which grows particularly well in an acidic
environment, i.e. an environment with a pH below 7.0.
Active compound – A marker compound which has been scientifically demonstrated
to be responsible for physiologic effects of a botanical. Most botanicals contain
multiple active compounds which combine to produce the botanical’s physiologic
effect(s).
Alkaline – An adjective used to describe compounds which are chemical bases or
environments containing chemical bases, i.e. having a pH above 7.0.
Arrhenius equation – A mathematical equation used in chemistry, which can predict
how fast a chemical reaction will proceed at different temperatures.
Basic – An adjective used to describe compounds which are chemical bases or
environments containing chemical bases, i.e. having a pH above 7.0.
Chelating agent – A molecule which binds to (chelates) metal ions.
Disintegration – A test which measures how quickly a unit dose (e.g. tablet or
capsule) will fall apart under conditions designed to mimic the gastrointestinal tract
(i.e. stomach and intestines).
Dissolution – A test which measures how quickly a unit dose (e.g. tablet or capsule)
will dissolve under conditions designed to mimic the gastrointestinal tract (i.e.
stomach and intestines).
Hygroscopic – An adjective describing materials which readily absorb and retain
moisture from the air or other sources.
Inert – An adjective describing molecules which do not react easily with other
molecules or elements; chemically inactive; unreactive; stable.
Marker compound – A chemical compound which occurs naturally in a botanical
material and which is selected for special attention by a researcher or manufacturer,
as a measure of the identity, quality, strength, stability, or physiologic activity of the
botanical material.

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Labile – An adjective describing molecules which readily undergo chemical change

or breakdown; chemically reactive with other molecules; unstable.
Overage – The extent to which a preparation is formulated to exceed its label claim
at the time of manufacture.
Oxidant – A chemical which takes an electron from other molecules, thereby
oxidizing them; alternately, a chemical which transfers an oxygen atom to other
molecules.
Phase separation – The physical separation of mixed materials such as occurs with oil
and water.
Potency – A measure of the magnitude of a physiologic effect of a preparation,
which in the case of drugs and certain nutrients can be correlated with the level of
individual physiologically active chemicals in the preparation.
Rancidity – The degree to which food, especially food oil, is oxidized.
Reductant – A chemical that transfers an electron to other molecules, thereby
reducing them, in a chemical reaction; alternately, a chemical which causes the loss
of oxygen or the gain of hydrogen in another chemical during a chemical reaction.
Solution – A liquid in which a solid material has been dissolved to form a
homogeneous mixture.
Strength – A measure of the chemical concentration of a preparation.
Stability-indicating method – A test method which distinguishes the target analyte
from its degradation products, and accurately and precisely quantifies the target
analyte alone.
Suspension – A liquid in which a solid material has been dispersed such that fine
particles of the solid are suspended in the liquid.
Water activity – A measure of the amount of free or unbound water available in a
food or other preparation.

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Appendix 2: Federal Register Excerpt: Remarks of

the Food and Drug Administration Regarding Shelf
Life Dating of Dietary Supplements
Federal Register: June 25, 2007 (Volume 72, Number 121)
From the Federal Register (FR): Main Page via GPO Access
([Link]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 111
Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or
Holding Operations for Dietary Supplements
ACTION: Final rule.
Pages 34855-34856
K. Comments on Shelf Life
In the preamble to the 2003 CGMP Proposal (68 FR 12157 at 12203), we stated that
we had considered whether to propose requirements for expiration dating, shelf life
dating, or “best if used by” dating (referred to in this preamble as shelf life or
expiration dating). We recognized that there are current and generally available
methods to determine the expiration date of some dietary ingredients, such as
vitamin C. However, we were uncertain whether there are current and generally
available methods to determine the expiration dating of other dietary ingredients,
especially botanical dietary ingredients. We did not propose to require expiration
dating because we had insufficient scientific information to determine the biological
activity of certain dietary ingredients used in dietary supplements, and such
information would be necessary to determine an expiration date. Further, because
official validated testing methods (e.g., AOAC International or FDA) for dietary
supplements are evolving, especially for botanical dietary ingredients, such
methods are not always available to assess the strength of a dietary ingredient in a
dietary supplement.
The preamble to the 2003 CGMP Proposal emphasized that, if you use an expiration
date on a product, you should have data to support that date (68 FR 12157 at 12204).

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 Shelf Life Dating of Botanical Supplement Ingredients and Products

We recommended that you have a written testing program designed to assess the
stability characteristics of the dietary supplement, and that you use the results of
the stability testing to determine appropriate storage conditions and expiration
dates.
In the 2003 CGMP Proposal (68 FR 12157 at 12204), we invited comment on whether
any final rule should contain provisions regarding expiration dating and the
feasibility of conducting tests needed to support such dates. We also invited
comment on whether to require expiration dating on certain dietary ingredients and
not others, for example, require expiration dating of vitamin, mineral, and amino
acid, but not of botanical dietary ingredients.
(Comment 200) Several comments agree with our decision not to require expiration
dating on labels for dietary supplements at this time, because of the wide range of
products and the need for additional data. Most of these comments state, however,
that manufacturers should be allowed to include a “best if used by” date. One
comment suggests addressing the issue in a separate rulemaking. Other comments
support an expiration date because consumers and retailers expect one, and some
markets require one. Some comments state that the expiration date or statement of
product shelf life will help ensure that the product meets its label claims and
potency.
Many comments state an expiration date on a label must be supported by a
rationale or data on stability testing. Some of those comments suggest that
manufacturers should have flexibility in the type of supporting data used.
Although label claims should be confirmed by shelf life testing when analytical
methods exist, data could come from a manufacturer's experience with the product
or accelerated stability testing on similar products with the same storage container.
One comment points out that some manufacturers already use stability testing.
Another comment recommends that we provide a guidance document on
supporting data.
One comment suggests stringent supporting data are not needed for a “best if used
by” date, because that date provides a recommended time frame to ensure the best
quality. Another comment asserts that the discussion about expiration dates in the
2003 CGMP Proposal gives the impression that the required level of supporting
data is similar to the requirements for drug labeling, rather than the requirements
for food shelf life labeling. Another comment recommends that a general maximum

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shelf life of 4 or 5 years should be included in the rule, with shortened or

lengthened shelf lives for individual products as data become available.
(Response) These comments do not provide data or information that would reduce
the uncertainty about the feasibility of conducting tests to support an expiration
date and, thus, do not persuade us to alter our position not to require that you
establish an expiration date for your product. Indeed, the comments generally
concur with that position. Because the final rule does not require that you establish
an expiration date, we decline to offer guidance on the type of data that are
acceptable to support an expiration date, other than to repeat that any expiration
date that you place on a product label (including a “best if used by” date) should be
supported by data.

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Appendix 3: References
(Accessed June 16, 2011)
“Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or
Holding Operations for Dietary Supplements,” Title 21 Code of Federal
Regulations, Pt. 111. 2010 ed. Available via [Link]
“Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or
Holding Operations for Dietary Supplements; Final Rule,” 72 Federal Register 21
(25 June 2007), pp. 34751-34958. Available via [Link]
FDA Guidance for Industry Q 1A (R2) Stability Testing of New Drug Substances
and Products, ICH, Revision 2, FDA 2003 available at
[Link]
pdf
ICH Topic Q 1A (R2) Stability Testing of New Drug Substances and Products, Note
for Guidance on Stability Testing (CPMP/ICH/2736/99), EMEA 2006 available at
[Link]
/2009/09/[Link]
Nutritional Adequacy and Shelf Life of Food Storage, Brigham Young University,
Woman’s Conference 2005, available at
[Link]
Research on Food Storage, Department Research Archive, Long-Term Food Storage
Archive, Brigham Young University, Food Science, available at
[Link]
[Link]

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