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STIMULI TO THE REVISION PROCESS
Stimuli articles do not necessarily reflect the policies
of the USPC or the USP Council of Experts
Factors to Consider in Setting Adequate Overages of Vitamins and Minerals in
Dietary Supplements
Seong Jae Yoo,a,d Steven L. Walfish,b John B. Atwater,c Gabriel I. Giancaspro,a and Nandakumara
Sarmaa
ABSTRACT
Currently, U.S. law requires that all fortified foods, including dietary supplements, containing a
Class I nutrient, e.g., vitamin, mineral, protein, or dietary fiber must contain, at minimum, 100%
of the label-claimed amount of the Class I nutrient. Thus, it is important for dietary supplement
manufacturers to ensure that the content of nutrients in a dietary supplement meets the
requirement of 100% of the label-claimed amount throughout the shelf life of the product.
Dietary supplement manufacturers typically formulate products to contain nutrients in amounts
greater than the label-claimed amount (i.e., overage amounts or overages) to compensate for
loss due to degradation of the nutrients during the product’s shelf life, and to compensate for the
inherent variability of the manufacturing process and product testing. However, it is desirable for
manufacturers to minimize overages, to help prevent individuals from consuming higher amounts
of nutrients than desired, especially amounts that exceed, without warning, the tolerable upper
intake levels (ULs). The use of USP public quality standards, detailed in compendial monographs,
can assist manufacturers in reducing overages. This Stimuli article discusses factors, such as
nutrient degradation, analytical testing, and manufacturing process variabilities, for dietary
supplement manufacturers to consider when determining overages of nutrients in products.
Furthermore, this Stimuli article recommends several strategies, such as the use of stabilized
ingredients, formulation adjustment by strength, and improved manufacturing processes, to
minimize manufacturing variability that may assist manufacturers reduce nutrient overages in
their products.
INTRODUCTION
The Nutrition Labeling and Education Act of 1990 provided the U.S. Food and Drug
Administration (FDA) with specific authority to require nutrition labeling of most foods regulated
by the FDA. In order to evaluate the accuracy of nutrition labeling information for compliance
purposes, the FDA regulations in 21 Code of Federal Regulations (CFR) §101.9(g)(3) and (g)(4)
defined two classes of nutrients, Class I and Class II. Nutrients are specific dietary ingredients for
which the Recommended Daily Intake or Daily Reference Values have been established by the
Institute of Medicine (IOM) and the FDA, respectively, and include vitamins, minerals, protein,
dietary fiber, total carbohydrate, polyunsaturated or monounsaturated fat, and potassium. Class
I nutrients are those that are added to fortified or fabricated food, and the content of those
nutrients has been controlled in some fashion. Class I nutrient content needs to be at least equal
to the value for that nutrient declared on the label, i.e., not less than (NLT) 100% of the label-
claimed amount. Class II nutrients are naturally occurring nutrients whose content needs to be
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NLT 80% of the label-claimed amount. However, FDA regulations indicate that no action will be
taken against Class II nutrients based on a determination of a nutrient value that falls below the
label-claimed amount by a factor less than the variability that is generally recognized for the
analytical method used on that food at the level involved.
The FDA established specific nutrition requirements and guidelines for nutrition labeling of
dietary supplements in 21 CFR §101.36. In 21 CFR §101.36(f)(1), the regulations state that
compliance with the nutrition labeling of dietary supplements will be determined according to the
nutrient labeling requirements in 21 CFR §101.9(g)(1) through (g)(8), and further stated in 21
CFR §101.36 (b)(3)(i) that the requirements on Class I and Class II nutrients are also applicable
to other dietary ingredients, for which adequate daily values have not been established. Because
the degradation of a dietary ingredient in a dietary supplement is foreseeable, the FDA expects
that manufacturers will take this into account when formulating dietary supplements with dietary
ingredient overages, while adhering to dietary supplement Current Good Manufacturing Practices
(GMPs). Consequently, the acceptance criteria that the FDA considers to be acceptable for dietary
ingredients are variable at the lower acceptance limit, based on analytical method variability (for
Class II nutrients), and at the upper limit based on reasonable excesses of dietary ingredients
due to manufacturing variability and the degradation to an extent considered acceptable within
GMPs (for Class I and II nutrients). An alternative approach was proposed by the Council for
Responsible Nutrition, who petitioned the FDA to recognize the 90% minimum acceptance criteria
to provide the expected level of a dietary ingredient, as in the United States Pharmacopeia
–National Formulary (USP–NF) monographs, given the inherent variability in manufacturing and
analytical testing (1).
Dietary supplement GMPs (21 CFR §111) require a manufacturer to use manufacturing
processes in a manner that will ensure that a product meets established specifications. As stated
in 21 CFR §111.210(e), GMP regulations require master manufacturing records to include a
statement of any intentional overage amount of a dietary ingredient. The amount of overage
should be limited to the amount needed to meet the weight or measure of each dietary
ingredient that will be declared on the supplement facts label of the dietary supplement (2).
Although the GMPs retain a requirement to state any intentional overage of a dietary ingredient,
it does not require the manufacturers to provide an explanation on how the overage amount was
determined.
USP–NF monographs define the quality of dietary ingredients and dietary supplements in terms
of science-based specifications (analytical methods and specific acceptance criteria) for the
identity, composition/ assay, and limit for contaminants. These public standards allow for
analytical variability and for degradation of dietary ingredients to the extent considered
acceptable under practical conditions. An official article must be formulated with the intent to
provide 100% of the quantity of each dietary ingredient declared on the label. In most cases for
a dietary supplement containing a single dietary ingredient, the USP–NF monograph acceptance
criteria are set at NLT 90.0% and not more than (NMT) 110.0% of the declared amount on the
label. However, per USP General Notices and Requirements, 4.10.20. Acceptance Criteria (3),
where the minimum amount of a substance present in a dietary supplement is required by law to
be higher than the lower acceptance criterion allowed for in the monograph, the upper
acceptance criterion contained in the monograph may be increased by a corresponding amount in
the U.S. Therefore, for example, although the USP monograph states that Folic Acid Tablets (4)
contain NLT 90.0% and NMT 110.0% of the labeled amount of folic acid, because of federal
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regulations in 21 CFR Part §101.9(g)(3) and (g)(4), the acceptance criteria become NLT 100.0%
and NMT 120.0% of the labeled amount of folic acid to meet the federal regulations.
USP has established public standard monographs for dietary ingredients and dietary
supplements, such as tablets or capsules containing a single vitamin or mineral as well as
multiple vitamin and mineral combinations. The lower and upper acceptance limits of dietary
ingredients are stated in the monographs to maintain the quality and accuracy of the content in
the dietary supplement against the declared amount on the product label. For example, the
acceptance criteria for Ascorbic Acid (5) as a dietary ingredient are NLT 99.0% and NMT 100.5%
of ascorbic acid (C6H8O6). Dietary supplement products that claim compliance with Ascorbic Acid
Tablets (6) should contain NLT 90.0% and NMT 110.0% of the labeled amount, whereas the
content of ascorbic acid in Water-Soluble Vitamins Tablets (7) should be NLT 90.0% and NMT
150.0%. The range of the lower and upper limits is wider in Water-Soluble Vitamins Tablets (7)
to account for the increasing complexity under practical conditions and the stability of the
ingredient while maintaining the accuracy of the label. In these defined limits, proper overages
based on scientific assessment, such as stability profile and/or testing variability, have been
incorporated into the upper and lower limits in the USP monographs.
As analytical instrument technology has evolved in recent decades, the variability of results
from test procedures using advanced analytical instrumentations, such as high performance
liquid chromatography or gas chromatography, has been smaller than with previous results using
quantitative microbiological assays. USP acknowledges that, as a part of the USP monograph
modernization activities, the lower and upper acceptance limits in the current USP monographs
for dietary ingredients and dietary supplements need to be adjusted to account for the
advancement of current analytical instruments that have reduced testing variabilities. Revision of
these USP monographs to adjust the lower and upper acceptance limits requires scientific
justification based on supporting data, followed by a period of public review and comment, and
subsequent approval by an Expert Committee composed of independent experts from
government, academia, and industry.
Since USP monograph acceptance criteria are defined for each dietary ingredient based on the
review of available information and public comment, the adoption of USP standards will help
ensure the quality of dietary ingredients and promote transparency among the users of the test
methods and acceptance criteria for the selection of quality ingredients used in the
manufacturing of dietary supplements. Accordingly, USP standards can help control any
uncertainty with the quality and the analytical variabilities of incoming raw materials.
Understanding health risks associated with an excessive overage is critical to ensuring that the
final dosage form of a dietary supplement is safe for consumers. For example, excessive intake of
vitamin D above the upper intake levels (ULs) for an extended period of time can lead to
nonspecific symptoms that may include anorexia, weight loss, polyuria, and heart arrhythmias.
This situation could eventually cause more serious adverse events over time, such as vascular
and tissue calcification with subsequent renal and cardiovascular damage, as well as increased
risk of pancreatic cancer (8). As another example, significantly higher amounts of folic acid above
the tolerable ULs may mask and potentially delay the diagnosis of vitamin B12 deficiency.
Eventually, it may lead to an increased risk of progressive, unrecognized neurological damage
(9).
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Tolerable ULs established by the IOM are the highest levels of daily consumption of nutrients
within which any adverse health effect is unlikely to take place in almost all individuals in the
general population, based on scientific data (10). Also, the UL is meant to be a caution against
excessive intake of nutrients for an extended period of time, which could lead to undesirable
health risks in the general population. The IOM has established ULs for vitamin A, vitamin C,
vitamin D, vitamin E, niacin, vitamin B6, folate, and choline. ULs have also been established for
boron, calcium, copper, fluoride, iodine, iron, magnesium, manganese, molybdenum, nickel,
phosphorus, selenium, vanadium, zinc, sodium, and chloride. The ULs established by the IOM
vary by gender, age, and status of pregnancy and lactation. For example, the safety profile of a
vitamin D supplement containing an overage of 20% above the label claim of 400 IUs (i.e., the
adequate daily intake) is different from a product also containing a 20% overage but with a label
claim of 4000 IUs (i.e., the UL).
In March 2015, the Dietary Supplement Ingredient Database (DSID) team, Nutrient Data
Laboratory, Agricultural Research Service at the U.S. Department of Agriculture made available
to the public regression results and research summaries on studies of adult, children's, and
nonprescription prenatal multivitamin/mineral (MVM) dietary supplements (11) that were
purchased in 2006–2007, 2008, and 2009 at mass market and natural health retail stores and
from the internet. The objective of these studies was to estimate the relationship between label
claims and analytical test results for vitamins and minerals, and to improve dietary intake
assessments by providing analytical estimates of the ingredient content of marketed dietary
supplements (11). Among the nutrients tested, vitamin D had mean models for overages in both
children's and nonprescription prenatal at 36.3% and 13.1% above the label claim, respectively.
Thiamin has a below label mean model for the nonprescription prenatal MVMs at −9.2% of the
label claim, a mean model for overages for children's MVMs at 8.6% above the label claim, and a
linear equation for adult MVMs predicted percent differences ranging from −6.5% to 8.6% of the
label claim. At the most commonly labeled amounts, mean overages >15% above the label claim
were predicted for vitamin A, vitamin B12, vitamin D, folic acid, calcium, chromium, iodine,
manganese, and selenium in one or more of the three MVM studies (adult, children, and/or
nonprescription prenatal).
These results indicate that products labeled at or above the UL were among those analyzed in
one or more of the MVM DSID studies for seven ingredients (vitamins A, vitamin B6, folic acid,
niacin, iron, magnesium, and zinc). However, even for the labeled levels at the UL, overages
were still measured for some ingredients. For example, the labeled range of niacin in the adult
MVMs is 5–150 mg/serving while the UL for niacin is only 35 mg/day. Using the online calculator
and based on predictive models, adult MVM products labeled at 150 mg/serving of niacin were
expected to contain an average of 152 mg/serving of niacin with a 95% confidence interval (CI)
of 148.3–155.7 mg/serving, and for an individual adult MVM product, the 95% CI for niacin is
112.8–191.2 mg/serving [95% CI = mean ± (SE × 1.96)]. Based on the DSID findings, it was
suggested that overage of nutrients was a common practice in the industry and that there were
challenges in maintaining label accuracy in some dietary supplement products being marketed.
Also, consumers should be aware of any potential risks associated with excessive intakes of
vitamins and minerals, especially if a product contains any vitamins or minerals above the ULs.
FACTORS AFFECTING OVERAGES
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Overages for dietary ingredients in a product formulation are typically determined based on the
anticipated loss of dietary ingredients due to degradation during the shelf life, as well as inherent
variabilities in the manufacturing process and product testing. The chemical nature of the
ingredient, the consistency in the manufacturing process, the dosage form type and/or product
packaging type are factors that alone or in combination can affect the necessary overages
needed to ensure the product meets 100% of the label-claimed amount of the nutrient
throughout the product's shelf life. Ingredient variability does not necessarily need to affect
overages in product formulation, since it can be offset by formulating a product based on the
strength of the ingredient. However, ingredient variabilities likely affect the upper acceptance
limit of dietary ingredients specified on the final product specifications as a product-release
criterion to the market, because the manufacturers typically design the formulation based on the
lower acceptance limit of ingredient purity specified on the ingredient specification release
criterion.
Degradation Nature of Vitamins
Some dietary ingredients, including several vitamins in certain dosage forms or packaging
conditions, may be susceptible to degradation or deterioration and may not remain in their native
form over the shelf life of the product. Degradation or deterioration of dietary ingredients is one
of the major factors that lead manufacturers to require overage amounts of dietary ingredients in
their dietary supplements. There are several chemical reactions that can cause dietary
ingredients to deteriorate over time. Oxidation is one of the major degradation pathways for
some vitamins, including vitamin A, vitamin C, vitamin D, and vitamin E. Typically, oxidative
degradation is accelerated under conditions of increased humidity and temperature, as well as in
the presence of transition metals (e.g., iron and copper), especially in dosage forms with high
moisture contents such as liquids, soft gelatin capsules, or gummies. Acidic conditions (i.e., low
pH) during manufacture of the final dosage form also affect the stability of vitamins such as
vitamin B5 (pantothenic acid) and folic acid in acidic dosage forms, such as gummies. Basic
conditions (i.e., high pH) can also affect the stability of vitamins; for example, thiamin becomes
increasingly unstable as alkalinity increases in product matrices with high moisture content.
Degradation of vitamin B12 (cyanocobalamin) can be accelerated in combination with vitamin B1
and vitamin B3 in matrices with high moisture content. Stability characteristics and degradation
pathways of vitamins were summarized by Deritter (12). Long-term stability studies, under
conditions that simulate realistic packaging and storage conditions, provide a reasonable means
of determining potential losses of dietary ingredients due to degradation up to and even beyond
the stated shelf life of dietary supplements. Based on an assessment of the resultant stability
data, overage amounts of dietary ingredients can be added to a product formulation to
compensate for degradation losses over the shelf life of the product. Supplement manufacturers
are responsible for assessing the stability of all dietary ingredients in their product formulations
and establishing proper overages in order to compensate for losses during the shelf life of the
dietary supplement product.
Process Variabilities
Dietary supplement GMPs emphasize, in 21 CFR §111 subpart E: Requirement to Establish a
Production and Process Control System, that manufacturers should monitor critical in-process
control points to ensure the consistency of product quality. The critical in-process control points
should be identified, and frequency of testing should be specified in the manufacturer’s written
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standard operating procedures. Master manufacturing records and executed batch production
records should document the process variables to ascertain the production of quality products in
compliance with GMPs. Poor in-process control or the failure to comply with established
procedures can result in serious consequences, including batch rejection or unintentional high
overages of dietary ingredients in the finished dietary supplement. A comprehensive approach
should be established to ensure product consistency, including monitoring the weight variation or
the content uniformity of the products at appropriate time points [see Weight Variation of Dietary
Supplements 〈2091〉 (13)].
Analytical Testing Variabilities
Manufacturers need to consider analytical testing variability when calculating overages in
dietary supplements, especially for multivitamin and multimineral supplements containing
microgram levels of nutrients per serving. Micronutrients, such as vitamin B12, biotin, folic acid,
chromium, and iodine, at extremely low concentrations and in complex product matrices that
cause interference with test responses, lead to high variability in test results, thereby affecting
both test method accuracy and precision. This is an important factor for consideration when
setting high overages. Dietary supplement GMPs, in 21 CFR §111.320(b): What requirements
apply to laboratory methods for testing and examination?, require manufacturers to use
“scientifically valid methods” that are accurate, precise, and specific for its intended purpose, for
testing any incoming raw ingredients and finished products. It is the manufacturers’ responsibility
to establish scientifically valid methods when compendial methods, such as USP monograph test
methods, are not available.
Validation of Compendial Procedures 〈1225〉 (14) provides manufacturers with guidance as to
how to establish testing procedures that are precise, accurate, specific, and robust. Quality by
design (QbD)-based experiments can facilitate method optimization in developing robust
methods by identifying, reducing, and controlling sources of analytical variability. Poorly
designed, poorly optimized, and non-validated test procedures result in highly variable test
results. Due to high variability of assay test results, manufacturers are often compelled to
increase overages to avoid the failure of products not meeting 100% of the label-claimed amount
of a dietary ingredient at both the time of product release to market and throughout the
product’s shelf life. For minerals at trace levels, such as with microgram amounts of selenium or
chromium per serving in supplements having complex matrices, the sensitive and reproducible
test methodology of inductively coupled plasma mass spectrometry has helped to reduce
uncertainty in test results, thereby allowing the acceptance limit range for microminerals to be
reduced.
Ingredient Variabilities
Dietary ingredient preparations that are prone to degradation are often manufactured to
contain high overages to compensate for any losses during transportation and storage prior to
use in the manufacture of dietary supplements. Although the high overages help ensure that the
ingredient preparation will comply with its specification, higher allowable overage may result in
high variability of ingredient strength, which directly and negatively affects dietary supplement
consistency (i.e., batch-to-batch variations in strength). This can lead to unintentional excessive
intake of dietary ingredients when consumed and can be a risk to consumer health.
Manufacturers often need to set high upper specification acceptance limits for dietary ingredients
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to encompass the variability of the content of the dietary ingredient in the component
preparation, because a finished product that fails to meet the specification must be rejected,
according to 21 CFR §111.123(b). Nevertheless, it is the manufacturer’s responsibility to ensure
that the upper limits of nutrients in a dietary supplement are below the ULs, to avoid any adverse
consequences resulting from use by consumers. Variability of dietary ingredient components can
be managed by setting up both a lower and upper acceptance limit for the content of the dietary
ingredient rather than just a lower acceptance limit. However, if consistency of the content of the
dietary ingredient in the component preparation cannot be tightly controlled, consistency in the
content of the dietary ingredient in the supplement can be achieved through formulation
adjustment on a batch-by-batch basis, following the determination of the content of the dietary
ingredient in the batch of the component preparation to be used in product manufacturing. To
maintain label accuracy, USP encourages manufacturers to implement a process of formulation
adjustment for each manufactured batch of dietary supplements that will help ensure the
consistency in the strength of the dietary ingredient.
DETERMINATION OF OVERAGE FACTORS
A systematic approach is needed for determining the necessary overage amount of a dietary
ingredient, to ensure that the dietary supplement meets 100% of the label-claimed amount of
that dietary ingredient. This systematic approach would allow dietary supplement manufacturers
to not only determine the factors for overage calculations, but also to better understand variables
from manufacturing processes, ingredients, and products that might be controlled to reduce the
overage amount. First and foremost, scientifically validated test procedures must be in place
prior to any assessment of losses due to degradation of dietary ingredients in a finished dosage
form. Without reducing and minimizing variability that is attributable to test results, it will be
difficult to separate that variability from any variability due to the manufacturing process and to
dietary ingredient deterioration.
Determination of Degradation Losses during the Shelf Life of the Dietary Supplement
Potential losses of dietary ingredients in finished dosage forms in a package during the shelf life
can be assessed by performing either long-term or accelerated stability studies under
standardized conditions of temperature and humidity, such as conditions described in the
International Conference on Harmonisation (ICH) Q1 guideline (15). The purpose of stability
studies is to establish a shelf life and label storage conditions applicable to all future batches of
the dietary supplement that are manufactured and packaged under similar circumstances.
Stability studies should be performed under long-term conditions [25 ± 2°/60 ± 5% relative
humidity (RH)]. Stability test samples should be obtained from full scale production batches and
packaged in the same or similar packaging configuration representative of the marketed product.
An adequate number of commercial batches of product, preferably a minimum of three, should
be tested for stability assessment to determine the rate of dietary ingredient degradation and
loss. If full scale production batches are not initially available, laboratory or pilot batch samples
(preferably no smaller than one tenth the size of a commercial batch) can be used to obtain an
initial understanding of the stability of the dietary ingredients.
In order to quickly estimate a shelf life for the product without having to wait as long as the full
shelf life of the product, stability assessment can be conducted under accelerated conditions.
There are at least two different standard stability conditions typically employed, i.e., intermediate
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conditions (30 ± 2°/65 ± 5% RH) and accelerated conditions (40 ± 2°/75 ± 5% RH) (15).
Although intermediate and/or accelerated stability studies are useful for making a reasonable
assessment of the product’s stability, long-term studies should be performed for confirmatory
purposes. The primary purpose of accelerated or intermediate stability studies is to evaluate the
effect of short-term excursions outside the label storage conditions that could occur during
shipping.
Procedures for stability testing must be scientifically valid as well as stability indicating. Prior to
the execution of a stability study, a protocol should be created specifying the batch ID,
specifications, storage conditions, sample size, testing frequency, and container–closure system.
A degradation trend can be assessed with an adequate number of time points (NLT three time
points). A simplistic way to assess degradation losses using a confidence interval is to draw a
trend line at designated time points using statistical software. The subsequent degradation loss,
using the trend line, can be calculated at a specific time point against the initial amount that had
been tested at the beginning of the study, rather than the theoretical values of formulation
inputs.
Determination of Testing Variabilities
Variation denotes the bias and dispersion from the overall mean value for the data set.
Commonly, variation is expressed as a variance or relative standard deviation (RSD). Variation
can result from the analytical test procedure or the manufacturing process including sampling for
a dietary supplement. In order to determine the impact of the variability to build further
confidence levels, an appropriate number of samples (n) should be tested using the formula:
Variability = s/√n
s = standard deviation of the means
n = size of samples
Chapter 〈1225〉 (14) defines validation of an analytical procedure as the process by which it is
established, by laboratory studies, that the performance characteristics of the procedure meet
the requirements for the intended analytical applications. Chapter 〈1225〉 (14) and ICH Q2R1
(16) explain the characteristics necessary for an analytical method to be validated.
The purpose of an analytical method validation is to provide experimental evidence that the
factors that impact the uncertainty associated with measurements are sufficiently controlled,
such that an acceptable level of measurement uncertainty based on the method’s purpose can be
met with confidence. The two most important elements of analytical variation are the accuracy
and precision of the test method. Accuracy is defined as the difference between the measured
result and the corresponding true value (i.e., standard value). In statistical terms, accuracy
consists of the true value plus systematic bias and random error. The random error is the
intermediate precision of the method.
It is the manufacturer’s responsibility to determine the testing variability as well as acceptance
criteria to determine if the method is suitable for its intended purpose. For an example, testing
variabilities can be determined through spike-and-recovery studies that are typically performed
to demonstrate the accuracy of the testing method with defined acceptance criteria during the
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method validation. Dietary ingredients can be spiked into separate placebos at various levels.
The root mean squared error at the spiked levels can be determined as a testing variability with
an adequate number of replicated tests (17).
Determination of Process Variabilities
Process variation is the inherent variability seen in the measurements attributed to factors
during the manufacturing process. Chapter 〈2091〉 (13) covers methods for testing weight
variation of dietary supplements for assessing acceptability of a batch of material. Other
performance tests, such as disintegration or dissolution testing [see Disintegration and
Dissolution of Dietary Supplements 〈2040〉 (18)], provide a measure of manufacturing quality
control. An extension of this would evaluate the overall process capability across multiple batches
to estimate the probability of a batch or content in an individual unit being outside the
specification. Process capability indices measure how close the process average is to the
specification. Tolerance intervals are another tool that provides insight into the distribution of the
individual values from a lot. The manufacturer should be able to determine variabilities of
blending, weighing, dosage weight, and content uniformity following well-designed studies.
Determination of Overages in a Dietary Supplement
Manufacturing process and measurement variability can be utilized to model the expected
distribution of any critical quality attributes of the finished dosage form. These statistical models
can be simplistic whereby the process and measurement errors are independent, allowing for a
summation of the errors to a more complex model where other sources are variabilities that can
be incorporated in to the model. For this Stimuli article, as a simple model, the total variation is
calculated as the sum of the measurement and process variations (17). In this model:
Typically, process and measurement variabilities are expressed as a percent, utilizing the RSD,
defined as the standard deviation divided by the mean. Since the summation of errors requires
the variance, and the coefficient of variation utilizes the standard deviation (square root of the
variance), each percentage of variability must be squared and summed, and then the square root
of the sum must be taken to get total uncertainty. If a process has 10% variation and the
measurement system has 10% uncertainty, the total uncertainty would be
If a degradation loss, based on stability studies, shows an upper 95% confidence level of a
decrease of 20% in the strength of a dietary ingredient at the end of the shelf life, the overage
would be a minimum of 34.1%, by combining the 20% with the 14.1% of the total uncertainty.
Finished product or final release testing is the seminal moment when lots are either accepted
or rejected based on the performance of the different assays. These results have both the assay
variation and process variation. The number of units tested during final release should allow for a
high probability that if a surveillance sample was taken, the product would be within the stated
label claims. USP is working with industry to develop methods and sample sizes that ensure a
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high confidence that results seen at release can be a surrogate for the results seen during a
surveillance audit. The propagation of error arises from the sum of the measurement error and
manufacturing error that creates a cumulative effect on the reported result. The relative error
statistic allows one to take the sum of the errors to determine the magnitude of the error. The
relative error is the absolute error divided by the exact value.
STRATEGIES TO MINIMIZE OVERAGES
An understanding of the variables associated with the safety and stability of the dietary
ingredients is critical to developing strategies for minimizing overages. Protection and/or
stabilization of the dietary ingredients in the final dietary supplement dosage forms will help
reduce overages if degradation is the major driver for overages. Microencapsulated ingredients
with enhanced stability are often used to help reduce overages in dietary supplements. Various
types of coating materials (e.g., gums, gelatin, resins, starch, or milk proteins) have been
successfully and commercially employed to microencapsulate dietary ingredients to protect those
ingredients from process damages, moisture and oxidation, and/or ingredient interaction. When
encapsulated ingredients are used, release of dietary ingredients from a coated form needs to be
ensured using a performance test described in 〈2040〉 as one of the acceptance criteria for the
manufacturing process (18). Additionally, packaging materials with good barrier properties,
product bottles with nitrogen filling, and non-vented liners would help prevent oxidative
degradation of the ingredients to enhance the stability of the product. However, a careful
assessment, such as stress testing to various types of packaging, is highly recommended. For
example, non-vented liners may cause a paneling effect to plastic bottles during the shelf life,
due to depletion of oxygen in the product bottle through product oxidation.
In addition, the QbD is a concept that quality should be built into a product from the beginning
of product development based on sound understanding of product, process, and testing. QbD has
gained wide-spread usage in the pharmaceutical industry (19), as the concept can be applied not
only to product development and manufacturing operations but also to testing method
development that can enhance the robustness of product quality and, consequently, reduce
variabilities in manufacturing process and testing results.
CONCLUDING REMARKS
Dietary supplement manufacturers are required by federal regulations to ensure that the
content of dietary ingredients meet the amount that is claimed on the label. It is the
manufacturer's responsibility that the dietary ingredient content during the shelf life be NLT the
claimed amount on the product label, to maintain label accuracy. In order to meet these
expectations, manufacturers usually formulate products with added overage amounts of dietary
ingredients so that the products, when tested, meet at least 100% of the amount claimed on the
label throughout the declared shelf life. While these provisions should help consumers make
purchase decisions based on accurate information provided on the label claim, there is concern
that exposure to excessive amounts of dietary ingredients or their degradation products could
pose safety concerns.
In order to meet the label claim over the shelf life of the product, manufacturers need to make
science-based decisions when adding overage amounts of dietary ingredients to specific
products, by understanding the product stability profile, manufacturing process variability,
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ingredient strength variability, and analytical testing variability, and how these factors can impact
the quality of the finished products. This will help ensure consumer safety and build consumer
trust in the quality of dietary supplements. Manufacturers should perform proper risk
assessments in consultation with subject-matter experts to avoid overage amounts that exceed
ULs. USP encourages the dietary supplement industry to use publically available standards to
help reduce variability associated with ingredient quality and analytical test results and help set
adequate overage amounts of dietary ingredients added to dietary supplements.
REFERENCES
1. Council for Responsible Nutrition Re: Docket No. FDA-2012-N-1210; Food labeling:
revision of the nutrition and supplement facts labels. Washington, DC: Council for
Responsible Nutrition; 2014. http://crnusa.org/pdfs/CRN_Comments_FDA_ProposedRule-
RevisionNutritionSupplementFactsLabels080114.pdf. Accessed on December 14, 2015.
2. Food and Drug Administration. Current good manufacturing practice in manufacturing,
packaging, labeling, or holding operations for dietary supplements: final rule. Petition to
request an exemption from 100 percent identity testing of dietary ingredients; interim
final rule. Fed Regist. 2007;72(121):34752–34958. Codified in 21 CFR §111.
3. General notices and requirements, 4.10.20 Acceptance criteria. In: USP 39–NF 34.
Rockville, MD: US Pharmacopeial Convention; 2016:5.
4. Folic acid tablets. In: USP 39–NF 34. Rockville, MD: US Pharmacopeial Convention;
2016:4034–4035.
5. Ascorbic acid. In: USP 39–NF 34. Rockville, MD: US Pharmacopeial Convention;
2016:2598–2599.
6. Ascorbic acid tablets. In: USP 39–NF 34. Rockville, MD: US Pharmacopeial Convention;
2016:2600–2601.
7. Water-soluble vitamins tablets. In: USP 39–NF 34. Rockville, MD: US Pharmacopeial
Convention; 2016:7053–7065.
8. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington,
DC: National Academy Press; 2010.
9. Institute of Medicine. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6,
Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National
Academy Press; 1998.
10. Institute of Medicine. Dietary reference intakes (DRIs): tolerable upper intake levels,
vitamins and minerals. Washington, DC: Institute of Medicine.
http://iom.nationalacademies.org/Activities/Nutrition/SummaryDRIs/~/media/Files/Activity
%
20Files/Nutrition/DRIs/ULs%20for%20Vitamins%20and%20Elements.pdf. Accessed on
November 5, 2015.
11. National Institutes of Health. The dietary supplement ingredient database (DSID).
Bethesda, MD: National Institutes of Health. http://dsid.usda.nih.gov. Accessed on
December 7, 2015.
12. Deritter E. Vitamins in pharmaceutical formulations. J Pharma Sci. 1982;71(10):1073
–1096.
13. 〈2091〉 Weight variation of dietary supplements. In: USP 39–NF 34. Rockville, MD: US
Pharmacopeial Convention; 2016:2051–2052.
14. 〈1225〉 Validation of compendial procedures. In: USP 39–NF 34. Rockville, MD: US
Pharmacopeial Convention; 2016:1640–1645.
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15. International Council on Harmonisation. Harmonized tripartite guideline stability testing of
new drug substances and products Q1A(R2). Geneva, Switzerland: International Council
on Harmonisation. http://www.ich.org. Accessed on November 3, 2015.
16. International Council on Harmonisation. Validation of analytical procedures: text and
methodology Q2(R1). Geneva, Switzerland: International Council on Harmonisation.
http://www.ich.org. Accessed on November 3, 2015.
17. Alasandro M, Little TA. Process and method variability modeling to achieve QbD targets.
AAPS PharmSciTech. 2015
18. 〈2040〉 Disintegration and dissolution of dietary supplements. In: USP 39–NF 34.
Rockville, MD: US Pharmacopeial Convention; 2016:2044–2051.
19. Kourti T, Davis B. Business benefits of quality by design (QbD). Pharma Eng. 2012;32
(4):1–10.
a Dietary Supplements and Herbal Medicines, US Pharmacopeial Convention, Rockville, MD, USA.
b General Chapters, US Pharmacopeial Convention, Rockville, MD, USA.
c Verification Programs, US Pharmacopeial Convention, Rockville, MD, USA.
d Correspondence should be addressed to: Seong Jae Yoo, PhD, Scientific Liaison, US Pharmacopeial Convention, 12601
Twinbrook Parkway, Rockville, MD, 20852-1790; tel. +1301.230.6366; email: SJY@usp.org.
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