Practical Challenges of Stability Testing

on Nutraceutical Formulations

By:

Jairaj (Jai) Mehta, R.Ph., M.S.

JM Pharma, LLC
Tel: 623-412-8515
Fax: 623-412-8525
Cell: 602-625-4801
Web: www.JM-Pharma.com
E-mail: jaimehta@jm-pharma.com
1. Introduction:

Nutraceuticals have been quickly gaining attention due to increasing consumer market

share for wellness products. Thus, there has been a heightened focus in the marketing,

claims substantiation, manufacturing, and FDA-based regulations of Nutraceuticals.

Loose definition of Nutraceuticals would include herbs, minerals, vitamins, medical

foods, dietary supplements, etc. The manufacturing of such products has been largely

unregulated and historically has lacked desired quality control systems. It can be argued

that up until now, the European countries have better regulated such products. The

congressional attention reflected in 1994, with passage of the Dietary Supplement Health

and Education Act (DSHEA). The United States FDA has just very recently in 2007,

issued a final rule for cGMP regulations of dietary supplements – a full thirteen years

after the passage of the DSHEA. Due to the volume and breadth of the comments

received in response to the proposed regulations, alas, the final regulations have been

much diluted. The manufacturing landscape therefore is about to change. Along with

these changes, better formulation and testing methods are getting attention. Among other

contradictions, the manufacturing practice recommendations in the USP for stability

testing and the analytical methods validation are significantly different than the new FDA

regulations. The industry scientists are just beginning to pay attention to the testing,

methods and stability of Nutraceuticals as the focus on GMPs increase, and the playing

filed is already challenging with the USP versus FDA regulations. The task of stability

testing of Nutraceuticals gets further challenging due to the potential interactions between

ingredients of various dosage forms, such as vitamins, herbal extracts and minerals in a

complex matrix.
Regulatory Challenges:

1.1. Dietary Supplement Health and Education Act (DSHEA):

The Dietary Supplement Health and Education Act (DSHEA) was enacted in Congress in

October 15th, 1994. It amended the Federal Food, Drug and Cosmetic Act (the Act) by

Adding Section 402(g).

Section 402(g) (2) of the Act provides in part the Secretary of Health and Human

Services the authority to issue regulations for Good Manufacturing Practices (GMPs) for

Dietary Supplements. It also requires that the standards may not be imposed for which

there are no current and generally available analytical methodology. This caveat along

with the requirement that the FDA pattern the GMPs for dietary

supplements/nutraceuticals after the food regulations and not the drug regulations

provided the FDA with limitations for enacting tough regulations.

1.2. Proposed Rule:

In the slow and painstaking regulatory evolution, the proposed rule for Current Good

Manufacturing Practice (CGMP) in manufacturing packing or holding nitrate ingredients

and dietary supplements, published on March 13, 2003, a full ten years after the

congressional passage of the DSHEA.

There were no requirements for dissolution, disintegration, bioavailability, or expiration

dating because scientific study was supposed to be still evolving. Especially for botanical

dietary ingredients, few official methods were available to assess the strength of a dietary

ingredient in a dietary supplement.

Nevertheless, the proposed regulations maintained that if the manufacturer were to use an

expiration date on a product, data to support that date should be available. There should

also be a written testing program designed to assess the stability characteristics of the

dietary supplement, and use the results of the stability testing to determine the appropriate

storage conditions and expiration dates.

Via the proposed regulations, the FDA also invited comment from the industry on

whether any final dietary ingredient and dietary supplement CGMP rule should contain

requirements regarding expiration dating and the feasibility of conducting tests needed to

support such dates. The FDA also requested input regarding creating a different subset of

products for which expiration dating would be required, for example where the analytical

method were fully characterized such as of vitamin, mineral and amino acid products

only. Botanical or animal source dietary ingredients, where the analytical methods were

still evolving could be exempted from the expiration dating requirements under the this

separation

1.3. The Final Rule:

On June 25, 2007, FDA Published Final Rule 21CFR Part 111 – Current Good

Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations

for Dietary Supplements. The final rule applies only to the finished formulations of the

nutraceuticals, and not to the dietary supplement ingredients that make up the dosage

forms. The quality control departments of the formulation manufacturer are held

accountable instead to assure the quality of the dietary ingredients employed to

manufacture the dosage forms. The final rule does get implemented over three years in a
sliding scale based on the size of the manufacturing company, the smaller companies

benefiting with more time to adjust to the new regulations.

21 CFR Part 111.70(e) of the new rule requires the establishment of finished product

specifications for identity, purity, strength, and composition of the finished batch of the

dietary supplement. For testing methods for these specifications 21 CFR Part 111.320(a)

requires the methods to be appropriate, and 21 CFR Part 111.320(b) requires the

identification and the use of appropriate, scientifically valid for each established

specification.

The FDA however, declined to define “test,” “scientifically valid analytical method,” or

“scientifically valid method” in this final rule “because methods for components are

evolving”. According to the FDA, these definitions could become obsolete by the time

they issued the regulations or by the time the methods are adopted in compendia.

Instead, the FDA maintains that it is the responsibility of quality control personnel to

approve the use of those scientifically valid tests that will ensure a product’s identity,

purity, strength, and composition whether or not such tests are contained in a particular

compendium.

Reference was made to invitation for comments on expiration dating and feasibility of

conducting stability tests needed to support such dates. According to FDA, no persuasive

comments received to alter its position not to require establishment of expiration dating

for dietary supplements. FDA also declined to offer guidance on the type of data that are

acceptable to support an expiration date, other than to repeat themselves that any

expiration date used, including a “best used by” date, should be supported by data.
2. Compendial USP Challenges:

2.1. Legal Authority of USP over Nutraceuticals/Dietary Supplements.

The United States Pharmacopoeia (USP) has been proactive in providing monographs

on dietary supplements, as well as disintegration/dissolution methods and guidance

on manufacturing practices for dietary supplements. The Mission and preface Chapter

of USP 30-NF25 (official August 1 st 2007-November 30th 2007) provides legal basis

for USP to address official standards for dietary supplements thusly -

The Dietary Supplement Health and Education Act of 1994 amendments to the FD&C

Act name USP and NF as the official compendia for dietary supplements. The 1994

amendments also provide that a dietary supplement may be deemed misbranded if it

is covered by a monograph in an official compendium, is represented as conforming

to this monograph, but fails to conform.

The dietary supplement must therefore be represented (labeled) as conforming to a

USP-NF dietary supplement monograph in order for the compendial standards to

apply. This contrasts with pharmaceutical products, wherein conformance to the

monograph is mandatory whether or not the product claims to conform.

2.2. Manufacturing Practices for Dietary Supplements – USP General Information

Chapter <2750>:

The General Information Chapter on Manufacturing Practices for Dietary

Supplements states that many of the principles in this general information chapter are

basic as that they apply equally to various types of products and levels of technology

and that they are derived from the current good manufacturing practices for drugs.
However, the practical application of these principles to dietary supplement may be

different.

It is recommended by this chapter in USP, for the finished product specifications to

include identity and strength testing prior to release. As for analytical methods, it is

recommended to establish and document the accuracy, linearity, sensitivity,

specificity and reproducibility when non-compendial methods are employed.

For stability testing, the USP recommends that there should be a protocol and the

results should be to assess storage and shelf-life assigned. The protocol should define

storage conditions, test intervals and statistical acceptance criteria. Reliable,

meaningful and specific test methods should be used, and accelerated studies with

other supportive data could be used to predict shelf-life, provided stability studies are

conducted under shelf-life conditions until the tentative shelf-life is verified.

As stated earlier, the FDA’s Final Rule on CGMPs for Dietary Supplements was

limited by Congress to be modeled after food GMPs, and FDA was hamstrung by the

congressional restriction to state of analytical science as well. As a result, the

dichotomy between the FDA regulations, based on food cGMPs and USP

requirements, based on drug cGMPs creates practical challenges for the manufacturer

as to how to label the Nutraceutical product with expiration dating and test the

stability of the product to support this expiration or “Use Before” date.

2.3. USP Verified Program for Dietary Supplements:

USP’s Verification Program is a multi-step process, fee for service program. The

company’s quality system infrastructure is pre-audited, and then it is audited on-site

against USP’s & FDA’s GMP requirements. After this initial paper audit, comes the
 step where random samples of the product are tested in the USP labs. Once the

product is verified by the USP, the “USP Verified” logo is available for marketing and

labeling of the nutraceutical product. At this step, the product undergoes market

surveillance of the products to ensure that they continue to retain ingredient strength

and stability over their shelf-life.

In the author’s opinion, if the manufacturers go the extra quality standards of

applying expiration dating on its Nutraceutical products based on scientifically valid

methods, validated according to the USP guidances, they should take advantage of the

USP verification program for the added marketing differentiation from less

conscientious manufacturers.

3. Analytical Methods/Technologies Challenges:

There are some products where test methods readily available and they are pretty decent,

for example the vitamins, minerals and vitamins with minerals. For these types of

products, USP monographs exist and methodologies are available, and the methods used

are relatively modern such as electrophoresis, HPLC, etc. Some vitamins in the USP still

have cumbersome inaccurate microbiology methods (e.g. cyanocobalamin, biotin,

vitamin D, etc.).

There are some other cases of nutraceutical products, where method development and

validation is challenging, such as identifying active ingredients in herbal products. Some

of the high quality botanical nutraceutical manufacturers employ standardized extracts

which are tested with well characterized marker components and well defined analytical

methods as USP, EP, WHO, AOAC, ANSI, AHP, etc. However, it is unknown if there is

more than one active ingredient in a product, for example garlic extract. Thus, it is
difficult to determine which ingredient must be routinely monitored. In addition, the

ratios of active ingredients and relative potencies are also an issue not well understood,

and it is still unknown how long those challenges will continue to exist and how far and

how quickly and how accurately the analytical science will go.

There are many herbal/natural products on the market, and constantly being added where

there are different combinations and sources (e.g.: vegetarian/animal, geographic

locations, etc.). For these types of products it is difficult to develop assay methods, even

with availability of marker compounds, let alone stability models or protocols.

4. Formulation Related Challenges:

The formulations of nutraceutical products can be very complicated, with many

ingredients in the same capsule, tablet or liquid. A very good example of

vitamins/minerals formulation challenges would be the change of active ingredient

source. Sometimes, the sources have different impurity profiles, this leads to method

interference with other vitamins. Another example would be the oxidative/reductive

interaction of minerals with vitamins like Ascorbic Acid, Vitamin D, and Vitamin A, etc.

The use of coated vitamins and minerals to improve the shelf life by minimizing

interactions could lead to poor analyte recovery. Trace quantities of vitamins or minerals

in presence of large quantities of other analytes or matrix would lead poor recovery and

detectability of the smaller quantity active ingredients.

As for shelf-life predictions, there is no clear-cut guidelines/science available, and

Arrhenius relationships do not hold in most instances for nutraceutical products. The

shelf-life prediction is challenging in some other cases also because of confounding due

to multiple active ingredients, and the unpredictable, effects of harsh accelerated

conditions that the product is subjected to, which is not representative of the labeled

conditions upon marketing. Container-closure system also has a large impact on the

formulation stability, i.e.: unit dose blister vs. HDPE bottles, etc.

5. Conclusion:

Complying with regulatory requirements, even with the new FDA regulations (finalized

in June 2007) for the dietary supplements do not require the conduct of a stability

program or expiration/shelf-life dating. However, to establish a shelf-life, and apply an

expiration or use-before date on a label, such a dating must be based on supportive data

arrived at using scientifically valid analytical methods.

As for USP requirements, the product should be compliant with USP monograph, if and

only if the product carries the USP legend. The USP general information chapter on

manufacturing practices of dietary supplements requires stability testing and shelf-life

determination, and validation of the test methods used.

The USP verification program verifies conformance with USP and FDA draft regulations,

and promotes customer confidence in you nutraceutical product formulation.