6 Components of Using Stability Indicating

Methods | IVT
Feb 10, 2014 11:18 am PST

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Stability indicating methods are defined by the US Food and Drug Administration as quantitative
analytical methods that are based on the characteristic structural, chemical or biological
properties of each active ingredient of a drug product and will distinguish each active
ingredient from its degradation products so that the active ingredient content can be accurately
measured. (1-2). Stability indicating methods are important because they detect the changes
with time in the chemical, physical, or microbiological properties of the drug substance and are
specific so that the contents of active ingredient, degradation products and other components of
interest can be accurately measured without interference. (2). Taken from an Alice Krumenaker
presentation given at IVTs Method Validation Week, the following are six components of
stability testing methods.

1. Determining API Stability

API stability should be determined in the early stages of formulation development. Proper
utilization will be helpful in gathering information on product stability and leading to an
optimized formulation. API stability must also be determined in final forum as it is necessary to
ensure efficacy and safety of the finished product.

2. Regulatory Requirements
Stability indicating methods are not specified, but implied in 21 CFR Part 211.165 and 211.166
(3):

211.165 (e) states that the accuracy, sensitivity, specificity, and reproducibility of test
methods employed by the firm shall be established and documented

211.166 (a) (3) requires that test methods be reliable, meaningful, and specific.

However, FDA's Expiration Dating and Stability Testing for Human Drug Products states
While 211.166 (a) (3) merely requires that test methods be reliable, meaningful, and specific,
section 211.165 (e) gives more guidance by stating that the accuracy, sensitivity, specificity, and
reproducibility of test methods employed by the firm shall be established and documented.
Section 211.194 (a) (2) further requires that all testing methods used shall be verified under
actual conditions of use. Testing procedures must include a stability indicating test which will
distinguish the active ingredient from any degradation products and be able to make a reliable
estimate of the quantity of any degradate. The stability indicating test does not have to be the
assay method used to determine product strength. (4).

3. Impurities and Degradates

Impurities are chemicals or solvents incorporated into a raw material during production. The
level of impurities does not typically change over time. Controlling the product process can
minimize impurities. By monitoring impurities, the impact on raw material can be determined.
Degradates are formed by component breakdown. They can cause a drop in efficacy or create
side effects from the finished product. You must ensure the ability of the method to detect
degradates; it can be difficult to separate from peak of interest. Typically, the level of ingredient
decreases as degradates increase; this is the difference between degradates and impurities.
Identification tests, which are usually compendial method, are performed to ensure the identity
of an analyte in a sample and reflect the purity characteristics. This characterization is important
because it provides information about the chemical and physical properties of the compound,
helps predict how the compound will act in the formulation, and helps assess the purity of the
material. Physical characterization techniques include:

Microscopy

Particle size

DSC: Differential scanning calorimetry

TGA: Thermogravimetric Analysis

SGA: Symmetrical Gravimetric Analyzers (Vapor Sorption Analysis)

XRD: X-Ray Diffraction

Chemical characterization techniques include:

LC/MS

GC/MS

IR

NMR

UV

Forced degradation is done to determine breakdown products of a material. Methods of forced

degradation include:

Accelerated temperatures

pH extremes

Oxidation

Photolytic conditions

4. Method Development
When developing a stability testing method, after thorough research, be sure that the selected
conditions are adequate for the API. You should check the placebo blank for interference from
excipients.
If interference is found, identify the source and, if possible, remove it. If the interference cannot
be removed, isolate the peak of interest. It should be noted that interference is possible when
using wet chemistry techniques as well as in instrumental methods.
Sample preparation is a critical, especially if the finished product is complex, has an unusual
matrix, or delivery system. Thus, you should take the time to ensure the extraction step is
sufficient.
After the sample preparation and extraction steps are finished, you should check and ensure that
the extraction was complete and there was no interference. By optimizing the parameters, you
will have the best separation.
When not starting a method from scratch, there will be additional considerations during method
development. If you are transferring the method from the analytical laboratory to the quality
control laboratory, you must make the method as efficient as possible by switching the gradient
to isocratic and reducing runtimes, if possible, without compromising separations. If you are
optimizing or modifying the method, ensure that impurities and degradates will be detected.
It is important to note, in method development, the common shortcomings in confirming that
methods are stability indicating are:

Using synthetic degradates rather than force degradation

Not using all methods of forced degradation

Using the finished product for forced degradation rather than the API.

5. Method Validation
While the main burden of establishing the stability indicating properties of a method occurs in
method development, in validation, the specificity step verifies that the peak of interest is
separated from other peaks in the chromatogram, including degradates. You should use forced
degradation to identify degradates. You may also find the use of a photo diode array detector
(PDA) to verify the peak purity helpful during method validation.

6. Compendial Methods
Many compendial methods are stability indicating, but do not assume they are! Knowing your
compounds impurity profile and checking for degradates will ensure that your method will
remain compliant.
If stability indicating compendial method is unavailable, you can develop and modify a method
to detect breakdown products before validation.

References
1. FDA, Guideline for Submitting Documentation for the Stability of Human Drugs and
Biologics, 1987.
2. FDA, Guidance for Industry: Stability Testing of Drug Substances and Drug Products
(Draft guidance), 1998
3. Code of Federal Regulations, Title 21 Part 211.
4. FDA, Expiration Dating and Stability Testing for Human Drug Products.
http://www.ivtnetwork.com/article/6-components-using-stability-indicating-methods