Stability Testing Requirements For OTC & Drug Products in the USA

All over-the-counter (OTC) and prescription (Rx) drug products distributed within the USA are required to display an expiration date that is supported by stability studies that have been conducted in accordance with the current FDA and ICH Guidelines. Each strength of a drug product, and each primary package and closure system in which it is distributed must be supported by stability testing. This requirement may be found in the Code of Federal Regulations, 21 CFR Part 211.137 – “Expiration Dating” and Part 211.166 – “Stability Testing”. If you are contracting this work to a third party laboratory be sure that they can provide guidance to help navigate the regulatory and compendial guidelines, and you perform a quality system audit of their facility.

What is a Stability Study and What is its Purpose?

A stability study is a program of testing that is designed to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity light, which enables recommended storage conditions, retest periods and shelf lives to be established. (Refer to FDA Guidance for Industry Q1A(R2) “Stability Testing of New Drug Substances and Products”)

What Types of Stability Studies are Commonly Conducted?

Stability testing is required to be conducted for OTC drug products under the recommended conditions of storage appearing on the label, and at any other condition, the drug product might be exposed to during manufacturing, storage and shipping activities. As a result, there are a number of stability conditions that are commonly utilized in determining the stability of a drug product in its marketed package(s). Examples of the most common stability conditions are as follows:

Real Time or Room Temperature (RT) Stability Study

A stability study conducted under controlled temperature and humidity approximating conditions of long-term storage. For drug products distributed within the USA, long-term stability storage conditions are 25 +/- 2oC with 60 +/- 5% RH.

Accelerated Stability Study

A stability study conducted under exaggerated conditions, in an attempt to accelerate the aging process, i.e., the rate of chemical degradation and/or physical change. For drug products sold within the USA, the most commonly used accelerated stability storage conditions are 40 +/- 2o C with 75 +/- 5% RH.

Intermediate Stability Study

A stability study that is conducted under conditions that are intermediate (between) long-term and accelerated storage conditions. For drug products sold within the USA, conditions are 30 +/-2oC with 65 +/- 5% RH. Samples stored under Intermediate conditions are typically only tested if a failure is encountered during the testing of samples stored under accelerated storage conditions.

Freeze / Thaw Stability Study

A study that is conducted at 5oC (no humidity control) to determine the effect that freezing and subsequent thawing has upon the stability of a product. Such studies may be conducted with single or multiple freeze/thaw cycles, with three cycles being the most commonly used.

Photostability Study

A study that is conducted to determine the effect that either whole or ultraviolet light has upon the stability of a product. This is not required for drug products packaged in completely opaque container systems. (Refer to ICH Guideline Q1B “Stability Testing: Photostability Testing of New Drug Substances and Products”.)

Bulk Hold Stability Study

A stability study that is conducted under long-term conditions to assess the stability of a product batch in its bulk container. This applies to situations where a drug product may be stored in a bulk container for a period of time prior to its placement into end-user packaging.

Period After Opening (PAO) Stability Study

A study that is conducted to assess the stability of a product after its container system has been opened and then reclosed (but not ‘resealed’). This was first introduced within the EU but is now beginning to find acceptance within the USA.

How is Expiration Dating Determined for the Launch of a New OTC Drug Product?

FDA requires that the expiration date of each OTC drug product be supported by Real Time (RT) stability studies. That being said, FDA understands that drug owners would face undue hardship if they were required to wait the full two years it would take to generate RT stability data before launching a new OTC drug product with a 2-year expiration date. As a result, FDA allows for the extrapolation of accelerated stability data for determining expiry dating for the initial launch, however, FDA also requires that the same batch that was used for the accelerated study must also undergo concurrent RT stability testing. Accelerated stability studies alone cannot be used to support the expiration dating of OTC drug products. The results of accelerated studies must be confirmed through the conducting of RT stability studies.


Interpretation of Accelerated Stability Studies

As stated in the previous section, the results of accelerated stability studies may be used to approximate the shelf life of a new OTC drug product for launch. Historically, the FDA has permitted three (3) months of acceptable accelerated stability test results to support a 2-year expiration date for a product launch. However, in recent years, FDA has tightened up its stability requirements for prescription (Rx) drugs, now requiring six (6) months of accelerated stability and one (1) year of RT stability data at the time of submission, and for it, granting only an 18-month (sometimes less) expiration date. Since OTC drug policy eventually tends to follow along the lines of Rx policy, it is prudent that for the launch of new OTC drug products, that six (6) months of accelerated stability testing now be conducted to support a 2-year expiry date for the launch.

It should also be noted that anything less than three (3) months of acceptable accelerated stability data cannot be routinely used to support any expiry date.

Once Expiration Dating of an OTC Drug Has Been Established in Each Container System Prior to Launch, What Other Stability Testing Is Required?

  • The first three (3) commercial batches of the drug product must be placed on RT Stability.
  • Each year that a drug product continues to be manufactured, one (1) batch must be placed on RT Stability.
  • Any substantial change that is made to the drug product such as (but not limited to) a change in formula, its container system, the site of manufacturing, or the process itself must be supported by stability testing so as to demonstrate the continuing stability of the product. Critical changes require the re-establishment of shelf life.

General GMP Requirements for Conducting Drug Stability Studies:

  1. Stability studies must be conducted in accordance with an approved Stability Protocol which indicates (at minimum) the testing to be performed, specifications, methods, storage conditions, test points, identification of the product under test, and a description of the container/closure system.
  2. Test methods used for drug Assay and Impurity testing must be validated and stability-indicating for the specific product formulation under test. (A stability-indicating assay is one which is demonstrated to be free from interferences from impurities, degradants, or other constituents which may be present in the product.)
  3. Stability studies must be conducted in marketed containers with primary labeling in place.
  4. FDA allows for “bracketing” or a “matrix” approach to conducting stability testing if the same basic formula is used for different strengths of the drug, or the product packaging is identical except for the size and quantity of product it contains. (Refer to FDA Guidance for Industry Q1D “Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products”.)
  5. Products packaged in containers equipped with dispensing devices (e.g., pump sprays, dispensing nozzles) or cap liners must be stored with the product in direct contact with the dispensing device or cap liner. (Either an “inverted” or “horizontal” orientation is acceptable.)
  6. “Stiff” ointments/gels packaged in tubes should be sliced open and the “top”, “middle” and “bottom” of the product each assayed separately at each test point.

Supporting a 3 Year Expiration Date

There are only two (2) ways to support a 3-year expiry date for an OTC drug product:

  1. By generating 3 years of acceptable Real-Time stability data.
  2. By taking samples which have been stored under RT stability conditions for two (2) years, and subjecting them to an additional three (3) months storage under accelerated conditions and then obtaining acceptable test results from the samples.

Extending the accelerated storage time or storing under harsher conditions will not routinely support 3-year expiration date.

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