Guidelines for the Stability Testing in Support of Changes to Nonprescription (OTC) Monograph Drug Products Not Regulated by an NDA/ANDA

Introduction

Due to the great variety of changes that may be encountered after an OTC monograph drug is marketed, it is impossible to address stability requirements for all changes in an exhaustive manner in this guideline. Some of the more common examples of changes that can occur are listed below. However, since a significant body of information typically exists for these OTC monograph drug products, general guidance from the examples provided within this guideline can be used in the decision-making process as to the extent of additional stability testing necessary to support a given product change.

The parent guideline “Guideline for the Stability Testing of Non-Prescription (OTC) Drug Products Not Regulated by an NDA/ANDA” describes the requirements for stability testing and data package(s) for new products. The parent guideline can be followed to generate stability data for OTC monograph drug product launches in the U.S. per climatic zone II.

Three underlying assumptions within this additional guidance to post-market changes are that 1) a post-market stability program is in place with pre-defined initial and ongoing requirements and 2) the capability exists to conduct accelerated stability testing concurrently or upfront prior to marketed product stability 3) the capability exists to assign a different expiration dating period to the changed product in the event that it is warranted.

Because of the significant body of information that typically exists for OTC monograph drug products, the significance of the change can be categorized into one of the three following categories:

• Minor – A change that has a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product.
• Moderate – A change that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product.
• Major – A change that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product.

In the case of multiple changes occurring simultaneously, the combined changes may or may not have an additive effect as to their impact and must be considered as well. Each situation should be evaluated appropriately.

Table 1 presented below outlines the recommended pre- and post-market stability requirements for each of the three types of changes. Within a given change category, the presence or absence of a significant body of information can lead to a more or less conservative approach. In general, the net impact to a product’s expiration dating period is that only certain types of major changes would warrant a change in the current expiration dating period. For moderate or minor category changes, it is anticipated that the current expiration dating period will be maintained for the changed product. If the generated stability data for the change is not comparative, a reevaluation of the change should be performed.

Table 1: Stability Data Packages to Support Product Changes

¹Alternative methods (i.e., MVTR, Extractables) and knowledge base are also used when deciding how much data is required to support a change.
²Pilot scale batches acceptable.
³If already part of the comparative stability package, no additional commercial lots are required.

Site Changes

A change in the manufacturing, packaging or testing site of the OTC monograph drug product can be supported by a sufficient body of data (Table 2) to show that such a change does not affect the stability of the drug product. If the data are found acceptable, the established expiration period may be retained.

Table 2: Stability Data to Support Manufacturing Site Changes

Formulation Changes

Historically, all changes in drug product formulation were grouped together and required stability documentation to support the change. An exception was the deletion of a color. Excipients may play a critical role in certain complex dosage forms. Table 3 provides information on stability recommendations to support formulation changes.

Table 3: Stability Data to Support Formulation Changes

Addition of a New Strength

The addition of a new strength for a monograph OTC drug product is permissible provided the new active concentration is within the approved drug monograph. Demonstration of equivalent stability between the current OTC drug product and the new strength will allow extension of the current OTC drug product expiration dating to the new strength. Depending on issues specific to the drug products (e.g. dosage form), availability of a significant body of information for the current OTC drug dosage form, a minor, moderate, or major category stability data package may be appropriate as shown in Table 4. New strengths intermediate to those of a current monograph OTC drug products may be supported by bracketing/matrixing studies.

Table 4: Stability Data to Support Addition of a New Strength

*No change in drug substance (API) to excipient(s) ratio from the current monograph OTC drug product.

Changes in Manufacturing Process and/or Equipment

A change limited to the manufacturing process of the OTC monograph drug product, such as a change in the type of equipment used, can be supported by a sufficient body of data to show that such a change does not compromise the stability of the drug product. The commitment to conduct stability studies on product produced by the revised manufacturing process may be appropriate as shown in table 5 below to generate a stability data package to support the manufacturing process or equipment change. If the data are found acceptable, the established expiration period may be retained.

Table 5: Stability Data to Support Manufacturing Process Changes

Change in Batch Size

A key question in considering an increase in batch size beyond the production batch size used to establish an expiration period is whether the change involves a change in equipment or its mode of operation, or other manufacturing parameters described for the approved batch size. If no equipment change is made, then the next concern is the size of the change relative to the approved batch size with larger changes expected to present a greater stability risk in the drug product. Table 6 below presents the recommended stability data packages for a variety of batch size situations not involving equipment or mode of operation changes.

If an equipment change is part of the batch size change, please refer to the previous section on manufacturing process and/or equipment changes.

Table 6: Stability Data to Support Batch Size Changes

Change in Container/Closure System (Primary Packaging)

The Stability data packages for changes in container and closure of OTC drug products vary (Table 7). The first factor used in determining the stability data package recommendation is whether or not the protective properties of the container/closure system are affected by the proposed change. Protective properties of the container/closure system include, but are not limited to, moisture permeability, oxygen permeability, and light transmission. Changes that may affect these properties should be supported by a greater amount of data to support the change. The second factor is the nature of the dosage form itself. A solid dosage form will generally be less affected by a container change than a liquid dosage form.

Table 7: Stability Data to Support Container/Closure Changes