Degree of Post-Approval Changes to Drug Packaging Impacts Reporting Requirements

Changes that are made to packaging for a drug after the New Drug Application (NDA) or Abbreviated New Drug Application (ANDA) for that drug has been approved are known as "post-approval" changes to drug packaging. Such post-approval changes range from a change in the shape or size of the package to the substitution of the resin used in the packaging (e.g., a change from low density polyethylene to polypropylene).

In 2004, after becoming increasingly concerned about the impact of post-approval packaging changes on the identity, strength, quality, purity, or potency of certain dosage forms (i.e., sterile liquids), the U.S. Food and Drug Administration (FDA) heightened reporting requirements for changes within a container/closure system for sterile drugs (except for solid dosage forms), even if the changes are made pursuant to an approved protocol or official compendium. At the same time, the agency relaxed, to some extent, the reporting requirements for changes to packaging for solid dosage forms and non-sterile drugs. These changes are included in a final rule, published in the Federal Register on April 8, 2004 (69 Fed. Reg. 18727-18767), which amended Title 21 of the Code of Federal Regulations (C.F.R.) Parts 206, 250, 314, 600, and 601.

Section 314.70 of FDA's drug regulations (21 C.F.R. 314.70) requires NDA and ANDA holders to notify FDA of any change to the information provided in an approved NDA or ANDA. Thus, once the holder of an approved NDA or ANDA (usually a drug company) is notified of a change to a packaging material described in its NDA or ANDA (or a packaging material described in a confidential Drug Master File that is referenced in its NDA or ANDA), the company is required to take the appropriate steps to notify FDA of the change. Depending upon the type of change and how it is categorized by FDA (i.e., major, moderate, or minor), the drug company is required to provide such notification either in a Supplemental New Drug Application (SNDA) or in an "annual report."

FDA's current position on post-approval packaging changes is articulated in several guidance documents, including one in draft form:

• Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics, May 1999, which covers packaging information that the agency would like to see in NDAs and ANDAs;
• Guidance for Industry: Changes to an Approved NDA or ANDA, April 2004, which covers compliance reporting requirements triggered by post-approval changes to the information in an approved NDA or ANDA;
• Guidance for Industry: Changes to an Approved NDA or ANDA; Specifications – Use of Enforcement Discretion for Compendial Changes, November 2004, which states that FDA does not intend to take action to enforce compliance with the compendial changes requirement as stated in 21 C.F.R. 314.70(c)(2)(iii) if manufacturers submit such changes in their annual reports; and
• Guidance for Industry: CMC Postapproval Manufacturing Changes Reportable in Annual Reports (Draft Guidance), June 2010, which describes chemistry, manufacturing, and controls (CMC) post-approval manufacturing changes that FDA has determined will likely have minimal potential to have adverse effects on product quality and, therefore, may be reported by applicants in an annual report.

Major Changes in Packaging

If a change in packaging is considered by FDA to have a "substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a product as these factors may relate to the safety of effectiveness of the product," it is defined as a "major change" and requires FDA approval of the SNDA before the change is made (21 C.F.R. 314.70 (b)(1)). The agency gives the example that changing the type of packaging (e.g., glass to HDPE) may affect the impurity profile of the drug product and, therefore, is considered a major change (21 C.F.R. 314.70 (b)(2)(vi)).

Moderate Changes in Packaging

If a change in packaging is considered by FDA to have a "moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety of effectiveness of the product," it is defined as a "moderate change." Any change in a container closure system that does not affect the quality of the drug product, and is not specified as a requiring prior approval in section 314.70 (b) or listed as a minor change in section 314.70 (d) is considered a moderate change.

There are two types of reporting requirements for moderate changes: one requires submission of a SNDA at least 30 days prior to distribution of the drug product made using the change, while the other allows distribution of the drug product once FDA receives the SNDA. Section 314.70 (b)(6) allows FDA to designate categories of changes within the "moderate change" category that allows distribution of the drug product once the agency receives the SNDA. As an example, one of these subcategories includes "a change in the size and/or shape of a container for a non-sterile drug product, except for solid dosage forms, without a change in the labeled amount of drug product or from one container closure system another" (21 C.F.R. 314.70 (b)(6)(ii)).

Minor Changes in Packaging

A change in packaging that has "a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety of effectiveness of the drug product" is considered a "minor change" and can be documented in the manufacturer's next annual report (21 C.F.R. 314.70 (d)). Minor changes include changes made to comply with a change to an official compendium. Another change that is considered minor and, therefore, would only require notice in an annual report, is one within the container closure system for a non-sterile drug provided that the new container is shown to be equivalent to the approved container based on a protocol published in an official compendium (21 C.F.R. 314.70 (d)(2)(v)).

In June 2010, FDA published a draft guidance on post-approval manufacturing changes to NDAs and ANDAs that "may be considered to have a minimal potential for an adverse effect on the identity, strength, quality, purity, or potency of the drug product and, therefore, may be classified as a change reportable in an annual report (e.g., notification of a change after implementation) rather than in a supplement." Specifically, the draft guidance provides a list of post-approval manufacturing changes that were previously submitted in supplements to NDAs and ANDAs that FDA would allow to be reported only in annual reports. One of the changes that would no longer require prior FDA approval under the draft guidance is a "change in the container/closure system for the storage of a non-sterile drug substance when the proposed container/closure system has no increased risk of leachable substances in the extractable profile (for liquids) and equivalent protection properties."

FDA requested that comments on the draft guidance be submitted by September 23, 2010 to ensure that the agency considers them prior to developing the final version of the guidance (see 75 Fed. Reg., 36421-36423). Once the final version of the guidance on post-approval manufacturing changes reportable in annual reports is published, FDA stated that it would revise Guidance for Industry: Changes to an Approved NDA or ANDA, 2004, to reflect the new recommendations. As of the publication of this article, the final version of the guidance on post-approval manufacturing has not yet been published.