What USP 661.1 and USP 661.2 Means to Pharma Packaging Regulations

Pharmaceutical packaging requirements tend to evolve along with processes and materials. Central to these advancements is US Pharmacopeia, or the USP. The world-renowned non-profit organization is responsible for addressing quality assurance, enhancing regulatory predictability, and helping pharmaceutical companies distribute safe health-related products.

The USP is active in 150 countries around the world, impacting an estimated 2 billion people. Health-related products carrying USP approval creates opportunities to introduce 50% more generic applications and decreases development time by 19%, which saves the pharmaceutical industry about $2.75 billion annually.¹

The backbone of these impressive statistics is the 6,800 active quality standards maintained by the USP. Of particular note for pharma packaging regulations is USP 661, which establishes related tests and acceptance criteria for packaging containing pharmaceuticals, biologics, dietary supplements, and devices.

In 2020, USP 661 was determined to be too vague and required revisions to make testing more specific and impactful. The resulting USP 661.1 and USP 661.2 were introduced in mid-2020 but soon relegated to unofficial status as the date for ending the existing USP 661 changed several times.

Currently, USP 661 is slated to end on December 1, 2025. On that date, USP 661.1 and USP 661.2 will take full force and effect.

The 2025 date suggests the transition isn’t of immediate concern. The reality is that pharmaceutical companies need to understand the changes and impact of USP 661.1 and USP 661.2, and know that they can implement the revised testing now with the help of a practice, prepared packaging supplier.

The future of USP 661 packaging regulations

To create the specificity required for pharma packaging quality and safety, the USP deemed it necessary to create two sections of 661:

• USP 661.1 deals with plastic materials of construction
• USP 661.2 focuses on the suitability/safety of the complete packaging system

In the time leading up to December 1, 2025, pharmaceutical companies launching products can choose to either comply with the guidelines laid out in the existing USP 661 OR choose to comply with both USP 661.1 and USP 661.2.

After December 1, 2025, the only option available is required compliance with USP 661.2, ideally supplemented by compliance with USP 661.1. Complying with both is not necessary, but may prove helpful as FDA reviewers may call for broader documentation. Also, while existing data from USP 661 may be leveraged to aid in applying USP 661.2, no materials can be grandfathered in as of 2025.

An Overview of USP 661.1: Materials Analysis

USP 661.1 contains more rigorous standards regarding how raw materials are tested and verified as safe to use for health-related product packaging in order to minimize risk in both low risk (topical/oral dose) and higher risk (injectables, inhalables, suppositories, etc.) products.

The requirements focus on direct contact, non-direct contact, and noninteractive materials, and align with specific polymers:

• Polyamide 6
• Polyethylene (PE)
• Polyethylene terephthalate (PET)
• Polyethylene terephthalate glycol (PETG)
• Ethylene vinyl acetate (EVA)
• Polypropylene (PP)
• Polyvinyl chloride (PVC)

USP 661.1 testing confirms the characteristics of these polymers in four areas:

• Identity of material that is backed by testing/documented proof
• Biological reactivity with other substances
• General physicochemical properties
• Composition

However, because of the large number of potential variables that exist — including those presented by most flexible packaging — an “Unaddressed Materials” category is in place. Should packaging materials fall in this category, it is up to the pharmaceutical company with the help of their packaging partner to determine what characteristics are sufficient.

It’s important to note that:

• Passing USP 661.1 testing doesn’t guarantee use of materials since every packaging system is different
• Failing USP 661.1 testing doesn’t preclude use of the material, rather it compels pharmaceutical companies to examine, understand, and justify what occurred and if the failure has larger consequences

Performing tests under USP 661.1 is not a prerequisite for conducting USP 661.2 tests, however it can provide insights into how materials may fare in the required compliance testing.

An Overview of 661.2: Packaging System Suitability/Safety

Testing under USP 661.2 largely mirrors the physicochemical and biocompatibility aspects of USP 661.1 for low risk and higher risk health-related product packaging, with one major difference.

USP 661.2 includes a chemical suitability/safety assessment using comprehensive extractable and leachable testing. USP 661.2 is not intended to replace ISO 1663 and 1664 standards that address these testing methodologies. Instead, USP 661.2:

• References the ISO chapters and provides guidance that informs pharmaceutical company decision making about exact testing and packaging requirements
• Can help forecast extractable and leachables profiling, depending on the testing conditions
• Provides toxicological evaluation of test data (stability studies)
• Determines chemical suitability of the packaging system in tandem with ISO 1663 and 1664, based on materials of construction, components of construction, and the packaged health-related product composition

The Benefits of Taking Action Now

Implementing USP 661.1 and USP 661.2 isn’t required until December 1, 2025. Savvy pharmaceutical companies are choosing to transition now in order to stay ahead of compliance requirements and the competition.

As a trusted pharma packaging partner, Amcor has proactively leaned into the what the revisions mean, and how being an early adopter can benefit pharmaceutical companies, including:

• Risk-based decision making based on comprehensive testing and suitability assessments
• Detailed capture of USP values that help build fields of history and trends, or mapping values to a product
• Verification of USP values align with final product values

SOURCE
¹Amcor Webinar (T. Harper, A. Kesselring), Pharmaceutical packaging designed for patient safety, Adapting to USP <661.1> and <661.2> Packaging Updates, 2022