USP Pharmaceutical Plastics Testing

  • Why Test Pharmaceutical Plastics?

    The United States Pharmacopoeia (USP) has set analytical standards to ensure polymer materials do not impact human health regardless of how or when those materials come in contact with a pharmaceutical product. Plastics may contain residues from the polymerization process and/or additives of concern such as antioxidants, stabilizers, lubricants, plasticizers, and colorants. To assess safety, in-depth analytical investigations are required for pharmaceutical plastics. The primary USP chapters for testing of pharmaceutical plastics are USP 〈661〉, USP 〈661.1〉, USP 〈661.2〉, and USP 〈665〉.

  • HPLC girl high performance liquid chromatography

What is USP 661?

USP 〈661〉 “Plastic Packaging Systems and Their Materials of Construction” formally assesses “plastic articles (materials, components, and systems) used to package medical articles (pharmaceuticals, biologics, and dietary supplements)”. In order for plastic packaging to be approved for use with an FDA-approved therapeutic product, data must show that the material/packaging conforms to USP 661 standards and performance criteria.

The polymers specifically outlined in USP 661 include high-density polyethylene (HDPE), low-density polyethylene (LDPE), polypropylene (PP), polyethylene terephthalate (PET), and polyethylene terephthalate G (PETG), though the chapter provides for other polymers. Each material is defined by its properties, and unique specifications are listed.

Testing includes:

  • Identification and characterization tests
    • Infrared Spectroscopy (IR)
    • Differential Scanning Calorimetry (DSC)
    • Determined concomitantly with reference standards per plastic type
  • Physicochemical tests
    • Extraction with water, alcohol, and hexane
    • Heavy Metals assessment on water extraction
    • Nonvolatile Residue (NVR) on all extractions
    • Residue on Ignition (ROI) following certain NVR results
  • Buffering Capacity for liquid containers
  • Biological testing per USP 〈87〉 for high risk applications (inhalation, parenteral, ophthalmics)
  • Additional tests unique to PET and PETG

In 2016, the USP expanded the analytical standards in chapter 661 to further support packaging safety; these new chapters are USP 〈661.1〉 and USP 〈661.2〉. These chapters become official on December 1, 2025, but early adoption is allowed and encouraged.

What is USP 661.1?

USP 〈661.1〉 “Plastic Materials of Construction” introduces more rigorous standards and testing to demonstrate that polymer raw material is well-characterized and suitable for its intended use. It formally assesses “plastic materials of construction used in packaging systems for drug products”.

USP 661.1 expands the materials list from USP 661 to also include:

    • cyclic olefins
    • polyamide 6
    • polycarbonate
    • poly(ethylene-vinyl acetate)
    • polyvinyl chloride
    • polyvinyl chloride, plasticized

Testing includes:

  • Identification and characterization tests
    • Infrared Spectroscopy (IR)
    • Differential Scanning Calorimetry (DSC)
    • Determined concomitantly with reference standards per plastic type
  • Physicochemical tests
    • Water extraction
    • UV Absorbance
    • Acidity/Alkalinity using indicators
    • Total Organic Carbon (TOC)
  • Biological testing per USP 〈87〉 for high risk applications
  • Material-specific tests for plastic additives and/or related substances

What is USP 661.2?

USP 〈661.2〉 “Plastic Packaging Systems for Pharmaceutical Use” focuses on “plastic packaging components and systems used for packaging final drug products”. This includes the primary packaging that comes in contact with the pharmaceutical product as well as any relevant secondary packaging. USP 661.2 is generally not material-specific.

Testing includes:

  • Physicochemical tests
    • Water extraction
    • Appearance (color and clarity of extraction)
    • UV Absorbance
    • Acidity/Alkalinity using indicators
    • Total Organic Carbon (TOC)
  • Biological testing per USP 〈87〉 for high risk applications
  • Spectral Transmission if light protection is necessary (identical to the spectral transmission requirement in USP 〈671〉 for light-resistant plastic packaging systems)
  • Two additional tests for PET and PETG
  • Chemical Suitability Assessment, dependent on risk assessment
    • Extractables per USP 1663
    • Leachables per USP 1664

What is USP 665?

USP 〈665〉 (formerly drafted as 661.3) titled “Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products” becomes official in May 2026. This new chapter emphasizes analysis of organic extractables in plastic manufacturing materials and components used in the conversion of raw starting materials into active pharmaceutical ingredients (APIs), drug substances, and drug products. The chapter applies to pharmaceutical and biopharmaceutical manufacturing. USP 665 includes risk assessment and extraction procedures, along with general guidelines for chemical testing of the extracts.

Testing includes:

  • Nonvolatile Residue (NVR)
  • UV Absorbance
  • Organic extractables profiling (USP 1663)

This testing encompasses all polymeric materials involved in solution transfer and transport, mixing and reacting, storage, and processing including:

  • Tubing and connectors
  • Tank liners and mixing bags
  • Raw material containers
  • Filters and chromatography columns

USP Pharmaceutical Plastics Testing at EKG Labs

With the increasing influence of the USP on polymers in the pharmaceutical industry, new chapters, and frequent changes, it can be difficult to stay on top of the latest recommendations. Fortunately, EKG Labs takes pride in keeping up-to-date with the latest USP revisions and is able to provide appropriate consulting and analytical services for companies seeking to conform to USP standards. Our experience working with polymer materials and active ingredients uniquely positions us an industry leader in packaging testing. Our team understands the complex interactions between pharmaceutical products and polymers, and we have years of experience guiding companies through the analytical portion of their product development.

Through our considerable experience in regulatory compliant polymer analysis, we are also able to provide guidance on the Chemical Safety Assessments required in the expanded guidance chapters 〈1663〉 “Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems”, 〈1664〉 “Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems”, and 〈1665〉 “Characterization and Qualification of Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products”.

EKG Labs supports USP 661 (for legacy and delayed 661.X implementation), 661.1, 661.2, and 665 analytical testing.

Analytical Techniques at EKG Labs

  • Infrared Spectroscopy
  • Differential Scanning Calorimetry
  • Heavy Metals
  • Nonvolatile Residue
  • Residue on Ignition
  • UV Absorbance
  • Buffering Capacity
  • Acidity/Alkalinity
  • Total Organic Carbon
  • Spectral Transmission