Plastics are a wide range of synthetic or semi-synthetic materials that use polymers as the main ingredient, having a range of molecular weights. Plastic materials may contain other substances such as residues from the polymerization process and additives such as plasticizers, stabilizers, antioxidants, pigments, and lubricants. Drug products can chemically interact with their associated packaging systems and the system’s plastic materials of construction while the drug product is being manufactured, shipped, stored, and administered. The magnitude of these interactions should not adversely affect the suitability of the packaged drug product, which includes both quality aspects and performance aspects such as efficacy, stability, purity, and compendial compliance. Suitability for use, as determined by the impact of the interaction between a drug product and its packaging system, is assessed and established via the appropriate testing of the materials of construction, components, and packaging systems. USP<661> general chapter had been historically used to evaluate chemical interactions from packaging systems and the systems plastic materials of construction. Initially effective May 1st, 2016, general chapter <661.1> and <661.2> were introduced to provide more robust chemical characterization of plastic material and package systems compared to the USP<661>, while simultaneously providing testing options for newer polymeric materials, which will be discussed further in this document.
What is USP<661>, <661.1> and <661.2>?
USP<661>: The purpose of the USP <661> Plastic Packaging Systems and Their Materials of construction chapter is to provide standards to evaluate physicochemical characterization for plastic articles (materials, components, and systems) used to package medical articles (pharmaceuticals, biologics, and dietary supplements).
USP<661.1>: Testing and characterizing materials of construction for attributes relevant to their suitability provide a rational basis for material selection in designing a packaging system and minimizing the risk that a system made from those materials will be . Therefore, the characterization of materials for construction is the first step in developing and qualifying suitable packaging materials. Chemical characterization data may also provide the basis for effective and appropriate change control. USP<661.1> aims to provide standards for plastic materials of construction used to manufacture a packaging system.
USP<661.2>: A packaging system contains or is intended to contain a drug product, including pharmaceuticals and biologics. The packaging system provides the means for storing and distributing drug products and, in some cases, the means for administering the drug product. A plastic packaging system is composed wholly or of a substantial portion of plastic materials and/or components and refers to the sum of packaging components that contain the drug product, including closures (e.g., rubber seals, foil closures, laminated closures). Considering the packaging system as the test article, USP<661.2> aims to provide standards for establishing the packaging system’s suitability.
Why is <661> being updated?
- USP<661> had 50-year-old standards, including qualitative and visual comparison techniques for the analyses.
- USP <661> was limited to only certain types of polymers (Polyethylene, Polypropylene, Polyethylene terephthalate, and Polyethylene terephthalate.) There was a need for a method to include new polymers available over the last 50 years being used for packaging drug products or drug substances.
- USP<661> general chapter was limited to only specific test procedures and required more comprehensive testing to ensure the suitability of plastic materials of the construction or packaging system.
What changes were made to the chapters?
- Eliminated component tests from USP <661>: Heavy Metals, Non-Volatile Residue, Residue on Ignition, Colorant Extraction,
- Added component tests per <661.1>: Bioreactivity (for dosage form other than Oral and Topical), Absorbance, Acidity/Alkalinity, Extractable Metals, Total Organic Carbon.
- Added Packaging system tests per <661.2>: Bioreactivity, Absorbance, Acidity/Alkalinity, Total Organic Carbon, Extractable/Leachable Safety Assessment, Spectral Transmission requirements for light-resistant Containers.
Why did USP delay the implementation of new general chapters USP<661.1> and USP<661.2>?
The revision process for the plastics packaging chapters of the USP-NF, including USP 661, has been underway for several years.
USP Packaging expert committee and global industry experts met between June 2018- and October 2018 to gain consensus on the timeline for implementing USP<661.1> and <661.2>.
The industry needed more time for the following reasons:
- Various packaging components manufacturers were required to scan a complete portfolio of materials of constructions and/ or packaging systems. The scoping efforts may vary within the industry depending on the portfolio of the packaging system.
- For the verification of risk-based recommendation, verification of compliance of complete portfolio of the packaging systems. Interdependencies for the availability of USP<661.1> certificates from raw materials suppliers, the capacity of external laboratories for new analysis, and the capacity of toxicologist was a big challenge for the industry.
- Change Control process, which includes:
- 3.1. Identification of compliant resin, validation of equipment at packaging component supplier, validation in the factory, validation compliance of new CCS with USP<661.1> and USP<661.2>.
- 3.2. For stability evaluation over projected shelf life and for report creation.
- 3.3. Industry needed time for filling preparation and filling submission to FDA.
- 3.4. Time required for HA approval.
How will one apply new chapters in the real world?
USP <661.1> and 661.2 can be applied depending on whether the end-user seeks to evaluate an individual plastic material or an entire packaging system.
For example, let’s consider a package system used that contains a bottle made up of a High-Density Polyethylene material and a cap. HDPE and PP resin used to develop this packaging system are considered well-characterized if they meet the USP requirements <661.1> chapter. USP<661.2> applies to the whole packaging system (HDPE Bottles with Cap) and is deemed suitable if it meets the requirements of the chapter.
Why should the industry implement new standards as per USP<661.1> and USP<661.2> now?
Work conducted as per USP <661> or <661.1>/<661.2> is valid now. However, the CS analytical team of experts strongly encourages drug product companies to plan accordingly with regards to early adoption of the requirements in general chapters USP <661.1> and USP <661.2>, a position supported by USP for various critical reasons.
Time and Associated Cost: Plastic Packaging systems and components currently qualified under USP <661> must be required requalified as per new standards outlined in USP<661.1> and USP <661.2> beginning Dec 01, 2025. At the same time, USP <661> will become obsolete. Essentially,early adopters save both time and the associated cost of retesting existing materials, as well as mitigate certain risks.
Liability: The goal of the General Chapters USP<661.1> and USP <661.2> is to improve product safety by introducing more robust and sensitive methodologies when compared to the General chapter USP <661>. The USP <661> chapter does not yield any indication of potential risk originating from packaging materials and system and does not adequately evaluate their safety. In comparison to that USP<661.1> and USP <661.2> are more robust and intended for a thorough assessment of such chemical concerns. When evaluated by more modern and stringent methods as per new chapters, packaging components and materials qualified as per the current USP<661> may risk failure. Drug products packed in that system and currently on the market may end up with critical consequences, including FARs (Field Alert Reports) and product recalls, which can primarily affect the reputation of the manufacturer and the end-users who used those systems to package their drug products.
Regulatory Requirement: Regulatory authority may ask for a risk assessment conducted on all plastic materials and packaging systems on the market approved under old general chapter USP <661>, and to provide evidence that these plastic materials and packaging systems for pharmaceutical use meet the requirement of USP General Chapters <661.1> and <661.2>. Early adoption of General Chapters <661.1> and <661.2> on these in-use plastic materials and packaging systems provides sufficient time to find alternative vendors if existing plastic materials and packaging systems do not meet new requirements.
Thus, proactively meeting the requirements of the revised chapter USP<661.1> and <661.2> will save qualification cost, time, and ultimately risk to patients’ safety.
Members of the CS Analytical Team were some of the first in the contract laboratory market to devise and offer cGMP, FDA-registered services according to the new standards and are ready to leverage years of hands-on experience to devise test plans according to the specific product-package system in question to ensure all regulatory requirements are met.