Introduction: The Foundation of Pharmaceutical Glass Packaging
Glass has been the material of choice for pharmaceutical primary packaging for over a century, and for good reason. Its chemical inertness, optical clarity, thermal stability, and impermeability make it uniquely suited to protect sensitive drug products from contamination and degradation. However, not all glass is created equal. The composition, manufacturing process, and surface treatment of a glass container directly influence its ability to maintain drug product quality and patient safety throughout the shelf life.
The United States Pharmacopeia (USP) established General Chapter <660> Containers – Glass to define the testing requirements for glass containers intended to come into direct contact with pharmaceutical preparations. This standard ensures that glass packaging materials meet the necessary criteria for hydrolytic resistance, chemical durability, and light protection—critical attributes that safeguard drug stability and efficacy.
At Vialab Pharmaceutical Packaging Co., Ltd. , we understand that the container closure system is only as strong as its weakest component. While our core expertise lies in aluminum caps and aluminum-plastic combination caps, we recognize that these closures must work in perfect harmony with USP <660>-compliant glass vials to ensure container closure integrity. Our caps are designed and manufactured to meet the dimensional and performance requirements that complement high-quality pharmaceutical glass packaging.
This article provides a comprehensive examination of USP <660>—exploring its scope, glass classification system, key test methods, the landmark 2023 revisions, and practical implications for pharmaceutical manufacturers.
1. Scope and Purpose of USP <660>
1.1 Definition and Applicability
USP <660> applies to glass containers for pharmaceutical use that are intended to come into direct contact with pharmaceutical products. Glass used for pharmaceutical containers is either borosilicate (neutral) glass or soda-lime-silica glass. The standard defines testing requirements to confirm that glass packaging materials meet the necessary criteria for pharmaceutical applications.
The chapter evaluates glass containers based on three primary attributes:
- Hydrolytic resistance: The ability of the glass to resist the release of soluble mineral substances into aqueous solutions
- Chemical durability: The glass’s resistance to chemical attack by the drug product and its contents
- Light transmission: For colored glass containers, the ability to protect light-sensitive drug products
1.2 Glass as a Critical Packaging Component
Glass containers for pharmaceutical use are identified by the bulk or base glass composition, description of treatment, coating or processing, and designated by type, by the inner surface composition, and by glass performance criteria. The inner surface of glass containers may be treated to improve hydrolytic resistance or water repellency, while the outer surface may be treated to reduce friction for protection against abrasion or breakage.
The chemical durability of glass is its ability to resist degradation when in contact with water, aqueous solutions, or other pharmaceutical formulations. This resistance is critical because the release of alkali or other extractable substances from the glass surface can compromise drug product quality, stability, and patient safety.
2. Glass Classification: The Evolution from Composition-Based to Performance-Based
2.1 Historical Classification by Composition
For decades, USP <660> classified pharmaceutical glass into three types based on composition:
| Glass Type | Composition | Primary Application |
|---|---|---|
| Type I | Borosilicate (neutral) glass | Most injectable and non-injectable products requiring high chemical resistance |
| Type II | Treated soda-lime-silica glass | Applications where surface treatment improves hydrolytic resistance |
| Type III | Soda-lime-silica glass | Non-parenteral or less demanding applications |
Type I borosilicate glass offers the highest hydrolytic resistance and is the preferred choice for most parenteral products, particularly biologics and sensitive formulations.
2.2 The 2023 Revision: A Paradigm Shift
On October 1, 2023, the final version of the revised USP <660> was published and made official. This revision represented a fundamental shift from a “composition-based” definition to a “performance-based” classification system.
Under the new framework, General Chapter <660> defines glass Types I, II, and III by performance characteristics rather than by composition alone, allowing for additional glass compositions to be considered Type I, II, or III based on their hydrolytic resistance.
This change was driven in part by a formal FDA request, which highlighted concerns about global glass vial shortages and resulting drug supply disruptions. The FDA expressed support for the use of new glass compositions—such as aluminosilicate glass—for parenteral products if they demonstrate suitability for the product.
2.3 New Glass Materials Added
The 2023 revision introduced two new glass materials to the chapter: aluminosilicate glass and quartz glass. These additions aim to provide more options with varying properties for different pharmaceutical applications.
Under the performance-based classification, aluminosilicate and quartz glasses that meet the testing requirements for Type I hydrolytic resistance can be classified as Type I glass, regardless of their specific composition. This flexibility paves the way for innovation and helps address supply chain challenges.
2.4 Impact on USP Monographs
To support this transition, revisions were made to 14 USP monographs that previously prescribed specific glass types by adding the word “preferably” in the packaging section. For example, a monograph requiring “Type I glass” now states “preferably of Type I glass”. This change gives manufacturers additional flexibility in their choice of packaging and facilitates the approval of new or different packaging types.
2.5 Global Harmonization Considerations
It is important to note that USP <660> and the European Pharmacopoeia (Ph. Eur.) Chapter 3.2.1—”Glass Containers for Pharmaceutical Use”—are not currently harmonized on this point. The Ph. Eur. still refers to borosilicate (“neutral”) glass for Type I glass containers. This divergence creates considerations for manufacturers seeking global regulatory compliance.
3. Key Test Methods in USP <660>
USP <660> specifies a series of analytical evaluations to confirm that glass packaging materials meet the required criteria. These tests assess the hydrolytic resistance of the glass surface and quantify the elemental composition of the bulk material.
3.1 Elemental Composition by Wavelength Dispersive X-Ray Fluorescence (WDXRF)
Replacement for the Glass Grains Test: The Glass Grains Test has been removed and replaced with a new identification test based on Wavelength Dispersive X-Ray Fluorescence (WDXRF). This modern method enhances the accuracy of identifying and characterizing glass materials.
The WDXRF test quantifies the elemental composition of the bulk glass material, providing a precise and objective means of verifying glass identity. Unlike the qualitative Glass Grains Test, WDXRF offers:
- Quantitative results: Precise measurement of elemental concentrations
- Enhanced accuracy: Reduced subjectivity in interpretation
- Improved efficiency: Faster and more reliable analysis
3.2 Inner Surface Hydrolytic Resistance Test
The Inner Surface Hydrolytic Resistance Test is retained as a core requirement. This test measures the release of soluble substances from the inner surface of the container into water under controlled conditions.
Test Procedure:
- Glass containers are filled with purified water to a specified volume
- The containers are subjected to autoclaving at elevated temperatures and pressures
- The resulting solution is titrated to measure the amount of alkali released
- The titration must be conducted within one hour after removing the samples from the autoclave
Why Timing Matters: During autoclaving, sodium (Na⁺) ions from the glass surface leach into the surrounding water. Immediately after autoclaving, the glass surface remains in a transient, highly reactive state for approximately one hour. During this period, released ions can be more readily titrated. Delaying titration beyond one hour may result in inaccurate measurements as the glass surface stabilizes and ion exchange slows.
The thermal cycle parameters specified in USP <660> must be precisely met to collect the correct amount of alkali—a key indicator of glass degradation.
3.3 Determination of Inner Surface Hydrolytic Resistance
The revised chapter provides added guidance on the application of autoclave instructions based on new studies, ensuring precise and reliable testing procedures.
3.4 Extractable Arsenic Test
A new extractable arsenic test has been added using inductively coupled plasma (ICP) technology, providing a more sensitive and accurate measurement of arsenic levels. This replaces the older colorimetric test based on USP <211>.
3.5 Spectral Transmission Test for Colored Glass Containers
The Spectral Transmission Test for Colored Glass Containers has been revised, incorporating data from both borosilicate and soda-lime-silica colored glass to refine the evaluation of light protection capabilities. This test ensures that colored glass containers provide adequate protection for light-sensitive drug products.
3.6 Removed or Eliminated Tests
The Surface Etching Test has been eliminated, streamlining the testing process and removing redundancies. This test was previously used to determine whether high hydrolytic resistance was due to chemical composition or surface treatment.
4. The Supporting Chapter: USP <1660>
USP <1660>—”Evaluation of the Inner Surface Durability of Glass Containers”—provides comprehensive guidelines on the formation, processing, and testing of glass containers used in pharmaceutical packaging. This general information chapter complements <660> by addressing:
- Glass delamination: A serious quality issue that can result in product recall
- Inner surface durability: Evaluation of the glass surface’s resistance to chemical attack
- Predictive screening: Identification of “early stage” indicators of glass degradation
- Collaboration: Emphasis on partnership between pharmaceutical manufacturers and glass vendors to maintain high-quality standards throughout the glass supply chain
The appearance of glass flakes is a lagging indicator of a strong interaction between the drug product and the inner surface of the glass. USP <1660> helps manufacturers identify potential issues before they become visible problems.
5. Practical Implications for Pharmaceutical Manufacturers
5.1 Supplier Qualification
Pharmaceutical manufacturers should procure glass containers only from qualified suppliers who provide a Certificate of Analysis (CoA) or test report showing USP <660> compliance. Key considerations include:
- Verification that the glass meets the required hydrolytic resistance classification
- Confirmation that elemental composition testing (WDXRF) has been performed
- Documentation of inner surface hydrolytic resistance test results
- Evidence of spectral transmission testing for colored glass containers
5.2 Preparing for the Performance-Based Classification
With the shift to performance-based classification, manufacturers have greater flexibility in glass selection. However, this flexibility comes with increased responsibility:
- Demonstrate suitability: Any glass composition used must pass the performance-based tests for the required Type classification
- Validate compatibility: The glass must be shown to be compatible with the specific drug product formulation
- Maintain documentation: Comprehensive records of testing and validation must be maintained for regulatory submission
5.3 Regulatory Submission Requirements
According to FDA Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics, each application should contain enough information to show that each proposed container system and its components are suitable for its intended use. This includes demonstration that glass containers meet USP <660> requirements for chemical resistance and light transmission (if indicated).
5.4 Stability Testing Considerations
USP <660> defines tests for glass containers, including hydrolytic resistance, thermal shock, and appearance checks. These tests should be performed before initiating stability testing to ensure that the glass packaging is suitable for the intended drug product.
Typically, all glass containers must be certified to both USP <660> and EP 3.2.1 requirements. Manufacturers should verify compliance with both standards when seeking global regulatory approval.
6. Vialab’s Commitment to Container Closure System Excellence
At Vialab Pharmaceutical Packaging Co., Ltd. , we recognize that the glass container is the foundation of any injectable container closure system. While our core products are aluminum caps and aluminum-plastic combination caps, we understand that these components must work in perfect harmony with USP <660>-compliant glass vials to ensure container closure integrity.
Our commitment to quality encompasses:
- Dimensional precision: Our caps are manufactured to tolerances that ensure proper fitment with standard glass vial neck finishes (13 mm, 20 mm, and 32 mm)
- Crimping compatibility: Our caps are designed to provide optimal crimping force distribution, maintaining stopper compression without over-compression that could stress the glass vial
- Sterilization compatibility: Our caps withstand the same sterilization methods (moist heat, irradiation, EtO) used for glass container processing
- Comprehensive documentation: We provide full traceability of our products, supporting our partners’ USP <660> compliance efforts
Whether you require aluminum caps or aluminum-plastic combination caps for your USP <660>-compliant glass vials, Vialab delivers components designed to work seamlessly with the complete container closure system.
Conclusion
USP <660> Containers – Glass establishes the foundational requirements for glass packaging used in pharmaceutical applications. Through its comprehensive test methods—including elemental composition by WDXRF, inner surface hydrolytic resistance, extractable arsenic testing, and spectral transmission for colored glass—the standard ensures that glass containers meet the necessary criteria for hydrolytic resistance, chemical durability, and light protection.
The October 2023 revision represents a significant evolution in the standard, transitioning from a composition-based to a performance-based classification system. This change provides manufacturers with greater flexibility in glass selection, facilitates innovation in glass materials (including aluminosilicate and quartz glass), and helps address supply chain challenges that have impacted the availability of critical drug products.
As the pharmaceutical industry continues to advance with new drug formulations and delivery systems, the importance of robust glass packaging standards will only grow. At Vialab, we remain committed to supporting our partners with high-quality packaging components and the technical expertise needed to navigate the evolving regulatory landscape.
References
- USP <660> – Containers – Glass
- USP <1660> – Evaluation of the Inner Surface Durability of Glass Containers
- USP <87> – Biological Reactivity Tests, In Vitro
- USP <88> – Biological Reactivity Tests, In Vivo
- Ph. Eur. 3.2.1 – Glass Containers for Pharmaceutical Use
- FDA Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics
- ISO 8362-1 – Injection containers and accessories — Part 1: Injection vials made of glass tubing
- ISO 8362-4 – Injection containers and accessories — Part 4: Injection vials made of moulded glass
- 21 CFR Part 211 – Current Good Manufacturing Practice for Finished Pharmaceuticals
This article is provided for informational purposes only and does not constitute regulatory advice. Manufacturers should consult with qualified experts and regulatory authorities for specific product validation and compliance.