FDA Modernizes Container Closure Guidance: What Is Changing And Why It Matters

By Tim Sandle, Ph.D.

In August 2026, the FDA issued a new draft guidance on container closure systems for human drugs and biological products.¹ When finalized, the document is intended to supersede both the FDA’s May 1999 guidance, Container Closure Systems for Packaging Human Drugs and Biologics,² and the associated May 2002 questions-and-answers guidance.³ The draft is currently available for comment.

The proposed revision reflects changes in pharmaceutical products, packaging technology, drug delivery systems, analytical science, quality risk management, distribution models, and international standards that have occurred since 1999.

The 1999 guidance required a container closure system to protect the dosage form, remain compatible with it, be made from safe materials, and perform correctly if a needle was required to pierce the closure. The extent of information that a manufacturer needed to assess depended on dosage form, route of administration, and the likelihood of interaction between the product and its packaging. These principles remain recognizable in the 2026 draft. However, the FDA is proposing to place these within a more explicit, product-specific, risk-based, and life cycle-oriented framework. The practical message is that packaging can no longer be treated merely as a passive collection of components to be assembled. This new holistic approach indicates that materials, manufacture, integrity, functionality, storage conditions, distribution stresses, and potential chemical interactions can affect product quality and patient safety, and therefore they need to be assessed as a system.

Why The FDA Is Replacing The 1999 Guidance

The 1999 document is organized primarily around established dosage form categories and conventional packaging technologies. It recognized that injectable and inhalation products required more extensive information than solid oral dosage forms, and that liquids were more likely than powders or solids to interact with packaging components.  The FDA explains that novel drug products and new container closure technologies have advanced considerably. Packaging may now help prepare a final dose, deliver a drug, measure a dose, or form a device constituent part of a combination product. The agency also points to newer and revised USP standards, more advanced methods for characterizing materials and components, and takes account of FDA and ICH guidance issued since 1999.

The old framework remains scientifically valuable, but it does not fully capture present-day packaging and delivery systems, contemporary extractables and leachables science, modern container closure integrity testing, or the expanding interface between pharmaceutical and medical device regulation.

From A General Risk Hierarchy To Product-Specific Risk Management

The 1999 guidance used a matrix that correlated the degree of concern associated with a route of administration with the likelihood of an interaction between the packaging component and dosage form. Inhalation aerosols and injectable solutions occupied high-concern positions, while oral tablets and capsules were placed at the lower end of the hierarchy. The 2026 draft retains a risk differentiation, but one that is expanded and places stronger qualifications around the risk level and the extent of testing. The guidance indicates that assessments should be product-specific and should consider the formulation, route of administration, dosage form, packaging materials, system design, manufacturing process, and clinical use. Relevant formulation variables may include pH, cosolvents, surfactants, chelating agents, preservatives, stabilizers, lipids, and drug load.

Notably, with testing, the revised approach discourages companies from treating a dosage form category as a sufficient justification for a reduced test package. Even a nominally low-risk oral or topical product requires an adequate evaluation of possible leachables, for example. Conversely, two products with the same route of administration could require different assessments because their formulations or packaging configurations present different risks. In essence, this moves things away from broad categorization as the primary decision mechanism and toward documented quality risk management.

Extractables And Leachables Move To The Center

The 1999 guidance addressed extraction studies and toxicological evaluation, especially for products likely to interact with packaging. It described extraction profiles and advised that extracting media should reflect the dosage form’s ability to extract substances from the packaging component. It also recognized that the drug product or placebo vehicle was often the preferred extraction medium. The 2026 draft gives extractables and leachables a much more prominent and structured role. It describes their assessment as an integral part of suitability evaluation for products likely to interact with packaging components.⁴ The studies should be designed using a product-specific, risk-based approach and should be considered throughout the product life cycle.

For leachables studies, the draft recommends evaluation throughout shelf life under the relevant stability conditions. The commercial packaging system should be represented, including secondary components such as labels, adhesives, over-pouches, wraps, and cartons when relevant. Analytical methods should be properly validated, and a relationship between extractables and leachables may be established where sufficient data is available. The draft also introduces a more defined toxicological framework, connecting chemical characterization, analytical capability, patient exposure, route-specific toxicity, and life cycle stability. It discusses the safety concern threshold, qualification threshold, and analytical evaluation threshold. It recommends a safety concern threshold of 1.5 micrograms per day for most chronic-use drugs, while recognizing that lower values may be appropriate for compounds of specific toxicological concern, including nitrosamines. Local tissue toxicity may also require a concentration-based qualification threshold for routes such as ophthalmic, intrathecal, or perineural administration.

Container Closure Integrity Receives A Detailed Framework

The 1999 guidance recognized the importance of product protection from microbial contamination and referred to container integrity, leak testing, vacuum leak testing, weight loss, and media fills. For injectables, sterility and container integrity were important suitability considerations. However, the document did not provide the consolidated CCIT framework. This is now included in the draft. For sterile products, CCIT should demonstrate that the selected system provides an adequate sterile barrier, supports validation of relevant manufacturing parameters such as capping settings, functions as an appropriate in-process control where applicable, and shows that integrity is maintained at labeled storage conditions through expiry. The draft draws particular attention to transient integrity loss at extreme temperatures. Elastomeric closures, for example, may temporarily lose sealing performance at very low temperatures and reseal after warming. A test conducted only after returning to ambient conditions might therefore fail to detect the event.⁵

The FDA also lists methods for vials, ampules, prefilled syringes, cartridges, flexible bags, blister packs, tubes, and pouches. These include helium leak testing, pressure or vacuum decay, dye ingress, mass extraction, high-voltage leak detection, bubble emission, seal integrity, and burst or creep testing. The agency encourages advanced deterministic technologies, although it does not categorically exclude probabilistic methods such as the dye ingress test.

The draft further encourages CCIT in place of sterility testing as the stability program measure for demonstrating maintenance of package integrity, reflecting the recognized limitations of sterility testing. The stability section states that integrity may typically be demonstrated annually and at expiry for sterile products. This should drive sterile manufacturers toward an integrated integrity strategy.⁶

Combination Products Come Fully Into View

Combination products are one of the clearest examples of why the guidance required modernization. The 1999 guidance discussed packaging performance and drug delivery for prefilled syringes, transdermal patches, droppers, sprays, and inhalers. However, the new draft explicitly addresses container closure systems that are also device constituent parts, including piston syringes, pumps, metered-dose inhalers, and intravenous bags. Where a container closure is also a device constituent part, additional considerations include device performance, engineering, the user interface, design controls, purchasing controls, and interactions between the device and the drug or biologic. The draft links these expectations to 21 CFR Part 4⁷ and, where applicable, ISO 13485:2016⁸ requirements incorporated into the amended device quality system regulation.

The FDA also expects performance testing to cover relevant conditions after shipping, during storage, and in use. For a prefilled syringe, this may include glide force, break-loose force, and seal integrity. For a metered-dose inhaler, the relevant outputs may include delivered-dose uniformity, valve delivery, aerodynamic particle-size distribution, and spray pattern. Human factors studies may also be pertinent where the user interface affects safe and effective operation.

Manufacturing, Shipping, And Extreme Storage Become Part Of The Assessment

The 1999 guidance stated that packaging should protect products throughout their shelf life and addressed bulk storage, compatibility, stability, and certain packaging treatments. The 2026 draft expands the life cycle view, requiring a risk assessment to evaluate the effects of washing, coating, lyophilization, sterilization, depyrogenation, irradiation, ethylene oxide, and vaporized hydrogen peroxide, as applicable. This is because such treatments may alter material properties, produce leachables, affect functionality, or contribute to glass delamination and particulate formation.

Shipping studies should examine environmental and mechanical stresses, including light, moisture, reactive gases, compression, vibration, shock, air pressure changes, and expansion. Cold chain systems should be qualified under worst-case temperature and transportation conditions. Freeze-thaw and thermal-cycling studies may be required to confirm that product quality, integrity, and functionality are retained.

Clearer Expectations For Submissions And Life Cycle Changes

The 1999 guidance described the information expected in NDAs, ANDAs, BLAs, INDs, and Type III drug master files. The new draft updates this for current electronic submissions and identifies where container closure information should be located within the electronic common technical document. The new draft includes a proposed table that maps descriptions, material identities, specifications, suitability, extractables and leachables, CCIT, process validation, stability, engineering drawings, and toxicological assessments to relevant eCTD sections. It also calls for summaries containing hyperlinks to related reports.

For post-approval changes, the draft guidance specifies that changes to components, materials of construction, device constituent parts, or associated manufacturing processes should be supported by a risk assessment addressing effects on identity, strength, quality, purity, and potency. Submissions should include relevant quality evaluations and scientifically justify any omitted testing.

To summarize the core differences between the current and draft guidance, the 1999 guidance focuses on whether packaging components and systems were suitable and adequately controlled. The 2026 draft asks companies to show how product-specific risks have been identified, how analytical and toxicological evidence addresses those risks, how integrity and performance persist under actual life cycle stress, and how packaging changes remain controlled.

References:

1. Container Closure Systems for Human Drugs and Biological Products, Guidance for Industry [draft guidance], U.S. Department of Health and Human Services, August 2026: https://www.fda.gov/media/194220/download
2. Guidance for Industry Container Closure Systems for Packaging Human Drugs and Biologics, U.S. Department of Health and Human Services, May 1999: https://www.fda.gov/media/70788/download
3. Container Closure Systems for Packaging Human Drugs and Biologics -- Questions and Answers, U.S. Department of Health and Human Services, May 2002: https://www.fda.gov/media/70794/download
4. Fu C, Zhang X, Lei S, Zou M, Wang L, Jiao J, Yang Q. Identification and quantification of extractables and leachables in laminated film and pouches for pharmaceutical packaging. J Pharm Biomed Anal. 2022;220:115015
5. Wuchner K, Brown HC, Canal F et al. Industry perspective on a holistic container closure integrity approach to parenteral combination products. Eur J Pharm Biopharm. 2024;194:20-35. doi: 10.1016/j.ejpb.2023
6. Sandle, T. (2023) Pharmacopeial sterility test: The statistical limitations of sampling, European Journal of Parenteral and Pharmaceutical Sciences, 2023; 28 (2): https://www.ejpps.online/post/pharmacopeial-sterility-test-the-statistical-limitations-of-sampling
7. 21 CFR Part 4 — Regulation of Combination Products, Subpart A — Current Good Manufacturing Practice Requirements for Combination Products, 78 FR 4321: https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-4
8. ISO 13485:2016 Medical devices — Quality management systems — Requirements for regulatory purposes, International Standards Organization for Standardization, Geneva

About The Author:

Tim Sandle, Ph.D., is a pharmaceutical professional with wide experience in microbiology and quality assurance. He is the author of more than 30 books relating to pharmaceuticals, healthcare, and life sciences, as well as over 170 peer-reviewed papers and some 500 technical articles. Sandle has presented at over 200 events and he currently works at Bio Products Laboratory Ltd. (BPL), and he is a visiting professor at the University of Manchester and University College London, as well as a consultant to the pharmaceutical industry. Visit his microbiology website at https://www.pharmamicroresources.com.