Unpacking The FDA Draft Guidance On Container Closure Systems

By Fran DeGrazio, Senior Industry & Technical Advisor, Drug Delivery Leader

Having worked in the sterile drug packaging industry for more than 40 years, I had been anticipating an update to the FDA’s 1999 Container Closure Guidance for quite some time. Over the past 25 years, especially, the industry has continued to advance its approach to bringing drugs, biopharmaceuticals, and combination products to market. A vital consideration along the way of product innovation is ensuring that container closure systems (CSSs) keep pace. So, when the new draft guidance, Container Closure Systems for Human Drugs and Biological Products, did appear, I was eager to read it. From my perspective,  the draft does not disappoint. It accurately reflects the industry’s progress and helpfully points toward the future.

Released by the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), and the Office of Combination Products (OCP), the document reinforces the industry’s broader evolution while providing important direction for organizations developing and commercializing these products. The document clearly states that it “applies to applications, for human drugs and biological products, as well as for combination products.”

Because the guidance remains in draft form, the FDA is seeking industry comments before finalizing it. Even so, the document offers a meaningful view into the agency’s current thinking. Once finalized, the guidance is likely to become a key reference for professionals involved in drug development, package and device engineering, and combination product development.

Below, I begin by outlining what I consider to be the guiding principles of the document. Then, I dive into some of the details in the document and offer my thoughts and recommendations about the significance of various points.

Reinforcing A Risk-Based Framework

First and foremost, the draft guidance consistently grounds concepts in a risk-based framework. This approach aligns closely with the direction of the U.S. FDA and many global regulatory agencies, which continue to emphasize that development and operational decisions should be based on the specific risks, needs, and intended use of each product. Per the draft guidance, “selection of the CSS for a drug depends on the characteristics of both the drug and the CSS.”

The 1999 Container Closure Guidance was one of the early documents to frame container closure expectations through a risk-based lens — well before risk-based thinking became an established regulatory standard. It helped clarify that higher-risk drug products require more extensive testing than lower-risk products.

• Higher-risk examples include inhalation products and injectable products.
• Lower-risk examples include solid oral dosage forms.

The 2026 draft guidance reinforces the previous guidance’s risk-based approach and extends it across the full development and commercialization life cycle. It outlines the guiding principles for container closure systems (CCS) used to package human drugs and biological products.

Basing Decisions On Science And Logic

A second clear theme is that the work performed — and the decisions made — should be logical, scientifically justified, and product-specific. Although the draft guidance provides direction, it does not prescribe a fixed set of requirements or a universal checklist.

For example, the guidance does not list, say, 10 specific tests that every organization must use to characterize a drug product or combination product. Instead, it encourages organizations to think carefully about the goals of their unique development programs.

This approach matters because every drug product is different, and each drug CCS is different. Each product may have distinct performance needs, risk considerations, and user groups. Requiring the same data package for every product — regardless of whether it is relevant to the final drug or its users — would not be risk-based or scientifically sound.

Moving Away From Checklist Thinking

This way of acknowledging distinctness may require a meaningful shift in thinking for some organizations. For years, I have heard people ask for a simple list of tests to complete. While a checklist approach may be easier for those developing and executing test plans, it often invites less critical evaluation.

The draft guidance moves organizations away from simplifying. It encourages teams to justify their decisions based on science, product understanding, and risk rather than rely on a generic set of tests that may or may not be appropriate for the product being developed.

The goal of the guidance is to ensure that testing and control measures confirm that the CCS does not adversely impact the safety, identity, strength, quality, and purity of the product.

What Does A Container Closure System Contain?

The draft guidance defines a container closure system (CCS) as the full set of packaging components used to protect the drug product. This can include secondary packaging when its function is to provide additional protection.

One clear example is a polymer syringe with an outer wrap. Unlike glass systems, polymer systems may allow moisture vapor or gas transmission through the barrel. For that reason, a foil overwrap or other secondary package may be needed to limit product changes over the shelf life. Because this secondary package can be essential to the performance of the overall drug or combination product, it must be thoroughly characterized, understood, and controlled.

Since guidance documents easily become outdated through the years, one of the recommendations  shared is to reference compendia such as the United States Pharmacopeia (USP) or the International Council for Harmonization (ICH) for the most updated industry guidance in reference to more comprehensive or advanced testing.

4 Key Reminders From The Draft Guidance

#1: Attend To The Entire Product Life Cycle

A critical point is that meeting drug specifications, USP criteria, and other applicable requirements should be considered development milestones to be demonstrated not only at time zero but throughout the product’s shelf life.

That means organizations need to build scientific understanding across the conditions a product may experience, including shipping, storage, distribution, and common stress conditions such as thermal cycling. The product must continue to meet its specifications after exposure to those conditions and at the end of shelf life.

#2: View The CCS Within A Holistic Context

A second important takeaway is one I have emphasized for many years and that this draft guidance reinforces: organizations must understand the materials of construction, the individual packaging components, and the container closure system as a whole.

Each element informs the next. Materials, components, and the overall system must be evaluated both individually and in combination so that teams understand how the CCS performs in the context of the specific drug product and its environmental conditions.

#3: Know When The CCS Is A Device Constituent Part

Another important takeaway is that a container closure system may also be considered a device constituent part when it performs more than one function. A metered dose inhaler (MDI), for example, both contains the drug and directly affects the particle size of the drug product it delivers.

When a CCS functions in this way, the applicable device constituent part or combination product requirements must also be considered, including the requirements described in 21 CFR Part 4, subparts A and B.

#4: Know Why You’re Selecting This CCS For This Product

A last point worth emphasizing is one I have discussed with pharmaceutical companies for many years: A CCS that was appropriate for one drug product cannot automatically be assumed to be appropriate for another.

This point is especially important because CCS platforms are often pre-qualified, and development teams may be encouraged to use existing approved components or systems. That approach can be effective, but only when the rationale for using those components in the specific application is clear and scientifically justified.

The explanation cannot simply be, “because we used it before.” Teams should be able to demonstrate why the selected CCS is appropriate for the particular drug product, its intended use, and the conditions it may encounter throughout its life cycle.

Several years ago, I worked with a customer at a global organization who explained that the company had selected what it considered to be the highest quality vial and stopper platform in order to minimize risk. During regulatory review, however, the agency asked a critical question: How do you know this system is appropriate for this specific drug product?

That question captures a key point reinforced throughout the draft guidance: Organizations must be able to clearly explain why each CCS decision was made.

• The rationale should be product specific.
• The selected system should be supported by scientific justification.
• The explanation should be clear to the regulatory reviewer.

This expectation is not new, but the draft guidance makes it more explicit. As a result, organizations should be prepared for similar questions in future submissions and should ensure that their development decisions are well documented, scientifically justified, and tied directly to the needs of the specific drug product.

Assessing Quality, Ensuring Control

The draft guidance also encourages organizations to build a clear understanding of the key areas that influence container closure system quality. These areas include:

• Safety
• Protection
• Performance
• The impact of the manufacturing process
• Storage and handling conditions

The guidance provides a practical framework for defining the related quality assessments and controls, making it easier for teams to align expectations and to document their rationale.

Integrity Testing Remains An Integral Activity

According to  the draft guidance a CCS must “protect against ingress from external contaminants and should prevent leakage.” Protection is one area where container closure integrity testing (CCIT) receives significant attention in the draft guidance. The guidance reinforces that CCIT should be approached through clear scientific rationale and method-specific understanding.

The draft guidance encourages the use of innovative, advanced, and deterministic integrity testing technologies. This reinforces the need for organizations to clearly explain why a particular test method was selected and why it is appropriate for the dosage form being evaluated.

Organizations should be prepared to demonstrate that they understand and have justified key aspects of the test method, including:

• Method validation for the specific container closure system
• The sensitivity of the test method being used
• The use of appropriate positive and negative controls
• The rationale for why the selected method is suitable for the product and CCS being evaluated.

Taken together, these points reinforce a central theme of the draft guidance: Good science must drive CCS testing decisions, rather than relying on a generic or unsupported testing approach.

Container integrity is an area where the industry has long relied on USP guidance. USP Chapter <1207>, which is also currently under review for updates, has been widely referenced around the world to support expectations for container closure integrity.

Emphasis On Extractables And Leachables

Another key area of focus in the draft guidance is extractables and leachables testing, particularly as it relates to safety and compatibility. This testing is a clear expectation as part of a CCS suitability evaluation.

Extractables and leachables studies, along with associated toxicological assessments, should be performed for any drug product from which leached substances could be introduced to the patient. As with other requirements in the guidance, leachables assessment should extend throughout the product’s shelf life and may be incorporated into the stability program.

Risk assessment for leachables should be performed on a case-by-case basis, taking into account the specific drug product, container closure system, route of administration, and potential patient exposure.

The draft guidance also provides direction on how toxicological risk assessments should be performed, including consideration of both safety and analytical thresholds. One particularly useful point of reference is the establishment of a 1.5 µg/day Safety Concern Threshold (SCT).

This threshold reflects much of the historical work completed by the Product Quality Research Institute (PQRI) on extractables and leachables. By comparison, the 1999 guidance focused more heavily on USP Chapters <87> and <88>, USP <381>, and USP <661>. Those chapters remain important for certain material and biological evaluations, but they would not be considered a complete substitute for modern extractables and leachables testing.

USP continues to update chapters related to these topics. At present, USP <1663> provides general guidance on extractables, while USP <1664> provides general guidance on leachables.

Per the draft document, “Test and evaluation methods for CCS quality assessments and controls should be selected based on the identified risks and potential methods of mitigating these risks,”

Integrating CCS Into The Quality Management System 

CCS management should be integrated into the formal quality system rather than treated as a standalone activity. Organizations developing new products, changing packaging materials or suppliers, or making other critical life cycle changes should ensure that each decision is scientifically justified, well documented, and ready for inspection.

The draft guidance also provides additional information on several related topics, including:

• Auxiliary packaging components
• Packaging components for device constituent parts of combination products
• Drug substance bulk containers
• Other CCS-related subjects that may affect packaging strategy and life cycle management

Leveraging The Draft Guidance Ahead Of Finalization

It is important for industry stakeholders to take the time to review the draft guidance and provide comments from a practical, industry-based perspective. Overall, the draft is consistent with the direction regulators have been communicating to the global pharmaceutical industry. For that reason, pharmaceutical organizations should begin using the draft to inform internal discussions, development strategies, and future planning related to container closure systems.