Annex 1 has been in force since 2023. Yet for many Indian sterile injectable manufacturers, practical implications, especially for elastomeric closures, may only become fully visible later in the program, including during inspection readiness activities and regulatory inspections, when remediation options can be more limited.
For companies targeting US FDA and EMA approvals, elastomeric closures and container closure integrity (CCI) have long been core topics. What has changed under the revised Annex 1 is the depth and explicitness of expectations: greater emphasis is being placed on contamination control, particles, and component qualification, and they expect the CCS narrative and supporting evidence to be consistent and inspection ready.
By the time a pre‑approval inspection begins, it is highly challenging to remediate fundamental gaps quickly.
So where are inspectors focusing today, and where do gaps most commonly appear?
Why Annex 1 has changed the conversation on elastomeric closures
The revised Annex 1 introduced clearer, more explicit expectations in three areas that directly affect primary packaging components:
Individually, none of these topics is new. What has changed is that they are now:
A holistic review against these pillars can help identify gaps early and align the closure strategy with current expectations.
Below are three gaps that typically emerge during inspection readiness reviews - and how manufacturers can address them.
Gap 1: Container Closure Integrity is missing - or weak - in the Contamination Control Strategy
One of the most consequential changes in the 2023 revision is the formal requirement for a documented Contamination Control Strategy. Importantly, Annex 1 now explicitly includes container closure integrity (CCI) within the scope of the CCS.
In practical terms, CCI has always been central to sterile product assurance. Annex 1 now makes those expectations more explicit within the CCS framework and, in many cases, more stringent in terms of how risks are assessed, how methods are justified (including deterministic approaches where appropriate), and how results are documented and defended during inspection.
During an inspection, manufacturers are increasingly expected to demonstrate:
This is often where difficulties arise for manufacturers who rely mainly on dye ingress testing. Dye ingress is a probabilistic method, and for many parenteral products, especially those with long shelf lives or very low doses, regulatory expectations have shifted toward deterministic methods, such as:
How this can be addressed Aptar Pharma provides elastomeric component data packages that include deterministic CCI testing, such as vacuum decay and laser headspace analysis, supported by helium leak testing down to −80 °C. These datasets may be referenced in regulatory submissions where appropriate; applicability depends on the product and dossier strategy. They may also help strengthen the CCI section of a manufacturer’s CCS.
Gap 2: Silicone oil is now firmly in scope for particle management
Particle management is another area where Annex 1 has raised expectations.
Section 10 of the revised Annex explicitly reinforces requirements around particle monitoring, investigation, and prevention. For elastomeric closures, this brings silicone oil shed from plunger surfaces clearly into scope.
The regulatory expectation is not zero silicone oil. Instead, inspectors expect a documented, risk‑based approach demonstrating that particulate levels remain within specification throughout the product’s shelf life.
For biosimilars and sensitive biologics, including GLP‑1 peptides, this has changed the nature of plunger coating decisions. What was once treated mainly as a formulation or device detail now carries broader regulatory and strategic implications.
This scrutiny is intensifying further with the revised USP <788>, harmonized with Ph. Eur. 2.9.19 and JP 6.07, which comes into force on 1 August 2026. The revision:
For manufacturers filing with both the US FDA and EMA, Annex 1 and the revised USP <788> are converging around the same core principle: contamination control must be demonstrated across the entire supply chain, not only at final release testing.
How this can be addressed Aptar Pharma’s PremiumCoat® ETFE film‑coated plungers are designed to help reduce silicone oil shed under conditions representative of commercial fill‑finish operations. Combined with PremiumFill® cleanroom manufacturing, these components can help reduce the baseline particulate load entering the filling line and provide documented, traceable evidence aligned with both Annex 1 and USP <788> expectations.
Gap 3: From individual component qualification to container–closure system qualification
The revised Annex 1 is also more explicit about what elastomeric component qualification must demonstrate. Components should be qualified under conditions that are representative of the final assembled system, not only tested in isolation.
This aligns with USP <382>, effective at the end of 2025, and existing FDA guidance. Across all three frameworks, the message is consistent: qualification of the complete container –closure system is expected.
For Indian manufacturers working with multiple glass suppliers, this creates a practical challenge. Closure components qualified with one glass manufacturer do not automatically transfer to another. Without cross‑platform qualification data, separate qualification exercises are required for each glass–closure combination, quickly multiplying validation effort and documentation.
How this can be addressed Aptar Pharma has completed cross‑platform qualification of PremiumCoat® components across primary containers from various major glassmakers. For manufacturers using multiple glass suppliers, this can help reduce the extent of repeated qualification work across certain glass–closure combinations, depending on the manufacturer’s qualification strategy.
Practical implications
India is a large source of US FDA‑approved medicines outside the United States, and inspection activity continues to increase. As European demand grows, Indian facilities are also increasingly under the review of the EMA.
Annex 1 compliance will be assessed during EU GMP inspections. Elastomeric closures -through CCS documentation, particle management, and component qualification - are fully inspectable.
Manufacturers best prepared for inspection are those that have already identified potential gaps, understand where their documentation is strong, and work with suppliers able to support rapid remediation when needed.
Preparation goes beyond data alone. It includes:
Next step
If you are preparing for a regulatory inspection - or if questions remain around elastomeric closure qualification - an Aptar Pharma international subject matter expert team will be in India in June 2026 visiting Hyderabad, Ahmedabad, Bangalore, Pune, and Mumbai.
Bring your questions.
We can share relevant data packages and discuss applicability to your program.
Please contact keval.ghadiali@aptar.com if you are interested in joining this Aptar Pharma organized event and/ or if you have any questions, we can help address.