From compliance to innovation – the key changes in pharmaceutical packaging regulations

Ellie McDermott, Regulatory Executive at G&L, explores the latest updates to pharmaceutical packaging regulations, their impact on the industry, and how companies can adapt to these changes in an increasingly complex regulatory landscape.

Introduction

The World Health Organization (WHO) defines pharmaceutical packaging as “the collection of different components (e.g., bottle, blister, vial, closure, cap, ampoule) which surround the pharmaceutical product from the time of production until its use."

These packaging systems protect drugs from external factors such as light and moisture, maintaining their stability and integrity (WHO, 2002). To ensure quality and compliance, pharmaceutical packaging must meet stringent regulatory guidelines.

This article reviews recent updates to pharmaceutical packaging guidance, including the European Pharmacopoeia Supplement 11.7, U.S. regulatory changes, and advancements in materials and manufacturing processes.

1. Key updates in Europe

1.1 European Pharmacopoeia Supplement 11.7 aligns the Ph. Eur. with ICH Q3D Guideline on Elemental Impurities.

Released in September 2024, Supplement 11.7 of the European Pharmacopoeia incorporates a new chapter on Extractable Elements in Plastic Materials for Pharmaceutical Use (2.4.35)[1], aligning the European Pharmacopoeia with the 2022 updates to the ICH Q3D Guideline on Elemental Impurities.

1.2 New Ph. Eur. Chapter on Elemental Impurities in Plastic Materials[2].

The release of Supplement 11.7 (2.4.35) has refocused attention on elemental impurities.

Parts of the Scope and the Introduction sections of the Q3D guideline are reproduced in the European Pharmacopoeia (Ph. Eur.) in general chapter 5.20 Elemental impurities. They are rendered legally binding by a cross reference in the general monograph on Pharmaceutical preparations (2619). This general monograph covers plastic containers for pharmaceutical preparations and closures.

Section 5.3 of ICH Q3D states that when a review of the materials of construction demonstrates that the container closure system does not contain elemental impurities, no additional risk assessment needs to be performed.

The new Ph. Eur. chapter on Extractable Elements in Plastic Materials for Pharmaceutical Use (2.4.35) provides a framework of analytical methods for testing container closure systems using plastic materials that extend beyond the review process established by ICH Q3D. Recommended limits for extractables will be included in general text 5.42 of the Ph. Eur. (EDQM, 2024).

1.3 Review of regulatory changes in pharmaceutical packaging between ICH Q3D and Supplement 11.7.

Globally, several other significant updates to guidance and regulation for pharmaceutical packaging have occurred since the update of ICH Q3D in 2022.

2. Updates in the USA

2.1 Revised Chapter <1031>: Biocompatibility of Pharmaceutical Packaging Systems[3].

The U.S. Pharmacopoeia (USP) has updated Chapter <1031>, now titled “Biocompatibility of Pharmaceutical Packaging Systems and Their Materials of Construction."

Effective December 1, 2024, this revision broadens the scope to include plastic and elastomeric components and adopts risk-based approaches for material classifications.

The concept of “Pharmaceutical Grade Polymeric Packaging Material” replaces the older classification system of plastics introduced in 1965.

The update emphasizes in vitro tests for cytotoxicity and Reconstructed Skin Epidermis Test for irritation as prerequisites for compliance (USP, 2024).

2.2 Chapter <382>: Elastomeric Components for Injectable Packaging Systems[4].

This newly introduced chapter will become effective on December 1, 2025, and replaces Section 4.3 of Chapter <381>. It will focus on the suitability of elastomeric materials in parenteral product packaging and delivery systems (USP, 2024).

2.3 New standards for metallic packaging Systems.

Chapter <662>, Metallic Packaging Systems and Their Materials and Components of Construction, is the first USP standard for metallic packaging used for prescription drugs and over-the-counter pharmaceuticals (Packaging Digest, 2024).

It outlines quality requirements for metallic materials used in drug containers, excluding certain components like aluminum caps.

An accompanying informational chapter, <1662>, Materials and Manufacturing Processes for Metallic Packaging Systems[5], guides manufacturing processes for metal packaging.

The proposal closed for comments on the USP website on 30th September 2024. The implementation date has yet to be announced (USP, 2024).

2.4 FDA guidance on glass vials and stoppers

In July 2024, the FDA consolidated guidance for container closure systems made of glass vials and stoppers[6]. This document harmonizes recommendations for New Drug Applications (NDAs), Biologics License Applications (BLAs), and Abbreviated New Drug Applications (ANDAs).

It also provides recommendations to the marketing authorization holders on submitting changes to container closure systems such as recommendations on suitable reporting categories (FDA, 2024).

3. Additional updates

3.1 EU GMP Annex 1: Sterile medicinal product packaging.

The revised EU GMP Annex 1, “Manufacture of Sterile Medicinal Products”[7], emphasizes validated sterilization processes for primary packaging components, holding manufacturers accountable for sterility assurance, even when outsourcing production.

As a result, manufacturers who perform the QP certification must ensure that they have full access to the sterility information as this can be subjected to audits.

The guidance is particularly relevant for ready-to-sterilize (RTS) and ready-to-use (RTU) packaging systems (ECA, 2024).

Conclusion

The regulatory landscape for pharmaceutical packaging continues to evolve, driven by advancements in materials, sustainability goals, and the rise of personalized medicine.

While regulations and the need for compliance have increased, recent clarifications on pharmaceutical packaging guidelines ultimately assist pharmaceutical manufacturers and companies in identifying the requirements to remain compliant.

These recent updates provide clearer frameworks for compliance, helping manufacturers navigate stricter standards while ensuring the safety and efficacy of pharmaceutical products.

References

Ball, D. (2016) USP Material Biocompatibility and Standard for Plastic Manufacturing Systems/Components Workshop, available at: https://www.usp.org/sites/default/files/usp/document/workshops/workshop-e-program-final.pdf (Accessed: 23 October 2024).

ECA Academy (2024) Biocompatibility of Pharmaceutical Packaging Systems. Available at: https://www.gmp-compliance.org/gmp-news/biocompatibility-of-pharmaceutical-packaging-systems (Accessed: 09 October 2024).

ECA Academy (2024), GMP Requirements for Ready to Sterilize (RTS) and Ready to Use (RTU) Containers. Available at: https://www.gmp-compliance.org/gmp-news/gmp-requirements-for-ready-to-sterilize-rts-and-ready-to-use-rtu-containers (Accessed 11 October 2024).

European Directorate for the Quality of Medicines and Healthcare (2024), New general chapter on Extractable elements in plastic materials for pharmaceutical use (2.4.35) adopted. Available at: https://www.edqm.eu/en/-/new-general-chapter-on-extractable-elements-in-plastic-materials-for-pharmaceutical-use-2.4.35-adopted (Accessed: 11 October 2024).

Packaging Digest (2024) USP Pens First Standard for Metal Packaging. Available at: https://www.packagingdigest.com/pharmaceutical-packaging/usp-pens-first-standard-for-metal-packaging (Accessed: 09 October 2024).

US Food & Drug Administration (2024) Container Closure System and Component Changes: Glass Vials and Stoppers. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/container-closure-system-and-component-changes-glass-vials-and-stoppers (Accessed: 09 October 2024).

US Pharmacopoeia (2024) ‘〈1031〉 The Biocompatibility of Materials Used in Drug Containers, Medical Devices, and Implants’, USP, Available at: https://doi.org/10.31003/USPNF_M99754_03_01 (Accessed: 09 October 2024).

US Pharmacopoeia (2024) ‘〈381〉 Elastomeric Components in Injectable Pharmaceutical Product Packaging/Delivery Systems’, USP, Available at: https://doi.org/10.31003/USPNF_M99140_60201_01 (Accessed: 09 October 2024).

US Pharmacopoeia (2024) ‘〈662〉 Metallic Packaging Systems and Their Materials and Components of Construction.’, USP, Available at: https://doi.org/10.31003/USPNF_M2315_10101_01 (Accessed: 09 October 2024).

World Health Organization (2002) ‘TRS 902 - Annex 9: Guidelines on packaging for pharmaceutical products’, WHO Technical Report Series No. 902, Available at: https://cdn.who.int/media/docs/default-source/medicines/norms-and-standards/guidelines/regulatory-standards/trs902-annex9.pdf?sfvrsn=82b4c57d_2 (Accessed: 11 October 2024).

[1]General chapter 2.4.35 Extractable Elements in Plastic Materials for Pharmaceutical Use will be referenced in the general chapters on Cyclo-olefin polymers (3.1.16), Cyclo-olefin copolymers (3.1.17), and Styrene block copolymers for containers and closures for parenteral preparations and ophthalmic preparations (3.1.18).

[2] Link to guidance: https://www.edqm.eu/en/-/new-general-chapter-on-extractable-elements-in-plastic-materials-for-pharmaceutical-use-2.4.35-adopted

[3] Link to guidance: https://doi.usp.org/USPNF/USPNF_M99754_03_01.html

[4] Link to guidance: https://doi.usp.org/USPNF/USPNF_M99140_60201_01.html

[5] Link to guidance: https://doi.usp.org/USPNF/USPNF_M2315_10101_01.html

[6] Link to guidance: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/container-closure-system-and-component-changes-glass-vials-and-stoppers

[7] Link to guidance: https://health.ec.europa.eu/document/download/e05af55b-38e9-42bf-8495-194bbf0b9262_en?filename=20220825_gmp-an1_en_0.pdf