Are We Set for the Revised EU GMP Annex 1?

Overview of EU GMP Annex 1
EU GMP Annex 1 is the European Union’s guidelines for good manufacturing practice (GMP) of sterile medicinal products for human and veterinary use.¹ It provides specific requirements for the manufacture of sterile medicinal products, including principles for cleanroom and clean zone design, personnel experience/qualification, and monitoring of manufacturing environments, just to name a few. The objective is to ensure product quality and potency, as well as patient safety, by minimizing risks of microbial, particulate and endotoxin/pyrogen contamination through manufacturing and environmental controls.
In August 2022, the final draft of EU GMP Annex 1 was released after years of development and took effect on 25 August 2023. In this blog, a summary of the key changes of relevance to primary packaging components and how West can help with the implementation will be discussed.

Key Changes to Annex 1 Requirements: Implementation of Contamination Control Strategy (CCS)

In the new revision of Annex 1, the implementation of the Contamination Control Strategy (CCS) is by far the most important and challenging to the Quality Management in the manufacturing of injectables.

CCS plays a vital role in the management and control of contamination from microbial, endotoxin/pyrogen and particulate, derived from the existing sterile medicinal product and/or the sterile manufacturing process understanding, to ensure the performance and quality of the product in the drug manufacturing process. This involves consideration of several elements such as raw material controls, equipment, and process design, including management of outsourced activities. Pharmaceutical manufacturers are expected to provide a comprehensive and formal documentation of the manufacturing process, from the receipt of raw materials to the distribution of the sterile drug products.

Challenges faced by Pharmaceutical Manufacturers

Since the release of the draft, pharmaceutical manufacturers face several obstacles in trying to prove compliance with the guidelines as the implementation of CCS requires a multi-disciplinary methodology. This may pose a challenge as the requirements and controls are not apparent. According to a survey conducted during a webinar hosted by STERIS titled “Contamination Control Strategy: Implementation Roadmap”, the majority of respondents saw the biggest challenge in identifying all the critical controls, followed by establishing the interlink between controls, and defining the CCS scope.²

Indeed, the design and implementation of a CCS is an intricate process, with emphasis on the importance of expertise and knowledge of the critical factors that may contribute to contamination within the manufacturing process.

Factors involving Primary Packaging Components

The EU GMP Annex 1 has multiple ramifications on our customers as they navigate through the new requirements with primary components as one of their concerns, i.e., elastomeric components, specifically stoppers and plungers, which is one of the considerations in the CCS.

The monitoring and reduction of particulates and microbial contaminants from primary packaging components is one of the many aspects in ensuring that the finished product is free from contamination. In aseptic manufacturing, the components are required to be cleaned using validated processes to ensure that particle, endotoxin/pyrogen and bioburden contamination is adequately controlled. Additionally, these specifications for raw materials, components and products should be clearly defined for the monitoring of CCS. The new revision also strongly recommends the use of barrier technology, such as restricted access barrier systems (RABS) and isolators, to minimize microbial contamination originating from human intervention in critical areas such as the fill and finish operation. Herein, the component packaging needs to be considered during the transfer into RABS and isolators. Depending on the drug manufacturers’ existing infrastructure, they may be required to install new equipment and/or make extensive adjustments to their fill and finish operation to comply with the new guidelines. Should the manufacturer choose not to adopt these technologies, the alternative method needs to be justified.

Container closure integrity (CCI) is also part of the CCS documentation and assessment to ensure package integrity and sterility at various product lifecycle stages. This includes validation of container/closure combinations used with drug products to ensure that the configurations used can maintain package integrity and sterility until the end of its shelf life.

All in all, these factors contribute to the efforts towards reduction of contamination as primary packaging components have an impact on the overall CCS.

Helping Customers with the new requirements

To help customers comply with Annex 1, the selection and evaluation of component quality is critical as the specifications for particulates, bioburden and endotoxins, will impact their overall CCS. West offerings include Westar™ Select quality level components, NovaPure® components and Daikyo Seiko’s D-Sigma™ components in ready-to-sterilize (RS) or ready-to-use (RU) formats to cater to customers with different needs based on quality levels according to their product application. As a manufacturer of pharmaceutical packaging components, West has a comprehensive CCS for limiting biological, loose and embedded contamination throughout the stages of design, installation, testing and manufacturing across the different sites. It is an ongoing and continuous effort to assess the manufacturing controls within the facilities, together with the current manufacturing processes, equipment and workflow against the requirements of EU GMP Annex 1.Upon establishing the wash and/or sterilization process for the elastomeric components, the container closure system should be assessed to determine its effectiveness in maintaining CCI. To help with this, the DeltaCube™ Modeling Platform was developed to utilize big data and statistical analysis to guide vial, stopper and seal combination choices, and better understand factors influencing CCI and mitigate the risks associated with CCI failures. By selecting various combinations of vial, stopper, and seal components, this tool allows for different configurations to be compared to select the desired optimized vial containment system. This enables customers to accelerate the drug development process by reducing risks due to poor or inconsistent CCI. Furthermore, West’s analytical services team has an extensive portfolio of CCI techniques and analysis to help customers make informed decisions in the selection of their containment systems to protect their drug products while meeting the requirements of the EU GMP Annex 1.

For customers upgrading to RABs or isolator technology, West can provide appropriate component packaging solutions according to the manufacturer’s needs when considering variability in manufacturing facility design, scale and compatibility with their fill/finish equipment. This is important because the component packaging determines how the components are introduced into the RABs or isolator. For example, West offers packaging in different formats such as ported bags for bulk stoppers, plungers and seals, as well as tub-nests for containers, such as vials and syringe barrels. An additional option in tube-nest format is Daikyo Seiko’s PLASCAP® RUV closure, a ready-to-use one-step press-fit closure that features an integrated stopper and plastic cap. A multitude of options ensures that drug manufacturers have choices to suit a variety of fill and finish equipment and operational requirements, but more importantly mitigates contamination during the transfer of the components into the aseptic zones of the manufacturing process.

West is well-equipped and prepared to help our customers comply with Annex 1.This includes working with our customers to select packaging components prepared with validated wash and/or sterilization processes that adhere to applicable cGMP requirements with specification limits for bacterial endotoxin, bioburden, particulate levels and/ or sterility; provide component packaging solutions for introduction into RABS or isolators; and assistance in CCI evaluations and testing services.

Conclusion

The revision of Annex 1 warrants some major changes to the pharmaceutical industry as it aims to further protect against product contamination and improve patient safety. At West, our holistic CCS encompasses the policies and procedures to proactively drive the reduction, control and monitoring of contamination. Moreover, it is embedded in West Quality Management System to identify continuous improvement through data driven decisions.

While it is the responsibility of the finished drug/biologic product manufacturer to comply with the regulations described in the EU GMP Annex 1, West is keen on collaborating with our customers to navigate through these new regulations simultaneously, to address any challenges they may face on the path to compliance.

For more information on how West can help, click here or contact an Account Manager or Technical Customer Support (TCS) representative.

References

1. 2022, EU GMP Annex 1: Manufacture of Sterile Medicinal Products, https://www.gmp-compliance.org/guidelines/gmp-guideline/eu-gmp-annex-1-manufacture-of-sterile-medicinal-products [Accessed on 02 August 2023]
2. Hoenen, I.; Azab, W E. Contamination Control Strategy: practices & a case study of a CCS implementation. https://www.a3p.org/en/contamination-control-strategy-practices-a-case-study-of-a-ccs-implementation/ [Accessed on 04 Sep 2023]

Westar, NovaPure, and DeltaCube are trademarks or registered trademarks of West Pharmaceutical Services, Inc. in the United States and other jurisdictions.

PLASCAP and D-Sigma are trademarks of Daikyo Seiko, Ltd.