What are the key considerations for assessing components in Annex 1?
When it comes to primary packaging, there are four key areas of consideration for ensuring Annex 1 readiness:
1. PRODUCT: Analysis of the current quality level of packaging components, understanding the specifications for particulate, bioburden, and endotoxins, and whether a tighter specification is required.
2. PROCESS (manufacturing design): Looking at whether products are sterilized in-house or delivered in pre-sterilized ready-to-use form by the component supplier. Also reflecting on how components will be introduced on the fill/finish line and whether sealing will occur in an aseptic environment.
3. PROTECTION (container closure integrity, CCI): Is there a robust understanding of the factors that will impact the CCI? Is there a monitoring and testing plan in place to manage CCI over the life of the drug product?
4. PROOF: Assessment of the component supplier’s own CCS and their emphasis on continual improvement. This includes verification of available documentation that can be incorporated into your ‘master’ CCS.
At West, we prioritized the development of our own CCS in 2021, aligning our activities to the more stringent regulatory stance on contamination control being introduced under Annex 1. When setting out on this path, our ambition was to design and establish a best-practice organization-wide model for the consistent manufacture and supply of quality packaging components for sterile drug products – one that delivers the fixed assurance of Annex 1 compliance while providing the flexibility necessary to accommodate continual improvement.
Achieving this goal demanded a top-level interrogation of all activities involved in the component production cycle in parallel with an assessment of how those activities can best dovetail with the needs of pharmaceutical partners. This resulted in a set of objectives and requirements that were captured, categorized and distilled into a master CCS document that acts as a single source of truth across the entire enterprise.
This is complemented by individualized Contamination Control Plans at each production facility to allow local differences to be addressed in line with overarching global requirements. Crystallizing our approach to contamination control in our own CCS provides a robust point of reference not only for internal stakeholders but also for external partners, who can leverage our best practices in support of their own CCS. We are able to provide them with all the documentation and product specifications needed to evidence that their primary packaging components comply with Annex 1.
It is important, however, that compliance in this context is not regarded in terms of achieving minimum standards or meeting threshold limits. Rather, it must reflect a commitment to the consistent adoption of practices that support better contamination control, drug product integrity and patient safety. As such, evolution is central to West’s approach. We have embedded lifecycle management and continuous benchmarking into our strategy, drawing on internal and external standards, customer feedback and gap analyses to constantly evaluate existing practice and identify potential areas for adaptation and improvement. Ultimately, this guarantees our approach to contamination control is aligned with the current expectations of customers and regulators, albeit with an emphasis on innovating to keep ahead of an ever-changing curve.
A critical aspect of West’s journey to align our sites with Annex 1 has been our focus on people. Components might be the physical representation of our output, but they should not be the only area of focus when it comes to contamination control. They should instead be seen in the wider context of a manufacturing process that might be highly dependent on advanced technologies and automation but is very much managed and controlled by skilled people.
As such, West has been sensitive to the importance of bringing our team with us on the Annex 1 journey, which demands that we approach compliance in a very human way.
The embodiment of this theory is our Change Management Communication Strategy. This is designed to provide our people with the rationale behind certain process changes and also to support them in thinking about contamination when fulfilling their operational responsibilities – an important factor in limiting avoidable sterility risks. Our ultimate goal is to reinforce a mindset shift towards the notion of continual improvement with regard to contamination risk, using the fact that every product we produce has a patient’s name on it as a motivating factor.
Complementing the understanding of our people is the implementation of highly controlled manufacturing processes designed to result in elastomer products with minimal levels of particulates, fewer visual defects, and fewer biological contaminants. In the early stages of production this includes the segregation of materials, the isolation of utensils and line clearance procedures, and the deployment of exhaust systems and filters. Premium molded components also undergo a validated wash process to control particle and microbiological contamination as well as a separate sterilization process to demonstrate bioburden control before being packed within low-particulate
controlled environments.
Taken together, all of these activities deliver a comprehensive platform for Annex 1 compliance, tying together the various disparate elements of a manufacturing process into an end-to-end solution underpinned by contamination control. Crucially, however, this platform is not intended to be self-contained. Rather, it is designed to provide pharmaceutical partners with a ‘plug-and-play’ answer to the packaging demands detailed extensively in Annex 1, which introduces additional responsibility for documenting and validating component quality as part of a holistic CCS.
Investment in state-of-the-art restricted access barrier systems (RABS) or isolators alone is not sufficient to ensure the components being used in fill/finish processes can deliver the assurances of quality and contamination control necessary to meet the mandates set out in Annex 1. For pharmaceutical companies the weight of this burden potentially increases when producing multiple drugs at multiple sites – a scenario that could require consideration of activities undertaken by a range of different component manufacturers employing a range of different sterilization processes. Furthermore, if there is a risk of noncompliance, pharmaceutical companies might decide to address this by carrying out washing and sterilization activities themselves, investing further time, cost and effort to avoid the worst-case scenario of a failed audit, with associated commercial implications such as financial penalties, reputational damage, and drug shortages for patients.
In summary, there is no doubt that Annex 1 lays strong foundations for achieving the unanimously supported ambition of suppressing risks that can lead to patient harm. At the same time, it has dramatically changed the regulatory landscape for pharmaceutical companies, which must now be able to demonstrate the strength and depth of their approach to contamination control throughout their entire supply chain.
To meet these demands, companies must rely on the support of a supply partner capable of addressing all elements of contamination control in a shareable CCS – one that encompasses people as well as processes and product; one that tackles sterility through psychology as well as systems. Only then can they receive full assurance that primary packaging components do not only comply with the specific rigorous demands of EU GMP Annex 1 but are managed via a holistic approach that supports continual improvement into the future.
About the authors
Niamh Bissett
Niamh Bissett has over 20 years of experience in Quality Compliance and Program Management. In her current role as Director Transformation, Niamh provides strategy, vision, direction and support for the Program Management Organization. She also leads Global Initiatives across the Containment & Device Organizations within West Pharmaceutical Services, in the focus areas of Intermix, Contamination Control and Risk Management. Prior to Niamh’s current role, she has held a variety of positions in both Quality and Program Management NPI, at West Pharmaceutical Services, Dublin. Niamh has a Bachelor of Arts (Hons) degree in Information Systems Technology from Atlantic Technological University, Sligo, Ireland.
Ana Kuschel, PhD
As Principal Scientific Affairs Europe, Ana Kuschel, PhD provides technical support relating to West’s packaging components and delivery systems for injectable drugs and healthcare products. She plays a key role in bridging scientific information through industry outreach. This complements her previous role as Manager of Material Development, where she worked on both existing and new rubber formulations. Ana holds a PhD in Macromolecular Chemistry and is an active member of the ISO TC 76 and PDA Packaging Science groups.
