The EU GMP Annex 1, which governs the manufacture of sterile medicinal products in the European Union (EU), came into effect 25 August 2023. This article explains the key changes that pharmaceutical companies and CMOs engaged in manufacturing and fill-finish need to consider, as well as what AbbVie Contract Manufacturing (AbbVie CMO) is doing to ensure its global operations and aseptic fill-finish sites are in compliance with the revised regulations.

AbbVie CMO operates aseptic fill-finish and parenteral facilities at multiple locations around the world. Two of AbbVie’s primary sites include one in Sligo, Ireland with full isolator and containment capabilities and another in Barceloneta, Puerto Rico with a restricted-access barrier system; they are both well suited for clinical and commercial supply of aseptic fill and finish products.

A working group of regulators from the EMA, the Pharmaceutical Inspection Cooperation Scheme (PIC/S), and the World Health Organization (WHO) reviewed and updated the existing document, which hasn’t been revised since it was last updated in 2009. The revisions were made to keep up with changes to process technology, to harmonize the interpretation of regulations between industry and regulators, and to align with significant changes in GMP since the adoption of ICH Q9 and Q10 guidelines, primarily quality risk management.

PIC/S, which oversees harmonization of regulations globally, was involved in the writing of Annex 1. PIC/S is a cooperation recognized by 54 different regulators around the world, meaning Annex 1 has a broad reach beyond the EU, including Australia, Canada, Japan, Taiwan, and a number of other global markets. While Annex 1 requirements do not directly apply to products sold in the US, the US FDA is a member of PIC/S, the working group included members from the FDA, and no general conflicts exist between each domain’s regulations.

Many companies using older processes still rely on procedural controls, like environmental monitoring and sterility testing, to ensure quality and safety of sterile medicinal products. However, monitoring alone cannot ensure sterility and is not meant to accommodate other potential deficiencies, such as a poorly designed process. Annex 1 clarifies the requirements for a designed control process with monitoring being only the final aspect of the quality risk management process.

One of the big changes with GMP has been the application of QRM, based on 2009 ICH Q9 and 10, throughout the document. Industry must develop quality strategies based on solid scientific and technical understanding of operations, including the appropriate design of facilities, equipment, and processes. This is followed by a review to identify residual risks that can’t be eliminated, and a plan to apply procedures and training to mitigate any remaining risk. Monitoring and testing follows to ensure design and procedures are correctly implemented and perform as expected.

A CCS contains process design and a risk assessment, including facility design, gowning procedures, and supply chain controls. This document functions as a roadmap to locate details related to design, procedures, and monitoring. Companies need to think of it as a living document to be updated with ongoing process experience or with the introduction of new technologies. It is essential that a CCS be written by those with an understanding of microbiology, engineering, processes, and other cross-functional, but relevant, disciplines.

The PQS includes general controls, change controls, deviation management, and control of suppliers. Annex 1 now emphasizes the role of senior management to provide the necessary resources to support change and investigation, including having the right number of people with the right technical knowledge and budgeting to ensure appropriately upgraded facilities and equipment.

This includes guidance on facility design, aseptic filling and supporting equipment, and various manufacturing and isolator systems, including the use of barrier systems.

Cleanroom classification and qualification

Annex 1 now provides more detail about how to classify cleanrooms and does this separately from monitoring. It uses a risk-based approach to classification and qualification beginning with ISO 14644 standards. Annex 1 follows this with the need for companies to do qualification based on specific process knowledge, identifying critical aspects. This should include the focus on areas with open product or open components. Re-qualification of cleanrooms, which ISO 14644 says should occur at least every 12 months, now must be done every six months for grade A and B areas. It also removes the 5 µm particulate constraint, although this is still required as part of monitoring and companies may decide to keep this as part of their overall background classification process.

Material airlocks and pass-throughs

The process of transporting materials through airlocks has been further clarified. Only an approved list of materials and equipment are allowed through an airlock or pass-through, and these need to be linked to a disinfection strategy within the CCS. Deviations need to be pre-approved as exceptions. If equipment can be sterilized, it should be; relying on an airlock should be a last resort. To move material through an airlock, the ideal is to have multiple wrappings so one can be removed at each boundary, leaving the layer underneath sterile. Annex 1 requires airlocks having an active filtered air supply with unidirectional airflow. 

RABS and isolators

Annex 1 lists both RABS and isolators as acceptable, while older cleanrooms with open-door interventions are no longer appropriate. For RABS, the equipment should include sterilization-in-place and clean-in-place (SIP/CIP) and the capability to do a vaporized hydrogen peroxide (VHP) clean. If sterilization is required, it should be completed once the equipment has been reassembled. If post-sterilization assembly is required, using intrinsic connectors helps mitigate risk inherent in open aseptic connections.

This is a new section in Annex 1, dealing with utilities that might contact sterile products, such as water, steam, gas, and vacuum systems. It includes an allowance for water for injection (WFI) systems to use reverse osmosis and describes the necessary controls to avoid the buildup of biofilms.

One big change in training has to do with expanding the operational mindset toward a more holistic patient centric attitude. For example, training needs to include not just technical training (the ‘hows’), but also address the reasons for doing things a certain way (the ‘whys’). This serves to make it clear that any intervention may have critical consequences, such as failed batches that could result in a product shortfall of an essential medicine or, worse, injecting a patient with a contaminated product.

Annex 1 discusses how smoke visualization studies have become helpful with this training. Smoke studies are used as a tool during qualification and can also be used to train operators. By showing how air moves within a sterile boundary, an operator can see the consequences of how air flows over their hand and straight into an open vial or syringe, as an example.

Annex 1 now contains operational requirements for Grade A and B cleanrooms, including more guidance for pre-use post-sterilization integrity testing (PUPSIT) and sterilization techniques. Although PUPSIT has been a requirement since 1997, discussions with industry and regulators leading up to the revisions raised the awareness of its importance. PUPSIT tests the integrity of a sterilized filter prior to use, detecting issues before filtration that could be masked by a viscous or proteinaceous product. Exceptions can be made, for example for small volume products that are critical to patients.

This section also includes guidelines for single-use systems and closed systems.

Many aseptic manufacturers are already in compliance; however, some are at various stages of preparation. For those that aren’t yet in compliance, they must have a well-designed strategy in place. For most aseptic manufacturers, they already have the easy quick wins in place, such as creating a gap assessment, having a CCS and other documentation in place, and assessing training needs. But the strategy may also need to include consideration of capital expenditure to update and replace older equipment of facilities.

Changes requiring significant CapEx are likely to take longer, but it’s still important to have a clear compliance strategy that recognizes gaps. For example, a compliance strategy that identifies the need to purchase a new isolator may have a three-year timeline. During the interim, product safety has to be ensured with current processes to help avoid a shortage of critical medicines.

Regulators may recognize that not everybody will be fully in compliance right away, but they need to let regulators know, “This is where we are, this is why our products are safe, and here is our plan to get to where we need to be.” This can’t be a 15-year plan. It needs to be sensible, and completed within the next couple of years. This will be a decision each regulator will make based on their own experience and based on the specific situation. There will be some situations where they deem the risk too great. Therefore, full compliance is the best route both from a compliance point of view and a patient safety point of view.

Annex 1 will increase regulatory scrutiny and all inspections now will be risk-based. For facilities with a strategy, regulators are likely to monitor regular updates on whether the facility has met its key milestones, which will be a focus for future inspections.

AbbVie CMO is committed to complying with the revised guidance and has taken a comprehensive approach to ensuring all AbbVie sites are managing to the EMA compliance standards.

AbbVie CMO draws on the knowledge and experience of a top-tier global operations team with a proven commercial track record of risk mitigation and quality compliance. This pharmaceutical infrastructure and experiential success, with a keen focus on patient care, may not exist at many contract manufacturers. It begins with our first client meeting, in which we discuss our approach to quality and assurance of supply, as we work hand-in-hand to help them continue to improve systems, operations, and a culture of successful compliance. As a CMO leader, AbbVie helps our clients succeed, from early-stage development and clinical manufacturing to commercialization.

A proactive team and ‘Speak Up’ culture

Annex 1 stresses the importance of knowledge, culture, and attitude. This involves making sure people know both how and why we do things appropriately. This is embraced further through AbbVie’s culture of keeping the patient central to all we do.  Everyone in the organization, especially Operations, knows that our efforts make an impact on ensuring patients have access to safe and timely medications.

At AbbVie, our ‘Speak Up’ culture is driven from the top. As part of their training, operators are encouraged to inform their supervisors if they see something that introduces risk to a process, such as reporting equipment issues that may affect the expected outcome. This culture is enforced through additional supervision, and correction when warranted, as part of training. Through practice and repetition, this embeds a reflexive approach to quality, safety, and risk mitigation.

Training with an industry expert

Training guidelines are included in Annex 1 but are applied inconsistently across the industry. AbbVie relies on trainers who have the right knowledge base to support workers, not just on changes to Annex 1, but every aspect of pharmaceutical operations. We follow up training with the right monitoring to ensure people have truly incorporated what they’ve been taught. We believe our operators should have a basic understanding of microbiology and the technical training they need to perform their jobs at a high level, in addition to understanding the potential pitfalls of sterility throughout the manufacturing landscape.

Andrew Hopkins leverages his network and regulatory expertise to support AbbVie compliance, training, and site auditing. His network and regulatory background help to support AbbVie’s efforts toward monitoring the evolution of Annex 1 across the regulatory landscape.

AbbVie has a long-term strategy to harmonize technologies and processes across all its sites. This includes:

• Gap assessments - Every site is doing a gap assessment to recognize what is needed to comply with changes to Annex 1.

• Equipment upgrades - The company has had discussions on financial inputs to upgrade some facilities to meet the requirements of Annex 1. This could mean, for example, taking on the large capital cost of a new isolator, and enhancing key training programs.

• Proactive planning - Our global working groups identify best practices across AbbVie’s different sites, then aim to introduce them across all sites. We train all our auditors in what to look for. We will conduct tours of all sites to assess readiness for Annex 1 changes, look at their CCS and gap assessments, and see how they match up.

AbbVie is committed to continuous improvement and continual compliance across its global manufacturing network. As a leading global pharmaceutical organization, AbbVie strives to have the right culture, strategy, and people in place to ensure we continue to meet compliance standards in an ever-changing environment. This includes exploring virtual training, including the use of virtual reality headsets to train in a simulated cleanroom; performing smoke visualization studies; and creating a mock cleanroom at one of our sites, which would allow mistakes to be made in a safe environment rather than with live product.

With this commitment to training, culture focused on safety and quality, and ongoing plans for continuous improvement, AbbVie (and AbbVie CMO) is well on its way to meeting the requirements of Annex 1 on behalf of all stakeholders, including our customers and their patients.