How Annex 1 Guidelines Will Affect You and Your Business
EU GMP Annex 1 has a far-reaching impact, affecting pharmaceutical manufacturers in the EU and beyond. Rather than focusing solely on end-product testing or specific stages, the revised annex now requires you as a manufacturer to implement comprehensive strategies at every stage of the manufacturing process to address potential contamination risks as the industry takes a proactive approach to quality. While the new document outlines EU GMP guidelines for sterile manufacturing, placing emphasis on manufacturers engaged in aseptic processing, biotechnology, and terminal sterilization, its scope also covers certain aspects of non-sterile manufacturing.This means that even though manufacturers might not produce sterile products themselves, if they are supplying materials and components used in sterile production such as packaging or excipients, among others, they must also adhere to certain parts of Annex 1, including the execution of the Contamination Control Strategy (CCS).
Contamination Control Strategy and Facility Design
The revised Annex 1 guideline introduced several pivotal changes, chief among these being the mandatory implementation of a Contamination Control Strategy (CCS) by manufacturers. This strategy is defined as a comprehensive, facility-wide approach that identifies all critical control points and evaluates how effectively contamination risks are prevented through a combination of design, procedural, technical, and organisational controls.
In line with the new Annex, the CCS, which is now the backbone of sterility assurance, must clearly document how microbial, particulate, and endotoxin risks are assessed, mitigated, monitored, and continually improved across the manufacturing process. Therefore, as a manufacturer, you need to approach CCS as not just a document but rather a core element of sterile manufacturing, which influences not only the way systems are operated but how they are designed from scratch.
Unlike before, where facility design was just concerned with structural issues, after the enactment of Annex 1, it must now directly reflect risk-based thinking to show how design choices such as airflow patterns and pressure cascades are intentional, justified, and most importantly, aligned with the broader contamination control strategy. This is exactly why Quality Risk Management (QRM) is essential, as the new Annex 1 demands its application from the earliest stages of facility and process design to serve as a framework for identifying risks and deciding the best way to contain them. QRM is therefore a level above routine monitoring, as it goes the extra mile to push manufacturers to design facilities that are built to reduce risk with quality in mind, which results in a shift from the traditional reactive oversight to proactive prevention, where decisions are taken based only on scientific evidence and rationale.
What makes a Contamination Control Strategy unique is that Annex 1 expects manufacturers to treat it as a living document and feed it with regular updates and conduct reviews and revisions over time. For the CCS to meet regulatory requirements, manufacturers should also go a step further in ensuring it includes an in-depth evaluation of cleanroom layout, airlocks, pass-through hatches, and the use of isolators or Restricted Access Barrier Systems (RABS), which are now highly recommended to reduce human interventions in critical zones.
Barrier Technologies: Isolators and RABS in the New Annex 1
Barrier technologies such as isolators and Restricted Access Barrier Systems (RABS) play a critical part in modern sterile manufacturing by separating the aseptic processing environment from the external environment and operators, which minimizes contamination risks during sterile manufacturing.
The protective environment created by these systems helps maintain the sterility and integrity of pharmaceutical products throughout the manufacturing process, as it significantly reduces the risk of microbial and particulate contamination. The new Annex 1 places strong emphasis on the proper use and design of barrier technologies in sterile manufacturing, as it outlines specific requirements for manufacturers to implement when designing these systems. These include ensuring unidirectional airflow patterns and first air protection in critical zones at all times to maintain Grade A conditions.
While we have already covered CCS earlier, it is important to point out that design choices for barrier technologies must also be justified and aligned with the site’s overall contamination control strategy, in adherence with Annex 1 guidelines. What this means for you as a sterile manufacturer is that you are now expected to be knowledgeable about how each barrier system functions within the broader cleanroom environment, in addition to integrating risk assessments for these systems into your overall CCS in line with quality risk management principles.
Aseptic Process Simulation (APS) in EU GMP Annex 1
Aseptic Process Simulation (APS), also known as Media Fill, is a vital validation tool used in aseptic manufacturing to verify whether contamination control measures are actually effective in practice. While the simulation should not be perceived as a replacement for the standard process validation, it works as a mirror, giving a true reflection of whether the facility, equipment, personnel, and procedures can work in harmony to maintain sterility during the most critical stages of production.
According to the updated Annex 1, APS must closely mimic actual production processes, using sterile nutrient media instead of the product to verify aseptic conditions in a way that produces results manufacturers can rely on. As a manufacturer, when using APS, you are expected to conduct comprehensive simulations that factor in all possible outcomes, including worst-case scenarios.
In addition, manufacturers must now take a risk-based approach in designing the simulation plan and justify all elements, including container sizes and equipment setups, while also ensuring simulations account for external factors such as environmental conditions, personnel shifts, and potential disruptions.
Annex 1 now mandates biannual testing for standard processes, with zero contamination as the acceptance criterion, and requires that any failures during the process be thoroughly investigated and remedied through corrective actions—with production only allowed to resume after three consecutive successful repeat runs.
Are You Already Annex 1 Compliant?
There is no doubt that Annex 1 is progressive and is making continuous monitoring the norm in sterile manufacturing, especially in critical areas we have explored earlier on, such as Grade A environments. Although it is impossible to sum up a 59-page document in one sentence, if we had to, it would be that Annex 1 stresses that sterility cannot be proven solely through finished product testing; it must be built into the process through good design, effective procedures, and constant verification.
Therefore, for manufacturers like you, data-driven ongoing improvements backed by CAPA systems and proactive assessments are no longer optional but rather expected by regulatory authorities, as required by the new sterile manufacturing standards. To succeed in the life sciences as a sterile manufacturer in line with Annex 1, you therefore need to embrace a new mindset focused on prevention, documentation, and absolute accountability to meet regulatory expectations and ensure safer medicines for patients.
If you have read up to here, it means you value your business’s success and want what’s best for it. PQE Group's tried and trusted tailored life sciences services, which span from world-class regulatory affairs, quality compliance, to training and everything you need from navigating Annex 1 compliance to building a robust contamination control strategy, are here to support you every step of the way.
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