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EU GMP Annex 1 and Its Importance for High-Purity Media Systems – Part 1
EU GMP Annex 1 and Its Importance
for High-Purity Media Systems
– Part 1
After a long drafting and review phase, the new version of Annex 1 came into effect on August 25, 2023, and is now legally binding.
Compliance with the updated guidelines requires new approaches in certain areas and, in some cases, fundamental changes to existing processes. In the following, we will take a closer look at the key requirements related to high-purity media systems, specifically Water for Injection (WFI) and Pure Steam, and highlight the conclusions we derive from these changes..
Our focus will be on the following points:
Part One:
- Scope of Application
- Principles
- Pharmaceutical Qualification System
Part two:
- Equipment
- Media Supply
- Personnel
Chapter 1: Scope of Application (Scope)
The goal of Annex 1 is to provide guidelines for the manufacturing of sterile products. It explicitly mentions the potential application to non-sterile products, where contamination control and reduction of microorganisms, particles, and endotoxins/pyrogens are critical.
EnviroFALK PharmaWaterSystems Assessment:
This means that the guidelines could also be applied to certain applications where Purified Water (PW) or endotoxin-controlled Purified Water is used. However, since these requirements often exceed established standards, their implementation would involve increased effort and resources.
Additionally, strict documentation is required for any application of these guidelines. This includes:
- Clearly defining which parts of Annex 1 are being implemented.
- Providing documented proof of compliance with the relevant requirements.
As a result, the extent to which these stricter guidelines will be adopted for non-sterile applications remains questionable and subject to industry-specific needs.
Chapter 2: Principles
To minimize the risk of contamination, equipment, systems, and processes must be designed, qualified, and/or validated accordingly. Where applicable, ongoing verification is required to ensure continuous compliance with GMP requirements.
Additionally, appropriate technologies and scientific advancements should be considered to rapidly detect potential contamination, thereby enhancing product protection and ensuring the highest quality standards.
EnviroFALK PharmaWaterSystems Assessment:
Comprehensive qualification and validation of new systems have been state-of-the-art for many years. However, uncertainty remains regarding how to handle existing systems where full qualification and validation were not completed or where documentation is incomplete.
The requirement for ongoing verification and the use of advanced technologies for rapid contamination detection will likely drive the modernization of older systems. This will increase the adoption of online or inline measurement technologies, further intensifying discussions on rapid methods for microbial contamination assessment.
Through Quality Risk Management (QRM), potential quality risks should be proactively identified, scientifically assessed, and controlled to prevent contamination of the final product by microorganisms, particles, and endotoxins/pyrogens.
In the case of an alternative approach, this should be supported by an appropriate justification, risk assessment, and mitigation measures. The main focus of QRM is on the design of the facility, equipment, and process, as well as the implementation of good procedures and monitoring methods.
Another very important role is played by the Contamination Control Strategy (CCS). With the help of CCS, critical control points should be defined, the effectiveness of controls should be reviewed, and monitoring measures should be integrated to assess risks concerning product quality and safety. The CCS should be regularly reviewed for updates and, if necessary, adapted accordingly. Additionally, its effectiveness should be periodically evaluated at the management level.
Existing control procedures do not need to be replaced, as long as they are adequately implemented, referenced in the CCS, and the interactions between the systems are understood. In relation to CCS, appropriate expertise is also required. Furthermore, several elements are mentioned that should be considered within the framework of CCS. The following aspects are particularly relevant for high-purity media systems:
- Design and documentation
- Facility, building, and equipment
- Personnel
- Media
- Supplier approvals / certifications, critical service providers
- Management of outsourced processes and availability/transfer of critical information
- Process risk management
- Process validation
- Preventive maintenance
- Cleaning and disinfection
- Monitoring systems (including the feasibility of implementing scientifically validated alternative methods)
- Preventive measures (including trend analyses, detailed investigations, root cause analysis, Corrective and Preventive Actions (CAPA), etc.)
EnviroFALK PharmaWaterSystems Assessment:
QRM and CCS introduce essential tools to ensure product quality by identifying, assessing, and implementing targeted risk reduction measures. These requirements will impact all processes that could influence product quality.
The scope of risk assessment is expected to become significantly more complex and extensive, likely encompassing the entire supply chain. A proactive, preventive approach with scientific evaluation remains a central focus. Additionally, the primary emphasis is once again on adequate system design, monitoring systems, and continuous evaluation of collected data (trend analysis, root cause investigation, etc.).
Other critical aspects include:
- Regular reviews with necessary adjustments
- Personnel expertise and training
- Preventive maintenance
- Integration of interfaces with other systems, processes, and suppliers
All these elements must now be precisely defined, assessed, and documented within the CCS, making it a key factor in inspections and audits. The requirement for management-level evaluation further increases corporate leadership’s accountability in ensuring compliance and quality assurance.
Chapter 3: Pharmaceutical Quality System (PQS)
This chapter also focuses on minimizing the risk of microbial, particulate, and endotoxin/pyrogen contamination, which should be monitored and controlled through the manufacturer’s PQS.
A new addition is the reference to the life cycle approach, requiring risk assessment throughout the entire system life cycle. Once again, the importance of:
- Specialized expertise,
- Root cause analysis in case of process or equipment failures,
- Proper handling of deviations,
- Implementation of CAPA (Corrective and Preventive Actions) and CCS,
is emphasized. Furthermore, management is required to oversee the status of controls across the entire company and throughout the system life cycle.
EnviroFALK PharmaWaterSystems Assessment:
The requirements largely align with those previously outlined for QRM and CCS. The new focus on the entire system life cycle highlights the need for forward-looking planning, particularly regarding maintenance and servicing.
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