Sterile Manufacturing Reinvented: What's Inside the Updated Annex 1

Sterile Manufacturing Reinvented: What's Inside the Updated Annex 1


Recently, on August 25, 2023, a new version of Annex 1 was published, except for Chapter 8.123, which pertains to "Product Transfer/Loading/Unloading Areas for Lyophilizers" and will become effective on August 25, 2024.

The primary objective of Annex 1 remains the same: to minimize the risk of particulate, pyrogenic, and microbiological contamination in sterile products.


What is the Annex 1?

Annex 1 is an integral part of Good Manufacturing Practice guidelines, providing general guidance for designing and controlling facilities, equipment, systems, and procedures used in the manufacture of sterile products, based on the principles of Quality Risk Management.

The European Union Commission has recently revised the European Union Good Manufacturing Practice Annex 1. Additionally, the EU has decided to integrate ICH guidelines, specifically ICH Guidelines Q9 – Quality Risk Management and Q10 – Pharmaceutical Quality System, while incorporating current regulatory and technological developments in the production of sterile medicinal products.

Now that we understand the purpose and reasons for updating Annex 1, let's delve into the specific changes.


Key changes in the new version:

The latest version of Annex 1 introduces three pivotal concepts into its scope:

  1. The potential application of the principles outlined in Annex 1 to non-sterile product areas.
  2. The introduction of Quality Risk Management (QRM) and Pharmaceutical Quality System (PQS) principles.
  3. The implementation of the Contamination Control Strategy (CCS).

While the first two concepts are not entirely new to the industry, the third presents a unique challenge for companies. The Contamination Control Strategy is now a mandatory document that must define all critical control points, measures, and assessments of effectiveness to manage all risks associated with product contamination.

Annex 1 obliges manufacturers of sterile products to design an effective Contamination Control Strategy based on a scientific assessment, comprehensive process understanding, and the implementation of Quality Risk Management principles.

Now, let's explore the sources of contamination in sterile areas.


Sources of Contamination:

The primary source of contamination in sterile areas, unfortunately, is human intervention.

Employees involved in sterile product manufacturing must possess appropriate qualifications, training, and experience. Their training should align with their roles and responsibilities, with a strong focus on the protection of sterile products.

Speaking of personnel, it's essential to mention specialized clothing designed for working in sterile conditions. This clothing must be exclusively intended for sterile work, and personnel handling it should undergo proper qualification for changing into and out of such attire.

The second source of contamination includes surfaces, air, and pharmaceutical media (e.g., water, gas, etc.). To prevent contamination, thorough monitoring of critical areas and items is essential, with their criticality detailed in the Contamination Control Strategy.

The third source of contamination arises from materials and equipment. The movement of materials and equipment in and out of cleanrooms carries the potential for contamination. Entry and exit procedures should always follow a flow from lower Grades to higher Grades, and disinfection protocols must be adhered to when introducing materials into cleanrooms.

Annex 1 encourages the adoption of new barrier technologies to mitigate contamination risks.


Introducing RABS: Restricted access barrier system

RABS, an abbreviation for Restricted Access Barrier System, serves as a physical barrier between the critical area (Grade A) and the less critical areas. This system utilizes localized airflow protection to control the environment where sterile products are manufactured.

Regarding sterile areas, the new version of Annex 1 incorporates several significant changes:

  1. A change in the frequency of qualifications: Grade A and Grade B qualifications must now occur every 6 months, while Grade C and Grade D qualifications are required every 12 months.
  2. Qualification tests: For the first time, Annex 1 introduces a list of tests that can be performed to qualify cleanrooms. The classification of cleanrooms is based on total particle concentration limits.

The updated Annex 1 also provides more detailed information on equipment, utilities, environmental and process monitoring, quality control, and production, including specific technologies such as Form-Fill-Seal (FFS), Blow-Fill-Seal (BFS), lyophilization, and more.


In Conclusion

The revised Annex 1 brings a strong focus on manufacturers' efforts to prevent and minimize the risk of particulate, pyrogenic, and microbiological contamination. It serves as a guideline for manufacturers, urging them to interpret and follow it diligently for their companies' benefit. Manufacturers should prioritize continuous improvement and preventive strategies, encompassing changes, risk assessments, deviation analysis, root cause determination, and corrective and preventive actions (CAPA).

Below, you will find a link to the full version of Annex 1.


Rescop: Your trusted Validation Provider for Annex 1 updates

Rescop offers comprehensive validation services to ensure compliance with industry regulations and standards, helping you meet your quality and safety objectives.

  • Validation Protocols: Creating customized validation protocols tailored to Annex 1 requirements.
  • Risk Assessment: Conducting comprehensive risk assessments to identify and mitigate contamination risks.
  • Cleanroom Qualification: Qualifying cleanrooms to meet Annex 1 particle concentration limits.
  • Documentation Support: Streamlining documentation processes for Annex 1 compliance.
  • Environmental Monitoring: Implementing effective environmental and process monitoring systems.
  • Equipment Validation: Validating equipment and systems for sterile product manufacturing.
  • Continuous Improvement: Developing strategies for continuous improvement and risk management.
  • Training: Offering training resources to keep teams updated on Annex 1 standards.


For more information contact us now!



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