Playing the Long Game: Benefits of Investing Now in Meeting New Annex 1 Requirements

What is Annex 1?

Annex 11 is a European Union (EU) guidance document for the manufacture of sterile medicinal products. Annex 1 was recently revised and published on 25 August 2022. The final draft has expanded the content from 16 to over 50 pages and includes new requirements as well as additional detail from the previous version of Annex 1 from 2008. The Annex will take effect on 25 August 2023, except for section 8.123 on lyophilizer sterilization, which takes effect on 25 August 2024.

What are some key points and changes in the revised Annex 1?

  • Expectation to have a Documented Risk Management System integrated into all areas of product lifecycle and included rationale for decisions taken to ensure quality of sterile product.
  • Risk of “people” being the source of contamination should be mitigated.
  • Requirement to have a holistic Contamination Control Strategy Document that is periodically reviewed.
  • Strong push to use Restricted Access Barrier Systems (RABS)/Isolators in Grade A environments. Grade A areas should not have personnel “dwell”.
  • Use of new technologies (e.g., rapid/automated microbial monitoring methods for environmental monitoring) can be used in place of lengthy and inconvenient testing.
    • Justification for use of rapid testing must be documented.
  • Transfer of materials, equipment, and components into and out of cleanrooms are moving from “spray and pray” to the use of unidirectional, double-ended sterilizers (e.g., autoclaves, ultraviolet tunnels, electron beams) into Grade A/B when possible.
  • Videos of airflow patterns (smoke studies) both at rest and in operation to demonstrate no ingress from lower to higher grades (including isolator mouse holes).
  • Defined frequency for isolator/RABs glove replacement with data to support.
  • Requalification of Grade A/B should occur every 6 months and include ISO 14644 sites for total particulates.
  • Cleaning of classified areas must be performed prior to disinfection of cleanrooms/equipment and demonstrate the process removes disinfectant residues.
  • Post-disinfection sampling of water systems must be performed, and the system should not be returned to use until after chemistry (e.g., Total Organic Carbon (TOC)) results are approved.
  • Grade A/B maximum duration of each gowning garment is defined through garment qualification and sterilization process is qualified (includes max number of laundry and sterilization cycles).
  • PUPSIT (Pre Use Post Sterilization Integrity Testing) is required on sterile filters.
  • For Aseptic Process Simulations, any contaminated units fails the process simulation regardless of media fill run size (Note: Used to be >99.9% at 95% confidence).

How does this affect you?

Even if you currently do not have product approved by the EU, United States Food and Drug Administration (FDA) leaders have already indicated a desire to align with these standards. It is better to close any compliance gaps sooner rather than later. Most importantly, following the guidance of Annex 1 will improve product quality and reduce time and resources spent on remediating sterility and contamination-related issues.

 What are some challenges in implementing Annex 1?

  • Many companies do not want to be trailblazers when implementing a new approach. They will put off aligning with Annex 1 as long as possible, hoping for extensions.
  • Many companies tend to be reactive and not proactive. One goal of the Annex 1 revision is to invest time and money into prevention of issues before they occur.

What do Kymanox experts have to say about the principles behind Annex 1?

  • Three aspects are essential for contamination control: People (e.g., unidirectional personnel flow, appropriate qualification), Procedures, and Engineering.
    • A single holistic document should touch on all these areas and outline the necessary policies and procedures for contamination control.
  • A regulatory document that supports the use of rapid methods will pave the way for the implementation of rapid methods in the Quality Control (QC) lab (e.g., bioburden/sterility).
  • Operators cannot be entirely removed as a contamination source and thus setting a good baseline prior to beginning operation is essential.
    • Personnel training and qualification in the revised guidelines are highlighted.
  • Smarter testing using documented risk-based sample plans can improve efficiencies without sacrificing quality.
  • Contamination control is a multidisciplinary endeavor.
  • Maintaining good practices in contamination control is not a one-time endeavor.
  • Ultimately, product quality and product safety are of utmost importance and thus undetectable contamination and other failure modes need to be addressed in the timeliest manner.

 How can Kymanox help you?

Kymanox is always keeping up with latest regulations, revisions and commentaries on Annex 1 and other regulatory regulations. Kymanox has extensive experience in QC and can help you align your practices to the new guidelines of Annex 1. Kymanox has expertise specifically in aseptic processing, microbiology, environmental monitoring, and contamination control, making us uniquely positioned to succeed in this task. Kymanox can help carry out risk assessments, assess root cause behaviors, establish an effective Corrective and Preventive Action (CAPA) system, set-up investigation procedures, and update procedures in the case of arising issues.

As a professional service company, Kymanox has a unique insight into any challenges that arise in the process as we work with several different clients, addressing different client types and needs.

Key Take-Away: The principles within the revised Annex 1 might take time and resources to implement, but it will have a huge return on investment as policies are implemented and processes are operational with improved overall contamination control. Kymanox and our QC experts can help you identify and close gaps to align with the revised Annex 1 and ensure that your processes minimize contamination-related risk. Procedures that quickly and efficiently address issues and that use a risk-based approach will improve product quality and reduce time and resources needed for remediation. Ultimately, complying with Annex 1 guidelines will help you achieve a comprehensive contamination control strategy and ensure your medicinal products continue to provide benefits to patients in need.

  1. Eudralex Volume 4, EU Guidelines to Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use, Annex 1: Manufacture of Sterile Medicinal Products