Notes on Annex-1
Part one

A new revision of EU-GMP Annex-1 is in the process of being implemented. Final consultation on this document ended on 20 July 2020 and implementation is expected in 2021. Progress has the expertise to translate these new requirements to your specific situation.

The revised Annex-1 further expands the mandatory role of Risk Management in important quality decisions and introduces the requirement for a Contamination Control Strategy (CCS). Risk Management should be a driving force in the CCS to prevent microbial, particulate and pyrogen contamination in the final product.

Furthermore, the new Annex-1 emphasizes that principles for manufacturing sterile products can also be applied to the manufacture of non-sterile products for which the prevention of contamination is important.

The recommended approach to the CCS follows basic critical control point principles based on HACCP where the product and process is reviewed in its entirety, to assess the potential contamination hazards and the preventive measures in place at each unit operation. The hazards are clearly defined in the guideline (microbial, endotoxins and particulate matter). The same HACCP principles can be applied to assess the risk of product (cross-) contamination and cleaning validation in the manufacture of sterile and non-sterile products. The revised Annex-1 outlines the elements to consider in a documented CCS strategy; a number of technical measures including facility, process and equipment design, as well as controls on materials, and cleaning and disinfection validation in conjunction with a series of organizational measures including quality systems, supplier and equipment qualification and process monitoring.

The CCS consists of a series of linked events and measures throughout the entire process and facility, informed by solid technical and process knowledge. The CCS should also be considered one of the driving forces behind continuous improvement of manufacturing and control methods. Therefore any system improvement should be followed by effectiveness checks, aimed at individual events as well as collective effectiveness, which could be incorporated in an ongoing process verification program.

The manufacturer is responsible for all required precautions necessary to ensure the sterility (or low bioburden level) of their products. To achieve this, emphasis should be on process knowledge, reliance should not be placed on terminal processes or finished product tests.

The process of surface disinfection is critical within the total concept of CCS in the new Annex-1. Disinfection processes should be validated and continually monitored for effectiveness(ongoing process verification). The validation of disinfection methods should aim to demonstrate a robust process for removal and reduction of microbial contamination to ensure a suitable environment for clean processing. The validation shall demonstrate the suitability and effectiveness of disinfectants in the specific way in which they are used. Validation should also extent to cleaning and disinfection of electronic devices used in the cleanroom, which must therefore be able to withstand repeated cleaning and disinfection. These sections in the newAnnex-1 indicate that a documented Contamination Control Strategy, containing robust and validated disinfection processes, is absolutely fundamental.

When designing disinfection validation studies at least the following should be considered before purchasing and validating disinfecting agents:

  • Perform an assessment of the surfaces to be disinfected.
  • Perform an assessment of known house-flora and potential risk factors, including production organisms (if applicable).
  • Define the critical control points throughout the facility and processes.
  • Define the user requirements for the disinfectant.

Subsequently a general disinfectant (with bactericidal and fungicidal properties) and a disinfectant with bactericidal, fungicidal and sporicidal properties should be selected. When working with live viruses in production a suitable disinfectant with virucidal properties should also be considered. Select disinfecting agents that are registered as a biocidal agent, and only choose products for which manufacturers can provide a sufficient package of qualification testing in line with your user requirements; this shall in general be at least the data that was used to register the product. The qualification package should refer to the following tests:

  • EN-ISO1276 for suspension studies on bactericidal effects,
  • EN-ISO1650 on fungicidal effects,
  • EN-ISO13704 on sporicidal effects, and
  • EN-ISO14476 on virucidal effect.

When disinfectants have been chosen and purchased then the disinfecting processes should be validated. Since it is not suitable to foul the actual production area with high doses of micro-organisms such validation studies are typically performed on coupons of representative surfaces in simulated models in a specialized contract laboratory.

A suitable validation program should be based on EN-ISO13697 for surface tests on bactericidal and fungicidal effect, EN-ISO 16777 for virucidal properties, and preferably also consider USP <1072> (informative article on Disinfectants and Antiseptics),especially since that is currently the only document providing guidance for sporicidal effect. The validation program should include at least the following steps;

  • Perform validation (PPQ) studies, show a sufficient log reduction for all tested organisms on surface-coupons which are representative for the actual surfaces in the manufacturing and laboratory areas.
  • Ensure that the validated processes are realistic; for example, contact times of disinfecting fluid and surface of more than 5 minutes may prove impossible to execute in practice.
  • Ensure that the actual use of disinfectants matches the validated conditions, and make sure logical and easy to follow procedures and adequate training are made available to staff.
  • Ensure that the validation studies either include worst-case conditions, or known upper and lower process limits.
  • The outcome of the validation program should be a process that can be executed relatively simply in daily practice and provides robust effectiveness for the removal and reduction of microbial contamination.

Our specialists can assist you with the necessary risk assessment and selection process and help you collect the required documentation and related information in order to make an educated decision on which disinfectants to select and include in further validation studies. Progress-PME can also help you define and plan these studies and introduce you to suitable contract laboratories capable of performing the necessary validation studies. Furthermore, we can support you in documenting the study results and setting up suitable procedures for disinfection in your facility.

For more information on disinfection we would like to invite you for a personal consultation to discuss what we can offer you.