Annex 1 Revisions: What are the Changes and Whom will they Affect?

by | Apr 13, 2022 | Blog Of The Day, Industry Focus, Regulatory Focus

The EU has released a draft version of Annex 1. Expected to be implemented either later this year (2022) or early next year, these new requirements will affect the manufacture of sterile medicinal products, including those imported from non-Member States. But what are the changes and what will they mean for manufacturing in the pharmaceutical and biotechnology industries? ADAMAS Consulting took a deeper look at some of the key questions concerning the new requirements:

Annex 1 was initially issued in 1992 and revised five times (last one in 2009). What were the main triggers for the ongoing revision?

The revision was prompted by several factors, namely:

  • The need to include state-of-the-art principles such as quality risk management (QRM) and consideration of new technologies and innovative processes
  • The wish to achieve alignment of standards (e.g., with WHO, PIC/S) and harmonizing with the FDA’s Guidance on Sterile Drug Products produced by aseptic processing (issued in 2004)
  • Warning letters and Statements of non-compliance with Good Manufacturing Practices (GMP) related to sterile manufacturing
  • Recalls that have occurred related to sterility failures or contamination.

Will the scope of the document be the same as the current version? 

One of the first things that stands out when comparing the current version and the draft version of Annex 1 is the title of both documents: “Manufacture of Sterile Medicinal Products” will most likely become “Manufacture of Sterile Products”, making it clear that the intended scope of Annex 1 will significantly extend the range of products covered.

The “Scope” section of the draft broadens its application not only to other sterile products (including sterile APIs and excipients), but also to additional areas where the general principles of the Annex can be applied.

The current wording of the draft opens the possibility of applying some of the principles and guidance to the manufacture of other products such as the production of certain liquids, creams, ointments and low bioburden biological intermediates. Although not intended to be sterile, a control/reduction of microbial, particulate or pyrogen contamination for such substances is considered important.

What are the main concepts presented in the draft revision of Annex 1?

The concept of “Contamination Control Strategy” (CCS), is expected to be much more developed than in the Annex 1 currently in force and really is the core of the document.

In fact, the CCS is no longer only a Quality Assurance (QA) mission, but a multidisciplinary effort, which should be comprehensively documented and supported in validated manufacturing and control methods.

The development of the CCS requires thorough technical and process knowledge:

  • All potential sources of contamination should be identified
  • Critical control points should be acknowledged (again, the need for robust risk assessments is key)
  • The effectiveness of the implemented controls (design, procedural, technical and organizational) should be monitored, assessed, investigated and trended.

The CCS should be periodically reviewed and updated as appropriate, in order to drive continuous improvement.

The Pharmaceutical Quality System (PQS) also gains importance here.

The general attributes of PQS were already described in Chapter 1 of Eudralex Volume 4 Part I, however, some aspects are expected to be added in Annex 1, to address the specific requirements of sterile product manufacture and to ensure that all activities are effectively controlled, resulting in reduced contamination in sterile products.

The sections on “Premises” and “Disinfection” have a lot of novelties on premises design and qualification. What are some of the areas that will be affected?

  • The transfer of equipment, components and material into clean areas is one of the main sources of contamination, and will very likely be subjected to new/clarified requirements. For example, only materials and equipment that have been included on an approved list, developed during the validation of the transfer process should be allowed to be transferred into Grade A or Grade B areas. This is a complete novelty, which adds up to the existing validation activities.
  • The use of barrier technologies, such as Isolators or Restricted Access Barrier Systems (RABS), will need to be designed to provide protection of the Grade A environment.
  • Cleanrooms, air supply of clean areas and pressure cascades will also have a number of new requirements to meet.
  • New requirements are also expected regarding the disinfection of premises, namely the need to establish a cleaning and disinfection written program (and to monitor its effectiveness) and the need to validate the disinfection process. The effective removal of disinfectant residues was briefly mentioned in Annex 15 and is also expected to become a requirement now.

Are there any other new requirements that should be highlighted?

Yes. Aseptic manufacturing poses the highest risk, as the product is not terminally sterilized. This revision of Annex 1 includes a number of new aspects on aseptic manufacturing.

Aseptic process simulation (APS), also known as “Media Fill” is a big topic in the revision. What are the main differences or clarifications that will be provided?

APS (Media Fill) is applicable to not only to filtered liquids but also to non-filterable formulations, sterile powders (including sterile APIs), lyophilized products and production campaigns.

Guidance is provided on the critical manufacturing steps (with focus also on lyophilized products) and expected interventions that should be included during the APS exercises; factors that should be considered when developing the APS plan (e.g., “worst case conditions” regarding container size/line speed/volumed filled/agitation, the use of bracketing approaches, holding times, selection of culture media, gas usage, APS duration, shift changeovers, etc.); initial validation and re-validation (including number of batches used and frequency).

Finally, what are the expected main challenges that manufacturers will face, to implement this guidance?

The revision of Annex 1 will introduce several new requirements and clarify some aspects that are not adequately defined in the current version. The two main concepts to retain are “Contamination Control Strategy” and “Quality Risk Management”, which are widely used throughout the document.

Implementing this guidance will be a demanding exercise and the industry faces several new challenges:

  1. Improved process and microbiological knowledge – this is crucial, as is good articulation and experience sharing between Departments (e.g., Engineering/Maintenance, Microbiology and Production).
  2. Process (re-)validation, equipment (re-)qualification and operator training and re-qualification are paramount for success.
  3. Establishing a robust cleaning and disinfecting program, based on several validations (biocides’ efficacy validation, validation of cleaning/disinfectant agents residues, cleaning validation, etc.) is also detrimental for achieving good contamination control.

Final Advice

This is a good example of the saying “fail to prepare and prepare to fail”!

The revised version of Annex 1 is yet to be published (thus, additional changes might be introduced), and the applicable transition period to be implemented is still unknown, however, companies should be proactive and start preparing.

Creating multidisciplinary teams, performing gap analysis, identifying training needs, revising risk analysis (to identify new risks or risks that are no longer acceptable in light of the foreseen requirements arising from the Annex 1 revision), detecting process weaknesses and drafting improvement strategies is a good way to kick off the adaptation process and ADAMAS Consulting can help.

By using ADAMAS’ extensive experience and expert knowledge you can ensure you have peace of mind for any new regulatory changes.

For further advice on the Annex 1 revisions or any other concerns relating to Good Manufacturing Practice, or for details of how ADAMAS can help you, please contact us or call us on +44 (0)1344 751 210 in Europe / +1-919-341-3361 in the US