March 20, 2024

Annex 1: All you need to know

GMP Annex 1, the European guideline for “Manufacture of sterile medicinal products”, has been updated in 2023. The revision’s changes have added several challenges, but also chances for manufacturers in order to comply with the new regulations.

The scope of Annex I, its implications and efficient solutions will be discussed in this article.

What is Annex 1?

Annex 1 is the European Union’s guidelines for the manufacturing of sterile medicinal products. The original draft of Annex 1, also known as “EU GMP Annex 1: Manufacture of sterile medicinal products”, from 1971, was expanded and updated in August 2022. It came into effect on August, 25 2023.

EU GMP Annex 1 outlines the GMP-specific requirements (Good manufacturing practice) needed to ensure product quality and patient safety when it comes to sterile medicinal products. The guidelines were not only directed at pharmaceutical manufacturers, but also towards partnerships between contract manufacturing organizations and their clients.1 

Areas of application of Annex 1

In terms of geography, the guidelines described in Annex 1 are effective for pharmaceutical manufacturers in the European Union, similarly to the FDA’s “Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice”.

The scope of Annex 1 and its revisions from 2022 encompasses biological active substances and auxiliary substances, as well as primary packaging products. The regulatory requirements of Annex 1 do not only concern controls of the final product, but require controls throughout the manufacturing process. This increases the chances to discover microbial contamination early and not only in routing controls.

In the past, individual components for advanced therapy medicinal products, like mRNA or viral vectors, were filtered aseptically and then filled into sterile components with a large share of manual handling (e.g. in laminar air flow or filling lines). Now, there is a greater focus on automated processes and closed systems.2 

The history of Annex 1 and GMP – the changes in 2023

The first version of Annex 1 was published in 1971. Since then, the document experienced several adaptations, but a complete revision process was only started in 2012. 

For the revision, the EU commission worked closely together with the World Health Organization (WHO), the Pharmaceutical Inspection Co-operation scheme (PIC/S) and the Food and Drug Administration (FDA)3. One of the goals was to achieve a more unified version of guidelines for the manufacturing of sterile medicinal products.

The aim of the mission was to react to new changes in manufacturing environments, which is mirrored by the strong focus of the guidelines on contamination risk management.3 

Annex 1 focus areas

Content of Annex 1 – the main focus areas

The main focus areas of Annex 1 include the application of Quality Risk Management (QRM)4. Manufacturers are required to implement a Contamination Control Strategy (CCS), include the Pharmaceutical Quality System (PQS) into their manufacturing process, and apply the principles of QRM (monitoring, disinfection and staff training).

Next to updated cleanroom requirements5, Annex 1 determines regulations for Pre Use Post Sterilization Testings (PUPSIT) for filters used in bioprocessing.6

Further, a new set of technologies is addressed in Annex 1, ranging from restricted access systems (RABS) for cleanrooms to isolators and single-use technologies.4 5 6 

Risk management and contamination control strategies

The revision of Annex 1 has a main focus on the aspects of Quality Risk Management and the development of Contamination Control Strategies for pharmaceutical manufacturers. CCS strategies are laid out as a “set of controls for microorganisms, endotoxin/pyrogen and particles, derived from current product and process understanding that ensures process performance and product quality.”7

As the revised guidelines aim for improved quality, safety, and overall-contaminant-free products, manufacturers have to come up with strategies to achieve this. These include regular controls of risk factors to cleanroom environments, such as raw materials, excipient and drug product components, as well as facility and equipment design. Further, thorough documentation of the whole process from design to the administration of the product has to be provided in order to comply with Annex 1.7 

Cleanroom regulations

In Annex 1, cleanrooms experience a heightened amount of attention. The most striking changes involve regulations on how to move within cleanrooms (slow and controlled movements, so not to shed more particles than needed), as well as specially designed clothing items.

The rules laid out for the different cleanroom classes from A to D can differ. While hair, for example, does not need to be covered in Grade A and B environments, members of staff need to wear a cap and cover beards and jewellery in C and D environments.

Further, it is laid out how technologies for cleanrooms like Restricted Barrier Access Systems (RABs) require special testing and control strategies. The integration of automated systems helps manufacturers reach GMP requirements more easily. Closed processes prevent exposure times and help to maintain sterility by reducing the need for manual intervention.

PUPSIT

PUPSIT is the abbreviation of Pre Use Post Sterilization Integrity Testing. The process helps pharmaceutical manufacturers to make sure that a filter is fully functional before it is used in bioprocessing.

Before a membrane filter, for instance, can be used in a bioreactor, the filter has to be sterilized. After that, testing is performed to verify the filter’s integrity, meaning it has not been damaged during sterilization.

The most widely used filter integrity testing method is the Bubble Point Test, during which water is injected to moisten the filter. The test depends on sterile filter test tubes, which are often made out of stainless steel. However, the use of single-use-technologies is on the rise. With single-use filtration assemblies, the whole system, and not just the filter, is replaced after every cycle. They eliminate the need for autoclaving procedures and help guarantee that the drug formulations are not diluted by water residues after filter testing.

To help manufacturers comply with the updated regulations, fluid management systems by Single Use Support can be expanded with PUPSIT racks for sterile filtration.

Put into proportion – Good Manufacturing Practices around the world

Good Manufacturing Practices are guidelines for the validation of product quality and safety that are not limited to the EU, but are in effect globally. They were first formulated by the WHO in 1969, with an annex for the control of biological medicines in 1991.

More than 100 countries have adopted GMP standards as set by the WHO and incorporated them for their national legislation on the controls of sterile drug manufacturing. Annex 1 is the European GMP guide, while the American equivalent by the FDA is titled “Guidance for industry: Sterile drug products produced by aseptic processing current good manufacturing practice”.9 In China, the National Medical Products Administration (NMPA) has issued equivalent regulations under the “Good Manufacturing Practice for Drugs”.10

While all of these guidelines orient themselves on the GMPs as published by the United Nations health agency, there are certain differences. One of them is the disparity in cleanroom specifications between FDA and EU GMPs with regard to permitted particle size and particle per m³.8 9 10 

Current challenges concerning Annex 1

Adopting the necessary changes to comply with Annex 1 sets a challenge for many manufacturers of biologic drugs. Defining the scope of a CCS can be a great difficulty because Annex 1 guidelines do not only include the products and components on-site, but also starting materials and other products provided by other parties.

With changes in cleanroom regulations and strategies to prevent contamination like regular filter controls, the necessary changes pharmaceutical and biotechnology companies have to make call for holistic solutions.

Outlook – what Annex 1 means for pharmaceutical manufacturing

The amendments in Annex 1 were made to provide a more comprehensible guide for manufacturers than the former version. While it has been criticized for changes in terminology that might be confusing and potentially too detailed, the guidelines are meant to help achieve standardization and an improved quality of drug products.12

While navigating the updated GMP guidelines can be challenging for manufacturers, they exist to ensure the highest amount of product safety and quality. The updated regulations are a reaction to new developments and technologies in the industry. Industry trends like single-use technologies are recognized as helpful tools for the compliance to industry standards.11 

Annex 1: All you need to know

Single Use Support aiding in Annex 1 compliance

GMP Annex 1 significantly influences the manufacturing process of biopharmaceuticals. By adopting a risk-based approach and integrating sterile single-use systems into the process, manufacturers can meet regulatory requirements more easily while prioritizing patient safety and product quality.

A combination of automated single-use technologies and closed protected systems significantly reduces the risk for contamination, as it eliminates the need for manual intervention.

The advanced filling and filtration system RoSS.FILL can be expanded with a PUPSIT rack for sterile filtration. It was designed by Single Use Support to guarantee compliance with Annex 1 guidelines. This closed automated system offers the benefits of modularity and scalability and is compatible with single-use bioprocessing containers in different sizes to cater to smaller and large-scale productions.

Single Use Support also offers the single-use assemblies needed for GMP-compliant fluid and cold chain management, from tubes to filters for sterile fluid management. With holistic process solutions, the company helps manufacturers achieve the highest product quality and patient safety.

  1. Second targeted stakeholders' consultation on the revision of Annex 1, on manufacturing of sterile medicinal products, of Eudralex volume 4, https://health.ec.europa.eu/consultations/second-targeted-stakeholders-consultation-revision-annex-1-manufacturing-sterile-medicinal-products_en, Published
  2. RNA-based drugs and regulation: Toward a necessary evolution of the definitions issued from the European union legislation, http://dx.doi.org/10.3389/fmed.2022.1012497, Published 2022-10-17
  3. The Rules Governing Medicinal Products in the European Union Volume 4 EU. Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, https://health.ec.europa.eu/system/files/2022-08/20220825_gmp-an1_en_0.pdf, Published
  4. ISO 14698 or EN 17141: Is There a Choice for Cleanroom Compliance?, http://dx.doi.org/10.2345/0899-8205-57.s1.15, Published 2023-05-05
  5. Sterilisation Methods, http://dx.doi.org/10.1007/978-3-031-20298-8_30, Published 2023-06-15
  6. Enhancing Compliance with EU GMP Annex 1 Requirements, https://www.americanpharmaceuticalreview.com/Featured-Articles/609715-Enhancing-Compliance-with-EU-GMP-Annex-1-Requirements/, Published 12/2023
  7. The Rules Governing Medicinal Products in the European Union Volume 4 EU. Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, https://health.ec.europa.eu/system/files/2022-08/20220825_gmp-an1_en_0.pdf, Published
  8. Guidance for industry: Sterile drug products produced by aseptic processing current good manufacturing practice, https://www.fda.gov/media/71026/download, Published
  9. Main Responsibilities of the National Medical Products Administration, https://english.nmpa.gov.cn/2019-07/18/c_377587.htm, Published 07/2019
  10. FDA and EU GMP Annex 1 Differences in Cleanroom Specifications, https://www.raps.org/News-and-Articles/News-Articles/2019/7/FDA-and-EU-GMP-Annex-1-Differences-in-Cleanroom-Sp#citation, Published 07.2019
  11. The long and winding Road of the Annex 1 Revision, https://www.gmp-journal.com/current-articles/details/the-long-and-winding-road-of-the-annex-1-revision.html, Published 03.2023
Annex 1: All you need to know

Michael Mühlegger

Head of Marketing & Inside Sales

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