Revised EU GMP Annex 1‐ Manufacture of sterile medicinal products

The long‐awaited revised Annex 1 on Manufacture of sterile medicinal products has finally been published by the European Commission on 25th August, 2022 (1). The main driver for the update was to reflect changes in regulatory and manufacturing environments which include a clear shift to apply principles of quality risk management. The new Annex 1 will come into force on 25th August, 2023.

The European Commission published their first draft in 2017 which was open to the public for comments at the time. And the industry commented: more than 6,000 comments during the first round of review and same amount during the second which included a targetted industry stakeholder review phase in 2020. The intense debates, surrounding the prominent PUPSIT (Pre‐Use Post-Sterilisation Integrity Test) for example, were not a surprise as there were significant revisions, additions and far more details added, which resulted in a document increase from 16 to 58 pages.

We should acknowledge the effort of both the industry and regulatory bodies, including the World Health Organization (WHO) and the Pharmaceutical Inspection Co‐Operation Scheme (PIC/S), to issue a much more state‐of‐the‐art guidance on the manufacture of sterile products. Though coming in force after a transition period of one year, it is expected that the current version will be the basis for inspection of sterile products and components intended to be used in sterile drug manufacture.

Scope: Relevance also for mRNA and viral vector manufacturing

Although the title “Manufacture of Sterile Medicinal Products” didn’t change, the intent of Annex 1 is to provide guidance for the manufacture of sterile products in general. Active substances, excipients, primary packaging materials and finished dosage forms are specifically outlined as sterile product types. In addition, some of the principles and guidance in Annex 1 may be applied for other products not intended to be sterile such as low bioburden biological intermediates. The overall scope is to prevent any microbial, particulate or endotoxin contamination in the final drug. To emphasise one of the most important principles of the previous and the new Annex 1: “Sole reliance for sterility or other quality aspects should not be placed on any terminal process or finished product test.”

These products are typically not released with a “sterile” claim but are sterile filtered and subsequently aseptically filled into previously sterilised containers or bags. Given the potential variability in filtration performance of these products, the overall contamination control strategy will get more important.

Must have: Contamination Control Strategy

“Contamination Control Strategy” (CCS) is the hot topic of all Annex 1 discussions. Papers and templates are published (2, 3) to support drug manufacturers in the set up their own CCS which will become a must have in the future, or to be precise, by 25th August, 2023. The objective of a holistic CCS is to move away from sterility reliance based on just any terminal process or final product test towards a detailed process knowledge and all potential sources of contamination. There is a long list of elements to be considered, starting with the plant and process design, and ending with corrective and preventive actions. It is acknowledged that the manufacturer might already have control systems in place which will not need to be replaced but will need to be referenced in the CCS.

Single‐Use Systems

The new Annex 1 acknowledges the use of Single‐Use Systems (SUS) in the manufacture of sterile products and includes a dedicated paragraph where “some specific risks associated with SUS which should be assessed as part of the CCS” are listed: interaction with drug product, integrity (“risk of holes and leakage”), and particulate contamination. Expectations, such as supplier qualification, extractables evaluation, verification of integrity throughout the process, incoming control, operator training, and more are listed. Another new and interesting chapter is about “closed systems” where considerations are given regarding how to design and use a closed system and which measures should be in place to ensure that the system remains integral, specifically if a closed system is used in a lower classified area than grade A. Closed processing considerations also include the use of a sterile connection device which is now consistently referenced throughout the Annex 1 document as “intrinsic sterile connection device.”

The sterilisation of a drug using a sterilising grade filter with a nominal pore size of a maximum of 0.22µm has been established for decades. However, as this is one of the most critical process steps in sterile manufacturing, the new Annex 1 provides greater details on validation, usage and control compared to the previous version. The main debate over the years covered the Pre‐Use Post Sterilisation Integrity Test (PUPSIT). A pre‐use test was established in the past to check if the, sometimes harsh, steaming in place conditions might have damaged the filter membrane. In addition, masking effects derived from the product stream could lead to a false integrity test result. The Parenteral Drug Association (PDA) and the BioPhorum (formerly BPOG) performed detailed scientific investigations of filter masking effects to gain more clarity and to support risk assessment approaches (4). PUPSIT is still a requirement with a workaround for “process constraints (e.g., the filtration of very small volumes of solution)”.