More than 10 years have passed since the last revision of Annex 1 of the EU GMP. On 20 December 2017, almost 3 years after its announcement, the EU published a draft of the new Annex 1 document. The consultation period runs until March 20, 2018.
The published text is aligned with the international standards of WHO and PIC / S. The new Annex 1 draft introduces a wide range of substantial changes.
- The new draft supplements the actual version with 100 extra paragraphs, covering new concepts.
- Seventy updated paragraphs will have a significant impact for laboratories involved in the manufacturing process.
- Only 40 of the 127 paragraphs of the current version remain unchanged.
The most significant changes are:
The general principles of the updated Annex 1 apply to additional areas in GMP. For example: sterile active substances.
Pharmaceutical quality system (PQS).
The new Annex 1 highlights the specific requirements of the PQS when applied to sterile drugs. It strongly emphasises the importance of analysing the root cause of the deviations to ensure that the associated risk is correctly mitigated by appropriate corrective and preventive actions.
In line with ISO 14644, the counting of particles of size ≥ 5 μm is not required for the classification of the room. But this same counting is obligatory during the environmental monitoring of non-viable particles. This section also describes the use of barrier technology: isolators and RABS.
The new Annex 1 draft for EU GMP defines requirements regarding the design, qualification and operation of equipment. For example, the equipment monitoring requirements must be determined during their qualification.
There are new requirements for water systems, steam used for sterilization, compressed gases and vacuum and refrigeration systems.
Production and specific technologies.
The new document specifies that containers should be closed by appropriately validated methods. Containers closed by fusion, e.g. Form-Fill-Seal Small Volume Parenteral (SVP) & Large Volume Parenteral (LVP) bags, glass or plastic ampoules, should be subject to 100% integrity testing. For other containers, a statistically valid sampling plan must be implemented. Visual inspection alone is explicitly excluded as an acceptable integrity test method.
Requirements for environmental monitoring and viable and non-viable particles.
Alert limits must be established based on the results obtained in the PQ, or based on the trend of the data taken during production. They need to be subject to periodic revisions. New requirements are defined for routine monitoring, as well as for the “Aseptic Process Simulation” (APS).