PIC/S/EMA/WHO: New Q&A on Annex 1

The revision of Annex 1 also made it necessary to update the previous PIC/S interpretation document, PI 032-2, “GMP Annex 1 Revision 2008, Interpretation of Most Important Changes for the Manufacture of Sterile Medicinal Products”. Based on a Swissmedic draft from 2023, the joint PIC/S–EMA–WHO working group developed a new Q&A document. Following review by the participating organisations, it was adopted to ensure a consistent technical interpretation of Annex 1 across PIC/S, the EU and WHO.

The document explicitly states that it does not introduce new GMP requirements. In practice, however, it sharpens inspection expectations in many areas.

Some particularly relevant points include:

Contamination Control Strategy (CCS)
The effectiveness of the Contamination Control Strategy should be assessed continuously against the results obtained and reviewed at least annually. It does not have to be a single document, but should be structured and effectively managed. Existing systems may be referenced. A CCS may also be relevant to non-sterile products, for example where grade C/D cleanrooms are used.

VHP is not a sterilisation method
Vaporized hydrogen peroxide (VHP) is regarded only as a means of surface bio-decontamination. Where sterilisation is required, this is insufficient unless an equivalent level of sterility assurance can be demonstrated. The statement on lyophilisers is particularly clear: VHP bio-decontamination alone, in place of sterilisation, should be considered a deficiency.

PUPSIT
PUPSIT should be performed on filters used for final sterilising filtration wherever technically feasible. Manufacturers should consider any necessary design changes. An alternative approach requires process constraints that are not attributable to design flaws, together with a comprehensive risk assessment and appropriate risk mitigation measures.

A redundant filter that has not undergone PUPSIT cannot be used to support batch release if the primary filter fails the post-use integrity test. Risk assessments should not be used to inappropriately justify the omission of PUPSIT.

Single-Use Systems (SUS)
For critical SUS, an on-site audit of the manufacturer is normally expected, or evidence of the manufacturing site’s compliance. Reliance on supplier integrity testing requires in-depth supplier qualification. Supplier testing does not automatically replace the end-user’s own integrity testing: transport, installation and the complete assembly should be taken into account.

Aseptic Process Simulation (APS)
Initial validation should cover the entire maximum filling duration. Risk-based approaches may be used for subsequent APS runs, provided that the full duration is covered at defined intervals. The “frequency” of interventions generally refers to their absolute number. During annual personnel requalification, each operator should perform every type of intervention they are expected to carry out.

Even for validated isolators, the standard expectation remains at least two APS runs per year, for each aseptic process, filling line and shift. ISO 13408-1 does not override this expectation. Following a failed APS run, three consecutive repeat runs are normally required. Any reduction requires robust supporting data. If the APS programme has not been maintained during an extended shutdown, the initial APS validation is expected to be repeated before operations resume.

Source:

PIC/S: Interpretation of the Most Important Changes in the Annex 1 on the Manufacture of Sterile Medicinal Products (2022)