9-11 April 2024
With the new Annex 1 and the ISO 14644 series, detailed guidelines apply to the planning and GMP-compliant operation of cleanrooms and their HVAC systems. Nevertheless, or precisely because of this, in practice there is often the question of the "recovery time" and the required "clean-up phase". Are these different requirements, or are they the same? Do they only apply to sterile or also to non-sterile medicinal products? Do they have to be measured in operation or at rest?
The determination of the clean-up phase is a requirement of Annex 1. It is defined as the time that elapses until the ventilation system has cleaned the particle concentration in the operating state "in operation" to the limit value of the particle concentration for the operating state "at rest". Consequently, the clean-up time is measured starting in the operating state "in operation" and ending in the operating state "at rest". The requirement is that the clean-up phase is less than 20 minutes.
Annex 1 applies to the production of sterile medicinal products, but can also be used for the production of other forms. This is also extremely sensible, as especially in the dusty production of e.g. solid dosage forms, the avoidance of cross-contamination during a product change is essential. Besides cleaning the manufacturing equipment, the premises and the air in the rooms must also be cleaned before a new product is produced. So it must be known how long the ventilation system needs to reach the clean (at rest) state again. The clean-up phase is determined for premises of cleanliness classes B, C and D (not for zone A) as well as in the non-sterile production areas, as far as reasonable (risk analysis or contamination control strategy).
So, in addition to cleaning validation, compliance with the clean-up phase after product changeover is part of the answer to a GMP inspector's question: "How do you prevent cross-contamination?". And it is also helpful to know the answer in the production of non-sterile, solid dosage forms.
The recovery time is a requirement of ISO 14644. The recovery time test is performed to determine whether the cleanroom is capable of returning to its specified cleanliness class within a limited period of time after brief exposure to a source of airborne particles. This test is not recommended for low-turbulence displacement flow (as for the clean-up phase, see above). The recovery time is thus measured in the state at rest, after an amount of particles has been added. The recovery time also provides information on the locking times in airlocks. It is therefore not only recommended for production rooms, but for all rooms with turbulent dilution flow. There is no normative requirement for a recovery time; each company is obliged to define a recovery time. Also, no time interval for measuring the recovery time is specified, but it is carried out during the initial qualification (classification) and is repeated in the event of a change in the room or the air change rate.
Since both measurements are completely different, measurements of both the recovery time and the clean-up phase have to be carried out.