Pharma Newsletter-April 2024

The Ardmac approach to applying the new ISO 14644-4 In our Annex 1 blog #4 we concluded that the key takeaway from the new ISO 14644-4 guidelines was the importance of science-based cleanroom design around the “surrounding” airflow patterns and contamination removal effectiveness, rather than a “rule of thumb” table of Air Change rates. Right now, our challenge in GMP Cleanrooms is to move focus away from the air change rate table. Instead, we need to understand the science around contamination control and change our narrative from a table of Air Change Rates to air volume flow rates with new metrics of Air Change Effectiveness (ACE) and Contamination Removal Effectiveness (CRE). Effective airflow design, verified through airflow visualisation studies and local airborne particle counts in cleanroom grades without unidirectional air flow (UDAF), promotes: Improved behaviour Enhanced cleaning and disinfection practices Confirmation of these benefits should be obtained through traditional viable Environmental Monitoring (EM) data.

processes, and activities, for effective contamination removal, i.e. the HVAC design. The good news is that this is a particular area of Ardmac’s technical expertise. We have advanced HVAC design tools, along with integrated BIM and CFD (Computational Fluid Dynamics). These tools, that were expensive in the past are now routinely used in an integrated cleanroom design approach. HVAC technology has moved forward significantly since the late 90’s when the original ISO 14644-4 was being developed. If we go back to the traditional table of air change rates again; the air change rate metric should not be discarded, it is still a useful reference. The recommended approach in Cleanroom design and adherence to Good Engineering Practice (GEP) suggests that the air change rate is an outcome of effective design. It should be calculated after establishing the supply air volume flow rate, rather than being the initial consideration. The more precise term introduced in the recent ISO 14644-4 is Air Change Effectiveness (ACE) Evolution and Application of ISO 14644-4:2022 The new ISO 14644-4:2002 recognises that cleanroom technology has matured since the standard was developed in the mid 1990’s, before the internet was freely available. As a result, the new standard is not a ‘cook book’, rather it contains the relevant “things to be considered” as best practice in cleanroom design. The new -ISO14644 Part 4 has an extensive bibliography as reference material for more detailed design guidance on

HVAC, utilities, material, and component selection, etc.

The downside of the new ISO 14644-4:2022 is that we need to understand the process and the contamination risks to carry out an effective cleanroom design. We’re back again to QRM (Quality Risk Management) and a CCS (Contamination Control Strategy) in the new Annex 1. When we apply the new ISO 14644-4:2022 standard in the context of the new Annex 1 then we design our GMP cleanroom, based on understanding the process(es) and risks to the product, with a focus on the user requirements and contamination removal effectiveness, considering energy efficiency (ISO 14644-16:2019). We apply the principles of QRM and develop a CCS taking into account the URS (User Requirements Specification) from Annex 15 (Q&V) and data integrity from Annex 11(DI), resulting in the most effective and efficient GMP Cleanroom design, all with a laser sharp focus on contamination removal effectiveness. The new ISO 14644-4:2022 presents several different formulas for calculating the correct supply air volume flow rates based on the process and expected emissions rates from the activities, including people movements and interventions, equipment processes and material handling. In addition, the new ISO 14644-4:2022 standard offers 2 types of ventilation effectiveness, called indices. These are Air Change Effectiveness (ACE), and Contamination Removal Effectiveness (CRE).

The Importance of assessing Air Change Rate Tables It’s probable that the Air Change Rate table has been quoted and misused for over 2 decades. To enhance energy efficiency without compromising product quality or patient well-being, it is advisable to implement best practices outlined in ISO 14644-4 and -16 within the context of the new Annex 1. By leveraging the clauses in Annex 1, users can address routine compliance challenges while simultaneously decreasing air volume flow rates, contributing to a more sustainable and efficient system. The airborne concentration in a non-UDAF cleanroom is determined by the airflow patterns created by the dilution of HEPA filtered air with room air and varies considerably depending on

the emission rates from the people, activities, the process, and material movements. The air change rate, which is the total air volume flow rate divided by room volume, is purely a mathematical formula. Therefore this simplistic formula should not be used as the starting point in the design of a cleanroom. This can lead to higher airborne concentrations than expected in small rooms. It can also lead to lower airborne concentrations than necessary in larger rooms, with associated high capital and energy costs. Contamination Control Strategy in HVAC Design A key element of the CCS (Contamination Control Strategy), required by the new Annex 1 is to understand the process, the hazards and impact of possible contamination, and then design the airflow patterns around the Cleanroom, the

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