Heating Ventilation and Air Conditioning (HVAC) – Part 3 Pharmaceutical Quality, Good manufacturing Practice & Bioequivalence Kiev, Ukraine 3 - 7 October 2005 Maija Hietava M.Sci.Pharm Quality Assurance and Safety: Medicines, Medicines Policy and Standards, Health Technology and Pharmaceuticals Cluster Tel: +41.22.791.3598 Fax: +41.22.791.4730 World Health Organization E-mail: hietavam@who.int

Characteristics of air handling systems In the following slides, we will study alternatives in air handling systems Turbulent or uni-directional airflows Filter position Air re-circulation vs fresh air Return air systems (positions) Overpressure requirements

Uni-directional / laminar displacement of dirty air Air flow patterns (1) Turbulent dilution of dirty air Uni-directional / laminar displacement of dirty air 0,30 m/s

Air flow patterns (2) Filtered air entering a production room or covering a process can be turbulent uni-directional (laminar) GMP aspect economical aspect New technologies: barrier technology/isolator technology.

AHU Air flow patterns (3) Uni-directional Turbulent Prefilter Main filter Uni-directional Turbulent 1 2 3 Annex 1, 17.3

Air flow patterns (4) Workbench (vertical) Cabin/ booth Ceiling

Positioning of filters (1) AHU mounted final filter Filter in terminal position HEPA Filter + Production Room Production Room HEPA Filter

Positioning of filters (2) Prefilter AHU Main filter Ceiling exhausts 2 3 1 Low level exhausts

Positioning of filters (3) AHU Prefilter Final filter 2 1 Positioning of filters (3)

Air re-circulation The filtered air entering a production room can be 100% exhausted or a proportion re-circulated GMP aspect economical reasons

Ventilation with 100% fresh air (no air re-circulation) Washer (optional) Exhaust Unit W Central Air Handling Unit Production Rooms

Ventilation with re-circulated air + make-up air Exhaust Unit Central Air Handling Unit Return air

Definition of Conditions air as built at rest in operation

Qualification / Validation issues A good design is essential, but it has to be complemented by: Qualification of air handling systems Process validation Maintenance and periodic re-qualification Adequate documentation

Qualification (OQ, PQ) (1) Test Differential pressure on filters Turbulent / mixed airflow Description Uni-directional airflow / LAF Room differential pressure Airflow velocity / uniformity Airflow volume / rate Parallelism Air flow pattern 2 N/A 2, 3 Optional 3 1 := As built (ideally used to perform IQ) 2 = At rest (ideally used to perform OQ) 3 = Operational (ideally used to perform PQ) IQ tests are not mentioned on this slide

Qualification (OQ, PQ) (2) Test Turbulent / mixed airflow Description Uni-directional airflow / LAF Recovery time Room classification (airborne particle) Temperature, humidity N/A 2 2,3 1 := As built (ideally used to perform IQ) 2 = At rest (ideally used to perform OQ) 3 = Operational (ideally used to perform PQ) IQ tests are not mentioned on this slide

Microbiological validation Definition of alert / action limits as a function of cleanliness zone Identification and marking of sampling points Definition of transport, storage, and incubation conditions Ask the question: “What are the alert and action Limits and what procedures are followed if these points are exceeded?”

Cleanroom monitoring program (1) Cleanrooms should be monitored for micro-organisms and particles air Sampling point

Cleanroom monitoring program (2) Routine monitoring program as part of quality assurance Additional monitoring and triggers Shutdown Replacement of filter elements Maintenance of air handling systems Exceeding of established limits Annex 1, 17.37

Cleanroom maintenance program (1)

Cleanroom maintenance program (2)

Documentation requirements Description of installation and functions Specification of the requirements Operating procedures Instructions for performance control Maintenance instructions and records Maintenance records Training of personnel (program and records)

Inspecting the air handling plant Verification of design documentation, including description of installation and functions specification of the requirements Operating procedures Maintenance instructions Maintenance records Training logs Environmental records Discussion on actions if OOS values Walking around the plant

Conclusion Air handling systems: Play a major role in the quality of pharmaceuticals Must be designed properly, by professionals Must be treated as a critical system