MCC PRESENTATION - GMP MANUFACTURING ENVIRONMENTS Module 4 Presented by : Deryck Smith Consulting Engineers

GMP Manufacturing Environments Air Handling Systems HVAC Systems Heating Ventilation Air Conditioning Module 4: Pressure Cascades & Building Layouts

GMP Manufacturing Environments Topics for this Module: The integration of air conditioning systems and building layouts. The requirements for pressure cascades and how to achieve them. How building finishes and plant components affect facility cleanliness. Pharmaceutical Equipment

Inter-dependence of Air Handling Systems & Buildings Building layouts, Pressure cascades, Air handling systems and Pharmaceutical equipment are all inter-related. No one can exist without the other.

What is a Pressure Cascade? A process whereby air flows from the cleanest area, which is maintained at the highest pressure to a less clean area at a lower pressure.

What Is the Purpose of a Pressure Cascade? Helps prevent cross-contamination between adjacent areas. Helps prevent ingress of contaminants from outside. Is used to enhance separation between areas of different cleanliness. The unit of measurement for pressure is the PASCAL (Pa)

Air Pressure Cascade A typical air pressure cascade

Measuring the Air Pressure Cascade The pressure differential over the doorway is measured with a portable magnahelic gauge or micro manometer. Permanently installed gauges are preferred. The American Institute of Architects stipulates that continuous visual monitoring is required.

Room Pressure & Air Movement A room pressure cascade system forces air to flow from clean areas to less-clean areas. Air movement, such as laminar flow (UDAF) over the product, protects the product. (aseptic packing / filling) Directional air movement helps carry contaminants away from a critical process.  Localised dust extract is one form of directional air movement. Directional airflow minimises product cross contamination – eg. Raw meat & processed meat Aseptic filling eg. Mineral water, long-life products, etc. The correct air change rate falls under the aspect of Air Movement. The high air change rates are required not only to flush contaminants but also there must be sufficient air to create directional movement to ensure contaminants are moved away from the open product. SABS 6.5.4: High Care – 2 micron filter plus positive pressure. SABS 8.4.1: Airflow opposite to product flow – Flows from more hygienic to less hygienic

Typical OSD Plant : Cross-contamination Protection Note the direction in which the door open. What is the significance of this ? What should the room pressures be ?

Dispensary Layout Is this a good layout ? What is the problem with this layout ? Mix-ups ! Is this a good layout ? PIC/S PH 1/97 (Rev.3) #3.3 & 3.12

Improved Dispensary Layout Airflow direction There are many different opinions about Dispensary pressure cascades. The one above is considered the most suitable What should the room pressures be ?

Sampling Booth Layout (1) EXTRACT HOOD SAMPLING BOOTH Layout liable to cause product contamination WAREHOUSE

Poor Design Extract System Operator contaminates product Product contaminates operator – dust inhalation Airflow direction must be such that the operator & the product is protected WHIRLEY BIRD Section Through Sampling Booth

Sampling Booth Layout (2) UDAF HOOD SAMPLING BOOTH AIR LOCK AIR LOCK Ideal sampling booth layout CHANGE Step-over-bench

Typical Section Through Sampling Boooth

What to Qualify in the Sampling Booth Suite Cleanroom class – ISO 8 HEPA filter integrity test Airflow rates UDAF velocity Room pressures Containment – smoke tests Temperatures (< 25°C)

Ablution Layout 1 Production Plant Toilets Staff Change Room Staff

Ablution Layout 2 Production Plant Toilets Change Room Staff Staff The correct way of laying out the ablutions Toilets Staff Staff

Change Room Layout Do not go to the canteen in protective garment It is pointless having a change room if it is not used properly. Note the use of a step-over-bench This is not a High Care Change room!

Protective Garments Outside ?? How often do you see staff walking around outside in their protective garments There should be noexit from the factory, other than an emmergency fire exit, which does not pass through a change room. Material airlocks between zones of different cleanliness should carry a sign which says: “NO PERSONNEL ENTRY OR EXIT” It is pointless having a change room if it is not used properly

Sterile Suite Pressure Cascade = Room Pressure = ISO Cleanroom Class T = Turbulent U = Uni-directional 8 FILLING MACHINE 15Pa AUTO- CLAVES STERILE FILLING RM FINISHED PRODUCT STAGING MAT. A/L FORMULATION ROOM PERSONEL CHANGE STAGING COMPONENT PREP 7 5T 6 9 5U 6/7 Simple layout only. For Aseptic filling – no terminal sterilisation. What should the pressures be ? What should the cleanroom classes be ?

Product Flow Diagram Wood free zone RAW MAT. RECEIPT PACK. MAT. DISPENSARY PACK. MAT STORE MANUFACTURING One such area which must be totally separated from other areas is a high care GMP zone Materials must go thyrough a pass through hatch PRIMARY PACK MAT. CLEAN DOWN PRIMARY PACKING GMP ZONE SECONDARY PACKING DISPATCH

Staff flow Diagram STAFF ENTRY CANTEEN RAW MAT. RECEIPT PACK. MAT. DISPENSARY CHANGE PACK. MAT STORE GMP CHANGE PRODUCTION PRIMARY PACK MAT. CLEAN DOWN PRIMARY PACKING GMP ZONE SECONDARY PACKING DISPATCH

Negative Pressure Facilities Required for facilities handling potent compounds such as penicillin & hormones. Special precautions required to prevent product contamination from the atmosphere. Exhaust air must be efficiently filtered and safe filter handling must be used. One often finds a penicillin plant focuses on the negative pressure aspects only and ignores other criteria such as product safety. Have found facilities under such high negative pressure that vast quantities of unfiltered outside air is drawn in causing significant product contamination.

Safe Change Filters Used for filtering hazardous materials: Dirty filters are removed into a plastic bag The bag is automatically sealed at the filter unit housing A new filter is inserted via a plastic bag and the cover closed At no time is the operator or the atmosphere exposed to the hazardous powder.

Case Study – Penicillin Plant MALE ABLUT. Add room pressures, Cleanroom class and comment on layout LAUNDRY FINISH. GOODS

Case Study – Penicillin Plant PRODUCTION PASSAGE -25Pa -15Pa ROOM PRESSURE RELATIVE TO AMBIENT AIR LEAKAGE DIRECTION LEGEND WEIGH ROOM -40Pa FINISHED GOODS AIR LOCK MALE ABLUTIONS GRANULATING SYRUPS FILLING SUPER- VISOR FEMALE CHANGE PACKING PRODUCT STORE A/L MAT DRY POWDER TABLET COMPRES- SION PREPARATION WASH UP MIXING CAPSULE STAGING -35Pa -30Pa -20Pa -10Pa -45Pa

Building Finishes: In module 1 we discussed the need for all facility components to complement each other. Therefore a good air handling system must be complemented by a building of good design and good finishes. On the next slide we will be looking at some of the Acceptable and Un-acceptable building finishes.

Building Finishes Not Acceptable Acceptable J PVA Paint L Epoxy or Enamel paint J Window sills Flush glazed windows Exposed pipes Smooth surfaces Horizontal pipes & services Concealed services Open floor drains Hygienic drains Floor cracks, flaking floor surfaces Homogonous sealed floors – epoxy finish or welded vinyl Ceiling cracks & joints Smooth sealed ceilings Exposed, open light fittings Flush light fittings Wooden furniture S/Steel or Melamine furniture Main criteria: Easy to clean Non-liberating Well sealed Also mention Floor Coving

Floors / drains Tiled Floor Epoxy Floor Photo on left has a tiled floor which was common on food plants years ago. Has also been used on pharma plants which is bad practice. New facility in Barcelona was delayed in opening for 12 months because the local inspectorate failed the floor and it had to be redone. Example on right is a self leveling epoxy floor and shows a sterile drain. Epoxy Floor

Poor & Good Windows Bacteria City !!!

Paint Finish… Not only building paintwork must be considered but also equipment Where have all the paint chips gone Is there anything wrong with this Tablet Press?

Building & Equipment Finishes No wall tiles Rust on blender - no rust should be present – fortunately the same colour as the product. Where are the bits of paint – let alone the rust particles

Services Distribution Impossible to clean! Easy to clean!

Don’t ignore building finishes… Keep a Balance Don’t ignore building finishes… … and then go overboard on staff dress code.

Services Distribution Where ever possible services should be located behind wall panels Exposed services & pipes are very difficult to clean & sometimes impossible to clean Equipment such as Film Coaters should be enclosed so that only the front face is in the GMP area. This makes cleaning much easier. Make use of service corridors behind equipment (but must be under negative pressure) Enclose machines for GMP reasons – also saves costs because GMP area is smaller.

Split Unit RETURN AIR SUPPLY AIR Poor quality Air filter Cooling Coil Condensate drip tray Fan liberates dust into the air

Fluid Bed Drier Is the quality of the supply air to the FBD correct? What filtration is used? Is the exhaust air filtered? Very often one encounters a facility where the air handling system is top notch, the buildings are of a good quality, but the air supplies to process equipment is totally inadequate. The facility AHU has HEPAs, but not the FBD or Coating equip.

Group session Airlock Add room pressures, cleanroom classes and suggest any building modifications

Modified Layout with Cascade MAL = Material Air Lock PAL = Personnel Air Lock

Work session: Connect the arrows between processes for Product Flow and Staff Flow Product Flow Diagram Raw Mat. Store Quarantine Released Materials Primary Change room Sampling A/L Sampling A/L GMP Change Room Sampling Booth Pack Mat. Store Dispensary Pre-Staging Dispensary Post-Staging Dispensary Weiigh Booth One such area which must be totally bseparated from other areas is a high care zone Materials must go through a pass through hatch Primary Pack Mat. Clean Down Pharmaceutical Manufacturing Secondary Packing Primary Packing F/G Dispatch

Work session: Connect the arrows between processes for Product Flow and Staff Flow Product Flow Diagram Raw Mat. Store Quarantine Released Materials Primary Change room Sampling A/L Sampling A/L GMP Change Room Sampling Booth Pack Mat. Store Dispensary Pre-Staging Dispensary Post-Staging Dispensary Weiigh Booth Primary Pack Mat. Clean Down Pharmaceutical Manufacturing Secondary Packing Primary Packing F/G Dispatch