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

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

3. 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

4. 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.

5. 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.

6. 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)

7. Air Pressure Cascade
A typical air pressure cascade

8. 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.

9. 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

10. 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 ?

11. 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

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 ?

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

14. 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

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

16. Typical Section Through Sampling Boooth

17. 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)

18. Ablution Layout 1
Production
Plant
Toilets
Staff
Change Room
Staff

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

20. 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!

21. 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

22. 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 ?

23. 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

24. 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

25. 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.

26. 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.

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

28. 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

29. 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.

30. 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

31. 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

32. Poor & Good Windows
Bacteria City !!!

33. 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?

34. 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

35. Services Distribution
Impossible to clean!
Easy to clean!

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

37. 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.

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

39. 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.

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

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

42. 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

43. 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