The document discusses design requirements for aseptic manufacturing facilities. Key points include: - Facility design must facilitate appropriate space, operations, material and waste flows to prevent contamination. - Critical areas require stringent controls for airborne particles, air changes, airflow velocity, and surface cleanliness. - Utilities like WFI, steam, and HVAC systems must be designed to stringent quality standards to prevent contamination. - Documentation and validation are required to prove the facility is built as designed and certified for use.

1. Facility Design

2. The Aseptic Manufacturing Plant
GMP Requirements:
o 21 CFR Part 211

3. 211.42 Design and Construction
Features for Aseptic Areas
Floors, walls & ceilings of smooth, hard and
cleanable surface materials
Temperature and humidity controls
Air supply filtered through HEPA filters under
positive pressure
Environmental monitoring program
Cleaning and disinfecting program
Equipment maintenance program

4. Walls, Floors and Ceiling
Surfaces
Smooth, cleanable finish that is impervious
to water, cleaning and sanitizing solutions
Constructed of materials that resist
chipping, flaking, oxidizing or other
deterioration
o epoxy terrazzo, Mipolam
o cement plaster
o plastics

5. Aseptic Filling Process Flow
Diagram
Raw
Formulation/ Sterile
Materials Filling Lyophilization
Compounding Filtration
Component
Preparation Capping
Packaging

6. Sterile / Aseptic Operations
Sampling
Raw & Packaging Material Storage
Dispensing
Formulation / Compounding
Sterile Filtration
Component Prep
Filling
Cleaning
Lyophilization (Freeze Drying)

7. Sterile / Aseptic Operations
(cont.)
Capping
Terminal / Post Sterilization
Labeling
Packaging
o Cartoning
o Case Packaging
Warehouse Distribution
o Conditioned Space
o Refrigerated
o Frozen

8. Sterile / Aseptic Operations
(cont.)
Support Areas
o Quality Control / Quality Assurance
o Laboratory
o Chemical
o Microbiology
o Stability
o Process Utilities
o Pure Steam
o PW, WFI
o Pharmaceutical Compressed Gasses

9. Critical Process Systems
Component Preparation
Formulation/Compounding
Filter/Steam Sterilization
Aseptic Processing Operation
Liquid Fill/Packaging

10. Critical Processing Zone

11. Process in Key Element (GMP)
Aseptic Processing Protect Product from
Area Contamination
o Product Formulated o By Process
o Product Sterilized o By People
(filtration) o By Environment
o Product Filled o By Materials
o Product Sealed

12. Definition-- Contaminant
Anything that should
not be in or on the
product
o Microorganisms
o Pyrogens
o Non-viable
particulates

13. Contamination Control
Terminal Sterilization
Aseptic Sterile
Manufacturing
o Type of Product
o Critical Processing
Steps
o Product Exposure
o Acceptance Criteria

14. Contamination Control
Personnel Gowning
Personnel Aseptic Gowning

15. Design Considerations
Closed Systems That do not Expose Products
Where Product Can be Exposed, Conduct
Operations in Clean Rooms
Design Equipment and Piping for Sterile
Operation
Use Pyrogen Free Water for process and Final
Rinses of Equipment
Sterile Filter Product Solutions
Low temperature Processing

16. Key Design Issues
Vessel Mixing - Agitator Design
Sanitary Piping Design
CIP Circuit Design
Temperature Control
Equipment Design
Process Controls - Interlocks
Equipment Arrangement - Facility Layouts

17. Key Facility Issues
Layout That
o Support the Process
o Facilitate Operations
o Provide Appropriate Space
o Provide Proper Flow of Materials,
People & Waste
o Prevent Mix - up
o Prevent Contamination
Material and Design Details that
o Do not Contaminate
o Provide Ease of Cleaning & Maintenance

18. Key Facility Issues (cont.)
Internal Environments
That
o Provide suitable Conditions
of Temperature, Humidity
& Particulate Control
o Room Pressurization &
Directional Airflows Which
Prevent Contamination
o Prevent Bacterial Growth or
Infestation
o Segregate Hazardous Area

19. Utility Requirements
Clean Utilities
o Water-for-Injection (WFI)
o Clean Steam
o USP Purified Water
o Clean-in-Place (CIP)
General Utilities
o Plant Steam
o Chilled Glycol and Water
o Compressed Gasses

20. Water-For-Injection (WFI)

21. WFI System Components
Feed Water Pretreatment
WFI Production
WFI Storage & Distribution
WFI Cooling For Use

22. Water-For-Injection (WFI)

23. Typical Storage & Distribution
Network

24. Key Definitions For Successful
System
Minimum Distance
Sloped Piping
Drainability
Valve Combinations
Component Selection
Access For Operation
Access For Maintenance

25. Common Pitfalls
Dead Legs
Excessive Clamps
The Use of Non Sanitary
o Instruments
o Valves
o Equipment

26. Clean In Place (CIP)

27. Cleaning Is Mandated By cGMP
21 CFR 211.67
“ Equipment and utensils shall be cleaned,
maintained, and sanitized at appropriate intervals
to prevent malfunctions or contamination that
would alter the safety, identity, strength, quality,
or purity of the drug product beyond the official or
other established requirements. “

28. CIP (Clean In Place System)

29. CIP System Design Steps
Identify Equipment and Systems to be Cleaned
Design Equipment to facilitate Cleaning
Arrange Equipment & Piping to Facilitate Cleaning
Establish Level of Cleanliness
o Define How Clean is Clean
Investigate Cleaning Compounds
Develop Cleaning Cycle Parameters
Design CIP Fluid Circulation System

30. Cleaning Process Variables
Time / Sequence
Temperature
Flow rate / Pressure
Cleaning Agent selection
Cleaning Agent Concentration
Return water Resistivity

31. Clean Steam System

32. Clean Steam Application
Autoclave Operation
Equipment Sterilization (SIP)
HVAC Humidification

33. SIP Advantages
Only Technique for Large Equipment
Obviates the Need for Large Autoclaves
Reduces Clean Room Operation Activity
Enhanced System Integrity
o Reduction of Aseptic Connections
o Reduction of Flexible Hoses

34. HVAC

35. Key HVAC Issues
Design to Eliminate Airborne Contamination
o Terminal HEPA Filters in Air Supply Duct
o Return Air Taken From Low Points
o Laminar Air Flow Over Exposed Product
o High Air Change Rate
o Higher Pressure in Cleaner Areas
Suppress Microbial Growth
o Relative Humidity 30 to 50 percent
o Temperature Control

36. Definitions--Cleanroom
A room in which the air supply, air distribution,
filtration of air supply, materials of construction,
and operating procedures are regulated to control
airborne particle concentrations so that appropriate
air cleanliness levels can be met.

37. Definitions--Unidirectional
airflow cleanroom (Laminar)
A cleanroom in which the filtered air entering the
room makes a single pass through the work area in
a parallel-flow pattern, with a minimum of
turbulent-flow areas. Unidirectional airflow rooms
typically have HEPA or ULPA filter coverage of
80% or more of the ceiling (vertical flow) or one
wall (horizontal flow).

38. Definitions--Non-unidirectional
airflow cleanroom
A cleanroom in which the filtered air entering the
room or passing through the work zone is
characterized by non-uniform velocity or turbulent
flow. Such rooms exhibit non-uniform, random
airflow patterns throughout the enclosure.

39. Definitions--Uniform airflow
An unidirectional airflow pattern in which the
point-to-point readings are within +20% of the
average airflow velocity for the total area of the
unidirectional flow work zone.

40. Definitions--HEPA Filter
High Efficiency Particulate Air filter--An
extended-medium, dry-type filter in a rigid frame
having a minimum particle-collection efficiency
of 99.97% for 0.3µm, near-monodisperse dioctyl
phthalate (DOP) particles (or equivalent substitute
such as poly-alpha olefin, PAO).

41. Definitions--ULPA Filter
Ultra-low Penetration Air filter--An extended-
medium, dry-type filter in a rigid frame having a
minimum particle-collection efficiency of
99.999% for particles 0.12µm and larger.

42. cGMPs Impact on HVAC Systems
AHU Systems
HVAC System Components
Building Automation Systems
Testing, Balancing, and Cleaning
Validation

43. Sterile Area HVAC Flow Diagram

44. HVAC Control
Temperature and Humidity
Air Pressure
Air Filtration
o Pre-filters
o HEPA Filters
o ULPA Filters

45. HVAC Control Diagram

46. Federal Standard 209E
Class 100 is not more than 100 0.5µm or greater
particles per cubic foot of air when at least two
sample locations are tested and a statistical
analysis of the test data is performed at a 95%
confidence limit.
Class 10,000 is the same with not more than
10,000 0.5µm or greater particles …
Class 100,000 is …100,000 0.5µm or greater
particles...

47. Typical Clean Zone
Classifications
Non-sterile equipment/component prep and
compounding-- Class 100,000
Aseptic Core-- Class 10,000
Filling Room-- Class 10,000 or 1000
Laminar Flow over Filling Line--Class 100

48. Area Classification

49. AHAC Area Coverage

50. Critical Areas for Aseptic
Processing
Airborne particle count: Class 100
Velocity of air: 90 FPM + 20%
Air changes: several hundred
per hour
Airborne microbes NMT 3 CFU/m3
Surface cleanliness 3 CFU per 24-30
cm3 (USP)
Personnel Aseptic Gowning

51. Controlled Areas for Aseptic
Processing
Airborne particle count: Class 10,000
Velocity of air: 60 FPM + 20%
Air changes (minimum): NLT 45 per hour
Airborne microbes: NMT 20 CFU/m3
Surface cleanliness: 5 CFU per 24-30
cm3 (USP)

52. Controlled Areas for Aseptic
Processing
Airborne particle count: Class 100,000
Velocity of air: N/A
Air changes (minimum): NLT 20 per hour
Airborne microbes: NMT 100 CFU/m3
Surface cleanliness: 5 CFU per 24-30
cm3 (USP)

53. ISO/TC209
International Organization for
Standardization, Technical Committee 209

54. GMP Compliance - Facility Design
Requirements
Layouts that:
o Facilitate appropriate space and operations
o Provide proper flow of material, people and waste
Material and design details that:
o Provide ease of cleaning and maintenance
o Wearing surface and impact resistance
Service maintenance access
o Utility requirements
o Service corridors and walkable ceilings

55. GMP Compliance - Facility Design
Requirements (Cont.)
Operational Adjacency and Process
Flow
o Personnel, Material, Product,
Equipment, Waste
Modular Design
Process Utilities and Building
Systems Integration/Access
Code Compliance
o Egress, ADA/Accessibility, Fire
Resistance, Safety

56. Area Classification

57. Construction
Material Selection HVAC Criteria
o Cleanability o Air cleanliness class
o Fit for intended use o Temperature and
o Sterilization relative humidity
Clean Build Protocol o Airflow and
pressurization
o Defines how
construction materials Support Services
and personnel enter o Water, steam, gases,
and exit the vacuum, electrical
construction site o Instrumentation

58. Documentation & Validation
Quality MUST be involved from the project
beginning
Must keep accurate records
Prove that the facility & equipment are built to the
design criteria
Tested and certified
Officially commissioned for use