4. 07/16/17 4
Country
Standard
Code
Year Description
Australia AS 1386 1989 Cleanrooms and Clean work stations
France AFNOR X44101 1981 Definition of Cleanroom levels
Germany VDI 2083:3 1993
Contamination control measuring technique
clean air room
Holland VCNN 1 1992 Dust and microorganism classification of air
Japan JIS-B-9920 1989
Measuring methods for airborne particles in
Cleanroom and evaluating methods etc.
Russia Gost-R 50766 1995 Cleanroom classification, General requirements
UK BS 5295 1989 Environmental cleanliness in enclosed spaces
US FS 209 E 1992
Airborne particulate cleanliness classes in
Cleanroom and clean zones
Too Many Cleanroom Standards....
in the past??
5. 07/16/17 5
Cleanroom Standards Depicted
In Recent Guidelines
FDA Guidance for Industry (Sterile Drug Products) –
September, 2004
EU Guide to GMP – Revision to Annex 1 – September, 2003
WHO Good Manufacturing Practices for Sterile
Pharmaceutical Products – 36th
Report, Geneva, World
Health Organization, 2002, Annex 6 (WHO Technical
Report Series, No. 902)
ISO 14644 Standards First Edition 1999-05-01
6. 07/16/17 6
ISO Document Title
ISO – 14644 - 1 Classification of Air Cleanliness
ISO – 14644 - 2 Cleanroom testing for Compliance
ISO – 14644 - 3 Bio-contamination Control of Surfaces
ISO – 14644 - 4 Cleanroom Design & Construction
ISO – 14644 - 5 Cleanroom Operations
ISO – 14644 - 6 Terms, Definitions & Units
ISO – 14644 - 7 Mini-environments & Isolators
ISO – 14698 - 1 Bio-contamination Control General Principles
ISO – 14698 - 2
Evaluation & Interpretation of Bio-contamination
Data
ISO – 14698 – 3 Bio-contamination Control of Surfaces
ISO Standards – A Step Towards
Harmonization!
7. 07/16/17 7
Area Classification As In Different
Guidelines
Non-viable Particle Count
..Area Classification Chart_Nonviable.xls
Viable Particle Count
..Area Classification Chart_Microbiological.xls
8. 07/16/17 8
Comparison of different airborne particulate classification
systems for clean areas
ISO / TC : International Organization for Standardization Technical
Committee;
EEC : European Commission.
Area Classification Comparison
9. 07/16/17 9
Four Grades Of Clean Areas For
Aseptic Applications
Grade
Type of
Operation
Examples of operations
A
Terminally
Sterilized
Filling of products, when unusually at risk
B
Terminally
Sterilized
Background Environment for Grade A
C
Terminally
Sterilized
Preparation of solutions, when unusually at risk.
Filling of products
D
Terminally
Sterilized
Preparation of solutions and components for
subsequent filling
A Aseptic Preparation Aseptic preparation and filling
B Aseptic Preparation Background Environment for Grade A
C Aseptic Preparation Preparation of solutions to be filtered.
D Aseptic Preparation Handling of components after washing
10. 07/16/17 10
Standards
Cleanroom Classifications
and
particle counting in the
room
Filter Classes
Testing filters
method
US - FDA US FED STD-209E
IEST-RP-
CC001.3
IEST-RP-CC006.2
IEST-RP-CC021.1
IEST-RP-CC034.1
EU / Europe ISO 14644 EN 1822 EN 1822
• Requirements set by ISO 14644 are stricter than the requirements on the
American (FDA) market
• In principle, ISO 14644 also sets the requirements for the American market
regarding Cleanroom Classifications and Particulate Testing
Still the confusion persists!
Which standards are valid, when and where?
Cleanroom classification, filter classification and
testing methods / standards differ
12. 07/16/17 12
General Layout:..AHU Schematic Drawing.xls
Basic Components of an AHU:
Fresh Air Intake Unit
–Fresh Air Filter
–Volume Control Dampers
Pre-Filters
–Correct pre-filters protect systems & prolong life of
final filters
Blower Assembly
–Ensure that the blower capacity is adequate to give you
required air volume
Air Handling Unit
13. 07/16/17 13
Basic Components of an AHU (continued):
Coil Assembly
– Chilled Water Coil, Brine Coil, Hot Water Coil
– Coils should be fixed in such a way that there is enough clearance
to compensate for expansion/contraction with rise/fall in fluid
temperatures
Drain Pan
Eliminate the potential for standing water in coil drain pans by
keeping:
– a generous slope to a drain equipped with a trap and a trap primer.
– traps deep enough to ensure that water will not be drawn back into
the pan.
– an air gap between the pipe end for inspection.
– sufficient space for continuously sloped drain piping, avoiding
high pockets.
Air Handling Unit
15. 07/16/17 15
Air Handling Unit
Basic Components of an AHU (continued):
Secondary Filtration
– Typically, semi-HEPA filters (rating 0.3 micron, but efficiency
less than 90%) are used
Inspection Doors
- All doors in the AHU shall have perfect alignment with the door
frames so that there is no space for external air to leak into the
AHU through them and thereby cause contamination
Piping
- Hydro-testing must be done
- Check whether instruments are provided wherever needed & their
calibration status
- Check pipe insulation
16. 07/16/17 16
DuctingDucting
Some Basics & Essentials of Ducting System:
MOC
– Galvanized Iron (GI)
– Pre-insulated Aluminium sandwiched panels
– Check for proper path & routing as per the approved
drawing
Provide access hatches for inspection & cleaning
- Provide access hatches and prominent identification signs
for inspection and cleaning of ducts
- Post a log at each such hatch, identifying dates and
observations of inspections and cleanings
17. 07/16/17 17
Some Basics & Essentials of Ducting System (continued):
Provide Access to Inject Challenge Aerosol for
Leak Testing of HEPA filters
Duct Leakage Testing using Titanium Dioxide
All dampers should have easy & smooth
functioning & shall clearly indicate direction:
‘open’ or ‘close’
Connection between ducting & AHU should be
such that there is no leakage.
DuctingDucting
19. 07/16/17 19
FiltersFilters
Criteria for selection
Type of Application/Pore Rating
Types of Filters
HEPA Filters
MOC of Media: Micro fiberglass
MOC of Separators: Aluminum/Craft Paper/ Separator less/ Minipleat
Type of adhesive: Polyurethane adhesive
Pre-Filter
MOC of Media : Non-woven synthetics / washable
Effective Uni-directional
Flow with the help of HEPA
filters
20. 07/16/17 20
FiltersFilters
Filter Testing – 2 phases
At Manufacturer’s site
- Determining Most Penetrating Particle Size (MPPS)
- Leak Test
- Overall Efficiency
At Site after installation
- Leak Test
- Overall Efficiency
Clean Absolute Filter Media
Dust on the inlet side of a used
Absolute Media
22. 07/16/17 22
FiltersFilters
New Standards from CEN TC 195 - Air Filtration 1
HEPA & ULPA Filters
--------------------------------------------------------------------------
�EN 1822-1 Requirements for testing & marking
�EN 1822-2 Aerosol Production
�EN 1822-3 Testing Planar Filter Medium
�EN 1822-4 Scan testing the filter element
�EN 1822-5 Testing the efficiency of the filter
26. 07/16/17 26
FiltersFilters
In-situ Testing (General)
Select test method, aerosol, and acceptance criteria
Determine challenge up-stream
Scan test final filter face for leaks
Determine acceptance or rejection
Carry out remedial work. Agree before repairing
filters
e.g., BS 5295:1989 does not allow repair, but the new
ISO EN 14644-1 to 3 family of standards will subject
to manufacturer’s approved method
Re-test
29. 07/16/17 29
VALIDATIONVALIDATION
The HVAC system must be Validated for the following tests according
to approved protocols and procedures:
- Filter integrity test (DOP test)
- Air changes test
- Air flow pattern
- Particle count test
- Temperature, Relative Humidity and Differential Pressure test
Sr. No. Tests Frequency
1. Air changes Biannually
2. DOP & leakage tests Biannually
3. Non viable Particle count For < ISO Class 5 – Biannually
For >ISO Class 5 - Annually
30. 07/16/17 30
VALIDATIONVALIDATION
Filter integrity test (DOP test)
Thermally Generated DOP: an aerosol generated by
quenching (condensing) vapor that has been evaporated from
liquid dioctyl phthalate by heat. The aerosol mean particle
diameter is between 0.2 and 0.4 µm with a geometric standard
deviation of 1.3.
Air Generated DOP: an aerosol generated by blowing air
through liquid dioctyl phthalate at room temperature. When
generated with a Laskin-type nozzle the approximate light
scattering mean droplet size distribution is as follows:
99+% less than 3.0 µm
50+% less than 0.7 µm
10+% less than 0.4 µm
31. 07/16/17 31
VALIDATIONVALIDATION
Filter integrity test (DOP test)
Aerosol Photometer:a light scattering mass concentration
indicator. Instruments of this type with threshold sensitivity of at least
10-3 mg/liter for 0.3 µm–diameter DOP particles, capable of
measuring concentration in the range of 80 to 120 mg/liter, and
having a sample flow rate of 1 cfm+10% of air are suitable for leak
testing.
Linear readout photometer:a photometer having a linear reading
scale graduated from 0 to 100 with a range switch to vary the full
scale response in multiples of 10, through at least four decades of
response. The instrument shall be capable of indicating 0.001% of a
concentration that registers 100% on the highest range.
Logarithmic read out photometer: a photometer having a
logarithmic response scale graduated 0, 1, 2, 3, 4, 5 covering the full
range of instrument sensitivity without range switches. For this type of
photometer, “one scale division” means the first intermediate scale
division following the zero.
34. 07/16/17 34
VALIDATIONVALIDATION
Air Changes Per Hour
ACPH design based on:
Room size
Nature of operation
Number of personnel present
Requirement : NLT 20 Air changes / hour
If the number of air changes is more than 20 per hour and
HEPA filters and return air risers are installed at
strategic locations, then throughout the room mixing of air
shall take place and it will not be difficult to get Class B, C
and D conditions
35. 07/16/17 35
VALIDATIONVALIDATION
Air Changes Per Hour
CFM of air supplied = Velocity x Area of air discharge unit
ACPH = (CFM x 60) / V
where, ACPH = Number of Air changes/hour
CFM = Total supply air flow to space (cu. ft./ min.)
V = Space Volume (cu. ft.)
Note: Velocity of air must be determined using
Calibrated Hot-wire Anemometer
36. 07/16/17 36
VALIDATIONVALIDATION
UDF (Uni-direction Flow) Modules
Class 100 is only obtained under the UDF-module (Laminar Flow Unit); the
surrounding room must be Class 1000 with a number of air changes set at minimum 20
per hour
Only UDF areas can exhibit Laminarity of
Air Flow
Laminar / Uni-directional
with Perforated Floor
(Low Air Velocity is required)
Laminar / Uni-directional
with Perforated Floor
(Low Air Velocity is required)
Perforated Floor Air Riser
Laminar / Uni-directional
with return air riser
(High Air Velocity is required)
Laminar / Uni-directional
with return air riser
(High Air Velocity is required)
Air Riser on Side Wall
OR
37. 07/16/17 37
VALIDATIONVALIDATION
Turbulent Air flow
Results in dilution of dirty air
Turbulent Air flow
Results in dilution of dirty air
Laminar / Uni-directional
with return air riser
(High Air Velocity is required)
Laminar / Uni-directional
with return air riser
(High Air Velocity is required)
Air Riser on Side Wall
40. 07/16/17 40
VALIDATIONVALIDATION
Particle Count Test
Optical Particle Counter : a light scattering instrument
with display or recording means to count and size discrete
particles in air, as defined by the American Society for
Testing Materials Standard (ASTM) F50-69
Instruments of this type having a sampling flow rate of at
least 0.1 cfm, (and preferably 1.0 cfm), and with size
discrimination capability to detect total particle
concentrations >0.5 µm size and >5.0 µm size are suitable
for leak testing.
Instrument of this type having a sampling flow rate of at
least 0.0067 cfm and with size discrimination capability
are suitable for particle counting.
42. 07/16/17 42
VALIDATIONVALIDATION
Particle Count Test
Recovery (clean up) period : Around
15 minutes after completion of operation
Major Particle Counter Manufacturers
Lighthouse
Met One
Climet
IQAi
43. 07/16/17 43
VALIDATIONVALIDATION
Other Instruments/Equipment used for
Validation
Air Pressure Gauge: an inclined manometer or
magehelic gauge capable of measuring 0.01 to 2.0 in
water gauge static pressure.
Wet/Dry Bulb Thermometers: instruments used
to measure moisture in air so that acceptable dew
point can be found.
Smoke Generator: ventilation smoke tube pencil
for generating visible smoke filament for air tracer
studies.
45. 07/16/17 45
Building Management SystemBuilding Management System
BMS has evolved over many years
alongside HVAC system
It has adopted “control system architectures
& philosophies” to satisfy the need for
advanced automation
Deployed in Healthcare companies with
modern day solutions based on standard
software & hardware design
46. 07/16/17 46
Building Management SystemBuilding Management System
BMS may cover in its scope a range of
computerized systems:
PLCs Programmable Logic Controllers
SCADA Supervisory Control & Data
Acquisition Systems
DCS Distributed Control System
Outstations/Controllers &Instrumentation
47. 07/16/17 47
BMS - BenefitsBMS - Benefits
BMS brings several benefits:
Effective control of building related processes &
equipment
Real time visibility of BMS performance
Early warning of process deviations
Predictive maintenance planning
Centralized and/or remote control
Optimization of utility costs
Secure management &storage of process &
equipment performance data
48. 07/16/17 48
BMS – Regulatory EnvironmentBMS – Regulatory Environment
Used to control, record, monitor & alarm a
variety of processes of varying risks to
product
Ability to readily detect product attributes
downstream of the process
BMS often cover both regulated & non-
regulated processes, concurrently
Can be sometimes difficult & expensive to
validate
49. Parking Facilities
Elevators
Office Air conditioning
Chilled Water
Production Air Conditioning
Building Management System
Autoclave
Purified Water System
BuildingManagementSystem
No ImpactGEP Only
Indirect Impact?
Direct Impact
The design
& use of
these
systems
affect their
impact!
BMS Validation - Impact Assessment
50. 07/16/17 50
BMS – Validation CriteriaBMS – Validation Criteria
The criticality of BMS is determined through a
risk assessment that considers consequence on
product attributes of failure of parameters
This is dictated by the impact of process
parameters being controlled on product purity,
safety, quality & efficacy, and not the
functionality of BMS itself
Validatability of BMS is determined by the direct
or indirect impact on the product’s quality, purity,
safety etc..
Some of the citations indicate a lack of
validation /qualification of controls
