Clean Room Design

and FMFA Model

Ahmed Ehab

Validation Senior Officer, Ex- Quality

Control Senior Analyst with +4 Years
Experience in Pharmaceutical
Manufacturing
Definition of Clean Room Clean Room Grades

Air Flow Patterns FMEA Risk Assessment

Differential Pressure FEMA Layout

Air Change Q&A

At Rest vs At Operation Testimonials

 Definitions
• Clean/ Controlled Room: An area with defined
environmental control of particulate and microbial
contamination, constructed and used in such a way as
to reduce the introduction, generation, and retention of
contaminants within the area. Controlled Rooms are
required For Both Sterile and Non Sterile Products.
• We control all Inputs inside the Clean Rooms including
Personnel Movement, Activities, Air Quality, utilities, etc.
• Factors that need to be Controlled inside the Clean
Rooms:1
Air:
Air include Large Visible Particles and Subvisible Particulates.
Microorganisms Need Carries to be dispensed (Non Viable
Particulate act as Carriers For Microbial Contaminants).
• Airborne Particulate Count: Number of Particulates of
Specific Size Range Per Unit Volume of Air.
• Airborne Viable Particulate Count: Recovered Number of
Colony Forming Unit Per Unit Volume of Air.
 Definitions
• Colony Forming Unit: A Single Macroscopic
Colony formed after the growth of one
Microorganism on Solid Growth Medium.
• Airborne Microorganisms can be Vegetative or
Dormant (Spore).
• There is a Correlation between Particulate Count
and Viable Count, the Higher the Particulate
Counter, the Higher the Viable Recovered
Microorganisms. (Positive Correlation).
 Definitions
In Order to Reduce the Particulates, we need to
install Filters inside the Clean/Controlled Room:
• Filters are installed as Part of HVAC Unit,
• Inside the HVAC Unit, Air is Filtered through Pre-
Filter to remove Large Particles then filtered
through HEPA Filters to Reduce the Particulate
Count.
• HVAC Unit Controls Most of Inputs inside the
Clean Room: Temperatures, Humidity, Air Flow
Patterns, Air Velocity, Air Filtration and
Differential Pressure.
1. Air Velocity: Is the distance travelled by Air Per
Seconds (Usually 0.36 to 0.54 meter/Second in
Case of Laminar Air Flow). (WHO Annex 6 and
EudraLex/ PIC/S Annex 1)
1) Air Flow Patterns in Clean Room

Turbulent/ Dilution Approach Laminar- Unidirectional/ Displacement Approach

In this Air Flow Design, HEPA Supply filters Supply In this Air Flow Design, HEPA Supply filters Supply Clean
Clean Air then diluted by Room Air to Achieve Air Air that displace the Room Air to Achieve Air Cleanliness,
Cleanliness, Used with Grade B,C&D Rooms Used with Grade A Rooms
Usually 0.3 meter/Second For Vertical Flow
0.45 meter/Second For Horizontal Flow
Ref: ISPE Article: https://ispe.org/pharmaceutical-engineering/september-october-2021/pharmaceutical-cleanroom-design-iso-14644-16
 Air Flow Patterns in Clean Room

Turbulent/ Dilution Approach Laminar- Unidirectional/ Displacement Approach

Reference: An Sight CFD

• Air Flow Visualization is required by EudraLex Volume 4 Annex 1 Point 4.15.

 2) Differential Pressure vs Obsolete Pressure
• Differential pressure is the pressure difference measured between two pressure sources.
• Obsolete Pressure is the Current Pressure inside the Room.
• Usually a Differential Pressure of 10-15 Pascals is needed between Adjacent Rooms. WHO Annex 6- Point 11

Reference: USP Training

Module 9 HVAC Systems
 Differential Air Pressure
• Airlocks should be designed and used to provide physical separation and to minimize microbial and particle
contamination of the different areas and should be present for material and personnel moving between different
grades (EudraLex Volume 4- Annex 1 Point 4.11 Under Premises Section)
• The final stage of the airlock should, in the “at rest” state, be of the same cleanliness grade (viable and total
particle) as the cleanroom into which it leads (EudraLex Volume 4- Annex 1 Point 4.11 Under Premises Section)

Cascade Air Lock is Used in Non Sink Air Lock is Used when Handling Bubble Air Lock is Used when Handling
Sterile/ Sterile Manufacturing to Hazardous Substances and it’s similar to Hazardous Substances, the Clean Room is
ensure that Positive Air Cascade but with one difference is that under Negative Pressure. This Airlock is
Movement is exerted to Prevent the Corridor exerts Positive Pressure on used to Quarantine Potent Products
Microbial Contamination from the Air Lock. it acts as a Sink For (Most Frequently Used For Potent
Lower Grade Rooms Contaminated Air in Clean Room and Products)
(Most Frequently Used) Prevent Mixing of Air with the Corridor
(Not Frequently Used)
 3) Air Change Per Hour
• (ACH) is the number of times inside and outside air is exchanged within a room.

(ACH)

Ref: ISPE Article: https://ispe.org/pharmaceutical-engineering/september-october-2021/pharmaceutical-cleanroom-design-iso-14644-16

4) Recirculated Air vs Total Fresh Air
Factors to be Controlled/ Tested For Clean Room

Personne
l
 Definitions
Sterile Drug Products can be Manufactured by Either
Ways:
• Aseptic Filtration, Accompanied by Aseptic
Processing : Is The Process of Aseptically
filtrating the Drug Product as a Method of
Sterilization. Aseptic Filtration is performed using
0.2 Micrometer Filter.
• Aseptic Processing, Accompanied by Terminal
Sterilization : A Process where the Product is
Sterilized in its Final Primary Packing
Configurations, Terminal Could be performed by
Autoclaving (Physical), Exposure to Radiation.
Example, Infusion Solutions are sterilized by
Exposure to Radiation (UV).
• Aseptic Processing: Handling of Product,
Materials, Packing Materials and Equipment in
Controlled Environment in Which Air Supply,
Materials, equipment and Personnel are
controlled to ensure Product Sterility.
 Question
Which is More Favored: Terminal Sterilization or
Aseptic Filtration:
• Terminal Sterilization is more favored since it
provide a Calculated SAL (Sterility Assurance
Level), meanwhile Aseptic Filtration relies on
cGMP and Overall Aseptic Processing
• SAL describes the probability that a viable unit or
colony forming unit (CFU) survives sterilization. If
your product is terminally sterilized it has a SAL
of 10-6 (i.e. only one in one million CFUs will
survive terminal sterilization) while an
aseptically processed product as a higher risk
SAL of 10-3 (a one in one thousand chance of
survival). Ref: Berkshire Sterile Manufacturing
• Aseptic Filtration is Performed for product that
can’t Withstand Terminal Sterilization including
Biologics, Vaccines, etc.
 Definitions
Operation State of Clean Room is described by two
Ways:
• At Rest (Static State) : Is the Condition of the
Environment in absence of Personnel, that
includes having equipment in Stand By For
Operation without Personnel.
• At Operation (Dynamic State): Is the Condition of
the Environment during Normal Operation, that
when the Usual equipment is operating and the
Operating Number of Personnel are Present.
Based on Air Quality, Type of Operation and Room Design, we have a
Classification For Clean Rooms:

Reference: PDA TR-13/ 2022

Revision
 Clean Room Grades Based on Operations:
• PDA TR-13/ 2022 Revision made a Comparision between EudraLex/ PIC/S Annex 1 and FDA/ ISO Clean Room
Classification

NB: The At Rest and At Operation ISO Classes are only applied For Non Viable Particulate Count, meanwhile
the Viable Counts are the Same For Each Grade, according to EudraLex/ PIC/S Annex 1
Clean Room Grades Based on Operations:

Reference: Eudralex and PIC/S Annex 1 Point 8.6

Clean Room Grades/Class Based on
Operations:
(Passive) (Active)
 FMEA
• The FMEA Model is a risk management tool used to identify and manage
risks within projects and across entire departments and organizations
• FMEA Risk Assessment is compromised of Severity and Probability to
determine the Risk Class.

1) Risk Matrix:

4 X 4 Risk Matrix
 FMEA
1) From Risk Matrix, we
obtain the Risk Score/ Class
• Risk Matrix could be 3 X3 , 4 X4 or
even Larger

10 X 10 Risk
Matrix
 FMEA

1) From Risk Matrix, we obtain the Risk

Score/ Class
• Level: 1 (C= 15 to 25)
• Means that the likelihood that this failure
appears high and that the impact on product
quality, patient safety or data integrity is high
• Level: 2 (C= 4 to 12)
• Means a moderate impact on product quality,
patient safety or data integrity
• Risk Controls for the Risk in the yellow zone
(“Medium Risk”)
• Level: 3 (C= 1 to 3)
• Means that we have practically no impact on
product quality, patient safety or data integrity
• The Risk is in the green zone (“Low Risk”).
 FMEA
2) After Obtaining Risk Score, we
implement Detectability to Obtain
Risk Priority Number (RPN)
Selection of EM Samples Based on FMEA
• To Define the Sample Locations, we use the Grid Layout of the Clean Room.
• Grid Layout divide the Room into Square Parts based on Activity.
• Risk Score is assigned For Each Square by Multiplying the Severity X Probability Risk Factor ,C = S * P.

Reference: PDA TR-13/2022

• Example of Risk Ranking/ Classification Per PDA- TR-12/2022:
 Selection of Locations of Environmental Monitoring Samples Based on
HVAC Layout

Selection of EM Samples Based on FMEA

• HVAC Layout as well as Smoke Test Visualization, help us determine the
Air Movement.
• Using Air Movement Pattern, we can determine Dead Zones & Areas
S3 with Highest Air Turbulence.
• The Example discussed is a Class C Room With Air Supply diffusers and
Ceiling Air Return Diffusers, Following Dilution of Air Approach to
S achieve the desired cleanliness as well as the Number of Air Exchange
A.S3
Per Hour.
4
Machine

• To Define the Sample Locations, we use the Grid Layout of the Clean Room.
S1

A.S2

S A.S1
2 • S1= Monitor Personnel Movement as well as Personnel Entry and Exit in
additional it’s an area with High Turbulence.
• S2= Monitor Personnel Exit and Entry and also Air Quality in this Dead
Zone with little Air Movement.

Wall
Air Supply
S: Settle Plate • S3= Monitor Personnel Movement as well as the Quality of Air being
Diffuser

S2
returned to the Ceiling Air Return Diffuser.
Air Movement
A.S: Air • S4= Monitor Personnel Movement as Well as Air Quality.
Sampler • A.S1= monitor Air Quality in Dead Zone away from Air Movement.
Ceiling Air Return Diffuser
• A.S2 & AS3= Monitor the Quality of Air Returned From the Entire room
Ahmed Ehab Salah towards the Ceiling Air Return Diffusers.

1
AS2
AS3 Machin AS1
e
Floor S1 Wall 2
S3

Reference: PDA TR-13/2022

Final Risk Matrix & RPN:
Thank You
For Your Attention

Q&A
 Ahmed Ehab

The PowerPoint and Material

Included are Personnel and
doesn’t reflect any entity or
organization

TESTIMONIAL 17