Lecture 1, Part 3 10/11/09

Report
Utility Systems
Process Systems – ‘Direct Impact Systems’

Contact the Product

Contact Materials that will Ultimately Become Part of the Product

Could Otherwise Directly Impact Product Quality
Examples
1

Purified Water (Deionised)

WFI

Clean Steam

Nitrogen

Sterile Air
Utility Systems
Process Systems – ‘Indirect Impact Systems’

Do Not Contact the product or Material that will Ultimately
Become part of the product

Generally Site or Building Systems (Not Tailored to Sterile
Manufacturing Facilities)

Deal with a Side Effect of the Manufacturing Process
Examples
2

HVAC for non classified areas

Chilled Water

Potable Water

Floor Drains

Waste Disposal
Exercise 3 - Direct or Indirect Utilities

A: What Utilities are Direct or Indirect for the
process of filling product into Mobile Vessels?
Instrument Air for isolation/ control valves
 Glycol for temperature control of vessel jacket
 WFI is used for CIP (Clean in Place)
 CS (Clean Steam) is used to Steam in Place (SIP) the
vessel before filling

3
Exercise Answers

A: What Utilities are Direct or Indirect for the process of
filling product into Mobile Vessels?

Instrument Air for isolation/ control valves


Glycol for temperature control of vessel jacket


Direct as it comes in contact with product path and potentially the
product. Quality is critical to successful cleaning also.
CS (Clean Steam) is used to Steam in Place (SIP) the vessel
before filling

4
Indirect as it will never come directly in contact with product.
WFI is used for CIP (Clean in Place)


Indirect as it will never come directly in contact with product.
Direct as it comes in contact with product path and potentially the
product. Quality is critical to successful cleaning also.
Utility Systems
Direct Impact Systems – Key Considerations
5

Material of Construction in Sterile Core Should be 316L Stainless Steel

Surface Finish Should be at Least 0.5m (Preferably < 0.4m)

Utilities May Require Point-of-Use Filtration in Sterile Core

Pipework in Sterile Core Should be Electropolished

Materials of Construction Must be Compatible with Sterilisation Methods
in Area

As Many Components as Possible Should be Located Outside Sterile
Core

Pipework and Components in Cleanroom Must be Designed and Installed
in Accordance with ASME BPE 2002 (Bio-Pharmaceutical Engineering)
HVAC – Heating, Ventilation & Air
Conditioning
Contamination From People is the Greatest Source of Contamination in an
Aseptic Facility

People Contribute 80% of Airborne Contamination in Cleanrooms

Special Cleanroom Clothing is Worn to provide a barrier Between person
and Environment

High Personal Hygiene Standards Essential

Minimise Number of People in Sterile Core
HVAC System Must Maintain the Cleanroom Environment Requirements by
Removing Airborne Contamination and Replacing it With Suitably Filtered Air

6
Definition of Environmental Requirement Depends on Cleanroom
Classification
Grade A Classification Table
ISO EN 14644
EUDRALEX
EUDRALEX
FS209D (#)
(at rest)
(in operation)
(in operation)
ISO 3
1
ISO 4
10
ISO 5
Grade A&B
Grade A
ISO 6
1,000
ISO 7
Grade C
Grade B
10,000
ISO 8
Grade D
Grade C
100,000
-
-
Grade D*
Pharmaceutical
-
-
-
* With local monitoring * Now Withdrawn
7
100
Unclassified
HVAC
Guideline on Sterile Drug Products Produced by Aseptic
Processing States:
8

Air in Critical Areas Should be Supplied at the Point-of-Use
as HEPA Filtered Laminar Flow Air Having a Velocity
Sufficient to Sweep Particulate Matter Away From the Filling
Area. Normally a Velocity of 90 Feet Per Minute (0.46
m/sec.), Plus or Minus 20% is Adequate.

Critical Areas Should Have a Positive Pressure Differential
Relative to Less Clean Areas; a Pressure Differential of 0.05
inch of Water (12.5 Pascals) is Acceptable.
HVAC - Exercise 4
Apply Pressure Cascade Principle to Aseptic Facility Layout
Below (Use Pressure of 37.5Pa for Aseptic Pressure Room 1)
Based on Figure 5.4: ISPE Guideline Volume 3
Airlock (Not Directly
Pressure Controlled)
Changing Room
Cooling Area
Aseptic Processing
Room 1
Packing
Hall
(Nor Directly
Pressure
Controlled)
Autoclave
Autoclave
Loading Room
Pass Through
Component
Preparation
Aseptic Processing
Room 2
(To Suite Connecting Areas)
Washing / Sterilising Tunnel
9
HVAC - Exercise Answers
Based on Figure 5.4: ISPE Guideline Volume 3
Airlock (Not Directly
Pressure Controlled)
Changing Room
12.5 Pa
Cooling Area
37.5 Pa
Aseptic Processing
Room 1
Packing
Hall
(Nor Directly
Pressure
Controlled)
Autoclave
25 Pa
Autoclave
Loading Room
12.5 Pa
37.5 Pa
Pass Through
Component
Preparation
Aseptic Processing
Room 2
12.5 Pa
(To Suite Connecting Areas)
Washing / Sterilising Tunnel
10
QUESTIONS???

11
[email protected]
Take 10 minutes!
12
Additional Slides
Sterilisation Example
13
Sterilisation Example

Given:
 Micro-organism : Bacillus Stearothermophilus


Initial Count: 1 million (106) spores
D121 Value: 1.5min (i.e. at 121oC it will take 1.5 mins to reduce
number of viable Bacillus Stearotherm – ophilus by 1 log
reduction)
Q1: What is the SAL?
 Q2: What sterilising time (t) is required to achieve
an SAL of 10-6?

14
Sterilisation Example

Answer 1

LRV = Sterilisation time
D121
LRV = 15 min
1.5 min
 LRV = 10 log reduction


15
SAL = Initial bioburden count – LRV
= 106 – 10 Logs
= 10-4
Sterilisation Example

Answer 2


LRV = t/D or LRV x D121 Value = t

16
SAL = 10-6
LRV Required = Initial Bioburden - SAL
LRV
= 106 – 10-6
= 12 Log Reduction
LRV = 12
LRV x D121 Value = Sterilisation hold time
12 x 1.5
= 18min

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