Sterility by
Design
How tto Design
H
D i and
dO
Operate
t P
Process
Equipment for Sterility Assurance
Bill Ogden
Bill Ogden
‹ 24 years experience in Biotech and Pharmaceutical Industries
‹ Utilities, Vaccines, Sterile, and Biotech
‹ 16 years at Merck
‹ 5 years at Amgen
‹ Currently Senior Manager of Technical Services for MedImmune
Clinical Bio-Manufacturing
Sterility by Design - Bill Ogden
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Sterility by Design – Agenda
‹ Sanitary Equipment Design – 101
‹ Advanced Design Principles – 201
‹ Advanced Principles in SIP / Steam Sterilization – 301
‹ Lessons Learned – 302
‹ Group Discussion / Q & A
Sterility by Design - Bill Ogden
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Sanitary Equipment Design – 101
‹ The Fundamentals of Sanitary Design
‹ Minimum Design Requirements
‹ Fundamentals of Equipment Cleaning
‹ Fundamentals of SIP / Steam Sterilization
‹ Maintenance Considerations
‹ Regulatory Guidance
Sterility by Design - Bill Ogden
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Fundamentals of Sanitary Design
Sanitary process equipment is designed to:
‹Run the intended process
‹Prevent Contamination
‹Be Easy to Clean
‹Be Easy to Sanitize / Sterilize
It should also Be:
‹
‹Easy
to Operate
‹Easy to Maintain
‹Easy to Validate
Sterility by Design - Bill Ogden
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Minimum Design Requirements
‹ Materials of Construction
‹ Surface
S f
finish
fi i h
‹ Crevice free
‹ Dead-legs minimized
‹ Free draining
– Slope to drain
– Low point drains
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Equipment Cleaning Fundamentals – CIP
‹ Removing product / “soil” / contaminants
– By Chemical Action (Dissolving it)
– By
B Mechanical Action (Turbulence
(T rb lence / Impact)
– By Physical Removal
‹ Considerations:
–
–
–
–
–
–
–
Characteristics of the “Soil” that must removed
Chemical Composition & Concentration
Contact (Duration and All surfaces)
Temperature
Flow rate / Pressure / Turbulence
Cleanliness Requirements / Limits
Measurement of Cleanliness
Sterility by Design - Bill Ogden
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Equipment Cleaning Fundamentals – CIP
‹ Additional Benefits:
– Viral Inactivation
– Surface Treatment
‹ Additional Considerations:
–
–
–
–
–
Dead Legs (Length & Orientation)
Crevices
Drainage
g
Removal of Cleaning Chemicals
Hold Time (Dirty and Clean)
Sterility by Design - Bill Ogden
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Fundamentals of SIP
‹ Saturated Steam
Saturated Steam Curve
‹ Air
Ai R
Removall
‹ Steam Penetration
‹ Condensate Removal
‹ Time at Temperature (Fo)
‹ Cool Down
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Maintenance Considerations
‹ Equipment reliability / robustness
‹ Spare parts (more of the same)
‹ Ease of access
‹ Ease of disassembly
‹ Tri-Clamp fittings and gaskets
‹ Safety
– Lock out / Tag out
– Tank entry
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Overview of Regulatory Guidance
CFR 21 Part 211
Sec. 211.58 Maintenance
Any building used in the manufacture,
manufacture processing,
processing packing
packing, or holding
of a drug product shall be maintained in a good state of repair.
Sec. 211.63 Equipment design, size, and location
Equipment used in the manufacture, processing, packing, or holding
of a drug product shall be of appropriate design, adequate size, and
suitably located to facilitate operations for its intended use and for
its cleaning and maintenance.
Facility Design & Environmental Control - Bill Ogden
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Overview of Regulatory Guidance
CFR 21 Part 211
Sec. 211.65 Equipment construction
‹(a) Equipment shall be constructed so that surfaces that contact
components, in-process materials, or drug products shall not be
reactive, additive, or absorptive so as to alter the safety, identity,
strength, quality, or purity of the drug product beyond the official or
other established requirements.
‹(b) Any substances required for operation, such as lubricants or
coolants, shall not come into contact with components, drug
product containers, closures, in-process materials, or drug products
so as to alter the safety, identity, strength, quality, or purity of the
drug product beyond the official or other established requirements.
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Overview of Regulatory Guidance
CFR 21 Part 211
Sec. 211.67 Equipment cleaning and maintenance
‹(a) Equipment and utensils shall be cleaned, maintained, and, as
appropriate for the nature of the drug, sanitized and/or sterilized at
appropriate intervals to prevent malfunctions or contamination . . .
‹(b) Written procedures shall be established and followed for
cleaning and maintenance of equipment . . .
– (1) Assignment of responsibility for cleaning and maintaining
equipment;
– (2) Maintenance and cleaning schedules, including, where
appropriate, sanitizing schedules;
– (3) A description in sufficient detail . . . as necessary to assure proper
cleaning and maintenance;
– (5) Protection of clean equipment from contamination prior to use
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EudraLex Vol. 4 – EU GMP Guidelines
Chapter 3 – Premises and Equipment
3.34 Manufacturing equipment should be designed,
located and maintained to suit its intended purpose.
purpose
3.35 Repair and maintenance operations should not
present any hazard to the quality of the products.
3.36 Manufacturing equipment should be designed so
th t it can be
that
b easily
il and
d thoroughly
th
hl cleaned.
l
d It should
h ld
be cleaned according to detailed and written procedures
and stored only in a clean and dry condition.
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EudraLex Vol. 4 – EU GMP Guidelines
Chapter 3 – Premises and Equipment
3.37 Washing and cleaning equipment should be chosen and used in
order not to be a source of contamination.
3.38 Equipment should be installed in such a way as to prevent
any risk of error or of contamination.
3.39 Production equipment should not present any hazard to the
products. The parts of the production equipment that come into contact
with the product must not be reactive, additive or absorptive to such
an extent that it will affect the quality of the product and thus present
any hazard.
Facility Design & Environmental Control - Bill Ogden
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Advanced Design Principles – 201
‹ 5-Steps to P&ID Design for New Equipment
‹ Designing
D i i with
ith Validation
V lid ti iin Mi
Mind
d
‹ Designing with People in Mind
‹ Mechanical Seals and Debris Wells
‹ Steam Traps
‹ Sampling Methods and Devices
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5-Steps to P&ID Design
1.
Develop Process Flow Diagram (PFD) & URS
2
2.
C
Convert
t to
t P&ID (How
(H
tto run th
the process))
3.
Add in Cleaning requirements (How to CIP)
–
4.
Add in Steaming requirements (How to SIP)
–
5.
CIP connections, flow paths, etc.
Low point drains,
drains steam traps,
traps spec breaks
breaks, etc
etc.
Review for process, CIP, SIP, safety requirements, and how to
validate
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Designing with Validation in Mind
‹ Beware of the Observer Effect
– Observation affects Operation; e.g.:
• BIs block condensate drainage
• Thermocouple wires cause gaskets to leak
‹ Minimum recommended tubing size = ½”
‹ Validation ports
‹ Accessibility
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Designing with People in Mind
‹ Easy to operate
‹ Easy to access
– Filter Installation and removal
– Valve operation
– Making and breaking connections
• Elbows
• Flex Hoses
• Piping Supports
– Sight glass location
– Man-way location
‹ Cleaning Considerations (external)
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Mechanical Seals and Debris Wells
‹ Bioreactor / Fermentor seals – Top vs. Bottom
‹ Double vs Single
g Seals
‹ Agitator Seals
‹ Debris wells
Flowserve VRA with Debris Well
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Steam Traps
‹ Designed to pass condensate while conserving steam
‹ Types
yp – Thermostatic is best
‹ Sub-cooling – Less is better
‹ Capacity
‹ Traps vs Orifices
‹ Specification Break
‹ Condensate leg
Nicholson DS100/DS110
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Sampling Methods and Devices
‹ Open
– Through valves
• Should be avoided for sterile processes
• Maintain positive pressure and flow
• Technique
‹ Closed
– Septums and Needles
– Sample valves (e.g.: NovAseptic, Asepco, Keofitt®) that are steam
sterilized before each use with attached sample devices
• Autoclaved bottle assembly with valves and vent filter
• Gamma irradiated bags with sterile quick connect valves
• Flow through NovaSeptum® device
– NovaSeptum® device attached to an NovAseptic Connector (or
equivalent)
Sterility by Design - Bill Ogden
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Advanced Principles in SIP – 301
Steam Sterilization
‹ Pressure Tests
‹ Air Removal
‹ Heat Up and Exposure
‹ Measuring Percentage of Retained Air
‹ Cool Down and Air Blow
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Pressure Tests
‹ To verify system integrity
–
–
–
–
Following maintenance
F ll i manuall manipulations
Following
i l ti
Periodically
For “Closed” processing / Sterility Assurance
‹ Medium
– Air (pneumatic)
– Water (hydro)
– Other (Helium,
(Helium steam,
steam vacuum,
vacuum etc
etc.))
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Pressure Tests
‹ Ensure NO isolations beyond the test boundary
– May need multiple test paths
‹ Temperature Considerations
– Room Temperature is Best
– Temperature compensation may be an option
‹ Fluctuating Jacket Temperatures May Cause Problems
– Either Control Jacket Temperature
– Or Turn temperature control off
Sterility by Design - Bill Ogden
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PT Temperature Compensation
• Equation for compensating for temperature changes during Air
Pressure Tests
• Based on the Ideal Gas Law (PV = nRT)
NOTE: Temperature is in Kelvin (C + 273)
Pressure is Absolute Pressure (Not gauge)
P1 / T1 = P2 / T2
P2 = (P1 / T1) x T2
P2psia = (P1 / T1) x T2 = (P1psia / (T1°C
C + 273)) x (T2°C
C + 273)
Example:
P1 = 34.7 psia ; T1 = 37°C ; T2 = 30°C
P2 = (34.7 psia / 310°K ) x 303°K = 33.9 psia
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Air Removal
‹ The Science of Air Removal – Vacuum
– Required for Autoclaves
– Removes
Remo es air from everywhere
e er here
– Keep boundaries closed until have positive steam pressure
‹ The Art of Air Removal – Steam Purge
–
–
–
–
–
–
–
Beware of Dead Legs / tight spaces with no flow
Beware of Parallel Paths trapping air
One steam supply path / many purge points
May need to alternate supply paths / pulse valves
Air is heavier than steam – so steam in the top
Bypass valve around bottom drain trap
Thermostatic traps
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Heat Up and Exposure
‹ Exposure Temperature Setpoint
– 121° C + Instrument Error + Overkill
– Best practice
p
– All locations monitored
– Worst case location must make temperature
‹ SIP Steam Control
– Steam supply Control Valve controlling vessel Pressure
– Pressure regulator on steam supply setting Pressure
– Controlling steam supply valve based on Temperature
‹ May need to alternate supply paths / pulse valves
‹ Adjacent system SIPs should overlap (e.g.: Add ports or transfer lines and
vessels)
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Measuring Percentage of Retained Air
‹ Based on Saturated Steam Curves and the Principle of Partial
Pressures
‹ “In a mixture of ideal gases, each gas has a partial pressure which is the pressure
which the gas would have if it alone occupied the volume.” (Charles Henrickson (2005).
Chemistry. Cliffs Notes. ISBN 0-7645-7419-1 )
‹ Assumptions:
– Air and steam are fully mixed
– Instruments are accurate
– Air and steam behave like ideal gases
‹ The partial pressure of saturated steam can be determined based on
the temperature
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Saturated Steam Table at Sea Level
Temperature - ° C
Pressure - PSIA
Pressure - Gauge
Temperature - ° C
Pressure - PSIA
Pressure - Gauge
121.0
29.7
15.0
129.6
38.7
24.0
121.5
30.2
15.5
130.1
39.2
24.5
122.0
30.7
16.0
130.5
39.7
25.0
122.6
31.2
16.5
131.0
40.2
25.5
123.1
31.7
17.0
131.3
40.7
26.0
123.6
32.2
17.5
131.7
41.2
26.5
124.1
32.7
18.0
132.1
41.7
27.0
124.6
33.2
18.5
132.6
42.2
27.5
125.1
33.7
19.0
133.0
42.7
28.0
125.6
34.2
19.5
133.4
43.2
28.5
126.1
34.7
20.0
133.7
43.7
29.0
126.6
35.2
20.5
134.1
44.2
29.5
127.0
35.7
21.0
134.5
44.7
30.0
127.4
36.2
21.5
134.9
45.2
30.5
127.9
36.7
22.0
135.3
45.7
31.0
128.4
37.2
22.5
135.6
46.2
31.5
128.8
37.7
23.0
136.0
46.7
32.0
129.2
38.2
23.5
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Bonus – Equation for calculating percentage
of retained air during SIP
‹ The partial pressure of air is the total pressure minus the partial pressure of
the steam
‹ The percent air is the partial pressure of air divided by the total absolute
pressure x 100
Percentage of Retained Air = ((TP – SP) / TP) x 100
((Total Pressure – Steam Saturation Pressure (based on temp))
Divided by Total Pressure) x 100%
Example:
SIP temperature = 123.6°C (steam press ~ 32.2 PSIA)
Total vessel pressure = 39.4 PSIA
Percent Air = ((39.4 – 32.2) / 39.4) x 100 = (7.2 / 39.4) x 100 = 18.3%
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Cool Down and Air Blow
‹ Steam condenses during cool down
– This results in vacuum formation unless the steam is replaced by
pressurized
i d air
i
– The entire system should be pressurized to the sterile boundaries (at
least until below 100°C)
– Water will be retained unless the low point drain is left open
‹ Cool Down Methods
–
–
–
–
Air blow
Ambient cooling
Jacket cooling
Combination of methods
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Cool Down and Air Blow
‹ A good air blow will:
– Keep your system pressurized
– Eliminate water and dry the equipment
– Speed up the cool down (a little)
‹ Jacket cooling considerations
– Beware of initiating jacket cooling too soon
• Cold coolant hitting hot metal causes thermal stress, resulting in leaks
• Starting above 100°C causes rapid condensation, and may result in
vacuum formation
‹ Leave the system closed and pressurized at cycle completion
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Lessons Learned – 302
‹ Failures During Air Removal
‹ Failures
F il
D
During
i C
Cooll D
Down
‹ Failures During Sampling
‹ Failures Due to Valve Leakage
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Failures During Air Removal
‹ Cold Dead Legs in systems using steam purge
– Inactive addition port on a 800L Fermentor
– 1” Tri-Clover ports with pH & DO probes
– Bioreactor sample valve, steam supply a dead leg during
Vessel SIP
‹ Opening Trap Isolation valves while under vacuum
Sterility by Design - Bill Ogden
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Failures During Cool Down
‹ Pulling vacuum
– Forced Cool Down too rapid
– Insufficient Air Supply
– This is a problem if the system leaks
‹ Leaving sterile boundary open to trap
– Closed tank bottom outlet valve
– Outlet piping was still considered sterile
– Left outlet p
piping
p g open
p to trap
p
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Failures During Sampling
‹ Bioreactor sampling with autoclaved bottle assembly
– A diaphragm valve leaked because it was misassembled
– Valve sequencing allowed reverse flow
‹ Roller Bottle inoculum transfer line contaminated
–
–
–
–
Open sample obtained in a ISO-5 hood
Valve sequencing compromised the “sterile boundary”
Bacillus grew through the sample line
Transfer line contaminated the next time the upstream isolation valve
was
as opened
opened.
‹ Reuse of Septum Sampling Device needle for Bioreactor sampling
– Septum Sampling Device needles are designed for single use
Sterility by Design - Bill Ogden
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Failures Due to Valve Leakage
‹ Fermentor Sparge isolation valve leaked air during SIP
‹ Boundary valve leakage into a previously sterilized system
‹ Improperly set travel stop on a manual valve
‹ Manual valve on transfer line low point to trap not closed
– Product lost during transfer
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Group Discussion / Q & A
‹ Attendees discuss equipment and validation problems,
contaminations,
t i ti
and
d problem
bl
solving
l i approaches.
h
‹ Any Questions?
Sterility by Design - Bill Ogden
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