ENGINEERING HANDBOOK

Steam Sterilization in Place

Version: 0.2

Date: 22/11/2017

Author: Jenwa Xu

Department: Cross-Applications China

 Revision: Page:

0.2 2 (7)
Document Description:

[ID#] Steam Sterilization in Place

CONTENT
1 Steam Sterilization in Place ...............................................................................................................3
1.1 Process and equipment characterization ..................................................................................3
1.1.1 Critical process parameters .........................................................................................3
1.1.2 The design of the steam SIP system should permit ....................................................4
1.1.3 The following factors should be considered when designing a steam SIP process. ...4
1.1.4 When using steam SIP to sterilize a filter, the following aspects should be taken into
consideration. ..............................................................................................................5
1.2 Quality of Steam ........................................................................................................................5
1.3 Validation of SIP ........................................................................................................................6
1.3.1 Validation protocol of SIP ............................................................................................6
1.3.2 Design qualification(DQ) of SIP ...................................................................................6
1.3.3 Installation qualification(IQ) of SIP ..............................................................................6
1.3.4 Operational qualification(OQ) of SIP ...........................................................................6
1.3.5 Performance qualification (PQ) of SIP .........................................................................7

DOCUMENT HISTORY
Date Revision Change Author
2017.11.10 0.1 First issue JW
2017.11.22 0.2 Changes in Headline Format B. Lengsfeld
 Revision: Page:

0.2 3 (7)
Document Description:

[ID#] Steam Sterilization in Place

1 STEAM STERILIZATION IN PLACE

Sterilization is very important for sterile production. Sterilization-in-place (SIP) can be achieved by using steam
or other gaseous or liquid sterilizing agents
Steam sterilization-in-place (steam SIP) is a widely adopted method for the in-line sterilization of processing
equipment. Adequate configuration of steam SIP systems is vital and must be considered at the early
conception stage of the plant. The critical requirements associated with SIP include proper steam distribution,
non-condensable gases removal, and continuous condensate elimination. Good engineering practices,
adequate piping design, steam traps, valves, and monitoring instrumentation are essential to ensuring SIP
validation.

1.1 Process and equipment characterization

1.1.1 Critical process parameters

• Critical process paramerters for steam SIP are time, temperature and steam pressure. Their minimum
and maximum limits should be specified and controlled throughout the sterilization cycle

• All configurations require the installation of a pressure-relief safety valve as well as pressure gauges
upstream and downstream of the filter. This ensures that the reverse differential pressure does not
exceed specifications throughout the SIP procedure. Temperature probes are located in the coldest
points of the filter assembly and the vessel (i.e., the drain points) to monitor the SIP process. Adding
steam traps downstream of the bleed valves allows condensate removal, reduces the steam flow rate,
and minimizes the pressure differential across the filter.
• Once the monitoring temperature probes located in the slowest heating points of the system (generally
the vessel and filter drains) indicate the set sterilization temperature, the SIP plateau begins and
continues for the required time period defined by the validation study. Both pressure and temperature
should be monitored to ensure that saturated steam conditions are met. The theoretical saturation
temperature calculated from the actual pressure should be in the range of ±2℃ from the actual
temperature, as accepted by the European standard EN 285.
 Revision: Page:

0.2 4 (7)
Document Description:

[ID#] Steam Sterilization in Place

1.1.2 The design of the steam SIP system should permit

• Complete displacement and elimination of air. Eliminating all non-condensable gases normally requires
flushing the system with 10 volumes of saturated steam, which might take between 5 and 20 min.

• Bleeding of steam at all low points to eliminate accumulation of condensate

The maximum amount of condensate is generated at the SIP start because of the high temperature
difference between steam and the heat transfer equipment. Steam traps shut automatically once
the steam exits the drain and vent valves and indicates that air and condensate have been removed.
This limits the steam flow and allows the system to be increased and maintained at the desired
sterilization temperature. Steam traps will open intermittently to evacuate condensate and allow
replacement with fresh saturated steam.
• Maintenance of sterility after completion of the sterilization process
The maintenance of sterility is ensured as long as the pressure gauges indicate a positive reading
in all parts. This operation also allows the cooling of the equipment and filter.

1.1.3 The following factors should be considered when designing a steam SIP process.

• Steam should be introduced in such a way as to facilitate distribution into all parts of the system
• The tank and/or vessel should be designed to avoid retention of air
• Vent filters are required for the sterile introduction of air or nitrogen during and after the process of
vessel sterilization.
• Condensate drains should be installed at low points in the system
• Valves, drains, dead legs, low points, gas filters and housing within the system are locations where air
can become entrapped and/or where condensate can accumulate. These are typically the most-
difficult-to-sterilize locations(also called “worst location” or “cold spot”) in a steam SIP system.
• Piping should be sloped to the drain, enabling the complete removal of condensate. Other parts that
may retain condensate should be constructed to facilitate complete drainage.
• The displacement of the air with steam shall be achieved by a well-designed system and strategically
placed bleeds. Gravity displacement is often used for the displacement of air with steam, though pre-
vacuums can also be used.
• A bleed location could require closing once air has been eliminated, unless it is also utilized for
condensate removal.
• After completion of the sterilization cycle, sterile gas(air or nitrogen) is usually introduced into the
system through a sterilizing grade filter while the total system is still under positive pressure. The gas is
used to purge the system of steam and condensate, and maintain it under a slight positive pressure
 Revision: Page:

0.2 5 (7)
Document Description:

[ID#] Steam Sterilization in Place

until ready for use. As the piping cools after sterilization, it could form a vacuum, so it is important to
maintain positive pressure with sterilized gas.

1.1.4 When using steam SIP to sterilize a filter, the following aspects should be taken into
consideration.
• Before starting the SIP cycle, it is important to check the leak-tightness of the system. A five-minute
pressure hold test is conducted at 2 barg pressure.
• Condensate drainage should be equipped at the lowest part of both the sterile side and the non-sterile
side of each filter housing

The filter housing must be designed and installed for correct drainage of condensate, with the inlet sterile
side of the cartridge fitted on the sterile vessel. This setup is preferred, since the housing closure as well
as the connections to vent and drain valves may present risks of leakage on the upstream side of the
filter. A reverse mounting would result in the filter bypass and would compromise the equipment’s sterility.
Figure above shows the correct installation of a vent filter. The in-line design of the housing allows the
drainage of downstream condensate from the vertical connection to the vessel. The T-type housing
needs a fall on pipework to ensure condensate drainage to the vessel. In both cases, the upstream
condensate is eliminated through a steam trap fitted on the drain port of the housing. A thermostatic
steam trap also must be installed on the top of the filter to evacuate non-condensable gases during the
sterilization cycle. This ensures the penetration of steam to all filter assembly extremities.
• Steam bleed(s) should be positioned, where necessary, in the part of housing that might cause air
retention.
• The pressure differential across the filter element at the operating temperature should not exceed the
manufacture’s recommendations.
• Steam pressure and differential pressure should be monitored
• Temperature should be measured downstream of the filter
• Cartridge filters should be oriented so that condensate drainage from both sides of the filter surface is
enabled.

1.2 Quality of Steam

• Non-condensable gases in steam, liquid water, oils from compressors, and other contaminants should
be controlled according to the specification of the steam
• Condensate of steam should meet the chemical requirements for “purified water”.
• Steam condensate should correspond to the WFI(water for injection) specification if the system is used
for parenteral products(and for systems used for any other process applications that require WFI)
• Steam used for the steam SIP should be dry, saturated and not superheated.
 Revision: Page:

0.2 6 (7)
Document Description:

[ID#] Steam Sterilization in Place

1.3 Validation of SIP

1.3.1 Validation protocol of SIP
• Written protocols shall be established specifying how qualification and validation are to be conducted.
Protocols specifying critical steps and acceptance criteria shall be reviewed and approved. Qualification
of equipment design, installation, operation and performance shall be performed in accordance with the
approved protocols. Any deviation from the protocols shall be documented, investigated and resolved.

1.3.2 Design qualification(DQ) of SIP

• The SIP system shall be designed for its intended use. The appropriateness of system design, process
design, design of all facilities, equipment and materials used shall, at the first stage of validation, be
confirmed to meet requirements for the intended use.

1.3.3 Installation qualification(IQ) of SIP

• Installation qualification shall be performed to demonstrate that equipment used to perform SIP and
deliver the sterilizing agent, equipment to be subjected to SIP, and any ancillary items, have been
supplied in accordance with their specifications.
• It shall be verified that:
a) The location of the equipment conforms to its specification;
b) The equipment is installed in accordance with installation instructions;
c) The services to the equipment conform to their specification.
d) The calibration of all measuring instruments critical to the process (including any test
instruments) used for monitoring, controlling, indicating or recording shall be comfirmed. Alternatively,
calibration may be confirmed at the commencement of operational qualification.

1.3.4 Operational qualification(OQ) of SIP

• Operational qualification shall demonstrate that the installed equipment is capable of performing the
specified SIP process throughout the equipment within defined tolerances.
• The operating procedures for the equipment shall be verified to meet established requirements. These
operating procedures shall include, but not be limited to:
a) Step-by-step operating instructions;
b) The method by which a failure to attain the operating cycle parameters can be identified, and
the actions to be taken;
c) Housekeeping, calibration and maintenance instructions;
d) The means by which an error in the result of a measurement for control, indication and
recording can be identified;
e) Details of contacts for technical support.
• the potential most-difficult-to sterilize locations of the equipment shall be determined by taking into
consideration the individual physical and/or chemical properties of the sterilizing agent and the
inactivation characteristics of the sterilization process.(dead legs and shoulder of tanks can be regarded
as potential worst case locations)
• data shall be generated to verify that the defined sterilizing conditions(e.g. time, pressure, temperature,
concentration of sterilizing agent and its distribution) are attained within specified tolerances throughout
the SIP system.
• the consequences of failure in the result from each measuring instrument fitted to the SIP
system(control, indication and recording) shall be determined at significant parts of the SIP process.
• the number and locations of sensors used for qualification, such as temperature and pressure, shall be
specified. Documented evidence shall be provided to show that the number and locations used are
sufficient to demonstrate that the requirements for SIP of the equipment have been met.
 Revision: Page:

0.2 7 (7)
Document Description:

[ID#] Steam Sterilization in Place

1.3.5 Performance qualification (PQ) of SIP

• Data generated during installation qualification and operational qualification shall be approved before
performance qualification is started
• The manner of presenting the equipment for sterilization shall be established and documented.
• Data shall be generated to demonstrate the attainment of the defined physical and/or chemical
conditions, within the specified tolerances throughout processing. The appropriateness of any routing
monitoring positions or devices shall be established. This is achieved by mapping the attainment of the
specified condition(s) at representative points throughout processing.
• Performance qualification shall include a comparison and evaluation of process parameters measured
in the SIP process to those provided at the time of the SIP system’s design. The acceptability of any
deviation from those specified at the time of design shall be confirmed by reference to existing data and
tests.
• Documented evidence shall be provided to show that the number of critical parameter sensors for
performance qualification is sufficient to demonstrate compliance with the specification for SIP of the
equipment.
• Biological indicators or inoculated carriers shall be used during the performance qualification. The
number and locations of biological indicators shall be specified. Documented evidence shall be provided
to show that the number and locations of biological indicators are sufficient to demonstrate that the
requirements for SIP of the equipment have been met at locations presenting the greatest sterilization
challenge.
• If chemical indicators are used as a part of the performance qualification, the number and locations of
chemical indicators shall be specified. Documented evidence shall be provided to show that the number
and locations of chemical indicators are sufficient to demonstrate that the requirements for SIP of the
equipment have been met at locations presenting the greatest sterilization challenge.
• Performance qualification shall include a series of at least three consecutive and successful runs of the
SIP process to demonstrate the reproducibility and effectiveness of the process. the successful SIP
runs shall be determined by measurement of physical parameters and inactivation of biological
indicators or inoculated carriers which shall demonstrate the required microbicidal effectiveness.