Sterilization Process Validation

Sterilization Process Validation
Title: Sterilization Process Validation
Manual Number: 039
Prepared by: Date: Supersedes:
Checked by: Date: Date Issued:
Approved by: Date: Review Date:
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4 Responsibilities
All sterile manufacturing sites or its contractors are responsible for ensuring that
sterilization processes used to produce items are properly validated.
5 Guideline
Validation of processes used to sterilize drug products and equipment are the most critical
validation activities undertaken. Common elements in the validation of any sterilization
process include:
􀂇 Sterilization Cycle Development
􀂇 Biological and Physical Measurement Controls
􀂇 Empty Chamber Studies
􀂇 Loaded Chamber Studies
􀂇 Routine Use/Ongoing Monitoring
􀂇 Validation Maintenance/Change Control/Revalidation
The sterilization method chosen depends on the application. The following methods are
typically available:
Method Typical application
Steam
sterilization
For the sterilization of fluids in ampoules, vials etc, or the
sterilization of processing equipment, reactors, preparation
tanks, solution delivery piping, etc. In general, sterilization
through the application of saturated steam under pressure is the
preferred method of sterilization. The principles apply to SIP
processes as well.
Sterilization by
filtration
Used for those products that cannot be sterilized due to the
heat sensitivity of the product or where heat labile packaging
is chosen since it provides a distinct patient benefit. Not the
preferred sterilization method.
Dry heat
sterilization and
Depyrogenation
Used to sterilize/depyrogenate containers (ampoules, vials,
etc.), pharmaceutical raw materials and processing equipment.
The use of dry heat has little application for the sterilization of
pharmaceutical drug products.
Radiation
sterilization
To sterilize packaging equipment, consumables, garments etc.
that are difficult to sterilize using steam or other methods.
Radiation sterilization is mostly used for medical devices.
5.1 Steam Sterilization
Steam Sterilization is the most common type of sterilization employed in the
pharmaceutical manufacturing environment. The principles of steam sterilization
are applicable to processes conducted within autoclaves as well as sterilizationin-
place (SIP) processes.
For the sterilization of fluids in e.g. vials and ampoules, a fluids load autoclave
cycle is used. The steam (or superheated water) is used as a heat transfer medium
to heat the contents of the vials/ampoules. The moisture required for sterilization
is derived from the contents in the vial/ampoule.
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minute of the exposure stage.
The difference between the control probe, recording chart probe and independent
sensor (usually a thermocouple) during the exposure stage should not exceed + 1.0􀂃C.
5.1.1.2 Loaded Chamber Temperature Distribution
This study must be included to demonstrate that the equipment loading
patterns do not significantly change the chamber temperature distribution
within the chamber. Typically thermocouples are distributed throughout the
chamber (not in contact with load items) as for the Empty Chamber Temperature
Distribution study and cycles may be run using both the maximum and minimum
loads.
Loaded Chamber Temperature Distribution studies should meet an acceptance
criteria for the temperature to be within + 1􀂃C of the mean loaded chamber
temperature after one minute of the exposure stage.
The difference between the control probe, recording chart probe and independent
sensor during the exposure stage should not exceed + 1.0􀂃C.
5.1.1.3 Heat Penetration Studies
Loaded chamber heat penetration studies must be performed to demonstrate
that the pre-required time at temperature criteria are met for the loads being
validated. The heat penetration locations to be monitored are assessed
using both temperature probes and BIs. The thermocouples and the BIs should
be placed at the same locations wherever possible. Special emphasis is placed on
those locations identified during cycle development studies as being difficult for
steam to penetrate/difficult to heat (cold spot determination). Such locations
typically include the interior of hoses, filter housings, large objects, filling
apparatus and items with multiple layers of protective wrapping.
The placement of temperature probes and BIs within the load must not enhance the
penetration of steam into the load item. Where the load includes multiple items of
the same configuration in the load (e.g. bags of stoppers), BIs should be placed in a
second item adjacent to that containing the thermocouple.
This is to prevent the presence of the thermocouple from enhancing the penetration of
steam to the BI.Where items in the load are unique, the BIs must be placed in the load
item near the probe and precautions taken to prevent enhanced steam penetration.
Heat penetration cycles performed, as part of an initial validation exercise
must be repeated several times, e.g. three times,to demonstrate consistency.
These studies should be performed using established load patterns, though a
minimum and maximum load may be used to represent each particular load
pattern for qualification purposes. The purpose of the heat penetration study is to
document that the load items (including the cold spot) receives the minimum
required pre-determined time at temperature/F0.
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Fans or blowers are generally used to help assure uniform distribution of heat
throughout the chamber. Fan speed should be determined during validation and
thereafter periodically monitored to assure operation within the acceptable range.
Typical test during the validation of a dry heat oven include:
5.4.1.1 Empty Chamber Temperature Distribution
Temperature probes (thermocouples) are distributed throughout the empty
chamber (in free space) and a temperature profile is produced. A uniform
temperature profile is expected. A probe should be located next to the controlling
sensor. Note the come-up time to temperature and cool-down times, as these
should be consistent in an empty chamber.
5.4.1.2 Loaded Chamber Temperature Distribution and Heat Penetration
In dry heat applications loaded chamber mapping and heat penetration
studies must be performed. Typically, these studies may be performed at the
same time. Thermocouples must be distributed throughout the chamber (in
free space) for heat distribution information. Thermocouples must also be
placed inside of the container, equipment or component being treated for the
heat penetration information. The penetration thermocouples need to make
contact with the surface of the item. This is because, due to the mass of the item,
the time to reach sterilization/depyrogenation temperature can substantially lag
behind the temperature of the surrounding air.
Biological indicators or endotoxin-spiked vials should be located adjacent to the
penetration thermocouples. Heat penetration studies, conducted as part of the
initial validation, should be repeated several times (e.g. three times) to
demonstrate consistency.
Product containers should have container mapping performed similar to that
described for steam sterilization. Load patterns are important as air is a poor
conductor of heat and the distribution of mass can greatly affect heating
characteristics. Assigning a temperature profile requirement is more problematic
as the profile is load specific. The temperature profile for a specific load should
how good reproducibility
5.4.2 Dry Heat Tunnels
Validation of dry-heat tunnels is demonstrated by both temperature measurements
and inactivation of bacterial endotoxins (depyrogenation).
Similar studies to dry-heat ovens are performed, i.e., empty tunnel temperature
distribution and loaded tunnel endotoxin challenge. The temperature variation
within the sterilization/depyrogenation zone may be greater than seen in an oven.
Higher temperatures are usually selected - ranging from 270􀂃􀂃 - 350􀂃C, due to the
shorter exposure time required and the greater temperature variation. Points to consider
for physical measurements include:
Belt Speed - determines the exposure time
Temperature - determines the time required for inactivation
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5.6 Validation Maintenance/Change Control/Revalidation
Validation of sterilization processes is not a one-time exercise. Validation
maintenance is a phrase that describes a number of activities that support the
ongoing validated state of a process. In the case of sterilization processes, routine
bioburden monitoring, preventive maintenance, calibration, cycle review and
approval and annual reviews are activities that make up validation maintenance.
Bioburden monitoring must take place for every batch of aseptically
produced drug product. The preventive maintenance program should provide
clear instructions on reporting any unusual observations or equipment
breakdowns/mechanical failures so that an evaluation can be made on impact to
the validated state. Cycle review and approval should be in accordance with
detailed SOPs that have a direct traceability to the qualification and validation
activities, set point parameters and acceptance ranges.
Chamber vacuum leak testing, air detector device performance (if so equipped),
Bowie-Dick type testing for steam penetration, thermometric testing for small
loads, and other types of testing or review that may be required by local
regulatory authority expectation or requirement should be understood and
implemented as appropriate. For example, steam quality testing is a requirement
of the UK authorities. These tests are also mentioned in the PDA Technical
Monograph #1 and FDA􀂶s Guideline on Drug Products Produced By Aseptic
Processing.
The change control program should ensure that technical experts and the Quality
Assurance Function assess any planned changes to the equipment, process, loads,
procedures or documentation as to whether the qualified or validated state may be
impacted by the change. Any additional work necessary to demonstrate the
ongoing validated state should be reviewed and approved as part of the change
control process. Sterilization processes are critical processes. Be vigilant in
assuring that any changes or repairs are fully assessed for potential impact
via the change control process. Perform a periodic assessment of the
potential cumulative effect of changes that individually may not be
significant enough to prompt revalidation but, taken together, indicate a
need to re qualify or revalidate.
Sterilization processes must be revalidated at least annually in the absence of
any change-driven revalidation. The revalidation can be a subset of the original
validation work. Some acceptable approaches include:
􀂇 Single runs rather than 3 consecutive runs are sufficient in the absence of
recurring problems
􀂇 The selection of a worst case load pattern for revalidation
􀂇 The revalidation of each type of cycle (e.g. cycle for stoppers, cycle for
filling parts, cycle for products, etc.) but not the revalidation of each cycle
loading pattern.
􀂇 The revalidation of the worst case loading pattern and one selected
loading pattern, with the rotation of the remaining loading patterns at
subsequent annual revalidations.
􀂇 The revalidation of the empty chamber, maximum and minimum loading