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THERMAL VALIDATION –
OVERCOME THE CHALLENGES
Jeanne Moldenhauer
Excellent Pharma Consulting
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1
OVERVIEW OF PRESENTATION
Expectations for Thermal Validation
How to Document the Validation Process
Dealing with Problems
2
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WHAT IS STERILIZATION?
Sterilization (or sterilisation) is a
term referring to any process that
eliminates (removes) or kills all forms
of life, including transmissible agents
(such as fungi, bacteria, viruses, spore
forms, etc.) present on a surface,
contained in a fluid, in medication, or
in a compound such as biological
culture media.
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WHAT IS STERILIZATION?
• Sterilization is an absolute
• We measure probability of sterilization –
PNSU or SAL
• PNSU of 10-6 is deemed minimum
acceptable for pharmaceuticals (per PDA
measured for both physical and biological
parameters)
• Methods for calculation are specified in
PDA TR1
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EXPECTATIONS
• Cycle development to show physical and
biological parameters are met
• Validation to show reproducibility and
efficacy – including PNSU
• Ongoing maintenance of the system
STERILIZATION IS A KEY COMPONENT OF
CONTAMINATION CONTROL
Types of Processes - Classic
Moist Heat Sterilization (Steam)
Dry Heat Sterilization
Gas Sterilization
Irradiation Sterilization
Chemical Sterilization
Aseptic Processing
Filtration
Exclusion
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USP GUIDANCE ON STERILIZATION
<1211> Sterilization and Sterility Assurance of Compendial Articles replaced by <1229 series>
<1229> Sterilization of Compendial Articles *
<1229.1> Steam Sterilization by Direct Contact *
<1229.2> Moist Heat Sterilization of Aqueous Liquids*
<1229.3> Monitoring of Bioburden
<1229.4> Sterilizing Filtration of Liquids
<1229.5> Biological Indicators for Sterilization *
<1229.6> Liquid Phase Sterilization
<1229.7> Gaseous Sterilization
<1229.8> Dry Heat Sterilization *
<1229.9> Physicochemical Integrators and Indicators for Sterilization*
<1229.10> Radiation Sterilization
7
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<1229.1> STEAM STERILIZATION BY DIRECT
CONTACT
• Same as saturated steam cycles –
frequently used to sterilize porous loads
or hard goods
• Mathematical models are used to predict
lethality: based upon the microbial
resistance (D-value), population levels,
and exposure time (at temperature)–
follows specific kinetics
• There are significant concerns for the
sterilization of porous items, e.g., filter
housings, long tubing, sponges, large bell
jars, etc. where it is difficult to remove
all of the entrapped air and hard for the
steam to penetrate into the item
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<1229.1> STEAM STERILIZATION BY DIRECT
CONTACT• Detailed validation discussions are
provided in PDA TR1
• For this type of cycle, an overkill approach is expected for use, where a significant level of heat is delivered and all biological indicators are inactivated
• Cycle Development procedures to determine loading and cycle times are critical. Need to show the chamber heats up and so do penetration probes – Jacket temperature
• Number and depth of pre-vacuum conditions (some concerns about 7 or more)
• Steam pulse levels
• Time and conditions for chamber heat-up
• Exposure time and temperature
• Time for cooling and drying
• Air breaks
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<1229.1> STEAM STERILIZATION BY DIRECT
CONTACT
Validation Parameters in TR1
Jacket temperature and/or pressure
Number and depth of vacuum pulses pre-exposure
Level of the steam charge
Number and requirements for positive pressure pulses
Chamber come-up time
Exposure time
Exposure temperature (cold spot or drain)
Allowable probe temperature range
Chamber pressure during exposure
Minimum Fo during exposure
Cooling time and Drying time
Rate for vacuum breaks
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<1229.1> STEAM STERILIZATION BY DIRECT
CONTACT
Validation Parameters
Replicate cycles, not less than 3 each
Minimum and maximum load cycles
qualified separately
Methods to qualify different loads?
Validation of supporting utilities, e.g.,
steam quality, compressed air
Uses
Equipment and supplies for aseptic
processes
Some small volume parenterals (limited)
Some medical devices
<1229.2> MOIST HEAT STERILIZATION -
AQUEOUS LIQUIDS
Moist Heat
Destroy microbes by coagulating and denaturing the cells
enzymes and structural proteins
Typical cycles, especially in Europe are 121oC for 15 minutes
Based upon sterilization models (approaches): overkill or
product-specific (used to be called bioburden cycles, or
absolute bioburden cycles)
Overkill cycles use the most heat and have the biggest
impact on the product (stability); requires total inactivation
of biological indicators
Product-specific cycles uses understanding of bioburden
resistance and biological indicator to use a shorter cycle with
less impact on the product. Most LVPs use this type of cycle
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<1229.2> MOIST HEAT STERILIZATION -
AQUEOUS LIQUIDS
Moist Heat
FDA requires more data on the heat resistance of the
biological indicator in specific products.
Resistance is dependent upon the item the biological
indicator is placed on or in.
Must provide data to show that the BI used is more
resistant that it would be based upon direct inoculation of
the product or component – Master Solutions
If you use a carrier, e.g., paper strip, disk, thread or wire,
the D-value must be determined on the carrier you use.
Aseptic guidance gives some provision allowance for not
confirming D-values
Sterilization by dry-heat takes much longer. For G. stearo
it is typically about 4x as resistant to dry heat as moist
heat
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<1229.2> MOIST HEAT STERILIZATION -
AQUEOUS LIQUIDS
Cycle Development Activities
Determine slowest to heat zone in the container (usually not
for containers less than 100 mL)
Determine cold spot in the sterilizer
Assess appropriate loading configuration for uniform
temperature distribution and heat penetration
Determine time parameters for the various parameters
monitored
Sterilization occurs at a variety of time and temperature
parameters, and in the USA many different combinations are
used
See PDA Technical Report 1 for more information on the
parameters to monitor based upon the type of sterilizer and
the sterilization model used
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<1229.2> MOIST HEAT STERILIZATION -
AQUEOUS LIQUIDS
D-values and z-values
With a z-value of 10oC, it means that for every 10oC you get a
10-fold change in the D-value
Changing from 120oC to 130oC achieves the lethality in much
less time and much less degradation to the product.
Increasing the temperature for a shorter time aids in
sterilizing heat sensitive solutions
Conversely, lowering temperature increases the time required
to get the same lethality
G. stearothermophilus, C. sporogenes, B. subtilis (5230) and B.
smithii (aka B. coagulans) are all used as biological indicators
for these processes
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<1229.2> MOIST HEAT STERILIZATION -
AQUEOUS LIQUIDS
Fo Values
It is the time in minutes required to deliver a
sterilization cycle equivalent to 121oC for moist heat
(assumes a z-value of 10oC
Derivation of calculations are shown in TR1
Allows you to calculate the probability of a non-sterile
unit (PNSU) and it is expected to be at least 10-6
The calculations can be rearranged to solve for each
parameter used in a sterilization evaluation
Uses
Sterilization of aqueous solutions
SVPs and LVPs
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<1229.2> MOIST HEAT STERILIZATION -
AQUEOUS LIQUIDS
Validation
Follows the typical equipment qualification process:
commissioning, installation, operational and performance
qualification
Detailed explanations in TR1 and also listing of specific
parameters to measure/evaluate
IQ and OQ should be performed before cycle development
Cycle development is performed before PQ
Cycle development used to determine the physical properties
required for appropriate sterilization, e.g., specific loading
pattern. You are looking for a range of acceptable parameters
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<1229.2> MOIST HEAT STERILIZATION -
AQUEOUS LIQUIDS
Validation
Cycle Development Parameters
Jacket temperature and/or pressure
Fan rotations per minute during cycle
Agitation rate during the cycle
Water flow rate during the cycle
Chamber water level prior to exposure
Heat-up rate prior to exposure
Rate of temperature heat-up prior to exposure
Pressure ramp-up rate prior to exposure
Temperature set-point during exposure
Exposure time
Chamber pressure during exposure
Redundant heating media temperature during exposure
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<1229.2> MOIST HEAT STERILIZATION -
AQUEOUS LIQUIDS
Validation
Cycle Development Parameters
Load probe temperature(s) during exposure
Minimum and maximum Fo
Temperature cool-down rate post exposure
Pressure ramp-down rate post exposure
Load cool-down rate
Maximum allowable load probe lethality post exposure
• See TR1 and 48
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<1229.2> MOIST HEAT STERILIZATION -
AQUEOUS LIQUIDS
Validation
Evaluation of physical and biological parameters
The concept of Fbio
Expect concurrent studies for heat distribution and
temperature penetration
At least 3 studies
Minimum and maximum loads qualified separately and/or
qualify all load configurations
Must show acceptable PNSU
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<1229.2> MOIST HEAT STERILIZATION -
AQUEOUS LIQUIDS
Types of Moist Heat Sterilization
Saturated Steam
Air Steam Mixtures
Air Steam Water Mixtures
Water Immersion
Rotary Sterilization
• Parameters monitored change somewhat depending upon
sterilization type utilized
• All are considered acceptable for use
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<1229.4> STERILIZING FILTRATION OF LIQUIDS
o Not a true “sterilization” cycle – but rather exclusion of
microorganisms present
o Pre-sterilization of all components and aseptic assembly
o Does not address removal of viral contamination
o Key considerations:
Type and number of microbes present
Properties of the liquid being filtered, e.g., viscosity
Design of the filter material
Material used for the filter
Process parameters for filtration, e.g., POP sheets
If key considerations change, FDA expects you to re-validate
Annex 1, PIC/s, FDA’s Aseptic guidance and others govern
the validation and maintenance of these processes
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<1229.4> STERILIZING FILTRATION OF LIQUIDS
Need data on leachables and extractables
Need filter retention data for the specific product and/or a
placebo of the product
Keys to validation study design:
Worst case conditions, risk assessment
Frequency and number of studies
Duration of studies
Size of runs, at least 5,000
Line speed
Environmental conditions
Media – growth-promoting
Incubation and examination of media-filled units
Interpretation of results
Filter pore size
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<1229.4> STERILIZING FILTRATION OF
LIQUIDS
Uses
• Filterable solutions that are heat sensitive
• Sterilization of non-aqueous solutions
• Some routinely use – where regulatory agencies do
not legally require terminal sterilization
Other
• Can NOT calculate SAL for aseptic processes
• So what is the 10-3?
• What is a contamination rate?
Expected requalification rate: 6 months
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Use of aseptic methods to assemble items which
have been previously sterilized individually and
cannot be processed with filtration
Uses
Suspensions
Dry powders
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<1229.4> STERILIZING FILTRATION OF
LIQUIDS
Validation
Similar to filtration of liquids
Process simulations performed
Nutrient media replaced by a placebo
powder/solution which may or may not be media
Data included to show why this material is
representative of product
Minimum of three studies
Acceptance criteria the same as for aseptic
filtration
<1229.4> STERILIZING FILTRATION OF
LIQUIDS
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<1229.6> LIQUID PHASE STERILIZATION
o Also known as chemical sterilization methods
Aldehydes: glutaraldehyde and formaldehyde
Acids: peracetic acid, nitric acid and sulfuric acid
Bases: sodium hydroxide, potassium hydroxide
Oxygenating Compounds: hydrogen peroxide, ozone, chlorine
dioxide
Halides: sodium hypochlorite, chlorine
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<1229.6> LIQUID PHASE STERILIZATION
• Sterilization is achieved by submersing the item in the
chemical for a specified time at specified conditions
Key Considerations
• Can the item withstand the sterilant? (chemically
compatible)
• Safety issues: e.g., how to remove the item from the sterilant
without contaminating it and injury to person doing removal
• Sterilization cycle: concentration of sterilant and
temperature, may be pH, mixing and amount/type of soil
present
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<1229.6> LIQUID PHASE STERILIZATION
Validation
Use Bacillus atrophaeus ATCC 9372 or Bacillus subtilis
ATCC 6633
Determine most difficult locations to sterilize and place
BIs there
Use direct inoculation
Use the half-cycle approach (kill all the BIs and then
double the sterilization time) to yield 10-6
Can use bracketing to do a min/max cycle for validation
• Key concern: Does the sterilant work for the entire
sterilization cycle? Some add a second challenge at “half
time” to show that the additional time will yield kill
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<1229.6> LIQUID PHASE STERILIZATION
o Key concern: Removal or inactivation of all sterilant at the
end of the cycle
o Uses:
-sterilize chromatography columns
-some tissue and cell cultures
-contaminated equipment
-some radiopharmaceuticals manufacturing
equipment
-water systems/drains
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<1229.7> GASEOUS STERILIZATION
Types of gases:
Ethylene oxide: restricted in many countries
Ozone:
Chlorine Dioxide
Nitrogen Dioxide
Key Parameters
Concentration
Relative humidity
Pressure
Temperature
Ability to penetrate into the item to be sterilized
Effects of the sterilant on the item being sterilized (compatibility)
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<1229.7> GASEOUS STERILIZATION
Validation
Equipment qualification – using the typical equipment qualification model
Empty chamber distribution study (no BIs)
Determining hardest to sterilize locations
Use B. atrophaeus for most types of sterilization
Process confirmation: Microbial Challenge studies (with physical evaluations)
Routine process control: change control, procedures for operation, periodic evaluations, and the like
Uses
Medical devices
Room fumigation
Some isolators/barriers
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VAPOR STERILIZATION
Types of Vapors
• Hydrogen peroxide
• Formaldehyde (not for the USA)
• Peracetic Acid
Uses
• May claim as sterilization
• May claim as decontamination
• Isolators/barriers
How it Works
• Many are mixed at higher temperatures than room temperature
• Hot air is mixed as it enters the chamber
• Condenses with contact on cool surfaces
• Needs aggressive mixing to get uniformity
• Minimal penetration – surface sterilant
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VAPOR STERILIZATION
Validation
Need to know that materials are compatible with the sterilant
(strong oxidizers)
Most papers are not compatible (Sterrad system) since it
absorbs hydrogen peroxide
May have safety concerns for personnel exposure
Not easy to measure concentration as in gas sterilization
Most also monitor humidity and temperature
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VAPOR STERILIZATION
Validation
Need reproducible attainment of the combined parameters
Some use fraction negative approach for biological indicator kill
and resistance
Typical to use half cycle qualification approach
Most cycles are set at 8-9 times the D-value (added safety) and
routine production at twice this time
Expect total kill of the biological indicator
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<1229.8> DRY HEAT STERILIZATION
Dry Heat
Exists in “hot air” sterilizers (batch or tunnel)
May also depyrogenate
Exists in places within steam sterilizers where steam does
not penetrate
Differing opinions on the predictive use of calculations for dry
heat inactivation of microbes – Akers article for theoretical
endotoxin reduction (app 16 minutes for 3 logs)
No one recognized D-value for dry heat; Tsuji and Lewis have
values from 49oC to 54oC
To depyrogenate – MUST show 3 log reduction
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<1229.8> DRY HEAT STERILIZATION
Validation
Similar to moist heat
Calculated equivalence of heat: FH for depyrogenation in
PDA TR3 and 7; Some use Tsuji and Lewis and calculate Fp –
don’t change between calculations to make a “failing” study
“pass”
If not performing depyrogenation – use B. atrophaeus as the
biological indicator.
For sterilization only – FH uses a reference temperature of
160oC and a z-value of 20oC
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<1229.8> DRY HEAT STERILIZATION
Validation
Use worst case conditions – e.g., lower temperature and/or time of exposure
Load size and configuration is important – some believe every configuration should be validated, not just minimum and maximum loading
Cycles should be monitored for exposure time, exposure temperature, cooling time and/or final temperature. Useful to monitor other conditions, e.g., blower used, speeds, arrangement, etc.
Extensive details on validation and models to use are provided in TR3 Revised 2013
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<1229.8> DRY HEAT STERILIZATION
Uses
Glassware
Heat tolerant items – some metal equipment
Note: Non stated uses include some medical devices
and equipment for other processes
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<1229.10> RADIATION STERILIZATION
Types of Radiation
Gamma Rays
Electron Beams
X-rays
Ultraviolet Light
Penetration differences
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<1229.10> RADIATION STERILIZATION
Advantages
• Simplicity
• Lack of mechanical complexity
• Reproducibility
• Overall efficiency
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<1229.10> RADIATION STERILIZATION
Key Concepts
Amount of radiation (dose) delivered
Dose can be precisely measured – ISO 11137-1 (methods to
determine dose)
Several different testing approaches, and indicate the
number of times to do for testing
Differences are based upon assumptions used for bioburden
No BIs used since there isn’t an accurate correlation to
bioburden destruction
Measurement process = dosimetry
Measured in kGy
Routine use of dosimeters in the process
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<1229.10> RADIATION STERILIZATION
Validation
Identify ISO standard to use
Evaluate minimum and maximum allowable dose does not
affect the item
Radiation dose – penetrates the object
Dose Setting –
o Method 1: dose is based upon radiation resistance of the
bioburden (literature based resistance)
Site performs a verification dose study and determines dose
from a table
Assumes <1000 cfu for 25 kGy sterilization dose and 0.1-1.5
CFUs/item
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<1229.10> RADIATION STERILIZATION
Validation
Dose Setting –
• Method 2: More complex
Series of incremental dose exposures to determine dose
Intent is that 1/100 treated with that dose will be non-
sterile
Compatibility of Materials establish max dose (added safety
factor) and ensure it doesn’t adversely affect material
Dose Verification: Amount is dependent upon the approach
used. Cycle efficacy depends upon appropriate control of
pre-sterilization bioburden and monitoring
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<1229.10> RADIATION STERILIZATION
Validation
Gamma: key parameters are equipment controls and the
parameters for the system’s capability
E-beam and X-rays: utilize controls for scan speed, source
intensity, and system timers
Empty Chamber Dose Mapping:
baseline data on the process performance
Load Mapping: I
arrangement of the items in the load to minimize variability
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<1229.10> RADIATION STERILIZATION
Validation
Biological Indicators: Not utilized
Dosimetry: Required for cycle development and qualification –
must be calibrated
Process Confirmation: replicatestdosimeters strategically
placed
Routine Process Control: Controls to be established to ensure
maintenance of the qualified status
Uses
• Medical devices
• Some APIs
• Terminal sterilization of lyophilization products
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EQUIVALENCE
• Some provisions are existing for sterilizer
equivalence, load equivalence, fill volume/size
equivalence exist
FDA Warning Letter description (Sterile
Recoveries)
See PDA Technical Reports for further guidance
EXPLORING STERILE
PROCESS VALIDATION
REQUIREMENTS
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FDA GUIDANCE
• FDA has the most explicit requirements for
the CTD submission in MAPP 5040.1 and
the 1994 Submission Guidance
• While there are some additional
requirements in other documents we will
use this document as a framework for what
is needed for thermal validation.
• The document covers other sterilization
methods, but these will not be addressed.
MOIST AND DRY HEAT STERILIZATION
A. Description of the Process and Product
1. Description of the Process and Product
- Describe drug product and the container-closure
system(s) to be sterilized (e.g., size(s), fill volume, or
secondary packaging).
2. The Sterilization Process
-Detailed description of the sterilization process
-Describe intermediate sterilization processes – Are you
doing an in-process cycle?
-Submit data to show these cycles are efficacious
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MOIST AND DRY HEAT STERILIZATION
3. The Autoclave Process and Performance
Specifications
-Describe autoclave number, the manufacturer
and model number, the autoclave process: e.g.,
type of cycle, cycle parameters, specifications,
temperature, time, pressure, and mini/max F0
4. Autoclave Loading Patterns
- Describe patterns – diagram/picture useful
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MOIST AND DRY HEAT STERILIZATION
5. Methods and Controls to Monitor Production
Cycles
-Describe the controls and methods used in
production and validation: thermocouples, pilot
bottles, and biological indicators.
-Specify the number and location of each
-Explain the acceptance and rejection
specifications.
6. Requalification of Production Autoclaves
-Routine
-Unplanned
-Frequency.
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MOIST AND DRY HEAT
STERILIZATION
7. Reprocessing
-Describe program for reprocessing, e.g., do you ever
resterilize, allow aborted cycles and reprocessing?
-Describe how you validated program for reprocessing
-Impact on stability
Note: Today you need to follow the ICH guidance
for stability
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MOIST AND DRY HEAT
STERILIZATION
B. Thermal Qualification of the Cycle
1. Heat Distribution and Penetration Studies
-Data summaries for distribution and
penetration
-Demonstrate uniformity and reproducibility
-Conformance to specifications
-Not less than three consecutive cycles
2. Thermal Monitors
-Number of monitors used
-Location of monitors (diagram useful)
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MOIST AND DRY HEAT
STERILIZATION
3. The Effects of Loading on Thermal Input
-Minimum and Maximum Loads
-Address different fill volumes on the same
line
-Data summaries: autoclave identification,
high and low temperatures (range), average
temperature during exposure, min/max F0,
dwell time, run date and time,
-Generate data in production vessels
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MOIST AND DRY HEAT
STERILIZATION
4. Information Included in the Batch
Record
-Copies of batch record pages that
describe sterilization and depyrogenation
-May have references to protocols or SOPs
NOTE: Currently regulators are not requiring
this for CTD submissions
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MOIST AND DRY HEAT
STERILIZATION
C. Microbiological Efficacy of the Cycle
-Validation studies that demonstrate the
efficacy (lethality) of the production cycle
-Must show a sterility assurance of 10 –6
or better
-Demonstrate SAL for all parts of the drug
product (including the container and
closure, which are claimed to be sterile.
-Describe the specific type of study and
the methods used (see following steps)
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MOIST AND DRY HEAT
STERILIZATION
1. Identification and Characterization of
Bioburden Organisms
-Describe methods and results used to identify
and characterize bioburden organisms.
-More data for product-specific sterilization
models
-Heat resistance information
2. Specifications for Bioburden
-Provide specifications (alert and action
levels) for bioburden.
-Describe monitoring program (frequency,
screening tests, etc.)
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3. Identification, Resistance, and Stability of
Biological Indicators
-Provide data for the identification, resistance
(D and Z values), and stability of biological
indicators used .
-If the biological indicators are purchased from
a commercial source, it may be necessary to
corroborate the microbial count and resistance,
and provide performance specifications.
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4. The Resistance of the Biological Indicator
Relative to That of Bioburden
-Studies to correlate the resistance of the biological
indicator relative to that of bioburden may be
necessary.
-Resistance in or on the product (i.e., in the product
solution, or on the surface of container or closure
parts or interfaces) should be determined.
-If spore carriers are used (e.g., spore strips), the
resistance of spores on the carrier relative to that
of directly inoculated product should be
determined.
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5. Microbiological Challenge Studies
-Submit validation studies that demonstrate the
efficacy of the minimum cycle to provide a sterility
assurance of 10–6 or better to the product under the
most difficult to sterilize conditions (e.g., the most
difficult to sterilize load with biological indicators at
microbiological master sites or in master product
or both).
-Selection of a microbiological master product or
site should be supported by scientific data.
(Typically D-values) Microbiological master sites
or solutions are those sites or solutions in which it is
most difficult to kill the biological indicator under
sterilization cycles that simulate production conditions.
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D. Microbiological Monitoring of the Environment
-Establish scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to ensure that components, drug product containers, closures, in-process materials, and drug products conform to appropriate quality standards.
-Establish a microbiological monitoring program for production areas along with a bioburden monitoring program for product components and process water.
- Process water includes autoclave cooling water. -Provide information describing this program. E.g.,
Frequency, methods used, action levels, and data
summaries
-Describe the actions taken when specifications are exceeded should be provided.
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E. Container-Closure and Package Integrity
-Provide scientific validation studies (and data) in support of the microbial integrity of the drug
packaging components.
-Include the following types of information
1. Simulation of the Stresses from Processing
-Simulate the stresses of the sterilization process, handling, and storage of the drug and their effects on the container-closure system. Physical, chemical, and microbiological challenge studies may be necessary.
2. Demonstrate Integrity Following the Maximum Exposure
-Studies conducted on product units that have been exposed to the maximum sterilization cycle(s).
- If a product is exposed to more than one process, then exposure to the maximum cycle of all processes should be incorporated into the study design
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3. Multiple Barriers
-Test each barrier that claims to be sterile should be and validated.
4. The Sensitivity of the Test
The sensitivity of the experimental method used for container-closure integrity testing should be specified and
provided.
5. Integrity Over the Product Shelf Life
Microbial integrity of the container-closure system should be demonstrated over the shelf life of the product.
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F. Bacterial Endotoxins Test and Method
-Provide method and validation data, include
qualification of the laboratory, inhibition and
enhancement testing and results, determination
of non-inhibitory concentration and maximum valid
dilution.
G. Sterility Testing Methods and Release Criteria
-Describe method and validation data
-Identify number of units tested and how they were
sampled
-Describe any matrixing / families
-Describe testing facility and how validated
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V. MAINTENANCE OF MICROBIOLOGICAL
CONTROL AND QUALITY: STABILITY
CONSIDERATIONS
A. Container-Closure Integrity
-Provide method used – See PDA TR 27 and update
-Provide sensitivity of the method
-Applies to all barriers claimed to be sterile
-Sterility testing is NOT ENOUGH
Validation: Worst case is highest temperature and
longest exposure time (in FDA Document)
OTHER PROBLEMS WITH STERILIZATION
VALIDATION
Failure to obtain good temperature distribution
Clogged drains and/or nozzles
Spray nozzles
Steam manifold
Fan issues
Consider quality of sterilizer truck shelves (trays)
Boxes or pans used to hold vials
Loading itself
Need sufficient space around trays to get distribution
Space from side of load
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Lack of Heat Penetration
Was the distribution good?
Is the item porous?
Is adhesive present?
How is air removed from the item?
How does steam get in?
How is the probe placed?
Multiple barriers?
Thermocouple connection good?
What is the footprint of the item on the shelf?
Is the item shingled against other items?
Is the item off the shelf or over an interface of the shelves? 68
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OTHER PROBLEMS WITH STERILIZATION
VALIDATION
Biological Indicators Survive
Was heat distribution and penetration good –
probably a porous load issue
Is the area dry heat or moist heat?
Were the right biological indicators used?
What do you know about the D-value of the organism
in the solution or on the item?
How were the items wrapped?
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OTHER PROBLEMS WITH STERILIZATION
VALIDATION
Come up time is too short
How many loads did you do in a row?
What was the starting temperature in the chamber?
May need to be sure temperature is back to ambient
before starting.
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OTHER PROBLEMS WITH STERILIZATION
VALIDATION
Other time windows out of expectations
Properly sized utilities suppling them
Ramping information is correct
Loading may affect some parameters
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OTHER PROBLEMS WITH STERILIZATION
VALIDATION
CPK (CAPABILITY ANALYSIS)
Doing these calculations can help significantly
We typically use value of 2.0 to be the desired
cycle
Some literature uses values from 1.3 – 1.67
When values are too low, most often adding more
space in the loading solves the problems.
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QUESTIONS(c)J
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KEY GUIDANCE FOR STERILIZATION
ISO 17665-1 Sterilization of Health Care Products – Moist Heat – Part 1 –Requirements for the development, validation, and routine control of a sterilization process for medical devices (2006)
ISO 17665-3 Sterilization of Health Care Products – Moist Heat – Part 3 – Guidance on the Designation of a Medical Device to a Product Family and Processing Category for Steam Sterilization (2013)
ISO 20857 Sterilization of Health Care Products – Dry Heat – Requirements for the development, validation and routine control of a sterilization process for medical devices (2010)
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KEY GUIDANCE FOR STERILIZATION
FDA’s Aseptic Processing Guidance (2004)
FDA’s Guidance for Submission of Sterilization Validation Documentation in Regulatory Submissions (1994)
EU Annex 1 – Manufacture of Sterile Medicines
EU Decision Trees for the Selection of SterilisationMethods (CPMP/QWP/054/98)
British Standard for Sterilization – Steam Sterilizers – Large Sterilizers, BS EN 285:2006, A2:2009 [EN284 for small sterilizers]
PDA Technical Report No.1 (r2007) Validation of Moist Heat Sterilization Processes: Cycle Design, Development, Qualification and On-going Control (2007)
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KEY GUIDANCE FOR STERILIZATION
PDA TR 3 Validation of Dry Heat Sterilization and Depyrogenation Cycles (Original and 2013 revision)
PDA TR 7 Depyrogenation (1981)
PDA TR 48 Moist Heat Sterilizer Systems: Design, Commissioning, Operation, Qualification and Maintenance (2010)
PDA TR 61 Steam in Place (2013)
ISO 13408-2006(r) Aseptic Processing of Health Care Products – Part 5 Sterilization in Place (2012)
ISO 14160 Sterilization of Health Care Products – Liquid Chemical Sterilizing Agents…. (2011)
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KEY GUIDANCE FOR STERILIZATION
ISO 17665-1 Sterilization of Health Care Products – Moist Heat – Part 1 – Requirements for the development, validation, and routine control of a sterilization process for medical devices (2006)
ISO 17665-3 Sterilization of Health Care Products – Moist Heat – Part 3 – Guidance on the Designation of a Medical Device to a Product Family and Processing Category for Steam Sterilization (2013)
ISO 20857 Sterilization of Health Care Products – Dry Heat – Requirements for the development, validation and routine control of a sterilization process for medical devices (2010)
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KEY GUIDANCE FOR STERILIZATION
ISO 25424 Sterilization of medical devices – low
temperature steam and formaldehyde –
Requirements of development, validation and
routine control of a sterilization process for
medical devices (2009)
ISO 11137 Sterilization of Health Care Products
Package
USP 1229 series of documents on sterilization
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Contact Information
www.excellpharma.com
jeannemoldenhauer@gmail.com
Office: +1.847.837.8191
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