THERMAL VALIDATION 5 OVERCOME THE CHALLENGES · PDF fileOVERCOME THE CHALLENGES Jeanne...

THERMAL VALIDATION –

OVERCOME THE CHALLENGES

Jeanne Moldenhauer

Excellent Pharma Consulting

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OVERVIEW OF PRESENTATION

Expectations for Thermal Validation

How to Document the Validation Process

Dealing with Problems

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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

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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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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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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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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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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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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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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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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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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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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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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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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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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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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


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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• 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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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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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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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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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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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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Advantages

• Simplicity

• Lack of mechanical complexity

• Reproducibility

• Overall efficiency

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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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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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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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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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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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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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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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MOIST AND DRY HEAT

STERILIZATION

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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MOIST AND DRY HEAT

STERILIZATION

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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MOIST AND DRY HEAT

STERILIZATION

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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MOIST AND DRY HEAT

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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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MOIST AND DRY HEAT

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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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MOIST AND DRY HEAT

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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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MOIST AND DRY HEAT

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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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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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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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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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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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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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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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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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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

[email protected]

Office: +1.847.837.8191

http://www.excellpharma.com/

mailto:[email protected]

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