CURRENT CONCEPTS OF ASEPTIC PROCESS SIMULATION · PDF file · 2015-08-19CURRENT...

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© 2015 PAREXEL INTERNATIONAL CORP. / 1 BOSTON, MASSACHUSETTS DILIP ASHTEKAR, PH.D. PRINCIPAL CONSULTANT STRATEGIC COMPLIANCE SERVICES CURRENT CONCEPTS OF ASEPTIC PROCESS SIMULATION TESTS (MEDIA FILL)

Transcript of CURRENT CONCEPTS OF ASEPTIC PROCESS SIMULATION · PDF file · 2015-08-19CURRENT...

Page 1: CURRENT CONCEPTS OF ASEPTIC PROCESS SIMULATION · PDF file · 2015-08-19CURRENT CONCEPTS OF ASEPTIC PROCESS SIMULATION TESTS ... Requirements of Aseptic Process Simulation ... process

© 2015 PAREXEL INTERNATIONAL CORP. / 1

BOSTON, MASSACHUSETTS

DILIP ASHTEKAR, PH.D.

PRINCIPAL CONSULTANT

STRATEGIC COMPLIANCE SERVICES

CURRENT CONCEPTS OF ASEPTIC

PROCESS SIMULATION TESTS

(MEDIA FILL)

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© 2015 PAREXEL INTERNATIONAL CORP. / 2

DISCLAIMER

The contents of this presentation represent my

personal views and opinions. These are based

on my experience. They are not the views or

opinions of either PAREXEL International or

USP

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Purpose of Aseptic Process Simulation (APS)

• Ensure that qualified process and personnel can aseptically

produce drug product that consistently and reliably meets the

required quality

• Assess the capability of facility, personnel, equipment, procedures

and process controls to aseptically produce a sterile drug product

• Demonstrate acceptability of appropriately designed changes

• Assess the robustness of the overall process when challenged with

worst-case microbial contamination risk

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Continued: Purpose of Aseptic Process Simulation

• Identify weaknesses of the process

• Evaluates proficiency of aseptic processing personnel

• Demonstrates the appropriateness of operating practices used in

support of aseptic processing

• Comply with current GMP requirements

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Requirements of Aseptic Process Simulation (APS/Media

Fill)

• The APS should closely simulate routine aseptic manufacturing

operations incorporating worst-case conditions that provide a

challenge to routine manufacturing operation

o Use of sterile microbial growth supportive medium

o Compounding

o Sterile filtration

o Aseptic packaging into sterile containers

• Entire sterile manufacturing process should be simulated to assure

the sterility of the aseptically filled drug product

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Requirements of Aseptic Process Simulation

• Media Fill includes simulation of manufacturing process from the

point of sterilization of components, product, product contact

surfaces and sealing of the filled units

• Media Fill includes all aseptic activities performed during dosage

form compounding

• The complexities and activities in the APS should be similar to

routine process

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Requirements of Aseptic Process Simulation

• All personnel who are authorized to enter the aseptic processing

room during manufacturing should participate in at least one APS

run/year

• Participation should be consistent with the nature of each

operator’s duties during routine production

• Each processing line should be requalified with a routine APS semi-

annually to assess the state of control of the aseptic process

• For multiple presentations on a given fill line a bracketing

requalification approach can be employed

o The bracketing approach can be based on the frequency of commercial

production and the contamination risk levels

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Media Selection for the Performance of Media Fill

• Media simulations for the aerobic processes are performed using

Soybean Casein digest medium (SCDM) or tryptic soy broth (TSB)

• Media simulations for the anaerobic processes are performed using

alternate fluid thioglycollate medium, in addition to aerobic

evaluation in SCDM/TSB

• For a typical aerobic process, anaerobic evaluation may be

considered if the frequency/recovery rate of anaerobic

microorganisms is high in routine environmental monitoring

• Facultative anaerobic organisms are recovered with high frequency

exclusively in FTM medium during sterility testing

• Anaerobic media simulations are performed for oxygen sensitive

products

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Media Sterilization for the Performance of APS: Sterile

Filtration Requirements

• The sterile filtration process should use duel filtration system

• Media sterilization by filtration should be performed when normal

production process requires aseptic handling of the filter and

sterile filtration

• Inclusion of each type of filter in APS program is not required if

aseptic handling and processing is comparable for different types

of filters

• When aseptic handling and aseptic process are different for a filter,

it should be included in APS and requalified at least once per year

• The sterilizing grade filter should be sized appropriately to process

the required worst-case largest volume of media

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Media Sterilization for the Performance of APS: Sterile

Filtration Requirements

• The selected filters should have sufficient capacity to remove

substantial amounts of particles and bioburden

• Sufficient quantity of media should be prepared to account for fluid

losses during filtration e.g. filter conditioning with media

• Sufficient quantity of media should also be prepared to cover the

fluid path to the filling machine and aseptic connections to

effectively simulate the normal production operations

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Requirements for Sterile Filtration

• When same type of filter is used, filtration process parameters

should be consistent with those used in normal production

• It is recommended to sterile filter media into a sterile holding tank

prior to start of the Media Fill

• The hold time between compounding and filtration of media into a

sterile vessel should be minimize

• Heat sterilization can be used when simulation of filtration is not

applicable

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Preparation of Media for Aseptic Process Simulation

• Gamma-irradiated nutrient medium should be used to reduce risk of

mycoplasma sp. contamination

• Media sterilization processes should not impact the growth

promoting properties of the media used

• Media bioburden should be determined prior to sterilization

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Microbiological Environmental Monitoring (EM)

• Environmental monitoring performed during APS should be

consistent with that performed during routine manufacturing

o Routine EM SOPs, sapling requirements and practices should be followed

o The monitoring should include set-up activities, during filling, intervention set-

up, personnel monitoring and end of the fill

o Demonstrates the state of environmental control during the APS runs

• Post-gowning personnel monitoring should be performed that is

consistent with that performed during routine manufacturing

• Environmental monitoring excursions should be investigated

o Investigation is needed, even if the Media Fill with an EM excursion passes

o Alert or action level excursion do not warrant conducting routine APS process

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Inert Gassing

• Nitrogen or other inert gases are used in processing of oxygen

sensitive products

• Nitrogen or other inert gases are also used to create overlays,

positive pressure for solution transfer and purging purposes

• If use of inert gases is the part of the routine process, gassing must

be performed during Media Fills

o In case of aerobic Media Fills, sterile, filtered compressed air should be

used in lieu of inert gases

o In case of anaerobic Media Fills, sterile filtered inert gas should be used

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Frequency and Numbers of Aseptic Process Simulation

Runs

• The number and type of process simulations to be performed

should be based on the risk assessment of process or significant

changes to the overall process

• For qualifying new facility, process/product or filling line, three

consecutive successful Media Fill runs are required

• For a Qualified facility, process/product or filling line Media Fill (one

run) is performed semiannually

o Periodic requalification of the process provides assurance that the cumulative

effect of changes do not impact the effectiveness of the qualified overall process

o Additional Media Fills may be required depending on risk assessment and extent

of changes to procedures, equipment configuration, facility or practices

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Duration of Aseptic Process Simulation and Number of

Units Filled

• Duration and Number of units filled should be sufficient

o To adequately challenge the aseptic process

o Operators that perform intervention

o To assess the capability of the processing environment

o To assess the potential microbiological impact of performing interventions

o Representative number of interventions should be consistent with normal

production, e.g. breaks, shift changes

o To accommodate the time operators spend without break in the clean room

• Justification for umber of units filled, duration and yield

• Alternate approaches

o Alternate between Media Filled and empty units

o Alternate between Media Filled units and WFI filled units

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Requirements for Simulation Run Sizes

Number of Units Filled

Production Batch

Description

Production Batch Size

( # Filled Units)

Minimum APS Batch Size

(# Filled Units)

Small scale ≤ 5,000 units ≤ 5,000 units

Mid-scale 5,000-10,000 units 5,000-10,000 units

Large scale > 10,000 units > 10,000 units *

Manual Fill Any Amount Same as production

batch size

• Sufficient number of units should be filled to mimic commercial production

conditions and ensure all defined interventions are assessed

• Sufficient number of units should be filled to accurately assess the potential for

commercial batch contamination

*For large commercial batches the number of units can be statistically determined

to represent the manufacturing process under normal conditions

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Compounding Process

• Non-aseptic equipment for compounding:

– If filtered quickly, compounding equipment used prior to the media sterilization

step is not required to be included in APS

• Aseptic compounding

o Compounding equipment should be included in the APS plan

o The frequency of inclusion of equipment should be based on risk assessment

o Equipment with the same design and construction materials cannot be

considered equivalent from APS perspective, and should be included in the

Media Fill process on a rotational basis if used after the sterilization step

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Continued: Compounding Process

• When dehydrated media powder is used to prepare the liquid

medium, it should be ensured that media is completely soluble in

WFI

• The amount of agitation required to dissolve the powder and time

required for complete dissolution should qualified

• Nutrient medium batches (dry powder or ready-to-use medium)

should be released by QA for use in APS

• The media batches should meet release specification (growth

promotion, pH and acceptance of the Certificate of Analysis)

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Continued: Compounding Process

• All routinely used aseptic manipulation should simulated e.g.,

sampling, aseptic connection etc.

• All aseptic manipulations performed during and the end of holding

period should be simulated, e.g. sampling, re-filtration and product

recirculation through the filter

• After media sterilization of the medium, further processing should

be consistent with that used in the actual batch

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Aseptic Filling Process: Set-up of the Filling Line

• The set-up of the filling line should be done according to routine

production practices and is considered as inherent interventions

o Set up process entails manual assembly of sterilized equipment

o Represents highest risk for contamination

o More manipulation of critical surfaces than subsequent processing

o The APS process should be designed to detect potential contamination risk from

set-up

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Aseptic Filling Process

• Line speed is rotated between the highest and slowest qualified

speed ranges

o Highest line speed for the smallest container (handling difficulty)

o Slowest line speed for the largest container (maximum opening)

• Worst-case filling speed can be defined based on risk assessment

for a specific container format

o The APS should be performed using worst-case filling speed for that specified

container format

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Aseptic Filling Process: Media Volume

• Container should contain sufficient medium to contact all interior

container-closure surfaces when container is inverted and swirled

• There should be sufficient amount of medium in the container to

detect microbial turbidity

• The amount of media should not be excessive to reduce oxygen

levels required for growth of aerobic organisms

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Worst-case Parameters

• Worst-case situations challenges the process. Conditions may be

on the edge of normal operating conditions

• Acceptable results of worst-case challenges offer greater

confidence and reliability of the system under routine conditions

• Worst-case situations should be pre-defined and based on process

and risk assessment

o Maximum holding time for equipment, equipment parts/components after

sterilization (clean hold)

o Longest duration of filling

o Maximum number of personnel performing APS activities

o Container closure configuration

o Line speed

o Interventions included in study

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Interventions

• Identification of intervention and their frequency can be determined

through the review of completed batch record, fill event log and

operator interviews

• Two Types of Interventions:

o Inherent Interventions are normal and planned activities that occur at

regular and planned intervals during aseptic processing, such as

equipment set up, expected weight adjustments, container/closure re-

supply, EM sampling

oCorrective interventions are performed to correct or adjust an aseptic

process and occur randomly and may not be part of every batch, such

as unscheduled actions for container breakage, closure jams, part

replacement, etc.

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Causes for Corrective Intervention

• Components with great variability either specification or

preparation that results in difficulties in further processing

• Poorly designed equipment that requires frequent adjustments or

difficult assembly

• Aging equipment

• Loosely defined setup procedure that results in variable

performance

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Frequency of Intervention

• Several approaches are available for assigning intervention

frequencies, required to be challenged in APS and justifying the

selected interventions

• Frequency and choice of interventions for APS should be

supported by a formal risk assessment and general quality risk

management concepts

• Review of completed batch record, fill event log and trending of

commercial lots

• Interventions can be categorized in various assessment categories

• Depending on the type of intervention, the frequency of

intervention can be determined mathematically or using statistical

methodology

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Frequency of Corrective Intervention

• Corrective Intervention should be captured in a Media Fill at least

once a year, where a portion may be performed the first half of the

year and the rest in the second half of the year per line

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Significance of Risk Assessment for Aseptic Processing

and APS

• Beneficial in designing an aseptic process

• Provides opportunities to assess product quality and patient safety

in APS study design

• Assume worst-case manufacturing scenarios, such as : container

size, configuration, line speed, batch size, operating conditions

• Provides opportunities for risk reduction through ongoing process

evaluation and improvement

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Use of Risk Based Approach for Designing Aseptic

Process Simulation

• Risk- includes impact of the hazard or unwanted event and its

likelihood of occurring and harming the patient

• Hazard in aseptic processing is loss of sterility and potential for

endotoxins

• Detection of unwanted event is unpredictable

• The risk assessment models for defining the frequency are based

on frequency, duration, complexity, proximity and criticality of

interventions

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Approaches for Determining the Frequency of Sterile

Component Replenishment: Mathematical Approach

• Mathematical approach can be employed to assess the frequency

for component replenishment interventions

o The frequency of the component replenishment interventions should be

representative number (worst-case) of aseptic additions performed in the normal

production run

o Mathematical approach provides opportunities to compare the component

(stopper, overseal, vials) replenishment frequencies associated with normal

commercial batch and Media Fill

o It provides opportunities assess the adequacy of component replenishment

frequency

o The calculation is based on the run size divided by the quantity per package

o The result should be rounded up to the nearest number to calculate percentage

Acceptance criteria: The minimum component (container and closure)

replenishment frequency should be ≥50% of the commercial batch

interventions in a shorter amount of time

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Frequency of Sterile Component Replenishment:

Mathematical Approach

ComponentQualified

Load Size

Calculated

Frequency

Commercial

Fill

Calculated

Frequency

Media Fill

Minimum

Frequency

Number of

Bags to

Achieve

Minimum

Frequency

(50%)

Minimum

Frequenc

y

Stoppers

Fixed

Load of

60K.

2,500 per

bag

60K÷2,500

per bag

= 24 bags

20K÷2,500

per bag

= 8 bags

34% 13 55%

Overseals

60K

3,000 per

bag

60K÷ 3,000

per bag

= 20 bags

20K ÷

3,000 per

bag

= 7bags

29% 10 50%

Proposed method for the determination of frequency for

components replenishment

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Determination of Frequency of Each Type of Intervention

Using Statistical Approach

• Data from batch records, batch related documents(fill log) and

commercial lots manufactured on a line should be statistically

analyzed

• The number of each type of intervention can be determined using

upper 95th percentile methodology

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Personnel Qualification: Initial Qualification

• Each person in the aseptic filling suite has the potential to

introduce microbial contamination

• Microbial contamination risk varies with specific job function

• Requirements for the qualification, de-qualification and

requalification of cleanroom personnel should be documented in a

formal SOP

• Must pass gowning certification requirements and should

successfully complete all the required training,

o cGMP, Gowning, basics of microbiology, good cleanroom practices and

operations, functions and relevant intervention procedure training

o Manufacturing process and APS training and/or EM sampling training

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Continued Initial Qualification: Demonstration of

Proficiency

• Successfully performing a qualification test entailing manual media

manipulation not associated with an APS

And/or

• Personnel should participate in a successful aseptic process

simulation run in which perform the same function(s) to the extent

that they will perform it during actual production at least once per

year

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Personnel Qualification: Periodic Qualification

• Personnel must participate in a successful APS run in which they

perform the same function(s) to the extent that they will perform it

during actual production at least once per year

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Loss of Qualification Status of Previously Qualified

Status

Conditions to lose qualification status

• Fail to qualify initial qualification

• Participate in a failed Media Fill and the failure was related to their

performance

• They perform in the cleanroom in a manner deemed unacceptable

• They fail to maintain gowning certification

• Conditions to Re-establish Qualification:

• Specific Deficiency (s) is properly corrected

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Incubation of Media Fill units and Growth Promotion

• All the filled and integral units must be incubated in a qualified

incubator for 7 calendar days at 20-25°C; followed by 7 calendar

days at 30-35°C

• Prior to incubation, units must be inverted or manipulated to ensure

internal surfaces are wetted with media

• Post 14 days incubation, growth promotion test is required

standard compendial organisms and representative in-house

isolates

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Inspection and Accountability of Media Filled Units

• Once the filling and capping operations phases are completed, all

filled units, are initially assessed by the manufacturing operator

o Non-integral units are rejected

• All integral Media Filled units are 100% inspected by qualified

personnel and the quantity 100% reconciled

• Before placing the Media Fill units into incubation; QC verifies the

quantity and quantities are 100% reconciled

• Qualified personnel in QC inspect at the end of seven days at

20-25 °C and at the end of the additional seven days at 30-35 °C

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Conclusions

• The complexities and activities in the APS should be similar to

routine process

• All personnel who are authorized to enter the aseptic processing

room during manufacturing should participate in at least one APS

run/year

• The number and type of process simulations to be performed

should be based on the risk assessment of process or significant

changes to the overall process

• Frequency and choice of interventions for APS should be based on

formal risk assessment and quality risk management concepts

• Frequency of interventions can be derived Mathematically or using

statistical methodology

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TAIPEI, TAIWAN

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