Validation of Integrated line by Media Fill Test

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Validation of Integrated line by Media Fill Test
A Seminar On
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INDEX

• Introduction
• What is media fill test ?
• Principle of media fill test
• Protocol
• Validation
• Objectives
• Scope
• Responsibilities
• Pre-requisites
• Equipment/ system description
• Study design
• Procedure

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Media Fill Test
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What is Media Fill Test ?

• Aseptic media fill test is used to quantify the
  aseptic technique of compounding personnel or
  processes and to insure that the processes used
  are able to produce a sterile product without
  microbial contamination
• During this test microbiological growth medium
  such as Soybean Casein Digest Medium (SCDM) is
  substituted for the actual drug product to
  simulate admixture compounding
• The final container is then incubated and
  checked for turbidity which indicate the
  microbial contamination

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Principles of Media Fill

• Why the validation of aseptic process is required
  by pharmaceutical regulations?
• A sterile product is defined as free of viable
  organisms
• As it is not practical examine every unit for
  confirmation of sterility.
• All efforts are made to minimise the risk of
  contamination (finishing, HVAC, pressure
  differentials, cleaning procedure, monitoring
  programme)

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Principles of Media Fill

• Despite of such measures, contamination is an
  ever-present danger because aseptic processing is
  a process being operated in a controlled but not
  sterile- environment and sample numbers are too
  small so that only gross contamination is likely
  to be detected
• So the sterility of the product is major
  requirement, But the sterility test of the whole
  batch is not possible to check whole batch
  because it is destructive method.
• It is better to validate the integrated line by
  media fill test

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Media Fill Protocol

• Number and frequency of runs
• Medium culture (to replace the product)
• Number of units filled
• Container (vial) size
• Fill volume
• Line speed (or filling speed)
• Duration of fill
• Operators shifts
• Monitoring activities
• Interventions both routine and non-routine
• Incubation method
• Acceptance criteria

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Validation of Integrated line by Media Fill test
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• OBJECTIVE
• The Objective of validation protocol is to
  establish documented evidence that the process
  employed for aseptic processing of Parenterals
  liquid/Ophthalmic solution will produce the
  desired results consistently, within the
  specified acceptance limits, when performed as
  per the latest Standard Operating Procedures.
• SCOPE
• The Validation protocol describes the procedure
  for the total Process Simulation (Media Fill) for
  integrated line.

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RESPONSIBILITIES
Sr. no . Responsibility Name of the department
1 Preparation of Protocol QC
2 Provision of qualified personnel to assist in the protocol preparation and execution QC, QA, Production and Maintenance
3 Verification of Protocol QC and Production
4 Approval of protocol QA
5 Final determination of System Acceptability QA
6 Review and assembling of data into a final report QA

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PREREQUISITES PREREQUISITES PREREQUISITES
PREREQUISITES PRE-REQUISITES

• Approved Soybean casein digest broth
• Environmental Monitoring of manufacturing areas
  by Plate Exposure, Air sampling and surface
  monitoring procedures and its SOPs.
• Qualified and validated manufacturing equipments,
  system facility (i.e. HVAC, water, compressed
  gases) CIP and SIP procedures.
• Trained operating personnels.
• Approved BMR for media fill trial.

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EQUIPMENT / SYSTEM DESCRIPTION

• Location Manufacturing Area integrated line (
  Mixing room and filling room)
• Equipments Mixing Tank, Holding Tank, Filtration
  housings, connected product line and FFS
  machines

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IDENTIFICATION OF CRITICAL CONTROL MONITORING
PARAMETER

• Check and ensure that-
• The equipment and system facility is validated.
• The HVAC system, compressed air, CIP and SIP
  procedures are qualified.
• All operations, cleaning/sanitization procedures
  are established and operating personnel are
  trained.
• Media used for Process Simulation is passed for
  GPT
• The WFI used for preparation of batch is complied
  to USP/IP

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STUDY DESIGN

• Worst Case Consideration
• Frequency, Duration, Number of runs Fill
  Volume
•  Environmental Consideration
•  Media
•  Incubation and examination of filled units
• Interpretation of Test Result

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STUDY DESIGN

• Worst Case Consideration
• Allow maximum number of personnel in the aseptic
  processing area , including the maintenances
  and house keeping personnel  
• Increased the time period to start the filling
  operation
• Increase the Duration of the media fill trial
  than that required for routine manufacturing
  operation.
• Simulating Process / Power breakdown during the
  process simulation test
•  Shift changes and breaks

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STUDY DESIGN

• Frequency, Duration, Number of runs Fill
  Volume
• Must be performed on semi-annual basis for each
  aseptic process and additional media fill trials
  should be performed in case of any change in
  procedure, practices or equipment configuration .
• Filled units in Media Fill run should be 10,000
  units or more. Fill minimum 3000 units in each
  production shift.
• The duration of Media Fill run must cover all the
  three operational shifts in each run turn by turn
  including worst cases as stated in steps
•  Fill volume for Media Fill run for SVP is 10 ml.

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STUDY DESIGN

• Environmental conditions
• Cleaning of Area must be done by using routine
  cleaning agent and disinfectant solution, as per
  latest SOP
• Microbiological Environmental Monitoring should
  be carried out by -
• Settle plate
• Air sampling
• Swab test and
• personnel monitoring as per the latest SOP.

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STUDY DESIGN

•   Media
• Soybean Casein Digest Medium, manufactured by Hi
  Media Laboratories should be used for Media fill
  trial
• The media must be passed the test for GPT as per
  SOP No. APL/QC/SOP/185 to promote the growth of
  gram-negative and gram-positive bacteria and
  yeast and molds
• For anaerobic microbs Fluid Thioglycollate
  Medium (FTM) is used

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STUDY DESIGN

•  Incubation and examination of filled units
• Incubate all media filled units in normal
  position after leak test at of 20 to 250C for 7
  days. Incubation temperature should be maintained
  within 22.5 2.50C .
• After completion of 7 days Incubation at 20 to
  250C, invert the units and incubate them at
  30-350C for next 7 days. Incubation temperature
  should be maintained within 32.52.50C .
• Each media filled unit should be examined by
  trained Microbiologist after 3rd day, 7th day,
  10th day and 14th day.
• All suspect units identified during the
  observation should be brought to the immediate
  attention of the QC Microbiologist.

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STUDY DESIGN

• Interpretation of Test Result
• Any contaminated unit should be considered
  objectionable and investigated. The microorganism
  should be identified to species level.
• The investigation should survey the possible
  causes of contamination.
• When filled units up to 10000, one contaminated
  unit should result in an investigation, including
  consideration of a repeat test.

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VALIDATION PROCEDURE

• Main steps for the Validation of the integrated
  line by media fill test
• Cleaning of the line
• Dispensing of Soybean Casein Digest Medium for
  150 L batch size
• Batch Preparation 150 L
• Filling And Sealing
• Incubation and Examination of Media Filled Units
•  Interpretation of Results

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VALIDATION PROCEDURE

• Cleaning of the SVP line
• Carry out cleaning of SVP mixing tank and holding
  tank along with product line and bottle pack
  machine as per respective SOP for CIP.
• At the end of cleaning, collect last rinses
  sample from sampling point and send to QC
  department with written information for testing
  of previous product traces.
•   After getting approval report from QC, affix
  status label on the tank READY FOR
  STERILIZATION.
• Immediately carry out the sterilization of SVP
  holding tank along with final filter and product
  line of bottle pack machine as per respective
  SOP.

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VALIDATION PROCEDURE

• Dispensing of Soybean Casein Digest Medium for
  150 L batch size
• Enter to dispensing room as per SOP for entry
  exit procedure to dispensing area.
• Check for the clearance of the area from any
  unwanted materials. Check for the cleanliness of
  the area, LAF, weighing pan as per checklist. Put
  ON the reverse LAF unit 15 minutes before
  dispensing of material.
• Check the availability of clean containers,
  pressure differentials, and temperature
  humidity should be not more than 250C and 45 to
  60 RH respectively.

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VALIDATION PROCEDURE

• Calibrate the balance as per SOP of Balance
  Calibration.
• Take the Approved Soybean Casein Digest Medium
  in pre-dispensing room, place on SS pallet and
  check the label of container for correctness and
  Approval of material.
• Transfer the material to Dispensing room, place
  the empty clean container on the balance and
  record the tare weight. Press ZERO of the
  balance and weigh the required quantity of
  material, note the weighed material and then
  remove the container from balance and press Zero.
• Close the dispensed material, affix the weighing
  tag and transfer the material in dispensed
  material storage room.

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VALIDATION PROCEDURE

• After dispensing, put OFF the balance and LAF.
  Clean the surrounding area, balance and spray
  with 70 IPA solution.
• Reseal the original container and shift to their
  original place.
• Batch Preparation 150 L
• Ensure that the area and product line is clean
  and free from the traces of previous product.
• Recheck gross weight of Soybean Casein Digest
  Medium (SCDM) to be used for manufacturing and
  ensure that they match as per entries made in the
  BMR weighing sheet.

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VALIDATION PROCEDURE

• Check the status board affixed on the tank READY
  FOR USE, also verify the records and ensure that
  the bottom outlet valve of the mixing tank is
  closed.
• Send the entry point sample of WFI from the user
  point to QC department for testing along with
  BMR.
• On approval of WFI sample from QC department,
  affix a status board on the Mixing tank UNDER
  MANUFCTURING with Product name and B. No.
• Collect approx 50 L water for injection at 80 to
  850C in a manufacturing tank fitted with stirrer.
• Start the stirrer and add SCDM through the
  mainhole of the tank.

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VALIDATION PROCEDURE

• Continue stirrer for complete dissolution of
  ingredients.
• Stop the stirrer.
• Make up the volume to the 150 L with water for
  injection.
• Start the stirring for complete dissolution of
  SCDM and homogeneous bulk solution (generally
  required 10 minutes).
• Collect sample of bulk solution in a sterile
  sampling bottle and send it to QC for testing of
  color clarity, pH and bioburden along with bulk
  intimation slip.
• After getting clearance of bulk analysis from
  Quality Control, start the filtration from mixing
  tank to Holding tank of line with the help of
  pump.

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VALIDATION PROCEDURE

• After getting clearance of bulk analysis from
  Quality Control, start the filtration from mixing
  tank to Holding tank of line with the help of
  pump.
• Perform the bubble point test of the final filter
  after holding tank as per SOP of Bubble point
  test.
• Filling And Sealing
• Start the filtration from holding tank to FFS
  machine using pump.
• Drain one buffer tank approx 1.3 liters of bulk
  solution from filling nozzle to eliminate any
  possibility of dilution of bulk by condensates in
  product line of the machine post SIP.

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VALIDATION PROCEDURE

• Check online cartridge filter integrity test as
  per its respective SOP.
• Start Machine line and discard initial 15 shots.
• Collect first cassette of vials from next shot
  and send the sample with written information to
  QC for testing.
• Arrange the out coming cassettes of vials
  sequentially in vacuum chamber tray and verify
  the results of testing from QC department.
• Now start the filling and sealing continuously
  as per SOP for Filling and sealing.

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VALIDATION PROCEDURE

• Collect the filled and sealed containers coming
  out of the filling area in plastic crates.
• During filling operation keep the filled ampoules
  separately for each breakdown, shift change,
  power breakdown, stoppage etc and assign lot
  number.
• Arrange the cassettes of vials lot wise in SS
  trays vertically in vacuum leak testing chamber
  tray and carry out the leak testing at 650 720
  mm Hg for 30 minutes. Do not use the leak vials
  for further media fill study.
• After leak test, transfer the goods vials in the
  clean plastic crates horizontally in cassette
  from one above the other, lot wise separately

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VALIDATION PROCEDURE

• Incubation and examination of filled units
• Incubate all media filled units in normal
  position after leak test at of 20 to 250C for 7
  days. Incubation temperature should be maintained
  within 22.5 2.50C .
• After completion of 7 days Incubation at 20 to
  250C, invert the units and incubate them at
  30-350C for next 7 days. Incubation temperature
  should be maintained within 32.52.50C .
• Each media filled unit should be examined by
  trained Microbiologist after 3rd day, 7th day,
  10th day and 14th day.
• All suspect units identified during the
  observation should be brought to the immediate
  attention of the QC Microbiologist.

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VALIDATION PROCEDURE

• Interpretation of Results
• When filling fewer than 5,000 units, no
  contaminated units should be detected. 
• When filling 5,000 to 10,000 units
• One contaminated unit should result in an
  investigation, including consideration of a
  repeat media fill
• Two contaminated units are considered cause for
  revalidation, following investigation.
• When filling more than 10,000 units
• One contaminated unit should result in an
  investigation
• Two contaminated units are considered cause for
  revalidation, following investigation. 

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REFERENCES

• Syed Imtiaz Haider, Validation Standard
  Operating Procedures 314-321
• R. A. Nash and A. H. Wachter Pharmaceutical
  Process validation Third edition
• Agalloco James, Carleton J. Fredric Validation
  of Pharmaceutical Processes Third edition
• Pharmaguideline.blogspot.com
• www.milipore.com
• www.nsdl.niscair.res.in/bitstream

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