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                Seminar
                  On

Validation of Integrated line by Media Fill
                   Test
                                  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
2                                         25 February 2012
Media Fill Test
                 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

4                                                          25 February 2012
               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)

5                                                   25 February 2012
                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
6                                                         25 February 2012
                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
7   Acceptance criteria                           25 February 2012
Validation of Integrated line by Media
                Fill test
 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.


9                                                         25 February 2012
                         RESPONSIBILITIES
     Sr. no .                    Responsibility                     Name of the
                                                                    department

     1          Preparation of Protocol                             QC

     2          Provision of qualified personnel to assist in the   QC, QA, Production
                protocol preparation and execution                  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



10                                                                        25 February 2012
                   PRE-REQUISITES
     Approved Soybean casein digest broth
     Environmental Monitoring of manufacturing areas by Plate
     Exposure, Air sampling and surface monitoring procedures and
     its SOP’s.
     Qualified and validated manufacturing equipments, system
     facility (i.e. HVAC, water, compressed gases) CIP and SIP
     procedures.
     Trained operating personnel’s.
     Approved BMR for media fill trial.


11                                                   25 February 2012
                 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




12                                                       25 February 2012
     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



13                                                              25 February 2012
                       STUDY DESIGN


     1. Worst Case Consideration
     2. Frequency, Duration, Number of runs & Fill Volume
     3.  Environmental Consideration
     4. Media
     5. Incubation and examination of filled units
     6. Interpretation of Test Result:




14                                                   25 February 2012
                          STUDY DESIGN
 1. Worst Case Consideration
 a.   Allow maximum number of personnel in the aseptic processing
      area , including the maintenances and house keeping personnel
 b.   Increased the time period to start the filling operation
 c.   Increase the Duration of the media fill trial than that required
      for routine manufacturing operation.
 d.    Simulating Process / Power breakdown during the process
      simulation test
 e.    Shift changes and breaks


15                                                        25 February 2012
                          STUDY DESIGN
 2. Frequency, Duration, Number of runs & Fill Volume
 a. 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 .
 b. Filled units in Media Fill run should be 10,000 units or more.
    Fill minimum 3000 units in each production shift.
 c. 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
 d. Fill volume for Media Fill run for SVP is 10 ml.


16                                                       25 February 2012
                           STUDY DESIGN
 3. Environmental conditions
 a.   Cleaning of Area must be done by using routine cleaning agent
      and disinfectant solution, as per latest SOP

 b.   Microbiological Environmental Monitoring should be carried out
      by -
      •   Settle plate
      •   Air sampling
      •   Swab test and
      •   personnel monitoring as per the latest SOP.


17                                                       25 February 2012
                       STUDY DESIGN
 4.    Media:
 a.   Soybean Casein Digest Medium, manufactured by Hi Media
      Laboratories should be used for Media fill trial

 b.   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

 c.   For anaerobic microbs Fluid Thioglycollate Medium (FTM)
      is used

18                                                25 February 2012
                          STUDY DESIGN
 5.   Incubation and examination of filled units:
 a. 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 .
 b. 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 32.5±2.50C .
 c. Each media filled unit should be examined by trained
    Microbiologist after 3rd day, 7th day, 10th day and 14th day.
 d. All suspect units identified during the observation should be
    brought to the immediate attention of the QC Microbiologist.
19                                                         25 February 2012
                          STUDY DESIGN
 6. Interpretation of Test Result:
 a.  Any contaminated unit should be considered objectionable and
    investigated. The microorganism should be identified to species
    level.
 b. The investigation should survey the possible causes of
    contamination.
 c. When filled units up to 10000, one contaminated unit should
    result in an investigation, including consideration of a repeat test.




20                                                         25 February 2012
                     VALIDATION PROCEDURE
         Main steps for theValidation of the integrated line by
          media fill test

     1.     Cleaning of the line
     2.     Dispensing of Soybean Casein Digest Medium for 150 L batch
            size
     3.     Batch Preparation 150 L
     4.     Filling And Sealing
     5.     Incubation and Examination of Media Filled Units
     6.      Interpretation of Results


21                                                         25 February 2012
 
                     VALIDATION PROCEDURE
1. 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.



22                                                                25 February 2012
                    VALIDATION PROCEDURE
2. 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.

23                                                            25 February 2012
                    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.
24                                                              25 February 2012
                  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.


3. 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.

25                                                           25 February 2012
                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.

26                                                         25 February 2012
                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.
27                                                         25 February 2012
                  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.
     4. 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.
28                                                            25 February 2012
                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.

29                                                         25 February 2012
                 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
30
     separately                                               25 February 2012
                  VALIDATION PROCEDURE
     5. Incubation and examination of filled units:
     a.  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 .
     b. 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
        32.5±2.50C .
     c. Each media filled unit should be examined by trained
        Microbiologist after 3rd day, 7th day, 10th day and 14th day.
     d. All suspect units identified during the observation should be
        brought to the immediate attention of the QC Microbiologist.
31                                                         25 February 2012
                      VALIDATION PROCEDURE
     6.    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,
32          following investigation.                               25 February 2012
                     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



33                                                 25 February 2012
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