sop for Media Fill Study
1.1 To lay down a procedure for Media Fill Study.
2.1 This Standard Operating Procedure is applicable for the Aseptic process simulation with documentary evidence in Liquid injection block
3.1 Quality Assurance
To organize the Activity.
To prepare the Protocol and Report.
To arrange the validation /calibration of instruments required for Activity.
To organize the study in consultation with Engineering, Production & Quality Control.
To record the observation during activity and prepared report.
To make co ordination with production, Engineering & other involve department during activity.
To get approval of protocol and report.
3.2 Quality Control / Micro
To analyze the sample.
To prepare the Specification.
Responsible for carry out the analysis according as per Specification.
To check the compliance of preventive maintenance of Equipment & engineering support.
To provide utilities and supportive services validation
To initiate the validation study.
To prepare the Batch Record.
Responsible for carryout the activity / process as per Batch Record.
Concern department Head / Head QA
5.1.1 All the personnel involved in the Process Simulation Study (Media Fill) shall be appropriately Trained both in their job related activities and on the Process Simulation Study (Media Fill) Protocol.
5.1.2 All Major Equipments used for Process, Facility and Utility shall be verified for their Performance Qualification and Calibration.
5.1.3 Throughout the media fill run Good Manufacturing Practices and aseptic techniques shall be followed.
5.1.4 No special precautions / care shall be taken while execution of the media fill exercise (All the Steps / stages are to be performed as followed during normal Production Batches).
5.1.5 Precaution must be taken with respect to handling of media.
5.1.6 At any stage none of the filled unit shall be removed unless verified and authorized by QA.
5.1.7 The destruction of the left over media (Bulk) and of the filled units after inspection shall be done as per the respective SOP.
5.1.8 The media fill shall emulate the regular product fill situation in terms of equipment, processes, personnel involved and time taken for filling as well as for holding.
5.1.9 Where filling takes place over extended periods, i.e. longer than 24 hours (Worst Case Study), the process simulation test shall be extend over the whole of the standard filling period.
5.1.10 For process simulations sterile filtered air shall be used instead of inert gases, Nitrogen Flushing / Purging shall not be done at any stage (irrespective of the normal product requirement) as the Inert Gas will prevent the growth of aerobic microorganisms also for breaking a vacuum.
5.1.11 Where anaerobes are detected in the Environmental Monitoring or Sterility Testing, the use of an Inert Gas shall be considered for a Process Simulation, as Inert Gas is supporting the growth of Anaerobes.
5.1.12 Where a Liquid Nutrient Medium is used it shall be prepared in a similar manner to the product. The medium shall be dissolved in Water for Injection in a standard manufacturing vessel. If heat is required to dissolve it then only minimal heat shall be used.
5.1.13 The pH of the medium shall be measured and, if necessary, adjusted to bring it into the required range. The medium shall be aseptically filtered into an aseptic holding vessel using the normal production filter and processing procedure. In justified cases it may be also acceptable to sterilize the media.
5.1.14 All Aseptic Holding Vessels shall be covered by a Process Simulation Test on a regular basis unless a Validated, Pressure Hold or Vacuum Hold Test is routinely performed.
5.2 PROCESS SIMULATION TEST CONDITIONS:
5.2.1 Test Performance:
5.2.2 As per scheduled date production person give the requisition to issue the BMR of media fill.
5.2.3 Prior to media fill start QA head will give training to all concern person as per protocol.
5.2.4 Do the process simulation as per approved protocol.
5.2.5 Only trained person can perform the media fill validation
5.2.6 Production person carry out all activity as per BMR throughout shift.
5.2.7 Micro person/IPQA person will do all the sampling as per sampling plan.
5.2.8 All the intervention will cover during filling as per protocol.
5.2.9 Compressed air shall be used instead of nitrogen.
5.2.10 Collect the Ampoule as per plan intervention with tray number.
5.2.11 The Process Simulation Test shall be followed as closely as possible the routine aseptic Manufacturing Process and include all critical subsequent Manufacturing Steps.
5.3 SELECTION OF MEDIA:
5.3.1 The Criteria for selection of Microbiological Growth Support Medium (MGSM) include:
Low Selectivity, Clarity, Medium Concentration and Filterability.
5.3.2 Ability to support growth of a wide range of microorganisms:
The medium should have a low selectivity i.e. be capable of supporting growth of a wide range of microorganisms such as Bacillus subtilis, Staphylococcus aureus, Candida albicans, Aspergillus brasiliensis and Environmental Isolates (e.g. Soya Bean Casein Digest).
5.3.3 Growth Promotion Test (GPT) to demonstrate that the medium supports recovery and growth of low numbers of microorganisms, i.e. 10-100 CFU/ unit or less.
5.3.4 Growth Promotion Testing of the media used in simulation studies to be carried out on completion of the incubation period to demonstrate the ability of the media to sustain growth if contamination is present. Growth should be demonstrated within 5 days at the same incubation temperature as used during the simulation test performance.
5.3.5 Clarity: The medium should be clear to allow for ease in observing turbidity.
5.3.6 Medium Concentration: Recommendations of the supplier shall be followed unless alternative concentrations are validated to deliver equal results.
5.3.7 Filterability: If a filter is used in the Aseptic Manufacturing Process, the medium should be capable of being filtered through the same grade as used in production.
5.3.8 Soya Bean Casein Digest Medium is used as Microbiological Growth Support Medium (MGSM) for Process Simulation Study.
5.3.9 The concentration of Soya Bean Casein Digest Medium (SCDM) is selected 3% w/v in Water for Injection on the basis of above selection parameters and Pre GPT Studies performed.
5.4 SELECTION OF PROCESS SIMULATION DILUENT:
5.4.1 A Process Simulation DILUENT is the material which enhances the Growth Promotion Properties of a Microbiological Growth Support Medium.
5.4.2 Various Process Simulation Diluents are available which can be used for Process Simulation Study (Media Fills) of Liquid Injection.
5.5 INCUBATION TEMPERATURE, CONDITIONS AND OBSERVATION:
5.5.1 After completion of process send the vials & Ampoule to micro department for incubation.
5.5.2 Incubate the filled vials at 20°C -25°C for 7 days for fungal growth and next 7 days 30°C -35°C for bacterial growth.
5.5.3 Visual observation will do daily at 20°C -25°C for 7 days and next 7 days at 30°C -35°C.
5.5.4 After the incubation period of the media-filled container will be examined for microbial growth, evidence of container/closer damage which might compromise the integrity of the packaging system. Damaged container should not be included as failures (positive) when evaluating results. Acceptance criteria should follow as per protocol.
5.5.5 After completion of incubation time and completion of relevant activities the media filled vials & Ampoule shall be de-activated by sterilizing the media filled vials & Ampoule by moist heat at 1210C for 15 minutes.
5.6 DESTRUCTION OF MEDIA:
5.6.1 After completion of observation after 14 days of incubation, destruction of vials & Ampoule shall be done by opening vials & Ampoule and media shall be poured in container having 5% Savlon Solution.
5.6.2 The vials & Ampoule shall be kept in another container having 5% Savlon Solution.
5.6.3 Rubber Stoppers & Seals shall be kept in another Container having 5% Savlon solution.
5.6.4 Leave it for one hour, then transfer the solution to Effluent Treatment Plant for its disposal and vials & Ampoule shall be sent to scrap yard for destruction by crushing.
5.7 FREQUENCY MEDIA FILL :
5.7.1 Media fill validation shall be performed twice in a year ± 30 days
5.8 REVALIDATION CRITERIA: Media fill shall be revalidated under following conditions:
5.8.1 Any major changes in facility or in Filling line machine.
5.8.2 Any modification of sterilization parameters.
5.8.3 After any major maintenance or major breakdown in vial & Ampoule falling machine or in HVAC system.
5.8.4 Periodic revalidation shall be carried out at least 1 run with each vial & Ampoule size in every 6 months as per frequency.
5.8.5 Any new introduction of Ampoule / Vial size.
5.9 NUMBERING SYSTEM FOR BATCH MANUFACTURING RECORD:
Batch manufacturing record shall bear a specific number as below:
FPPL: Plant Code
/ : Indicates Separator
BMR : Batch manufacturing record
/ : Indicates Separator
MF: Media Fill
/ : Indicates Separator
PI: Production Injection
001 : Indicates Serial Number 001, 002, 003 … etc.
– : Indicates Dash
00: Indicates Revision Number starts from 00, 01, 02, 03…..etc.
Batch manufacturing record Number shall be pre-printed in Header part of the document.
5.10 MEDIA FILL BATCH NUMBERING SYSTEM:
Batch numbering system shall bear a specific number as below:
MF: Media Fill
– : Indicates dash
001 : Indicates Serial Number 001, 002, 003 … etc.
5.11 FAILURE INVESTIGATION AND CORRECTIVE ACTION:
5.11.1 Investigate on Quality Control level and ensure the procedure and handling of sterility of containers.
5.11.2 A contaminated container shall be carefully examined for any breach in the integrity of the container system.
5.11.3 Damaged containers shall not be considered an evaluation (acceptance) of an aseptic processing capability of the process. However, a ampoule that is broken during incubation should be addressed.
5.11.4 All positives from integral containers shall be identified to at least genus and species whenever possible.
5.11.5 Identify the contaminant and compare the result to the database of the organisms most recently identified.
5.11.6 Processing records should be reviewed. Critical systems shall be reviewed and documented for changes.
5.11.7 Calibration records shall be checked.
5.11.8 All HEPA Filters in the Filling Area shall be inspected and decertified if warranted.
5.11.9 Personnel involved in the media fill shall be assessed to assure the proper training was provided.
5.11.10 Validation and change control records shall be reviewed for any procedure or process changes.
5.11.11 A full risk analysis should be performed.
5.11.12 A media failure signals an underlying weakness of the system or the process.
5.11.13 The final investigation report should contain the following:
A summary of the occurrence
All systems investigated, not just the systems tied to the failure
A conclusion as to the cause and supporting documentation
Potential effect on previous batches since last media fill
Outcome of additional process simulation tests if they were performed
5.11.14 This investigation needs to be completed in a timely fashion. It may be necessary to issue an interim report.
5.11.15 Three consecutive successful process simulations are required to qualify a new or significantly revised change aseptic line or area.
5.11.16 If assignable cause found revalidation will be consider of media fill.
5.11.17 If assignable cause not found treated as new facility and validate the process simulation study.
5.11.18 Invalidation of a Media Fill:
A media fill can only be invalidated for reasons that would absolutely result in the discard of a Product Batch. These conditions must be filled out explicitly and the written justification for the media fill discard and the decision shall be made on the day of execution.
Under following condition Process Simulation is considered invalidated:
Failure of Growth Promotion of media provided there are no positive units in the process simulation.
Failure of physical conditions in the aseptic processing area (Power Outage, Pressurization Loss, HEPA Filter Failure)
Failure of operators to follow proper procedures not permitted in normal production which would lead to
the discontinuation of a batch and rejection of all vials filled to that point.
Clear documentation of the event that caused the discontinuation shall be performed and maintained. Process simulations can be invalidated for any or all of the above reasons.
5.12 Media Fill Planner shall be prepared by Quality Assurance Department as per format shown in Annexure-I and shall be checked by
Operating Manager & approved By Head QA.
5.13 Execution Details shall be filled by Concerned Department Head & shall be verified by Head QA in format as shown in Annexure-II.
5.14 Failure investigation shall be carried out as per format shown in Annexure-III (Media Fill Failure Investigation Report).
|S. No.||Abbreviations used||Full form of Abbreviation used|
|2.||SOP||Standard Operating Procedure|
|3.||HOD||Head of department|
|4.||ETP||Effluent treatment plant|
7.0 ATTACHMENTS (ANNEXES) :
7.1.1 Annexure-I Process Simulation Study (Media Fill) Planner
7.1.2 Annexure-II Process Simulation Study (Media Fill) Execution Record.
7.1.3 Annexure-III Media Fill Failure Investigation Report.
|S. No.||Reference Title|
|1.0||PIC/S -Explanatory Notes for Media fill study|
Annexure-I Process Simulation Study (Media Fill) Planner
Annexure-II Process Simulation Study (Media Fill) Execution Record.
Annexure-III Media Fill Failure Investigation Report.
MEDIA FILL FAILURE INVESTIGATION REPORT
|Media Fill Due On:||Media Fill Performed on:|
|Performed on (Line):|
|No. of Contaminated Units:||Interventions Details:|
|Summary of Occurrence:
Production Quality Control Quality Assurance
Sign & Date Sign & Date Sign & Date
|Details of Potential Effect on Previous Batches (Since Last Media Fill):
|Outcome of Additional Process Simulation Tests (if Performed):
Checked By Approved By
Head Production Head QA
Sign & Date Sign & Date: