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SOP On Process Simulation by Media Fill study

  • Objective:
    • To lay down a guideline for Designing, Planning, Executing, Reviewing of results, investigating the failures and approving aseptic media fill study.
  • Scope:
    • This SOP applies to Sterile Powder Injectable section of pharmaceutical plant.
  • Responsibilities:
    • Microbiology Laboratory
      • Microbiology Department has overall responsibility of conducting, supervising the aseptic media fill.
      • Responsible for environmental and personnel monitoring during aseptic media fill.
      • Responsible for inspecting media filled units, in order to detect probable contamination, and investigating to find the root cause of the contamination if any.
    • Quality Assurance
      • QA department shall schedule media fill according to validation planner in coordination with the other departments.
      • Shall prepare Protocol & BMR in line with this SOP.
      • Shall review and prepare final report upon completion of the Aseptic Media Fill activity.
      • Investigates to find out root causes, in-case media fill results are beyond the acceptance criteria.
    • Manufacturing:
      • Production department shall execute the aseptic media fill as per the schedule.
      • Identifying and executing the interventions.
      • Manufacturing shall schedule involvement of operating personnel and department personnel for each media fill, in order to assure that all personnel involved in aseptic area operations participates at least once a year in aseptic media fill.
    • Warehouse
      • The warehouse shall maintain the required inventory of primary packaging components, and nutrient media required by the media fill program in coordination with Production, QA and microbiology department.
    • Accountability:
      • Head Q.A, Head – Microbiology and Head – Production are accountable for planning, implementation and compliance of aseptic media fill with this SOP.
  • Abbreviations and Definitions
  • SCD    :           Soyabean Casein Digest
  • NLT     :           Not Less than
    • Procedure:
      • To ensure the sterility of products purporting to be sterile, sterilization, aseptic filling and closing operations must be adequately validated.

“The goal of even the most effective sterilization processes can be defeated if the sterilized elements of a product (the drug formulation, the container, and the closure) are brought together under conditions that contaminate any of those elements. Hence aseptic media fill is required to simulate actual and worst case conditions to ensure the products produced by aseptic processing remains sterile”.

  • This process simulation, also known as aseptic media fill, normally includes exposing the microbiological growth medium to product contact surfaces of equipment, container closure systems, critical environments, and process manipulations to closely simulate the same exposure that the product itself will undergo. In case of aseptic process simulations for sterile powders, filling of liquid nutrient media into the vials along with powder is an additional activity.
  • An aseptic processing operation shall be validated using a microbiological growth medium in place of actual product.

“In case of sterile powder Injectables the powder filling operation shall be simulated using microbiologically inert  or growth promoting material (Ex: Sterile Mannitol/ sterile Lactose) and a liquid nutrient media (Ex: 3% sterile Soyabean casein digest medium in water for injection) to support growth of microorganisms”. However a justification for the use of these media shall be addressed in the protocol.

  • In place of routinely used sterile Nitrogen or Carbon dioxide (for specific products) flushing sterile filtered compressed air shall be used.
    • In order to achieve a confidence in the aseptic process designed, simulation of the total process shall be carried out using all the equipment routinely used in the production excepting the product.
    • The process simulation test should imitate as closely as possible the routine aseptic manufacturing steps except where the activity may lead to any potential microbial contamination.
    • The production process should be accurately simulated using media and conditions that optimize detection of any microbiological contamination.
  • The sealed containers filled with the nutrient medium are then incubated to detect microbial contamination.
  • Results are then interpreted to assess the potential for a unit of drug product to become contaminated during actual operations (e.g., start-up, sterile ingredient additions, and aseptic connections, filling, and closing).
  • Environmental monitoring data from the process simulation shall also be collected in order to get useful information for the processing line evaluation and failure investigation if any.
  • Considerations for Planning and Execution Of Aseptic Media Fills
    • The following are some considerations for planning and execution of the media fill
    • All the calibrations and Validations carried out shall be reviewed for the completeness in order to ensure that the equipment, systems and support systems are performing satisfactorily.
    • The following material shall be made available before planning executing media fill studies.
      • Sterile Mannitol: Gamma irradiated (Sterilized) Mannitol shall be procured from approved vendors. This material shall be packed in trilaminated pouches and shall be fixed with gamma irradiation indicators. A sample pouch shall also accompany each pack for sterility testing before use.
      • Required quantity of SCD media powder shall procured based on the vial size i.e. the fill volume to be filled in each vial.
      • Required quantity of Glass vials which are used in routine production shall be selected. Quantity shall be as per the batch size planned for aseptic media fill.
      • Rubber stoppers of both Non-RFS and RFS shall be simulated in the aseptic media fill, as both the processes are different. Both 20mm and 32mm shall be used in the media fill depending on the size of the neck of the bottle.
      • Aluminum seals of any color may be used. However both sterile and non-sterile seals shall be simulated during the aseptic media fill.
    • Other considerations
      • Other material like disinfectants shall be the ones used in routine practice.
      • Required routine utilities and specific to media fill (Ex: compressed air connection) shall be ensured before start up.
      • GPT shall be done to arrive appropriate concentration of Mannitol in 3% SCDM.
      • Area Preparation, Component preparation, Sterilizations, Transfer and Holding of the sterilized material before use, Environmental monitoring, Personnel monitoring shall be in line with routine practices. Sterilized equipment parts and accessories may be stored for longest holding period possible after sterilization.
      • Preparation of Liquid nutrient media: shall be done in the presence of microbiologist.
      • Filling machine set up; Sampling during filling shall be in-line with the designed BMR.
      • Filling activity and Interventions shall follow instruction of BMR
      • Collection and marking of vials shall approximately indicate the interventions conducted at that time. Record in BMR and crate label in which vials are collected.
      • Filled vials shall be inspected, after gentle swirling of vials to dissolve the solid material, by microbiologists. Do not shake the vials for dissolving the contents.
      • All the vials shall be accounted and reconciled.
    • Study Design
      • A media fill program should incorporate the contamination risk factors that occur on a production line, in order to assess the state of process control.
      • Media fill studies should closely simulate aseptic manufacturing operations incorporating, as appropriate, worst-case activities and conditions that provide a challenge to aseptic operations.
      • Media fill program shall address the following issues:
    • Identify the factors associated with the longest permitted run on the processing line that can pose contamination risk (e.g., operator fatigue)
    • Identify representative number, type, and complexity of normal interventions that occur with each run, as well as non-routine interventions and events (e.g., maintenance, stoppages, equipment adjustments)
    • Aseptic assembly of equipment (e.g., at start-up, during processing)

During processing adjustments of the equipment assembly like removal and replacement of filling wheel pistons, adjustment of alignment of other components shall be considered.

To assess contamination risks during initial aseptic setup (before fill), valuable information can be obtained by incubating all such units that may be normally removed. These units are typically incubated separately, and would not necessarily be included in the acceptance criteria for the media fill.

  • Number of personnel and their activities.

Identify number of personnel involves in the routine aseptic operations and assume the possibility of maximum number of persons at a time in the aseptic area for different activities/ reasons and simulate this worst case condition in the media fill.

All personnel who are authorized to enter the aseptic processing room during manufacturing, including technicians and maintenance personnel, should participate in a media fill at least once a year. Participation should be consistent with the nature of each operator’s duties during routine production. The personnel includes

  • Machine operators.
  • Helpers supporting the aseptic operations in the aseptic area.
  • Production supervisory staff.
  • IPQA personnel.
  • Maintenance personnel.
  • Any other senior personnel who are required to enter the areas less frequently. For example All department Head, senior department staff who are required to enter aseptic areas when occasion demands.
  • Activities and interventions representative of each shift, and shift changeover, should be incorporated into the design of the semi-annual qualification program.

Example: Movement of personnel into and out of the aseptic processing and gowning change rooms during a shift change. Change of the total set of operators at the end of shift shall be considered at least in one day media fill runs. Men exit and entry during Breakfast/ lunch/ tea breaks shall be considered. Gowning changes may be done deliberately.

  • Written procedures regarding aseptic interventions should be clear and specific (e.g., intervention type; quantity of units removed), providing for consistent production practices and assessment of these practices during media fills
  • If a production procedure requires removal of 10 units after an intervention at the stoppering station infeed, batch records (i.e., for production and media fills) should clearly document conformance with this procedure. In case of no units are removed during a media fill intervention than would be cleared during a production run.

Identify representative number of aseptic additions like charging of closures as well as sterile material and transfer materials.

Shift changes, breaks, and gowning changes. Type of aseptic equipment disconnections / connections.

Ex: Connection of canister to filling machine.

  • Aseptic sample collections.

Collection of vials, stoppers, and filled vials for in-process checks shall be considered at different intervals.

  • Line speed and configuration.

The aseptic media fill for sterile powder filling activity needs simulation of powder filling along with some liquid nutrient media to support growth of microorganisms. As the liquid filling assembly is not a permanent set-up with the filling machine, the speed of this may be a constraint. Further the speed of liquid filling needs to be controlled to avoid flying of powder, during liquid dispensing into vial on-line, and escaping into the aseptic area to avoid contamination issues.

  • Weight checks: Collection of vials for in-process weight checks shall be at regular intervals similar to routine production.
  • Container closure systems (e.g., sizes, type, compatibility with equipment).

The following vials used and expected to be used in routine commercial production, are considered for simulation during Aseptic Media Fill, and may be matrixed as required to rotate all the vials in use at least in one year.

Rubber stoppers in RFS bags and 20mm rubber stoppers in Non-RFS (which are washed and siliconised) are considered for simulation.

Ruber with plastic PP disc (both gamma radiation sterilized and non-sterile) are considered for simulation during aseptic media fill.

  • Designing of Batch Record.
  • The documentation of production conditions and simulated activities during the each aseptic media fill run shall be recorded in the form of batch record.
  • Similar formats of Batch Manufacturing Record shall be used to record media fill runs in-line with routine production runs.
  • The firm’s rationale for the conditions and activities simulated during the media fill should be clearly defined.
  • It is very important to understand that the aseptic media fills should not be used to justify practices that pose unnecessary contamination risks.
  • Specific provisions in written procedures relating to aseptic processing (e.g., conditions permitted before line clearance etc.,)

Table showing vials under use or proposed for commercial production:

Vial description Manufacturer Body OD (mm) Height (mm) Neck ID (mm) Neck OD (mm) Overflow volume (ml) Empty Vial weight (g)
10ml moulded
10 ml TUBULAR
15ml moulded
15ml TUBULAR
20ml tubular
50ml moulded
100ml moulded
  • Frequency and Number of Runs
    • For initial processing line qualification, individual media fills should be repeated enough times to ensure that results are consistent and meaningful. US FDA recommends, at least three consecutive separate successful runs be performed during initial line qualification.
  • During initial qualification study, each vial proposed to be used in routine production activity shall be subjected to process simulation study for three consecutive days.
    • This approach is important because a single run can be inconclusive, while multiple runs with divergent results signal a process that is not in control.
    • Semi-annual qualification (every six months) shall be conducted for each processing line to assure the state of control of the aseptic process.
    • Semi-annual qualification shall be conducted at least for three consecutive days. If there are more number of vial types, Matrixing approach may be used by verifying the equivalency of the vials by size and neck/ mouth diameter. However all the vials under routine production shall be rotated at least once a year.
  • Duration of Runs:
    • The duration of aseptic processing operations is a major consideration in media fill design.
    • The duration of the media fill run shall be determined by the time it takes to incorporate manipulations and interventions, as well as appropriate consideration of the duration of the actual aseptic processing operation.
    • Interventions that commonly occur should be routinely simulated, while those occurring rarely can be simulated periodically.
    • The duration of the process simulation should generally be not less than the length of the actual manufacturing process to best simulate contamination risks posed by operators. However at least on one of the three days media fill activity 16hours operation shall be carried out.
  • Size of Runs
    • The simulation run sizes should be adequate to mimic commercial production conditions and accurately assess the potential for commercial batch contamination.
    • A generally acceptable run size is in the range of 5,000 to 10,000 units. As batches are produced over extended shift to fill units over 100,000 vials. Based on these factors the following batch sizes are proposed to adequately address conditions and any potential risks associated with the production batches.
  • Each day fill size should be 20,000 vials in case of 10ml to 20ml and 10000 vials in case of 50ml to 100ml vials.
  • In case of introducing a new vial a full day run may be considered appropriate, using above mentioned run sizes.
    • Line Speed
      • The aseptic media fill for sterile powder filling activity needs simulation of powder filling along with some liquid nutrient media to support growth of microorganisms. As the liquid filling assembly is not a permanent set-up with the filling machine, the speed of this may be a constraint. Further the speed of liquid filling needs to be controlled to avoid flying of powder, during liquid dispensing into vial on-line, and escaping into the aseptic area to avoid contamination issues.
      • In this case of sterile powders use of slow line speed will be appropriate for evaluating manufacturing processes with prolonged exposure of the containers and closures in the aseptic area.
    • Collection of filled vials
      • All the media filled vials shall be collected on hourly basis to identify the interventions conducted at that particular time interval.
      • Each crate of vials shall be identified with date and time of collection which is approximately equal to the filling time.
      • Other details like B. Number or Run Number, Batch/ run size, Date of fill, time of fill, Crate number shall be recorded on the status label.
    • Environmental Conditions
      • Media fills should be adequately representative of the conditions under which actual manufacturing operations are conducted.
      • To the extent standard operating procedures permit stressful conditions (e.g., maximum number of personnel present and elevated activity level); it is important that media fills include related challenges to support the validity of these studies.
      • Stressful conditions do not include artificially created environmental extremes, such as reconfiguration of HVAC systems to operate at worst-case limits.
    • Media
      • The criteria for the selection of growth medium include: low selectivity, clarity, medium concentration and filterability. In general, a microbiological growth medium, such as soybean casein digest medium, shall be used.
      • Low Selectivity: The medium selected should be capable of supporting a wide range of microorganisms, which might reasonably be encountered and be based also on the in house flora (e.g. isolates from monitoring etc.).
      • Media used in the evaluation must pass a growth promotion test. The control organisms used should include those relevant strains of test micro-organisms identified by relevant Pharmacopoeias (growth of gram-positive and gram-negative bacteria, and yeast and mold Ex: USP indicator organisms) as being suitable for use in the growth promotion test. The QC laboratory should determine if USP indicator organisms sufficiently represent production-related isolates.
      • Growth promotion tests should demonstrate that the medium supports recovery and growth of low numbers of microorganisms, i.e. 10-100 CFU/unit or less.
      • Growth promotion testing of the media used in simulation studies should 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.
    • If the growth promotion testing fails, the origin of any contamination found during the simulation should nonetheless be investigated and the media fill promptly repeated.
      • Clarity: The medium should be clear to allow for ease in observing turbidity.
      • Medium Concentration: Recommendations of the supplier should be followed unless alternative concentrations are validated to deliver equal results.
      • Each unit should be filled with an appropriate quantity and type of microbial growth medium to contact the inner container closure surfaces (when the unit is inverted or thoroughly swirled) and permit visual detection of microbial growth. The following shall be considered.
    • Sterile Mannitol powder to simulate powder filling process and Soyabean Casein Digest Medium having 3% concentration shall be used to support growth of microorganisms.
    • Find out quantity liquid nutrient media required to be more than half of the volume of each size of vial under up-right and inverted conditions.
    • Quantity of the solid media to be dispensed in each vial shall be based on the concentration in the liquid derived from the above volume. This concentration shall be finalized by Microbiology department after verifying growth promotion testing at each concentration to find out ideal concentration of powder which does not affect the growth of the microorganisms.

Note: The medium should be handled properly and is promptly followed by the cleaning, sanitizing, and, where necessary, sterilization of equipment, so that subsequently processed products are not compromised.

  • Incubation and Examination of Media-Filled Units
    • Incubation conditions and duration
  • Media units should be incubated under conditions adequate to detect microorganisms that might otherwise be difficult to culture. Incubation conditions should be established in accord with the following general guidelines:
  • Two Incubation temperatures (22.5±2.50C and 5±2.50C) are selected to have suitable for recovery of bioburden and environmental isolates.
  • Two different rooms with the above said temperatures are identified for this incubation purpose and the filled vials shall be incubated. After incubation at 22.5±2.50C media filled vials shall be transferred to another room with 32.5±2.50C temperature condition.
  • Total incubation time should not be less than 14 days. As two temperatures are used for the incubation of the media filled units, the units should be incubated for at least 7 days at each temperature (starting with the lower temperature).
  • First seven days the vials shall be incubated in Up-right position and the next seven days the vials shall be incubated in inverted position.
    • Microbiological Support:
  • Following incubation and inspection the Microbiologist shall withdraw a specified number of sterile filled units. The media in these units shall be tested for its ability to support growth of a small inoculum (10-100 cf) of each of an array of challenge microorganisms (Growth Promotion Test – GPT).
  • The array of challenge microorganisms used for the GPT shall include all of those microorganisms specified in the pharmacopoeias to be used for SCDM when used in the Test for Sterility plus representative of locally isolated microorganisms.
  • Each challenge microorganism shall be tested for GPT against two uncontaminated filled containers.
  • Following incubation and inspection the Microbiological Quality function shall withdraw a specified number of sterile filled units and perform the Container Clouse Test by Microbiological Method.
    • Inspection of media filled vials
  • Each media-filled unit should be examined for contamination by microbiologists who have appropriate training, and experience in inspecting media fill units for microbiological contamination.
  • All suspect units identified during the examination should be brought to the immediate attention of the Head-QC. If required visual detection of doubtful units may be done by using magnifying glass.
  • Ensure gentle swirling of all the vials immediately after filling, in order to dissolve the Mannitol in SCDM.
  • Perform final product inspection of units immediately following the media fill run, all integral units should proceed to incubation. Units found to have defects not related to integrity (e.g., cosmetic defect) should be incubated; units that lack integrity should be rejected. Erroneously rejected units if any should be returned promptly for incubation with the media fill lot.
  • During incubation period, any unit found to be damaged should be included in the data for the media fill run. Any decision to exclude such incubated units (i.e., non-integral) from the final run tally should be fully justified and the deviation explained in the media fill report.
  • If a correlation emerges between difficult to detect damage and microbial contamination, a thorough investigation should be conducted to determine its cause.
  • Appropriate criteria should be established for yield and accountability (reconciliation of filled units). Media fill record reconciliation documentation should include a full accounting and description of units rejected from a batch.
    • Interpretation of Test Results
      • The process simulation run should be conducted under the supervision of the Microbiologists.

Contaminated units should be reconcilable with the approximate time and the activity being simulated during the media fill. (Total units incubated/total number of units filled)

  • Video recording of a media fill shall be used as a useful aid in identifying personnel practices that could negatively affect the aseptic process.
  • Any contaminated unit should be considered objectionable and investigated. The microorganisms should be identified to species level. The investigation should survey the possible causes of contamination. In addition, any failure investigation should assess the impact on commercial drugs produced on the line since the last media fill.
  • Whenever contamination exists in a media fill run, it should be considered indicative of a potential sterility assurance problem, regardless of run size. The number of contaminated units should not be expected to increase in a directly proportional manner with the number of vials in the media fill run.
  • Test results should reliably and reproducibly show that the units produced by an aseptic processing operation are sterile, should normally yield no media fill contamination.
  • Acceptance criteria:
    • The target for any media fill run should be zero contaminated units. However for the following criteria for assessing state of aseptic line control shall be followed:
  • When filling fewer than 5000 units, no contaminated units should be detected.

One (1) contaminated unit is considered cause for revalidation, following an investigation.

  • When filling from 5,000 to 10,000 units:

One (1) contaminated unit should result in an investigation, including consideration of a repeat media fill.

Two (2) contaminated units are considered cause for revalidation, following investigation.

  • When filling more than 10,000 units:

One (1) contaminated unit should result in an investigation.

Two (2) contaminated units are considered cause for revalidation, following investigation.

  • Reconciliation of Media Fill units
    • Reconciliation of the following shall be done as per the formats in the BMRs.
  • Liquid nutrient medium.
  • Sterile Mannitol powder.
  • Rubber stoppers
  • Glass vials
  • Aluminum seals
    • Abortion or Invalidation:
  • A simulation run may be aborted or abandoned if an event occurs as a result of which the trial cannot continue, for example media spillage, serious mechanical breakdown of equipment etc
  • Permission to abort or invalidation a simulation trial shall be on the decision of the Head – QA.
  • Product units filled in an aborted simulation trial shall not be incubated.
    • A simulation trial may be invalidated if, within 48 hours of completion of the trial, the Unit Head or Unit Head of Production notifies the Unit Head of Quality that an event occurred during the trial which would not be permitted in routine production.
  • Invalidation of a simulation trial shall be on the joint authority of the Unit Head and the Unit Head of Quality.
  • Product units filled in an invalidated simulation trial shall be removed from incubation.
    • Reasons for contamination
      • The following are some of the identified causes for contamination, but not limited to:

Aseptic practices:

  • Operator reaches over open vials to remove fallen vial on line with gloved hands
  • Poor personnel flow.
  • Damage of the protective gowning observed during the activity
  • Poor gowning practice

Poor aseptic connections

  • Improper connection of butterfly valve to the powder container,
  • Improper connection to main hopper,

Poor Sanitization:

  • Procedures deficient
  • Poorly executed procedures
  • Contaminated disinfectants.
  • Disinfectants not-suitable for the purpose

HVAC related:

  • Variable velocities between filters.
  • Inadequate laminar flow resulted.
  • Low or undetectable velocity at work surface.
  • Leakages found in the HEPA filter grid,
  • Excursion of temperature and Relative Humidity.
  • Excursion in the differential pressures between different classes.

Mechanical failures:

  • Vacuum pump failure,
  • Compressed gas filter failure,
  • Leakage of the filling vessel and
  • Pinholes in the tubing used for liquid nutrient media
  • Power failure and resuming times.

Other reasons

  • Improperly dried hands and foot especially during rainy seasons.
  • Personnel hygiene.
  • Personnel with un-noticed communicable diseases. 

Note: Any observations that may cause contamination shall be added to this list, whenever observed and reported.

  • Action failure
  • When data from a media fill indicate the process may not be in control,
  • An investigation should be conducted to determine the origin of the contamination and the scope of the problem.
  • Once corrections are instituted, process simulation run(s) should be performed to confirm that deficiencies have been corrected and the process has returned to a state of control.
  • When an investigation fails to reach well-supported, substantive conclusions as to the cause of the media fill failure, three consecutive successful runs in tandem with increased scrutiny of the production process may be warranted.
  • Actions that shall be taken in the event of a Media Fill failure are described below:
  • The investigations shall be performed by an investigation team comprising of experts from Production, Maintenance, Quality Assurance and Microbiology.
  • Isolation and Identification of the micro-organism observed shall be done up to the genus level and species level.
  • Possible source of the contaminating micro-organism into Media Fill process shall be investigated.
  • This shall include statistical tools for investigation, such as, “Cause and Effect Analysis” or other tools to find out the root cause(s) or the most probable root cause(s).
  • Batch Records for Media Fill studies shall be closely examined by the investigation team for any deviation or incident.
  • All Media Fill study records shall be reviewed. These shall include sterilization records, depyrogenation records, disinfection records, and microbiological monitoring records, physical monitoring records for temperature, RH and ∆P of the aseptic processing and adjacent rooms and Video recording, if done.
  • Any deviation from the relevant SOPs or aseptic practices shall be investigated.
  • The operating personnel who have participated in the Media Fill studies shall be interviewed to check for any untoward incident or lack of proper aseptic practice.
  • Any deviation from the validation protocol shall be investigated.
  • If any deviation is found, it shall be reported.
  • Outcome of Investigation: The investigation report shall be discussed by the investigation team members.
  • Detailed investigation report shall be made. Deficiencies shall be discussed.
  • The corrective actions and preventive actions shall be identified, justified and approved before implementing.
  • The operating team members shall be identified and entrusted with the responsibility to undertake the corrective actions and preventive actions.
  • Corrective actions may demand the process simulation to be either fully or partly re-qualified as decided by the investigation team. This shall be decided based on the causes and stage of failure.
  • There shall be follow-up by the investigation team to determine whether the corrective actions and preventive actions have been indeed implemented and were effective.
  • The Investigation and CAPA shall be closed only after full satisfaction of its implementation and effectiveness is ascertained.
  • The Investigation report and CAPA implementation shall be signed by the investigation team members and approved by the QA Head.
  • The QA Head shall communicate to the senior management about the Media Fill failure, cause of failure, its implications on the productivity, facility, GMPs, Regulatory and Action Plan for CAPA and re-qualification of the facility.
  • The senior management shall review the points of investigation and implications of media fill failure and provide directions to the manufacturing facility.
  • The QA Head shall also communicate to the Quality Person (QP) or clients / customers who are affected through Quality Agreement or Technical Agreement.
  • Decision on Disposition of products
  • The investigation team shall determine through discussion the fate of the products and the batches that were:
  • Processed immediately after the last Media Fill run was completed,
  • Processed between the execution of last Media fill study and the execution of this Media fill study.
    • The decision may not necessarily result in Product Recall from the market as the cause could be due to operator one-off error, operational deviation or an accidental effect or an incident from a worst-case scenario or equipment breakdown; in either case it may not reflect on true batch failure.
    • However, if the cause is identified to be a systemic contamination failure due to Facility failure, HVAC system failure, LAF failure, Tunnel or autoclave sterilization process failure, inadequate competency of personnel, then it could result in a decision for Product Recall.
    • In such a case, the investigation team shall decide the products and number of batches to be recalled. The QA Head shall finally approve of such a decision and initiate Product Recall as per current SOP on Product Recall.
    • Re-qualifications:
      • Normally process simulation tests should be repeated twice a year. However ± 30 days deviation from the pre-scheduled activity may be allowed if required.
      • Each change to a product or line change should be evaluated using a written change control system.
      • Any changes or events that have the potential to affect the ability of the aseptic process to exclude contamination from the sterilized product should be assessed through additional media fills.

For example, facility and equipment modifications, line configuration changes, significant changes in personnel, anomalies in environmental testing results, container closure system changes, extended shutdowns, or end product sterility testing showing contaminated products may be cause for revalidation of the system.

  • After completion of de-activation these vials shall be destroyed by crushing, and liquid is drained into ETP system.
  • After completion of incubation time and completion of relevant activities the media filled vials shall be de-activated by sterilizing the media filled vials by moist heat at 1210C for 1 hour.
  • List of Annexure / Formats
    • None
  • Reference (If any):
    • US Guidance for Industry Sterile Drug Products Produced by Aseptic Processing – 2004.
    • PICS Recommendation on the Validation of aseptic process (PI 007-6/ 1 January 2011)
    • WHO Technical Report Series, No. 961, 2011.
    • EU guideline (EUGMP) for Manufacture of sterile Medicinal Products Volume 4 Annexure1
  • Forms and Records (Annexures)
  • Proposed types of Interventions during Media Fill runs – Annexure – I
    • Distribution
      • Master copy   –       Quality Assurance
      • Controlled copies –   Quality Assurance, Production, Quality Control, Stores, Engineering.
    • History:
    Date Revision Number
    Reason for Revision
    00   NEW SOP

    

                                                  Annexure-I

Proposed types of Interventions during Media Fill runs
Worst case factor Normal Production condition Worst case scenario Justification for selection
Normal Aseptic Routine Interventions Aseptic filling stoppages very few More aseptic filling stoppages to adjust for extended run time; More exposure time and of contamination and Sterility Assurance.
In-process fill weight checks only; More number of In-process fill weight & fill volume checks; Risk to contamination and Sterility Assurance.
Normal powder Filling Vial sampling & inspection; Powder Filling, extra liquid SCDM Filling, Vial sampling & inspection; Extra activity of SCDM filling hence more Risk to contamination and Sterility Assurance.
Adjustment of hopper of powder filling.

 

More adjustments of hopper of powder filling and adjustment of SCDM liquid filling machine. Risk to contamination and Sterility Assurance.
Non-Routine Aseptic Interventions Filling equipment adjustments not done routinely; Filling equipment adjustments for powder & SCDM filling; Risk to contamination and Sterility Assurance.

 

Bunging equipment adjustments not done routinely; Bunging equipment non-routine adjustments done; Risk to contamination and Sterility Assurance.
Breakdown maintenance not done during aseptic filling, Breakdown maintenance attempted once during aseptic filling,  Risk to contamination and Sterility Assurance.
Entry of maintenance technician normally not enters during aseptic filling process; Entry of maintenance technician allowed during aseptic filling process. Risk to contamination and Sterility Assurance.
Line speed adjustments Vial Washing Equipment Speed adjustments i.e. staggered supply of vials into tunnel sterilizer. Vial feeding in to tunnel little disturbed; Extended exposure of the vials to the environment. Hence chances of capturing any microorganisms in the environment will be more.
Vial feeding to aseptic filling line little disturbed leading to over-exposure of empty vials;
Aseptic filling Line speed adjustments and stoppages to adjust time for normal production time; Mannitol powder filling into vials as well as subsequent liquid SCDM filling will have intermittent stoppages. Risk to contamination and Sterility Assurance.
Extra personnel More number of personnel inside the aseptic processing area. More personnel can add to contamination (viable & non-viable) Risk to contamination and Sterility Assurance.

 

 

 

About Pharmaceutical Guidanace

Mr. Shiv Kumar is the Author and founder of pharmaceutical guidance, he is a pharmaceutical Professional from India having more than 14 years of rich experience in pharmaceutical field. During his career, he work in quality assurance department with multinational company’s i.e Zydus Cadila Ltd, Unichem Laboratories Ltd, Indoco remedies Ltd, Panacea Biotec Ltd, Nectar life Science Ltd. During his experience, he face may regulatory Audit i.e. USFDA, MHRA, ANVISA, MCC, TGA, EU –GMP, WHO –Geneva, ISO 9001-2008 and many ROW Regularities Audit i.e.Uganda,Kenya, Tanzania, Zimbabwe. He is currently leading a regulatory pharmaceutical company as a head Quality. You can join him by Email, Facebook, Google+, Twitter and YouTube

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