SOP FOR PROCEDURE FOR ASEPTIC PROCESS SIMULATION (MEDIA FILL)
PURPOSE: To define the procedure to be followed for validation of aseptic processes by process simulation study through a media fill. Process simulation study provides a way-
- To demonstrate the capability of the aseptic process in producing the sterile drug product.
- To qualify the personnel involved in aseptic processing.
- To evaluate impact of any changes made to aseptic processing line.
SCOPE: This SOP is applicable for carrying out aseptic media fill run on vial filling line in production area.
RESPONSIBILITY
Preparation of SOPs: Officer of Quality Assurance Departments
Checking and Review of the SOPs: Officer of Quality Assurance Department
Approval of the SOPs: Executive/His Designee of Quality Assurance Department
Authorization of SOP: Head QA/ His or her Designee
Head / Designee (Production) Department: Review of media fills Protocol and BMR, Review of executed media fills BMR & report, ensuring media fill participation of personnel involved in aseptic operation.
Microbiology Personnel: Sampling, testing of sterilized liquid media and PPM, Environmental and personnel monitoring in aseptic area & Visual inspection of media fill vial for microbial growth.
Head / Designee QC (Microbiology) Department: Review of media fills BMR, Protocol, Report & Ensuring media fill participation of personnel involved in aseptic operation & Environmental monitoring.
Engineering Personnel: Ensuring that utility support shall be provided during media fill & Simulation of maintenance activity during media fill run.
Head / Designee Engineering Department: Review of media fills BMR, Protocol, report & ensuring media fill participation of the engineering personnel involved in maintenance activity in aseptic area.
Quality Assurance Personnel: Monitoring of over all media fill activity, carrying out in process testing during media fill, Review of executed media fills BMR / report & Ensuring media fill participation of QA personal involved in IPQA.
Head QA / Designee: Head QA shall be responsible for final approval of media fill Protocol,media fill report & for final certification.
ACCOUNTABILITY: Head-QA or Designee shall be accountable for compliance of SOP.
PROCEDURE:
PRECAUTIONS: All the personnel involved in the Aseptic Process Simulation (Media Fill) shall be appropriately trained both in their job-related activities and on the Aseptic Process Simulation Study (Media Fill) Protocol.
All Major Equipment’s used for Process, Facility and Utility shall be verified for their Performance Qualification and Calibration.
Throughout the media fill run Good Manufacturing Practices and aseptic techniques shall be followed
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).
Precaution must be taken with respect to handling of media.
Entire product exposing area like filling & sealing shall be cleaned as per respected SOP.
At any stage none of the filled unit shall be removed unless verified and authorized by QA.
The destruction of the left-over media (Bulk) and of the filled units after inspection shall be done as per the respective SOP.
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.
Where filling takes place over extended periods, i.e. longer than 24 hours (Worst Case Study), the Aseptic process simulation test shall be extended over the whole of the standard filling period.
For Aseptic 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.
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.
All Aseptic pressure 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.
Media fill Batch Document Numbering: The BPR number shall be assigned as –
BPR/MFC/CI-NNN – Where,
BPR – Batch Processing Record.
MFC – Stand for media fill Cephalosporin.
CI – Stand for Cephalosporin Injection.
NNN – Stand for Sequence No.
Example: BPR/MFC/CI-001
Batch Numbering: Media fill batch numbering shall be assigned as per following procedure: MXXX. Where, M- Media Fill, XXX -Serial Number of the media fill
Example: CDM001 Represents the first media fill batch in cephalosporin dry powder injection area.
Operation:
3% w/v SCDM shall be used for media fill simulation following by dosing of sterile mannitol equivalent to product filling.
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.
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.
Manufacturing of media shall be done as per the batch manufacturing record.
For new aseptic processing line initially as startup qualification, three consecutive separate successful aseptic media fill run shall be carried out for each size of vial with respect to all configuration of vial and stopper system. Three runs also shall be taken on container closure integrity change. Subsequently periodically Media fill run shall be planed semiannually with one media fill run and each vial size with respect to all configuration of vial and stopper system shall be covered annually in media fill.
Perform manufacturing, sample collection, filling; visual inspection operation and reconciliation of the media as per procedure given in media fill BPR.
Carry out steam sterilization of garments, manufacturing and filling machine parts, manufacturing, filling and filtration accessories as per respective SOP.
Fill volume of media shall be sufficient enough to wet all inner surface of the container on inverting or as per the batch size to be simulated.
The fill volume of the containers should be sufficient to enable contact of all the container-closure seal surfaces when the container is inverted and also sufficient to allow the detection of microbial growth.
In process checks during filling shall be carried out as per respective SOP.
Filling line shall be simulated over Minimum, Optimum and Maximum Filling machine speed.
Duration of runs shall be equal to or more than longest run taken in actual production or expected to take in production and shall be specified in the protocol.
Where filling takes place over extended periods, i.e. longer than 24 hours, the process simulation test shall extend over the whole of the standard filling period.
Media fill batch shall mimic the actual batch size of commercial production if batch size is lower than 5000 units.
Batch Size of the media fill shall be taken equivalent to the size of individual API Container.
All the steps and events shall be recorded in batch processing record.
The process simulation test shall represent a “worst case” situation and shall include all manipulations and interventions likely to be represented during a shift.
After completion of media fill activity reconciliation shall be done.
Personnel:
All personnel shall follow the entry and exit procedure as per respective SOP of area and only authorized personnel shall enter the aseptic area.
All personnel shall follow SOP (SOP/C/DI002) in aseptic area.
All personnel working in aseptic area shall participate in aseptic media fill at least once a year.
It is mandatory to participate in aseptic media fill for new personnel working in aseptic area & QA issue a certificate for working in aseptic area.
Number of maximum allowable persons in filling area shall be established after media filling operation.
Interventions during Media Fill:
During the aseptic media fill activity, planned interventions shall be performed that mimic the actual process interferences that can be encountered during the routine product manufacturing.
All interventions shall be recorded in BPR & vial shall be incubated separately to represent the each intervention. Two types of interventions are as follows:
Routine Interventions: Routine intervention is also called inherent interventions as these interventions are the inherent part of the media fill run. Routine intervention is as given below:
Inherent intervention (Routine intervention):
- Aseptic Assembly of machine parts
- Recharge Mannitol into powder filling hopper
- Fill weight adjustment (Mannitol)
- Fill volume adjustment of SCDM during validation
- Assembling of Stoppering Unit
- Transfer of stoppers to vibrator
- Adjustment fitting and filling of syringe/nozzles
- Microbial Environment monitoring
- Picking of filled vials for in-process checks
- Breakfast / Lunch / Dinner break line stoppage
- Vial stuck in the in feed
- Microbiological sample collection
- Cleaning of infeed and outfeed conveyor by stopping the filling machine
- Unavailability of vials on the feed turn table (line stoppage)
- Filling at Minimum And maximum filling speed
- Shift Change over
- Pushing the seal cap in the seal rail and seal bowl by sterile forceps
- Loading of seals into hopper
- Height adjustment of seal chute, seal head and seal hopper
Routine Interventions/ Rare interventions (non-routine intervention):
- Removals of tilted/fallen, filled/unfilled vials from the infeed turntable.
- Removals of tilted/fallen, filled/unfilled vials from the outfeed turntable.
- Movement of swing conveyor during the rubber stopper loading.
- Removal of empty vials broken form the conveyor online
- O-RABS glove replacement
- Handling of spillage in filling line
- Operator Fatigue due to extended working hours
- Simulation of maintenance in Vial filling infeed tum table
- Entry of maximum number of persons (07 persons)
- Filling machine stoppage due non availability of compressed air
Environment Monitoring:
Environmental monitoring during media fill shall be equivalent to normal product filling.
Environment monitoring include Settle plate, Air sampling, surface monitoring (Swab/Contact plate), non-viable particle, Temperature, Relative Humidity and pressure differential monitoring shall be planned as per respective SOP.
Utility monitoring compressed air monitoring / water sampling shall be planed as per respective SOP.
Temperature, RH & Differential Pressure.
Personal Monitoring by RODAC Plate & Finger Dab of all persons involved in Media Fill at each exit.
Incubation of media fills units:
Inspected good units including cosmetic defects units (e.g. Particulate problem, Volume Variation etc.) shall be transferred for incubation.
Damaged (Cracked) units or broken or missing seal shall be rejected (not to incubate) and documented in aseptic simulation record. After visual inspection is completed, 100 % reconciliation of all filled units shall be done, and any deviation shall be justified.
The units filled during initial start-up for priming the machine as well as volume adjustments shall be incubated separately.
Production personnel shall handover the Media fill vials to Quality Control department for incubation as per SOP.
Before incubation at each stage all containers shall be inverted in such way that internal surfaces of closure of unit shall come in contact with the medium.
Incubation Temperature for Ist 7 days at inverted position (NLT 168 Hours) suitable for Yeast & Mold growth: 22.5 0C ± 2.5 0C.
Incubation Temperature for Next 7 days at upright position (NLT 168 Hours) suitable for Bacterial Growth: 32.5 0C ± 2.5 0C.
The temperature shall be recorded continuously through the circular charts. At the end of the incubation period, these shall be attached to the BMR.
Incase temperature recording device is not functioning then temperature shall be monitored manually at frequency of twice a day.
Any excursion of temperature in incubation rooms shall be investigated and its impact on the incubation of the media filled units shall be evaluated.
Examination:
Visual inspection of each incubated unit shall be carried out after 7 days and 14 days for microbiological contamination using inspection hood with white background.
The examination of the filled units shall be performed by Trained and Qualified Microbiologist with + Ve & – Ve control.
If any unit (s) shows microbiological growth integrity of the unit(s) shall be checked and removed from incubation with appropriate labeling.
The cosmetic defects shall be considered for process evaluation along with good vials.
The passed leak test vials shall be counted for process evaluation.
The contamination (s) shall be identified up to the species level.
Sampling Plan:
Perform sampling as per Sampling Plan attached with respective protocol.
Interpretation and Acceptance Criteria:
If no contaminated unit found, then the aseptic media fill run is valid.
Following steps/actions shall be taken for assigning the state of control in the aseptic manufacturing process.
If contamination unit is found, an investigation shall be carried out Respective SOP which includes an investigation of processing conditions, environmental data, and identification of the contaminating organism up to the species level, to identify the source of the contamination detected.
| Batch size (Units) | No. of contaminated units | Interpretation |
| ≤ 5,000 | 1 | Cause for revalidation, following an investigation. |
| 5,000 to 10,000 | 1 | Investigations, including consideration for repeat media fill. |
| 2 | Cause for revalidation, following an investigation. | |
| ≥ 10,000 | 1 | Investigation |
| 2 | Cause for revalidation, following an investigation. |
Investigation shall also be considered during following conditions:
If pre and post GPT test (after 14days incubation) of SCDM is not comply.
Media negative control shows any Microbial growth.
Destruction of media filled vials:
Destruction of the media fill vials after the incubation period shall be done as per respective SOP.
Cleaning after media fill:
The cleaning after aseptic media fill shall be carried out as per respective SOP.
Cleaning and disinfection of instrument and equipment shall be done as per the respective SOP of equipment and instrument.
In addition to verify the cleaning process of the equipments shall evaluate by TOC, pH, conductivity & visually cleaning check. The acceptance criteria of limits shall be given as:
| Test | Limit |
| pH | 5.0-7.0 |
| Conductivity | NMT 1.3µs/Cm2 |
| TOC | 500 ppm |
Media Fill failure investigation: If any growth observed than investigation shall be carried out as per Respective SOP.
A contaminated container shall be carefully examined for any breach in the integrity of the container system.
Damaged containers shall not be considered an evaluation (acceptance) of an aseptic processing capability of the process. However, a vial that is broken during incubation should be addressed.
All positives from integral containers shall be identified to at least genus and species whenever possible.
Identify the contaminant and compare the result to the database of the organisms most recently identified.
Processing records should be reviewed. Critical systems shall be reviewed and documented for changes.
Calibration records shall be checked.
All HEPA Filters in the Filling Area shall be inspected and decertified if warranted.
Personnel involved in the fill shall be assessed to assure the proper training was provided.
Validation and change control records shall be reviewed for any procedure or process changes.
A full risk analysis should be performed.
A media failure signals an underlying weakness of the system or the process.
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
Corrective action
Outcome of additional process simulation tests if they were performed
This investigation needs to be completed in a timely fashion. It may be necessary to issue an interim report.
Three consecutive successful process simulations are required to qualify a new or significantly revised change aseptic line or area. If there has been a failure on any process simulation without an assignable cause, one process simulation is required for re-qualification of an aseptic processing line
Frequency of Aseptic media fill run:
Aseptic media fill run shall be carried out once in six months (once in six months ±01month).
After modification / shutdown in aseptic area.
Introduction of new container closure System,
If no assignable cause for sterility failure during routine manufacturing.
REFERENCE:
SOP for SOP
PIC/S recommendation on the “Validation of Aseptic Process”, January 2011.
Guidance for Industry Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice September 2004 Pharmaceutical CGMPs.
PDA Technical Report No. 22 (Revised 2011), Process Simulation for Aseptically Filled Products.