SOP ON MEDIA FILL

This Document describes (Standard Operating procedure) SOP for media fill operation in the sterile dry powder filling area to evaluate the capability of the aseptic process to produce sterile product.

SOP ON MEDIA FILL

OBJECTIVE :

To lay down the procedure for Media fill operation in the sterile dry powder filling area to evaluate the capability of the aseptic process to produce sterile product.

SCOPE :

This SOP is applicable for Media fill operation in the sterile dry powder filling area

RESPONSIBILITY:

Clean Room Operator :To follow the SOP while conducting the Media fill operation.

Production : To prepare and carry out aseptic filling of media in sterile containers.  Record the all activity and complete the documents submitted to be QA for review and approval.

QC-Micro :  Perform sampling and testing as per the sampling plan. Incubation and inspection of filled containers. Conduct the environmental monitoring of production area during activity.

Quality Assurance along with QC, Production & Engineering :  If Acceptable levels are exceeded then investigate and follows necessary action.

Quality Assurance : To supervise over all media fill activity. Prepare Summary Report of Media Fill.

PROCEDURE :

PRE- START UP:

• Media fill should follow the regular product fill situation in terms of equipment’s, processes, personnel involved & time taken for filling as well as for holding.
• All the personnel to be involved in the media fill study are required to be trained prior to execution of the study.
• Primary packaging material and raw material shall meet its specification. Required number of containers / closures to be made available by production.
• Before starting the media fill run, check the status of all equipments Qualification, Validation/Calibration status and area used in media fill must be qualified.
• Ensure the media GPT should be complies before use.
• The routinely used Nitrogen gas for the production to be replaced by the filtered compressed air during the media fills study. During the manufacturing / Filtration / aseptic filling process, the nitrogen gas to be replaced by the filtered compressed air.
• Before starting the vial washing machine check the WFI for its pH and conductivity. WFI shall meet the acceptance criteria for pH and conductivity.
• Check the differential pressure, temperature and relative humidity of washing, manufacturing and aseptic area and LAF’s prior to filling activity
• Check the WFI release report before using for preparation of media which should meet WFI specification.
• Ensure that solubility test report and growth promotion/inhibition test report of sterile SCDM is available.
• Ensure that all the contact parts of Dry Powder Filling machine are duly cleaned and sterilized.
• Ensure that the Liquid Filling peristaltic pump is kept inside the sterile filling area on the previous day after sanitization.
• Ensure that the cleaning, sanitization and fumigation of the area is done on the previous day.

OPERATION :

Container size & Frequency :

• Process simulation trials will entail the filling of following containers size (3 runs each) on a given filling line i.e.10 ml, & 20 ml. The rationale for selecting smallest and largest size of vials is:
• The same filling line is used for different products having vials size range from 10 ml and 20 ml with double stroke filling.
• Single fill for smallest container and double fill/dose largest container.

Revalidation Frequency of media fill Simulation :

• Media fill activity shall be repeated on every six months ± 1 month.
• Facility and/or equipment modification.
• The container size of the new product is out of the container size bracketed for the filling line.
• Failure of initial validation and routine media fill.
• Anomalies in environmental monitoring result. (Continuous out of trend found during the environmental monitoring).

Filling speed :

• Filling operation shall be carried out at low speed to provide maximum exposure to containers to the environment.
• Set the speed of machine at NLT 30 vials/minute for 10 ml vials where as the usual speed is 110-120 vials/minutes.
• Set the speed of machine at NLT 20 vials/minute for 20 ml vials where as the usual speed is 50-60 vials/minutes.

Volume of Medium to be filled :

• The containers should not be completely filled with media in order to provide sufficient oxygen in the head space for the growth of microbes. (NLT 50% of container volume)
• There must be enough medium in the container to contact all the container-closure surfaces when the container is inverted and swirled.
• There must be enough medium in the container to contact all the inner portion of container to allow for detection of microbial growth.
• The chosen volume are

Sr. No	Vial Size	Sterile powder (Lactose Monohydrate)	Media (SCDM)
1	10 ml	500 mg	5 ml
2	20 ml	1000 mg	10 ml

Selection of media :

• The selected medium for Process Simulation test will be Soya Casein Digest Medium (SCDM) since, it is capable of supporting a wide range of microorganisms and is clear to allow observation for turbidity with ease.

Dispensing of Raw material:

• Calculate the batch quantity of media, and Lactose monohydrate required for Media Filling.
• Raise the “Raw Material Requisition” to procure the media and get it Authorized by Head Production.
• Get the line clearance from QA.
• Issue the required quantity of media as per the SOP  and transfer to Production for manufacturing.
• Dispensing activity should be done in microbiology area.

Media preparation :

• The WFI using for manufacturing to be tested for both Chemical and Microbiological after the release proceeds for manufacturing.
• Calculate the quantity of media to prepare 3% SCDM concentration.
• Collect 50 % freshly generated Water for Injection (Temperature NLT 80%) of media fill batch size in previously washed pressure vessel.
• Then add the medium with continuous stirring by using S.S. Rod.
• Ensure complete dissolution of Media in WFI without showing any lumps.
• Make up the final volume by adding the WFI and stir to get a uniform solution of Broth.
• Sample the freshly prepared media before filtration from the vessel and send the sample to QC to conduct bioburden & pH.
• Carry out the media filtration activity through the membrane filter used of which pre-sterilization and pre filtration Bubble point test performed as per SOP.
• Sample the filtered media as per the sampling plan from the vessel under LAF and send the sample to QC to conduct the Growth Promotion test, sterility and pH check at filtration stage.
• Sterilize the filtered SCDM liquid media at 121°C for 60 minutes.

Issuance of primary packing material:

• Calculate the batch quantity of Vials, Rubber plugs, Aluminium flip off seals required for Media Filling.
• Raise the “PM Material Requisition” and get it Authorized by Head Production.
• Get the line clearance from QA.
• Issue the required quantity of Vials, Rubber plugs, Aluminium flip off seals as per the SOP  and transfer to area.

Rubber bungs and machine part sterilization :

• Rubber bung are processed and sterilized in bung processor (Autoclave) as per SOP
• Sterilize the machine parts in bung processor at 121.1°C for 30 minutes and dry the parts under the vacuum using HPHV cycle as per SOP.

Decartoning :

• Dedust the cartons. Decarton and remove the vials. Arrange in the S.S. trays and stack for feeding to the vials washing machine.
• Inspect the vials visually for absence of black particles, broken glasses, fiber and other damages. As per SOP.

Vial washing :

• Feed the good vials into the conveyor belt of rotary vial washing machine.
• Vials are washed from inside and outside with 10 µm filtered recycled water in the first cycle followed by air.
• Vials are further washed from inside and outside in the second cycle with 3µm filtered purified water followed by air.
• Finally vials are washed from inside with 0.2µm filtered WFI (above 80°) followed by filtered air.
• Washed vials are passed to the conveyor of the sterilizing & Depyrogenating tunnel, as per SOP.

Depyrogenation :

• Vials are sterilized & Depyrogenated at 310-350°C for at least 3 minutes in the tunnel, as per SOP
• Depyrogenated vials are cooled, stabilized and passed directly to the aseptic filling area.

Filling operation :

• Bring the autoclaved SCDM liquid media container near the liquid filling assembly.
• Assemble the filling machine parts on the filling line taking all precautionary measurement for not contaminating any part of the filling line.
• Transfer sterile rubber bungs in to the hopper of stoppering unit.  Send sample for sterility testing simultaneously.
• Transfer the sanitized aluminum seals to sealing machine hopper and set the machine for proper sealing.
• Put the inlet suction tube of Liquid Filling Assembly into the SCDM liquid media container.
• Set the fill volume on peristaltic pump for the respective dose.
• Set powder filling machine as per SOP.
• Fill the Sterile Lactose to powder filling machine hopper.
• Set the machine for required dose.
• Start the powder filling followed by filling of liquid SCDM media followed by rubber plug stoppering and sealing.
• Ensure that all normal & non routine interventions & events are carried out at the beginning & during of media fill activity.
• After completion of filling, remove filling machine parts and all contact parts, disinfect, clean and sterilize.

Media fill interventions :

• Carryout the interventions as mentioned in below table
• Number the each carat and keep the vials in respective carets.
• Record the time and quantity vials of intervention in BMR

List of Permitted Interventions

Sr. No.	Planned permitted interventions	Min. No of  times	Frequency
			For 20ml	Initial 10 ml
1.	Adjustment of weight in the dosing wheel	3	After every 800 vials	After every 3000 vials
2	Adjustment of stopper chute	4	After every 700 vials	After every 1400 vials
3	Transfer of powder from container To hopper	10	After every 1400 vials	After every 1000 vials
4	Transfer of stoppers to hopper	5	After every 900 vials	After every 1000 vials
5	Stoppering of  un stoppered vials on conveyor & turntable	15	After every 200 vials	After every 400 vials
6	Adjustment of separator	2	After every 1100 vials	After every 2000 vials
7	Picking up of fallen vials from turn table	20	After every 150 vials	After every 300  vials
8	Cleaning of spilled powder with the lint-free mop	4	After every 700 vials	After every 900 vials
9	Adjustment of stoppering channel height	2	After every 1000 vials	After every 2000 vials
10	Adjustment of a piston from a wheel	2	After every 1200 vials	After every 1200 vials
11	Adjustment of turn table over load sensor	2	After every 900 vials	After every 900 vials
12	Crossing of a acrylic glass barrier by the technician	4	After every 600 vials	After every 2000 vials
13	Checking the weight in balance	6	After every 500 vials	After every 1000 vials
14	Adjustment of dosing air	2	After every 1000 vials	After every 1000 vials
15	Power interruption(samples should be segregated)	1	At least 200 vials to be filled after completion of targeted filled vials	At least 200 vials to be filled after completion of targeted filled vials
16	Entry of maintenance person	1	After every 2000 vials	After every 5000 vials
17	Entry of Microbiologist	2	Initial & after 5000 vials	Initial & after 5000 vials
18	Shift change	1	NA	NA
19	At low level hopper , tapering of hopper	3	NA	NA
20	Opening & Closing of aseptic filling area door	25	Initial & After every 500 vials	Initial & After every 500 vials

 Sealing :

• Aluminium seals are soaked in 70% IPA and allow seals for 4-5 minutes for sanitization. Transfer the treated seals with the help of perforated SS bowl to sanitized SS container. Transfer the SS container containing treated seals in aseptic process area under LAF and store it under mobile LAF till required for sealing as per SOP.
• Filled vials must be sealed by Aluminium flip off seal as per SOP.

POST MEDIA FILL RUN :

Visual inspection:

• At the end of the media filling activity; collect all the carets containing media filled containers
• Inspect the vials for presence of black particle, sealing defect, moulding defect, broken vials, glass particles, low and high weight and empty vials as per SOP.
• After completion of inspection transfer only the good inspected vials to incubation room.
• Record the quantity of good filled vials.
• Contamination rate shall be calculated against this good filled quantity.

Incubation :

• Swirl of all media filled and sealed vials before incubation.
• Incubate all the vials at 20-25°C for 7 days in upright position.
• Incubate all the vials at 30-35°C for next 7 days in inverted position
• The temperature mapping shall perform for incubation to qualify the incubation to qualify the incubation room.
• The selected temperature will be controlled and monitored continuously throughout the incubation period. Temperature logs will be maintained

Visual inspection :

• The vials shall be examined visually for evidence of growth.
• Inspect the vials by visual examination on 3rd, 7th, 11th and 14th day of incubation.
• Any positive (s) noted during routine inspection should be tallied and immediately removed from incubation.

Interpretation of result :

• Observe and interpret incubated media filled and sealed vials at incubation for its contamination on 3^rd, 7^th, 11^th and 14^th
• The process simulation results should be observed by the trained Microbiologist.
• Any contaminated vial should be considered objectionable and investigated.

Acceptance criteria :

• When filling less than 5,000 units, no contaminated units should be detected. One contaminated unit is considered cause for re-validation, following an investigation.
• When filling from 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 re-validation, following an investigation.
• When filling more than 10,000 units: One contaminated unit should result in an investigation. Two contaminated units are considered cause for re-validation, following an investigation.

In case of failure in media fill :

• When there is no assignable cause, media fill shall be repeated three times and production should commence only after all the three runs meet the acceptance criteria.
• When there is assignable cause, after rectification of the cause, repeat the media fill run once.
• Before and during media fill run no special cleaning shall be carried out.
• Normal production can resume only after minimum one day of environmental monitoring compliance report.
• Batches filled before the final result of the media fill run shall not be released to the market till the media fill run passes in case of initial validation.
• The routine environmental monitoring plates shall be kept for 14 days (in case of any growth) to help in investigation of any positive growth in the media filled vials.
• If for any reason the media fill run is considered invalid vials shall not be incubated.
• Media fill runs can be aborted for the same reason that a product lot would be aborted. All media filled units filled before an incident that would cause an aborted fill must be incubated.
• During media fill all the Operators, Officers and Maintenance staff who are authorized to do the sterile filling, supervision and maintenance must be involved in media fill trial.
• The volume of liquid filled must be sufficient to wet all surfaces including the closure and to facilitate inspection.
• The line must be run at a slower speed than normal production run to give greater exposure time.
• Total duration of the routine media fill must be the same or more as the longest process conducted on that line.
• The incubation temperature of the filled containers must be sufficient to promote microbial growth at 20-25^o For 168 hrs (stored upright) followed by 30-35^oC. For 168 hrs. (Stored upside down).
• Personnel that conduct the inspection of incubated media fills must have training on basic microbiological concepts, concepts of media fill and examples of contaminated container showing various stages of growth.

Disposal of media filled vials :

• Media fill vials shall be collected after its incubation and observation.
• Media filled vials should be transfer from incubator to autoclave.
• All media filled vials shall undergo for sterilization at 121.4^oC for 60 minute.
• After completion of sterilization the sterilized vials shall be left up to cooling then open at least 10 media filled vials for GPT (Growth promotion Test) of media, then perform the GPT of the sterilizes media filled vials.
• After GPT if no growth observed then open all sterilizes vials and collect the media, transfer to SS container having 5% Lysol solution.
• Transfer the solution to ETP (Effluent Treatment Plant) for its disposal.
• The vials / seals / Rubber stoppers rinsed with WFI water and vials crushing and transfer to scrap yard its disposal.
• The data / report maintained separately.

 

ANNEXURE:

Annexure I  : Media Fill Matrix Line

Annexure II  : Selection of media Fill Batch Size

Annexure III : Tally Sheet for Interventions.

Annexure IV :  Disposal / Destruction Record of Media Filled Vials

REFERENCES:

SR. NO.	CODE	TITLE
1	USP 2013	USP 2013 (USP 36 / NF 31) Page no. 784 (1116) Microbiological Control and Monitoring of Aseptic Processing Environments
2	PI 007 – 6 1 January 2011	Guideline – Pharmaceutical Inspection Co-operation Scheme. [PIC/S] Validation Of Aseptic Processes.
3	N. A.	Guidance for Industry – Sterile Drug Products Produced by Aseptic Processing- cGMP (USFDA).
4	TR No.: 22 PDA	Process simulation testing for aseptically filled products.

  

ANNEXURE-I

MEDIA FILL MATRIX

   

Year
Container Size

                                     

Prepared By:                                      Checked By:                                    Approved By:

 

ANNEXURE-II

SELECTION OF MEDIA FILL BATCH SIZE

  The following table represents the batch size to be used for the study:

Container Size	Maximum batch size for the container	Intended filling duration	Media fill batch size	Duration of media fill
Vials
10 ml
15 ml
20 ml

         

              

Prepared By:                                   Checked By:                                Approved By:

 

  ANNEXURE-III

TALLY SHEET FOR INTERVENTIONS

Name of the Product:		Batch No.:					Filling Date:
Sr. No.	Interventions	TALLY SHEET (Record number of times performed. 5 per cell)*					Total

Note: Record 5 observations per cell as represented below.

Where: One bar denotes one intervention. Likewise 4 vertical bars for 4 interventions and 5^th cross bar denotes 5^th intervention

 

ANNEXURE-IV

DISPOSAL / DESTRUCTION RECORD OF MEDIA FILLED VIALS                                                                                                                                                      

Date	Product Name	Batch No.	Qty. of vials Sterilized	Cycle No.	Cycle Start at	Sterilization Hold Time		Cycle  Completed at	Done by	Checked by	Remark
						Start	End

• GLOSSARY:

SOP	Standard  Operating  Procedure
QA	Quality Assurance
QC	Quality Control
IPA	Iso Propyl Alcohol
SCDM	Soyabean Casein Digest Medium
GPT	Growth Promotion Test.
HVAC	Heating, Ventilation and Air Conditioning
AHU	Air Handling Unit.
LAF	Laminar Air Flow.
RLAF	Reverse Laminar Air Flow
BMR	Batch Manufacturing Record
WFI	Water For Injection
GMP	Good Manufacturing Practice.
Sterile	Free from viable microorganisms.
Media Fill (Process Simulation)	A Media Fill/Process Simulation is the performance of an aseptic manufacturing procedure using a sterile microbiological growth medium in place of the drug. Microbiological growth medium is used in place of the drug during media fills to test whether the aseptic procedures are adequate to prevent contamination during actual drug production.
Aseptic Filling	Operation whereby the product is sterilized separately then filled and packaged using sterilized container and closures in critical processing zones.
Bioburden	Total number of viable microorganisms “on or in” pharmaceutical product prior to sterilization.
Growth Promotion Test	Test performed to demonstrate that media will support microbial growth