A Media Fill --- also known as Process Simulation

MEDIA FILL
&
REGULATORY EXPECTATIONS
Arvind Kumar Srivastava

Dy. Manager Quality Assurance
Department at BETA DRUGS LTD ,
ONCOLOGY STERILE PLANT , BADDI
Generally, Good GMP-Compliance is based on Good
Understanding.
When you understand the reasons for a particular GMP

requirement, the chances are high that you will be able to comply
with it – in procedures, records and actions.
In this session we will understand

what GMP intends to gain from media fills.
Arvind Kumar Srivastava , Quality Assurance Department , arvindsri82@gmail.com

MEDIA FILL
Method of evaluating an aseptic process and find out the
weakest Link , By using a microbial growth medium.
It is a tool that is used to assess the capability of an Aseptic
process to deliver a drug product that is sterile and free from
microbiological contamination
( Media fills are understood to be synonymous to
Simulated Product Fills , Broth Trials , Broth Fills etc.)

Media Fill is A Chain of Linked Activities of Aseptic Processing & Aseptic Behaviour
& During Media Fill Find out the ,Where is the weakest link ??

REGULATORY GUIDELINE FOR MEDIA FILL VALIDATION AND ITS
DEFINITION

REGULATORY GUIDELINE FOR MEDIA FILL VALIDATION AND ITS
DEFINITION
FDA GUIDANCE FOR INDUSTRY – STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC
PROCESSING — CURRENT GOOD MANUFACTURING PRACTICE
EU GMP ANNEX – 1: MANUFACTURE OF THE STERILE MEDICINAL PRODUCTS.
PIC/S PI 007-2 “RECOMMENDATIONS ON THE VALIDATION OF ASEPTIC PROCESS”
WHO GMP GUIDELINES –TECHNICAL REPORT SERIES NO. 937; ANNEX- 4
INDUSTRY DOCUMENTS – PDA TECH REPORT 22 PDA TECH REPORT 28

Guidance for Industry Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing
Practice , September 2004 , Pharmaceutical CGMPs.
An aseptic processing operation should be validated using a microbiological growth

medium in place of the product.
This process simulation, also known as a 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.
The sealed containers filled with the 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, aseptic
connections, filling, closing).
Environmental monitoring data from the process simulation can also provide useful
information for the processing line evaluation.
PHARMACEUTICAL INSPECTION CONVENTION , PHARMACEUTICAL INSPECTION CO-
OPERATION SCHEME PI 007-6 , 1 January 2011 , RECOMMENDATION ON THE
VALIDATION OF ASEPTIC PROCESSES
Process simulation studies (media fills) are simulating the whole process in order to evaluate
the sterility confidence of the process.
Process simulation studies include formulation (compounding), filtration and filling with suitable
media. Simulations are made to ensure that the regular process for commercial batches
repeatedly and reliably produces the finished product of the required quality. However, each
process simulation trial is unique and so it is not possible to extrapolate these results directly to
actual production contamination rates.

WHO Good Manufacturing Practices for Sterile Pharmaceutical Products , Annex 6 , WHO Technical
Report Series, No. 961, 2011.
4.23 Validation of aseptic processing should include a process simulation test using a nutrient medium
(media fill). Selection of the nutrient medium should be made based on dosage form of the product and
selectivity, clarity, concentration and suitability for sterilization of the nutrient medium.
4.24 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.
4.25 Process simulation tests should be performed as part of validation by running three consecutive
satisfactory simulation tests. These tests should be repeated at defined intervals and after any significant
modification to the heating, ventilation and air-conditioning (HVAC) system, equipment or process. Process
simulation tests should incorporate activities and interventions known to occur during normal production as
well as the worst-case situation.
The process simulation tests should be representative of each shift and shift changeover to address any
time-related and operational features.

EU GMP ANNEXURE 1 , Manufacture of Sterile Medicinal Products , 01 March 2010.
EU GMP Annex- 1 : "Validation of aseptic processing should include a

process simulation test using a nutrient medium (media fill).Selection
of the nutrient medium should be made based on dosage form of the
product and selectivity, clarity, concentration and suitability for
sterilization of the nutrient medium.“

ISO 13408-1:2008 Aseptic processing of health care products –Part 1: General
requirements (parts 2-8 also deal with aseptic processing)
ISO 13408-1:2008 states “Process simulation shall cover all parts of the
aseptic process and include all aseptic manipulations. It is possible to divide
the process into unit operations but all parts of the process shall be simulated
(Clause 10.1.1)"

Guidance on the Manufacture of Sterile Pharmaceutical Products by Aseptic
Processing , Pharmaceuticals and Medical Devices Agency , from Ministry of Health,
Labour and Welfare of Japan. , PMDA - Pharmaceuticals and Medical Devices Agency ,
Japan
Process simulation test or media fills: One of the processing validations employed to
evaluate the propriety of the aseptic processing of pharmaceutical products using
sterile media instead of actual product.

USP CHAPTER 797PHARMACEUTICAL COMPOUNDING—STERILE PREPARATIONS
Media-fill test: A simulation used to qualify processes and personnel engaged in
sterile compounding to ensure that the processes and personnel are able to prepare
Compound Sterile Preparations (CSPs ) without contamination.

PART 211 -- CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED
PHARMACEUTICALS
Subpart F - Production and Process Controls
Sec. 211.113 Control of microbiological contamination.
(a) Appropriate written procedures, designed to prevent objectionable microorganisms in
drug products not required to be sterile, shall be established and followed.
(b) Appropriate written procedures, designed to prevent microbiological contamination of

drug products purporting to be sterile, shall be established and followed. Such procedures
shall include validation of all aseptic and sterilization processes.
21 CFR 211.113
21 CFR 211.113 : " To ensure the sterility of Products Purporting to be sterile, both
sterilization and aseptic filling and closing operations must be adequately validated"

Purpose
of
A Process Simulation
Test

PURPOSE OF A PROCESS SIMULATION TEST IS TO:
1. IT IS USEFUL IN IDENTIFY POTENTIAL WEAKNESS IN AN ASEPTIC PROCESSING OPERATION

WHICH MIGHT CONTRIBUTE TO THE MICROBIOLOGICAL CONTAMINATION OF THE PRODUCT.
2. DEMONSTRATE THE CAPABILITY OF THE ASEPTIC PROCESS TO PRODUCE STERILE DRUG

PRODUCTS.
3. QUALITY OR CERTIFY PROCESSING PERSONNEL.
4. COMPLY WITH CURRENT GOOD MANUFACTURING PRACTICE REQUIREMENTS.

Why Perform Media Fill

WHY PERFORM MEDIA FILL
• “PROCESS SIMULATION STUDIES (MEDIA FILLS) ARE SIMULATING THE WHOLE
PROCESS IN ORDER TO EVALUATE “THE STERILITY CONFIDENCE OF THE PROCESS.”
• “PROCESS SIMULATION STUDIES INCLUDE FORMULATION (COMPOUNDING),
FILTRATION AND FILLING WITH SUITABLE MEDIA.”

PRE-REQUISITES TO MEDIA FILL VALIDATION
1. CRITICAL AREA ARE QUALIFIED AND HVAC HEPA FILTERS CERTIFIED
2. ENVIRONMENTAL MONITORING PROCEDURES ARE QUALIFIED
3. ENVIRONMENTAL MONITORING MEDIA IS APPROVED FOR USE
4. EQUIPMENT AND COMPONENT STERILIZATIONS STEPS ARE VALIDATED
5. STERILE FILTRATION OF BULK PRODUCTS IS VALIDATED
6. MEDIA USED IN SIMULATIONS IS QUALIFIED & PRE GPT OF MEDIA ARE

COMPLETED
7. STAFF INVOLVED IN THE MEDIA FILL ARE QUALIFIED IN ASEPTIC GOWNING
8. STAFF ENTERING THE FILLING AREA ARE TRAINED IN ASEPTIC TECHNIQUE.
9. MEDIA FILL INSPECTORS ARE TRAINED TO DETECT TURBIDITY

WHEN ARE MEDIA TRIALS PERFORMED ?
NEW PRODUCTION LINES
CHANGES TO EXISTING PRODUCTION LINES
ROUTINE RE-VALIDATION OF ASEPTIC FILLING LINES
FACILITY SHUTDOWNS AND RE COMMISSIONING
 FAIL IN STERILITY

IMPORTANT ELEMENTS
THERE ARE TOTAL 8 ELEMENTS FOR SUCCESSFUL COMPLETION OF MEDIA FILL VALIDATION
STAFF TRAINING
STUDY DESIGN
FREQUENCY AND NUMBER OF RUNS
DURATION OF RUNS
SIZE OF RUNS
LINE SPEED
ENVIRONMENTAL CONDITIONS
MEDIA
INCUBATION
EXAMINATION OF MEDIA FILLED UNITS
INTERPRETATION OF TEST RESULTS

STAFF TRAINING
• The Training is very important prior to start the media Fill validation ; because of
Special Emphasis As a People or Person are
Potentially One of the most Main Source of Microorganisms of any Type of Contamination
in the Environment of Cleanroom.
SO
CAN’T VALIDATE A PERSON BUT CAN TRAIN THEM
• TRAINING ENCOMPASSES BEFORE MEDIA FILL VALIDATION
BASIC MICROBIOLOGY,
GOOD MANUFACTURING PRACTICE PRINCIPLES,
HYGIENE (DISINFECTION AND SANITIZATION),
ASEPTIC CONNECTIONS,
GOWNING PROCEDURES.
STUDY DESIGN
• A MEDIA FILL PROGRAM SHOULD INCORPORATE THE CONTAMINATION
RISK FACTORS THAT OCCUR ON A PRODUCTION LINE, AND ACCURATELY
ASSESSES 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.
STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING; FDA; SEP 2004

STUDY DESIGN
MEDIA FILL PROGRAM SHOULD ADDRESS APPLICABLE ISSUES SUCH AS:
• FACTORS ASSOCIATED WITH THE LONGEST PERMITTED RUN ON THE

PROCESSING LINE THAT CAN POSE CONTAMINATION RISK (E.G., OPERATOR
FATIGUE)
• 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)
• LYOPHILIZATION, WHEN APPLICABLE
• ASEPTIC ASSEMBLY OF EQUIPMENT (E.G., AT START-UP, DURING

PROCESSING)
• NUMBER OF PERSONNEL AND THEIR ACTIVITIES

STUDY DESIGN
• REPRESENTATIVE NUMBER OF ASEPTIC ADDITIONS (E.G., CHARGING
CONTAINERS AND CLOSURES AS WELL AS STERILE INGREDIENTS) OR TRANSFERS
• SHIFT CHANGES, BREAKS, AND GOWN CHANGES (WHEN APPLICABLE)
• TYPE OF ASEPTIC EQUIPMENT DISCONNECTIONS/CONNECTIONS
• ASEPTIC SAMPLE COLLECTIONS
• LINE SPEED AND CONFIGURATION
• WEIGHT CHECKS
• CONTAINER CLOSURE SYSTEMS (E.G., SIZES, TYPE, COMPATIBILITY WITH

EQUIPMENT)
• SPECIFIC PROVISIONS IN WRITTEN PROCEDURES RELATING TO ASEPTIC

PROCESSING (E.G., CONDITIONS PERMITTED BEFORE LINE CLEARANCE IS
MANDATED)

FREQUENCY & NO. OF RUNS
• THE FREQUENCY & NUMBER OF RUNS ARE DEFINED AS STAR TUP
AND ON-GOING RUNS:

• A “START-UP” SIMULATION TEST CONSISTS OF THREE CONSECUTIVE
SATISFACTORY SIMULATION TESTS PER SHIFT AND SHOULD BE CARRIED OUT
BEFORE ROUTINE MANUFACTURING CAN START.
• “START–UP” SIMULATION TESTS ARE PERFORMED FOR EXAMPLE FOR NEW

PROCESSES, NEW EQUIPMENT OR AFTER CRITIC AL CHANGES OF PROCESSES ,
EQUIPMENT OR ENVIRONMENT AS FOR EXAMPLE SIGNIFICANT PERSONNEL
CHANGES (A NEW SHIFT), MODIFICATIONS IN EQUIPMENT DIRECTLY IN CONTACT
WITH THE PRODUCT OR MODIFICATIONS IN THE HVAC SYSTEM.
PIC/S PI 007 -2; VALIDATION OF ASEPTIC PROCESS; JAN 2011

• AN “ON-GOING” SIMULATION TEST CONSISTS OF ONE SATISFACTORY
SIMULATION TEST PER SHIFT AND IS MAINLY PERFORMED FOR THE
PERIODIC MONITORING OF ASEPTIC
CONDITIONS DURING ROUTINE MANUFACTURING BUT ALSO FOR
EXAMPLE AFTER LESS CRITICAL CHANGES OF PROCESSES, EQUIPMENT OR
ENVIRONMENT OR IF PROCESSING LINES STAND IDLE FOR MORE THAN 6
MONTHS.
• “ON-GOING” SIMULATION TESTS SHOULD BE PERFORMED

WITH EACH SHIFT OF EACH PROCESS LINE AT LEAST TWICE
PER YEAR UNDER THE CONDITION THAT THERE WERE NO
CHANGES IN THE NORMAL PRODUCTION PROCEDURES AND
NO ACTION LIMITS WERE EXCEEDED.

• WHEN A PROCESSING LINE IS INITIALLY QUALIFIED, INDIVIDUAL MEDIA FILLS
SHOULD BE REPEATED ENOUGH TIMES TO ENSURE THAT RESULTS ARE
CONSISTENT AND MEANINGFUL.
• 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.
• AT LEAST THREE CONSECUTIVE SEPARATE SUCCESSFUL RUNS BE PERFORMED

DURING INITIAL LINE QUALIFICATION.
PRINCIPLE:
MINIMUM: THREE (3) TO QUALIFY THE LINE INITIALLY
MAXIMUM: ENOUGH TO ENSURE THAT RESULTS ARE CONSISTENT AND
MEANINGFUL.
ROUTINE RE-VALIDATION: EACH PROCESSING LINE EVERY 6 MONTHS.
ALL PERSONNEL WHO ARE AUTHORIZED TO ENTER THE ASEPTIC PROCESSING
ROOM DURING MANUFACTURING SHOULD PARTICIPATE AT LEAST ONCE A YEAR.
STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING; FDA; SEP
2004

• ROUTINE SEMI-ANNUAL QUALIFICATION CONDUCTED FOR EACH PROCESSING

LINE, EVALUATES T HE STATE OF CONTROL OF THE ASEPTIC PROCESS.
• ACTIVITIES AND INTERVENTIONS REPRESENTATIVE OF EACH SHIFT, AND SHIFT

CHANGEOVER, SHOULD BE INCORPORATED INTO THE DESIGN OF THE SEMI –
ANNUAL QUALIFICATION PROGRAM.

• ALLPERSONNEL 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.

DURATION OF RUNS
• THE MOST ACCURATE SIMULATION MODEL WOULD BE THE FULL BATCH SIZE
AND DURATION BECAUSE IT MOST CLOSELY SIMULATES THE ACTUAL
PRODUCTION OPERATIONS.
• THE DURATION OF THE MEDIA FILL RUN SHOULD 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.

DURATION OF RUNS
• WHERE FILLING TAKES PLACE OVER EXTENDED PERIODS,
I.E. LONGER THAN 24 HOURS, THE PROCESS SIMULATION
TEST SHOULD EXTEND OVER THE WHOLE OF THE STANDARD
FILLING PERIOD.
• IN ORDER T O PREVENT EXCESSIVELY HIGH NUMBERS OF

UNITS BEING FILLED IT IS USUALLY ACCEPTABLE TO JUST RUN
T HE MACHINE FOR A REASONABLE TIME, IF THE VALIDITY OF
THE SIMULATION IS NOT DIMINISHED BY THIS PROCEDURE.

SIZE OF RUNS
• THE SIMULATION RUN SIZE S SHOULD BE ADEQUATE T O MIMIC
COMMERCIAL PRODUCTION CONDITIONS AND ACCURATELY
ASSESS THE POTENTIAL FOR COMMERCIAL BATCH
CONTAMINATION.
• A GENERALLY ACCEPTABLE STARTING POINT FOR R UN SIZE IS IN

THE RANGE OF 5,000 TO 10,000 UNITS.
• FOR OPERATIONS WITH PRODUCTION SIZE S UNDER 5,000, THE

NUMBER OF MEDIA FILLED UNITS SHOULD AT LEAST EQUAL THE
MAXIMUM BATCH SIZE MADE ON THE PROCESSING LINE.
STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING; FDA;

SEP 2004
SIZE OF RUNS
• IF BATCHES SMALLER THAN 3000 UNITS ARE PRODUCED, THE MINIMUM

NUMBER OF CONTAINERS USED FOR THE PROCESS SIMULATION SHOULD BE
EQUAL TO THAT OF THE COMMERCIAL BATCH SIZE.

SIZE OF RUNS
• SIMULATION TESTS SHOULD BE PERFORMED ON DIFFERENT DAYS AND

HOURS DURING THE WEEK AND NOT ONLY AT THE BEGINNING OF A WORK
DAY.
• IF THE SAME PROCESS IS CONDUCTED IN A SEPARATE CLEAN ROOM,

THIS SHOULD ALSO BE VALIDATED.

SIZE OF RUNS
• IT IS ESSENTIAL TO INCLUDE IN A SIMULATION TEST THE VARIOUS
INTERVENTIONS THAT ARE KNOWN TO OCCUR DURING NORMAL
PRODUCTION RUNS, E.G. REPAIR OR REPLACEMENT OF NEEDLES/TUBES,
REPLACEMENT OF ONLINE FILTERS, MICROBIAL SAMPLING BY
MONITORING PERSONNEL AND SAMPLING DEVICE, DURATION OF STOPS
ON THE LINE, FILLING AND HANDLING OF STOPPERS ETC.
• THE PROCESS SIMULATION TEST SHOULD LAST LONG ENOUGH TO
ACCOMMODATE ALL POSSIBLE INTERVENTIONS AND A “WORST CASE
SCENARIO”, WHICH MAY INCLUDE SEVERAL UNFAVORABLE CONDITIONS
WHICH ARE OCCURRING DURING ROUTINE PROCESSING.
LINE SPEED
• THE MEDIA FILL PROGRAM SHOULD ADEQUATELY ADDRESS THE RANGE
OF LINE SPEEDS EMPLOYED DURING PRODUCTION.
• EACH MEDIA FILL RUN SHOULD EVALUATE A SINGLE LINE SPEED, AND
THE SPEED CHOSEN SHOULD BE JUSTIFIED.
STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING;

FDA; SEP 2004

LINE SPEED
• FOR EXAMPLE, USE OF HIGH LINE SPEED IS OFTEN MOST APPROPRIATE IN THE
EVALUATION OF MANUFACTURING PROCESSES CHARACTERIZED BY FREQUENT
INTERVENTIONS OR A SIGNIFICANT DEGREE OF MANUAL MANIPULATION.
• USE OF SLOW LINE SPEED IS GENERALLY APPROPRIATE FOR EVALUATING

MANUFACTURING PROCESSES WITH PROLONGED EXPOSURE OF THE STERILE DRUG
PRODUCT AND CONTAINERS/CLOSURES IN THE ASEPTIC AREA.

2004

LINE SPEED
• WORST CASE CONDITIONS ARE OFTEN THOUGHT TO BE THE
LARGEST CONTAINER WITH THE WIDEST MOUTH AS IT IS EXPOSED
LONGER TO THE ENVIRONMENT.
• HOWEVER, THERE ARE EXCEPTIONS TO THIS AND ONE OF THEM

IS SMALL AMPOULES RUN AT THE HIGHEST SPEED AS THE
AMPOULES MAY BE UNSTABLE AND CAUSE FREQUENT JAMS THUS
NECESSITATING FREQUENT OPERATOR INTERVENTION.
• APPROPRIATE COMBINATIONS OF CONTAINER SIZE AND

OPENING AS WELL AS SPEED OF THE PROCESSING LINE SHOULD BE
USED (PREFERABLY AT THE EXTREMES).

• MEDIA FILLS SHOULD BE ADEQUATELY REPRESENTATIVE OF THE

CONDITIONS UNDER WHICH ACTUAL MANUFACTURING OPERATIONS ARE
CONDUCTED.
•STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING;

FDA; SEP 2004

• 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 ANALOGOUS
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.

2004

MEDIA
• IN GENERAL, A MICROBIOLOGICAL GROWTH MEDIUM, SUCH AS SOYBEAN
CASEIN DIGEST MEDIUM, SHOULD BE USED.
• USE OF ANAEROBIC GROWTH MEDIA (E.G., FLUID THIOGLYCOLLATE MEDIUM)

SHOULD BE CONSIDERED IN SPECIAL CIRCUMSTANCES.
• THE MEDIA SELECTED SHOULD BE DEMONSTRATED TO PROMOTE GROWTH OF

GRAM- POSITIVE AND GRAM-NEGATIVE BACTERIA, AND YEAST AND MOLD (E.G.,
USP INDICATOR ORGANISMS).
• ENVIRONMENTAL MONITORING AND STERILITY TEST ISOLATES

CAN BE SUBSTITUTED (AS APPROPRIATE) OR ADDED TO THE GROWTH
PROMOTION CHALLENGE.

2004

MEDIA
• 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.
• GROWTH PROMOTION UNITS SHOULD BE INOCULATED WITH A <100 CFU

CHALLENGE.
• 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.

MEDIA
• 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
MICROORGANISMS IDENTIFIED BY RELEVANT PHARMACOPOEIAS AS BEING SUITABLE
FOR USE IN THE GROWTH PROMOTION TEST.

MEDIA
• 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.

MEDIA
• CLARITY: THE MEDIUM SHOULD BE CLEAR TO ALLOW FOR EASE IN OBSERVING TURBIDITY.
• MEDIUM CONCENTRATION: RE COMMENDATIONS OF THE SUPPLIER SHOULD BE

FOLLOWED UNLESS ALTERNATIVE CONCENTRATIONS ARE VALIDATED T O DELIVER EQUAL
RESULTS.
• 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.

INCUBATION CONDITIONS
• IT IS GENERALLY ACCEPTED TO INCUBATE AT 20-25° C FOR A MINIMUM OF 7 DAYS

FOLLOWED IMMEDIATELY, OR AFTER A FIRST READING, BY INCUBATION AT 30-35°
C FOR A TOTAL MINIMUM INCUBATION TIME OF 14 DAYS.
• OTHER INCUBATION SCHEDULES SHOULD BE BASE D ON SUPPORTING

VALIDATION DATA.

• ISOLATES AND SHOULD AT NO TIME BE OUTSIDE THE RANGE OF 20-350C.
INCUBATION TEMPERATURE SHOULD BE
MAINTAINED WITHIN +2.50C OF THE TARGET TEMPERATURE.
• INCUBATION TIME SHOULD NOT BE LESS THAN 14 DAYS.
• IF 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).

2004
• PRIOR TO INCUBATION THE CONTAINERS WITH THE MICROBIOLOGICAL GROWTH
MEDIUM SHOULD BE INVERTED OR OTHERWISE MANIPULATED TO ENSURE THAT

ALL SURFACES, INCLUDED THE INTERNAL SURFACE OF THE
CLOSURE, ARE THOROUGHLY WETTED BY THE MEDIUM.
• THE CONTAINERS SHOULD NOT BE COMPLETELY FILLED WITH MEDIUM IN

ORDER TO PROVIDE SUFFICIENT OXYGEN FOR THE GROWTH OF OBLIGATE
AEROBES.
• SIMILARLY, CONTAINERS SHOULD NOT BE OVERLAID WITH INERT GASES EVEN
THOUGH THE PRODUCT MAY BE.

EXAMINATION OF MEDIA FILL UNITS
• EACH MEDIA -FILLED UNIT SHOULD BE EXAMINED FOR CONTAMINATION

BY PERSONNEL WITH APPROPRIATE EDUCATION, 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 QC MICROBIOLOGIST.

2004

• WHEN INSPECTING THE CONTAINERS THEY SHOULD BE COMPARED TO A
KNOWN STERILE CONTAINER FOR COMPARISON AS SOME MICROBIAL
GROWTH SHOWS UP AS A FAINT HAZE WHICH IS DIFFICULT TO DETECT
UNLESS THERE IS A CONTROL CONTAINER TO COMPARE AGAINST.
• PERSONNEL SHOULD BE TRAINED FOR THIS TASK.

• TO ALLOW FOR VISUAL DETECTION OF MICROBIAL GROWTH, WE RECOMMEND
SUBSTITUTING CLEAR CONTAINERS (WITH OTHERWISE IDENTICAL PHYSICAL
PROPERTIES) FOR AMBER OR OTHER OPAQUE CONTAINERS. IF APPROPRIATE,
OTHER METHODS CAN ALSO BE CONSIDERED TO ENSURE VISUAL DETECTION.
2004

• WHEN A FIRM PERFORMS A FINAL PRODUCT INSPECTION OF UNITS IMMEDIATELY
FOLLOWING THE MEDIA FILL RUN, ALL INTEGRAL UNITS SHOULD PROCEED T O INCUBATION.
• UNITS FOUND TO HAVE DEFECTS NOT RELATED T O INTEGRITY (E.G., COSMETIC DEFECT )
SHOULD BE INCUBATED
• UNITS THAT LA CK INTEGRITY SHOULD BE REJECTED. ERRONEOUSLY REJECTED UNITS

SHOULD BE RETURNED PROMPTLY FOR INCUBATION WITH THE MEDIA FILL LOT.

• APPROPRIATE CRITERIA SHOULD BE ESTABLISHED FOR YIELD AND

ACCOUNTABILITY (RE CONCILIATION OF FILLED UNITS).
• MEDIA FIL RECORD RÉCONCILIATION DOCUMENTATION SHOULD INCLUDE A

FULL ACCOUNTING AND DESCRIPTION OF UNITS REJECTED FROM A BATCH.

INTERPRETATION OF RESULTS
• THE PROCESS SIMULATION RUN SHOULD BE OBSERVE D BY THE QC UNIT, AND
CONTAMINATE D UNITS SHOULD BE RECONCILABLE WITH THE APPROXIMATE
TIME AND THE ACTIVITY BEING SIMULATED DURING THE MEDIA FILL.
• VIDEO RECORDING OF A MEDIA FILL MAY SERVE AS A USE FULAIDE IN
IDENTIFYING PERSONNEL PRACTICES THAT COULD NEGATIVELY AFFECT THE
ASEPTIC PROCESS.
2004

• IN ORDER TO FIND THE POSSIBLE SOURCE OF CONTAMINATION IT MAY BE A
GOOD ADVISE TO VIDEO TAPE THE ASEPTIC FILL AND ALSO NUMBER THE
INDIVIDUAL VIALS OR SEGREGATE VIALS IN CHRONOLOGICAL ORDER DURING
INCUBATION.
• 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.
STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING, FDA, SEP- 2004

• RECOMMENDED CRITERIA FOR ASSESSING STATE OF ASEPTIC LINE CONTROL:
• WHEN FILLING FEWER THAN 5000 UNITS:
NO CONTAMINATED UNIT S 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.
1.0 STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING, FDA, SEP- 2004
2.0 PIC/S PI 007 -2; VALIDATION OF ASEPTIC PROCESS; JAN 2011

A Media Fill --- also known as Process Simulation

Uploaded by

Copyright:

Available Formats

You might also like

A Media Fill --- also known as Process Simulation

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

A Media Fill --- also known as Process Simulation

Uploaded by

Copyright:

Available Formats

MEDIA FILL

Arvind Kumar Srivastava

When you understand the reasons for a particular GMP

In this session we will understand

Arvind Kumar Srivastava , Quality Assurance Department , arvindsri82@gmail.com

Method of evaluating an aseptic process and find out the

weakest Link , By using a microbial growth medium.

It is a tool that is used to assess the capability of an Aseptic

process to deliver a drug product that is sterile and free from

( Media fills are understood to be synonymous to

Simulated Product Fills , Broth Trials , Broth Fills etc.)

Arvind Kumar Srivastava , Quality Assurance Department , arvindsri82@gmail.com

Arvind Kumar Srivastava , Quality Assurance Department , arvindsri82@gmail.com

FDA GUIDANCE FOR INDUSTRY – STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC

PROCESSING — CURRENT GOOD MANUFACTURING PRACTICE

EU GMP ANNEX – 1: MANUFACTURE OF THE STERILE MEDICINAL PRODUCTS.

PIC/S PI 007-2 “RECOMMENDATIONS ON THE VALIDATION OF ASEPTIC PROCESS”

WHO GMP GUIDELINES –TECHNICAL REPORT SERIES NO. 937; ANNEX- 4

INDUSTRY DOCUMENTS – PDA TECH REPORT 22 PDA TECH REPORT 28

Arvind Kumar Srivastava , Quality Assurance Department , arvindsri82@gmail.com

An aseptic processing operation should be validated using a microbiological growth

Arvind Kumar Srivastava , Quality Assurance Department , arvindsri82@gmail.com

Arvind Kumar Srivastava , Quality Assurance Department , arvindsri82@gmail.com

EU GMP Annex- 1 : "Validation of aseptic processing should include a

Arvind Kumar Srivastava , Quality Assurance Department , arvindsri82@gmail.com

requirements (parts 2-8 also deal with aseptic processing)

aseptic process and include all aseptic manipulations. It is possible to divide

Arvind Kumar Srivastava , Quality Assurance Department , arvindsri82@gmail.com

Processing , Pharmaceuticals and Medical Devices Agency , from Ministry of Health,

evaluate the propriety of the aseptic processing of pharmaceutical products using

sterile media instead of actual product.

Arvind Kumar Srivastava , Quality Assurance Department , arvindsri82@gmail.com

Media-fill test: A simulation used to qualify processes and personnel engaged in

Compound Sterile Preparations (CSPs ) without contamination.

Arvind Kumar Srivastava , Quality Assurance Department , arvindsri82@gmail.com

(b) Appropriate written procedures, designed to prevent microbiological contamination of

Arvind Kumar Srivastava , Quality Assurance Department , arvindsri82@gmail.com

Arvind Kumar Srivastava , Quality Assurance Department , arvindsri82@gmail.com

1. IT IS USEFUL IN IDENTIFY POTENTIAL WEAKNESS IN AN ASEPTIC PROCESSING OPERATION

2. DEMONSTRATE THE CAPABILITY OF THE ASEPTIC PROCESS TO PRODUCE STERILE DRUG

3. QUALITY OR CERTIFY PROCESSING PERSONNEL.

4. COMPLY WITH CURRENT GOOD MANUFACTURING PRACTICE REQUIREMENTS.

Arvind Kumar Srivastava , Quality Assurance Department , arvindsri82@gmail.com

Arvind Kumar Srivastava , Quality Assurance Department , arvindsri82@gmail.com

• “PROCESS SIMULATION STUDIES (MEDIA FILLS) ARE SIMULATING THE WHOLE

PROCESS IN ORDER TO EVALUATE “THE STERILITY CONFIDENCE OF THE PROCESS.”

• “PROCESS SIMULATION STUDIES INCLUDE FORMULATION (COMPOUNDING),

FILTRATION AND FILLING WITH SUITABLE MEDIA.”

Arvind Kumar Srivastava , Quality Assurance Department , arvindsri82@gmail.com

2. ENVIRONMENTAL MONITORING PROCEDURES ARE QUALIFIED

3. ENVIRONMENTAL MONITORING MEDIA IS APPROVED FOR USE

4. EQUIPMENT AND COMPONENT STERILIZATIONS STEPS ARE VALIDATED

5. STERILE FILTRATION OF BULK PRODUCTS IS VALIDATED

6. MEDIA USED IN SIMULATIONS IS QUALIFIED & PRE GPT OF MEDIA ARE

7. STAFF INVOLVED IN THE MEDIA FILL ARE QUALIFIED IN ASEPTIC GOWNING

8. STAFF ENTERING THE FILLING AREA ARE TRAINED IN ASEPTIC TECHNIQUE.

9. MEDIA FILL INSPECTORS ARE TRAINED TO DETECT TURBIDITY

NEW PRODUCTION LINES

CHANGES TO EXISTING PRODUCTION LINES