Media Fill (Aseptic Process Simulation)

COMPARISON OF GUIDELINE
PIC/S
PDA
USFDA September 2004 PHARMACEUTICAL EU (EUROPEAN
Sr.NO. TOPIC PDA Technical Report
Sterile Drug Products INSPECTION CO- COMMISSION) Annex-1
No. 22 (Revised 2011)
Produced by Aseptic OPERATION SCHEME 22.8.2022
2011 Parenteral Drug
Processing PI 007-6 1 January 2011 Manufacture of Sterile
Association
Medicinal Products
Aseptic Processing Process simulation, also known as Process simulation studies Aseptic Process Simulation
Simulation (APS) a media fill, normally includes (media fills) are simulating (APS) – A simulation of the
A means for establishing the exposing the microbiological the whole process in entire aseptic manufacturing
capability of an aseptic growth medium to product Order to evaluate the sterilityprocess in order to verify the
Process as performed using a contact surfaces of equipment, confidence of the process. capability of the process to
growth medium. container closure systems, critical Process simulation assure product sterility.
Note: Aseptic processing environments, and process studies include formulation Includes all aseptic
simulations are understood manipulations to closely simulate (compounding), filtration and operations associated with
to be synonymous with the same exposure that the filling with suitable routine manufacturing, e.g.
media fills, product itself will undergo. The Media. equipment assembly,
Process simulations, sealed containers filled with the Ref. page number:- 02 formulation, filling,
simulated product fills, medium are then incubated to lyophilization and sealing
1. Definition of media fill Broth trials, etc. detect microbial contamination. processes as necessary.
Ref. page number:- 5 Results are then interpreted to Ref. page number:- 3
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 can
also provide useful information
for the processing line evaluation.
Ref. page number:- 21
 The most common  In general, a microbiological  The criteria for the  Selection of an
medium for process growth medium, such as selection of growth appropriate nutrient media
simulation is Soybean- soybean casein digest medium, medium include: low and/or surrogate should be
2. Selection of Media
Casein Digest Medium should be used. selectivity, clarity, made based on the ability
(SCDM).  Use of anaerobic growth media Medium concentration and of the media and/or
(e.g., fluid thioglycollate filterability. surrogate to imitate
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 Media Fill (Aseptic Process Simulation)
COMPARISON OF GUIDELINE
PIC/S
PDA
USFDA September 2004 PHARMACEUTICAL EU (EUROPEAN
Sr.NO. TOPIC PDA Technical Report
Sterile Drug Products INSPECTION CO- COMMISSION) Annex-1
No. 22 (Revised 2011)
Produced by Aseptic OPERATION SCHEME 22.8.2022
2011 Parenteral Drug
Processing PI 007-6 1 January 2011 Manufacture of Sterile
Association
Medicinal Products
SCDM is a general medium) should be considered  Low Selectivity: The physical product
purpose growth medium in special circumstances. medium selected should be characteristics assessed to
well suited for the  The media selected should be capable of supporting a pose a risk to product
recovery of aerobic demonstrated to promote growth wide sterility during the aseptic
microorganisms of gram-positive and gram- range of microorganisms, process. Where processing
of the types commonly negative bacteria, and yeast and which might reasonably be stages may indirectly
associated with human mold (e.g., USP indicator encountered and be impact the viability of any
borne contamination organisms). The QC laboratory Based also on the in house introduced microbial
Refer page number-22. should determine if USP flora (e.g. isolates from contamination, (e.g.
 The growth promotion indicator organisms sufficiently monitoring etc.). aseptically produced semi-
properties of the incubation represent production-related  Media used in the solids, powders, solid
media should be evaluated isolates. evaluation must pass a materials, microspheres,
using pharmacopeia  Growth promotion units should growth promotion test. Refer page number-47.
methods The inclusion of be inoculated with a <100 CFU Growth promotion tests
tests for environmental challenge. should demonstrate that the
organisms or those isolated  Container closure surfaces medium supports
from sterility test (when the unit is inverted or Recovery and growth of low
 Positives are recommended thoroughly swirled) and permit numbers of microorganisms,
(6). Growth promotion visual detection of microbial i.e. 10-100 CFU/unit or less.
studies are commonly growth.  Clarity: The medium
performed after 14 days of Refer page number-24. should be clear to allow for
incubation. ease in observing turbidity.
Refer page number-27.  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.
Refer page number-07 &
08.

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 Media Fill (Aseptic Process Simulation)
COMPARISON OF GUIDELINE
PIC/S
PDA
USFDA September 2004 PHARMACEUTICAL EU (EUROPEAN
Sr.NO. TOPIC PDA Technical Report
Sterile Drug Products INSPECTION CO- COMMISSION) Annex-1
No. 22 (Revised 2011)
Produced by Aseptic OPERATION SCHEME 22.8.2022
2011 Parenteral Drug
Processing PI 007-6 1 January 2011 Manufacture of Sterile
Association
Medicinal Products

The volume filled per

First, there must be enough
container, which should be
medium in the container to The fill volume of the
sufficient to ensure that the
contact all the container- Each unit should be filled with an containers should be
media contacts all equipment
closure seal surfaces when appropriate quantity and type of sufficient to enable contact
and component surfaces that
the container is inverted and microbial growth medium to of all the container-closure
may directly contaminate the
swirled. Second, there must contact the inner container closure seal surfaces when the
3. Fill Volume sterile product. The volume
be enough medium in the surfaces (when the unit is inverted container is inverted and also
used should provide
container to allow for the or thoroughly swirled) and permit sufficient to allow the
sufficient headspace to
detection of microbial visual detection of microbial detection of microbial
support potential microbial
growth. growth. growth.
growth and ensure that
Ref. page number:- 23 to Ref. page number:- 24 Ref. page number:- 7
turbidity can be detected
24
during inspection.
Ref. page number:-48
 All the inherent (part  Any intervention or  Intervention The APS should take into
of the process) and stoppage during an aseptic Monitoring: It is essential account various aseptic
corrective (problem process can increase the risk of to include in a simulation manipulations and
resolution) interventions contamination. The design of test the various interventions known to occur
That occur during an equipment used in aseptic. interventions that are during normal production as
aseptic filling process. Ref. page number:- 10 known to occur during well as worst-case situations,
Ref. page number:- 48  Unplanned interventions: normal production runs, e.g. and take into account the
Inherent Interventions should be sufficiently repair or replacement of following:
4.
Type of intervention Inherent interventions are documented in batch records needles/tubes, replacement of  Inherent and corrective
normal and planned with the associated time and on-line filters, microbial interventions
activities that occur during duration of the event machine sampling by monitoring representative of the
an aseptic filling process adjustments and any repairs, personnel and sampling routine process should
(e.g., equipment set-up, should be established. Such device, duration of stops on be performed in a
weight adjustments, closure interventions should be the line, filling and handling manner and frequency
re-supply, container re- documented with more detail of stoppers etc similar to that during the
supply, EM sampling, than minor events. Interventions routine aseptic process.
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 Media Fill (Aseptic Process Simulation)
COMPARISON OF GUIDELINE
PIC/S
PDA
USFDA September 2004 PHARMACEUTICAL EU (EUROPEAN
Sr.NO. TOPIC PDA Technical Report
Sterile Drug Products INSPECTION CO- COMMISSION) Annex-1
No. 22 (Revised 2011)
Produced by Aseptic OPERATION SCHEME 22.8.2022
2011 Parenteral Drug
Processing PI 007-6 1 January 2011 Manufacture of Sterile
Association
Medicinal Products
Etc.). Inherent interventions that result in substantial activity  The process simulation
are not corrections to events near exposed product or test should last long enough  The inclusion and
that occur on the filling line. container closures or that last to accommodate all frequency of
 Corrective beyond a reasonable exposure possible interventions and a interventions in the APS
Interventions: Corrective time should, where appropriate, “worst case scenario”, which should be based on
interventions are result in a local or full line may include several assessed risks posed to
performed to correct or clearance. Unfavorable conditions product sterility.
adjust an aseptic process Ref. page number:- 42 which are occurring during Ref. page number:-
during its execution. routine processing. 48
While not part of the
planned aseptic process, they
are well understood
operations and are
recognized to sometimes
occur during processing.
Corrective interventions
include: container break-
age, tip-over of a container,
stopper jam, change in
filling needle, change in
filling equipment, dose
adjustments/
samples, clearing
automatically rejected units,
etc. Ref. page number:- 28
Batch size/Size of runs  Duration and  Size of Runs: A  When filling fewer  An investigation to
Duration of Number of Units Filled generally acceptable starting than 5000 units, no determine the most
run :The duration and number point for run size is in the range contaminated units should probable root cause(s).
5.
of units filled for an aseptic of 5,000 to 10,000 units. For be detected. Determination and
process simulation should operations with production sizes  When filling 5,000 implementation of The
be sufficient to under 5,000, the number of to 10,000 units: number of units processed
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 Media Fill (Aseptic Process Simulation)
COMPARISON OF GUIDELINE
PIC/S
PDA
USFDA September 2004 PHARMACEUTICAL EU (EUROPEAN
Sr.NO. TOPIC PDA Technical Report
Sterile Drug Products INSPECTION CO- COMMISSION) Annex-1
No. 22 (Revised 2011)
Produced by Aseptic OPERATION SCHEME 22.8.2022
2011 Parenteral Drug
Processing PI 007-6 1 January 2011 Manufacture of Sterile
Association
Medicinal Products
adequately challenge the media filled units should at least a) One (1) contaminated unit (filled) for APS should be
aseptic process, equal the maximum batch size should result in an sufficient to effectively
Small scale: < 5,000 units made on the processing line. investigation, including simulate all activities that
(APS batch size should be at  When the possibility of consideration of a repeat are representative of the
least equal to production contamination is higher based media fill; aseptic manufacturing
batch size.) on the process design (e.g., b) Two (2) contaminated process. Justification for
Mid-scale: 5,000 to 10,000 manually intensive filling lines), units are considered cause the number of units to be
units (APS batch size should a larger number of units, for revalidation, following filled should be clearly
be of comparable generally at or approaching the investigation. captured in the CCS.
Size to the production batch full production batch size,  When filling more Typically, a minimum of
size. should be used. than 10,000 units: 5000 to 10000 units are
For high speed filling or Ref. page number:- 23 filled. For small batches
with maximum a) One (1) contaminated unit (e.g. those under 5000
size production batches) should result in an units), the number of
Large scale: > 10,000 units investigation; containers for APS should
Ref. page number:- 25 b) Two (2) contaminated at least equal the size of the
units are considered cause production batch.
for revalidation, following Ref. page number:- 49
investigation For any run
size, intermittent incidents of
microbial contamination may
be indicative of low-level
contamination that should be
investigated. Investigation of
gross failures should include
the potential impact on the
sterility assurance of batches
manufactured since the last
successful media fill.
Ref. page number:- 11

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 Media Fill (Aseptic Process Simulation)
COMPARISON OF GUIDELINE
PIC/S
PDA
USFDA September 2004 PHARMACEUTICAL EU (EUROPEAN
Sr.NO. TOPIC PDA Technical Report
Sterile Drug Products INSPECTION CO- COMMISSION) Annex-1
No. 22 (Revised 2011)
Produced by Aseptic OPERATION SCHEME 22.8.2022
2011 Parenteral Drug
Processing PI 007-6 1 January 2011 Manufacture of Sterile
Association
Medicinal Products
Each media fill run should Filling line speed : In general, Worst case conditions are Identification of worst case
evaluate a single line speed, the fill speed to be used for most often thought to be the conditions covering the
and the speed chosen should containers should be set at the largest container with the relevant variables, such as
be justified. For example, production filling speed Widest mouth as it is container size and line speed,
use of high line speed is Range for that size container in exposed longer to the and their impact on the
often most appropriate in the commercial production. Where environment. However, there process. The outcome of the
evaluation of manufacturing production filling speeds on a line are assessment should justify
processes characterized by are exceptions to this and one of thevariables selected.
frequent interventions or a variable, if higher or lower speeds them is small ampoules run Ref. page number:- 48
significant degree of manual in the speed range result in the at the highest
manipulation. Use of slow potential for greater interventions speed as the ampoules may
line speed is generally or other adverse impact such as be unstable and cause
Machine speed/Line
6. appropriate for evaluating increased product exposure to frequent jams thus
speed during media fill
manufacturing processes environment, that speed can be necessitating frequent
with prolonged exposure of considered ‘worst case’ and operator intervention.
the sterile drug product and should be considered when Ref. page number:- 16
containers/closures in the selecting process simulation
aseptic area parameters (See
Ref. page number:- 24 Section 3.2 i.e. Using the slowest
fill speed for the largest container
(maximum opening)
• Using the highest fill speed for
the smallest container (handling
difficulty)).
Ref. page number:- 23
Current regulatory guidance Guidance on media simulation For all aseptic processes,
in major studies. Process simulation An “on-going” simulation aseptic process simulations
regions recommends aseptic studies for the formulation stage test consists of one should be performed as part
7. Frequency of media fill
process simulations as part should be performed at least twice satisfactory simulation test of initial validation and
of ongoing process per year. per repeated thereafter every six
evaluation once every six Ref. page number:- 53 months in line
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 Media Fill (Aseptic Process Simulation)
COMPARISON OF GUIDELINE
PIC/S
PDA
USFDA September 2004 PHARMACEUTICAL EU (EUROPEAN
Sr.NO. TOPIC PDA Technical Report
Sterile Drug Products INSPECTION CO- COMMISSION) Annex-1
No. 22 (Revised 2011)
Produced by Aseptic OPERATION SCHEME 22.8.2022
2011 Parenteral Drug
Processing PI 007-6 1 January 2011 Manufacture of Sterile
Association
Medicinal Products
Months Ref. page number:- Shift and is mainly Ref. page number:- 49
22,35 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. PI
007-6 1 January 2011 Ref.
page number:- 6
Prior to incubation the
containers with the
microbiological growth
Filled APS units should be
filled APS units should be medium
When the unit is inverted or agitated, swirled or inverted
inverted or manipulated to should be inverted or
thoroughly swirled) and permit before incubation to ensure
aseptic process simulation ensure contact of the otherwise manipulated to
visual detection of microbial Contact of the media with all
8. units/container are Medium with all internal ensure that all surfaces,
growth. interior surfaces in the
inverted/or upright position surfaces of the closure included the internal surface
Ref. page number:- 24 container. Cosmetic defects,
system before they are of the closure, are thoroughly
Ref. page number:- 43
incubated for 7 day. wetted by the
Medium.
Ref. page number:- 8

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 Media Fill (Aseptic Process Simulation)
COMPARISON OF GUIDELINE
PIC/S
PDA
USFDA September 2004 PHARMACEUTICAL EU (EUROPEAN
Sr.NO. TOPIC PDA Technical Report
Sterile Drug Products INSPECTION CO- COMMISSION) Annex-1
No. 22 (Revised 2011)
Produced by Aseptic OPERATION SCHEME 22.8.2022
2011 Parenteral Drug
Processing PI 007-6 1 January 2011 Manufacture of Sterile
Association
Medicinal Products

Incubation temperature should be

suitable for recovery of bioburden Filled APS units should be
and environmental isolates and is generally accepted to incubated without
should at no time be outside the incubate at 20-25°C for a unnecessary delay to achieve
APS units should range of 20-35oC. Incubation minimum of 7 days the best possible recovery of
be incubated for a minimum temperature should be maintained followed immediately, or potential contamination. The
of 14 days, A single within +2.5oC of the target after a first reading, by selection of the incubation
Incubation and
incubation temperature in temperature. incubation at 30-35°C for a conditions and duration
9. examination of media filled
the range of • Incubation time should not be Total minimum incubation should be scientifically
units
20-35°C may be used less than 14 days. If two time of 14 days. Other justified and validated to
Ref. page number:- 27 temperatures are used for the incubation schedules should provide an appropriate level
incubation of the media filled Be based on supporting of sensitivity of detection of
units, the units should be validation data. microbial contamination
incubated for at least 7 days at Ref. page number:- 8 Ref. page number:- 50
each temperature (starting with
the lower temperature).
Ref. page number:- 25
unit Accountability and  Number of containers for
 The target should be zero
Reconciliation:  When filling fewer than 5000 media fills should at least
growth and the following
 The ultimate goal units (One (1) contaminated unit equal the size of the product
should
for the number of is considered cause for batch. The target should be
apply:
positives in any revalidation, following an zero growth and the
 When filling fewer than
process simulation investigation.) following should
5000 units, no contaminated
10. Acceptance criteria should be zero apply:
units should be detected.
the target acceptance  When filling from 5,000 to When filling fewer than 5000
 When filling 5,000 to
criterion for an aseptic 10,000 units: units, no contaminated units
10,000 units:
process simulation study is  - One (1) contaminated unit should be detected.
a) One (1) contaminated unit
zero contaminated units, should result in an investigation, When filling 5,000 to
should result in an
Ref. page number:- 27 including consideration of a 10,000 units:
investigation, including
repeat media fill.
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 Media Fill (Aseptic Process Simulation)
COMPARISON OF GUIDELINE
PIC/S
PDA
USFDA September 2004 PHARMACEUTICAL EU (EUROPEAN
Sr.NO. TOPIC PDA Technical Report
Sterile Drug Products INSPECTION CO- COMMISSION) Annex-1
No. 22 (Revised 2011)
Produced by Aseptic OPERATION SCHEME 22.8.2022
2011 Parenteral Drug
Processing PI 007-6 1 January 2011 Manufacture of Sterile
Association
Medicinal Products
 -- Two (2) contaminated units consideration of a repeat a) One (1) contaminated unit
are considered cause for media fill; should result in an
revalidation, following b) Two (2) contaminated investigation, including
investigation. units are considered cause consideration of a repeat
 When filling more than 10,000 for revalidation, following media fill;
units: Investigation. b) Two (2) contaminated
 -- One (1) contaminated unit  When filling more than units are considered cause for
should result in an investigation. 10,000 units: revalidation, following
-- Two (2) contaminated units are a) One (1) contaminated unit Investigation.
considered cause for revalidation, should result in an When filling more than
following investigation. Ref. investigation; 10,000 units:
page number:- 26 b) Two (2) contaminated a) One (1) contaminated unit
units are considered cause should result in an
for revalidation, following investigation;
Investigation. b) Two (2) contaminated
 For any run size, units are considered cause for
intermittent incidents of revalidation, following
microbial contamination Investigation.
may be indicative of Ref. page number:- 49
Low-level contamination that
should be investigated.
Investigation of gross
failures should
Include the potential impact
on the sterility assurance of
batches manufactured since
the last successful media fill.
Ref. page number:- 11

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 Media Fill (Aseptic Process Simulation)
COMPARISON OF GUIDELINE
PIC/S
PDA
USFDA September 2004 PHARMACEUTICAL EU (EUROPEAN
Sr.NO. TOPIC PDA Technical Report
Sterile Drug Products INSPECTION CO- COMMISSION) Annex-1
No. 22 (Revised 2011)
Produced by Aseptic OPERATION SCHEME 22.8.2022
2011 Parenteral Drug
Processing PI 007-6 1 January 2011 Manufacture of Sterile
Association
Medicinal Products
Process simulation In order to find the possible 
observation should be source of contamination it
documented and/or video may be a good advice to
recorded. The use of video  Video recording of a media fill video tape the aseptic fill.
may serve as a useful aide in
recording has advantages as page number -7
process simulation activity identifying personnel practices
11. Video recording
can be reviewed in detail to that could negatively affect the
assist with aseptic process.
Training or failure Page-26
investigation.
page number-20
To be include……..
 Hold time of SS accessories
 RABS/ open door intervention
 Maximum person , for max time stay inside the filling room
12.  online particle counter challenge during APS
 Video of APS can be delete after successful completion?
 New operator qualification during APS procedure.

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