MEDIA FILL 483’S
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Media fill (process stimulation) is the performance of an
aseptic manufacturing procedure using a
sterile microbiological growth medium in place of the drug solution. Media fill
studies stimulating the whole aseptic
process in order to evaluate the sterility confidence of the process. Hence
FDA inspectors are increasingly focused on media fill studies.
Media fill violations are the top deficiency in the
manufacture of sterile drugs for decades. Many of the observations provided by
the FDA to various companies are quite basic and repetitive in nature. In this
article “pharma Treasures” sharing few of this inspectional observations with
its viewers.
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1.
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Media fill
conducted by the firm within the ISO 5 environments are inadequate in that
the firm does not record the results of the positive control to indicate the
media was able to support growth. In addition the media fill record does not
include sufficient detail to establish that the conditions mimic those that
occur during routine production (such as number of individuals in the room,
equipment placement, door opening and closing etc.) the total time for
completion of media fill is not recorded. Furthermore, there is no
documentation made of which ISO 5 environment or room was used to conduct
each media fill.
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2.
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SOP
XXXX did not indicate that vials were to be re-inverted after the seven day
incubation period.
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3.
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The firm failed to establish maximum holding
times for vials used in media fills, prior to incubation. The media fill
protocol for batch does not establish a set timeframe between completion of
filling vials and placing filled vials in the incubators. It was found that,
during a media fill operation the vials filled on July 24 and July 25, 2012,
and did not incubate them until July 30, July 31, and August 1, 2012. The
delay incubation is justified as ‘lack of space to perform the visual
inspection’ and to ‘personnel resource constraints’.
Note: Upon completion of filling the media fill
vials, the vials should be incubated under conditions (time and temperature) adequate
to allow detection of microorganisms that might otherwise be difficult to
culture. Data should be maintained to show monitoring of, and conformance to,
those conditions.
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4.
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SOP
XXX did not define the circumstances under which media fill could be aborted
or invalidated.
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5.
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The
media fill protocol XXX does not provide specific instructions for
performance of media fill interventions nor does it provide instructions for
remedial actions in the event of a failure.
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6.
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Not
all units filled during media fills were incubated.
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7.
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Procedures designed to prevent microbiological
contamination of drug products purporting to be sterile are not established
and followed.
Specifically, The firm has yet to complete a media fill
that simulates the commercial batch inspection process. From 4/18/2008 to
present, ten media fills have been performed. All ten media fills have
undergone a manual visual inspection. The proposed commercial batches,
including the process validation batches, are scheduled to undergo an
automated inspection process which includes the vibrator/shaker table.
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8.
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The
firm failed to conduct adequate investigations of three media fill failures
in the aseptic filling line used to produce sterile products.
The
firm performed the last successful media fill using the xxx vials on November 28, 2010, and the
last successful media fill lot for yyy vials on February 26, 2011. Significantly,
the three media fill failures on filling line 123 occurred from May to
September 2011. While the last successful xxx media fill on this line (123) was conducted on
November 28, 2010, the firm released batches manufactured on this same
filling line between November 28, 2010 and February 26, 2011. The firm failed
to adequately evaluate the impact of the contamination hazards revealed by
these media fill failures on commercial batches.
The
firm’s investigation found that the media fill batches were contaminated with
Burkholderia cepacia. But the investigation was not extended to other
areas of the aseptic operation. For example, deficient design or control of
rooms, equipment, or the Water for Injection (WFI) system, may also have
caused the introduction of these water-borne microbes to the aseptically
processed vials.
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9.
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There
was no reconciliation of the quantity of the units inspected against the
quantity incubated.
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10.
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Media
fill do not stimulate production process under normal operating conditions.
Some of the deficiencies include
a. The operator mixes the
sterile media powder in an uncontrolled area instead of the ISO7 area where
non sterile powders are handled during routine production.
b. The filled beaker where
this media is prepared is sanitized with disinfectants prior to entering in
to the ISO 7 area & ISO 5 hoods thus exposing the open media to disinfectants.
c. Growth promotion tests
are not performed on the media used for media fills.
d. As per SOP XXX, no
environmental monitoring i.e finger tip, air & surface is conducted
during media fills.
e. SOP XXX requires the
removal of the sterilizing filter during media fills of “medium risk” product
thus not representing actual production operations.
f. The media fill did not
incorporate worst case conditions such as longer process times, extended
exposure of components, interruptions/breaks or other applicable routine
stimulations that could potentially impact the sterility of the products.
g. 10 ml sterile vials used
in the media fills do not represent the larger 50ml vials used in regular
production.
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11.
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Firms media fill studies were insufficient to
establish that the aseptic process is in control. During media fill studies,
firm failed to establish appropriate
criteria for reconciliation of filled vials (total units evaluated/incubated
as compared to the total number of units filled) resulting in inconsistent and
inaccurate media fill results. For six media fill lots manufactured from 2009
to 2011, the number of units filled did not match the number being
evaluated/incubated. The number of units evaluated/incubated in some media
fill runs was smaller than what had been filled, and in other media fill
runs, the number of units evaluated/incubated was greater than what had been
filled.
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12.
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Multiple
interventions occur simultaneously during routine aseptic filling, but
multiple simultaneous interventions are not included in the media fill
process simulations.
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13.
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The
firm does not have a scientific rationale to support discarding and not incubating
the vials from the intervention zone.
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14.
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Interventions
on filling nozzles were not stimulated during media fills.
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15.
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A
list of personnel qualified through media fills participation and the
validity period of their qualification, was not mentioned.
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16.
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Media
fill procedures were inadequate in demonstrating that the commercial process
is capable of consistently producing sterile units. For example
a. Interventions were not
documented.
b. Media fills have been
invalidated due to contamination during “difficult aseptic connections”
although documentation does not support any problems.
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