FDA 483 Observations on Media Fill / Aseptic Process Stimulations

MEDIA FILL 483’S

Aseptic processing attracts high level of regulatory scrutiny due to the risks associated with this type of manufacturing and its potential adverse effect on the patients.

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.

1.	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.
2.	SOP XXXX did not indicate that vials were to be re-inverted after the seven day incubation period.
3.	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.
4.	SOP XXX did not define the circumstances under which media fill could be aborted or invalidated.
5.	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.
6.	Not all units filled during media fills were incubated.
7.	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.
8.	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.
9.	There was no reconciliation of the quantity of the units inspected against the quantity incubated.
10.	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.
11.	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.
12.	Multiple interventions occur simultaneously during routine aseptic filling, but multiple simultaneous interventions are not included in the media fill process simulations.
13.	The firm does not have a scientific rationale to support discarding and not incubating the vials from the intervention zone.
14.	Interventions on filling nozzles were not stimulated during media fills.
15.	A list of personnel qualified through media fills participation and the validity period of their qualification, was not mentioned.
16.	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.