Teva Pharmaceutical Works Pvt. Ltd. receives “Microbiologically Loaded” Warning Letter (Click Here) as a result of a FDA inspection which occurred from January 21 -29, 2016. As a result of this inspection, a Form FDA 483 and a Warning Letter (October 13, 2016) were issued. The Warning Letter consisted of seven citations, many of them dealing with media fills and aseptic filling.
Teva was cited as per 21 CFR 211.192, a general “catch-all” section of 21 CFR 211 that will periodically pertain to microbiological issues. In this case media fills were the primary issue. Within 1(a), the FDA stated:
- a. Media Fills
“You did not adequately investigate media fill contamination in your aseptic manufacturing lines. For example, media fill run (b)(4), performed September 14-16, 2015, in the closed Restricted Access Barrier System (RABS) small volume parenteral line in (b)(4), yielded 31 contaminated units. In addition, media fills for other filling lines at your facility yielded one or more contaminants.
You attributed the contamination in these media fills to aseptic technique breaches by different operators. Various breaches were identified relating to set-up, filling, and changing of the filling tank. However, your investigations were insufficient. For example, you failed to identify the microorganisms found in the contaminated units. It is imperative that you determine the identity of microorganisms found in media filled units in order to adequately understand the potential sources and scope of the contamination.
Any contamination in a media fill run indicates a potentially significant sterility assurance problem and should be thoroughly investigated.”
COMMENT: The FDA has indicated for at least twelve years that all microorganisms found within an ISO 5/6 environment be identified as to genus and species, if possible. A good reference for this is the “FDA Guidance for Industry. Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice. September 2004.”
b. Sterility Test Positive Investigations
“You also did not thoroughly investigate sterility test positives. For example, your investigation of a sterility test failure for (b)(4) injection (batch (b)(4)) did not adequately assess the hazards in the aseptic manufacturing operation that led to the sterility failure. You also did not determine whether other batches made on the same production line were affected.
In addition, you invalidated multiple sterility test positive results obtained during batch release testing. However, we note that your firm uses a sterility test (b)(4) as well as a sterility testing kit that minimizes potential for adventitious contamination that could cause false positives.
Your response is inadequate. In response to this letter, provide the following information:
- a comprehensive review of all sterility positive and media fill failure investigations since January 2014 to reassess your root causes, corrections, conclusions, and effect of your lack of aseptic processing control on the sterility of marketed commercial batches.
- revised media fill contamination investigation standard operating procedures (SOP), including but not limited to identification of microorganisms from each contaminated unit, thorough assessment of possible causes, and assurance of appropriate corrective actions to prevent contamination.
- revised sterility failure investigation SOP, including but not limited to a thorough assessment of potential manufacturing root causes, identification of actions to prevent contamination, and assurance that invalidation of a sterility positive does not occur unless there is a robust and conclusive laboratory root cause.
- a retrospective evaluation of videos of your aseptic manufacture of all in-date batches distributed to the United States to determine contamination hazards posed by deficient aseptic practices. Also review the video of the production activities associated with the (b)(4)injection sterility failure to help identify the source of contamination in that batch.
- a thorough assessment of the adequacy of your facility, equipment, and process. Determine failure modes relating to design, control, and maintenance. Include a comprehensive corrective action and preventive action (CAPA) plan that fully identifies microbial contamination risks throughout your operation and describes improvements to assure high confidence in the sterility of your products.
COMMENT: USP has very strict criteria for the passage of a sterility test that has previously failed. Please review USP<71> Sterility Tests. To determine when a failed sterility test unit/vial may be retested. Please note that 21 CFR 211.192 also discusses a review of all other batches made on the same production line were affected.
- Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes. (21 CFR 211.113(b))
a. Poor Aseptic Behavior
During the inspection, our investigators observed poor aseptic processing techniques that had been previously videotaped at your facility. For example, video from September 8 and 9, 2015, showed the following during the set-up and filling of the sterile injectable drug (b)(4):
- an operator passing a pen directly over the stopper bowl to another operator.
- an operator sitting on the clean room floor during set-up of the filling line and not changing the gown after standing up.
- operators leaning against the cleanroom walls.
- an operator leaving the RABS (b)(4)open for extended periods of time during filling line set-up, even when he was not working in the immediate area.
Your response is inadequate. In response to this letter, provide the following:
- a risk assessment of the poor aseptic techniques observed during the inspection.
- a broader evaluation of any additional aseptic technique breaches that have occurred in your operation (e.g., through review of videos).
- updated information to demonstrate that each of your aseptic processing lines is in a state of control.
In addition to implementing enhancements to your aseptic processing operation design, describe how you will improve staff competencies, supervisory oversight of daily operations, and other controls.
COMMENT: A number of very simple deviations from good aseptic techniques were noted during the audit. Had one of these occurred, it would have been a minor compliance issue. However, with such a myriad of poor aseptic technique issues, it does not appear that the personnel were ever trained or, if trained, then very poorly.
b. Mechanical Failure During Media Fill
Your firm rejected numerous integral vials during media fill batches due to mechanical problems or other causes without appropriate justification. For example, media fill batch (b)(4) was aborted due to a mechanical failure of the conveyor belt motor. Although 3,696 integral vials had been filled, the vials were not incubated, and the media fill was invalidated without adequate justification. Your firm indicated that it would have released a commercial batch as a sub-lot under these circumstances.
You also did not have a procedure describing production and disposition practices after such a mechanical failure.
Your response is inadequate. In response to this letter, provide the following:
- a list of commercial batches rejected as a result of mechanical problems or other reasons and the CAPA that was implemented in each case.
- a list of all media fills conducted since January 2011 with fill date, number of units run, number of units incubated, number of positive units, and annotation of whether the fill was aborted.
- descriptions of circumstances under which any portion of a media fill batch was incubated as a separate segment, and whether you detected any positive units.
- changes made to your written procedures to ensure that media fills accurately simulate actual production practices and to address when it is appropriate to abort a media fill run.
COMMENT: SOPs should be in place to describe how to manage mechanical failures or any aborted fill.
NOTE: Additional Teva Warning Letters may be found on my Blog site (Click Here)