APOTEX INC RECEIVES WARNING LETTER FOR MULTIPLE CANADIAN SITES (2/21/13)

FIRM FAILED TO ESTABLISH AND FOLLOW PROCEDURES DESIGNED TO PREVENT MICROBIOLOGICAL CONTAMINATION (21 CFR 211.113(b))

The FDA, during August and October 2012 inspected two Apotex, Inc. sites.  This Blog only discusses the facilities located at 150 Signet Drive, Toronto, Canada.  The U.S. Food and Drug Administration (FDA) identified significant violations of current good manufacturing practice (CGMP) regulations during the audit for finished pharmaceuticals, Title 21, Code of Federal Regulations, Part 210 and 211.

1. “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)).
For example, you failed to perform adequate unidirectional airflow pattern studies (i.e., smoke studies) for the aseptic filling line used for the production of (b)(4) Injection. The smoke studies did not include examination of airflow during set-up and at points of process intervention.  Moreover, your airflow pattern studies for the class 100 area of the (b)(4) filling line show clear evidence of turbulent airflow in your filling line located in Room (b)(4) both above the (b)(4) just prior to entry into the filling zone and over the stopper bowl adjacent to the filling zone. Although this lack of unidirectional airflow can compromise sterility, you failed to take appropriate action to ensure that your parenteral drug products were protected from these contamination hazards.

COMMENT

Smoke studies in Aseptic Processing Areas (APA) have continued to “gain traction” from the regulatory authorities over the past several years.  Once the APA is “buttoned up”, smoke testing should commence.  As noted above, the studies should be initiated as early as set-up and definitely occur during any process interventions which need to be noted during any aseptic filling activities.  Any lack of unidirectional flow may compromise the integrity of the fill and problems around a stopper bowl are especially notable.

An in situ air pattern analysis should be conducted in all critical areas under dynamic conditions, to demonstrate unidirectional airflow and sweeping action at critical work areas.
These studies should evaluate the impact of aseptic manipulations (e.g., interventions) and equipment design, document the activities performed, and include written conclusions. In your response to this letter, provide a copy of your new smoke study recordings along with supporting documentation.”
“According to your September 14, 2012 response, you committed to conduct smoke studies by December 31, 2012.  In your response to this letter, provide an update of all airflow pattern studies conducted, your evaluation of the results, and your proposed corrective and preventive actions.  In addition, provide your risk assessment for all sterile products within expiry that were manufactured under these unacceptable conditions.”

COMMENT

When regulatory agencies determine that sterile products may not have been manufactured under acceptable conditions, it is not unusual for them to request a risk assessment for all sterile products that have not expired that were manufactured under these adverse conditions.  In addition, while it is not noted here, regulators also often request a separate “scientific rationale” as to why these products should not be recalled.  While the FDA has requested an update of the data and an evaluation of the results, there is also no mention of a demonstration of the successful completion of these studies through visual monitoring (photographic results) of successful smoke studies to include a script that describes each of the scenes, e.g., the historic movement of smoke around the stopper bowl and the activities that were completed to demonstrate the changes that were initiated within this critical area.

“In addition, your firm failed to establish maximum holding times for vials used in media fills, prior to incubation. Your media fill protocol for batch (b)(4) does not establish a set timeframe between completion of filling vials and placing filled vials in the incubators.  Our investigator found that, during a media fill operation you filled the vials on July 24 and July 25, 2012, and did not incubate them until July 30, July 31, and August 1, 2012. Your manager attributed the delay to lack of space to perform the visual inspection and to personnel resource constraints.  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.

COMMENT

Media fills should have Batch Records and SOPs to support them.  The time that is set between the final filled vial and placing the vials within an incubator should be set by the SOPs and/or the Batch Record.  Lack of space for the incubation of media vials is unacceptable.  Gantt Charts or other time lines should be in place to assure that the Company understands any limitations or “bottlenecks” with the incubation of their media fills.  If incubators are lacking, media fills should not be initiated.
Your response indicates that you initiated a change control to have a maximum hold time of (b)(4) from end of filling to start of incubation of the media fill vials.  In your response, provide your justification for the (b)(4) maximum hold time.  In addition, specify the required storage conditions for the media vials during this hold period and their justification.  In your response please also provide a summary of your assessment regarding whether the vial hold conditions between filling and incubation for batch (b)(4) affected the conclusions of your media fill studies, including whether you plan to repeat the studies and the rationale supporting this decision.
COMMENT

The prior paragraph is loaded with potential “bombshells” waiting to explode.  Moving away from standard practices to adapt to a “one of a kind” issue is only going to create problems.  The last sentence “including whether you plan to repeat the studies and the rationale supporting this decision” needs to be considered very carefully — especially if the media studies are not repeated.