AUROBINDO PHARMA LIMITED, UNITS III AND VI, RECEIVE WARNING LETTER (MAY 20, 2011)

 AUROBINDO PHARMA RECEIVES IMPORT BAN FOLLOWED BY WARNING LETTER  — AN UNUSUAL SEQUENCE OF EVENTS 

COMMENT 

The receiving of an Import Ban prior to receiving a Warning Letter has not been a common occurrence.  However, because of the FDA’s recent and previous audits, and the lack of continuing compliance, the FDA must have had the belief that receipt of these products would be detrimental to the health of the American public.  Please note that this Import Ban was received by Aurobindo Pharma in February 2011 while the Warning Letter was not received until May 2011.  The Warning Letter also indicated that the Company “should within five days of receipt of this letter you contact…to schedule a regulatory meeting at our office” (in Maryland).  

Please note that Dr. Reddy’s Mexico facilities, Ranbaxy Laboratories Ltd, Lupin Ltd and Sun Pharmacetical Industries Ltd U.S. subsidiary Caraco Pharmaceutical Laboratories Ltd received similar import bans within recent years. 

Unit VI  

We have reviewed your January 13, 2011 response to the Form FDA-483 issued at the conclusion of the December 2010 Unit VI inspection, and note that it lacks sufficient corrective actions.    

Specific violations observed during the inspection include, but are not limited, to the following:

1. Your firm’s laboratory records fail to include complete data derived from all tests necessary to assure compliance with established specifications and standards [21 C.F.R. §211.194]. 

For example,

1. On December 13, 2010, the FDA investigator observed a microbiological plate that contained one (1) large colony forming unit (CFU) of mold. However, your firm’s laboratory documentation reported 0 CFU for the same microbiological plate. 

The inspection found that the laboratory manager had documented “NIL,” (i.e. no growth for this plate), while the same laboratory manager confirmed microbial growth in the presence of the investigators.  Later during the inspection, the FDA investigator asked to see the original plate and was told that it had been destroyed. On December 21, 2010, your firm prepared a corrective and preventive action (CAPA) stating that the laboratory manager misread the plate count, and that this deficiency was the result of a human error. We are concerned that your firm lacks documentation to support this conclusion and moreover, that the original plate was destroyed during the FDA inspection, as reported. 

Your response of January 13, 2011, raises some additional concerns as it includes a photo of the original plate that your firm stated was destroyed and a second photo of a plate that was allegedly misread. Please explain this discrepancy. 

We are concerned that this is a repeat violation. During the inspection of Unit VI conducted in May 2007, investigators also reported your failure to document positive results for a microbial plate that was confirmed as containing microbial growth. 

COMMENT 

Misreading of plates within the Microbiology Laboratory at Aurobindo Pharma Limited, Unit VI has become a serious issue in that the same issue arose during a FDA inspection in May 2007 when investigators reported the failure to document positive results for a microbial plate that was confirmed as containing microbial growth.  The December 13, 2010 audit confirmed that the laboratory manager had documented “NIL”, i.e., no growth for a plate, when the same laboratory manager confirmed microbial growth in the presence of the investigators.  On December 21, the firm prepared a CAPA stating the laboratory manager misread the plate count, and that this deficiency was the result of a human error.  However, the company’s response to the FDA on January 13, 2011 raised additional concerns as it included a photo of the original plate that the firm stated was destroyed and a second photo of a plate that was allegedly misread. 

This reporting of “NIL” appears to not be unique to this one Indian facility since the same issue occurred within the Cadila Healthcare Ltd Zyfine facility where “NIL” equated to zero (see my Blog of July 19, 2011 and the Cadila Warning Letter).  One must question this reoccurrence of the same issue within two Indian facilities and whether this issue reflects the training in microbiology that these personnel received.

2. On December 17, 2010, the investigator noted that many microbial plates containing environmental monitoring and personnel samples, collected on December 12, 2010 during production, were missing from the incubator.  Your response confirmed that 33 of 150 (22%) of the personnel monitoring samples were missing and that in one instance, 9 of 10 samples were missing for a single operator.

Your response indicates that no missing plates were reported for the period of January 2009 through November 2010.  We have determined that this conclusion is not reliable because neither reconciliation procedures nor data regarding the number of microbial plates used for environmental monitoring and microbiology laboratory samples were available at the time. Please explain how your firm determined the effectiveness of this review of 2009 and 2010 plates, without having a procedure in place for the reconciliation. 

COMMENT 

Companies should not use the FDA as their Quality Control Unit.  Further, the FDA takes a very dim view of a Company whenever this occurs.  When the FDA finds plates or other data missing, the solution is not to ignore their findings, but to explain the discrepancy.  These findings call into question the reliability of the firm’s Quality Assurance System and the training of the personnel within the Company. 

Our inspection found that your environmental monitoring data for 2009 and 2010 reported no alert or action level results in the Grade (b)(4) areas used to manufacture products intended for the U.S. market. This finding is questionable in that during an FDA visit to your microbiology laboratory on December 13, 2010, twenty-eight (28) plates, collected as part of the environmental monitoring program were found inside an incubator in the microbiology laboratory with visible growth of microorganisms.  According to your response to the inspectional observations, many of the microorganisms recovered were identified as “new isolates”, which had not been previously recovered in Unit VI. 

We are concerned that similar situations were observed by other FDA investigators during previous inspections conducted in November 10 – 17, 2005, and May 7 – 15, 2007.  This disproportionate detection of microbial contamination during FDA inspections questions the validity of the data generated by your microbiology laboratory. Accurate and reliable microbial management data is essential to support the aseptic processing operations used during the manufacturing of sterile active pharmaceutical ingredients (API) and finished drug product intended for distribution in the United States.  

COMMENT 

Since the FDA inspected these facilities during November 2005, May 2007 and December 2010, one must assure that the issues raised above relate to the data essential to support the aseptic processing operations used during the manufacturing of sterile active pharmaceutical ingredients (API) and finished drug product intended for distribution in the United States.  Although the areas involved for both the Alert and Action Levels have been redacted above (see Grade (b)(4)), it must be assumed that the areas must be either ISO Class 5 or 7.  Having this number of positive plates from either active or passive viable airborne monitoring results appears to be excessive.  Because a similar situation was observed during November 2005 and also May 2007, it calls into question the personnel qualifications of those involved within the accurate and reliable management of microbiological data. 

2. Your firm has not established or followed appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile [21 C.F.R. § 211.113(b)].    

For example, during the December 2010 inspection, the investigators found that your SOPs related to your environmental programs failed to adequately identify (e.g., diagrams) the locations where active and passive environmental monitoring samples are to be collected from. The inspection also found that your procedure for environmental sampling does not require that employees be sampled (b)(4) time they exit the Class (b)(4) clean rooms.                                                                  

This deficiency increases our concern regarding the reliability of the data generated and your ability to identify the source of your microbial contamination. We expect that SOPs related to Environmental Monitoring include sufficient instructions to ensure that the plates intended to detect microbial growth are appropriately located. These procedures should also include specific instructions for the collection of microbiological samples. 

Your firm needs to establish a robust environmental monitoring program capable of generating meaningful data, and that would serve as an early warning system to detect possible environmental contaminants that may impact the sterility of the sterile APIs and finished drug products manufactured at your facility. There is no assurance that your current environmental monitoring program is capable of detecting microbiological contaminants. 

COMMENT 

Standard Operating Procedures (SOP) should be available to the facility that demonstrate where both active and passive environmental monitoring samples are to be collected.  These locations are frequently based upon ISO 14644-1/2 and a Risk Based analysis (see ICH Q9).  Further both Annex 1 (revised March 2009) and FDA’s Aseptic Processing Guidance for Industry (May 2004) require that employees be sampled each time they exist the Aseptic Processing Area (APA).  The FDA concludes that this firm is lacking a robust environmental program that is capable of detecting microbiological contamination. 

In addition to the items listed above, the inspection uncovered additional deficiencies that increase our concerns regarding the validity of the data generated in the microbiology laboratory, and the quality of the sterile API and finished drug products manufactured at your facility. These issues include, but are not limited, to: 

• Discrepancies in the procedures and documentation practices related to use of extra plates to replace missing or damaged plates that are collected as part of the environmental monitoring program.
• The device used to handle (b)(4) stoppers during the aseptic filling of sterile API is not sampled.
• Failure to follow established procedures for control of all pages in the batch production records.

COMMENT

In these last several paragraphs, the FDA reiterates its issues with the procedures and documentation practices within the Company, but also mentions issues surrounding control of the pages within the Batch Production Records as well as additional sampling issues with the device that handles stoppers during aseptic processing.