PHARMACEUTICAL COMPANY JELFA SA (POLAND) RECEIVES WARNING LETTER (7/14/11)

JELFA SA DISTRIBUTES FINAL PRODUCT WITH QUESTIONABLE STERILITY

1.  Your firm has not thoroughly investigated the  failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. § 211.192]. For example,

The inspection documented that (b)(4) Injection,  batch # (b)(4), failed the sterility test. Your quality control unit  repeated the test on a new sample to confirm the original result prior to initiating an investigation. The quality control unit’s decision to  perform a retest without conclusive assignable laboratory cause is not in accord with USP <71> and is an unacceptable practice.

COMMENT 

Retesting of product that fails USP<71> Sterility Tests should not occur until a failure investigation has been initiated and conclusive assignable evidence is present that the laboratory caused the error.

The retest again revealed non-sterility.  Although the  lot was eventually rejected, there is no assurance that other lots manufactured and filled in the same production line were not contaminated.  The inspection found that the results were valid and that no laboratory error was identified.  However, no investigation of the manufacturing process and facility controls was performed to identify the root cause of the sterility failure.  This information from the failure investigation also helps determine how many additional other batches may be affected.

COMMENT 

Although this lot, when retested, was deemed to be non-sterile, no root cause analysis was performed to determine the non-sterility cause.  In addition, firms cannot assume that because one lot is found to be non-sterile that product previously released, in the
warehouse or in the process of being manufactured is also not sterile.  A Company cannot operate within a “silo” when
it comes to ascertaining the magnitude of a problem.

Please note that when microbial growth is observed, a lot
should be considered nonsterile and an investigation conducted.  An initial positive test would be invalid only in an instance in which microbial growth can be unequivocally ascribed to laboratory error.  Only if conclusive and documented evidence clearly shows that the contamination occurred as part of testing should a new test be performed. When available evidence is inconclusive, batches should be rejected as not conforming to sterility requirements.  After considering all relevant factors concerning the manufacture of the product and testing of the samples, the comprehensive written investigation should include specific conclusions and identify
corrective actions.

COMMENT 

The FDA has provided in the above paragraph a very concise explanation of how to manage an initial positive finding within a sterility test.  Too often a Company will perform a second
test based on their interpretation of USP<71>, rather than following the intended meaning of the test procedure.

Please include in the response to this letter a copy of your
final sterility failure investigation report for (b)(4) Injection,
batch # (b)(4). Your response should include a detailed explanation
of your root cause analysis and the corrective actions implemented to prevent recurrence of the event(s) that lead to the contamination of the lot.  Your firm should also indicate if a media fill was conducted as part of your sterility failure evaluation.  If so, provide a copy of the media fill protocol and report as part of your response to this letter.  Also include a list of all lots of sterile drug products manufactured at your facility that initially failed the sterility test, and that were released based on a passing re-sample or re-test result.  Provide the product name, original test and re-test date, microorganism isolated and product destination.

COMMENT 

Media fills are an integral part of the commissioning of a Laminar Air Flow Hood and of the personnel that are using it. Typically, three media fills are performed on three different days to
demonstrate an individual’s proficiency. Historically, I would suggest that the use of Trypticase Soy Agar would be sufficient.  However, following the revelation from Accugenix, Inc, Newark, DE that they observed a very high percentage of  Propionibacterium acnes within their DNA Sequencing results from 2010, I would encourage at least one of the three media fills to be conducted  with Fluid Thioglycollate Medium. 

We noted during our review that SOP No. JZ-V/JV-051: “Proceeding
in case of unexpected result obtainment” references the FDA Guidance for Industry:  Investigating Out-of-Specification Test Results for Pharmaceutical Production. Please note that the scope of this guidance is intended for chemistry-based laboratory testing of drugs regulated by CDER, and not for microbiological testing investigations. For information on sterility testing, see Section XI of the FDA’s Guidance on Sterile Drug Products Produced by Aseptic Processing. 

Your response includes procedural corrections and training
of your analyst.  Please describe in your response to this letter the
specific training offered and corrections made.

COMMENT 

Ironically, even though the FDA notes the above regarding OOS, they do comment on microbiology within this 2006 Guidance for Industry OOS document.