BAXTER HEALTHCARE CORP RECEIVES WARNING LETTER (05/31/13) — PART III

REPEAT VIOLATION CITES CRITICAL DEFECTS THAT CAN IMPACT PRODUCT STERILITY AND STABILITY

The FDA recently audited two Baxter Healthcare facilities to include Marion, NC (November 7 to 16,2012) , and Jayuya, Puerto Rico (March 13, 2013 to April 19, 2013).  Their Investigators identified significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals.

Observations at the Jayuya, Puerto Rico facility included the following:

1. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
For example,
a. On February 13, 2012, this site generated a nonconformance investigation report–number 81986–addressing a bag leak detected during routine microbiology testing.  The investigation concluded that the root cause for bag leaking was weak membrane defects within the port component of the bag.  According to the referenced investigation, the defective closure component resulted from machinery problems during the manufacturing process at the supplier (b)(4).  The investigation identified at least thirty-nine (39) lots of finished drug product affected by this defect that were released for distribution.
Upon identification of the defect you placed portions of the impacted lots remaining under your control on hold and you developed sampling/inspection protocols to evaluate the impact of the bag closure system defect on the referenced lots.  According to the inspection protocol of the product lots tested did not meet the established acceptance criteria of (b)(4).  Based on this result, you discarded the portions in stock of at least twenty five (25) product lots.  Nonetheless, you did not take any actions to mitigate risks posed by affected product lot portions (pertaining to at least 27 product lots) that you had already distributed to the market.  You based your decision not to intervene on a Medical Risk Assessment (MRA) in which you evaluated the product defect and determined that it presented a low risk to patient health.  Your MRA concluded that product sterility was not compromised by the defective closure on the grounds that the closure assembly is sealed off from the environment by a blue cap.  According to your evaluation, “if the membrane were to leak the cap will maintain sterility of the product until use.”

COMMENT:

The bag leak was initially determined during routine microbiological testing.  The root cause as identified by the investigation concluded that the defective closure component resulted from machinery problems during the manufacturing process at the supplier.  A total of at least 39 lots were identified as being defective.  A decision was made not to intervene and allow 27 lots previously distributed to remain distributed to the market based on a Medical Risk Assessment (MRA) wherein Baxter evaluate the product defect and determined that it presented a low risk to patient health on the grounds that the closure assembly is sealed off from the environment by a blue cap.  Baxter’s assessment was that if the membrane were to leak the cap would maintain the sterility of the product until use.
However, your firm received several complaints reporting inadequate fitting of the blue cap.  One complaint reports that in approximately 30% of the bags the blue cap was either unattached or barely attached to the port, often falling without being touched.  Therefore, your assumption that the blue cap represents a reliable extra barrier to contamination and your dependent conclusion that product sterility and patient safety are not compromised by poorly fitting caps may be unfounded.  Your evaluation of the membrane defect should have considered all common failure modes associated with container and closure integrity, including the loss of the blue cap.  We note that you initiated recall of the impacted portion of these lots only after FDA brought the matter to your attention (author’s emphasis).  In your response to this letter, please describe how your firm will be correcting the root causes of these defects, including describing any remediation plans to improve manufacturing robustness.

COMMENT:

Baxter only initiated the recall of the impacted portion of these lots following the encouragement of the FDA.  The firm had not sufficiently reviewed the complaint wherein as many as 30% of the blue caps were either unattached or barely attached to the port, often falling off without being touched.  Thus Bayer’s conclusion that the product sterility was not compromised by the poorly fitting caps may be unfounded and that all common failure modes should have been considered. 

2. Your firm failed to ensure your container closure system provided adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product (21 CFR 211.94(b)).
For example, you received consumer complaints identifying at least ten (10) membrane leaks and one hundred fifty-five (155) inadequately-fitting blue caps during the period of November 2011 to March 2013. These are critical defects that can impact the sterility and stability of your products.
This is a repeat violation cited in our Warning Letter 11-SJN-WL-04 dated January 20, 2011, issued to you corporation that discussed the Jayuya, Puerto Rico Facility.

COMMENT: 

This violation, as noted above, represents a repeat violation of the Warning Letter issued on January 20, 2011 and reported within this Blog on February 9, 2011.  (Please visit the Blog using the “Search” function.) 

Baxter identified 542 incidences through consumer complaints of product defects such as leaks, bursts, and premature activation during the period of January 2008 and August 2010.  These were identified as critical defects that can impact sterility and stability of the product.  Baxter identified that the probable cause was the result of defective materials used in the manufacture of the container closure system.  The FDA within the previous Warning letter suggests that the sampling plans “are not based on appropriate statistical criteria”.

During this subsequent FDA visit, the FDA noted that Baxter had received consumer complaints identifying at least ten (10) membrane leaks and one hundred fifty-five (155) inadequately-fitting blue caps during the period of November 2011 to March 2013. Nothing was mentioned of the intervening period between September 2010 and October 2011. Again the FDA reemphasized that these defects are critical that can impact the sterility and stability of their products.