VUAB PHARMA, CZECH REPUBLIC, RECEIVES WARNING LETTER (MAY 27, 2015, con’t)

Objectionable Bacillus spp. Found During Customer Sampling 

During the FDA’s inspection of VUAB Pharma a.s., Vltayska 53, Roztoky, Czech Republic, from June 09, 2014, through June 13, 2014, an investigator from the U.S. Food and Drug Administration (FDA) identified significant deviations from current good manufacturing practice (CGMP) for the manufacture of active pharmaceutical ingredients (APIs). On May 27, 2015 the FDA subsequently issued a Warning Letter. This followed the issuance of an Import Alert on April 10, 2015.

During the June 2014 audit, the investigator observed specific violations during the inspection, including, but not limited to, the following. The enclosed represents “Part B” of Observation 1.

In April 2014, your firm received a customer complaint concerning Bacillus spp. contamination of (b)(4), API lot (b)(4). Your tests of the returned customer samples confirmed microbial contamination, including both high levels of bioburden and Bacillus spp. contamination.  During your investigation, your firm did not extend the investigation to any other batches potentially affected. In addition, deficient sampling procedures compromised your firm’s ability to detect the contamination your customer found. Your firm sampled (b)(4) per batch and had no statistical justification that this sample was representative of the entire batch.

COMMENT: 

21 CFR 211.192 Production Record Review states that “investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and follow-up.”  In this particular Warning Letter, this did not occur.  211.192 represents one of the ten most common Observations that the FDA lists on an annual basis.  Please visit my Blog site to view its frequency as well as the frequency of other oft cited Observations. Statistical evaluations based on the American Society for Quality (ASQ) also represent a reliable source for statistical justification.

While your response focuses on detecting future contaminations prior to release, it fails to adequately identify the potential root causes of the contamination. Your response states that you have updated your Final Product Adjustment SOP and Product Homogenization SOP to add a step: (b)(4), API. However, you have no data to support this will adequately remediate the contamination issues.

Your response states that you will now sample from (b)(4) those samples before testing. While your response proposes using (b)(4) samples, your customer complaint shows that (b)(4) samples are not representative. For example, the returned sample from lot (b)(4) container number (b)(4) had gross contamination of 4,800 cfu/g; while returned samples from the other (b)(4) containers ranged from (b)(4) to (b)(4) cfu/g, within specification.   We are concerned that testing a (b)(4) sample could mask an out-of-specification (OOS) result for a single container.

In response to this   letter, provide data and information from a detailed root cause investigation into the source of this contamination. In addition, provide a summary of your investigation into other batches potentially affected by this contamination, including testing of retain samples of all potentially affected batches. Furthermore, revise your sampling plans to ensure they are statistically appropriate and non-uniform contamination can be detected. The revisions should encompass finished API testing, in-process testing, and raw material acceptance testing. 

COMMENT:

Non-uniform contamination represents a difficult area when it comes to microbiological detection of organisms.  Individual containers must be tested and cannot be composited in these cases where it is suspected because of the potential for one container with “gross contamination” masking the balance of the tested containers.