VUAB PHARMA, CZECH REPUBLIC, RECEIVES WARNING LETTER (MAY 27, 2015)

Objectionable Anaerobe 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 a 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.

1. Failure to adequately investigate and resolve all quality-related customer complaints, and to investigate other batches that may have been associated with specific failures.

Your quality unit released API with objectionable microbial contamination into distribution. For example,

1. In January 2014, your firm received a customer complaint regarding microbial contamination of (b)(4), API lot (b)(4). Your customer tested samples of this lot produced by your firm and identified Clostridium sphenoides. During your customer complaint investigation, you were unable to detect the contamination in the samples your customer returned. Your customer’s May, 2014, on-site audit of your firm revealed differences in microbiological test methods: your test method was inadequate to detect Clostridium sphenoides growth. Once you modified the test method per your customer’s recommendation, your firm confirmed Clostridium sphenoides contamination in your retain sample. However, you failed to identify the source of the contamination or to implement meaningful corrective actions to prevent future microbial contamination.

COMMENT: 

Correct test methodology is quite important to assuring that a procedure is being properly performed.  Several USP test methods to include USP<61> and USP<62> are available to assist with the proper testing protocol. However, as noted within the above paragraph, the microorganism that was avoiding detection was an anaerobe, and would have required modifications to the standard USP<61>/<62> methodologies. Thus, when attempting to follow a USP monograph, it remains quite important to understand both what is within as well as what remains outside of the monograph.

Test results exhibiting objectionable microbial contamination represent a significant deficiency in the safety and quality of your APIs. Since microbial contamination is typically non-uniform, the risk of patient exposure to a contaminated drug is exacerbated by low detectability of a test of limited sample size.  In addition, your customers may not perform any additional microbiological testing upon receipt of your API.  Furthermore, objectionable microbiological contamination in your API, which is intended for (b)(4) and (b)(4) suspensions, indicates a significant failure in your capability to prevent microbiological contamination in your operation.

COMMENT: 

21 CFR 211.160 General Requirements (b) states that “laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality and purity…(b)(1) Samples shall be representative and adequately identified…(b)(2) Such samples shall be representative and properly identified. “

And although a non-U.S. customer made this complaint, the Agency is concerned about your firm’s poor investigation because you manufacture (b)(4), API, using common equipment, materials and personnel in the operation, regardless of the destination of a given batch.

Your response states that you will retroactively test (b)(4) batch per (b)(4) to cover January, 2013, to June, 2014, when you implemented the modified test method. However, your rationale for testing (b)(4) batch per (b)(4) is not scientifically sound. This approach does not evaluate all batches that could be contaminated with objectionable organisms. It relies on the false assumption that retroactively testing a limited number of API batches will assure that all batches distributed to customers were of acceptable quality. Your investigation did not sufficiently pursue or determine root causes. Corrections you have described are insufficient.

COMMENT: 

When perform testing for Out of Specifications (OOS) or Corrective/Preventive Actions (CAPA), one must recall that this is not the time to use ASQ skip lot testing techniques. Nor is it the time to take samples that are less than of a scientifically sound size.

In addition, you do not mention any improvements to your procedure for deviation and corrective action and preventive action (CAPA) management. Please note that your senior management is responsible for ensuring the quality and safety of your APIs.  Additionally, your senior management is responsible for assuring quality defects are thoroughly investigated and resolved quickly as well as for preventing the distribution of defective APIs.

In response to this letter, provide an accelerated timeline for completing retroactive testing of all potentially affected batches and a commitment to respond with all results promptly. Also provide a detailed update on whether your firm has determined root cause of this contamination problem and implemented any further risk controls. Provide your improved deviation and CAPA management procedure, as well as a review of all microbial test methods to ensure they are suitable for their intended use. Finally, provide documentation of all changes implemented as a result of your review and remediation of these issues.

COMMENT: 

Microbial contamination problems are often difficult to determine as to the “root cause”. The microbial test methods can be verified or validated; however, even assuring that they are acceptable for the intended method may not assure the determination of the “root cause”.