API MANUFACTURING FACILITY IS CITED FOR SEVERAL REPEAT WATER RELATED OBSERVATIONS
During the time frame of March 13 to March 23, 2012 the FDA inspected Abbey Color, an active pharmaceutical ingredient (API) manufacturing facility in Philadelphia, PA. Following a detailed review of the firm’s response, dated April 12, 2012, the FDA concluded that the response lacked sufficient corrective actions.
Specific violations included the following:
- Failure to validate and monitor the water purification system to ensure that water is of appropriate quality.
Specifically, “your firm failed to demonstrate that your purified water system can consistently produce water that is suitable for use in the manufacture of this API. This is a repeat observation from the July 21-August 8, 2010 inspection. … you continued to get periodic out-of-specification (OOS) endotoxin and total organic carbon (TOC) test results. …you indicated your firm’s intention to conduct a comprehensive gap analysis of the purified water system. However, you have failed to indicate when you will initiate this gap analysis and when it will be completed.
Your firm also failed to detail how you will determine the source(s) of high endotoxin and TOC in your purified water and how your firm will remedy identified problem(s). We note that, for example, your firm installed an endotoxin removal unit on your purified water system in January 2011 in response to the OOS results for endotoxin in the water used for API. However, your firm has not demonstrated that the water produced by the purified water system is now suitable for use in production. The operational parameters and effectiveness of the new endotoxin removal unit have not been qualified. Your firm does not monitor the microbial and chemical attributes of the feed water, and have no assurances that the purified water system is capable of consistently producing water that meets specifications for a given quality of feed water. Your gap analysis should also include evaluation of factors such as feed water quality, whether each component of the purified water system is meeting its performance specifications, and whether the system’s output is reproducible. Your firm has not determined the source of the endotoxin failures in the past, and it is essential that you demonstrate that changes in design and operational procedures have resulted in a reliable water system.”
COMMENT
Repeat Observations in today’s FDA environment have become a very successful mode for inviting Warning Letters. Historically, the FDA often required three Repeat Observations before they would issue a Warning Letter. That is no longer the norm.
Observation 1 suggests that the Company has little understanding of how to perform an investigation of a contaminated water system. Their lack of sampling of each Unit operation, the lack of attention to feed water quality, and the use of a endotoxin removal filter that acts as a “band aid” or a “quick fix”, rather that determining the root cause of the problem suggest that the Company study how to attack a problem using the FDA Guidance for Industry re: Out of Specifications.
2. Failure to adequately investigate and document OOS test results.
“For example, your rinse water from cleaning equipment used to manufacture (b)(4) lots of Fluorescein, USP from October 2010, to December 2011, had (b)(4) results that were OOS for endotoxin and/or total organic carbon (TOC). Your firm failed to document that these were OOS results, conduct an investigation to determine the root cause of these recurring failures, or implement corrective actions. Executive management of your firm is responsible for assuring quality system effectiveness. A basic part of this responsibility is prompt identification and remediation of problems that indicate manufacturing control problems, including an evaluation of the impact of these deviations on the quality of your APIs.”
COMMENT
In this Observation, the Client again is encountering OOS results for both endotoxin and total organic carbon. From the above paragraph, it appears that the Client did not realize that the Company was experiencing these problems and neither documented them as OOS nor conducted an analysis to determine the root cause of these recurring failures — much less implemented corrective actions.
Barry A Friedman, PhD LLC 
Dear Dr. Friedman:
Not going into the merits of the citation against this specific company I’m kind of concerned about the FDA referring to a failure in endotoxin levels as OOS in a 483 when this term is excluded for biological assays as established in the FDA OOS guidance. Are the FDA resistant to use the term MDD? or even more, does not accept the term? How can we reconcile this perceived contradiction? Thanks
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