API MFG CITED FOR OOS AND MICROBIOLOGICAL ISSUES (B. cepacia) — REFERENCES RECENT PDA J. PHARM SCI & TECH
1. Your firm failed to have an adequate out-of-specification (OOS) procedure to conduct thorough and scientifically sound investigations including corrective actions.
For example, the OOS report number (b)(4) for lot (b)(4) of Simethicone Emulsion USP (30%), MED-341, dated September 17, 2010, states that your firm performed two retests as part of the investigation of a microbial test result of> 11,000 CFU/g. You released the lot based on the results of retesting, which were within the specification of (b)(4). You did not justify the invalidation of the original results, nor identify the root cause of the failure. You relied solely on the acceptable retest results to release the lot. Your OOS Report procedure (SOP#(b)(4)), is deficient because it does not require an analysis of the data, assessment as to whether a significant problem exists, identification of root causes, or allocation of the tasks for corrective actions.
In your response, you stated that you have modified your SOP# (b)(4) to include testing of lots before and after a failing result in your procedure. However, your response is inadequate because you failed to provide evidence that your firm will scientifically justify and document retesting of a lot that fails to meet a microbiological specification, and conduct an appropriate investigation.
COMMENT
Not justifying the invalidation of the original test results nor the identification of the root cause of a failure prior to the release of an API (Active Pharmaceutical Ingredient) is a major Quality issue. All non-conformances require investigation and identification prior to closing a batch record. Finding >11,000 CFU/gm is at least one to two logs higher than what is deemed acceptable based upon USP<1111> and far from results that would be normally acceptable. The finding of B. cepacia within the water system which comprises a high percentage of the Simethicone Emulsion USP (30%) strongly suggests that the microorganism may have been within the initial and retested API. Based upon current USP<62>, B. cepacia is not considered as a “specified†microorganism which is unacceptable in APIs and final product. However, the FDA has recently published an article (see PDA J Pharm Sci and Tech 2011, 65 535-543) wherein they make their case for B. cepacia becoming a “specified” bacterium. Please also visit the Letter to the Editor by Scott Sutton, Ph.D. and his response from the FDA.
2. Your firm failed to establish procedures to adequately clean and store equipment and utensils to prevent contamination or carry-over of material that would alter the API beyond the established specifications.
For example, our inspection established that you do not routinely perform equipment cleaning after each manufacturing run. Your cleaning procedure requires you to clean the equipment when it has been more than (b)(4) since you manufactured the last batch in the same equipment, yet your cleaning validation does not contain data to support a (b)(4)Â “dirty hold time.” Your firm determined that failure to clean a transfer hose before use was the probable cause of the microbial contamination of the Simethicone Emulsion USP (30%).
In your response, you stated that you performed a study to evaluate the cleaning step for the transfer hose and that you will sanitize the cleaned hoses with a dry heat treatment prior to use for future batches. Your response is inadequate because it does not provide data to support that your cleaning procedure for the transfer hose cleans and sanitizes the hose adequately. Please provide a validation report that includes microbial test data that evaluates whether your cleaning and sanitization procedures for your transfer hoses and other equipment is adequate.
COMMENT
Making conclusions without support data is a common occurrence observed within Warning Letters. Validation reports provided to the Agency will provide the data that “backs up” a Client’s assumptions.
3. Your firm failed to adequately validate and monitor the treatment process for your purified water system.
For example, your firm uses purified water as a key ingredient in the manufacture of Simethicone Emulsion USP (30%), MED-341. Between September 2009 and January 2011, you have conducted microbiological tests and found recurrent Burkholderia cepacia contamination.
Your firm failed to assure that your water system is suitably designed and operated to produce appropriate water quality. Regarding the latter, your firm has not established and validated appropriate cleaning and sanitizing schedules for your purified water system.
You have hired a water process subject matter expert and taken other steps to strengthen monitoring of the purified water system. Your response is not acceptable because you have not demonstrated that your purified water system is capable of operating in a continuing state of control. Please provide a validation plan for your purified water system and describe any interim actions that your firm will take to ensure that purified water used in manufacture of your drug products meets its action limits.
COMMENT
The hiring of a “water process subject matter expert†is a step forward for the monitoring of a purified water system. However, the development and execution of a Cleaning and Sanitization Plan as part of a total Validation Plan which ultimately requires intensive sampling and testing over a prolonged period of time of the Purified Water System is essential to maintaining the water. In addition, since the use of temperature to minimize the number of microorganisms appears to be an intermittent feature of the process, it can only be surmised that heat may not have been an on-going requirement to assist in control this contamination problem.
4. Your firm has failed to identify and define critical process parameters and the ranges expected that could affect critical quality attributes.
For example, your firm states that the Simethicone Emulsion USP (30% ), MED-341, manufacturing process is designed to prevent objectionable microbiological contamination with the use of pH and temperature controlling steps. However, your validation protocol and report did not identify pH and temperature as critical parameters. Using this manufacturing process, between September 2010 and November 2010, you produced and distributed several Simethicone lots later found to be contaminated with microbiological organisms, particularly Burkholderia cepacia.
We acknowledge your voluntary recall of Simethicone Emulsion USP 30% lots potentially contaminated with Burkholderia cepacia. In your response, you stated you relied on pH and temperature controlling steps to prevent objectionable microbiological contamination of your active pharmaceutical ingredients. Your response failed to provide information and data to support other specific manufacturing (including but not limited to quality of the input ingredients and storage time limitations) operation provisions that are needed to provide assurance that objectionable microbial contamination is prevented by your process design. Furthermore, your manufacturing process has multiple steps after your pH and heating step that would provide vectors for microbial contamination. For more information on Burkholderia cepacia contamination and control please refer to the article Burkholderia cepacia: This Decision Is Overdue, (PDA J Pharm Sci and Tech 2011, 65 535-543) which can be viewed at the following link, http://joumal.pda.org/content/65/5/535.full.pdf+html. Please provide a report in which you fully identify your manufacturing failure modes and critical control points to prevent objectionable microbiological contamination’ and provide documentation to justify significant manufacturing ranges established.
COMMENT
Many manufacturing operations contain multiple steps. With these operations multiple steps occurred following the pH and heating step that could provide vectors for microbial contamination. Developing the failure modes and critical control points throughout each unit operation is critical to prevent objectionable microbial contamination and understanding and justifying the manufacturing ranges that should be utilized in developing an Active Pharmaceutical Ingredient (API).
I am stunned that FDA would reference their B. cepacia article especially in light of Scott Sutton’s reply. It seems that FDA has now made B. cepacia a specified microorganism.
The FDA has taken many actions on companies related to B. cepacia–even for non-sterile products. In the current regulatory environment, it appears that many things have become defacto regulations without formally making them so.
I’m wondering if a proper response to a future FDA observation regarding B. cepacia in non-steriles (not Nusil’s observations – that had problems from top to bottom), in which they quote the FDA’s “Burkholderia cepacia: This Decision Is Overdue” article, would be to include Scott Sutton’s response to it. He pretty well refutes most of the FDA’s points that they tried to make.