Milbar Laboratories Receives Warning Letter (July 23, 2018) for Failure to Meet Purified Water Specifications

Milbar Laboratories Receives Warning Letter (July 23, 2018) for Failure to Meet Purified Water Specifications.  The U.S. Food and Drug Administration (FDA) inspected Milbar Laboratories located at 20 Commerce Street, East Haven, CT from December 7–27, 2017.  On July 23, 2018 they received a Warning Letter based on their audit.

Several notable Observations included those regarding their OTC topical drug products with Purified Water.

1. Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a)).

You distributed over the counter (OTC) topical drug product lots with objectionable microbial contamination.

For example, you distributed part of (b)(4) Anti-Blemish Wash lot (b)(4) although your contract-testing laboratory (CTL) found excessive microbiological counts (aerobic plate count of more than 25,000 CFU/g) and objectionable gram-negative bacteria (Enterobacter sp.) in the product. Your out-of-specification (OOS) investigation form stated that the lot disposition decision was “reject.”

Your response states that you have implemented a more in-depth batch review, and that “all outstanding OOS” results will be “addressed with appropriate corrective action.”

Your response is inadequate. You did not explain why you distributed drug product lots despite objectionable microbiological contamination. In addition, you did not sufficiently address the need for improvements in your quality system to correct flaws in lot disposition decision-making and other quality assurance functions.

We acknowledge that you recalled certain lots following our inspection after further discussions with the FDA.

In response to this letter, provide:

• Complete investigations into all lots found to have objectionable microbial contamination. The updated investigations should detail your findings regarding the likely root causes of the contamination.
• A comprehensive assessment of the adequacy of your firm’s manufacturing operations.
• A detailed corrective action and preventive action (CAPA) plan to ensure that failing drug products are not distributed in the future.
• A comprehensive assessment and CAPA for your quality unit (QU) to ensure it is given the adequate authority and resources to effectively discharge its function. The assessment should also include, but not be limited to, determining if procedures used by your firm are robust and appropriate, conducting oversight of manufacturing operations to ensure procedures are followed, approving all investigations, and discharging all other QU duties.
• A detailed risk assessment addressing the potential effects of distributing objectionably contaminated drug product. Specify actions that you will take in response to the risk assessment, such as further customer notifications and product recalls.

COMMENTS:

OTC products should follow USP<1111> for non-sterile products and contain no more than 1,000 bacteria/gm.  When in-coming materials to include purified water are not tested as used, or when hoses and other equipment are not properly cleaned, there exists a high probability that they final product will likely also be contaminated.  Purified water has a specification of 100 Colony Forming Units (CFU)/mL and no objectionable nor specified microorganisms.  Because counts of over 25,000 CFU/ml and Enterobacter sp. were observed, the product was definitely Out of Specification.   

2. Your firm failed to reject any lot of components that did not meet the appropriate written specification for identity, strength, quality, and purity (21 CFR 211.84(e)).

You used water from your (b)(4) purified water system with microbiological contamination that is objectionable in view of the component’s intended use. This water is a component used in manufacturing your topical OTC drug products.

On September 12, 2017, your aerobic plate count result for water was 8400 CFU/mL, exceeding the limit (b)(4). You used water from this system as a component to manufacture multiple lots of OTC drug products without investigating and remediating the system. Several days later, your contract-testing laboratory tested a new sample from the system that passed the action limit. You accepted the passing result and released multiple lots of OTC drug products on September 21, 2017.

Your contract laboratory’s investigation, approved on October 4, 2017, found the growth to be gram-negative rods. The microbes were not speciated. The investigation concluded there was no assignable cause.

Your response states that you now perform all water microbiological testing (b)(4). You also implemented a cleaning and “sanitation” record for the (b)(4) water hose and water system, and perform (b)(4) water testing. In addition, you initiated a preventive maintenance schedule for your (b)(4) water system, updated your standard operating procedures (SOPs), and trained your staff.

Your response is inadequate. Your response failed to adequately address the potential risk to your product posed by objectionable microbiological contamination in your water system.

In response to this letter, provide a thorough investigation and root cause analysis of the sources of microbiological contamination in your water system. Also provide an enhanced program for ongoing control, maintenance, and monitoring to ensure the remediated water system consistently meets Purified Water, USP, monograph specifications and appropriately stringent microbial limits.

COMMENTS: 

On September 12, 2017, the aerobic plate count yielded results that were 84 times greater than the specification for Purified Water (100 CFU/mL).  A few days later the contract laboratory’s investigation, which was approved on October 4, 2017 found the growth to be Gram negative microorganisms which were not speciated.  Speciation should always be performed when water quality is OOS and especially when one obtains Gram negative bacteria by Gram Stain.  By requesting that the Client provide a thorough investigation and root cause analysis of the sources of microbiological contamination in their water system, the FDA expects that the Client should be able to produce OTC products that will meet the microbiological specifications.  The FDA is also requesting that the Client provide an enhanced program for ongoing control, maintenance, and monitoring to ensure the remediated water system consistently meets Purified Water, USP, monograph specifications and appropriately stringent microbial limits.