Ms. Cherry A. Robinson
- Milbar Laboratories, Inc.
20 Commerce Street
East Haven, CT 06512-4145
- Issuing Office:
- New Jersey District Office
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Division of Pharmaceutical Quality Operations I
10 Waterview Blvd, 3rd Floor
Parsippany, NJ 07054
Telephone: (973) 331-4900
FAX: (973) 331-4969
VIA UNITED PARCEL SERVICE
July 23, 2018
Ms. Cherry A. Robinson
President and CEO
Milbar Laboratories, Inc.
20 Commerce Street
East Haven, CT 06512-4145
Dear Ms. Robinson:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Milbar Laboratories at 20 Commerce Street, East Haven, from December 7–27, 2017.
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211.
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).
We reviewed your January 14, 2018, response in detail and acknowledge receipt of your subsequent correspondence.
During our inspection, our investigator observed specific violations including, but not limited to, the following.
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.
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.
3. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
Your contract laboratory reported low failing assays for (b)(4) active ingredients in your OTC drug product (b)(4) SPF 30 (b)(4) lot (b)(4). The OOS final investigation report summary stated that the low OOS sunscreen actives were confirmed through retesting, and there was no indication of laboratory error. The investigation was approved by QA personnel. No further assessment was performed, and the investigation lacked corrective actions. Despite this OOS, your firm distributed lot (b)(4) to U.S. customers.
You did not fully investigate consumer complaint (b)(4) for (b)(4) SPF30 lots (b)(4). The customer stated that “too many patients were returning the drug” and “it is separating and just running out like oil.” You issued a credit to the customer and failed to perform an investigation. Additionally, you received additional consumer complaints about products’ separation and burning the skin. You did not adequately investigate these complaints.
Your response stated you would perform a thorough review of all OOS investigations prior to final batch disposition decisions in the future.Regarding complaint investigations, your response indicates that you have revised your complaint SOP and conducted relevant training. Your response is inadequate. You did not provide sufficient evidence demonstrating that you have fully investigated OOS results and complaints to determine the root causes, evaluate all potentially compromised batches, and implement appropriate CAPA to prevent recurrence of these defects.
In response to this letter, provide a thorough assessment of your overall system for investigating deviations, discrepancies, OOS results, complaints, and other failures. In addition, provide a retrospective review of all distributed lots within expiry to determine whether your firm released other lots not conforming to established specifications or appropriate manufacturing standards.
4. Your firm failed to establish written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).
Production process validation
You did not validate the processes used to manufacture (b)(4) your OTC drug products. You did not perform process qualification studies, and lacked an ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality.
For example, you manufactured (b)(4) SPF 30 lot (b)(4) using a process that was not in a state of control, and distributed units from the lot. The lot failed assay for (b)(4) active ingredients. Products made from processes that lack validation studies are unsuitable for distribution due to insufficient confidence that they can conform to appropriate specifications.
Your firm lacks an adequate ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality. See FDA’s guidance document, Process Validation: General Principles and Practices
, for general principles and approaches that FDA considers appropriate elements of process validation, at https://www.fda.gov/downloads/drugs/guidances/ucm070336.pdf
Inadequate control of water system
You failed to validate your “(b)(4)” water system. Your firm has not demonstrated that you could effectively control, maintain, sanitize, and monitor the system so it consistently produces pharmaceutical grade water that, at a minimum, meets the USP monograph for purified water and appropriately stringent microbiological limits. You use water from this unvalidated system as a component in your drugs. You must design your water system to reproducibly yield suitable water for use in production operations.
In addition, your laboratory tests do not sufficiently monitor the water system to detect control problems in a timely fashion and determine the extent of contamination issues. In 2017, you performed (b)(4) water testing (b)(4). You started testing water (b)(4). There is no scientific rationale for this sampling scheme.
Your response stated that, due to (b)(4) and demand by your international customers to receive fresh product, it is not feasible to perform process validations on three consecutive batches.
Your response is inadequate. You failed to adequately address the potential risk to your products posed by a lack of validation and lack of robust water system control. Additionally, you did not provide a detailed plan for validating your drug manufacturing processes.
In your response to this letter, provide:
- A data-driven and scientifically-sound process validation program that appropriately identifies sources of variability, and ensures oversight of intra-batch and inter-batch variation on an ongoing basis throughout the product lifecycle.
- Timelines for performing prospective process qualification for your drug products.
- A comprehensive, independent assessment of your current water system design, including a summary of your validation activities and any failing results for microbial testing.
- An effective program for ongoing control, maintenance, and monitoring that ensures the remediated system consistently produces water that meets Purified Water, USP, monograph specifications and appropriately stringent microbial limits.
Previous similar deficiencies
In previous inspections, dated January 2010, March 2013, and April 2016, FDA cited CGMP observations similar to all of those described above. You proposed specific remediation for these observations in your responses. For example, in response to the March 2013 inspection, you committed to finishing your process validation studies by the end of 2014. As of the date of this letter, you have failed to complete these actions.
Your firm’s continued failure to remediate these deficiencies demonstrates that management oversight and control over drug manufacturing is inadequate.
Quality Unit authority
Your inspectional history indicates that your quality unit is not able to fully exercise its authority and/or responsibilities. Your firm must provide the quality unit with appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality.
CGMP consultant recommended
Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. We also recommend that the qualified third party perform a comprehensive audit of your entire operation for CGMP compliance, and evaluate the effectiveness of your corrective actions and preventive actions.
Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance.
Violations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these violations, for determining the causes, for preventing their recurrence, and for preventing other violations in your facility.
Correct the violations cited in this letter promptly. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Unresolved violations in this warning letter may also prevent other Federal agencies from awarding contracts.
Until these violations are corrected, we may withhold approval of pending drug applications listing your facility. We may re-inspect to verify that you have completed your corrective actions. We may also refuse your requests for export certificates.
After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.
Your written notification should refer to the Warning Letter Number above (CMS# 552061). Please address your reply to:
Maya M. Davis
US Food & Drug Administration
One Montvale Avenue, 4th Floor
Stoneham, MA 02180
If you have questions regarding the contents of this letter, telephone Maya Davis, Compliance Officer, by telephone at 860-240-4289 x25, or by email Maya.Davis@fda.hhs.gov
Division Director/OPQO Division I
New Jersey District Office